FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Arroyo, JG You, T Bossi, KE AF Arroyo, JG You, T Bossi, KE TI Illuminated lens fixator for bimanual pars plana lensectomy SO OPHTHALMIC SURGERY AND LASERS LA English DT Article ID MANAGEMENT AB Pars plana vitrectomy and lensectomy are effective methods for removing posteriorly dislocated lens material. We describe an illuminated nucleus fixator that assists in the removal of posteriorly dislocated lens fragments. We tested the efficacy of the illuminated nucleus fixator compared to a standard endoilluminator in removing lens nuclei from the vitreous cavity of a cadaveric eye model. Use of the illuminated nucleus fixator as compared to a standard endoilluminator significantly reduced the time needed to remove lens nuclei from the vitreous cavity. This instrument could penetrate and fixate lens nuclei and could safely stabilize small and intermediate-sized lens fragments against the activated fragmatome. Bimanual lensectomy using the illuminated nucleus fixator significantly shortens the surgical time needed to remove posteriorly dislocated lens fragments. Shortening the surgical time for lensectomy may minimize such complications as retinal tears, trauma, and phototoxicity. C1 Brigham & Womens Hosp, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Arroyo, JG (reprint author), Brigham & Womens Hosp, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St,12th Floor, Boston, MA 02114 USA. NR 6 TC 2 Z9 2 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0022-023X J9 OPHTHALMIC SURG LAS JI Ophthalmic Surg. Lasers PD SEP-OCT PY 2001 VL 32 IS 5 BP 438 EP 440 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 472JT UT WOS:000170981100014 PM 11563792 ER PT J AU Peters, GB Meyer, DR Shields, JA Custer, PL Rubin, PA Wojno, TH Bersani, TA Tanenbaum, M AF Peters, GB Meyer, DR Shields, JA Custer, PL Rubin, PA Wojno, TH Bersani, TA Tanenbaum, M TI Management and prognosis of Merkel cell carcinoma of the eyelid SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY OCT 22, 2000 CL DALLAS, TEXAS SP Amer Acad Ophthalmol ID SURGICAL-MANAGEMENT; RADIATION-THERAPY; NATURAL-HISTORY; CHEMOTHERAPY AB Objective. To evaluate the clinical presentation, treatment, and long-term follow-up of eyelid Merkel cell carcinoma. Design: Retrospective noncomparative interventional case series. Participants: Fourteen patients with primary eyelid Merkel cell carcinoma. Methods: Cases of Merkel cell carcinoma for which long-term follow-up was available were solicited from members of the American Society of Ophthalmic Plastic and Reconstructive Surgery through an on-line e-mail/news group. Main Outcome Measures: Follow-up period, treatment history, presence and type of recurrence, and mortality. Results. Average follow-up was 33.4 months. Of the 14 cases identified, only 2 patients (14%) received prophylactic therapy beyond wide surgical excision. Three patients (21%) had recurrences, none of whom initially received prophylactic therapy (i.e., radiation therapy, lymph node dissection, and/or chemotherapy) beyond wide surgical excision. One patient (7%) died of metastatic Merkel cell carcinoma. Conclusions: Merkel cell carcinoma is a rare skin malignancy that occasionally affects the eyelid, with the potential for regional and distant metastasis. Consideration should be given to the use of prophylactic adjunctive therapies beyond wide surgical excision while simultaneously considering the morbidity of these therapies. (C) 2001 by the American Academy of Ophthalmology. C1 Albany Med Ctr, Lions Eye Inst, Albany, NY 12208 USA. Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Hosp, Philadelphia, PA 19107 USA. Washington Univ, St Louis, MO 63130 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. Syracuse Univ, New York, NY USA. Bascom Palmer Eye Inst, Miami, FL 33136 USA. RP Meyer, DR (reprint author), Albany Med Ctr, Lions Eye Inst, 35 Hackett Blvd, Albany, NY 12208 USA. NR 18 TC 21 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2001 VL 108 IS 9 BP 1575 EP 1579 DI 10.1016/S0161-6420(01)00701-1 PG 5 WC Ophthalmology SC Ophthalmology GA 467PV UT WOS:000170713700026 PM 11535453 ER PT J AU Lutz, SC Anderson, SF Wu, CY Townsend, JC AF Lutz, SC Anderson, SF Wu, CY Townsend, JC TI Non-Hodgkin's orbital lymphoma SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE external beam irradiation; monoclonal antibody therapy; non-Hodgkin's lymphoma; orbit; orbital lymphoma; proptosis; radiation retinopathy ID RADIATION RETINOPATHY; FOLLICULAR LYMPHOMA; THERAPY; TUMORS; IRRADIATION; MANAGEMENT; PROGNOSIS; CARCINOMA; DIAGNOSIS AB Background. The non-Hodgkin's lymphomas (NHL) are a group of neoplasms characterized by proliferation of malignant lymphocytes. Patients with NHL have a wide variety of presenting signs and symptoms, depending largely on the site of involvement and aggressiveness of the disease. Many organs in the body may be affected, including the eye and orbit. Case Report. A 47-year-old male with a 3-year history of stage IV non-Hodgkin's lymphoma who had undergone recent monoclonal antibody therapy presented with a complaint of blur in the left eye with occasional diplopia. Significant ocular findings of the left eye included ptosis, mild proptosis, increased intraocular pressure, and choroidal folds. Magnetic resonance imaging of the orbit revealed an orbital lymphoma that completely resolved after 2400 rads of external beam irradiation therapy. Eight months later, the patient developed a secondary radiation retinopathy. Conclusion. The prevalence of NHL is on the rise, and orbital involvement may occur at any time during the course of the disease. The standard treatment for non-Hodgkin's orbital lymphoma is external beam irradiation therapy, although the optimal dose for obtaining local tumor control without complications remains to be determined. Non-Hodgkin's lymphoma, orbital lymphoma, and various treatment options are discussed. C1 VA Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Sepulveda Ambulatory Care Ctr & Nursing Home, Sepulveda, CA USA. VA Greater Los Angeles Healthcare Syst, Santa Barbara Ambulatory Care Ctr, Santa Barbara, CA USA. So Calif Coll Optometry, Fullerton, CA USA. RP Lutz, SC (reprint author), Univ Calif Davis, Davis Med Ctr, Dept Ophthalmol, 4860 Y St, Sacramento, CA 95817 USA. NR 56 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD SEP PY 2001 VL 78 IS 9 BP 639 EP 645 DI 10.1097/00006324-200109000-00008 PG 7 WC Ophthalmology SC Ophthalmology GA 479LP UT WOS:000171406100013 PM 11587197 ER PT J AU August, M AF August, M TI Cerebrovascular and carotid artery disease SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID STROKE PREVENTION C1 Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP August, M (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Warren 1201,32 Fruit St, Boston, MA 02114 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD SEP PY 2001 VL 92 IS 3 BP 253 EP 256 DI 10.1067/moe.2001.117000 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 474QE UT WOS:000171117700005 PM 11552139 ER PT J AU Harris, WH AF Harris, WH TI Porous hemispherical sockets: When round is right SO ORTHOPEDICS LA English DT Article C1 Massachusetts Gen Hosp, Orthoped Biomech & Biomat Lab, Boston, MA 02114 USA. RP Harris, WH (reprint author), Massachusetts Gen Hosp, Orthoped Biomech & Biomat Lab, 55 Fruit St,GRJ 1126, Boston, MA 02114 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 J9 ORTHOPEDICS JI Orthopedics PD SEP PY 2001 VL 24 IS 9 BP 877 EP 878 PG 2 WC Orthopedics SC Orthopedics GA 474PX UT WOS:000171117000017 PM 11570466 ER PT J AU Poe, DS Abou-Halawa, A Abdel-Razek, O AF Poe, DS Abou-Halawa, A Abdel-Razek, O TI Analysis of the dysfunctional eustachian tube by video endoscopy SO OTOLOGY & NEUROTOLOGY LA English DT Article DE eustachian tubal dilation; eustachian tube; middle ear disease; video endoscopy ID MIDDLE-EAR; CAVITY AB Objective: Human eustachian tubes with known pathologic conditions of the ear were inspected endoscopically, and video recordings were made for slow-motion analysis of the pathophysiologic changes. Setting: Ambulatory office in a tertiary referral center. Subjects: Forty-four adults with 64 ears having pathologic conditions. Interventions: Transnasal endoscopic examination of the nasopharyngeal opening of the eustachian tube during rest, swallowing, and yawning to study the dilatory movements of the eustachian tube. Main Outcome Measures: Slow-motion video analysis of the dilatory movements of the eustachian tube. Results: Sixty-four ears and eustachian tubes with pathologic changes were studied. Tubal function was graded on (1) the extent of lateral excursion and progression of dilatory wave as estimates of tensor veli palatini and dilator tubae muscle function, reduced function being observed in 43 tubes; (2) the decree of mucosal disease, which was significant in 48 tubes; (3) obstructive mucosal changes, which were present in 15 tubes; (4) ease and frequency of tubal dilation with maneuvers-26 tubes opened moderately, 21 opened minimally, and I I were unable to open; and (5) patulous tubes-all 6 clinically patulous tubes showed concavities in the superior third of the tube, which is convex in normal subjects. All tubes with active pathologic conditions of the ear (otitis media with effusion, tympanic membrane retraction, draining ear, cholesteatoma) had significant abnormal it ies. A correlation could not be made between the severity of middle car disease and the severity of observed eustachian tube dysfunction. Conclusions: Slow-motion endoscopic video analysis is a potentially useful technique in classifying types of pathologic changes in the eustachian tube. Additional studies of dysfunctional tubes are needed to predict outcomes in operative ear cases and to design intratubal therapy for chronically dysfunctional tubes. C1 Suez Canal Univ, Dept Otolaryngol, Ismailia, Egypt. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Poe, DS (reprint author), Zero Emerson Pl,Suite 2C, Boston, MA 02114 USA. NR 13 TC 42 Z9 48 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2001 VL 22 IS 5 BP 590 EP 595 DI 10.1097/00129492-200109000-00005 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 470EA UT WOS:000170856400005 PM 11568663 ER PT J AU Rahman, MU Poe, DS Choi, HK AF Rahman, MU Poe, DS Choi, HK TI Etanercept therapy for immune-mediated cochleovestibular disorders: Preliminary results in a pilot study SO OTOLOGY & NEUROTOLOGY LA English DT Article DE cochleovestibular disorders; etanercept; immune-mediated inner-ear disease; sensorineural hearing loss ID INNER-EAR DISEASE; SENSORINEURAL HEARING-LOSS; MENIERES-DISEASE; RHEUMATOID-ARTHRITIS; METHOTREXATE; RECEPTOR; PROTEIN; HEAT-SHOCK-PROTEIN-70; GRANULOMATOSIS; ANTIBODIES AB Objective: Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a management challenge to the otolaryngologist. Antirheumatic agents, commonly used for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The authors describe the preliminary result of their experience in patients with IMCVDs who have been treated with etanercept, a tumor necrosis factor alpha receptor blocker, recently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis. Study Design: Retrospective case series. Setting: Tertiary care hospital. Patients: Twelve patients suspected of having IMCVD who did not respond to conventional therapies or experienced side effects of the conventional therapies. Intervention: Etanercept 25 mg by subcutaneous injection twice per week. Main Outcome Measures: The main outcome measurement was assessment of hearing change by air conduction pure tone audiograms and/or word discrimination. When present, vertigo, tinnitus, and aural fullness were assessed as well. Results: Follow-up of more than 5 months was available for all patients (range, 5-12 months). Eleven (92%) of 12 patients had improvement or stabilization of hearing and tinnitus, seven (88%) of eight patients who had vertigo and eight (89%) of nine patients who had aural fullness had resolution or significant improvement of their symptoms. The benefit persisted until the last visit (5-12 months after etanercept was begun). The condition of one patient improved dramatically at first but deteriorated after 5 months. The patient's hearing was rescued and stabilized with the addition of leflunomide to etanercept. Similarly, three other patients required a second antirheumatic agent to stabilize their hearing. There were no significant side effects from the etanercept therapy. Conclusions: Our limited data suggest that etanercept therapy is safe and may be efficacious in carefully selected patients with IMCVDs, at least on a short-term basis. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of etanercept for IMCVDs. C1 Massachusetts Gen Hosp, Rheumatol Unit, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Rahman, MU (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Dept Med, Bulfinch 165,Fruit St, Boston, MA 02114 USA. NR 41 TC 30 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2001 VL 22 IS 5 BP 619 EP 624 DI 10.1097/00129492-200109000-00010 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 470EA UT WOS:000170856400010 PM 11568668 ER PT J AU Sperling, NM Franco, RA Milhorat, TH AF Sperling, NM Franco, RA Milhorat, TH TI Otologic manifestations of Chiari I malformation SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Chiari I malformation; cranial nerve function ID CLASSIFICATION; DECOMPRESSION; MANAGEMENT AB Objective: To assess the prevalence of otologic symptoms in patients undergoing surgical decompression for symptomatic Chiari I malformation. Study Design: Cross-sectional, prospective, nonrandomized. Setting: Urban tertiary referral center. Patients: Patients with Chiari I malformation before surgical intervention. Main Outcome Measure: Results of completed questionnaire. Results: Sixteen consecutive patients with Chiari I malformation completed the self-administered questionnaire. Eighty-one percent of patients reported episodic aural fullness, 81% reported tinnitus, 69% reported vertigo, and 56% reported fluctuating hearing loss. Headaches were reported as frequently as aural fullness and tinnitus. Conclusions: Most patients with Chiari I malformation have symptoms that mimic primary otologic pathologic changes. The existence of common pathophysiologic mechanisms is proposed. C1 SUNY Hlth Sci Ctr, Dept Otolaryngol, Brooklyn, NY 11203 USA. SUNY Hlth Sci Ctr, Dept Neurosurg, Brooklyn, NY 11203 USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Sperling, NM (reprint author), SUNY Hlth Sci Ctr, Dept Otolaryngol, Box 126,450 Clarkson Ave, Brooklyn, NY 11203 USA. NR 17 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2001 VL 22 IS 5 BP 678 EP 681 DI 10.1097/00129492-200109000-00020 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 470EA UT WOS:000170856400020 PM 11568678 ER PT J AU Gearan, T Castillo, OA Schwarzschild, MA AF Gearan, T Castillo, OA Schwarzschild, MA TI The parkinsonian neurotoxin, MPP+ induces phosphorylated c-Jun in dopaminergric neurons of mesencephalic cultures SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE stress-activated protein kinase; c-Jun N-terminal kinase; apoptosis; 1-methyl-4-phenylpyridinium; ventral mesencephalon ID SUBSTANTIA-NIGRA; ACTIVATION; APOPTOSIS; JNK; KINASES; EXPRESSION; DEATH AB The stress-activated protein kinase (SAPK) cascade serves a critical role in the apoptotic death of neuronal cells in response to a variety of cellular stresses. Recent in vitro and in vivo evidence has directly implicated this kinase in the death of dopaminergic nigral neurons in the MPTP model of Parkinson's disease (PD). To assess the involvement of c-Jun, a key transcription factor substrate of SAPK (also known as c-Jun N-terminal kinase, or JNK) in the MPTP-induced death of dopaminergic nigral neurons, we determined the ability of MPP+, the active toxin metabolite of MPTP, to induce the phosphorylated form of c-Jun in dopaminergic neurons in nigral (ventral mesencephalon) cultures. At a dose of MPP+ that specifically induces apoptotic changes in nuclear morphology in tyrosine hydroxylase-positive (dopaminergic) cells in these cultures, MPP+ induces nuclear phospho-c-Jun immunoreactivity (IR). The peak induction of phospho-c-Jun IR was observed 16 h after beginning MPP+ exposure, and preceded the maximal induction of apoptotic nuclear changes by approximately 8 h. These data support an important role for the SAPK/JNK pathway including its c-Jun transcriptional target in the apoptotic death of dopaminergic nigral neurons in the MPTP model of PD. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Mol Neurobiol Lab, Charlestown, MA 02129 USA. RP Schwarzschild, MA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Mol Neurobiol Lab, CNY 6616,Bldg 149 13th St, Charlestown, MA 02129 USA. FU NINDS NIH HHS [NS01729] NR 17 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2001 VL 8 IS 1 BP 19 EP 22 DI 10.1016/S1353-8020(00)00078-X PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 467BF UT WOS:000170680100003 PM 11472876 ER PT J AU Lloyd, RL Pekary, AE Sattin, A Amundson, T AF Lloyd, RL Pekary, AE Sattin, A Amundson, T TI Antidepressant effects of thyrotropin-releasing hormone analogues using a rodent model of depression SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE depression; TRH; ECS; Porsolt test; antidepressant treatment ID SEIZURES INCREASE LEVELS; RAT LIMBIC FOREBRAIN; ELECTROCONVULSIVE-THERAPY; DEGRADING ECTOENZYME; RECEPTOR-BINDING; TRH; BRAIN; EXPRESSION; THRESHOLD; PROSTATE AB The antidepressant potential of two naturally occurring analogues of thyrotropin-releasing hormone (TRH), pGLU-GLU-PRO-NH2 (EEP) and pGLU-PHE-PRO-NH2 (EFP), were examined using a rodent model of antidepressant efficacy. The Porsolt Swim Test was used to assay the antidepressant proper-ties of these two peptides. Both analogues of TRH produced significant antidepressant effects, with EEP producing the stronger response. No effect of EEP upon triiodothyronine (T-3) was observed at the dosage used. EFP, which has previously been demonstrated to crossreact with the TRH receptor, significantly increased serum T-3. Since an effect upon T-3 was only observed in the weaker of the two compounds, these data suggest that the behavioral effect of EEP was not secondary to stimulation of thyroid hormone. Additionally, the differential behavioral response to the two compounds suggests a degree of sequence specificity in the ability of TRH-like tripeptides to produce an antidepressant effect. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Univ Minnesota, Dept Psychol, Duluth, MN 55812 USA. W Los Angeles Vet Affairs Med Ctr, Endocrinol Res Lab, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Psychiat Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA USA. RP Lloyd, RL (reprint author), Univ Minnesota, Dept Psychol, 332 Bohannon Hall,10 Univ Dr, Duluth, MN 55812 USA. NR 42 TC 29 Z9 30 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD SEP PY 2001 VL 70 IS 1 BP 15 EP 22 DI 10.1016/S0091-3057(01)00555-X PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 472LF UT WOS:000170985000002 PM 11566138 ER PT J AU Okano, GJ Malone, DC Billups, SJ Carter, BL Sintek, CD Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Dombrowski, R Geraets, DR Amato, MG AF Okano, GJ Malone, DC Billups, SJ Carter, BL Sintek, CD Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Dombrowski, R Geraets, DR Amato, MG TI Reduced quality of life in veterans at risk for drug-related problems SO PHARMACOTHERAPY LA English DT Article ID AFFAIRS MEDICAL-CENTERS; HEALTH SURVEY SF-36; OF-LIFE; VALIDITY; CARE; SELECTION; SEVERITY; OUTCOMES; DISEASE AB The relationships between drug therapy and health-related quality of life in 1054 patients who received care from Department of Veterans Affairs medical centers (VAMCs) were assessed. Patients at high risk for drug-related problems were enrolled into a pharmaceutical care study at nine VAMCs. On enrollment, the short form (SF)-36 was completed and medical records were examined for evidence of coexisting illness. Drug therapy in the year before enrollment was analyzed in relation to SF-36 scores. Mean SD SF-36 scores ranged from 37.99 +/- 41.70 for role physical to 70.78 +/- 18.97 for mental health domains, with all domain scores significantly below age-adjusted national norms (p <0.05). Patients taking a drug that required therapeutic monitoring had significantly lower SF-36 scores (p=0.0001 to p=0.0033) across all domains except for bodily pain and mental health, compared with patients not taking these agents. C1 CareSci Inc, Strateg Outcomes Serv, Res Triangle Pk, NC 27709 USA. Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. Kaiser Permanente, Denver, CO USA. Univ Iowa, Coll Pharm, Iowa City, IA USA. Denver Vet Affairs Med Ctr, Denver, CO USA. James A Haley Vet Hosp, Tampa, FL 33612 USA. Idaho State Univ, Coll Pharm, Boise, ID USA. Boise Vet Affairs Med Ctr, Boise, ID USA. Vet Affairs Sierra Nevada Hlth Syst, Reno, NV USA. Univ Nevada, Reno Vet Affairs Med Ctr, Reno, NV 89557 USA. John L McClellan Mem Vet Hosp, Little Rock, AR USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. Iowa City Vet Affairs Med Ctr, Iowa City, IA USA. Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. RP Okano, GJ (reprint author), CareSci Inc, Strateg Outcomes Serv, POB 12844, Res Triangle Pk, NC 27709 USA. NR 29 TC 3 Z9 3 U1 1 U2 5 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD SEP PY 2001 VL 21 IS 9 BP 1123 EP 1129 DI 10.1592/phco.21.13.1123.34620 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 470BC UT WOS:000170849700011 PM 11560202 ER PT J AU Kollias, N Stamatas, GN Youn, JI AF Kollias, N Stamatas, GN Youn, JI TI Suppression of UVB-induced cutaneous erythema by a previous UVB exposure SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID SKIN; PIGMENTATION; INDIVIDUALS AB People who vacation in sunny places are exposed to the sun on multiple occasions at least on a daily basis. The clinical assessment of sun exposure is erythema in the first 48 h after exposure and pigmentation at times greater than 3-5 days. The purpose of this investigation was to determine the extent to which consecutive erythemogenic exposures result in additive erythema responses. Studies were conducted in which volunteers were first exposed to a graded series of fluences of UVB radiation and then on subsequent days (1-3 days) the same sites along with the surrounding unexposed skin were challenged with varying fluences of UVB radiation. The erythema reactions were assessed clinically and were objectively documented with diffuse reflectance spectroscopy. The sites that received two exposures always showed a reduced erythema response compared to a single erythemogenic exposure. The suppression of erythema was more pronounced when the second exposure was given 48 h after the first. The erythema suppression was maximal when the first exposure was at 1.3 minimum erythema dose (MED). The pigment response to the first exposure was completely suppressed for fluences less than 1.5 MED. We thus provide evidence for a decoupling of the classical sequence of erythema-pigmentation response. We also show that the erythema induced by a second exposure may be substantially suppressed by an earlier exposure, and that this cannot be due to melanin photoprotection or due to substantial thickening of the stratum corneum. We propose that the cause may be some diffusible element of yet unknown origin. C1 Johnson & Johnson Consumer Prod Inc, Skillman, NJ 08558 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Labs, Boston, MA USA. Seoul Natl Univ Hosp, Dept Dermatol, Seoul, South Korea. RP Kollias, N (reprint author), Johnson & Johnson Consumer Prod Inc, 199 Grandview Rd, Skillman, NJ 08558 USA. NR 11 TC 15 Z9 15 U1 1 U2 1 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD SEP PY 2001 VL 74 IS 3 BP 471 EP 476 DI 10.1562/0031-8655(2001)074<0471:SOUICE>2.0.CO;2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 478RV UT WOS:000171359900016 PM 11594063 ER PT J AU Jacobo, MC AF Jacobo, MC TI Revolutions in psychoanalytic theory of lesbian development - Dora to Dykes and back again SO PSYCHOANALYTIC PSYCHOLOGY LA English DT Article ID HOMOSEXUALITY; VIEWS AB Nowhere is the therapeutic action in psychoanalytic theory, away from Freud and back again, more striking than in the realm of homosexuality. Theories of lesbian development have evolved to appreciate the complexity of sexuality and gender as expressed in sexual object choice, foregrounded within psychoanalysis by proponents of relational and intersubjectivity theories. In this article, I argue that it was not until psychoanalysis came to embrace this complex and contextualized understanding of homosexuality that therapists could become curious with patients about conflict-based aspects of their homosexual selves without risk of pathologizing. I elaborate the ways in which contemporary psychoanalytic theories of lesbian development have provided a theoretical context from which therapists may allow ideas of drive, conflict, and object relations to inform and to advance work with their lesbian patients. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Jacobo, MC (reprint author), Massachusetts Gen Hosp, Warren 1220,55 Fruit St, Boston, MA 02114 USA. NR 24 TC 0 Z9 0 U1 0 U2 0 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0736-9735 J9 PSYCHOANAL PSYCHOL JI Psychoanal. Psychol. PD FAL PY 2001 VL 18 IS 4 BP 667 EP 683 PG 17 WC Psychology, Clinical; Psychology, Psychoanalysis SC Psychology GA 492HT UT WOS:000172162900003 ER PT J AU Bovasso, GB Alterman, AI Cacciola, JS Cook, TG AF Bovasso, GB Alterman, AI Cacciola, JS Cook, TG TI Predictive validity of the Addiction Severity Index's Composite Scores in the assessment of 2-year outcomes in a methadone maintenance population SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article ID MENTAL-ILLNESS; RELIABILITY; OUTPATIENTS; INSTRUMENT AB The current research tested the predictive validity of 6 of the 7 Composite Scores (CSs) of the Addiction Severity Index (ASI) in 310 methadone maintenance patients assessed at treatment entry using the ASI and other measures, and followed for 2 years. Logistic regression was used to estimate the sensitivity and specificity of the CSs at intake in predicting their respective validity criterion measures at follow up. Except for the Medical CS, each of the other 5 CS measures significantly predicted its validity criterion measure. The CSs measuring drug use, alcohol abuse, psychopathology, and legal problems had high specificity (79% for the Drug CS, 91% for the Alcohol CS, 96% for the Legal CS, and 100% for the Psychological CS). The CSs measuring employment problems had high sensitivity (76%). The results support the predictive validity of most of the ASI CSs as measures of specific problems as well as the validity of the multidimensional construct on which the ASI is based. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Bovasso, GB (reprint author), Treatment Res Ctr, Dept Psychiat, Bldg 3,3900 Chestnut St, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [DA05186]; PHS HHS [D-05858] NR 13 TC 49 Z9 50 U1 1 U2 3 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD SEP PY 2001 VL 15 IS 3 BP 171 EP 176 DI 10.1037//0893-164X.15.3.171 PG 6 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 471CT UT WOS:000170910500001 PM 11563793 ER PT J AU Cargill, BR Emmons, KM Kahler, CW Brown, RA AF Cargill, BR Emmons, KM Kahler, CW Brown, RA TI Relationship among alcohol use, depression, smoking behavior, and motivation to quit smoking with hospitalized smokers SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article ID CAGE QUESTIONNAIRE; MAJOR DEPRESSION; MENTAL-HEALTH; CESSATION; DEPENDENCE; CIGARETTE AB Relationships among depression, alcohol use, and motivation to quit smoking were examined in a sample of 350 hospitalized smokers. Multivariate multiple regression and logistic regression analyses indicated that participants with depressed mood were more likely to have a history of problematic drinking. Participants with depressed mood and a history of problematic drinking were more likely to be nicotine dependent and anticipated greater difficulty refraining from smoking while hospitalized. Alcohol use in heavier amounts was associated with a decreased concern with negative aspects of smoking, whereas history of depression was associated with increased concern in that area, Finally, current drinking was associated with increased confidence in quitting in 1 month whereas depressed mood was associated with decreased confidence in quitting. Overall, depression and alcohol use had stronger associations with smoking-related variables than with smoking cessation motivation variables. C1 Miriam Hosp, Providence, RI 02906 USA. Brown Univ, Dept Psychiat, Providence, RI 02912 USA. Butler Hosp, Providence, RI 02906 USA. RP Emmons, KM (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. FU NHLBI NIH HHS [1RO1HL48180, 1RO1HL50017] NR 21 TC 22 Z9 22 U1 0 U2 3 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD SEP PY 2001 VL 15 IS 3 BP 272 EP 275 DI 10.1037/0893-164X.15.3.272 PG 4 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 471CT UT WOS:000170910500017 PM 11563809 ER PT J AU Grossman, P Wilhelm, FH Kawachi, I Sparrow, D AF Grossman, P Wilhelm, FH Kawachi, I Sparrow, D TI Gender differences in psychophysiological responses to speech stress among older social phobics: Congruence and incongruence between self-evaluative and cardiovascular reactions SO PSYCHOSOMATIC MEDICINE LA English DT Article DE anxiety disorders; social phobia; cardiovascular reactivity; heart rate variability; autonomic control; mental stress ID FINGER BLOOD-PRESSURE; NATIONAL-COMORBIDITY-SURVEY; AVOIDANT PERSONALITY-DISORDER; RESPIRATORY SINUS ARRHYTHMIA; GENERALIZED ANXIETY DISORDER; NONINVASIVE CARDIAC-OUTPUT; CORONARY HEART-DISEASE; PANIC DISORDER; PUBLIC-SPEAKING; COMMUNITY SAMPLE AB Objective: Evidence suggests increased cardiovascular risk and autonomic impairment among individuals with chronic anxiety. Little attention, however, has been paid to the anxiety disorder of social phobia despite its high prevalence. Additionally, gender- and age-related cardiovascular profiles have not been examined in relation to social phobia. This study investigated cardiovascular responses to a socially threatening situation among older men and women with social phobia and control subjects. Methods: Thirty subjects with social phobia and 30 control subjects (mean age = 65 years) were assessed during baseline, paced breathing, speech preparation, and speech presentation. Electrocardiographic variables, blood pressure, respiration, and emotional state (self-reported) were monitored. Hemodynamic variables included heart rate, blood pressure, cardiac output, and systemic vascular resistance; autonomic measures were respiratory sinus arrhythmia and baroreflex sensitivity, both markers of cardiac vagal control, and 0.10-Hz systolic blood pressure variability, an index of sympathetic vasomotor tone. Results: Subjects with social phobia, in contrast to nonanxious control subjects, manifested more anxiety, embarrassment, and somatic complaints in response to stress; however, physiological measures generally did not distinguish groups. Interaction effects indicated that socially phobic women were hyperresponsive to the stressor with respect to self-reported, hemodynamic, and autonomic parameters. Socially phobic men manifested no physiological differences in comparison with control subjects, but they reported more psychological and somatic complaints. Conclusions: Gender differences in subjective and physiological responses to a socially threatening situation indicate congruence between perceived social anxiety and physiological responses in older women but not men. We found no evidence of impaired cardiovascular autonomic regulation among socially phobic men despite other reports that phobically anxious men are at greater cardiovascular risk. C1 Breathing Space, Inst Yoga Meditat & Hlth, D-79100 Freiburg, Germany. Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. US Dept Vet Affairs, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Grossman, P (reprint author), Breathing Space, Inst Yoga Meditat & Hlth, Konradstr 32, D-79100 Freiburg, Germany. RI Grossman, Paul/A-6279-2009 NR 71 TC 63 Z9 66 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2001 VL 63 IS 5 BP 765 EP 777 PG 13 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 475KQ UT WOS:000171163500010 PM 11573025 ER PT J AU Deykin, EY Keane, TM Kaloupek, D Fincke, G Rothendler, J Siegfried, M Creamer, K AF Deykin, EY Keane, TM Kaloupek, D Fincke, G Rothendler, J Siegfried, M Creamer, K TI Posttraumatic stress disorder and the use of health services SO PSYCHOSOMATIC MEDICINE LA English DT Article DE posttraumatic stress disorder; primary care; health services utilization; veterans; health status ID NATIONAL COMORBIDITY SURVEY; MALE VIETNAM VETERANS; SOCIAL SUPPORT; ALCOHOL-ABUSE; PSYCHIATRIC-DISORDERS; HIGH UTILIZERS; CARE; DEPRESSION; PTSD; CONSUMPTION AB Objective: Prior research has demonstrated increased use of medical services among persons with anxiety and depression. This investigation examined the possible association of posttraumatic stress disorder (PTSD) with the use of nonmental health services. Method: A case-comparison design enrolled 102 high users of health services and 54 low users who were assessed for PTSD diagnosis and severity of PTSD symptoms. Subjects were male veterans receiving services from the primary care clinics of the VA Boston Healthcare System during an 18-month period. Data were collected by interview by use of standardized instruments including the Clinician Administered PTSD Scale for DSM-IV, the Life Events Checklist, and the Beck Depression Inventory. Data analysis employed odds ratios, linear and logistic regression, and path analyses, Results: High users of health care were almost twice as likely as low users (27.5% vs. 14.8%) to meet diagnostic criteria for current PTSD. The two groups differed significantly on both symptom frequency and intensity. Path analyses showed an indirect positive association between PTSD and health services use, with physician-diagnosed health conditions as a mediating variable. Auxiliary analysis demonstrated that the combined mental health burden of PTSD and depression symptoms also is positively associated with number of health conditions. Conclusions: The findings indicate that PTSD, alone and in combination with depression, has a direct negative relationship with physical health that, in turn, is associated with more frequent use of primary health care services. These results do not suggest that PTSD leads to inappropriate (eg, distress-motivated) use of services. C1 Vet Adm Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. Vet Adm Boston Healthcare Syst, Med Serv, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Vet Adm Med Ctr, HSR&D Serv, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. RP Keane, TM (reprint author), Vet Adm Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave, Boston, MA 02130 USA. NR 30 TC 82 Z9 83 U1 8 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2001 VL 63 IS 5 BP 835 EP 841 PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 475KQ UT WOS:000171163500018 PM 11573033 ER PT J AU Baumann, BD Hilsenroth, MJ Ackerman, SJ Baity, MR Smith, CL Smith, SR Blagys, MD Price, JL Heindselman, TL Mount, MK Holdwick, DJ AF Baumann, BD Hilsenroth, MJ Ackerman, SJ Baity, MR Smith, CL Smith, SR Blagys, MD Price, JL Heindselman, TL Mount, MK Holdwick, DJ TI The capacity for dynamic process scale: An examination of reliability, validity, and relation to therapeutic alliance SO PSYCHOTHERAPY RESEARCH LA English DT Article ID PATIENT PERSONALITY-VARIABLES; OBJECT RELATIONS SCALE; SUPPORTIVE FORMS; FOLLOW-UP; PSYCHOTHERAPY; MOTIVATION; QUALITY; TERMINATION; PREDICTORS; SELECTION AB This study investigated the reliability and validity of the Capacity for Dynamic Process Scale (CDPS; Thackrey, Butler, & Strupp, 1993) as well as the relationship of this scale to therapeutic alliance and termination in an outpatient sample. The sample consisted of 38 outpatients who were admitted over a 22-month period at a university-based community psychological clinic. The results of this study indicated that the CDPS can be reliably scored and is internally consistent. In addition, the CDPS showed discriminant validity based on Diagnostic and Statistical manual of Mental Disorders (fourth edition; DSM-IV; American Psychiatric Association, 1994) scales of functioning and other self-report measures of psychopathology. The CDPS was also significantly related to clinician-rated therapeutic alliance during evaluation and could be used effectively to differentiate between those patients who terminated psychotherapy and those who continued treatment. These results support the reliability and validity of the CDPS in relation to the engagement of patients in outpatient psychodynamic psychotherapy. C1 Univ Arkansas, Dept Psychol, Fayetteville, AR 72701 USA. Adelphi Univ, Derner Inst Adv Psychol Studies, Adelphi, MD USA. Massachusetts Mental Hlth Ctr, Boston, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Univ Arkansas, Dept Psychol, Fayetteville, AR 72701 USA. St Louis Internship Consortium, St Louis, MO USA. Metropolitan St Louis Psychiat Ctr, St Louis, MO USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Dartmouth Coll Sch Med, Lebanon, NH USA. Dept Behav Hlth, San Bernardino, CA USA. Univ Arkansas, Dept Psychol, Fayetteville, AR 72701 USA. Wyoming State Hosp, Psychol Serv, Evanston, WY USA. RP Baumann, BD (reprint author), Univ Arkansas, Dept Psychol, 216 Mem Hall, Fayetteville, AR 72701 USA. EM bdbauma@comp.uark.edu NR 53 TC 8 Z9 8 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1050-3307 J9 PSYCHOTHER RES JI Psychother. Res. PD FAL PY 2001 VL 11 IS 3 BP 275 EP 294 DI 10.1093/ptr/11.3.275 PG 20 WC Psychology, Clinical SC Psychology GA 473BR UT WOS:000171019900003 ER PT J AU Aquino, SL AF Aquino, SL TI Esophageal resection: Indications, techniques, and radiologic assessment - Invited commentary SO RADIOGRAPHICS LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Aquino, SL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP-OCT PY 2001 VL 21 IS 5 BP 1138 EP 1138 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 472HJ UT WOS:000170977800004 ER PT J AU Aquino, SL Duncan, GR Hayman, LA AF Aquino, SL Duncan, GR Hayman, LA TI Nerves of the thorax: Atlas of normal and pathologic findings SO RADIOGRAPHICS LA English DT Article DE nerves; nerves, CT; nerves, diseases; thorax, anatomy; thorax, CT ID RECURRENT LARYNGEAL NERVE; COMPUTED-TOMOGRAPHY; VAGAL PARAGANGLIOMA; PALSY SECONDARY; VAGUS NERVE; PARALYSIS; DYSFUNCTION; DISEASE; TUMORS; ADULT AB An anatomic and imaging atlas was created to provide detailed information about the six pairs of thoracic nerves (phrenic nerves, vagus nerves, recurrent laryngeal nerves, sympathetic trunks, costal nerves, long thoracic nerves). Serial axial computed tomographic (CT) scans of the normal thorax were obtained and included in the atlas, along with drawings showing the proper location of each nerve relative to adjacent anatomic structures. CT scans obtained in both symptomatic and asymptomatic patients with various thoracic diseases were paired with appropriate drawings and normal CT scans in the atlas. This format was designed to help determine the presence and severity of related disease, including injury from surgery, trauma, or penetrating injury, metastatic disease involvement, and, rarely, primary tumor. Although the nerves of the thorax are rarely identified at cross-sectional imaging, their location can be inferred by localizing easily identified anatomic landmarks. Familiarity with the functional anatomy and clinical significance of the nerves of the thorax is important for the correct interpretation of thoracic images. C1 Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Baylor Coll Med, Frensley Ctr Imaging Res, Houston, TX 77030 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Hayman, LA (reprint author), Baylor Coll Med, Dept Radiol, 1 Baylor Plaza, Houston, TX 77030 USA. NR 43 TC 14 Z9 15 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP-OCT PY 2001 VL 21 IS 5 BP 1275 EP 1281 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 472HJ UT WOS:000170977800018 PM 11553833 ER PT J AU Ferrucci, JT Barish, MA Eustace, SJ Melhem, ER Mueller, PR Swensen, SJ Wilson, SR AF Ferrucci, JT Barish, MA Eustace, SJ Melhem, ER Mueller, PR Swensen, SJ Wilson, SR TI Image interpretation session - Sunday, November 25, 2001 SO RADIOGRAPHICS LA English DT Article DE image, interpretation; Radiological Society of North America, 87th scientific assembly and annual meeting AB The Sunday afternoon Image Interpretation Session remains a highly attended and anticipated highlight of the annual meeting of the Radiological Society of North America. Now an established RSNA tradition since its introduction in 1939, this year's session promises to be another challenging and entertaining encounter with 10 unknown cases, two each in the categories of musculoskeletal, abdominal, thoracic, ultrasound, and neurologic imaging. All of the cases for discussion have been seen at Boston Medical Center over the past year, and thus reflect the disease mix of an active urban academic medical center. The panel is composed of five internationally known authorities, who will have the opportunity to demonstrate their individual approach to elucidating and organizing the radiologic findings to arrive at a reasonable differential diagnosis. We hope to make this session not the "ultimate board certification examination," but rather a real-life approach by experienced radiologists to cases encountered in an actual clinical environment. The entire Image Interpretation Session, including questions, answers, and discussion, will be available online in early 2002 through RSNA Link in the InteractEd pages (www.rsna.org/education/interactive/sunday_image/index.html) and may be viewed for category 1 continuing medical education credit. C1 Boston Med Ctr, Dept Radiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Cappagh Orthoped Hosp, Dublin, Ireland. Johns Hopkins Univ, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. Toronto Gen Hosp, Toronto, ON, Canada. RP Ferrucci, JT (reprint author), Boston Med Ctr, Dept Radiol, 88 E Newton St, Boston, MA 02118 USA. RI Melhem, Elias/E-5205-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP-OCT PY 2001 VL 21 IS 5 BP 1323 EP 1338 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 472HJ UT WOS:000170977800024 ER PT J AU Bosch, JL Beinfeld, MT Halpern, EF Lester, JS Gazelle, GS AF Bosch, JL Beinfeld, MT Halpern, EF Lester, JS Gazelle, GS TI Endovascular versus open surgical elective repair of infrarenal abdominal aortic aneurysm: Predictors of patient discharge destination SO RADIOLOGY LA English DT Article DE aneurysm, abdominal; aneurysm, therapy ID HEALTH-CARE; COST; MULTICENTER; TRIAL; EXPERIENCE; GRAFT AB PURPOSE: To evaluate patient discharge destination after elective endovascular or open surgical repair of infrarenal abdominal aortic aneurysm and to determine predictors for discharge to home or to a rehabilitation center. MATERIALS AND METHODS: All patients electively treated for infrarenal abdominal aortic aneurysm with endovascular repair (n = 182) or open surgery (n = 274) between January 1997 and September 1999 were included. From the hospital database, information on discharge destination, patient characteristics, complications, and length of stay was retrieved. Multiple logistic regression analysis was performed to determine predictors for discharge to home or to a rehabilitation center. RESULTS: Patient characteristics did not differ significantly between the treatment groups, with the exception of age (mean age, 75.1 vs 72.9 years in the endovascular and open surgical group, respectively; P = .005). Patient discharge destinations differed significantly between the treatment groups (P = .001). After endovascular procedures, 156 (85.7%) of 182 patients went home and 19 (10.4%) of 182 patients went to a rehabilitation center. After open surgery, 187 (68.2%) of 274 patients went home and 64 (23.4%) of 274 patients went to a rehabilitation center. The odds ratio of discharge to a rehabilitation center, instead of home, following endovascular procedures versus open surgery was 0.23 (95% Cl: 0.13, 0.43). CONCLUSION: Following elective repair of infrarenal abdominal aortic aneurysm, significantly more patients went home after an endovascular procedure than after open surgery. Procedure type was a significant predictor of discharge destination. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Erasmus Univ, Med Ctr, Dept Epidemiol & Biostat, Rotterdam, Netherlands. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Bosch, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Zero Emerson Pl,Suite 2H, Boston, MA 02114 USA. NR 29 TC 13 Z9 13 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2001 VL 220 IS 3 BP 576 EP 580 DI 10.1148/radiol.2202010147 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 465YC UT WOS:000170616700003 PM 11526250 ER PT J AU Hahn, PF Gervais, DA O'Neill, MJ Mueller, PR AF Hahn, PF Gervais, DA O'Neill, MJ Mueller, PR TI Nonvascular interventional procedures: Analysis of a 10-year database containing more than 211,000 cases SO RADIOLOGY LA English DT Article DE interventional procedures; radiology and radiologists, departmental management ID RADIOLOGY; NEED; MANAGEMENT AB PURPOSE: To analyze all procedures performed during 10 years in a nonvascular interventional practice. MATERIALS AND METHODS: Date, organ location, and type of all 21,324 procedures performed between October 1990 and September 2000 were recorded in a database; also included were patient age and inpatient or outpatient status, Because genitourinary procedures were not included during the first 4 years, nephrostomies were added retrospectively. Yearly interventional caseload was compared with the department caseload and the assignment of new medical record numbers. Trends in individual procedure location and type were analyzed, as well as patient age, inpatient status, daily caseloads, and day of the week when the procedure was performed. RESULTS: Caseloads have increased 10.8% per year, exceeding increases in radiology department and hospital activity. Abdomen, outside of a specific organ, was the most common location; catheter deployment was the most common procedure. Abscess drainage, placement of chest tubes, and nephrostomies have increased, but biliary drainages have decreased. Inpatients outnumbered outpatients in all years except 1995, but the trend was toward an increase in the proportion of outpatients. The average patient was 59.6 years old, with average age diminishing. Friday was the busiest day, but weekend procedures have increased. CONCLUSION: Nonvascular interventional procedures have increased, with more currently being performed on weekends. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Hahn, PF (reprint author), Massachusetts Gen Hosp, Dept Radiol, White 270,55 Fruit St, Boston, MA 02114 USA. NR 15 TC 6 Z9 6 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2001 VL 220 IS 3 BP 730 EP 736 DI 10.1148/radiol.2203001840 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 465YC UT WOS:000170616700025 PM 11526275 ER PT J AU Basile, JN AF Basile, JN TI Hypertension 2001: How will JNC VII be different from JNC VI? SO SOUTHERN MEDICAL JOURNAL LA English DT Article ID RANDOMIZED TRIAL; BLOOD-PRESSURE; SYSTOLIC HYPERTENSION; MORTALITY; MORBIDITY C1 Ralph H Johnson VA Med Ctr, Dept Primary Care, Charleston, SC USA. Med Univ S Carolina, Dept Med, Div Gen Internal Med Geriatr, Charleston, SC USA. RP Basile, JN (reprint author), VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU SOUTHERN MEDICAL ASSN PI BIRMINGHAM PA 35 LAKESHORE DR PO BOX 190088, BIRMINGHAM, AL 35219 USA SN 0038-4348 J9 SOUTHERN MED J JI South.Med.J. PD SEP PY 2001 VL 94 IS 9 BP 889 EP 890 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 479EB UT WOS:000171390000010 PM 11592748 ER PT J AU Deck, AJ Yang, CC AF Deck, AJ Yang, CC TI Perinephric abscesses in the neurologically impaired SO SPINAL CORD LA English DT Article DE abscess; spinal cord injury; multiple sclerosis; calculus; urinary tract infection AB Study design: Retrospective chart review. Objectives: To document the occurrence and management of large perinephric abscesses in neurologically impaired patients at high risk for this infectious complication. Setting: US Veterans Affairs hospital. Methods: The records, radiographs, operative findings and outcomes of all patients who presented with perinephric abscesses evident on physical exam within the last 5 years were reviewed. Results: Four patients presented with large perinephric abscesses evident on physical examination. All had severe neurologic impairment with high sensory levels; three had spinal cord injuries, one had advanced multiple sclerosis. All had neurogenic bladders and recurrent urinary tract infections. The diagnosis was made through a combination of history, physical examination and computed tomography (CT) examination. All were found to have upper tract obstruction. All were managed with immediate abscess drainage and three had elective nephrectomy once the infection had resolved. No patients died of their perinephric abscess. Conclusions: These four cases illustrate that although advances in antibiotics, imaging and percutaneous management have improved the speed of diagnosis and reduced the mortality in patients with perinephric abscesses, the neurologically impaired population continues to remain at significant risk for the development and the delayed diagnosis of these morbid renal infections. C1 VA Puget Sound Hlth Care Syst, Urol Sect, Seattle, WA 98108 USA. RP Yang, CC (reprint author), VA Puget Sound Hlth Care Syst, Urol Sect, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 19 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD SEP PY 2001 VL 39 IS 9 BP 477 EP 481 DI 10.1038/sj.sc.3101188 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 473XY UT WOS:000171075500003 PM 11571659 ER PT J AU Lev, MH Segal, AZ Farkas, J Hossain, ST Putman, C Hunter, GJ Budzik, R Harris, GJ Buonanno, FS Ezzeddine, MA Chang, YC Koroshetz, WJ Gonzalez, RG Schwamm, LH AF Lev, MH Segal, AZ Farkas, J Hossain, ST Putman, C Hunter, GJ Budzik, R Harris, GJ Buonanno, FS Ezzeddine, MA Chang, YC Koroshetz, WJ Gonzalez, RG Schwamm, LH TI Utility of perfusion-weighted CT imaging in acute middle cerebral artery stroke treated with intra-arterial thrombolysis - Prediction of final infarct volume and clinical outcome SO STROKE LA English DT Article DE cerebral ischemia; stroke; thrombolysis; tomography, perfusion-weighted ID ACUTE ISCHEMIC STROKE; COMPUTED-TOMOGRAPHY; HYPERACUTE STROKE; BLOOD-FLOW; THERAPY; ANGIOGRAPHY; BRAIN; VARIABILITY; VALIDATION; DIFFUSION AB Background and Purpose-The goal of this study was to evaluate the utility of perfusion-weighted CT (PWCT) in predicting final infarct volume and clinical outcome in patients with acute middle cerebral artery (MCA) stroke. Methods-Twenty-two consecutive patients with MCA stem occlusion who underwent intra-arterial thrombolysis within 6 hours of stroke onset had noncontrast CT and CT angiography with whole-brain PWCT imaging before treatment. Infarct volumes were computed from the initial PWCT and follow-up scans; clinical outcome was measured with the modified Rankin scale. Results-Initial PWCT lesion volumes correlated significantly with final infarct volume (P = 0.0002) and clinical outcome (P = 0.01). For the 10 patients with complete recanalization, the relationship between initial and final lesion volume was especially strong (R-2 = 0.94, P < 0.0001, slope of regression line = 0.92). For those without complete recanalization, there was progression of lesion volume on follow-up imaging (R-2 = 0.50, P = 0.01, slope of regression line = 1.61). All patients with either initial PWCT lesion volumes >100 mL or no recanalization had poor outcomes (Rankin scores, 4 to 6). Mean admission NIH Stroke Scale scores and mean lesion volumes in the poor outcome group were significantly different compared with the good or fair outcome (Rank-in scores, 0 to 3) group (21 +/- 4 versus 17 +/- 5, P = 0.05, and 106 +/- 79 versus 29 +/- 37 mL, P = 0.01). Patients with initial volumes <100 mL and partial or complete recanalization all had good (Rankin scores, 0 to 2) or fair (Rankin score, 3) outcomes. Conclusions-Lesion volumes on admission PWCT images approximate final infarct volume for patients with early complete recanalization of MCA stem occlusion. For those without complete recanalization, there is subsequent enlargement of lesion volume on follow-up. Initial PWCT lesion volumes also have predictive value; volumes >100 mL are associated with a poor clinical outcome. In these highly selected patients, initial PWCT lesion volume was a stronger predictor of clinical outcome than was initial NIH Stroke Scale score. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol GRB285, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Lev, MH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol GRB285, POB 9657, Boston, MA 02114 USA. OI Schwamm, Lee/0000-0003-0592-9145 FU NCRR NIH HHS [RR-13213]; NINDS NIH HHS [NS-34626] NR 32 TC 216 Z9 222 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2001 VL 32 IS 9 BP 2021 EP 2027 DI 10.1161/hs0901.095680 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 471KX UT WOS:000170929500017 PM 11546891 ER PT J AU Khuri, SF AF Khuri, SF TI Invited Commentary: Surgeons, not General Motors, should set standards for surgical care SO SURGERY LA English DT Editorial Material ID RISK ADJUSTMENT; QUALITY; OPERATIONS; OUTCOMES; PROGRAM; VOLUME C1 Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Khuri, SF (reprint author), Surg Serv, 1400 VFW Pkwy, Boston, MA 02132 USA. NR 11 TC 35 Z9 35 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD SEP PY 2001 VL 130 IS 3 BP 429 EP 431 DI 10.1067/msy.2001.117138 PG 3 WC Surgery SC Surgery GA 475FF UT WOS:000171151000006 PM 11562665 ER PT J AU Perez, AR Moncure, AC Rattner, DW AF Perez, AR Moncure, AC Rattner, DW TI Obesity adversely affects the outcome of antireflux operations SO SURGICAL ENDOSCOPY-ULTRASOUND AND INTERVENTIONAL TECHNIQUES LA English DT Article DE antireflux surgery; esophagitis; gastroesophageal reflux disease; GERD; obesity ID LAPAROSCOPIC NISSEN FUNDOPLICATION; GASTROESOPHAGEAL REFLUX DISEASE; SURGERY; FAILURE AB Background: We hypothesized that obesity was associated with long-term failure of antireflux procedures, and that in obese patients antireflux operations were easier to perform via thoracotomy, and therefore likely to have a higher success rate than transabdominal (laparoscopic or open) antireflux procedures. The aims of this study was to determine the impact of obesity on the success of antireflux operations, and to compare the success rates of transthoracic and laparoscopic approaches in obese patients with gastroesophageal reflux. Methods: The records of 224 consecutive patients undergoing antireflux surgery by two surgeons in a university-based tertiary care center were reviewed and patients contacted for follow-up assessment. The patients were classified into groups based on the type of operation performed and the calculated body mass index (BMI): normal (BMI < 25), overweight (BMI = 25-29.9). and obese (BMI > 30). Recurrences were documented by symptoms responsive to acid-suppressive medication and radiologic or pH probe studies. Results: Among the 224 patients included in this study, 187 underwent laparoscopic Nissen fundoplications (LNF) and 37 underwent Belsey Mark IV (BM4) procedures. The mean follow-up period was 37 months. The three groups included 89 (39.7%) patients classified as having normal weight, 87 (38.8%) as overweight and 48 (21.4%) as obese. Normal, overweight, and obese patients were similar in terms of age, gender. hiatal hernia size, degree of esophagitis, and comorbid conditions. A total of 26 recurrences occurred. giving an overall recurrence rate of 11.6%. There were 4 recurrences in the normal group (4.5%), 7 in the overweight group (8.0%; p not significant vs normal), and 15 in the obese group (31%; p < 0.001 vs normal, p < .001 vs overweight). The recurrence rate was similar between LNF and BM4 in each BMI subgroup. although in aggregate, the recurrence rate after BMW was greater than after LNF (10/37 vs 16/187:1 p < 0.02). Conclusions: Obesity adversely affects the long-term success of antireflux operations. Although athoracotomy provides optimal exposure of the hiatal structures in obese patients, a transthoracic approach was associated with a higher recurrence rate than LNF. Given the high failure rate of antireflux operations in obese patients, intensive efforts at sustained weight loss should be made before consideration of surgery. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Rattner, DW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Fruit St, Boston, MA 02114 USA. NR 22 TC 99 Z9 103 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0930-2794 J9 SURG ENDOSC-ULTRAS JI Surg. Endosc.-Ultrason. Interv. Tech. PD SEP PY 2001 VL 15 IS 9 BP 986 EP 989 DI 10.1007/s004640000392 PG 4 WC Surgery SC Surgery GA 468TH UT WOS:000170773900019 PM 11443428 ER PT J AU Melki, SA Azar, DT AF Melki, SA Azar, DT TI LASIK complications: Etiology, management, and prevention SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE complications; corneal surgery; keratomileusis; lasers; LASIK; microkeratome; photorefractive keratectomy; refractive surgery ID IN-SITU KERATOMILEUSIS; DIFFUSE LAMELLAR KERATITIS; LASER PHOTOTHERAPEUTIC KERATECTOMY; CORNEAL LIGHT-SCATTERING; STERILIZER RESERVOIR BIOFILMS; COCHET-BONNET AESTHESIOMETER; STEEP CENTRAL ISLANDS; SOFT CONTACT-LENSES; 2-YEAR FOLLOW-UP; PHOTOREFRACTIVE KERATECTOMY AB Laser in situ keratomileusis (LASIK) is a rapidly evolving ophthalmic surgical procedure. Several anatomic and refractive complications have been identified. Anatomic complications include corneal flap abnormalities, epithelial ingrowth, and corneal ectasia. Refractive complications include unexpected refractive outcomes, irregular astigmatism, decentration, visual aberrations, and loss of vision. Infectious keratitis, dry eyes, and diffuse lamellar keratitis may also occur following LASIK. By examining the etiology, management, and prevention of these complications, the refractive surgeon may be able to improve visual outcomes and prevent vision-threatening problems. Reporting outcomes and mishaps of LASIK surgery will help refine our approach to the management of emerging complications. (C) 2001 by Elsevier Science Inc. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. Boston Cornea Ctr, Boston, MA USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. NR 295 TC 187 Z9 195 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2001 VL 46 IS 2 BP 95 EP 116 DI 10.1016/S0039-6257(01)00254-5 PG 22 WC Ophthalmology SC Ophthalmology GA 473PJ UT WOS:000171054300001 PM 11578645 ER PT J AU Dzik, S Anderson, JK O'Neill, M Assmann, SF Kalish, LA Stowell, C AF Dzik, S Anderson, JK O'Neill, M Assmann, SF Kalish, LA Stowell, C TI A prospective randomized clinical trial of universal leukoreduction SO TRANSFUSION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Baxter Healthcare Corp, Deerfield, IL 60015 USA. Amer Red Cross, Dedham, MA USA. New England Res Inst, Watertown, MA 02172 USA. NR 0 TC 4 Z9 4 U1 0 U2 3 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2001 VL 41 IS 9 SU S BP 1S EP 1S PG 1 WC Hematology SC Hematology GA 472TV UT WOS:000171001800002 ER PT J AU Vamvakas, EC Carven, J AF Vamvakas, EC Carven, J TI Blood transfusion and postoperative length of mechanical ventilation: Effects of red cell supernatant, platelet supernatant, fresh frozen plasma/cryoprecipitate, and total transfused fluid SO TRANSFUSION LA English DT Meeting Abstract C1 NYU, Med Ctr, New York, NY 10016 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2001 VL 41 IS 9 SU S BP 5S EP 6S PG 2 WC Hematology SC Hematology GA 472TV UT WOS:000171001800021 ER PT J AU Vamvakas, EC Carven, J AF Vamvakas, EC Carven, J TI Exposure to allogeneic plasma and risk of postoperative pneumonia and/or wound infection in patients undergoing coronary artery bypass graft surgery SO TRANSFUSION LA English DT Meeting Abstract C1 NYU Med Ctr, New York, NY 10016 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2001 VL 41 IS 9 SU S BP 6S EP 6S PG 1 WC Hematology SC Hematology GA 472TV UT WOS:000171001800022 ER PT J AU Schultze, JL Vonderheide, RH AF Schultze, JL Vonderheide, RH TI From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens SO TRENDS IN IMMUNOLOGY LA English DT Review ID CYTOTOXIC T-LYMPHOCYTES; CLASS-I MOLECULES; GENE-EXPRESSION; DENDRITIC CELLS; AUTOIMMUNE-DISEASE; MYELOID-LEUKEMIA; DNA MICROARRAYS; TRANSGENIC MICE; HUMAN-MELANOMA; EPITOPES AB Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptide-specific T cells can be qualitatively and quantitatively analyzed at the single-cell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy. C1 Brigham & Womens Hosp, Dept Adult Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Schultze, JL (reprint author), Brigham & Womens Hosp, Dept Adult Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. RI Schultze, Joachim/D-7794-2011 OI Schultze, Joachim/0000-0003-2812-9853 NR 65 TC 69 Z9 76 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2001 VL 22 IS 9 BP 516 EP 523 DI 10.1016/S1471-4906(01)02015-4 PG 8 WC Immunology SC Immunology GA 468JF UT WOS:000170753800011 PM 11525943 ER PT J AU Zietman, AL Grocela, J Zehr, E Kaufman, DS Young, RH Althausen, AF Heney, NM Shipley, WU AF Zietman, AL Grocela, J Zehr, E Kaufman, DS Young, RH Althausen, AF Heney, NM Shipley, WU TI Selective bladder conservation using transurethral resection, chemotherapy, and radiation: Management and consequences of Ta, T1, and Tis recurrence within the retained bladder SO UROLOGY LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; NEOADJUVANT CHEMOTHERAPY; PROGNOSTIC FACTORS; CANCER; PRESERVATION; TRIAL; RADIOTHERAPY; CYSTECTOMY; SURVIVAL; THERAPY AB Objectives. Although radical cystectomy remains the standard of care for invasive bladder cancer in the United States, many groups are exploring the use of trimodality therapy using transurethral resection of the bladder tumor, radiation, and chemotherapy in an attempt to spare patients the need for cystectomy. As transitional cell carcinoma often arises from a urothelial field change, there is concern that the retained bladder is at risk of subsequent superficial (Ta, T1, Tis) tumors, some of which may have lethal potential. This study reports the outcomes of those patients with superficial relapse of transitional cell carcinoma after trimodality therapy. Methods. One hundred ninety patients were treated using a series of trimodality therapy protocols between 1986 and 1998. All patients received induction chemotherapy and radiation and were selected for bladder preservation on the basis of a cytologic and histologic complete response. One hundred twenty-one patients had a complete response and formed the subjects of this study. Results. With a median follow-up of 6.7 years for patients still alive, 32 experienced a superficial relapse (26%). The median time to this failure was 2.1 years. Sixty percent of the superficial failures were carcinoma in situ (Tis) and 67% arose at the site of the original invasive tumor. The risk of superficial failure was higher among those who had Tis associated with their original muscle-invasive tumor. Twenty-seven of these 32 cases were managed conservatively with transurethral resection and intravesical therapy. The irradiated bladder tolerated this therapy well and only 3 patients required treatment breaks. The 5 and 8-year survival was comparable for those who experienced superficial failure (68% and 54%, respectively) and those who had no failure at all (n = 74, 69% and 61%, respectively). However, a substantially lower chance of being alive with the native bladder owing to the need for late salvage cystectomies (61% versus 34%) was found. Cystectomy became necessary in 31% (10 of 32) either because of additional superficial recurrence (n = 7) or progression to invasive disease (n = 3). Conclusions. A trimodality approach to transitional cell bladder cancer mandates lifelong cystoscopic surveillance. Although most completely responding patients retain their bladders free from invasive relapse, one quarter will develop superficial disease. This may be managed in the standard fashion with transurethral resection of the bladder tumor and intravesical therapies but carries an additional risk that late cystectomy will be required. UROLOGY 58: 380-385, 2001. (C) 2001, Elsevier Science Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Canc Ctr, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Canc Ctr, Cox 3, Boston, MA 02114 USA. NR 17 TC 72 Z9 72 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD SEP PY 2001 VL 58 IS 3 BP 380 EP 385 DI 10.1016/S0090-4295(01)01219-5 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 472HW UT WOS:000170978900016 PM 11549485 ER PT J AU D'Amico, AV Whittington, R Malkowicz, SB Renshaw, AA Tomaszewski, JE Bentley, C Schultz, D Rocha, S Wein, A Richie, JP AF D'Amico, AV Whittington, R Malkowicz, SB Renshaw, AA Tomaszewski, JE Bentley, C Schultz, D Rocha, S Wein, A Richie, JP TI Estimating the impact on prostate cancer mortality of incorporating prostate-specific antigen testing into screening SO UROLOGY LA English DT Article ID DIGITAL RECTAL EXAMINATION; RADICAL PROSTATECTOMY; RADIATION-THERAPY; MEN; DIAGNOSIS; ELEVATION; PREDICT; TRIAL AB Objectives. Whether early detection using prostate-specific antigen (PSA) and digital rectal examination (DRE) compared with DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the impact that early detection could have on prostate cancer-specific survival can be estimated by assuming that PSA failure after radical prostatectomy (RP) will translate into death from prostate cancer. Methods. The study population consisted of 1274 men with clinically localized prostate cancer who underwent RP in Boston, Massachusetts or Philadelphia, Pennsylvania between 1989 and 2000 and had a preoperative PSA level greater than 4 but not more than 10 ng/mL. The primary endpoint was actuarial freedom from PSA failure (defined as PSA outcome). Results. The relative risk of PSA failure after RP for patients diagnosed with a PSA of greater than 4 to 5, 5 to 6, 6 to 7, or 7 to 8 ng/mL compared with greater than 8 up to 10 ng/mL was 0.3 (95% confidence interval [CI] 0.2 to 0.5), 0.5 (95% CI 0.4 to 0.8), 0.6 (95% Cl 0.4 to 0.9), or 0.9 (95% Cl 0.6 to 1.3), respectively. On the basis of the estimates of the 5-year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781 of 1274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 4 to 7 ng/mL compared with greater than 8 to 10 ng/mL (93% versus 78%, P <0.0001). A benefit to early detection was not found for the vast majority (266 of 312; 88%) of patients who had a biopsy Gleason score of 7 or higher. Conclusions. Early detection using both PSA and DRE-based screening may benefit men who present with biopsy Gleason score 5 or 6 prostate cancer and a PSA level greater than 4 to 7 ng/mL compared with greater than 8 up to 10 ng/mL. This finding awaits validation from ongoing prospective randomized trials. UROLOGY 58: 406-410, 2001. (C) 2001, Elsevier Science Inc. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Urol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. Millersville Univ, Dept Math, Millersville, PA 17551 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Urol, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. NR 19 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD SEP PY 2001 VL 58 IS 3 BP 406 EP 410 DI 10.1016/S0090-4295(01)01204-3 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 472HW UT WOS:000170978900020 PM 11549489 ER PT J AU Back, AL Curtis, JR AF Back, AL Curtis, JR TI When does primary care turn into palliative care? SO WESTERN JOURNAL OF MEDICINE LA English DT Editorial Material ID CANCER C1 Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98108 USA. RP Back, AL (reprint author), Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 10 TC 2 Z9 2 U1 0 U2 0 PU B M J PUBLISHING INC PI SAN FRANCISCO PA 221 MAIN ST, PO BOX 7690, SAN FRANCISCO, CA 94120-7690 USA SN 0093-0415 J9 WESTERN J MED JI West. J. Med. PD SEP PY 2001 VL 175 IS 3 BP 150 EP 151 DI 10.1136/ewjm.175.3.150 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 468CY UT WOS:000170741600003 PM 11527831 ER PT J AU Cole, J Tsou, R Wallace, K Gibran, N Isik, F AF Cole, J Tsou, R Wallace, K Gibran, N Isik, F TI Early gene expression profile of human skin to injury using high-density cDNA microarrays SO WOUND REPAIR AND REGENERATION LA English DT Article ID TISSUE MICROARRAYS; CELLS; FIBROBLASTS; INHIBITORS; PROTEIN; MICE AB Disturbances in normal wound healing may be traced to perturbations in gene expression following injury. To decipher normal and abnormal genetic responses to cutaneous injury, baseline gene expression of uninjured skin and injured skin must be better defined. Our aim for this study was to determine the gene expression profile of human skin immediately following injury using cDNA microarrays, Samples of normal and injured skin were obtained from 5 healthy females undergoing breast reduction surgery. Specimens of the epidermis and dermis were obtained at 30 minutes and 1 hour after the initial injury, RNA was extracted, reverse transcribed into cDNA and hybridized onto high-density cDNA microarray membranes of 4,000 genes. At 30 minutes, injury resulted in a consistent increase (> 2x) in gene expression of 124 out of 4,000 genes (3%), These genes were primarily involved in transcription and signaling, None of the 4,000 genes were decreased (< 2 x) at 30 minutes, At 1 hour only 46 out of the 4,000 genes were increased in expression (1.15%) but 264 out of 4,000 (6.6%) genes were decreased greater than 2 fold, indicating a silencing of many structural genes. We have identified several genes, namely, suppressor of cytokine signaling-1, rho HP1, and BB1, that are highly expressed after injury and may have an unappreciated role in regulating the initial inflammatory response. These data provide an initial high-throughput analysis of gene expression immediately following human skin injury and show the utility and future importance of high-throughput analysis in skin biology and wound repair. C1 Univ Washington, Med Ctr, Dept Surg, Seattle, WA 98195 USA. Univ Washington, Harborview Med Ctr, Dept Surg, VA Puget Sound Hlth Care Syst, Seattle, WA 98104 USA. RP Cole, J (reprint author), Univ Washington, Med Ctr, Dept Surg, Box 356410,1959 NE Pacific St, Seattle, WA 98195 USA. FU NIGMS NIH HHS [R01 GM57426] NR 25 TC 59 Z9 62 U1 2 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD SEP-OCT PY 2001 VL 9 IS 5 BP 360 EP 370 DI 10.1046/j.1524-475x.2001.00360.x PG 11 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 509EQ UT WOS:000173133700006 PM 11896979 ER PT J AU Ogretmen, B Kraveka, JM Schady, D Usta, J Hannun, YA Obeid, LM AF Ogretmen, B Kraveka, JM Schady, D Usta, J Hannun, YA Obeid, LM TI Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REVERSE-TRANSCRIPTASE GENE; CATALYTIC SUBUNIT HTERT; BREAST-CANCER CELLS; C-MYC; IN-VITRO; PROTEIN PHOSPHATASE; HUMAN FIBROBLASTS; PROMOTER REGION; DNA-BINDING; TUMOR-CELLS AB This study was aimed at identifying the molecular mechanisms by which ceramide inhibits telomerase activity in the A549 human lung adenocarcinoma cell line. C-6-ceramide (20 mum) caused a significant reduction of telomerase activity at 24 h as detected using the telomeric repeat amplification protocol, and this inhibition correlated with decreased telomerase reverse transcriptase (hTERT) protein. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot analyses showed that C-6-ceramide significantly decreased hTERT mRNA in a time-dependent manner. Electrophoretic mobility shift and supershift assays demonstrated that the binding activity of c-Myc transcription factor to the E-box sequence on the hTERT promoter was inhibited in response to C.-ceramide at 24 h. These results were also confirmed by transient transfections of A549 cells with pGL3-Basic plasmid constructs containing the functional hTERT promoter and its E-box deleted sequences cloned upstream of a luciferase reporter gene. Further analysis using RT-PCR and Western blotting showed that c-Myc protein but not its mRNA levels were decreased in response to C-6-ceramide at 24 h. The effects of ceramide on the c-Myc protein were shown to be due to a reduction in half-life via increased ubiquitination. Similar results were obtained by increased endogenous ceramide levels in response to nontoxic concentrations of daunorubicin, resulting in the inhibition of telomerase and c-Myc activities. Furthermore, the elevation of endogenous ceramide by overexpression of bacterial sphingomyelinase after transient transfections also induced the inhibition of telomerase activity with concomitant decreased hTERT and c-Myc protein levels. Taken together, these results show for the first time that both exogenons and endogenous ceramides mediate the modulation of telomerase activity via decreased hTERT promoter activity caused by rapid proteolysis of the ubiquitin-conjugated c-Myc transcription factor. C1 Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pediat, Div Hematol Oncol, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Adm, Dept Med, Charleston, SC 29425 USA. Amer Univ Beirut, Dept Biochem, Beirut, Lebanon. RP Ogretmen, B (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, POB 250779, Charleston, SC 29425 USA. OI obeid, lina/0000-0002-0734-0847 FU NCI NIH HHS [CA87584]; NIA NIH HHS [AG16583, AG12467]; NIGMS NIH HHS [GM43825] NR 66 TC 67 Z9 72 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2001 VL 276 IS 35 BP 32506 EP 32514 DI 10.1074/jbc.M101350200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 468EW UT WOS:000170746000019 PM 11441001 ER PT J AU Van Nostrand, WE Melchor, JP Cho, HS Greenberg, SM Rebeck, GW AF Van Nostrand, WE Melchor, JP Cho, HS Greenberg, SM Rebeck, GW TI Pathogenic effects of D23N Iowa mutant amyloid beta-protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE CELLS; HEREDITARY CEREBRAL-HEMORRHAGE; DUTCH-TYPE MUTANT; PRECURSOR PROTEIN; ALZHEIMER-DISEASE; ENDOTHELIAL-CELLS; ANGIOPATHY; GENE; DEGENERATION; MUTATION AB Cerebral amyloid beta -protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. In these conditions the CAA is characterized by the deposition of A beta within the cerebral vessel wall and, in severe cases, hemorrhagic stroke. Several mutations have been identified within the A beta region of the A beta protein precursor (A beta PP) gene that appear to enhance the severity of CAA. We recently described a new mutation within the A beta regio (D23N) of A beta PP that is associated with severe CAA in a Iowa kindred (Grabowski, T. J., Cho, H. S., Vonsattel, J. P. G., Rebeck, G. W., and Greenberg, S. M. (2001) Ann. Neurol 49, 697-705). In the present study, we investigated the effect of this new D23N mutation on the processing of A beta PP and the pathogenic properties of A beta. Neither the D23N Iowa mutation nor the E22Q Dutch mutation affected the amyloidogenic processing of A beta PP expressed in H4 cells. The A21G Flemish mutation, in contrast, resulted in a 2.3-fold increase in secreted A beta peptide. We also tested synthetic wild-type and mutant A beta 40 peptides for fibrillogenesis and toxicity toward cultured human cerebrovascular smooth muscle (HC-SM) cells. The E22Q Dutch, D23N Iowa, and E22Q,D23N Dutch/Iowa double mutant A beta 40 peptides rapidly assembled in solution to form fibrils, whereas wild-type and A21G Flemish A beta 40 peptides exhibited little fibril formation. Similarly, the E22Q Dutch and D23N Iowa A beta 40 peptides were found to induce robust pathologic responses in cultured HCSM cells, including elevated levels of cell-associated A beta PP, proteolytic breakdown of smooth muscle cell a-actin, and cell death. Double mutant E22Q,D23N Dutch/Iowa A beta 40 was more potent than either single mutant form of AP in causing pathologic responses in HCSM cells. These data suggest that the different CAA mutations in A beta PP may exert their pathogenic effects through different mechanisms. Whereas the A21G Flemish mutation appears to enhance A beta production, the E22Q Dutch and D23N Iowa mutations enhance fibrillogenesis and the pathogenicity of Ap toward HCSM cells. C1 SUNY Stony Brook, Hlth Sci Ctr, Dept Med, Stony Brook, NY 11794 USA. Massachusetts Gen Hosp, Alzheimer Res Unit, Charlestown, MA 02129 USA. RP Van Nostrand, WE (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Dept Med, T-15-081, Stony Brook, NY 11794 USA. FU NIA NIH HHS [AG00725]; NINDS NIH HHS [NS35781] NR 41 TC 141 Z9 144 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2001 VL 276 IS 35 BP 32860 EP 32866 DI 10.1074/jbc.M104135200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 468EW UT WOS:000170746000066 PM 11441013 ER PT J AU Mummidi, S Catano, G Lam, L Hoefle, A Telles, V Begum, K Jimenez, F Ahuja, SS Ahuja, SK AF Mummidi, S Catano, G Lam, L Hoefle, A Telles, V Begum, K Jimenez, F Ahuja, SS Ahuja, SK TI Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms - Inter-individual variation in expression of DC-SIGN transcripts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; C-TYPE LECTIN; PRE-MESSENGER-RNA; OPEN READING FRAME; T-CELLS; GENE-EXPRESSION; TRANSLATIONAL CONTROL; 5'-UNTRANSLATED REGION; NUCLEOTIDE-SEQUENCE; COMPLEMENTARY DNAS AB Expression in dendritic cells (DCs) of DC-SIGN, a type II membrane protein with a C-type lectin ectodomain, is thought to play an important role in establishing the initial contact between DCs and resting T cells. DC-SIGN is also a unique type of human immunodeficiency virus-1 (HIV-1) attachment factor and promotes efficient infection in trans of cells that express CD4 and chemokine receptors. We have identified another gene, designated here as DC-SIGN2, that exhibits high sequence homology with DC-SIGN. Here we demonstrate that alternative splicing of DC-SIGN1 (original version) and DC-SIGN2 pre-mRNA generates a large repertoire of DC-SIGN-like transcripts that are predicted to encode membrane-associated and soluble isoforms. The range of DC-SIGN1 mRNA expression was significantly broader than previously reported and included THP-1 monocytic cells, placenta, and peripheral blood mononuclear cells (PBMCs), and there was cell maturation/activation-induced differences in mRNA expression levels. Immunostaining of term placenta with a DC-SIGN1-specific antiserum showed that DC-SIGN1 is expressed on endothelial cells and CC chemokine receptor 5 (CCR5)-positive macrophage-like cells in the villi. DC-SIGN2 mRNA expression was high in the placenta and not detectable in PBMCs. In DCs, the expression of DC-SIGN2 transcripts was significantly lower than that of DC-SIGN1. Notably, there was significant inter-individual heterogeneity in the repertoire of DC-SIGN1 and DC-SIGN2 transcripts expressed. The genes for DC-SIGN1, DC-SIGN2, and CD23, another Type II lectin, colocalize to an similar to 85 kilobase pair region on chromosome 19p13.3, forming a cluster of related genes that undergo highly complex alternative splicing events. The molecular diversity of DC-SIGN-1 and -2 is reminiscent of that observed for certain other adhesive cell surface proteins involved in cell-cell connectivity. The generation of this large collection of polymorphic cell surface and soluble variants that exhibit inter-individual variation in expression levels has important implications for the pathogenesis of HIV-1 infection, as well as for the molecular code required to establish complex interactions between antigen-presenting cells and T cells, i.e. the immunological synapse. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. RP Ahuja, SK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, Mail Code 7880, San Antonio, TX 78229 USA. RI Mummidi, Srinivas/C-1004-2008 OI Mummidi, Srinivas/0000-0002-4068-6380 FU NIAID NIH HHS [AI43279, AI46326] NR 97 TC 77 Z9 87 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2001 VL 276 IS 35 BP 33196 EP 33212 DI 10.1074/jbc.M009807200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 468EW UT WOS:000170746000106 PM 11337487 ER PT J AU Yuan, MS Konstantopoulos, N Lee, JS Hansen, L Li, ZW Karin, M Shoelson, SE AF Yuan, MS Konstantopoulos, N Lee, JS Hansen, L Li, ZW Karin, M Shoelson, SE TI Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK beta SO SCIENCE LA English DT Article ID KAPPA-B KINASE; NECROSIS-FACTOR-ALPHA; INDUCED TYROSINE PHOSPHORYLATION; SKELETAL-MUSCLE; ACTIVATION; RECEPTOR; ASPIRIN; IMPAIRS; GLUCOSE; AGENTS AB We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the I kappaB kinase beta (IKK beta) attenuated insulin signaling in cultured cells, whereas IKK beta inhibition reversed insulin resistance. Thus, IKK beta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikk beta (+/-)) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKK beta pathway as a target for insulin sensitization. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. RP Shoelson, SE (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. FU NIAID NIH HHS [AI43477]; NIDDK NIH HHS [DK51729, DK45493] NR 29 TC 1162 Z9 1261 U1 5 U2 70 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 31 PY 2001 VL 293 IS 5535 BP 1673 EP 1677 DI 10.1126/science.1061620 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 469FA UT WOS:000170802900067 PM 11533494 ER PT J AU Jayaraman, A Walton, SP Yarmush, ML Roth, CM AF Jayaraman, A Walton, SP Yarmush, ML Roth, CM TI Rational selection and quantitative evaluation of antisense oligonucleotides SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE antisense; quantitative polymerase chain reaction; hybridization; mRNA dynamics ID THEORETICAL APPROACH; SECONDARY STRUCTURE; RNA LEVELS; RT-PCR; PREDICTION; DNA; STIMULATION; MECHANISMS; PARAMETERS; CYTOKINES AB Antisense oligonucleotides are an attractive therapeutic option to modulate specific gene expression. However, not all antisense oligonucleotides are effective in inhibiting gene expression, and currently very few methods exist for selecting the few effective ones from all candidate oligonucleotides. The lack of quantitative methods to rapidly assess the efficacy of antisense oligonucleotides also contributes to the difficulty of discovering potent and specific antisense oligonucleotides. We have previously reported the development of a prediction algorithm for identifying high affinity antisense oligonucleotides based on mRNA-oligonucleotide hybridization. In this study, we report the antisense activity of these rationally selected oligonucleotides against three model target mRNAs (human lactate dehydrogenase A and B and rat gp130) in cell culture. The effectiveness of oligonuclectides was evaluated by a kinetic PCR technique, which allows quantitative evaluation of mRNA levels and thus provides a measure of antisense-mediated decreases in target mRNA, as occurs through RNase H recruitment. Antisense oligonucleotides that were predicted to have high affinity for their target proved effective in almost all cases, including tests against three different targets in two cell types with phosphodiester and phosphorothioate oligonucleotide chemistries. This approach may aid the development of antisense oligonucleotides for a variety of applications. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Surg Serv, Ctr Engn Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Shriners Burns Hosp, Boston, MA 02114 USA. RP Roth, CM (reprint author), Rutgers State Univ, Dept Chem & Biochem Engn, 98 Brett Rd,C-257, Piscataway, NJ 08854 USA. RI Walton, S. Patrick/A-7007-2008; OI Walton, S. Patrick/0000-0003-1708-8603; Roth, Charles/0000-0002-4924-0721 NR 38 TC 19 Z9 20 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD AUG 30 PY 2001 VL 1520 IS 2 BP 105 EP 114 DI 10.1016/S0167-4781(01)00229-9 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 465UU UT WOS:000170609000001 PM 11513951 ER PT J AU Maril, A Wagner, AD Schacter, DL AF Maril, A Wagner, AD Schacter, DL TI On the tip of the tongue: An event-related fMRI study of semantic retrieval failure and cognitive conflict SO NEURON LA English DT Article ID INFERIOR PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; POSITRON EMISSION TOMOGRAPHY; EPISODIC MEMORY RETRIEVAL; FUNCTIONAL MRI; RECOGNITION; ANATOMY; STROOP AB The tip of the tongue (TOT) state refers to a temporary inaccessibility of information that one is sure exists in long-term memory and is on the verge of recovering. Using event-related fMRI, we assessed the neural correlates of this semantic retrieval failure to determine whether the anterior cingulate-lateral prefrontal neural circuit posited to mediate conflict resolution is engaged during metacognitive conflicts that arise during the TOT. Results revealed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. During a TOT, cognitive control mechanisms may be recruited in attempts to resolve the conflict and retrieval failure that characterize this state. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. RP Maril, A (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. OI Schacter, Daniel/0000-0002-2460-6061 FU NIA NIH HHS [AG08441]; NIDCD NIH HHS [DC04466]; NIMH NIH HHS [MH60941] NR 45 TC 79 Z9 82 U1 5 U2 16 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 30 PY 2001 VL 31 IS 4 BP 653 EP 660 DI 10.1016/S0896-6273(01)00396-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 468LM UT WOS:000170759200018 PM 11545723 ER PT J AU Magari, SR Hauser, R Schwartz, J Williams, PL Smith, TJ Christiani, DC AF Magari, SR Hauser, R Schwartz, J Williams, PL Smith, TJ Christiani, DC TI Association of heart rate variability with occupational and environmental exposure to particulate air pollution SO CIRCULATION LA English DT Article DE air pollution; heart rate; nervous system; autonomic; epidemiology ID MORTALITY AB Background-Airborne particulate matter has been linked to excess morbidity and mortality. Recent attention has focused on the effects of particulate exposure on cardiac autonomic control. Inhaled particulates may affect the autonomic nervous system either directly, by eliciting a sympathetic stress response, or indirectly, through inflammatory cytokines produced in the lungs and released into the, circulation. Methods and Results-This longitudinal study examined the association of particulates less than or equal to2.5 mum in diameter (PM2.5) with heart rate variability (HRV) in an occupational cohort (N = 40). Continuous monitoring of exposure and HR was performed during and away from work. PM2.5 levels were higher than ambient levels typically reported in Boston, 0.167 +/- 3.205 mg/m(3) (geometric mean geometric SD). We found a 2.66% decrease (95% CI, -3.75% to -1.58%) in the 5-minute SD of normal RR intervals (SDNN) for every 1 mg/m(3) increase in the 4-hour moving PM2.5 average and a 1.02% increase (95% CI, 0.59% to 1.46%) in HR after adjusting for potential confounding factors. The decrease in SDNN became larger as the averaging interval increased. Conclusions-Workers experienced altered cardiac autonomic control after exposure to occupational and environmental PM2.5. There appears to be either a long-acting (several hours) and a short-acting (several minutes) component to the mechanism of action that may be related to the production of cytokines and the sympathetic stress response, respectively, or a cumulative effect that begins shortly after exposure begins. The clinical significance of these effects in a healthy working population is unclear. C1 Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Environm Epidemiol Program, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Environm Sci & Engn Program, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, 665 Huntington Ave,Bldg 1 Room 1402, Boston, MA 02115 USA. FU NIEHS NIH HHS [ES 00002, ES09860, T32 ES07069]; NIOSH CDC HHS [OH00152] NR 15 TC 150 Z9 159 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2001 VL 104 IS 9 BP 986 EP 991 DI 10.1161/hc3401.095038 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 468TN UT WOS:000170774400014 PM 11524390 ER PT J AU Asthana, S Baker, LD Craft, S Stanczyk, FZ Veith, RC Raskind, MA Plymate, SR AF Asthana, S Baker, LD Craft, S Stanczyk, FZ Veith, RC Raskind, MA Plymate, SR TI High-dose estradiol improves cognition for women with AD - Results of a randomized study SO NEUROLOGY LA English DT Article; Proceedings Paper CT World Alzheimer Congress 2000 CY JUL 09-18, 2000 CL WASHINGTON, D.C. ID ESTROGEN-REPLACEMENT THERAPY; GROWTH-FACTOR-I; CENTRAL-NERVOUS-SYSTEM; CEREBRAL-BLOOD-FLOW; ALZHEIMERS-DISEASE; POSTMENOPAUSAL WOMEN; CONTROLLED-TRIAL; MEMORY FUNCTION; MOLECULAR-BASIS; RATING-SCALE AB Objective: To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. Methods: Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta -estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. Results: Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. Conclusions: Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established. C1 VA Puget Sound Health Care Syst, Ctr Geriatr Res Educ & Clin, Amer Lake Div, Tacoma, WA 98493 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. RP Asthana, S (reprint author), VA Puget Sound Health Care Syst, Ctr Geriatr Res Educ & Clin, Amer Lake Div, A-182, Tacoma, WA 98493 USA. EM sasthana@u.washington.edu NR 55 TC 177 Z9 183 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 28 PY 2001 VL 57 IS 4 BP 605 EP 612 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 466BF UT WOS:000170623900007 PM 11524467 ER PT J AU Stavropoulos, N Lu, NF Lee, JT AF Stavropoulos, N Lu, NF Lee, JT TI A functional role for Tsix transcription in blocking Xist RNA accumulation but not in X-chromosome choice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INACTIVATION CENTER; DIFFERENTIATION; CELLS; GENE; IGF2; METHYLATION; EXPRESSION; NUCLEUS; REPEATS; INVITRO AB In female mammals, up-regulation of Xist triggers X-chromosome inactivation in cis. Up-regulation is inhibited by sequences 3 ' to Xist contained within the antisense locus, Tsix. inhibition could depend on transcription of Tsix and/or on DNA elements therein. Here we test the role of Tsix transcription by augmenting the duration and strength of Tsix expression. We find that Tsix hypertranscription is sufficient to block Xist RNA accumulation in a cis-limited manner. We propose that Tsix transcription is necessary to restrict Xist activity on the future active X and, conversely, that Tsix repression is required for Xist RNA accumulation on the future inactive X. We also find that Tsix hypertranscription does not affect X-chromosome choice. Thus, choice is mediated by elements within Tsix that are independent of promoter activity. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. OI Stavropoulos, Nicholas/0000-0001-5915-2760 NR 29 TC 114 Z9 117 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2001 VL 98 IS 18 BP 10232 EP 10237 DI 10.1073/pnas.171243598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468BJ UT WOS:000170738000040 PM 11481444 ER PT J AU Biswas, DK Dai, SC Cruz, A Weiser, B Graner, E Pardee, AB AF Biswas, DK Dai, SC Cruz, A Weiser, B Graner, E Pardee, AB TI The nuclear factor kappa B (NF-kappa B): A potential therapeutic target for estrogen receptor negative breast cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID KINASE COMPLEX; SELECTIVE-INHIBITION; B/REL EXPRESSION; IKK COMPLEX; ACTIVATION; GROWTH; PROGRESSION; CELLS; GENE; MICE AB The effect of a kinase inhibitor Go6796 on growth of epidermal growth factor (EGF)-stimulated estrogen receptor negative (ER-) breast cancer cells in vivo and role of nuclear factor kappa B (NF-kappaB) on tumorogenesis have been investigated. This was studied in an animal model by implanting ER- mouse mammary epithelial tumor cells (CSMLO) in syngeneic A-J mice. (i) Local administration of Go6976 an inhibitor of protein kinases C alpha and beta inhibited growth of tumors and caused extensive necrotic degeneration and regression of the tumors without causing any microscopically detectable damage to the vital organs liver and lung. (ii) Stable expression of dominant-negative mutants of the beta subunit (dnlkk beta) of the inhibitory kappa B (I kappaB) kinase (dnlkk) that selectively blocked activation of NF-kappaB caused loss of tumorigenic potential of CSMLO cells. Stable expression of dnlkk beta also blocked phorbol 12-myristate 13-acetate (PMA)-induced activation of NF-A and overexpression of cyclin D1, concomitantly with the loss or reduced tumorigenic potential of these cells. Thus, results from in vivo and in vitro experiments strongly suggest the involvement of NF-kappaB in ER- mammary epithelial cell-mediated tumorigenesis. We propose that blocking NF-kappaB activation not only inhibits cell proliferation, but also antagonizes the antiapoptotic role of this transcription factor in ER- breast cancer cells. Thus, NF-kappaB is a potential target for therapy of EGFR family receptor-overexpressing ER- breast cancers. C1 Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Biswas, DK (reprint author), Dana Farber Canc Inst, Div Canc Biol, 44 Binney St, Boston, MA 02115 USA. RI Graner, Edgard/K-4411-2012 NR 41 TC 130 Z9 139 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2001 VL 98 IS 18 BP 10386 EP 10391 DI 10.1073/pnas.151257998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468BJ UT WOS:000170738000066 PM 11517301 ER PT J AU Yuan, YZ Zhou, LM Miyamoto, T Iwasaki, H Harakawa, N Hetherington, CJ Burel, SA Lagasse, E Weissman, IL Akashi, K Zhang, DE AF Yuan, YZ Zhou, LM Miyamoto, T Iwasaki, H Harakawa, N Hetherington, CJ Burel, SA Lagasse, E Weissman, IL Akashi, K Zhang, DE TI AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; PIM-1 TRANSGENIC MICE; PROMYELOCYTIC LEUKEMIA; TRANSCRIPTION FACTOR; FUSION GENE; CHROMOSOMAL TRANSLOCATION; DEFINITIVE HEMATOPOIESIS; LYMPHOID PROGENITORS; RAR-ALPHA; MOUSE AB The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expression of AML1-ETO is under the control of the human MRP8 promoter (hMRP8-AML1-ETO). AML1-ETO is specifically expressed in myeloid cells, including common myeloid progenitors of hMRP8-AML1-ETO transgenic mice. The transgenic mice were healthy during their life spans, suggesting that AML1-ETO alone is not sufficient for leukemogenesis. However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia. Our results provide direct evidence that AML1-ETO is critical for causing myeloid leukemia, but one or more additional mutations are required for leukemogenesis. The hMRP8-ALM1-ETO-transgenic mice provide an excellent model that can be used to isolate additional genetic events and to further understand the molecular pathogenesis of AML1-ETO-related leukemia. C1 Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. Stanford Univ, Sch Med, Dept Pathol & Dev Biol, Stanford, CA 94305 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Zhang, DE (reprint author), Scripps Res Inst, Dept Mol & Expt Med, MEM-L51,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NCI NIH HHS [CA72009, P01 CA072009] NR 46 TC 280 Z9 288 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2001 VL 98 IS 18 BP 10398 EP 10403 DI 10.1073/pnas.171321298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468BJ UT WOS:000170738000068 PM 11526243 ER PT J AU Chartoff, EH Marck, BT Matsumoto, AM Dorsa, DM Palmiter, RD AF Chartoff, EH Marck, BT Matsumoto, AM Dorsa, DM Palmiter, RD TI Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LOCOMOTOR-ACTIVITY; SUPER-SENSITIVITY; C-FOS; AMPHETAMINE; 6-HYDROXYDOPAMINE; SUPERSENSITIVITY; AGONISTS; BEHAVIOR; RATS; MICROINJECTION AB Motor stereotypies are abnormally repetitive behaviors that can develop with excessive dopaminergic stimulation and are features of some neurologic disorders. To investigate the mechanisms required for the induction of stereotypy, we examined the responses of dopamine-deficient (DD) mice to increasing doses of the dopamine precursor L-DOPA. DD mice lack the ability to synthesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robust hyperlocomotion relative to wild-type (WT) mice when treated with L-DOPA, which restores striatal DA tissue content to approximate to 10% of WT levels. To further elevate brain DA content in DID mice, we administered the peripheral L-amino acid decarboxylase inhibitor carbidopa along with L-DOPA (C/L-DOPA). When striatal DA levels reached > 50% of WT levels, a transition from hyperlocomotion to intense, focused stereotypy was observed that was correlated with an induction of c-fos mRNA in the ventrolateral and central striatum as well as the somatosensory cortex. WT mice were unaffected by C/L-DOPA treatments. A D1, but not a D2, receptor antagonist attenuated both the C/L-DOPA-induced stereotypy and the c-fos induction. Consistent with these results, stereotypy could be induced in DD mice by a DI, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereotypy and c-fos induction by C/L-DOPA. These results indicate that activation of D1 receptors on a specific population of striatal neurons is required for the induction of stereotypy in DD mice. C1 Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. Univ Washington, Dept Biochem, Seattle, WA 98195 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Ctr Geriatr Res Educ & Clin, Seattle, WA 98195 USA. Univ Washington, Grad Program Neurobiol & Behav, Seattle, WA 98195 USA. RP Palmiter, RD (reprint author), Univ Washington, Howard Hughes Med Inst, Box 357370, Seattle, WA 98195 USA. FU NINDS NIH HHS [NS-20311, R01 NS020311] NR 37 TC 52 Z9 55 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2001 VL 98 IS 18 BP 10451 EP 10456 DI 10.1073/pnas.181356498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468BJ UT WOS:000170738000077 PM 11517332 ER PT J AU Hamilton, ML Van Remmen, H Drake, JA Yang, H Guo, ZM Kewitt, K Walter, CA Richardson, A AF Hamilton, ML Van Remmen, H Drake, JA Yang, H Guo, ZM Kewitt, K Walter, CA Richardson, A TI Does oxidative damage to DNA increase with age? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIETARY RESTRICTION; CALORIC RESTRICTION; MITOCHONDRIAL-DNA; RAT-LIVER; SUPEROXIDE-DISMUTASE; DIFFERENT TISSUES; FISCHER-344 RATS; C57BL/6 MICE; NUCLEAR-DNA; REPAIR AB The levels of 8-oxo-2-deoxyguanosine (oxo8dG) in DNA isolated from tissues of rodents (male F344 rats, male B6D2F1 mice, male C57BL/6 mice, and female C57BL/6 mice) of various ages were measured using sodium iodide to prevent oxidative damage to DNA during DNA isolation. Oxo8dG was measured in nuclear DNA (nDNA) isolated from liver, heart, brain, kidney, skeletal muscle, and spleen and in mitochondrial DNA (mtDNA) isolated from liver. We observed a significant increase in oxo8dG levels in nDNA with age in all tissues and strains of rodents studied. The age-related increase in oxo8dG in nDNA from old mice was shown not to the result of the tissue's reduced ability to remove the oxo8dG lesion. Rather, the increase in oxo8dG levels appears to arise from an age-related increase in the sensitivity of these tissues to oxidative stress. We also observed an age-related increase in oxo8dG in mtDNA isolated from the livers of the rats and mice. Dietary restriction, which is known to retard aging and increase the lifespan of rodents, was shown to significantly reduce the age-related accumulation of oxo8dG levels in nDNA in all tissues of male B6D23F1 mice and in most tissues of male F344 rats. Our study also showed that dietary restriction prevented the age-related increase in oxo8dG levels in mtDNA isolated from the livers of both rats and mice. C1 Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Sam & Ann Bishop Ctr Longev & Aging Studies, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Richardson, A (reprint author), Univ Texas, Hlth Sci Ctr, Dept Physiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIA NIH HHS [AG13319, P01AG14674, P03AG13319, P30 AG013319] NR 46 TC 433 Z9 451 U1 4 U2 27 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2001 VL 98 IS 18 BP 10469 EP 10474 DI 10.1073/pnas.171202698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 468BJ UT WOS:000170738000080 PM 11517304 ER PT J AU Sabolic, I Herak-Kramberger, CM Brown, D AF Sabolic, I Herak-Kramberger, CM Brown, D TI Subchronic cadmium treatment affects the abundance and arrangement of cytoskeletal proteins in rat renal proximal tubule cells SO TOXICOLOGY LA English DT Article DE actin; cytoskeleton; immunocytochemistry; kidney; microtubules; nephrotoxicity; villin ID BORDER MEMBRANE-VESICLES; BRUSH-BORDER; INTOXICATED RATS; CULTURED-CELLS; TREATED RATS; KIDNEY; TRANSPORT; METALLOTHIONEIN; ACTIN; CHLORIDE AB Disfunction of proximal tubules (PT) in cadmium (Cd) nephrotoxicity in mammals results from the diminished functional capacity of brush-border membrane (BBM) caused by (a) direct inhibition of BBM transporters by Cd, (b) shortening and loss of microvilli, and (c) loss of specific BBM transporters. The loss of transporters may partially result from impaired intracellular vesicle recycling due to loss or/and inhibition of vacuolar H+-ATPase in the PT cell organelles. Cytoskeleton plays an important role in vesicle-mediated recycling and processing of BBM transporters in PT cells. Experiments in vitro have indicated that Cd may affect the state of polymerization of some cytoskeletal proteins. In this work we studied the in vivo effect of CdCl2-treatment in rats (2 mg Cd/kg b. m., s.c., daily for 14 days) upon abundance and arrangement of actin filaments, actin-bundling protein villin, and microtubules (MT) in PT cells. Cd-treatment elicited a dramatic accumulation of Cd in the kidney cortex (200 mug/g tissue wet mass after 14 days) and a strongly increased abundance of metallothionein in PT cells. As revealed by immunocytochemistry in tissue cryosections, the staining intensity of actin and villin in PT cells of Cd-treated rats was generally decreased, without a marked change in their intracellular distribution, whereas MT became largely irregular, diminished in most cells, and lost in many cells. However, the immunoblots revealed an increased content of villin and alpha -tubulin in cortical tissue homogenates from Cd-treated rats, thus indicating an impaired bundling of actin and greatly depolymerized MT in cells intoxicated with Cd. The partial loss of apical actin and villin in PT cells of Cd-treated rats may reflect (or cause) shortening and loss of microvilli, whereas derangement and depolymerization of MT may contribute to the impairment of intracellular recycling of BBM proteins, and lead to the loss of BBM transporters. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Inst Med Res & Occupat Hlth, Unit Mol Toxicol, HR-10001 Zagreb, Croatia. Massachusetts Gen Hosp East, Renal Unit, Boston, MA 02129 USA. RP Sabolic, I (reprint author), Inst Med Res & Occupat Hlth, Unit Mol Toxicol, Ksaverska Cesta 2, HR-10001 Zagreb, Croatia. FU FIC NIH HHS [1-R03-TW01057-01] NR 48 TC 26 Z9 32 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD AUG 28 PY 2001 VL 165 IS 2-3 BP 205 EP 216 DI 10.1016/S0300-483X(01)00450-4 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 470HT UT WOS:000170865900014 PM 11522379 ER PT J AU Rader, AE Avery, A Wait, CL McGreevey, LS Faigel, D Heinrich, MC AF Rader, AE Avery, A Wait, CL McGreevey, LS Faigel, D Heinrich, MC TI Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kit SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT Fall Meeting of the American-Society-of-Clinical-Pathologists/College-of-American-Pathologis ts CY OCT 14-19, 2000 CL SAN DIEGO, CALIFORNIA SP Amer Soc Clin Pahtologists, Coll Amer Pathologists DE gastrointestinal stromal tumor; GIST; cytology; fine-needle aspiration ID MUSCLE TUMORS; INTERSTITIAL-CELLS; PROGNOSIS; DOMAIN; CAJAL; GENE AB BACKGROUND. Differentiating gastrointestinal stromal tumors (GISTs) from other intramural mesenchymal tumors of the GI tract on fine-needle aspiration biopsies (FNABs) is difficult. Recent studies have shown that GISTs are immunophenotypically and genetically distinct. GISTs exhibit consistent immunohistochemical ex pression of CD-117 (KIT) and often express activating mutations of this protooncogene. The aim of the current study was to employ immunocytochemistry and mutational analysis of the c-kit gene to aid in the diagnosis of GISTs on FNAB. METHODS. Five endoscopic ultrasound-guided FNABs of gastrointestinal spindle cell neoplasms performed at the Veterans Affairs Medical Center (VAMC) in Portland, Oregon, from 1998-1999 were reviewed. A panel of immunocytochemical stains was performed on each cellblock including CD-117 (KIT), smooth muscle actin (SMA), desmin, S-100, and CD34. Genomic DNA (gDNA) was extracted, and amplification of exons 9, 11, 13 and 17 of c-kit was performed by polymerase chain reaction (PCR) on CD-117 (KIT) and CD34 positive cases. Direct sequencing of amplicons identified the mutations. RESULTS. Five patients were diagnosed with GISTs based on morphology and immuno cyto chemical positivity for CD-117 and CD34. PCR analysis of c-kit exon 11 revealed three cases with novel-sized PCR bands in addition to the expected wild-type-sized PCR product. Amplicons from these cases contained an in-frame deletion mutation. One of the two cases with wild-type-;sized exon 11 amplicons was found to be heterozygous for a point mutation producing an amino acid substitution (W557R). No mutations in exon 9, 11, 13, or 17 of c-kit were found in the remaining case. CONCLUSIONS. Ancillary techniques such as immuno cyto chemistry and c-kit gene mutational analysis may aid in the diagnosis of GISTs on FNABs. (C) 2001 American Cancer Society. C1 Oregon Hlth Sci Univ, Dept Pathol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Dept Pathol, Portland, OR USA. Oregon Hlth Sci Univ, Div Hematol & Oncol, Dept Med, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Dept Med, Div Hematol & Oncol, Portland, OR USA. Canc Pathol Core Facil, Portland, OR USA. Oregon Hlth Sci Univ, Div Gastroenterol, Dept Med, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Div Gastroenterol, Dept Med, Portland, OR USA. RP Rader, AE (reprint author), Oregon Hlth Sci Univ, Dept Pathol, L471,3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. NR 25 TC 69 Z9 74 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2001 VL 93 IS 4 BP 269 EP 275 DI 10.1002/cncr.9041 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 464DX UT WOS:000170518900007 PM 11507701 ER PT J AU Wieczorek, TJ Faquin, WC Rubin, BP Cibas, ES AF Wieczorek, TJ Faquin, WC Rubin, BP Cibas, ES TI Cytologic diagnosis of gastrointestinal stromal tumor with emphasis on the differential diagnosis with leiomyosarcoma SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 03-09, 2001 CL ATLANTA, GEORGIA SP US & Canadian Acad Pathol DE gastrointestinal neoplasms; gastrointestinal stromal tumor (GIST); sarcoma; leiomyosarcoma (LMS); fine-needle aspiration (FNA); immunohistochemistry; protooncogene protein c-kit; CD117; cytology ID FINE-NEEDLE ASPIRATION; DENDRITIC CELL-SARCOMA; SOFT-TISSUE SARCOMAS; C-KIT; ENDOSCOPIC ULTRASOUND; ELECTRON-MICROSCOPY; SYNOVIAL SARCOMA; BIOPSY; TRACT; PATHOGENESIS AB BACKGROUND. Gastrointestinal stromal tumor (GIST) has only recently been distinguished histologically and immunochemically from morphologically similar neoplasms of the abdomen. METHODS. The authors reviewed 15 cytologic cases of GIST (14 fine-needle aspiration [FNA] specimens and 1 peritoneal fluid specimen) and compared them with 23 cases of leiomyosarcoma (LMS) arising in the abdomen or pelvis (all FNAs). Immunochemistry (IC) was performed on both the cytologic and subsequent tissue specimens if sufficient specimen was available. RESULTS. Cytologic samples of GISTS typically showed irregularly outlined clusters of uniform spindle cells that were spread easily without crush artifact. The cells had wispy cytoplasm with long, delicate, filamentous extensions (13 cases; 87%). A prominent vascular pattern was common (9 cases; 60%); pleomorphism (I case; 7%) was uncommon. The LMSs showed three-dimensional, rightly cohesive, sharply marginated syncytia of spindle cells, often with nuclear crush artifact. The cytoplasm/stroma had a distinct wiry, refractile appearance (21 cases; 91%); delicate filamentous cytoplasmic extensions (5 cases; 22070) and prominent vessels (3 cases; 13%) were less common. LMSs more commonly exhibited pleomorphism (14 cases; 61%). Epithelioid cytomorphology, mitoses, and necrosis occasionally were observed in both tumor types. IC for c-kit (on cytologic material) was positive in 10 of 10 cases of GIST (usually diffuse and strong) and 2 of 19 cases of LMS (focal). CD34 positivity favored GIST (4 of 9 cases) over LMS (I of 19 cases). Smooth muscle actin was positive in 20 of 20 LMSs (strong and diffuse) and 6 of 10 GISTS (usually focal). Desmin was positive in 12 of 20 LMSs and was only focally positive in 1 of 11 GISTS. Correlation of IC results was excellent between cytologic and tissue specimens. CONCLUSIONS. Delicate cytoplasmic processes; a prominent vascular pattern; a lack of nuclear pleomorphism; and a c-kit-positive, desmin-negative immunoprofile are characteristic features of GIST and help distinguish these tumors from LMS in cytologic specimens. (C) 2001 American Cancer Society. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. RP Cibas, ES (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. NR 36 TC 40 Z9 40 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2001 VL 93 IS 4 BP 276 EP 287 DI 10.1002/cncr.9042 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA 464DX UT WOS:000170518900008 PM 11507702 ER PT J AU Pastores, GM Thadhani, R AF Pastores, GM Thadhani, R TI Enzyme-replacement therapy for Anderson-Fabry disease SO LANCET LA English DT Editorial Material C1 NYU, Sch Med, Dept Neurol & Pediat, Neurogenet Program, New York, NY 10003 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA 02114 USA. RP Pastores, GM (reprint author), NYU, Sch Med, Dept Neurol & Pediat, Neurogenet Program, New York, NY 10003 USA. NR 12 TC 48 Z9 50 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 25 PY 2001 VL 358 IS 9282 BP 601 EP 603 DI 10.1016/S0140-6736(01)05816-0 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 465XP UT WOS:000170615500004 PM 11530143 ER PT J AU Li, XG Josef, J Marasco, WA AF Li, XG Josef, J Marasco, WA TI HIV-1 Tat can substantially enhance the capacity of NIK to induce I kappa B degradation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1; Tat; NF-kappa B; I kappa B; NIK; HIV-1 LTR ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1-INFECTED T-CELLS; KINASE KINASE KINASE-1; TRANS-ACTIVATOR GENE; TRANSCRIPTION FACTOR; TYPE-1 TAT; HUMAN-IMMUNODEFICIENCY-VIRUS-1 TAT; SIGNAL-TRANSDUCTION; C-REL; PROTEIN AB The human immunodeficiency virus type 1 (HIV-1) Tat is a virally encoded protein that dramatically upregulates viral replication through interactions with the HIV-1 5' long terminal repeat (LTR) and cellular transcription factors. The HIV-1 LTR is divided into three major regions: modulatory, core and TAR. The modulatory region contains numerous cis-acting sequences for the binding of transcription factors including NF-kappaB, NF-AT, and AP-1. In several reports, Tat has been found to induce NF-kappaB activation of the HIV-1 LTR, while in other studies Tat has been reported to have no effect on activation of NF-kappaB. These discrepancies may arise from differences in experimental conditions such as the source of Tat (exogenous versus endogenous), the detection methods for NF-kappaB activation (DNA binding capability versus I kappaB degradation), and the types of reporters used (HIV-1 versus non-HIV-1 derived). To reconcile these differences we examined the effect of endogenous Tat on NF-kappaB activation, on I kappaB degradation and its interaction with upstream MAP3Ks. We demonstrate that although an 80% reduction in Tat-induced HIV-1 LTR activity can be detected if the kappaB binding sites are mutated, surprisingly endogenous Tat (expressed intracellularly by transfection) lacks direct effect on I kappaB degradation. Further analysis demonstrates that although Tat alone lacks direct effect on I kappaB alpha degradation or dissociation from NF-kappaB, Tat can substantially enhance the capacity of NF-kappaB-inducing kinase (NIK), but not MEKK1, to accelerate degradation of I kappaB. We propose a model to explain these collective experimental findings. (C) 2001 Academic Press. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Marasco, WA (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, JFB 824,44 Binney St, Boston, MA 02115 USA. NR 53 TC 9 Z9 9 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 24 PY 2001 VL 286 IS 3 BP 587 EP 594 DI 10.1006/bbrc.2001.5442 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 468FY UT WOS:000170748500024 PM 11511100 ER PT J AU Vincent, S Perkins, AL Perrimon, N AF Vincent, S Perkins, AL Perrimon, N TI Doublesex surprises SO CELL LA English DT Review ID DROSOPHILA-MELANOGASTER C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Surg Res Labs, Boston, MA 02114 USA. RP Perrimon, N (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, 200 Longwood Ave, Boston, MA 02115 USA. RI vincent, stephane/M-7231-2016 OI vincent, stephane/0000-0003-2757-6926 NR 11 TC 17 Z9 17 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 24 PY 2001 VL 106 IS 4 BP 399 EP 402 DI 10.1016/S0092-8674(01)00468-8 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 466UU UT WOS:000170665200003 PM 11525726 ER PT J AU Kourtzi, Z Kanwisher, N AF Kourtzi, Z Kanwisher, N TI Representation of perceived object shape by the human lateral occipital complex SO SCIENCE LA English DT Article ID INFERIOR TEMPORAL NEURONS; PRIMARY VISUAL-CORTEX; OCCLUDED OBJECTS; RECOGNITION; AREAS; SELECTIVITY; RESPONSES; SURFACES; CONTOURS; V1 AB The human lateral occipital complex (LOC) has been implicated in object recognition, but it is unknown whether this region represents low-level image features or perceived object shape. We used an event-related functional magnetic resonance imaging adaptation paradigm in which the response to pairs of successively presented stimuli is tower when they are identical than when they are different. Adaptation across a change between the two stimuli in a pair provides evidence for a common neural representation invariant to that change. We found adaptation in the LOC when perceived shape was identical but contours differed, but not when contours were identical but perceived shape differed. These data indicate that the LOC represents not simple image features, but rather higher level shape information. C1 Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02128 USA. RP Kourtzi, Z (reprint author), Max Planck Inst Biol Cybernet, Spemannstr 38, D-72076 Tubingen, Germany. FU NEI NIH HHS [EY13455] NR 30 TC 517 Z9 521 U1 9 U2 62 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 24 PY 2001 VL 293 IS 5534 BP 1506 EP 1509 DI 10.1126/science.1061133 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465XV UT WOS:000170616000049 PM 11520991 ER PT J AU Szot, P Weinshenker, D Rho, JM Storey, TW Schwartzkroin, PA AF Szot, P Weinshenker, D Rho, JM Storey, TW Schwartzkroin, PA TI Norepinephrine is required for the anticonvulsant effect of the ketogenic diet SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE ketogenic diet; flurothyl; norepinephrine; dopamine beta-hydroxylase; mouse; pediatric epilepsy ID RAT-BRAIN; LOCUS-COERULEUS; MONOAMINE LEVELS; CARBAMAZEPINE; MICE; SEIZURES; STIMULATION; HYDROXYLASE; CERULEUS; REGIONS AB Ketogenic diet (KD) is a high fat, low carbohydrate diet used to treat children with epilepsy that are refractory to conventional antiepileptic drugs (AEDs). The anticonvulsant mechanism of the KD is unknown. To determine if the noradrenergic system has a role in mediating the anticonvulsant action of the KD, dopamine beta -hydroxylase knockout (Dbh -/-) mice that lack norepinephrine (NE) and Dbh +/- littermates that have normal NE content were fed either a standard rodent chow or the KD. When exposed to the convulsant flurothyl, Dbh +/- mice fed the KD had significantly longer latencies to myoclonic jerk (MJ) and generalized clonic-tonic (CT) seizures than Dbh +/- mice fed normal chow. In contrast, Dbh mice fed the KD had seizure latencies to both MJ and CT comparable to Dbh -/- mice fed normal chow. These results suggest that an intact, functional noradrenergic nervous system is required for the KD to exert an anticonvulsant effect. Published by Elsevier Science B.V. C1 VA Puget Sound Hlth Care Syst, GRECC 182B, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ Washington, Dept Behav Sci, Seattle, WA 98195 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Dept Biochem, Seattle, WA 98195 USA. Univ Calif Irvine, Coll Med, Dept Pediat, Irvine, CA 92697 USA. Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. Univ Washington, Dept Physiol Biophys, Seattle, WA 98195 USA. RP Szot, P (reprint author), VA Puget Sound Hlth Care Syst, GRECC 182B, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 39 TC 53 Z9 54 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD AUG 23 PY 2001 VL 129 IS 2 BP 211 EP 214 DI 10.1016/S0165-3806(01)00213-9 PG 4 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 475VM UT WOS:000171190300009 ER PT J AU Lieberman, DA Weiss, DG Harford, WV Ahnen, DJ Provenzale, D Sontag, SJ Schnell, TG Chejfec, G Campbell, DR Durbin, TE Bond, JH Nelson, DB Ewing, SL Triadafilopoulos, G Ramirez, FC Lee, JG Collins, JF Fennerty, B Johnston, TK Corless, CL McQuaid, KR Garewal, H Sampliner, RE Morales, TG Fass, R Smith, RE Maheshwari, Y AF Lieberman, DA Weiss, DG Harford, WV Ahnen, DJ Provenzale, D Sontag, SJ Schnell, TG Chejfec, G Campbell, DR Durbin, TE Bond, JH Nelson, DB Ewing, SL Triadafilopoulos, G Ramirez, FC Lee, JG Collins, JF Fennerty, B Johnston, TK Corless, CL McQuaid, KR Garewal, H Sampliner, RE Morales, TG Fass, R Smith, RE Maheshwari, Y CA Veterans Affairs Cooperative Study TI One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FLEXIBLE SIGMOIDOSCOPY; ASYMPTOMATIC ADULTS; HEMOCCULT; MORTALITY; SENSITIVITY; COLONOSCOPY; NEOPLASIA; TRIAL AB Background: Fecal occult-blood testing and sigmoidoscopy have been recommended for screening for colorectal cancer, but the sensitivity of such combined testing for detecting neoplasia is uncertain. At 13 Veterans Affairs medical centers, we performed colonoscopy to determine the prevalence of neoplasia and the sensitivity of one-time screening with a fecal occult-blood test plus sigmoidoscopy. Methods: Asymptomatic subjects (age range, 50 to 75 years) provided stool specimens on cards from three consecutive days for fecal occult-blood testing, which were rehydrated for interpretation. They then underwent colonoscopy. Sigmoidoscopy was defined as examination of the rectum and sigmoid colon during colonoscopy, and sensitivity was estimated by determining how many patients with advanced neoplasia had an adenoma in the rectum or sigmoid colon. Advanced colonic neoplasia was defined as an adenoma 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. Results: A total of 2885 subjects returned the three specimen cards for fecal occult-blood testing and underwent a complete colonoscopic examination. A total of 23.9 percent of subjects with advanced neoplasia had a positive test for fecal occult blood. As compared with subjects who had a negative test for fecal occult blood, the relative risk of advanced neoplasia in subjects who had a positive test was 3.47 (95 percent confidence interval, 2.76 to 4.35). Sigmoidoscopy identified 70.3 percent of all subjects with advanced neoplasia. Combined one-time screening with a fecal occult-blood test and sigmoidoscopy identified 75.8 percent of subjects with advanced neoplasia. Conclusions: One-time screening with both a fecal occult-blood test with rehydration and sigmoidoscopy fails to detect advanced colonic neoplasia in 24 percent of subjects with the condition. C1 Oregon Hlth Sci Univ, Portland Vet Affairs Med Ctr, Div Gastroenterol, Portland, OR 97207 USA. Vet Affairs Med Ctr, Perry Point, MD USA. RP Lieberman, DA (reprint author), Oregon Hlth Sci Univ, Portland Vet Affairs Med Ctr, Div Gastroenterol, P3-GI,POB 1034, Portland, OR 97207 USA. NR 24 TC 364 Z9 379 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 23 PY 2001 VL 345 IS 8 BP 555 EP 560 DI 10.1056/NEJMoa010328 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 464ZH UT WOS:000170562900001 PM 11529208 ER PT J AU Turenne, GA Paul, P Laflair, L Price, BD AF Turenne, GA Paul, P Laflair, L Price, BD TI Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53 SO ONCOGENE LA English DT Article DE ATM; p53; chk2; phosphorylation; bleomycin ID DAMAGE-INDUCED PHOSPHORYLATION; DNA-DAMAGE; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; PROTEIN-KINASE; DEPENDENT PHOSPHORYLATION; CHECKPOINT PATHWAY; CELLULAR-RESPONSE; IN-VITRO; CDS1 AB The ATM protein kinase regulates the cell's response to DNA damage by regulating cell cycle checkpoints and DNA repair. ATM phosphorylates several proteins involved in the DNA-damage response, including p53. We have examined the mechanism by which ATM regulates p53's transcriptional activity. Here, we demonstrate that reintroduction of ATM into AT cells restores the activation of p53 by the radio-mimetic agent bleomycin. Further, p53 activation is lost when a kinase inactive ATM is used. or if the N-terminal of ATM is deleted. In addition, AT cells stably expressing ATM showed decreased sensitivity to Ionizing Radiation-induced cell killing, whereas cells expressing kinase inactive ATM or N-terminally deleted ATM were indistinguishable from AT cells. Finally, single point-mutations of serines 15, 20, 33 or 37 did not individually block the ATM-dependent activation of p53 transcriptional activity by bleomycin. However, double mutations of either serines 15 and 20 or serines 33 and 37 blocked the ability of ATM to activate p53. Our results indicate that the N-terminal of ATM and ATM's kinase activity are required for activation of p53's transcriptionl activity and restoration of normal sensitivity to DNA damage. In addition, activation of p53 by ATM requires multiple serine residues in p53's transactivation domain. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Price, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St,D810A, Boston, MA 02115 USA. FU NCI NIH HHS [CA64585] NR 62 TC 46 Z9 49 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 23 PY 2001 VL 20 IS 37 BP 5100 EP 5110 DI 10.1038/sj.onc.1204665 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 463EN UT WOS:000170464000003 PM 11526498 ER PT J AU Michaud, DS Giovannucci, E Willett, WC Colditz, GA Stampfer, MJ Fuchs, CS AF Michaud, DS Giovannucci, E Willett, WC Colditz, GA Stampfer, MJ Fuchs, CS TI Physical activity, obesity, height, and the risk of pancreatic cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BODY-FAT DISTRIBUTION; NATIONAL DEATH INDEX; GROWTH-FACTOR-I; DIABETES-MELLITUS; ACTIVITY QUESTIONNAIRE; NUTRITIONAL FACTORS; INSULIN; MORTALITY; MEN; GLUCOSE AB Context Diabetes mellitus and elevated postload plasma glucose levels have been associated with an increased risk of pancreatic cancer in previous studies. By virtue of their influence on insulin resistance, obesity and physical inactivity may increase risk of pancreatic cancer. Objective To examine obesity, height, and physical activity in relation to pancreatic cancer risk. Design and Setting Two US cohort studies conducted by mailed questionnaire, the Health Professionals Follow-Up Study (initiated in 1986) and the Nurses' Health Study (initiated in 1976), with 10 to 20 years of follow-up. Participants A total of 46648 men aged 40 to 75 years and 117041 women aged 30 to 55 years who were free of prior cancer at baseline and had complete data on height and weight. Main Outcome Measures Relative risk of pancreatic cancer, analyzed by self-reported body mass index (BMI), height, and level of physical activity. Results During follow-up, we documented 350 incident pancreatic cancer cases. Individuals with a BMI of at least 30 kg/m(2) had an elevated risk of pancreatic cancer compared with those with a BMI of less than 23 kg/m(2) (multivariable relative risk [RR], 1.72; 95% confidence interval [CI], 1.19-2.48), Height was associated with an increased pancreatic cancer risk (multivariable RR, 1.81; 95% CI, 1.31-2.52 for the highest vs lowest categories). An inverse relation was observed for moderate activity (multivariable RR, 0.45; 95% CI, 0.29-0.70 for the highest vs lowest categories; P for trend <.001). Total physical activity was not associated with risk among individuals with a BMI of less than 25 kg/m(2) but was inversely associated with risk among individuals with a BMI of at least 25 kg/m(2) (pooled multivariable RR, 0.59; 95% CI, 0.37-0.94 for the top vs bottom tertiles of total physical activity; P for trend=.04). Conclusion In 2 prospective cohort studies, obesity significantly increased the risk of pancreatic cancer. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Michaud, DS (reprint author), NCI, 6120 Execut Blvd,EPS Room 7026, Rockville, MD 20852 USA. RI Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 86102, CA 55075, CA 87969] NR 50 TC 326 Z9 333 U1 2 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 22 PY 2001 VL 286 IS 8 BP 921 EP 929 DI 10.1001/jama.286.8.921 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 465EU UT WOS:000170577300026 PM 11509056 ER PT J AU Kraus, M Pao, LI Reichlin, A Hu, Y Canono, B Cambier, JC Nussenzweig, MC Rajewsky, K AF Kraus, M Pao, LI Reichlin, A Hu, Y Canono, B Cambier, JC Nussenzweig, MC Rajewsky, K TI Interference with immunoglobulin (Ig)alpha immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B cell development, depending on the availability of an Ig beta cytoplasmic tail SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE mb-1 protein; B cell antigen receptor; ITAM; B cell subsets; gene targeting ID RECEPTOR SIGNAL-TRANSDUCTION; LYMPHOCYTE ANTIGEN RECEPTOR; PHOSPHATASE 1C; T-CELLS; RAG-1-DEFICIENT MICE; CD22-DEFICIENT MICE; POSITIVE SELECTION; NEGATIVE REGULATOR; KINASE ACTIVATION; ALLELIC EXCLUSION AB To determine the function of immunoglobulin (Ig)alpha immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation, we generated mice in which Ig alpha ITAM tyrosines were replaced by phenylalanines (Ig alpha (FF/FF)). Ig alpha (FF/FF) mice had a specific reduction of B1 and marginal zone B cells, whereas B2 cell development appeared to be normal, except that lambda1 light chain usage was increased. The mutants responded less efficiently to T cell-dependent antigens, whereas T cell-independent responses were unaffected. Upon B cell receptor ligation, the cells exhibited heightened calcium flux, weaker Lyn and Syk tyrosine phosphorylation, and phosphorylation of Ig alpha non-ITAM tyrosines. Strikingly, when the Iga ITAM mutation was combined with a truncation of Ig beta, B cell development was completely blocked at the pro-B cell stage, indicating a crucial role of ITAM phosphorylation in B cell development. C1 Univ Cologne, Inst Genet, D-50931 Cologne, Germany. Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Univ Colorado, Hlth Sci Ctr, Integrat Dept Immunol, Denver, CO 80206 USA. Natl Jewish Med & Res Ctr, Denver, CO 80206 USA. Howard Hughes Med Inst, New York, NY 10021 USA. RP Kraus, M (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. NR 78 TC 85 Z9 88 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 20 PY 2001 VL 194 IS 4 BP 455 EP 469 DI 10.1084/jem.194.4.455 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 466DH UT WOS:000170628700009 PM 11514602 ER PT J AU Goetz, MB Boscardin, WJ Wiley, D Alkasspooles, S AF Goetz, MB Boscardin, WJ Wiley, D Alkasspooles, S TI Decreased recovery of CD4 lymphocytes in older HIV-infected patients beginning highly active antiretroviral therapy SO AIDS LA English DT Article ID PROTEASE INHIBITOR; IMMUNE RECONSTITUTION; CLINICAL PROGRESSION; VIROLOGICAL FAILURE; AGE; DETERMINANTS; COHORT AB Among virological responders, the area under the curve of the CD4 count minus baseline (AUCMB) after 3, 9, 15 and 18 months of highly active antiretroviral therapy (HAART) was less in individuals 55 years or older (P < 0.05). Fewer older individuals achieved increases of 50, 100, or over 150 CD4 cells/mul. A random quadratic time course model estimated that the AUCMB decreased 35 cells/year for each 10 years of additional age during the first 12 months after HAART (P < 0.005). C1 VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Nursing, Primary Care Sect, Los Angeles, CA 90024 USA. RP Goetz, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. OI Goetz, Matthew/0000-0003-4542-992X NR 17 TC 46 Z9 49 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 17 PY 2001 VL 15 IS 12 BP 1576 EP 1579 DI 10.1097/00002030-200108170-00017 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 463KA UT WOS:000170474300017 PM 11504992 ER PT J AU Rao, VLR Dogan, A Todd, KG Bowen, KK Dempsey, RJ AF Rao, VLR Dogan, A Todd, KG Bowen, KK Dempsey, RJ TI Neuroprotection by memantine, a non-competitive antagonist after traumatic brain injury NMDA receptor in rats SO BRAIN RESEARCH LA English DT Article DE excitotoxicity; glutamate antagonist; memantine; neuroprotection; secondary neuronal death; traumatic brain injury ID METHYL-D-ASPARTATE; CHANNEL BLOCKER MEMANTINE; GLUTAMATE; ISCHEMIA; PHARMACOTHERAPY; HYPOTHERMIA; ACTIVATION; EXPRESSION; SYMPTOMS; BINDING AB This study investigated whether memantine, a non-competitive NMDA receptor antagonist is neuroprotective after traumatic brain injury (TBI) induced in adult rats with a controlled cortical impact device. TBI led to significant neuronal death in the hippocampal CA2 and CA3 regions (by 50 and 59%, respectively), by 7 days after the injury. Treatment of rats with memantine (10 and 20 mg/Kg, i.p.) immediately after the injury significantly prevented the neuronal loss in both CA2 and CA3 regions. This is the first study showing the neuroprotective potential of memantine to prevent the TBI-induced neuronal damage. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Wisconsin, Dept Neurol Surg, Madison, WI 53792 USA. Univ Wisconsin, Cardiovasc Res Ctr, Madison, WI 53792 USA. Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. Univ Alberta, Dept Psychiat, Edmonton, AB, Canada. RP Dempsey, RJ (reprint author), Univ Wisconsin, Dept Neurol Surg, H4-336 CSC,600 Highland Ave, Madison, WI 53792 USA. FU NINDS NIH HHS [NS31220, NS28000] NR 30 TC 63 Z9 67 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 17 PY 2001 VL 911 IS 1 BP 96 EP 100 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 468JC UT WOS:000170753500012 PM 11489449 ER PT J AU Cheng, SH Sheen, J Gerrish, C Bolwell, GP AF Cheng, SH Sheen, J Gerrish, C Bolwell, GP TI Molecular identification of phenylalanine ammonia-lyase as a substrate of a specific constitutively active Arabidopsis CDPK expressed in maize protoplasts SO FEBS LETTERS LA English DT Article DE phenylalanine ammonia-lyase; protein kinase; calmodulin-like domain protein kinase; Arabidopsis ID CALMODULIN-LIKE DOMAIN; PROTEIN-KINASE; INTRAMOLECULAR BINDING; SIGNAL-TRANSDUCTION; ESCHERICHIA-COLI; PLANTS; PHOSPHORYLATION; ACTIVATION; CALCIUM; CASCADE AB Phenylalanine ammonia-lyase (PAL) is a key enzyme in pathogen defence, stress response and secondary metabolism and is subject to post-translational phosphorylation. In order to address the significance of this phenomenon it is necessary to identify the protein kinase (PK) responsible and place it in its regulatory circuit. Using protoplast transient expression of Arabidopsis kinase genes coupled to immunocomplex kinase assay, it has been possible to screen for specific PAL kinase. We show here that AtCPK1 (calcium dependent PK), but not other closely related PKs could phosphorylate both a recombinant PAL protein and a peptide (SRVAKTRTLTTA) that is a site phosphorylated in vivo. Identification of the specific CDPK as a PAL kinase now opens up the possibility of exploring the calcium link in biotic stress signalling, salicylate and phytoalexin production as well as the significance of PAL phosphorylation. The protoplast transient expression system is a potentially powerful method to determine and screen for plant gene functions utilising genomic and proteomic data. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science BN. All rights reserved. C1 Univ London Royal Holloway & Bedford New Coll, Sch Biol Sci, Div Biochem, Egham TW20 0EX, Surrey, England. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. RP Bolwell, GP (reprint author), Univ London Royal Holloway & Bedford New Coll, Sch Biol Sci, Div Biochem, Egham TW20 0EX, Surrey, England. NR 22 TC 56 Z9 60 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 17 PY 2001 VL 503 IS 2-3 BP 185 EP 188 DI 10.1016/S0014-5793(01)02732-6 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 466HW UT WOS:000170641000014 PM 11513879 ER PT J AU Kaneto, H Xu, G Song, KH Suzuma, K Bonner-Weir, S Sharma, A Weir, GC AF Kaneto, H Xu, G Song, KH Suzuma, K Bonner-Weir, S Sharma, A Weir, GC TI Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INSULIN GENE-TRANSCRIPTION; O-LINKED GLYCOSYLATION; GLUCOSE TOXICITY; TRANSGENIC MICE; IN-VIVO; GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; SKELETAL-MUSCLE; HOMEOBOX FACTOR; HIT-T15 CELLS; GROWTH-FACTOR AB It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic beta -cell function remains unclear. In this study, we found that in isolated rat islets adenovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway, leads to deterioration of beta -cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment with glucosamine results in impaired glucose-stimulated insulin secretion and reduction irk the expression levels of several beta -cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an important transcription factor for these three genes, was markedly reduced. These phenomena were not mimicked by the induction of O-linked glycosylation with an inhibitor of O-GlcNAcase, PUG-NAc. It was also found that glucosamine increases hydrogen peroxide levels and that several hexosamine pathway-mediated changes were suppressed by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, activation of the hexosamine pathway leads to deterioration of beta -cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of beta -cell function found in diabetes. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK-35449] NR 44 TC 182 Z9 194 U1 2 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2001 VL 276 IS 33 BP 31099 EP 31104 DI 10.1074/jbc.M104115200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 463JG UT WOS:000170472900068 PM 11390407 ER PT J AU Riballo, E Doherty, AJ Dai, Y Stiff, T Oettinger, MA Jeggo, PA Kysela, B AF Riballo, E Doherty, AJ Dai, Y Stiff, T Oettinger, MA Jeggo, PA Kysela, B TI Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; RNA CAPPING ENZYMES; V(D)J RECOMBINATION; ATAXIA-TELANGIECTASIA; CRYSTAL-STRUCTURE; REPAIR; FIBROBLASTS; PATIENT; CELLS; GENES AB DNA ligase IV functions in DNA non-homologous end-joining, in V(D)J recombination, and during brain development. We previously reported a homozygous mutation (R278H) in DNA ligase IV in a developmentally normal leukemia patient who over-responded to radiotherapy. The impact of this hypomorphic mutation has been evaluated using cellular, biochemical, and structural approaches. Structural modeling using T7 DNA ligase predicts that the activity and conformational stability of the protein is likely to be impaired. We show that wild type DNA ligase IV-Xrcc4 is an efficient double-stranded ligase with distinct optimal requirements for adenylate complex formation versus rejoining. The mutation impairs the formation of an adenylate complex as well as reducing the rejoining activity. Additionally, it imparts temperature-sensitive activity to the protein consistent with the predictions of the structural modeling. At the cellular level, the mutation confers a unique V(D)J recombination phenotype affecting the fidelity of signal joint formation with little effect on the frequency of the reaction. These findings suggest that hypomorphic mutations in ligase IV may allow normal development but confer marked radiosensitivity. C1 Univ Sussex, MRC, Cell Mutat Unit, Brighton BN1 9RR, E Sussex, England. Univ Cambridge, Wellcome Trust Ctr Mol Mechanisms, Inst Med Res, Cambridge CB2 2XY, England. Univ Cambridge, Dept Haematol, Cambridge CB2 2XY, England. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Jeggo, PA (reprint author), Univ Sussex, MRC, Cell Mutat Unit, Brighton BN1 9RR, E Sussex, England. NR 32 TC 84 Z9 86 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2001 VL 276 IS 33 BP 31124 EP 31132 DI 10.1074/jbc.M103866200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 463JG UT WOS:000170472900071 PM 11349135 ER PT J AU Lavigne, M Polomack, L Buc, H AF Lavigne, M Polomack, L Buc, H TI DNA synthesis by HIV-1 reverse transcriptase at the central termination site - A kinetic study SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROOVE BINDING TRACK; VERTICAL-SCANNING MUTAGENESIS; MINOR-GROOVE; CRITICAL TRYPTOPHAN; SECONDARY STRUCTURE; COMPLEX-FORMATION; THUMB SUBDOMAIN; INITIATION; MECHANISM; GENOME AB Human immunodeficiency virus, type 1 (HIV-1) reverse transcriptase (RT) terminates plus-strand DNA synthesis at the center of the HIV-1 genome, a process important for HIV-1 infectivity. The central termination sequence contains two termination sites (Ter1 and Ter2) located at the 3 ' -end of A(n)T(m) motifs, and the narrowing of the DNA minor groove generated by these motifs is responsible for termination. Kinetic data associated with the binding of RT and its ability to elongate in vitro various DNA duplexes and triplexes surrounding the Ter2 terminator were analyzed using a simple kinetic scheme. At Ter2, RT still displays a reasonable affinity for the corresponding DNA, but the binding of the next nucleotide and above all its incorporation rate are markedly hampered. Features affecting the width of the minor groove act directly at this last step. The constraint exerted against elongation by the A(n)T(m). tract persists at two positions downstream of the terminator. C1 Inst Pasteur, Unite Physicochim Macromol Biol, URA1773, CNRS, F-75724 Paris 15, France. RP Lavigne, M (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10,Fruit St, Boston, MA 02114 USA. NR 33 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2001 VL 276 IS 33 BP 31429 EP 31438 DI 10.1074/jbc.M102974200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 463JG UT WOS:000170472900109 PM 11402036 ER PT J AU Lavigne, M Polomack, L Buc, H AF Lavigne, M Polomack, L Buc, H TI Structures of complexes formed by HIV-1 reverse transcriptase at a termination site of DNA synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRAND TRANSFER-REACTIONS; RNASE-H; DRUG-RESISTANCE; NUCLEOCAPSID PROTEIN; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURES; POLYPURINE TRACT; KINETIC-ANALYSIS; RIBONUCLEASE-H AB This study presents structural parameters associated with termination of human immunodeficiency virus, type 1 (HIV-1) reverse transcriptase (RT) at Ter2, the major termination site located in the center of the HIV-1 genome. DNA footprinting studies of various elongation complexes formed by RT around wild type and mutant Ter2 sites have revealed two major structural transformations of these complexes when the enzyme gets closer to Ter2. First, the interactions between RT and the DNA duplex are less extended, although the global affinity of the enzyme for this duplex is only decreased by 2-fold. Second, there is an atypical positioning of the RT RNase H domain on the DNA duplex. We interpret our data as indicating that the A(n)T(m) motif located upstream of Ter2 prevents a classical positioning of the enzyme on the double-stranded part of the DNA duplex at some precise positions of elongation downstream of this motif. Instead, novel species of binary and/or ternary complexes, characterized by atypical footprints, are formed. The new rate-limiting step of the reaction, characterized in the preceding paper (Lavigne, M., Polomack, L., and Buc, H. (2001) J. BioL Chem. 276,31429-31438), would be a transition leading from these new species to a catalytically competent ternary complex. C1 Inst Pasteur, Unite Physicochim Macromol Biol, CNRS, URA 1773, F-75724 Paris 15, France. RP Lavigne, M (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10,Fruit St, Boston, MA 02114 USA. NR 60 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2001 VL 276 IS 33 BP 31439 EP 31448 DI 10.1074/jbc.M102976200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 463JG UT WOS:000170472900110 PM 11402037 ER PT J AU Tuveson, DA Willis, NA Jacks, T Griffin, JD Singer, S Fletcher, CDM Fletcher, JA Demetri, GD AF Tuveson, DA Willis, NA Jacks, T Griffin, JD Singer, S Fletcher, CDM Fletcher, JA Demetri, GD TI STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications SO ONCOGENE LA English DT Article DE Gastrointestional Stromal Tumors (GIST); c-KIT; STI571 ID TYROSINE KINASE INHIBITOR; CELL-LINE; BCR-ABL; B-CELLS; MUTATIONS; GROWTH; PATHOGENESIS; EXPRESSION; PROGNOSIS; STI-571 AB Mutations in the c-KIT receptor occur somatically in many sporadic Gastrointestinal Stromal Tumors (GIST), and similar mutations have been identified at the germline level in kindreds with multiple GISTs. These mutations activate the tyrosine kinase activity of e-KIT and induce constitutive signaling. To investigate the function of activated c-KIT in GIST, we established a human GIST cell line, GIST882, which expresses an activating KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain. Notably, the K642E substitution is encoded by a homozygous exon 13 missense mutation, and, therefore, GIST882 cells do not express native KIT. GIST882 c-KIT protein is constitutively tyrosine phosphorylated, but tyrosine phosphorylation was rapidly and completely abolished after incubating the cells with the selective tyrosine kinase inhibitor STI571. Furthermore, GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell death after prolonged incubation with STI571. Similar results were obtained after administering STI571 to a primary GIST cell culture that expressed a c-KIT exon I I juxtamembrane mutation (K558NP). These cell-culture-based studies support an important role for c-KIT signaling in GIST and suggest therapeutic potential for STI571 in patients afflicted by this chemoresistant tumor. C1 MIT, Ctr Canc, Cambridge, MA 02139 USA. Dept Biol, Cambridge, MA 02139 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Tuveson, DA (reprint author), MIT, Ctr Canc, 77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 30 TC 449 Z9 481 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 16 PY 2001 VL 20 IS 36 BP 5054 EP 5058 DI 10.1038/sj.onc.1204704 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 462VE UT WOS:000170439800015 PM 11526490 ER PT J AU Vidrih, JA Walensky, RP Sax, PE Freedberg, KA AF Vidrih, JA Walensky, RP Sax, PE Freedberg, KA TI Positive Epstein-Barr virus heterophile antibody tests in patients with primary human immunodeficiency virus infection SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID HIV-INFECTION; MONONUCLEOSIS AB PURPOSE: To describe three cases of primary human immunodeficiency virus (HIV) infection in patients who had laboratory studies consistent with infectious mononucleosis. SUBJECTS: We describe 3 patients who presented with a viral syndrome, had a positive heterophile antibody test, and were diagnosed with primary HIV infection. RESULTS: The results of Epstein-Barr virus serology studies in each of these patients were consistent with chronic, but not acute, Epstein-Barr virus infection. HIV antibody tests were negative, and HIV RNA was > 500 000 copies/mL in each patient. CONCLUSIONS: Clinicians should recognize that a positive heterophile antibody test in the setting of an acute viral illness does not exclude the diagnosis of primary HIV infection, although reactivation of latent Epstein-Barr virus infection cannot be ruled out. Patients presenting with nonspecific viral syndromes should be assessed for HIV risk behaviors and tested for primary HIV infection when appropriate. (C) 2001 by Excerpta Medica, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Gen Med, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Clin AIDS Program, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston Med Ctr, Evans Med Fdn, Boston, MA 02118 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Walensky, RP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Infect Dis, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NIAID NIH HHS [AI42006, R01 AI042006]; PHS HHS [CCU114927, CCU119525] NR 12 TC 19 Z9 19 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 15 PY 2001 VL 111 IS 3 BP 192 EP 194 DI 10.1016/S0002-9343(01)00804-X PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 490LK UT WOS:000172053200003 PM 11530029 ER PT J AU Kanter, ED Wilkinson, CW Radant, AD Petrie, EC Dobie, DJ McFall, ME Peskind, ER Raskind, MA AF Kanter, ED Wilkinson, CW Radant, AD Petrie, EC Dobie, DJ McFall, ME Peskind, ER Raskind, MA TI Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE PTSD; adrenal cortex; ACTH; cortisol; metyrapone; DHEA ID CORTICOSTEROID-BINDING GLOBULIN; DEXAMETHASONE SUPPRESSION TEST; PITUITARY-ADRENAL AXIS; PLASMA-CORTISOL; VIETNAM VETERANS; RECEPTOR BALANCE; DEPRESSION; COMBAT; BRAIN; COMORBIDITY AB Background: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. Methods: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenozis feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours, were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). Results: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed: however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. Conclusions: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD. (C) 2001 Society of Biological Psychiatry. C1 VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr 116, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Kanter, ED (reprint author), VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr 116, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 42 TC 100 Z9 102 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2001 VL 50 IS 4 BP 238 EP 245 DI 10.1016/S0006-3223(01)01158-1 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 466QF UT WOS:000170655700002 PM 11522257 ER PT J AU Alyea, E Weller, E Schlossman, R Canning, C Webb, I Doss, D Mauch, P Marcus, K Fisher, D Freeman, A Parikh, B Gribben, J Soiffer, R Ritz, J Anderson, K AF Alyea, E Weller, E Schlossman, R Canning, C Webb, I Doss, D Mauch, P Marcus, K Fisher, D Freeman, A Parikh, B Gribben, J Soiffer, R Ritz, J Anderson, K TI T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; LEUKOCYTE INFUSIONS; HOST DISEASE; RELAPSE; TRANSFUSIONS; RISK AB Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell-depleted allogeneic BMT was combined with prophylactic CD4(+) DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (greater than or equal to 11) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41 %) (P = .13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell-depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (C) 2001 by The American Society of Hematology. C1 Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Hematol Oncol, Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Hematol Oncol, Dept Radiat Therapy, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Biostat, Dept Radiat Therapy, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Biostat, Dept Med, Boston, MA 02115 USA. RP Alyea, E (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA78378]; NIAID NIH HHS [AI29530] NR 20 TC 129 Z9 133 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2001 VL 98 IS 4 BP 934 EP 939 DI 10.1182/blood.V98.4.934 PG 6 WC Hematology SC Hematology GA 461KU UT WOS:000170364100006 PM 11493435 ER PT J AU Westerberg, L Greicius, G Snapper, SB Aspenstrom, P Severinson, E AF Westerberg, L Greicius, G Snapper, SB Aspenstrom, P Severinson, E TI Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes SO BLOOD LA English DT Article ID T-CELL; ARP2/3 COMPLEX; RHO-GTPASES; ACTIN POLYMERIZATION; HUMAN NEUTROPHILS; N-WASP; ACTIVATION; INTERLEUKIN-4; ANTIGEN; IL-4 AB Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4- and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells. (C) 2001 by The American Society of Hematology. C1 Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. Ludwig Inst Canc Res, Ctr Biomed, S-75124 Uppsala, Sweden. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Westerberg, L (reprint author), Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, S-17177 Stockholm, Sweden. NR 65 TC 58 Z9 59 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2001 VL 98 IS 4 BP 1086 EP 1094 DI 10.1182/blood.V98.4.1086 PG 9 WC Hematology SC Hematology GA 461KU UT WOS:000170364100027 PM 11493455 ER PT J AU Hochberg, EP Chillemi, AC Wu, CJ Neuberg, D Canning, C Hartman, K Alyea, EP Soiffer, RJ Kalams, SA Ritz, J AF Hochberg, EP Chillemi, AC Wu, CJ Neuberg, D Canning, C Hartman, K Alyea, EP Soiffer, RJ Kalams, SA Ritz, J TI Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults SO BLOOD LA English DT Article ID RECENT THYMIC EMIGRANTS; NEGATIVE SELECTION; IMMUNE RECONSTITUTION; BLOOD; LYMPHOCYTES; REPERTOIRE; REQUIREMENT; GENERATION; THYMOCYTES; ACTIVATION AB Following myeloablative therapy, it is unknown to what extent age-dependent thymic involution limits the generation of new T cells with a diverse repertoire. Normal T-cell receptor gene rearrangement in T-cell progenitors results in the generation of T-cell receptor rearrangement excision circles (TRECs). In this study, a quantitative assay for TRECs was used to measure T-cell neogenesis in adult patients with leukemia who received myeloablative therapy followed by transplantation of allogeneic hematopoietic, stem cells. Although phenotypically mature T cells had recovered by I to 2 months after bone marrow transplantation (BMT), TREC levels remained low for 3 months after BMT. T-cell neogenesis became evident by 6 months, and normal levels of adult thymic function were restored at 6 to 12 months after BMT. Subsequent leukemia relapse in some patients was associated with reduced TREC levels, but infusion of mature donor CD4(+) T cells resulted in rapid restoration of thymic function. These studies demonstrate that T-cell neogenesis contributes to immune reconstitution in adult patients and suggest that thymic function can be manipulated in vivo. C1 Dana Farber Canc Inst, Dis Ctr Hematol Oncol, Dept Adult Oncol, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, Dis Ctr Hematol Oncol, Dept Adult Oncol, Dept Biostat, 44 Binney St, Boston, MA 02115 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NHLBI NIH HHS [K08 HL04293-01]; NIAID NIH HHS [AI39966, AI29530] NR 36 TC 85 Z9 103 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2001 VL 98 IS 4 BP 1116 EP 1121 DI 10.1182/blood.V98.4.1116 PG 6 WC Hematology SC Hematology GA 461KU UT WOS:000170364100031 PM 11493459 ER PT J AU Sasaki, H Auclair, D Fukai, I Kiriyama, M Yamakawa, Y Fujii, Y Chen, LB AF Sasaki, H Auclair, D Fukai, I Kiriyama, M Yamakawa, Y Fujii, Y Chen, LB TI Serum level of the periostin, a homologue of an insect cell adhesion molecule, as a prognostic marker in nonsmall cell lung carcinomas SO CANCER LA English DT Article DE periostin; chemiluminescence; lung carcinoma; prognosis ID GROWTH-FACTOR-BETA; E-SELECTIN; METASTASIS; DISEASE; CANCER; EXPRESSION; RECEPTORS; PROTEIN; CLONING; ICAM-1 AB BACKGROUND. Periostin protein shares structural and sequence homology with fasciclin I, which is an insect adhesion molecule. Periostin has a typical signal peptide at the N-terminal end, which suggests that it is a secreted protein. Recently, the authors developed a novel sandwich chemiluminescence assay to determine serum concentrations of periostin. METHODS. The authors investigated the serum periostin level in lung carcinoma patients and attempted to determine the influence of serum periostin level on clinical outcome for patients with nonsmall cell lung carcinoma (NSCLC) who had undergone surgery between January 1994 and July 1996. Expression of periostin messenger RNA was also examined by in situ RNA hybridization for lung carcinomas. RESULTS. The periostin gene was shown to be highly expressed at the tumor periphery of lung carcinoma tissue but not within the tumor by in situ RNA hybridization. Serum periostin levels were not significantly different between the NSCLC patients (1142.1 +/- 89.2 ng/mL) and the normal control (962.0 +/- 118.6 ng/mL) (P = 0.2985). There was no relation between serum periostin level and gender, stage, bone metastasis, N status, or T status. However, the serum periostin levels of NSCLC patients had decreased significantly by 4 weeks after the resection of the tumor. The NSCLC patients with high periostin level (> 962 ng/mL) had significantly poorer survival than the patients with normal periostin level (P = 0.0406). Using the Cox proportional hazards regression model, the authors found that stage (P < 0.0001) and serum periostin level (P = 0.0226) were independent prognostic factors. CONCLUSIONS. The in situ RNA hybridization data from the current study suggested that expression of periostin may be involved in tumor invasionand that the serum periostin level may serve as a prognostic marker for NSCLC. (C) 2001 American Cancer Society. C1 Nagoya City Univ, Sch Med, Dept Surg 2, Mizuho Ku, Nagoya, Aichi 4678601, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. RP Sasaki, H (reprint author), Nagoya City Univ, Sch Med, Dept Surg 2, Mizuho Ku, 1 Kawasumi, Nagoya, Aichi 4678601, Japan. NR 28 TC 80 Z9 86 U1 0 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2001 VL 92 IS 4 BP 843 EP 848 DI 10.1002/1097-0142(20010815)92:4<843::AID-CNCR1391>3.0.CO;2-P PG 6 WC Oncology SC Oncology GA 465UR UT WOS:000170608800018 PM 11550156 ER PT J AU Fukumura, D Xu, L Chen, Y Gohongi, T Seed, B Jain, RK AF Fukumura, D Xu, L Chen, Y Gohongi, T Seed, B Jain, RK TI Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo SO CANCER RESEARCH LA English DT Article ID SOLID TUMORS; FACTOR EXPRESSION; INTERSTITIAL PH; CANCER; CELLS; ANGIOGENESIS; INTERLEUKIN-8; EXPLOITATION; ACTIVATION; INDUCTION AB Hypoxia and acidosis are hallmarks of tumors as well as critical determinants of response to treatments. They can upregulate vascular endothelial growth factor (VEGF) in vitro. However, the relationship between tissue oxygen partial pressure (PO2)/pH and VEGF transcription in vivo is not known. Thus, we developed a novel in vivo microscopy technique to simultaneously measure VEGF promoter activity, PO2, and pH. To monitor VEGF expression in vivo, we engineered human glioma cells that express green fluorescent protein (GFP) under the control of the VEGF promoter. These cells were implanted into the cranial windows in severe combined immunodeficient mice, and VEGF promoter activity was assessed by GFP imaging. Tissue PO2 and pH were determined by phosphorescence quenching microscopy and ratio imaging microscopy, respectively. These techniques have allowed us to show, for the first time, that VEGF transcription in brain tumors is independently regulated by the tissue PO2 and pH. One week after tumor implantation, significant angiogenesis was observed, with increased GFP fluorescence throughout the tumor. Under hypoxic or neutral pH conditions, VEGF-promoter activity increased, with a decrease in PO2 and independent of pH. Under low pH or oxygenated conditions, VEGF-promoter activity increased, with a decrease in pH and independent of PO2. In agreement with the in vivo findings, both hypoxia and acidic pH induced VEGF expression in these cells in vitro and showed no additive effect for combined hypoxia and low pH. These results suggest that VEGF transcription in brain tumors is regulated by both tissue PO2 and pH via distinct pathways. C1 Harvard Univ, Dept Radiat Oncol, Edwin L Steele Lab, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. Harvard Univ, Dept Biol Mol, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. RP Fukumura, D (reprint author), Harvard Univ, Dept Radiat Oncol, Edwin L Steele Lab, Massachusetts Gen Hosp,Med Sch, 100 Blossom St,COX-7, Boston, MA 02114 USA. FU NCI NIH HHS [P01-CA80124] NR 26 TC 251 Z9 265 U1 0 U2 25 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2001 VL 61 IS 16 BP 6020 EP 6024 PG 5 WC Oncology SC Oncology GA 464EW UT WOS:000170521100013 PM 11507045 ER PT J AU Zhang, XB Gaspard, JP Chung, DC AF Zhang, XB Gaspard, JP Chung, DC TI Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia SO CANCER RESEARCH LA English DT Article ID BETA-CATENIN; TUMOR ANGIOGENESIS; CARCINOMA CELLS; FACTOR GENE; KINASE; ACTIVATION; EXPRESSION; TARGET; PHOSPHORYLATION; TRANSCRIPTION AB Angiogenesis is not restricted to advanced stages of tumor development but is also observed in benign precursor lesions. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but the genetic mechanisms controlling its expression in premalignant lesions are poorly described. The Writ signaling pathway, which is commonly mutated in benign colonic adenomas, was found to strongly up-regulate VEGF. A T-cell factor-4-binding element at -805 bp in the VEGF promoter is an important mediator of this effect. Signaling through the K-ras oncogene, also frequently mutated in benign colonic polyps, up-regulated VEGF in a phosphatidylinositol 3-kinase-dependent manner. Furthermore, K-ras activation appeared to enhance Wnt signaling, which suggests a unique interaction between these two pathways. These studies thus identify VEGF as a novel target of the Writ pathway in early colonic neoplasia and serve to underscore the importance of angiogenesis in premalignant disease. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit, Boston, MA 02114 USA. RP Chung, DC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit, GRJ 825,70 Blossom St, Boston, MA 02114 USA. NR 24 TC 261 Z9 274 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2001 VL 61 IS 16 BP 6050 EP 6054 PG 5 WC Oncology SC Oncology GA 464EW UT WOS:000170521100020 PM 11507052 ER PT J AU Walensky, RP Rosenberg, ES Ferraro, MJ Losina, E Walker, BD Freedberg, KA AF Walensky, RP Rosenberg, ES Ferraro, MJ Losina, E Walker, BD Freedberg, KA TI Investigation of primary human immunodeficiency virus infection in patients who test positive for heterophile antibody SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID PRIMARY HIV-INFECTION; ANTIRETROVIRAL THERAPY; TYPE-1 INFECTION; MONONUCLEOSIS; DIAGNOSIS; FEATURES AB In light of a recent report of 3 false-positive results of Epstein-Barr virus heterophile tests caused by HIV infection, we sought to assess the frequency of this occurrence. One hundred thirty-two positive heterophile antibody-tested serum samples were obtained from 2 tertiary care facilities in Boston to assess for HIV, and all tested negative for HIV plasma RNA. This study shows that false-positive results of heterophile tests are not frequently associated with primary HIV infection. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Partners AIDS Res Ctr, Boston, MA 02114 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. RP Walensky, RP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NIAID NIH HHS [R01-AI42006, R01 AI042006] NR 18 TC 11 Z9 15 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2001 VL 33 IS 4 BP 570 EP 572 DI 10.1086/321903 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 456WB UT WOS:000170104800027 PM 11462197 ER PT J AU Evans, RL Hendricks, RD AF Evans, RL Hendricks, RD TI Comparison of subacute rehabilitative care with outpatient primary medical care SO DISABILITY AND REHABILITATION LA English DT Article ID STROKE REHABILITATION; SOCIAL SUPPORT; ADJUSTMENT; TRIAL AB Purpose: Prior rehabilitation outcome studies have had many weaknesses, but they gradually observe a lack of long-term benefits from inpatient care alone. The goal of this study was to measure the additive effect of outpatient. subacute rehabilitation (compared with usual outpatient primary medical care) for adults diagnosed with a disabling disorder in four major diagnostic groups (nervous. circulatory, musculoskeletal and injury). Method: A randomized clinical trial was conducted to determine the effects of outpatient. subacute rehabilitative care on: (1) physical function, (2) health; (3) well being; (4) family function: and (5) social support. Patients hospitalized for the first time with a disabling condition (n = 180) were provided inpatient rehabilitation and then were randomly assigned to either outpatient. subacute rehabilitation at home (n = 90) or to usual outpatient follow-up (n = 90) in which only primary care medical services were provided. To compare the two groups. univariate analyses of covariance were conducted for the outcome variables. Results: The major finding of this study was that of no significant eff:ct of the intervention on any outcome variable. Conclusions : Based on current study results, we conclude that any long term additive benefit of outpatient, subacute rehabilitation may not be detectable across disability categories and may require closer evaluation in studies with a more homogeneous population than in the current study. Providing complex follow-up case management services to all clients is apparently not beneficial and might better be provided using selection criteria based on need. Future studies should determine if services are more effective when provided to those with the most unmet rehabilitative needs. Further outpatient, subacute care rehabilitation studies should address the specific needs of the patients and be adapted individually to those needs. C1 VA Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98136 USA. Univ Washington, Sch Social Work, Seattle, WA 98195 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. RP Evans, RL (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div, 1660 S Columbian Way S-182-SW, Seattle, WA 98136 USA. NR 30 TC 6 Z9 6 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0963-8288 J9 DISABIL REHABIL JI Disabil. Rehabil. PD AUG 15 PY 2001 VL 23 IS 12 BP 531 EP 538 PG 8 WC Rehabilitation SC Rehabilitation GA 446ZL UT WOS:000169544000005 PM 11432650 ER PT J AU Frolov, MV Huen, DS Stevaux, O Dimova, D Balczarek-Strang, K Elsdon, M Dyson, NJ AF Frolov, MV Huen, DS Stevaux, O Dimova, D Balczarek-Strang, K Elsdon, M Dyson, NJ TI Functional antagonism between E2F family members SO GENES & DEVELOPMENT LA English DT Article DE E2F; cell cycle; Drosophila ID NUCLEAR ANTIGEN GENE; CELL-CYCLE PROGRESSION; DIHYDROFOLATE-REDUCTASE PROMOTER; B-MYB TRANSCRIPTION; S-PHASE ENTRY; RETINOBLASTOMA PROTEIN; DROSOPHILA DEVELOPMENT; HISTONE DEACETYLASE; DISTINCT ROLES; BINDING-SITE AB E2F is a heterogenous transcription factor and its role in cell cycle control results from the integrated activities of many different E2F family members. Unlike mammalian cells, that have a large number of E2F-related genes, the Drosophila genome encodes just two E2F genes, de2f1 and de2f2. Here we show that de2f1 and de2f2 provide different elements of E2F regulation and that they have opposing functions during Drosophila development. dE2F1 and dE2F2 both heterodimerize with dDP and bind to the promoters of E2F-regulated genes in vivo. dE2F1 is a potent activator of transcription, and the loss of de2f1 results in the reduced expression of E2F-regulated genes. In contrast, dE2F2 represses the transcription of E2F reporters and the loss of de2f2 function results in increased and expanded patterns of gene expression. The loss of de2f1 function has previously been reported to compromise cell proliferation. de2f1 mutant embryos have reduced expression of E2F-regulated genes, low levels of DNA synthesis, and hatch to give slow-growing larvae. We find that these defects are due in large part to the unchecked activity of dE2F2, since they can be suppressed by mutation of de2f2. Examination of eye discs from de2f1; de2f2 double-mutant animals reveals that relatively normal patterns of DNA synthesis can occur in the absence of both E2F proteins. This study shows how repressor and activator E2Fs are used to pattern transcription and how the net effect of E2F on cell proliferation results from the interplay between two types of E2F complexes that have antagonistic functions. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Univ Cambridge, Dept Oncol, Canc Res Campaign, Cambridge CB2 2XY, England. Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RI Huen, David/F-3676-2014 OI Huen, David/0000-0002-9900-2297 FU NIGMS NIH HHS [R01 GM053203, GM53203] NR 75 TC 114 Z9 119 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2001 VL 15 IS 16 BP 2146 EP 2160 DI 10.1101/gad.903901 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 463ZM UT WOS:000170507300013 PM 11511545 ER PT J AU Sheen, VL Dixon, PH Fox, JW Hong, SE Kinton, L Sisodiya, SM Duncan, JS Dubeau, F Scheffer, IE Schachter, SC Wilner, A Henchy, R Crino, P Kamuro, K DiMario, F Berg, M Kuzniecky, R Cole, AJ Bromfield, E Biber, M Schomer, D Wheless, J Silver, K Mochida, GH Berkovic, SF Andermann, F Andermann, E Dobyns, WB Wood, NW Walsh, CA AF Sheen, VL Dixon, PH Fox, JW Hong, SE Kinton, L Sisodiya, SM Duncan, JS Dubeau, F Scheffer, IE Schachter, SC Wilner, A Henchy, R Crino, P Kamuro, K DiMario, F Berg, M Kuzniecky, R Cole, AJ Bromfield, E Biber, M Schomer, D Wheless, J Silver, K Mochida, GH Berkovic, SF Andermann, F Andermann, E Dobyns, WB Wood, NW Walsh, CA TI Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females SO HUMAN MOLECULAR GENETICS LA English DT Article ID ACTIN-BINDING PROTEIN; DOUBLE CORTEX SYNDROME; TUBEROUS SCLEROSIS; TARGETS FILAMIN; DOUBLECORTIN; MIGRATION; EPILEPSY; REGION; IDENTIFICATION; MACROPHAGES AB Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fall to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration. C1 Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. UCL, Inst Neurol, Dept Clin Neurol, Neurogenet Unit, London WC1N 3BG, England. Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA. UCL, Inst Neurol, Dept Clin Neurol, Epilepsy Grp, London WC1N 3BG, England. McGill Univ, Montreal Neurol Inst, Dept Neurogenet, Montreal, PQ, Canada. McGill Univ, Montreal Neurol Inst, Epilepsy Serv, Montreal, PQ, Canada. Univ Melbourne, Austin & Repatriat Med Ctr, Dept Neurol, Melbourne, Vic, Australia. Med Clin, Dept Neurol, Pensacola, FL USA. Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Kokubu Seikyo Hosp, Dept Pediat, Kagoshima, Japan. Univ Connecticut, Dept Pediat, Farmington, CT USA. Univ Rochester, Dept Neurol, Rochester, NY USA. Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. Massachusetts Gen Hosp, Epilepsy Serv, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Univ Texas, Dept Pediat Neurol, Houston, TX USA. Loyola Univ, Med Ctr, Dept Pediat Neurol, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Walsh, CA (reprint author), Harvard Inst Med, Room 816,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cwalsh@caregroup.harvard.edu RI Scheffer, Ingrid/G-1668-2013; Wood, Nicholas/C-2505-2009; OI Scheffer, Ingrid/0000-0002-2311-2174; Wood, Nicholas/0000-0002-9500-3348; Berkovic, Samuel/0000-0003-4580-841X; Dobyns, William/0000-0002-7681-2844 FU NIMH NIH HHS [K08 MH063886]; NINDS NIH HHS [1PO1 NS40043, 5RO1 NS35129] NR 31 TC 162 Z9 167 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2001 VL 10 IS 17 BP 1775 EP 1783 DI 10.1093/hmg/10.17.1775 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 474UQ UT WOS:000171125600007 PM 11532987 ER PT J AU Campbell, EG Weissman, JS Moy, E Blumenthal, D AF Campbell, EG Weissman, JS Moy, E Blumenthal, D TI Status of clinical research in academic health centers - Views from the research leadership SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article AB Context The changing state of the health care system in the United States may be adversely affecting clinical research conducted in academic health centers (AHCs). Few formal data have been gathered about the nature and extent of the problems facing clinical research or the effects of remedies undertaken by AHCs. Objectives To assess the perceived quality and health of the clinical research enterprise and to determine challenges and adaptations to current environmental pressures. Design, Setting, and Participants Mailed survey conducted between December 1998 and March 1999 of a subsample of department chairs and senior research administrators (SRAs) in all US medical schools. Of the 712 potential respondents, 478 completed a questionnaire, yielding an overall response rate of 67.1% (64.8% for SRAs and 67.8% for department chairs). Main Outcome Measures Ratings of overall health/robustness of clinical research, quality of research in 5 domains, extent of challenges to performing research, and sense of urgency in responding to research challenges; formal strategies for research-related tasks and their effects. Results Slightly more than half (52%) of all respondents rated the health of the clinical research enterprise as good or excellent compared with 63% for nonclinical research (P<.001). Respondents were most likely to rate nonclinical research as high in quality (79%) compared with 70% for phase 3 clinical trials, 67% for translational research, 65% for phase 1 and 2 trials, and 57% for health services research (for all comparisons with nonclinical research, P<.001). Pressure on clinical faculty to see patients was perceived as a moderate-to-large problem for clinical research by the largest percentage of respondents (93%), followed by insufficient clinical revenues (89%), recruiting trained researchers (75%), lack of external support for clinical research (72%), competition from contract research organizations (48%), problems introduced by the institutional review board process (38%), and finding research participants (37%). In total, 81% of respondents considered the challenges facing clinical research in AHCs to be urgent or extremely urgent. Conclusions Academic leaders perceive clinical research activities in AHCs to be less healthy, of poorer quality, and facing greater challenges than nonclinical research activities. Many AHCs do not have policies or mechanisms to address challenges facing the clinical research mission. Even among those with such policies, more than half do not believe these policies have had large positive effects. Our findings support the view that the clinical research workforce and infrastructure may need to be expanded and strengthened to keep pace with advances in basic research. C1 Massachusetts Gen Hosp, Inst Hlth Policy, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Assoc Amer Med Coll, Washington, DC USA. RP Campbell, EG (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 13 TC 54 Z9 57 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 15 PY 2001 VL 286 IS 7 BP 800 EP 806 DI 10.1001/jama.286.7.800 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 462PU UT WOS:000170429600027 PM 11497533 ER PT J AU Balch, CM Buzaid, AC Soong, SJ Atkins, MB Cascinelli, N Coit, DG Fleming, ID Gershenwald, JE Houghton, A Kirkwood, JM McMasters, KM Mihm, MF Morton, DL Reintgen, DS Ross, MI Sober, A Thompson, JA Thompson, JF AF Balch, CM Buzaid, AC Soong, SJ Atkins, MB Cascinelli, N Coit, DG Fleming, ID Gershenwald, JE Houghton, A Kirkwood, JM McMasters, KM Mihm, MF Morton, DL Reintgen, DS Ross, MI Sober, A Thompson, JA Thompson, JF TI Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; METASTATIC MALIGNANT-MELANOMA; MM PRIMARY MELANOMA; PROGNOSTIC FACTORS; SENTINEL LYMPHADENECTOMY; I MELANOMA; LONG-TERM; MULTIFACTORIAL ANALYSIS; MICROSCOPIC SATELLITES; LACTATE-DEHYDROGENASE AB Purpose: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). Materials and Methods: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. Results: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. Conclusion: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002. J Clin Oncol 19:3635-3648. (C) 2001 by American Society of Clinical Oncology. C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Hosp Sirio Libanes, Sao Paulo, Brazil. Univ Alabama, Birmingham, AL USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. WHO, Melanoma Program, Milan, Italy. Ist Nazl Tumori, I-20133 Milan, Italy. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Methodist Hosp, Ctr Canc, Memphis, TN USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Louisville, Med Ctr, Louisville, KY 40292 USA. John Wayne Canc Inst, Santa Monica, CA USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. Univ Sydney, Sydney Melanoma Unit, Sydney, NSW 2006, Australia. RP Balch, CM (reprint author), Amer Soc Clin Oncol, 1900 Duke St,Ste 200, Alexandria, VA 22314 USA. NR 83 TC 1701 Z9 1738 U1 3 U2 46 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 15 PY 2001 VL 19 IS 16 BP 3635 EP 3648 PG 14 WC Oncology SC Oncology GA 462ZZ UT WOS:000170453500006 PM 11504745 ER PT J AU Cutler, C Giri, S Jeyapalan, S Paniagua, D Viswanathan, A Antin, JH AF Cutler, C Giri, S Jeyapalan, S Paniagua, D Viswanathan, A Antin, JH TI Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: A meta-analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROGENITOR-CELL; HEMATOLOGIC MALIGNANCIES; MYELOGENOUS LEUKEMIA; COST-ANALYSIS; HIGH-RISK; METAANALYSIS; TRIAL; EXPERIENCE; RECOVERY; DONORS AB Purpose: Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. Methods: An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. Results: Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P = .006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P < .001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P < .001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). Conclusion: Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk. J Clin Oncol 19:3685-3697. (C) 2001 by American Society of Clinical Oncology. C1 Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Cutler, C (reprint author), Dana Farber Canc Inst, Div Hematol Oncol, 44 Binney St,G540, Boston, MA 02115 USA. NR 38 TC 291 Z9 303 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 15 PY 2001 VL 19 IS 16 BP 3685 EP 3691 PG 7 WC Oncology SC Oncology GA 462ZZ UT WOS:000170453500011 PM 11504750 ER PT J AU Bar, M AF Bar, M TI Viewpoint dependency in visual object recognition does not necessarily imply viewer-centered representation SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; STRIATE CORTEX; MEMORY; MONKEY; INVARIANCE; MECHANISMS; HIPPOCAMPUS; NEURONS; NETWORK; HUMANS AB The nature of visual object representation in the brain is the subject of a prolonged debate. One set of theories asserts that objects are represented by their structural description and the representation is "object-centered." Theories from the other side of the debate suggest that humans store multiple "snapshots" for each object, depicting it as seen under various conditions, and the representation is therefore "viewer-centered." The principal tool that has been used to support and criticize each of these hypotheses is subjects' performance in recognizing objects under novel viewing conditions. For example, if subjects take more time in recognizing an object from an unfamiliar viewpoint, it is common to claim that the representation of that object is viewpoint-dependent and therefore viewer-centered, it is suggested here, however, that performance cost in recognition of objects under novel conditions may he misleading when studying the nature of object representation, Specifically, it is argued that viewpoint-dependent performance is not necessarily an indication of viewer-centered representation. An account for the neural basis of perceptual priming is first provided. In light of this account, it is conceivable that viewpoint dependency reflects the utilization of neural paths with different levels of sensitivity en route to the same representation, rather than the existence of viewpoint-specific representations. New experimental paradigms are required to study the validity of the viewer-centered approach. C1 Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Bar, M (reprint author), Harvard Univ, Dept Psychol, Room 864,William James Hall, Cambridge, MA 02138 USA. NR 54 TC 21 Z9 23 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD AUG 15 PY 2001 VL 13 IS 6 BP 793 EP 799 DI 10.1162/08989290152541458 PG 7 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 469CY UT WOS:000170797200008 PM 11564323 ER PT J AU Benn, SC Costigan, M Tate, S Fitzgerald, M Woolf, CJ AF Benn, SC Costigan, M Tate, S Fitzgerald, M Woolf, CJ TI Developmental expression of the TTX-resistant voltage-gated sodium channels Na(v)1.8 (SNS) and Na(v)1.9 (SNS2) in primary sensory neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE sodium channels; TTXr; dorsal root ganglia (DRG); development; sensory neurons; growth factors ID DORSAL-ROOT GANGLION; NERVE GROWTH-FACTOR; SPONTANEOUS CALCIUM TRANSIENTS; SUBUNIT MESSENGER-RNAS; RAT SPINAL-CORD; DRG NEURONS; UP-REGULATION; NEUROTROPHIC FACTOR; ALPHA-SUBUNIT; IN-VIVO AB The development of neuronal excitability involves the coordinated expression of different voltage-gated ion channels. We have characterized the expression of two sensory neuron-specific tetrodotoxin-resistant sodium channel alpha subunits, Na(v)1. (SNS/PN3) and Na(v)1.9 (SNS2/NaN), in developing rat lumbar dorsal root ganglia (DRGs). Expression of both Na(v)1.8 and Na(v)1.9 increases with age, beginning at embryonic day (E) 15 and E17, respectively, and reaching adult levels by postnatal day 7. Their distribution is restricted mainly to those subpopulations of primary sensory neurons in developing and adult DRGs that give rise to unmyelinated C-fibers (neurofilament 200 negative). Na(v)1.8 is expressed in a higher proportion of neuronal profiles than Na(v)1.9 at all stages during development, as in the adult. At E17, almost all Na(v)1.8-expressing neurons also express the high-affinity NGF receptor TrkA, and only a small proportion bind to IB4, a marker for c-ret-expressing (glial-derived neurotrophic factor-responsive) neurons. Because IB4 binding neurons differentiate from TrkA neurons in the postnatal period, the proportion of Na(v)1.8 cells that bind to IB4 increases, in parallel with a decrease in the proportion of Na(v)1.8-TrkA co-expressing cells. In contrast, an equal number of Na(v)1.9 cells bind IB4 and TrkA in embryonic life. The differential expression of Na(v)1.8 and Na(v)1.9 in late embryonic development, with their distinctive kinetic properties, may contribute to the development of spontaneous and stimulus-evoked excitability in small diameter primary sensory neurons in the perinatal period and the activity-dependent changes in differentiation they produce. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. Glaxo Wellcome Res & Dev Ltd, Stevenage SG1 2NY, Herts, England. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 13th St,Bldg 149 4309, Charlestown, MA 02129 USA. EM Woolf.clifford@mgh.harvard.edu RI Fitzgerald, Maria/C-5760-2008 FU NINDS NIH HHS [NS38253-01, NS39518-01] NR 97 TC 83 Z9 88 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 2001 VL 21 IS 16 BP 6077 EP 6085 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 460PR UT WOS:000170318200029 PM 11487631 ER PT J AU Georges, F Aston-Jones, G AF Georges, F Aston-Jones, G TI Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine neurons; ventral tegmental area; bed nucleus of the stria terminalis; depolarization blockade; noradrenaline-dopamine interactions; extracellular recording techniques ID VENTRAL TEGMENTAL AREA; RAT; CONNECTIONS; TRANSPORT; AMYGDALA; REGION; PART AB Recent studies have revealed an important role of the ventrolateral (subcommissural) aspect of the bed nucleus of the stria terminalis (vBNST) in motivational aspects of drug abuse (Delfs et al., 2000). Dopaminergic (DA) neurons in the ventral tegmental area (VTA) have also long been linked to motivation and drug abuse (Koob and Le Moal, 2001). The present study tested whether activity in the vBNST influences discharge of midbrain DA neurons. Responses of DA neurons in the VTA to activation of the vBNST were characterized in anesthetized rats using extracellular recording techniques. Electrical or chemical [10-50 mM glutamate (Glu)] stimulation of the vBNST consistently activated DA cells (122% increase in activity with 50 mM Glu). However, stronger chemical stimulation of the vBNST (100 mM Glu) completely inactivated DA neurons. In addition, apomorphine restored the activity of DA neurons that were inactivated by 100 mM Glu stimulation of the vBNST, indicating possible depolarization blockade of DA cells by vBNST activity. These findings reveal that the vBNST exerts a strong excitatory influence on DA neurons. Also striking was the finding that chemical stimulation (50 mM Glu) of the vBNST yielded long-lasting oscillatory activity (>15 min) in VTA DA neurons. These results indicate that the vBNST can generate long-lasting alterations in the activity of DA neurons in vivo. C1 Dept Vet Affairs Med Ctr, Dept Psychiat, Lab Neuromodulat & Behav, Philadelphia, PA 19104 USA. RP Aston-Jones, G (reprint author), Dept Vet Affairs Med Ctr, Dept Psychiat, Lab Neuromodulat & Behav, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [DA06214] NR 21 TC 95 Z9 95 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 2001 VL 21 IS 16 BP art. no. EP RC160 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 460PR UT WOS:000170318200002 PM 11473131 ER PT J AU Xie, AL Skatrud, JB Dempsey, JA AF Xie, AL Skatrud, JB Dempsey, JA TI Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO2 in sleeping humans SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID VENTILATORY RESPONSES; HEART-FAILURE; HIGH-ALTITUDE; BRAIN-STEM; APNEA; ACETAZOLAMIDE; HYPOCAPNIA; NEURONS; DOGS; INHIBITION AB 1. Rhythmic breathing during sleep requires that P-CO2 be maintained above a sensitive hypocapnic apnoeic threshold. Hypoxia causes periodic breathing during sleep that can be prevented or eliminated with supplemental CO2. The purpose of this study was to determine the effect of hypoxia in changing the difference between the eupnocic P-CO2 and the P-CO2 required to produce hypopnoea or apnoea (hywpopnoea/apnoeic threshold) in sleeping humans. 2. The effect of hypoxia on eupnoeic end-tidal partial pressure of CO2 (P-ET,P-CO2) and hypopnoea/apnoeic threshold P-ET,P-CO2 was examined in seven healthy, sleeping human subjects. A bilevel pressure support ventilator in a spontaneous mode was used to reduce P-ET,P-CO2 in small decrements by increasing the inspiratory pressure level by 2 cmH(2)O every 2 min until hypopnoea (failure to trigger the ventilator) or apnoea (no breathing effort) occurred. Multiple trials were performed (luring both normoxia and hypoxia (arterial O-2 saturation, S-a,S-O2 = 80%) in a random order, The hypopuoea/apnoeic threshold was determined by averaging P-ET,P-CO2('01-1 Of the last three breaths prior to each hypopnoea or apnoea. 3. Hypopnoeas and apnoeas were induced in all subjects during both normoxia and hypoxia. Hypoxia reduced the eupnoeic P-ET,P-CO2 compared to normoxia (42.4 +/- 1.3 vs, 45.0 +/- 1.1 mmHg, P < 0.001). However, no change was observed in either the hypopnoeic threshold P-ET,P-CO2 (42.1 +/- 1.4 vs. 43.0 +/- 1.2 mmHg, P > 0.05) or the apnoeic threshold P-ET,P-CO2 (41.3 +/- 1.2 vs. 41.6 +/- 1.0 mmHg, P > 0.05). Thus, the difference in P-ET,P-CO2 between the eupnoeic and threshold levels was much smaller during hypoxia than during, normoxia (-0.2 +/- 0.2 vs. -2.0 +/- 0.3 mmHg, P < 0.01 for the hypopnoea threshold and -1.1 +/- 0.2 vs. -3.4 +/- 0.3 mmHg, P < 0.01 for the apnoeic threshold). We concluded that hypoxia causes a narrowing of the difference between the baseline P-ET,P-CO2 and the hypopnoea/apnoeic threshold P-ET,P-CO2, which could increase the likelihood of ventilatory instability. C1 Univ Wisconsin, William S Middleton Mem Vet Hosp, Pulm Physiol Lab, Dept Med, Madison, WI 53705 USA. Univ Wisconsin, William S Middleton Mem Vet Hosp, Dept Prevent Med, Madison, WI 53705 USA. RP Xie, AL (reprint author), Univ Wisconsin, William S Middleton Mem Vet Hosp, Pulm Physiol Lab, Dept Med, 2500 Overlook Terrace, Madison, WI 53705 USA. FU NHLBI NIH HHS [R01 HL62561-02] NR 42 TC 53 Z9 55 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 15 PY 2001 VL 535 IS 1 BP 269 EP 278 DI 10.1111/j.1469-7793.2001.00269.x PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 468AG UT WOS:000170735500025 PM 11507176 ER PT J AU Gotter, AL Reppert, SM AF Gotter, AL Reppert, SM TI Analysis of human Per4 SO MOLECULAR BRAIN RESEARCH LA English DT Article DE period gene; circadian rhythm; pseudogene; interspersed repeat element ID DROSOPHILA PERIOD GENE; CIRCADIAN CLOCK; L1 RETROTRANSPOSITION; MAMMALIAN GENOMES; SEQUENCES; ELEMENTS; LOOP AB The molecular mechanism of the circadian pacemaker depends on the oscillatory expression of clock gene constituents. The Drosophila period gene is central to the clock mechanism in these animals. Three homologs of this gene identified in mice (mPer1-3) and humans (hPer1-3) display rhythmic expression and are important for normal clock function. Recently, analysis of the draft sequence of the human genome has revealed the presence of a fourth Per gene family member. Surprisingly, the deduced hPer4 cDNA has no open reading frame encoding a full-length PER-like protein. This sequence is characterized by numerous deletions, insertions, frame shifts and base pair changes, and its genomic structure is devoid of introns. The presence of an MER-2 mobile element fossil within the Per4 locus predicted that this gene would also be present in non-human primates. Rhesus monkey Per4 displays similar sequence anomalies and is 92.8% identical to hPer4. Sequence comparisons indicate that Per4 originated from a Per3 predecessor and that it is relatively new to the Period gene family. We conclude that hPer4 and RmPer4 are pseudogenes and descended from the retrotransposition of an ancestral Per3 gene. (C) 2001 Published by Elsevier Science B.V. C1 Massachusetts Gen Hosp, MasGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Reppert, SM (reprint author), Massachusetts Gen Hosp, MasGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. NR 26 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 15 PY 2001 VL 92 IS 1-2 BP 19 EP 26 DI 10.1016/S0169-328X(01)00115-2 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 469HK UT WOS:000170808300003 ER PT J AU Su, M Young, AJ He, CF West, CA Swanson, SJ Mentzer, SJ AF Su, M Young, AJ He, CF West, CA Swanson, SJ Mentzer, SJ TI Biphasic response of the regional lymphatics in the normal lymphocyte transfer reaction SO TRANSPLANTATION LA English DT Article ID PROPIDIUM IODIDE; CELLS AB Background. Initially developed for histocompatibility testing, the normal lymphocyte transfer (NLT) reaction involves the intradermal injection of allogeneic lymphocytes from one individual to another. Because of the unique kinetics of the immunological response to allogeneic lymphocytes, the NLT reaction has been considered an informative system for the analysis of transplant immunity. Methods. In this study, we used bilateral efferent lymph duct cannulations in sheep to examine the regional lymphatic response to the NLT reaction. Our studies used monoclonal antibodies to define lymphocyte population dynamics and DNA flow cytometry to reflect lymphocyte proliferative responses. Results. The results confirmed a biphasic NLT reaction. An unexpected finding was the marked differences between the early and late NLT responses. The early response was characterized by T-lymphocyte proliferation, as reflected by S-phase DNA, which was comparable in both the NLT-stimulated and contralateral control efferent lymphocytes. This bilateral proliferative response was observed in both CD4(+) and CD8(+) lymphocytes. In contrast, the late response was restricted to the efferent lymph from the NLT-stimulated lymph node. Dual-parameter flow cytometry demonstrated that the dominant component of this unilateral NLT response was CD8(+) lymphocytes. Conclusions. These results suggest important functional distinctions between systemic and regional lymphatic responses to intradermal alloantigens. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp,Dana Farber Canc Inst, Dept Surg,Surg Res Labs,Lab Immunophysiol, Boston, MA 02115 USA. RP Mentzer, SJ (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Dana Farber Canc Inst, Dept Surg,Surg Res Labs,Lab Immunophysiol, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL47078] NR 44 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2001 VL 72 IS 3 BP 516 EP 522 DI 10.1097/00007890-200108150-00026 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 465JZ UT WOS:000170587000026 PM 11502985 ER PT J AU Kunisaki, SM Haller, GW Fuchimoto, Y Huang, CA Sachs, DH AF Kunisaki, SM Haller, GW Fuchimoto, Y Huang, CA Sachs, DH TI Peripheral regulation of graft-versus-host alloreactivity in mixed chimeric miniature swine SO TRANSPLANTATION LA English DT Article ID SYNGENEIC BONE-MARROW; LARGE-ANIMAL-MODEL; ALLOGENEIC CHIMERAS; RENAL-ALLOGRAFTS; CLASS-I; TOLERANCE; DISEASE; PROTECTION; ANTIGEN AB Background. Despite the presence of circulating donor-derived T cells during the induction of mixed chimerism across MHC barriers in miniature swine, severe graft-versus-host disease was avoided in the majority of animals. In this study, we investigated the possible roles of recipient and donor lymphoid populations in the regulation of donor-anti-recipient alloreactivity. Methods. Mixed chimerism. across a full MHC-mismatch barrier was established in miniature swine using a high-dose allogeneic peripheral blood stem cell protocol. Peripheral blood mononuclear cells from mixed chimeric swine were co-cultured with naive donor-matched responders and naive recipient-matched stimulators in mixed lymphocyte reactions. Results. Peripheral blood mononuclear cells from mixed chimeras inhibited donor-anti-recipient proliferation. This suppression was radioresistant to 25 Gy. Suppression of donor-anti-recipient alloreactivity was not observed in mixed lymphocyte co-cultures when donor-derived cells were added in the absence of recipient-derived cells. Conclusions. These results suggest an association between the presence of an active and relatively radioresistant cell population, demonstrable in vitro, and the regulation of graft-versus-host disease across MHC barriers in mixed chimeric miniature swine. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Transplantat Biol Res Ctr,MGH E, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Transplantat Biol Res Ctr,MGH E, Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2001 VL 72 IS 3 BP 523 EP 526 DI 10.1097/00007890-200108150-00027 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 465JZ UT WOS:000170587000027 PM 11502986 ER PT J AU Mendez, MF Ghajarnia, M AF Mendez, MF Ghajarnia, M TI Agnosia for familiar faces and odors in a patient with right temporal lobe dysfunction SO NEUROLOGY LA English DT Article ID IDENTIFICATION; PROSOPAGNOSIA; RECOGNITION AB The authors studied a 53-year-old man with progressive prosopagnosia and inability to recognize his favorite foods by smell. He could not identify pictures of familiar faces, but he could match unfamiliar faces and distinguish them from familiar ones. He could not identify familiar odors, but he could detect them and could perceive them as pleasant or familiar. Neuroimaging revealed temporal lobe changes, especially on the right. Right temporal lesions may produce face and odor agnosia by preventing perceptual familiarity units from accessing semantic associations. C1 Univ Calif Los Angeles, Neurobehav Unit 116AF, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, VA Greater Los Angeles Healthcare Ctr, Los Angeles, CA 90073 USA. RP Mendez, MF (reprint author), Univ Calif Los Angeles, Neurobehav Unit 116AF, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 10 TC 31 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 14 PY 2001 VL 57 IS 3 BP 519 EP 521 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 462FR UT WOS:000170410500030 PM 11502924 ER PT J AU Santini, MP Talora, C Seki, T Bolgan, L Dotto, GP AF Santini, MP Talora, C Seki, T Bolgan, L Dotto, GP TI Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYCLOSPORINE-A; TRANSCRIPTION FACTORS; HAIR-GROWTH; ACTIVATION; FAMILY; SP1; INHIBITOR; PROMOTER; CALCIUM; PROTEIN AB Calcium functions as a trigger for the switch between epithelia I cel I growth and differentiation. We report here that the calcium/calmodulin-dependent phosphatase calcineurin is involved in this process. Treatment of primary mouse keratinocytes with cyclosporin A, an inhibitor of calcineurin activity, suppresses the expression of terminal differentiation markers and of p21(WAF1/Cip1) and p27(KIP1), two cyclin-dependent kinase inhibitors that are usually induced with differentiation. in parallel with down-modulation of the endogenous genes, suppression of calcineurin function blocks induction of the promoters for the p21(WAF1/Cip1) and loricrin differentiation marker genes, whereas activity of these promoters is enhanced by calcineurin overexpression. The calcineurin-responsive region of the p21 promoter maps to a 78-bp Sp1/Sp3-binding sequence next to the TATA box, and calcineurin induces activity of the p21 promoter through Sp1/Sp3-dependent transcription. We find that the endogenous NFAT-1 and -2 transcription factors, major downstream targets of calcineurin, associate with Sp1 in keratinocytes in a calcineurin-dependent manner, and calcineurin up-regulates Sp1/Sp3-dependent transcription and p21 promoter activity in synergism with NFAT1/2. Thus, our study reveals an important role for calcineurin in control of keratinocyte differentiation and p21 expression, and points to a so-far-unsuspected interconnection among this phosphatase, NFATs, and Sp1/Sp3-dependent transcription. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Life Sci Res Ctr, Skin Biol Res Labs, Kanazawa Ku, Yokohama, Kanagawa 236, Japan. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA73796, R01 CA073796, P01 CA016038, CA16038]; NIAMS NIH HHS [R01 AR039190, AR39190] NR 43 TC 112 Z9 115 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9575 EP 9580 DI 10.1073/pnas.161299698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600023 PM 11493684 ER PT J AU Harada, H Andersen, JS Mann, M Terada, N Korsmeyer, SJ AF Harada, H Andersen, JS Mann, M Terada, N Korsmeyer, SJ TI p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEPENDENT PROTEIN-KINASE; DEATH AGONIST BAD; BCL-X-L; BH3 DOMAIN; S6 KINASE; PHOSPHORYLATION; RAPAMYCIN; MITOCHONDRIA; RIBOSOME; BINDING AB Cytokines often deliver simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) is known to regulate cell growth by inducing protein synthesis components. We purified membrane-based p70S6K as a kinase responsible for site-specific phosphorylation of BAD, which inactivates this proapoptotic molecule. Rapamycin inhibited mitochondrial-based p70S6K, which prevented phosphorylation of Ser-136 on BAD and blocked cell survival induced by insulin-like growth factor 1 (IGF-1). Moreover, IGF-1-induced phosphorylation of BAD Ser-136 was abolished in p70S6K-deficient cells. Thus, p70S6K is itself a dual pathway kinase, signaling cell survival as well as growth through differential substrates which include mitochondrial BAD and the ribosomal subunit S6, respectively. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst,Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Florida, Dept Pathol, Gainesville, FL 32610 USA. Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. RP Korsmeyer, SJ (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst,Dept Pathol, Boston, MA 02115 USA. RI Mann, Matthias/A-3454-2013; Andersen, Jens/L-2100-2015 OI Mann, Matthias/0000-0003-1292-4799; Andersen, Jens/0000-0002-6091-140X FU NCI NIH HHS [R37 CA050239, CA50239-13, R01 CA050239] NR 51 TC 352 Z9 377 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9666 EP 9670 DI 10.1073/pnas.171301998 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600038 PM 11493700 ER PT J AU Ma, FR Zhang, CH Prasad, KVS Freeman, GJ Schlossman, SF AF Ma, FR Zhang, CH Prasad, KVS Freeman, GJ Schlossman, SF TI Molecular cloning of Porimin, a novel cell surface receptor mediating oncotic cell death SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MONOCLONAL-ANTIBODY; TNF RECEPTOR; APOPTOSIS; NECROSIS; ONCOSIS; SUPPRESSION; ADHESION; CD43; ACTIVATION; INJURY AB Anti-Porimin (Pro-oncosis receptor inducing membrane injury) mAb mediates oncosis-like cell death in Jurkat cells. Porimin cDNA was isolated from a Jurkat cell cDNA library by COS cell-expression cloning, The 3,337-bp cDNA has an ORF of 567 bp, encoding a type I transmembrane protein of 189 amino acids. The extracellular domain of Porimin contains many O-linked and seven N-linked glycosylation sites that define it as a new member of the mucin family. COS7 and 293 cells transiently transfected with Porimin cDNA were specifically recognized by anti-Porimin Ab in cell staining and immunoblotting experiments. When expressed in Jurkat cells, a His-tagged Porimin cDNA construct resulted in the generation of a specific 110-kDa-size protein that matched the molecular mass of the endogenous Porimin protein. Crosslinking of the Porimin receptor expressed on COS7 transfectants resulted in the loss of cell membrane integrity and cell death as measured by the leakage of intracellular lactate dehydrogenase. Both COS7 and 293 cells expressing transfected Porimin at a relatively high level lost their ability to adhere to culture dishes, suggesting a role for Porimin in cell adhesion. The Porimin gene was mapped to human chromosome 11q22.1 and is composed of four exons spanning 133 kb of genomic DNA. C1 Harvard Univ, Sch Med, Div Tumor Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Dana Farber Canc Inst,Dept Adult Oncol, Boston, MA 02115 USA. Univ Illinois, Dept Micro Immunol, Chicago, IL 60612 USA. RP Schlossman, SF (reprint author), Harvard Univ, Sch Med, Div Tumor Immunol, Boston, MA 02115 USA. FU NCI NIH HHS [CA84500, R01 CA084500]; NIAID NIH HHS [AI12069] NR 29 TC 36 Z9 54 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9778 EP 9783 DI 10.1073/pnas.171322898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600058 PM 11481458 ER PT J AU Krop, IE Sgroi, D Porter, DA Lunetta, KL LeVangie, R Seth, P Kaelin, CM Rhei, E Bosenberg, M Schnitt, S Marks, JR Pagon, Z Belina, D Razumovic, J Polyak, K AF Krop, IE Sgroi, D Porter, DA Lunetta, KL LeVangie, R Seth, P Kaelin, CM Rhei, E Bosenberg, M Schnitt, S Marks, JR Pagon, Z Belina, D Razumovic, J Polyak, K TI HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BREAST-CANCER; PROMOTER HYPERMETHYLATION; GENE-EXPRESSION; DNA HYPERMETHYLATION; METHYLATION; INACTIVATION; PROGRESSION; CARCINOMA; MORPHOGENESIS; TUMORS AB To identify molecular alterations implicated in the initiating steps of breast tumorogenesis, we compared the gene expression profiles of normal and ductal carcinoma in situ (DCIS) mammary epithelial cells by using serial analysis of gene expression (SAGE). Through the pair-wise comparison of normal and DCIS SAGE libraries, we identified several differentially expressed genes. Here, we report the characterization of one of these genes, HIN-1 (high in normal-1). HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of preinvasive lesions, such as ductal and lobular carcinoma in situ. This decrease in HIN-1 expression is accompanied by hypermethylation of its promoter in the majority of breast cancer cell lines (> 90%) and primary tumors (74%). HIN-1 is a putative cytokine with no significant homology to known proteins. Reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Univ Zagreb, Univ Hosp Rebro, Dept Cardiac Surg, Zagreb 10000, Croatia. Univ Zagreb, Univ Hosp Rebro, Dept Pathol, Zagreb 10000, Croatia. Univ Zagreb, Zagreb Med Sch, Zagreb 10000, Croatia. RP Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. EM Kornelia_Polyak@dfci.harvard.edu NR 33 TC 103 Z9 113 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9796 EP 9801 DI 10.1073/pnas.171138398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600061 PM 11481438 ER PT J AU Chung, RT He, WP Saquib, A Contreras, AM Xavier, RJ Chawla, A Wang, TC Schmidt, EV AF Chung, RT He, WP Saquib, A Contreras, AM Xavier, RJ Chawla, A Wang, TC Schmidt, EV TI Hepatitis C virus replication is directly inhibited by IFN-alpha in a full-length binary expression system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell-based assay; amantadine; ribavirin ID PROTEIN 5A GENE; MOLECULAR MECHANISMS; ANTIVIRAL THERAPY; UNITED-STATES; CELL-LINE; INTERFERON; RIBAVIRIN; RNA; INFECTION; KINASE AB Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of culture systems permissive for HCV replication has presented a major bottleneck to antiviral development. We sought to recapitulate the early steps in the life cycle of HCV by means of DNA-based expression of viral genomic sequences. Here we report expression of replicating HCV RNA by using a, to our knowledge, novel binary expression system in which cells were transfected with a T7 polymerase-driven full-length HCV cDNA plasmid containing a cis-acting hepatitis Delta ribozyme to control 3 ' cleavage, and infected with vaccinia-T7 polymerase. HCV genomic and replicative strand synthesis, in addition to protein synthesis, was detectable and depended on full-length HCV sequences. Moreover, the system was capable of generating HCV RNA quasispecies, consistent with the action of the low-fidelity HCV NS5B RNA polymerase. IFN-a, but not ribavirin, directly inhibited the viral replicative cycle in these cells, identifying the virus itself and not solely the immune system as a direct target of IFN action. The availability of a cell-based test for viral replication will facilitate screening of inhibitory compounds, analysis of IFN-resistance mechanisms, and analysis of virus-host cell interactions. C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Hosp Children, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [R01 AI43478]; NIDDK NIH HHS [R01 DK57857, R01 DK057857, K08 DK02209] NR 27 TC 50 Z9 55 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9847 EP 9852 DI 10.1073/pnas.171319698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600070 PM 11493707 ER PT J AU Charles, M Perez, M Kobil, JH Goldberg, MB AF Charles, M Perez, M Kobil, JH Goldberg, MB TI Polar targeting of Shigella virulence factor IcsA in Enterobacteriacae and Vibrio SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIN-BASED MOTILITY; ESCHERICHIA-COLI; FLEXNERI 2A; UNIPOLAR LOCALIZATION; FUNCTIONAL-ANALYSIS; CELL-DIVISION; VIRG PROTEIN; RAPID POLE; PLASMID; SEQUENCE AB Asymmetric localization is key to the proper function of certain prokaryotic proteins important to virulence, chemotaxis, cell division, development, motility, and adhesion. Shigella IcsA is localized to the old pole of the bacterium, where it mediates assembly of an actin tall inside infected mammalian cells. IcsA (VirG) is essential to Shigella intracellular motility and virulence. We used translational fusions between portions of IcsA and the green fluorescent protein (GFP) to determine the regions of IcsA that are necessary and sufficient for its targeting to the bacterial old pole. An IcsA-GFP fusion that lacks a signal peptide localized to the old pole, indicating that signal peptide-mediated secretion is not required for polar localization. Two regions within IcsA were required for localization of an IcsA-GFP fusion to the old pole. Further characterization of these regions indicated that amino acids 1-104 and 507-620 were each independently sufficient for polar localization. Finally, when expressed in Escherichia coli, Salmonella typhimurium, Yersinia pseudo tuberculosis, and Vibrio cholerae, each of the two targeting regions localized to the pole, indicating that the mechanism of polar targeting used by IcsA is present generally among Enterobacteriacae and Vibrio. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Goldberg, MB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL07118, T32 HL007118]; NIAID NIH HHS [R01 AI035817, AI35817]; NIGMS NIH HHS [F31 GM016654, GM16654] NR 32 TC 75 Z9 77 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2001 VL 98 IS 17 BP 9871 EP 9876 DI 10.1073/pnas.171310498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464NX UT WOS:000170539600074 PM 11481451 ER PT J AU Staudinger, R Wang, XH Bandres, JC AF Staudinger, R Wang, XH Bandres, JC TI Allosteric regulation of CCR5 by guanine nucleotides and HIV-1 envelope SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE chemokine receptor; CCR5; G-protein-coupled receptor; HIV-1 envelope; macrophage inflammatory protein-1 beta; guanine nucleotides ID CHEMOKINE RECEPTOR CCR-5; CHEMOTACTIC CYTOKINES; SIGNAL-TRANSDUCTION; CORECEPTOR ACTIVITY; TROPIC HIV-1; PROTEIN; ENTRY; INFECTION; BINDING; MIP-1-ALPHA AB The chemokine receptor CCR5 is the principal coreceptor for R5 (macrophage-tropic) strains of HIV-1. CCR5 uses G-proteins as transducing elements. Here we report the biochemical consequences of the interaction between CCR5 and G-proteins. Macrophage inflammatory protein-1 beta (MIP-1 beta) binding to CCR5 was potently and specifically inhibited by guanine nucleotides. The molecular mechanism of this inhibitory effect was shown to be a dose-dependent reduction in MIP-1 beta receptors. We also show that the MIP-1 beta binding site is allosterically regulated by monovalent cations and that binding of this endogenous agonist is highly temperature sensitive and dependent on divalent cations, characteristic of a G-protein-coupled receptor (GPCR). HIV-1 envelope glycoprotein decreased the affinity of CCR5 for MIP-1 beta but also altered the kinetics of MIP-1 beta binding to CCR5, proving that it interacts with a distinct, but allosterically coupled binding site. The findings described herein contribute to our understanding of how CCR5 interacts with chemokines and HIV-1 envelope. (C) 2001 Academic Press. C1 Bronx Vet Adm Med Ctr, Bronx, NY 10468 USA. Mt Sinai Sch Med, Dept Med, Bronx, NY 10468 USA. NYU, Sch Med, Dept Neurol, New York, NY USA. NYU, Sch Med, Dept Pathol, New York, NY USA. RP Bandres, JC (reprint author), Bronx Vet Adm Med Ctr, 130 Kingsbridge Rd,ID Sect 111F, Bronx, NY 10468 USA. FU NIAID NIH HHS [AI-07382-09] NR 41 TC 12 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 10 PY 2001 VL 286 IS 1 BP 41 EP 47 DI 10.1006/bbrc.2001.5345 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 464DZ UT WOS:000170519100007 PM 11485305 ER PT J AU Sudhakar, S Katz, MS Elango, N AF Sudhakar, S Katz, MS Elango, N TI Analysis of type-I and type-II RUNX2 protein expression in osteoblasts SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE osteoblast differentiation; transcription factor; RUNX2 specific antibodies; translational regulation ID TRANSCRIPTION FACTOR; CLEIDOCRANIAL DYSPLASIA; OSTEOCALCIN GENE; BONE-FORMATION; CBFA1; DIFFERENTIATION; MOUSE; BETA; PROMOTER; DOMAIN AB Runt-related transcription factor-2 (RUNX2) is expressed as two isoforms (type-I and type-II) differing only in their amino terminal sequences. The ami-no terminus of type-I contains MRIPV instead of MASNSLF-SAVTPCQQSFFW in type-II. Although type-II mRNA has been considered osteoblast specific, the RUNX2 protein isoforms expressed in osteoblasts have not yet been identified. Using antisera generated against the two different amino terminal sequences of type-I and type-Il RUNX2, we show the expression of both isoforms in cells with the mature osteoblast phenotype (fetal rat calvarial cells, and ROS 17/2.8, SaOS-2 and U2OS osteosarcoma cell lines), but only type-I in partially differentiated osteoblast-like cells (the LTAM-106 osteosarcoma cell line). Since LTMR-106 cells express both type-I and type-II mRNAs, our results suggest that the translation of type-II mRNA is repressed in these cells. No RUNX1 and RUNX3 proteins are detected in any of the osteoblastic cells tested. The antisera we have generated will be useful for studies relating expression of RUNX2 isoforms to control of osteoblast differentiation. (C) 2001 Academic Press. C1 Univ Texas, Hlth Sci Ctr, Geriatr Res Educ & Clin Ctr, S Texas Vet Hlth Care Syst,Audie L Murphy Div, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Geriatr & Gerontol, San Antonio, TX 78284 USA. RP Elango, N (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, GRECC 182, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. NR 35 TC 22 Z9 25 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 10 PY 2001 VL 286 IS 1 BP 74 EP 79 DI 10.1006/bbrc.2001.5363 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 464DZ UT WOS:000170519100012 PM 11485310 ER PT J AU Ghosh-Choudhury, N Choudhury, GG Harris, MA Wozney, J Mundy, GR Harris, SE AF Ghosh-Choudhury, N Choudhury, GG Harris, MA Wozney, J Mundy, GR Harris, SE TI Autoregulation of mouse BMP-2 gene transcription is directed by the proximal promoter element SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE BMP-2 mRNA initiation sites; transcriptional regulation; BMP-2 autoinduction ID BONE; DIFFERENTIATION; OSTEOBLASTS; RECEPTOR AB Bone morphogenetic protein-2 (BMP-2) stimulates the commitment and differentiation of precursor mesenchymal cells to mature bone. We have isolated and sequenced 2712 base pairs (bp) of the 5 ' flanking region of mouse BMP-2 gene. Using RNase protection assay we identified two transcription initiation sites within this 2712 bp region of the BAM-2 gene. The distal start site was mapped to -736 bp in relation to the proximal start site (+1). Recombinant BMP-2 preferentially stimulated transcription initiation from the proximal start site. To investigate the mechanism of transcription initiation from these two start sites, we identified two promoter elements upstream of the proximal and distal transcription initiation sites. Transfection of promoter-luciferase reporter constructs into cells of different organs demonstrated differential transcriptional activity of proximal and distal promoters, with highest activity in the osteoblast cell lineage. In osteoblasts, BMP-2 stimulated transcription from the proximal promoter only. Together our data provide the first evidence for the presence of two transcription initiation sites with two upstream promoter elements in mouse BMP-2 gene. Furthermore, we demonstrate for the first time that BMP-2 autoregulates its expression in osteoblasts through the proximal promoter-dependent transcriptional mechanism. (C) 2001 Academic Press. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. Genet Inst Inc, Andover, MA USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIAMS NIH HHS [AR07464, AR 28149, AR 44728]; NIDDK NIH HHS [DK 50190, DK 55815] NR 21 TC 52 Z9 55 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 10 PY 2001 VL 286 IS 1 BP 101 EP 108 DI 10.1006/bbrc.2001.5351 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 464DZ UT WOS:000170519100016 PM 11485314 ER PT J AU Fuchs, M Gerber, J Drapkin, R Sif, S Ikura, T Ogryzko, V Lane, WS Nakatani, Y Livingston, DM AF Fuchs, M Gerber, J Drapkin, R Sif, S Ikura, T Ogryzko, V Lane, WS Nakatani, Y Livingston, DM TI The p400 complex is an essential E1A transformation target SO CELL LA English DT Article ID CHROMATIN REMODELING COMPLEX; HISTONE ACETYLASE COMPLEX; ESSENTIAL COFACTOR; C-MYC; ACETYLTRANSFERASE COMPLEX; SWI/SNF COMPLEX; PROTEIN; TRANSCRIPTION; BINDING; ONCOPROTEINS AB Here, we report the identification of a new E1A binding protein complex that is essential for E1A-mediated transformation. Its core component is a SWI2/SNF2-related, 400 kDa protein (p400). Other components include the myc- and p/CAF-associated cofactor, TRRAP/PAF400, the DNA helicases TAP54 alpha/beta, actin-like proteins, and the human homolog of the Drosophila Enhancer of Polycomb protein. An E1A mutant, defective in p400 binding, is also defective in transformation. Certain p400 fragments partially rescued this phenotype, underscoring the role of E1A-p400 complex formation in the E1A transforming process. Furthermore, E1A and c-myc each alter the subunit composition of p400 complexes, implying that physiological p400 complex formation contributes to transformation suppression. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Ohio State Univ, Sch Med, Columbus, OH 43210 USA. Harvard Univ, Microchem & Proteom Anal Facil, Cambridge, MA 02138 USA. Inst Andre Lwoff, Villejuif, France. RP Livingston, DM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. RI Ogryzko, Vasily/M-6665-2015; Drapkin, Ronny/E-9944-2016 OI Ogryzko, Vasily/0000-0002-8548-1389; Drapkin, Ronny/0000-0002-6912-6977 FU NHLBI NIH HHS [T32-HL07627-16] NR 36 TC 220 Z9 225 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 10 PY 2001 VL 106 IS 3 BP 297 EP 307 DI 10.1016/S0092-8674(01)00450-0 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 462RJ UT WOS:000170433300008 PM 11509179 ER PT J AU Gupta, RA Brockman, JA Sarraf, P Willson, TM DuBois, RN AF Gupta, RA Brockman, JA Sarraf, P Willson, TM DuBois, RN TI Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE; GELATINASE-ASSOCIATED LIPOCALIN; IMMUNOGLOBULIN SUPERGENE FAMILY; HUMAN PROSTATE-CANCER; PPAR-GAMMA; CARCINOEMBRYONIC ANTIGEN; ORPHAN RECEPTORS; COLON-CANCER; REG PROTEIN; FATTY-ACIDS AB Activation of the nuclear hormone peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibits cell growth and promotes differentiation in a broad spectrum of epithelial derived tumor cell lines. Here we utilized microarray technology to identify PPAR gamma gene targets in intestinal epithelial cells. For each gene, the induction or repression was seen with two structurally distinct PPAR gamma agonists, and the change in expression could be blocked by co-treatment with a specific PPAR gamma antagonist. A majority of the genes could be regulated independently by a retinoid X receptor specific agonist. Genes implicated in lipid transport or storage (adipophilin and liver fatty acid-binding protein) were also activated by agonists of PPAR subtypes alpha and/or delta. In contrast, PPAR gamma -selective targets included genes linked to growth regulatory pathways (regenerating gene IA), colon epithelial cell maturation (GOB-4 and keratin 20), and immune modulation (neutrophil-gelatinase-associated lipocalin). Additionally, three different genes of the carcinoembryonic antigen family were induced by PPAR gamma. Cultured cells treated with PPAR gamma ligands demonstrated an increase in Ca2+-independent, carcinoembryonic antigen-dependent homotypic aggregation, suggesting a potential role for PPAR gamma in regulating intercellular adhesion. Collectively, these results will help define the mechanisms by which PPAR gamma regulates intestinal epithelial cell biology. C1 Vanderbilt Univ, Med Ctr, Dept Med GI, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Cell Biol, Nashville, TN 37232 USA. Vet Affairs Med Ctr, Nashville, TN 37232 USA. Res Genet Inc, Huntsville, AL 35801 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA. RP DuBois, RN (reprint author), Vanderbilt Univ, Med Ctr, Dept Med GI, MCN C-2104,1161 21st Ave S, Nashville, TN 37232 USA. FU NCI NIH HHS [P01CA-77839]; NIDDK NIH HHS [R01DK 47279]; NIEHS NIH HHS [P030 ES-00267-29] NR 69 TC 153 Z9 165 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 10 PY 2001 VL 276 IS 32 BP 29681 EP 29687 DI 10.1074/jbc.M103779200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 464XE UT WOS:000170558000013 PM 11397807 ER PT J AU Sheridan, AM Sapirstein, A Lemieux, N Martin, BD Kim, DK Bonventre, JV AF Sheridan, AM Sapirstein, A Lemieux, N Martin, BD Kim, DK Bonventre, JV TI Nuclear translocation of cytosolic phospholipase A(2) is induced by ATP depletion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; ARACHIDONIC-ACID RELEASE; PROXIMAL TUBULAR CELLS; RENAL EPITHELIAL-CELLS; INTRACELLULAR PH; MDCK-CELLS; PHOSPHORYLATION SITES; INDUCED CYTOTOXICITY; MESANGIAL CELLS; CHEMICAL ANOXIA AB Phospholipase A(2) (PLA(2)) enzymes may play a role in cellular injury due to ATP depletion. Renal Madin-Darby canine kidney cells were subjected to ATP depletion to assess the effects of cellular energy metabolism on cytosolic PLA(2) (cPLA(2)) regulation. ATP depletion results in a decrease in soluble cPLA2 activity and an increase in membrane-associated activity, which is reversed upon restoration of ATP levels by addition of dextrose. In ATP-depleted cells cPLA(2) mass shifts from cytosol to nuclear fractions. GFP-cPLA(2) is localized at the nuclear membrane of stably transfected ATP-depleted LLC-PK1 cells under conditions where [Ca2+](i) is known to increase. ePLA(2) translocation does not occur if the increase in [Ca2+](i) increase is inhibited. If [Ca2+](i) is allowed to increase when ATP is depleted and the cells are then lysed, cPLA2 remains associated with nuclear fractions even if the homogenate [Ca2+] is markedly reduced. In contrast, ePL(A)2, which becomes associated with the nucleus when [Ca2+], is increased using ionophore, readily dissociates from the nuclear fractions of ATP-replete cells upon reduction of homogenate [Ca2+]. Okadaic acid inhibits the ATP depletion-induced association of cPLA(2) with nuclear fractions. Thus energy deprivation results in [Ca2+]-induced nuclear translocation, which is partially prevented by a phosphatase inhibitor. C1 Massachusetts Gen Hosp, Med Serv, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Anesthesia Serv, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Anesthesia, Charlestown, MA 02129 USA. RP Massachusetts Gen Hosp, Med Serv, 149-4002 13th Str, Charlestown, MA 02129 USA. EM asheridan@partners.org FU NIDDK NIH HHS [DK 02356, DK 38452, DK 39773, DK 54741]; NINDS NIH HHS [NS 10828] NR 51 TC 24 Z9 25 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 10 PY 2001 VL 276 IS 32 BP 29899 EP 29905 DI 10.1074/jbc.M103758200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 464XE UT WOS:000170558000040 PM 11395512 ER PT J AU Berezovska, O Jack, C Deng, A Gastineau, N Rebeck, GW Hyman, BT AF Berezovska, O Jack, C Deng, A Gastineau, N Rebeck, GW Hyman, BT TI Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE; A-BETA; CELL FATE; PRESENILIN-1 MUTATIONS; NUCLEAR TRANSLOCATION; INTRACELLULAR DOMAIN; SIGNAL-TRANSDUCTION; PROTEOLYTIC RELEASE; IN-VIVO; NEURONS AB Proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma -secretases results in the production of a highly amyloidogenic A beta peptide, which deposits in the brains of Alzheimer's disease patients. Similar gamma -secretase processing occurs in another transmembrane protein, Notch1, releasing a potent signaling molecule, the Notch C-terminal domain. It has been shown that both events are dependent on a presenilin-dependent protease. We now test the hypothesis that activated Notch1 and APP are competitive substrates for the same proteolytic activity in neurons. Treatment of neurons with the native Notch ligand, Delta, induces endogenous Notch1 intramembraneous cleavage. and diminishes A beta production in a dose-dependent manner. Complementary experiments showed that the converse was also true. Overexpressing human APP (APP(695SW)) in neurons leads to a decrease in endogenous Notch1 signal transduction, as assessed by a CBF1 luciferase transcription assay, by Notch C-terminal domain nuclear translocation in vitro and by analysis of Notch C-terminal domain generation and Notch1 staining in vivo. In summary, two complementary approaches suggest that APP and Notch1 are physiologically relevant competitive substrates for gamma -secretase activity. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Alzheimers Dis Res Lab,Alzheimers Dis Unit, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Alzheimers Dis Res Lab,Alzheimers Dis Unit, Rm 2009,114-16th St, Charlestown, MA 02129 USA. FU NIA NIH HHS [P01 AG15379, AG14744] NR 54 TC 56 Z9 56 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 10 PY 2001 VL 276 IS 32 BP 30018 EP 30023 DI 10.1074/jbc.M008268200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 464XE UT WOS:000170558000055 PM 11408475 ER PT J AU Saurin, AJ Shao, ZH Erdjument-Bromage, H Tempst, P Kingston, RE AF Saurin, AJ Shao, ZH Erdjument-Bromage, H Tempst, P Kingston, RE TI A Drosophila Polycomb group complex includes Zeste and dTAFII proteins SO NATURE LA English DT Article ID SEQUENCE DATABASES; HISTONE OCTAMER; CHROMATIN; IDENTIFICATION; INFORMATION; REPRESSION; EXPRESSION; TRITHORAX; BINDING; SITES AB A goal of modern biology is to identify the physical interactions that define 'functional modules'(1) of proteins that govern biological processes. One essential regulatory process is the maintenance of master regulatory genes, such as homeotic genes, in an appropriate 'on' or 'off' state for the lifetime of an organism. The Polycomb group (PcG) of genes maintain a repressed transcriptional state, and PcG proteins form large multiprotein complexes(2,3), but these complexes have not been described owing to inherent difficulties in purification. We previously fractionated a major PcG complex, PRC1, to 20-50% homogeneity from Drosophila embryos. Here, we identify 30 proteins in these preparations, then further fractionate the preparation and use western analyses to validate unanticipated connections. We show that the known PcG proteins Polycomb, Posterior sex combs, Polyhomeotic and dRING1 exist in robust association with the sequence-specific DNA-binding factor Zeste and with numerous TBP (TATA-binding-protein)-associated factors that are components of general transcription factor TFIID (dTAFIIs). Thus, in fly embryos, there is a direct physical connection between proteins that bind to specific regulatory sequences, PcG proteins, and proteins of the general transcription machinery. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. NR 29 TC 276 Z9 290 U1 0 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 9 PY 2001 VL 412 IS 6847 BP 655 EP 660 DI 10.1038/35088096 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 460PP UT WOS:000170318000045 PM 11493925 ER PT J AU Filley, CM Kleinschmidt-DeMasters, BK AF Filley, CM Kleinschmidt-DeMasters, BK TI Current concepts: Toxic leukoencephalopathy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; CEREBRAL WHITE-MATTER; SOLVENT VAPOR ABUSE; ABSTINENT ALCOHOLICS; ORGANIC-SOLVENTS; TOLUENE ABUSE; BRAIN CHANGES; ATROPHY; ENCEPHALOPATHY; METHOTREXATE C1 Univ Colorado, Sch Med, Dept Neurol, Behav Neurol Sect, Denver, CO 80262 USA. Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. Denver Vet Affairs Med Ctr, Denver, CO USA. RP Filley, CM (reprint author), Univ Colorado, Sch Med, Dept Neurol, Behav Neurol Sect, UCHSC B-183,4200 E 9th Ave, Denver, CO 80262 USA. NR 60 TC 152 Z9 163 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 9 PY 2001 VL 345 IS 6 BP 425 EP 432 DI 10.1056/NEJM200108093450606 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 460EJ UT WOS:000170295000006 ER PT J AU Kosslyn, SM Thompson, WL Wraga, M Alpert, NM AF Kosslyn, SM Thompson, WL Wraga, M Alpert, NM TI Imagining rotation by endogenous versus exogenous forces: Distinct neural mechanisms SO NEUROREPORT LA English DT Article DE mental imagery; mental rotation; PET; primary motor area ID MENTAL ROTATION; ACTIVATION; OBJECTS; PET; CORTEX; HANDS AB Previous neuroimaging studies of mental image transformations have sometimes implicated motor processes and sometimes not. In this study, prior to neuroimaging the subjects either viewed an electric motor rotating an angular object, or they rotated the object manually. Following this, they performed the identical mental rotation task in which they compared members of pairs of such figures, but were asked to imagine the figures rotating as they had just seen the model rotate. When results from the two rotation conditions were directly compared, motor cortex (including area MI) was found to be activated only when subjects imagined the rotations as a consequence of manual activity. Thus, there are at least two, qualitatively distinct, ways to imagine objects rotating in images, and these different strategies can be adopted voluntarily. NeuroReport 12:2519-2525 (C) 2001 Lippincott Williams & Wilkins. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Smith Coll, Dept Psychol, Northampton, MA 01063 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Kosslyn, SM (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. FU NIMH NIH HHS [R01 MH60743-01] NR 21 TC 138 Z9 142 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 8 PY 2001 VL 12 IS 11 BP 2519 EP 2525 DI 10.1097/00001756-200108080-00046 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 457MP UT WOS:000170141600047 PM 11496141 ER PT J AU Cannon, CP AF Cannon, CP TI Importance of TIMI 3 flow SO CIRCULATION LA English DT Editorial Material DE editorials; angioplasty; catheterization; myocardial infarction; platelet aggregation inhibitors; stents; thrombolysis ID ACUTE MYOCARDIAL-INFARCTION; TISSUE-PLASMINOGEN-ACTIVATOR; CORONARY ANGIOPLASTY; RANDOMIZED TRIAL; THROMBOLYSIS; MORTALITY; IMMEDIATE C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. NR 25 TC 27 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 7 PY 2001 VL 104 IS 6 BP 624 EP 626 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 462CF UT WOS:000170402600001 PM 11489764 ER PT J AU Belham, C Comb, MJ Avruch, J AF Belham, C Comb, MJ Avruch, J TI Identification of the NIMA family kinases NEK6/7 as regulators of the p70 ribosomal S6 kinase SO CURRENT BIOLOGY LA English DT Article ID PROTEIN-KINASE; IN-VIVO; 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN-KINASE-1; PHOSPHORYLATION SITES; MITOTIC REGULATOR; MAMMALIAN TARGET; ACTIVATION; P70(S6K); CYCLE; CLONING AB Background: The p70 S6 kinase, like several other AGC family kinases, requires for activation the concurrent phosphorylation of a site on its activation loop and a site carboxyterminal to the catalytic domain, situated in a hydrophobic motif site FXXFS/TF/Y, e.g.,Thr412 in p70 S6 kinase (al). Phosphorylation of the former site is catalyzed by PDK1, whereas the kinase responsible for the phosphorylation of the latter site is not known. Results: The major protein kinase that is active on the p70 S6 kinase hydrophobic regulatory site, Thr412, was purified from rat liver and identified as the NIMA-related kinases NEK6 and NEK7. Recombinant NEK6 phosphorylates p70 S6 kinase at Thr412 and other sites and activates the p70 S6 kinase in vitro and in vivo, in a manner synergistic with PDK1. Kinase-inactive NEK6 interferes with insulin activation of p70 S6 kinase. The activity of recombinant NEK6 is dependent on its phosphorylation, but NEK6 activity is not regulated by PDK1 and is only modestly responsive to insulin and PI-3 kinase inhibitors. Conclusion: NEK6 and probably NEK7 are novel candidate physiologic regulators of the p70 S6 kinase. C1 Massachusetts Gen Hosp, Med Serv, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Cell Signalling Technol, Beverly, MA 01915 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Med Serv, Diabet Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK17776] NR 28 TC 59 Z9 63 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 7 PY 2001 VL 11 IS 15 BP 1155 EP 1167 DI 10.1016/S0960-9822(01)00369-4 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 461HZ UT WOS:000170360000016 PM 11516946 ER PT J AU Yin, HL Morioka, H Towle, CA Vidal, M Watanabe, T Weissbach, L AF Yin, HL Morioka, H Towle, CA Vidal, M Watanabe, T Weissbach, L TI Evidence that HAX-1 is an interleukin-1 alpha N-terminal binding protein SO CYTOKINE LA English DT Article DE interleukin-1 alpha; HAX-1; intracrine signalling; yeast two-hybrid; in vitro binding ID NUCLEAR-LOCALIZATION SIGNALS; FIBROBLAST-GROWTH-FACTOR; HORMONE-RELATED PROTEIN; HUMAN ENDOTHELIAL-CELLS; KAPPA-B; TYROSINE PHOSPHORYLATION; HS1 PROTEIN; T-CELLS; IN-VITRO; RECEPTOR AB During studies aimed at understanding the function of the N-terminal peptide of interleukin-1 alpha (IL-1 NTP, amino acids 1-112), which is liberated from the remainder of IL-1 alpha during intracellular processing, we identified by yeast two-hybrid analysis a putative interacting protein previously designated as HAX-1. In vitro binding studies and transient transfection experiments confirmed that HAX-1 can associate with the IL-1 NTP. HAX-1 was first identified as a protein that associates with HS1, a target of non-receptor protein tyrosine kinases within haematopoietic cells. Recent data have also revealed interactions between HAX-1 and three disparate proteins, polycystin-2 (derived from the PKD2 gene), a protein linked to polycystic kidney disease, cortactin, and Epstein-Barr virus nuclear antigen leader protein (EBNA-LP). Sequence analysis of different HAX-1 binding domains revealed a putative consensus binding motif that is present in various intracellular proteins. Overlapping peptides comprising the IL-1 NTP were synthesized, and binding experiments revealed that discrete peptides were capable of interacting with HAX-1. HAX-1 may serve to retain the IL-1 NTP in the cytoplasm, and complex formation between the IL-1 NTP and HAX-1 may play a role in motility and/or adhesion of cells. (C) 2001 Academic Press. C1 Massachusetts Gen Hosp, Orthopaed Res Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Kyushu Univ, Med Inst Bioregulat, Fukuoka 812, Japan. RP Weissbach, L (reprint author), Massachusetts Gen Hosp, Orthopaed Res Labs, GRJ 1124,55 Fruit St, Boston, MA 02114 USA. NR 86 TC 26 Z9 27 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1043-4666 J9 CYTOKINE JI Cytokine PD AUG 7 PY 2001 VL 15 IS 3 BP 122 EP 137 DI 10.1006/cyto.2001.0891 PG 16 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 473WA UT WOS:000171070700002 PM 11554782 ER PT J AU Ji, H Gauguier, D Ohmura, K Gonzalez, A Duchatelle, V Danoy, P Garchon, HJ Degott, C Lathrop, M Benoist, C Mathis, D AF Ji, H Gauguier, D Ohmura, K Gonzalez, A Duchatelle, V Danoy, P Garchon, HJ Degott, C Lathrop, M Benoist, C Mathis, D TI Genetic influences on the end-stage effector phase of arthritis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE rheumatoid arthritis; animal model; genetics; complement; autoimmunity ID COLLAGEN-INDUCED ARTHRITIS; PRISTANE-INDUCED ARTHRITIS; COMPLEMENT COMPONENT C5; RHEUMATOID-ARTHRITIS; T-CELL; AUTOIMMUNE-DISEASES; MURINE MODEL; GENOME SCAN; NOD MICE; RECEPTOR AB K/B X N T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/BXN animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leapfrogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. Fl analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57B1/6 X NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/B X N serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal dir1, coinciding with the Sle I locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chrl2 and dr;,18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/B X N model will bear fruit. C1 Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. Univ Strasbourg 1, CNRS, INSERM, Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, France. Ctr Natl Genotypage, F-91057 Evry, France. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. Hop Beaujon, Serv Anat & Cytol Pathol, F-92118 Clichy, France. Hop Necker Enfants Malad, INSERM U25, F-75015 Paris, France. RP Mathis, D (reprint author), Joslin Diabet Ctr, Sect Immunol & Immunogenet, 1 Joslin Pl, Boston, MA 02215 USA. RI Gonzalez, Antonio/C-4444-2008 OI Gonzalez, Antonio/0000-0002-2624-0606 NR 42 TC 110 Z9 112 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 6 PY 2001 VL 194 IS 3 BP 321 EP 330 DI 10.1084/jem.194.3.321 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 461UQ UT WOS:000170382200011 PM 11489951 ER PT J AU Gensure, RC Gardella, TJ Juppner, H AF Gensure, RC Gardella, TJ Juppner, H TI Multiple sites of contact between the carboxyl-terminal binding domain of PTHrP-(1-36) analogs and the amino-terminal extracellular domain of the PTH/PTHrP receptor identified by photoaffinity cross-linking SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN PARATHYROID-HORMONE; PTH-RELATED PEPTIDE; PROTEIN-RECEPTOR; REGION; LIGAND; LOOP; MUTAGENESIS; FRAGMENTS; RESIDUES; COMPLEX AB The carboxyl-terminal portions of parathyroid hormone (PTH)-(1-34) and PTH-related peptide (PTHrP)-(1-36) are critical for high affinity binding to the PTH/ PTHrP receptor (P1R), but the mechanism of receptor interaction for this domain is largely unknown. To identify interaction sites between the carboxyl-terminal region of PTHrP-(1-36) and the P1R, we prepared analogs of [I-5,W-23,Y-36]PTHrP-(1-36)-amide with individual p-benzoyl-L-phenylalanine (Bpa) substitutions at positions 22-35. When tested with LLC-PK1 cells stably transfected with human P1R (hP1R), the apparent binding affinity and the EC50 of agonist-stimulated cAMP accumulation for each analog was, with the exception of the Bpa(24)-substituted analog, similar to that of the parent compound. The radiolabeled Bpa(23)-, Bpa(27)-, Bpa (28)-, and Bpa(33)-substituted compounds affinity-labeled the hP1R sufficiently well to permit subsequent mapping of the cross-linked receptor region. Each of these peptides cross-linked to the amino-terminal extracellular domain of the P1R: [I-5,Bpa(23),Y-36]PTHrP-(1-36)-amide crosslinked to the extreme end of this domain (residues 33-63); [I-5,W-23 Bpa(27),Y-36]PTHrP-(1-36)-amide cross-linked to residues 96-102; [1(5),W-23 Bpa (28),Y-36] PTHrP-(1-36). amide cross-linked to residues 64-95; and [15,W23, Bpa(33),Y-36]PTHrP-(1-36)-amide cross-linked to residues 151-172. These data thus predict that residues 23, 279 28, and 33 of native PTHrP are each near to different regions of the amino-terminal extracellular receptor domain of the P1R. This information helps define sites of proximity between several ligand residues and this large receptor domain, which so far has been largely excluded from models of the hormone-receptor complex. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK11794, 1F32DK10034-01] NR 39 TC 53 Z9 53 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 3 PY 2001 VL 276 IS 31 BP 28650 EP 28658 DI 10.1074/jbc.M100717200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 461BX UT WOS:000170346000004 PM 11356832 ER PT J AU Zhang, LJ Lawrence, R Schwartz, JJ Bai, XM Wei, G Esko, JD Rosenberg, RD AF Zhang, LJ Lawrence, R Schwartz, JJ Bai, XM Wei, G Esko, JD Rosenberg, RD TI The effect of precursor structures on the action of glucosaminyl 3-O-sulfotransferase-1 and the biosynthesis of anticoagulant heparan sulfate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-DEACETYLASE/N-SULFOTRANSFERASE; EMBRYONAL CARCINOMA-CELLS; HAMSTER OVARY CELLS; MOLECULAR-CLONING; ANTITHROMBIN-III; CDNA CLONING; PROTEOGLYCANS; EXPRESSION; BINDING; ACID AB To understand how 2-O-sulfation of uronic acid residues influences the biosynthesis of anticoagulant heparan sulfate, the cDNA encoding glucosaminyl 3-O-sulfotransferase-1 (3-OST-1) was introduced into wild-type Chinese hamster ovary cells and mutant pgsF-17 cells, which are defective in 2-O-sulfation. 3-OST-1-transduced cells gained the ability to bind to antithrombin. Structural analysis of the heparan sulfate chains showed that 3-OST-1 generates sequences containing GlcUA-GlcN(SO3)3(SO3) and GlcUA-GlcN(SO3)3(SO3)6(SO.) in both wild-type and mutant cells. In addition, IdoUA-GIcN(SO3)3(SO3) and IdoUA-GIcN(SO3)3(SO3)6(SO3) accumulate in the mutant chain. These disaccharides were also observed by tagging [6-H-3]GIcN-labeled pgsF-17 heparan sulfate in vitro with [S-35]PAPs and purified 3-OST-1. Heparan sulfate derived from the transduced mutant also had similar to2-fold higher affinity for antithrombin than heparan sulfate derived from the transduced wildtype cells, and it inactivated factor Xa more efficiently. This study demonstrates for the first time that (i) 3-O-sulfation by 3-OST-1 can occur independently of the 2-O-sulfation of uronic acids, (ii) 2-0-sulfation usually occurs before 3-O-sulfation, (iii) 2-0-sulfation blocks the action of 3-OST-1 at glucosamine residues located to the reducing side of IdoUA units, and (iv) that alternative antithrombin-binding structures can be made in the absence of 2-0-sulfation. C1 MIT, Dept Biol, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, BIDMC, Dept Med, Boston, MA 02215 USA. Univ Calif San Diego, Dept Cellular & Mol Med, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. RP Rosenberg, RD (reprint author), MIT, Dept Biol, Bldg 68-480,77 Massachusetts Ave, Cambridge, MA 02139 USA. FU NHLBI NIH HHS [5P01-HL41484, 5R01-HL58479]; NIGMS NIH HHS [R37-GM33063] NR 41 TC 35 Z9 36 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 3 PY 2001 VL 276 IS 31 BP 28806 EP 28813 DI 10.1074/jbc.M100204200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 461BX UT WOS:000170346000023 PM 11375390 ER PT J AU Jun, CD Carman, CV Redick, SD Shimaoka, M Erickson, HP Springer, TA AF Jun, CD Carman, CV Redick, SD Shimaoka, M Erickson, HP Springer, TA TI Ultrastructure and function of dimeric, soluble intercellular adhesion molecule-1 (ICAM-1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; SURFACE-PLASMON RESONANCE; ELECTRON-MICROSCOPY; MASS-TRANSPORT; LIGAND-BINDING; COILED-COILS; RHINOVIRUS; RECEPTOR; DOMAINS; LFA-1 AB Previous studies have demonstrated dimerization of intercellular adhesion molecule-1 (ICAM-1) on the cell surface and suggested a role for immunoglobulin superfamily domain 5 and/or the transmembrane domain in mediating such dimerization. Crystallization studies suggest that domain I may also mediate dimerization. ICAM-1 binds through domain 1 to the I domain of the integrin alpha (L)beta (2) (lymphocyte function-associated antigen 1). Soluble C-terminally dimerized ICAM-1 was made by replacing the transmembrane and cytoplasmic domains with an a-helical coiled coil. Electron microscopy revealed C-terminal dimers that were straight, slightly bent, and sometimes U-shaped. A small number of apparently closed ring-like dimers and W-shaped tetramers were found. To capture ICAM-1 dimerized at the crystallographically defined dimer interface in domain 1, cysteines were introduced into this interface. Several of these mutations resulted in the formation of soluble disulfide-bonded ICAM-1 dimers (domain 1 dimers). Combining a domain I cysteine mutation with the C-terminal dimers (domain 1/C-terminal dimers) resulted in significant amounts of both closed ring-like dimers and W-shaped tetramers. Surface plasmon resonance studies showed that all of the dimeric forms of ICAM-1 (domain 1, C-terminal, and domain 1/C-terminal dimers) bound similarly to the integrin alpha (L)beta (2) I domain, with affinities similar to1.5-3-fold greater than that of monomeric ICAM-1. These studies demonstrate that ICAM-1 can form at least three different topologies and that dimerization at domain 1 does not interfere with binding in domain I to alpha (L)beta (2). C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. RI Carman, Christopher/L-8108-2016 OI Carman, Christopher/0000-0001-7358-2548 NR 38 TC 53 Z9 54 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 3 PY 2001 VL 276 IS 31 BP 29019 EP 29027 DI 10.1074/jbc.M103394200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 461BX UT WOS:000170346000053 PM 11390397 ER PT J AU Aikawa, T Segre, GV Lee, K AF Aikawa, T Segre, GV Lee, K TI Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETINOBLASTOMA PROTEIN; FACTOR RECEPTOR-3; BONE-DEVELOPMENT; TRANSGENIC MICE; INDIAN HEDGEHOG; DIFFERENTIATION; PROLIFERATION; EXPRESSION; ACTIVATION; ARREST AB Fibroblast growth factor (FGF) and its receptor (FGFR) are thought to be negative regulators of chondrocytic growth, as exemplified by achondroplasia and related chondrodysplasias, which are caused by constitutively active mutations in FGFR3. To understand the growth-inhibitory mechanisms of FGF, we analyzed the effects of FGF2 on cell cycle-regulating molecules in chondrocytes. FGF2 dramatically inhibited proliferation of rat chondrosarcoma (RCS) cells and arrested their cell cycle at the G(1) phase. FGF2 increased p21 expression in RCS cells, which assembled with the cyclin E-Cdk2 complexes, although the expression of neither cyclin E nor Cdk2 increased. In addition, the kinase activity of immunoprecipitated cyclin E or Cdk2, assessed with retinoblastoma protein (pRb) as substrate, was dramatically reduced by FGF-2. Moreover, FGF2 shifted pRb to its underphosphorylated, active form in RCS cells. FGF2 not only induced p21 protein expression in proliferating chondrocytes in mouse fetal limbs cultured in vitro but also decreased their proliferation as assessed by the expression of histone H4 mRNA, a marker for cells in S phase. Furthermore, inhibitory effects of FGF2 on chondrocytic proliferation were partially reduced in p21-null limbs, compared with those in wild-type limbs in vitro. Taken together, FGF's growth inhibitory effects of chondrocytes appear to be mediated at least partially through p21 induction and the subsequent inactivation of cyclin E-Cdk2 and activation of pRb. C1 Harvard Univ, Endocrine Unit, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Lee, K (reprint author), Harvard Univ, Endocrine Unit, Massachusetts Gen Hosp, Sch Med, 50 Blossom St,Wellman 501, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK53343] NR 36 TC 70 Z9 75 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 3 PY 2001 VL 276 IS 31 BP 29347 EP 29352 DI 10.1074/jbc.M101859200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 461BX UT WOS:000170346000095 PM 11384971 ER PT J AU Hutvagner, G McLachlan, J Pasquinelli, AE Balint, E Tuschl, T Zamore, PD AF Hutvagner, G McLachlan, J Pasquinelli, AE Balint, E Tuschl, T Zamore, PD TI A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA SO SCIENCE LA English DT Article ID DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; C-ELEGANS; REGULATORY RNA; MESSENGER-RNA; GENE; LIN-14; ARABIDOPSIS; DROSOPHILA; SEQUENCE AB The 21-nucleotide small temporal RNA (stRNA) let-7 regulates developmental timing in Caenorhabditis elegans and probably in other bilateral animals. We present in vivo and in vitro evidence that in Drosophila melanogaster a developmentally regulated precursor RNA is cleaved by an RNA interference-like mechanism to produce mature let-7 stRNA. Targeted destruction in cultured human cells of the messenger RNA encoding the enzyme Dicer, which acts in the RNA interference pathway, leads to accumulation of the let-7 precursor. Thus, the RNA interference and stRNA pathways intersect. Both pathways require the RNA-processing enzyme Dicer to produce the active small-RNA component that represses gene expression. C1 Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Max Planck Inst Biophys Chem, Dept Cellular Biochem, D-37077 Gottingen, Germany. RP Hutvagner, G (reprint author), Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01655 USA. RI Zamore, Phillip/A-8941-2013; OI Hutvagner, Gyorgy/0000-0002-7231-9446 FU NIGMS NIH HHS [GM62862-01] NR 36 TC 1560 Z9 1656 U1 10 U2 105 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 3 PY 2001 VL 293 IS 5531 BP 834 EP 838 DI 10.1126/science.1062961 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 459FU UT WOS:000170241000037 PM 11452083 ER PT J AU Pak, DTS Yang, SY Rudolph-Correia, S Kim, E Sheng, M AF Pak, DTS Yang, SY Rudolph-Correia, S Kim, E Sheng, M TI Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP SO NEURON LA English DT Article ID METHYL-D-ASPARTATE; POSTSYNAPTIC DENSITY FRACTION; GTPASE-ACTIVATING PROTEIN; NMDA RECEPTOR SUBUNITS; CENTRAL-NERVOUS-SYSTEM; ACTIN-BASED PLASTICITY; HIPPOCAMPAL-NEURONS; GUANYLATE KINASES; SYNAPTIC ACTIVITY; DENTATE GYRUS AB The PSD-95/SAP90 family of scaffold proteins organizes the postsynaptic, density (PSD) and regulates NMDA receptor signaling at excitatory synapses. We report that SPAR, a Rap-specific GTPase-activating protein (RapGAP), interacts with the guanylate kinaselike domain of PSD-95 and forms a complex with PSD-95 and NMDA receptors in brain. In heterologous cells, SPAR reorganizes the actin cytoskeleton and recruits PSD-95 to F-actin. In hippocampal neurons, SPAR localizes to dendritic spines and causes enlargement of spine heads, many of which adopt an irregular appearance with putative multiple synapses. Dominant negative SPAR constructs cause narrowing and elongation of spines. The effects of SPAR on spine morphology depend on the RapGAP and actin-interacting domains, implicating Rap signaling in the regulation of postsynaptic structure. C1 Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. RP Sheng, M (reprint author), MIT, Ctr Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RI Kim, Eunjoon/C-1566-2011 FU NINDS NIH HHS [NS10886, NS35050] NR 67 TC 266 Z9 283 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 2 PY 2001 VL 31 IS 2 BP 289 EP 303 DI 10.1016/S0896-6273(01)00355-5 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 459XX UT WOS:000170277700013 PM 11502259 ER PT J AU Wagner, AD Pare-Blagoev, EJ Clark, J Poldrack, RA AF Wagner, AD Pare-Blagoev, EJ Clark, J Poldrack, RA TI Recovering meaning: Left prefrontal cortex guides controlled semantic retrieval SO NEURON LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SURFACE-BASED ANALYSIS; VERBAL WORKING-MEMORY; FRONTAL-CORTEX; FUNCTIONAL MRI; REPETITION; SPECIALIZATION; ACTIVATION; GENERATION; KNOWLEDGE AB Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRl study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Harvard Univ, Grad Sch Educ, Cambridge, MA 02138 USA. RP Wagner, AD (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM awagner@psyche.mit.edu NR 58 TC 577 Z9 583 U1 7 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 2 PY 2001 VL 31 IS 2 BP 329 EP 338 DI 10.1016/S0896-6273(01)00359-2 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 459XX UT WOS:000170277700016 PM 11502262 ER PT J AU Welch, CA AF Welch, CA TI Sacred secrets - The privacy of medical records SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Welch, CA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 7 TC 19 Z9 19 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 2 PY 2001 VL 345 IS 5 BP 371 EP 372 DI 10.1056/NEJM200108023450512 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 458KM UT WOS:000170193600013 PM 11484697 ER PT J AU Wexler, DJ Chen, J Smith, GL Radford, MJ Yaari, S Bradford, WD Krumholz, HM AF Wexler, DJ Chen, J Smith, GL Radford, MJ Yaari, S Bradford, WD Krumholz, HM TI Predictors of costs of caring for elderly patients discharged with heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID OUTCOMES; CARE; HOSPITALIZATION; READMISSION AB Background investments in programs to improve outcomes and reduce readmissions for patients who survive hospitalization with heart failure will be economically most favorable for those who have the highest risk. Little information is available, however, to stratify the risk of these patients incurring costs after discharge. in this study, we sought to determine correlates of costs in a representative sample of patients with heart failure in the 6 months after discharge. Methods We reviewed medical records of 2181 patients aged greater than or equal to 65 years who were discharged alive from 18 Connecticut hospitals in 1994 and 1995 with a principal discharge diagnosis of heart failure. Outcomes 6 months after discharge, including all-cause readmission and cost, heart failure-related readmission and cost, and death, were obtained from the Medicare administrative database. A 2-stage sample selection model was used to identify the independent correlates of cost. Risk scores were calculated to identify subsets of patients at risk for generating high costs. Results On average, patients discharged with heart failure incurred costs of $2388 resulting from heart failure-related admissions and $7101 resulting from admissions from any cause during the 6 months after discharge. An average admission for heart failure cost $7174, whereas an admission resulting from any cause cost $8589. The multivariate models explained 7% of the variation in cost, although clinical characteristics such as recent heart failure admissions, kidney failure, and hypertension were significant independent correlates of increased cost. Older age and a history of stroke were independently associated with decreased cost. Patients without any of the risk factors associated with increased costs still incurred $1500 to $5000, on average, in the 6 months after discharge. Conclusions Patients with heart failure generate substantial hospital costs in the 6 months after discharge. Given the emerging evidence for effective programs to reduce readmission, investments in interventions that produce even modest reductions in risk would be economically favorable. C1 Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sect Cardiovasc Med, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT 06510 USA. Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. Qualidigm, Middletown, CT USA. Bar Ilan Univ, Ramat Gan, Israel. Med Univ S Carolina, Dept Hlth Policy & Adm, Charleston, SC 29425 USA. RP Wexler, DJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Radford, Martha/0000-0001-7503-9557 NR 12 TC 22 Z9 22 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2001 VL 142 IS 2 BP 350 EP 357 DI 10.1067/mhj.2001.116476 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 459XC UT WOS:000170275900024 PM 11479477 ER PT J AU Han, RO Schwartz, RS Kobayashi, Y Wilson, SH Mann, JT Sketch, MH Safian, RD Lansky, A Popma, J Fitzgerald, PJ Palacios, IF Chazin-Caldie, M Goldberg, S AF Han, RO Schwartz, RS Kobayashi, Y Wilson, SH Mann, JT Sketch, MH Safian, RD Lansky, A Popma, J Fitzgerald, PJ Palacios, IF Chazin-Caldie, M Goldberg, S CA Stent COmparative REStenosis TI Comparison of self-expanding and balloon-expandable stents for the reduction of restenosis SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; ANGIOPLASTY; PLACEMENT; NITINOL AB To compare the efficacy of self-expanding (SE) and balloon-expandable (BE) stents in native coronary arteries, we randomly assigned 1,096 patients with new and restenotic lesions to receive either device. Baseline demographics and coronary angiographic characteristics were similar in the 2 groups. The incidence of major adverse cardiac events including death, myocardial infarction, bypass surgery, and repeat intervention was similar for both groups at 1 month (2.9% vs 3.1% for SE vs BE, respectively) and at 9 months (19.3% vs 20.1%, SE vs BE respectively). In a subgroup of patients who underwent follow-up angiography (n = 250), the binary restenosis rates (24.2% vs 18.7%, p = 0.30), late loss (0.98 vs 94 mm, p = 0.60), and loss index (0.55 vs 55, p = 0.95) were not significantly different for both groups. In 62 patients who underwent intravascular ultrasound examination (IVUS), there was a trend toward a lower incidence of edge tears in the SE group (6% vs 23%, p = 0.06). Follow-up IVUS analysis showed that the minimum stent area of the SE stent increased by 33% at 6 months, whereas no change occurred in the BE stents; this was accompanied by a greater degree of intimal proliferation in the SE stents compared with BE stents (3.1 +/- 2.0 vs 1.7 +/- 1.7 mm(2)). Thus, the SE stents had similar clinical and angiographic outcomes in patients with lesions in native coronary arteries. (C) 2001 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. Wake Heart Associates, Raleigh, NC USA. Duke Univ, Durham, NC USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Washington Hosp Ctr, Washington, DC 20010 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Stanford Univ, Stanford, CA 94305 USA. Boston Sci, Maple Grove, MN USA. Cooper Univ Med Ctr, Camden, NJ USA. RP Goldberg, S (reprint author), MCPHU, Univ Hosp, Dept Med, 245 N 15th St,MS 487, Philadelphia, PA 19102 USA. NR 8 TC 42 Z9 43 U1 1 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2001 VL 88 IS 3 BP 253 EP 259 DI 10.1016/S0002-9149(01)01636-8 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 456PC UT WOS:000170090500010 PM 11472703 ER PT J AU El-Serag, HB Richardson, PA Everhart, JE AF El-Serag, HB Richardson, PA Everhart, JE TI The role of diabetes in hepatocellular carcinoma: A case-control study among United States veterans SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PRIMARY LIVER-CANCER; C VIRUS-INFECTION; HEPATITIS-C; RISK-FACTORS; MULTIVARIATE-ANALYSIS; CIRRHOSIS; MELLITUS; PROGRESSION; DISEASE; TAIWAN AB OBJECTIVE: Diabetes mellitus (DM) has been reported to increase the risk of hepatocellular carcinoma (HCC). We carried out a case-control study to examine the role of DM while controlling for several known risk factors of HCC. METHODS: All hospitalized patients with primary liver cancer (PLC) during 1997-1999 were identified in the computerized database of the Department of Veterans Affairs, the Patient Treatment File. Controls without cancer were randomly assigned from the Patient Treatment File during the same time period. The inpatient and outpatient files were searched for several conditions including DM, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic cirrhosis, autoimmune hepatitis, hemochromatosis, and nonspecific cirrhosis. Adjusted odds ratios (OR) were calculated in a multivariable logistic regression model. RESULTS: We identified 823 patients with PLC and 3459 controls. The case group was older (62 yr [+/- 10] vs 60 [+/- 11], p < 0.0001). had more men (99% vs 97%. 0.0004), and a greater frequency of nonwhites (66% vs 71%, 0.0009) compared with controls. However, HCV- and HBV-infected patients were younger among cases than controls. Risk factors that were significantly more frequent among PLC cases included HCV (34% vs 5%, p < 0.0001), HBV (11% vs 2%. p < 0.0001), alcoholic cirrhosis (47% vs 6%, p < 0.0001). hemochromatosis (2% vs 0.3%, p < 0.0001), autoimmune hepatitis (5% vs 0.5%. p < 0.0001), and diabetes (33% vs 30%. p = 0.059). In the multivariable logistic regression, diabetes was associated with a significant increase in the adjusted OR of PLC (1.57, 1.08-2.28, p = 0.02) in the presence of HCV, HBV. or alcoholic cirrhosis. Without markers of chronic liver disease, the adjusted OR for diabetes and PLC was not significantly increased (1.08, 0.86-1.18. p = 0.4). There was an increase in the HCV adjusted OR (17.27, 95% CI = 11.98-24.89) and HBV (9.22, 95% Cl = 4.52-18.80) after adjusting for the younger age of HCV- and HBV-infected cases. The combined presence of HCV and alcoholic cirrhosis further increases the risk with an adjusted OR of 79.21 (60.29-103.41). The population attributable fraction for HCV among hospitalized veterans was 44.8%, whereas that of alcoholic cirrhosis was 51%. CONCLUSION: DM increased the risk of PLC only in the presence of other risk factors such as hepatitis C or B or alcoholic cirrhosis. Hepatitis C infection and alcoholic cirrhosis account for most of PLC among veterans. C1 Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. NIDDKD, NIDDK, Bethesda, MD USA. RP El-Serag, HB (reprint author), Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 38 TC 154 Z9 156 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2001 VL 96 IS 8 BP 2462 EP 2467 DI 10.1111/j.1572-0241.2001.04054.x PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 462TA UT WOS:000170434800036 PM 11513191 ER PT J AU Gralnek, IM AF Gralnek, IM TI Diagnosis and management of gastroesophageal reflux disease in the primary care setting: Can health-related quality of life play a role? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID OF-LIFE C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Med, Ctr Study Digest Healthcare Qual & Outcomes, Los Angeles, CA 90073 USA. CURE Digest Dis Res Ctr, Div Digest Dis, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Gralnek, IM (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Med, Ctr Study Digest Healthcare Qual & Outcomes, 11301 Wilshire Blvd,CURE Bldg 115 Room 318, Los Angeles, CA 90073 USA. NR 14 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2001 VL 96 IS 8 SU S BP S54 EP S56 DI 10.1016/S0002-9270(01)02586-2 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 463PH UT WOS:000170484200012 PM 11510772 ER PT J AU Goldie, SJ Freedberg, KA Weinstein, MC Wright, TC Kuntz, KM AF Goldie, SJ Freedberg, KA Weinstein, MC Wright, TC Kuntz, KM TI Cost effectiveness of human papillomavirus testing to augment cervical cancer screening in women infected with the human immunodeficiency virus SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID SQUAMOUS INTRAEPITHELIAL LESIONS; ACTIVE ANTIRETROVIRAL THERAPY; HIV-NEGATIVE WOMEN; NATURAL-HISTORY; HIGH-RISK; EARLY REGRESSION; PLUS INDINAVIR; PREVALENCE; NEOPLASIA; DISEASE AB PURPOSE: To determine the cost effectiveness of incorporating molecular testing for high-risk types of human papillomavirus into a cervical cancer screening program for women infected with the human immunodeficiency virus (HIV). SUBJECTS AND METHODS: We developed a Markov model to simulate the natural history of cervical cancer precursor lesions in HPV-infected women. Probabilities of progression and regression of cervical lesions were conditional on transient or persistent infection with human papillomavirus, as well as stage of HIV and effectiveness of antiretroviral therapy. Incorporating data from prospective cohort studies, national databases, and published literature, the model was used to calculate quality-adjusted life expectancy, life expectancy, lifetime costs, and incremental cost-effectiveness ratios for two main strategies: targeted screening-human papillomavirus testing is added to the initial two cervical cytology smears obtained after an HIV diagnosis and subsequent screening intervals are modified based on the test results; and universal screening-no testing for human papilloma-virus is performed, and a single cytology screening interval is applied to all women. RESULTS: In HIV-infected women on anti-retroviral therapy, a targeted screening strategy in which cervical cytology screening was conducted every 6 months for women with detected human papillomavirus DNA, and annually for all others, cost $10,000 to $14,000 per quality-adjusted life year gained compared with no screening. A universal screening strategy consisting of annual cervical cytology for all women was 15% less effective and had a less attractive cost-effectiveness ratio. Targeted screening remained economically attractive in multiple sensitivity analyses, although when the overall incidence of cervical cancer precursor lesions was lowered by 75%, the screening interval for women with detected human papillomavirus DNA could be widened to I year. CONCLUSIONS: Adding human papillomavirus testing to the two cervical cytology smears obtained in the year after an HIV diagnosis, and modifying subsequent cytology screening intervals based on the results, appears to be an effective and cost-effective modification to current recommend at ions for annual cytology screening in HIV-infected women. (C) 2001 by Excerpta Medica, Inc. C1 Harvard Univ, Program Econ Evaluat Med Technol, Ctr Risk Anal, Dept Hlth Policy & Management,Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Gen Internal Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Partners AIDS Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. RP Goldie, SJ (reprint author), Harvard Univ, Program Econ Evaluat Med Technol, Ctr Risk Anal, Dept Hlth Policy & Management,Sch Publ Hlth, 718 Huntington Ave,2nd Floor, Boston, MA 02115 USA. FU AHRQ HHS [1-RO1-HS07317] NR 59 TC 41 Z9 42 U1 1 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2001 VL 111 IS 2 BP 140 EP 149 DI 10.1016/S0002-9343(01)00780-X PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 466BN UT WOS:000170624600009 PM 11498068 ER PT J AU Cook, AF Hoas, H Joyner, JC AF Cook, AF Hoas, H Joyner, JC TI No secrets on main street SO AMERICAN JOURNAL OF NURSING LA English DT Editorial Material C1 Univ Montana, Natl Rural Bioeth Project, Rural Inst, Curry Hlth Ctr, Missoula, MT 59812 USA. US Dept Vet Affairs, Off Gen Counsel, Washington, DC USA. RP Cook, AF (reprint author), Univ Montana, Natl Rural Bioeth Project, Rural Inst, Curry Hlth Ctr, Missoula, MT 59812 USA. NR 11 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD AUG PY 2001 VL 101 IS 8 BP 67 EP + PG 4 WC Nursing SC Nursing GA 529AA UT WOS:000174276800032 PM 12134788 ER PT J AU Low, QEH Drugea, IA Duffner, LA Quinn, DG Cook, DN Rollins, BJ Kovacs, EJ DiPietro, LA AF Low, QEH Drugea, IA Duffner, LA Quinn, DG Cook, DN Rollins, BJ Kovacs, EJ DiPietro, LA TI Wound healing in MIP-1 alpha(-/-) and MCP-1(-/-) mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; MONOCYTE CHEMOATTRACTANT PROTEIN-1; CHEMOKINE RECEPTOR-2; GENE-EXPRESSION; REPAIR; ATHEROSCLEROSIS; RECRUITMENT; DEFICIENT; CYTOKINE; INJURY AB A salient feature of normal wound healing is the development and resolution of an acute inflammatory response. Although much is known about the function of inflammatory cells within wounds, little is known about the chemotactic and activation signals that influence this response. As the CC chemokines macrophage inflammatory protein-1 alpha (MEP-1 alpha) and monocyte chemotactic protein-1 (MCP-1) are abundant in acute wounds, wound repair was examined in MIP-1 alpha (-/-) and MCP-1(-/-) mice. Surprisingly, wound re-epithelialization, angiogenesis, and collagen synthesis in MIP-1 alpha (-/-) mice was nearly identical to wildtype controls. In contrast, MCP-1(-/-) mice displayed significantly delayed wound re-epithelialization, with the greatest delay at day 3 after injury (28 +/- 5% versus 79 +/- 14% re-epithelialization, P < 0.005). Wound angiogenesis was also delayed in MCP-1(-/-) mice, with a 48% reduction in capillary density at day 5 after injury. Collagen synthesis was impeded as well, with the wounds of MCP-1(-/-) mice containing significantly less hydroxyproline than those of control mice (25 3 versus 50 +/- 8 mug/wound at day 5, P < 0.0001). No change in the number of wound macrophages was observed in MCP-1(-/-) mice, suggesting that monocyte recruitment into wounds is independent of this chemokine. The data suggest that MCP-1 plays a critical role in healing wounds, most likely by influencing the effector state of macrophages and other cell types. C1 Loyola Univ, Med Ctr, Burn & Shock Trauma Inst, Dept Microbiol & Immunol, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Dept Surg, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Dept Cell Biol Neurobiol & Anat, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Immunol & Aging Program, Maywood, IL 60153 USA. Schering Plough Res Inst, Dept Immunol, Kenilworth, NJ USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP DiPietro, LA (reprint author), Loyola Univ, Med Ctr, Burn & Shock Trauma Inst, Dept Microbiol & Immunol, 2160 S 1st Ave, Maywood, IL 60153 USA. FU NIA NIH HHS [AG 16067]; NIAID NIH HHS [AI 44861-01]; NIGMS NIH HHS [GM 50875, GM 55238, GM 55344, R01 GM050875, R01 GM055238] NR 44 TC 176 Z9 186 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2001 VL 159 IS 2 BP 457 EP 463 DI 10.1016/S0002-9440(10)61717-8 PG 7 WC Pathology SC Pathology GA 461GL UT WOS:000170356500010 PM 11485904 ER PT J AU Arbiser, JL Yeung, R Weiss, SW Arbiser, ZK Amin, MB Cohen, C Frank, D Mahajan, S Herron, GS Yang, JW Onda, H Zhang, HB Bai, XH Uhlmann, E Loehr, A Northrup, H Au, P Davis, I Fisher, DE Gutmann, DH AF Arbiser, JL Yeung, R Weiss, SW Arbiser, ZK Amin, MB Cohen, C Frank, D Mahajan, S Herron, GS Yang, JW Onda, H Zhang, HB Bai, XH Uhlmann, E Loehr, A Northrup, H Au, P Davis, I Fisher, DE Gutmann, DH TI The generation and characterization of a cell line derived from a sporadic renal angiomyolipoma - Use of telomerase to obtain stable populations of cells from benign neoplasms SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUBEROUS-SCLEROSIS; TSC2 GENE; TRANSCRIPTION FACTOR; SUGAR TUMOR; EXPRESSION; DIFFERENTIATION; KIDNEY; MICROPHTHALMIA; HAMARTIN; TISSUES AB Angiomyolipomas are benign tumors of the kidney derived from putative perivascular epithelioid cells, that may undergo differentiation into cells with features of melanocytes, smooth muscle, and fat. To gain further insight into angiomyolipomas, we have generated the first human angiomyolipoma cell fine by sequential introduction of SV40 large T antigen and human telomerase into human angiomyolipoma cells. These cells show phenotypic characteristics of angiomyolipomas, namely differentiation markers of smooth muscle (smooth muscle actin), adipose tissue (peroxisome proliferator-activator receptor gamma, PPAR gamma), and melanocytes (microophthalmia, MITF), thus demonstrating that a single cell type can exhibit all of these phenotypes. These cells should serve as a valuable tool to elucidate signal transduction pathways underlying renal angiomyolipomas. C1 Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Winship Canc Inst, Atlanta, GA USA. Univ Washington, Sch Med, Dept Internal Med, Seattle, WA 98195 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Stanford Univ, Sch Med, Dept Dermatol, Stanford, CA 94305 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Univ Texas, Dept Pediat Med Genet, Div Pediat Hematol Oncol, Houston, TX USA. RP Arbiser, JL (reprint author), Emory Univ, Sch Med, Dept Dermatol, WMB 5309,1639 Pierce Dr, Atlanta, GA 30322 USA. FU NIAMS NIH HHS [AR02030, P30 AR042687, P30 AR42687] NR 51 TC 31 Z9 31 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2001 VL 159 IS 2 BP 483 EP 491 DI 10.1016/S0002-9440(10)61720-8 PG 9 WC Pathology SC Pathology GA 461GL UT WOS:000170356500013 PM 11485907 ER PT J AU Andress, DL AF Andress, DL TI IGF-binding protein-5 stimulates osteoblast activity and bone accretion in ovariectomized mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE bone formation; bone mineral density; estrogen deficiency ID GROWTH-FACTOR-I; CELLS; RESORPTION; HORMONE; PROLIFERATION; ESTRADIOL; OSTEOPOROSIS; MITOGENESIS; EXPRESSION; APOPTOSIS AB Insulin-like growth factor binding protein-5 (IGFBP-5) is an osteoblast secretory protein that becomes incorporated into the mineralized bone matrix. In osteoblast cultures, IGFBP-5 stimulates cell proliferation by an IGF-independent mechanism. To evaluate whether IGFBP-5 can stimulate osteoblast activity and enhance bone accretion in a mouse model of osteoblast insufficiency, daily subcutaneous injections of either intact [IGFBP-5 (intact)] or carboxy-truncated IGFBP-5 [IGFBP-5-(1-169)] were given to ovariectomized (OVX) mice for 8 wk. Femur and spine bone mineral density (BMD), measured every 2 wk, showed early and sustained increases in response to IGFBP-5. Bone histomorphometry of cancellous bone showed significant elevations in the bone formation rate in both the femur metaphysis [IGFBP-5(1-169)] only) and spine compared with OVX controls. IGFBP-5 also stimulated osteoblast number in the femur IGFBP-5-( 1-169) only) and spine. These data indicate that IGFBP-5 effectively enhances bone formation and bone accretion in OVX mice by stimulating osteoblast activity. The finding that IGFBP-5-(1-169) is bioactive in vivo indicates that the carboxy-terminal portion is not required for this bone anabolic effect. C1 VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA 98108 USA. Univ Washington, Dept Med, Seattle, WA 98105 USA. RP Andress, DL (reprint author), VA Puget Sound Hlth Care Syst, Dept Med, 111A,1660 S Columbian Wy, Seattle, WA 98108 USA. FU NIAMS NIH HHS [R01 AR-44911] NR 27 TC 31 Z9 34 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2001 VL 281 IS 2 BP E283 EP E288 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 460HV UT WOS:000170302900011 PM 11440904 ER PT J AU Tillfors, M Furmark, T Marteinsdottir, I Fischer, H Pissiota, A Langstrom, B Fredrikson, M AF Tillfors, M Furmark, T Marteinsdottir, I Fischer, H Pissiota, A Langstrom, B Fredrikson, M TI Cerebral blood flow in subjects with social phobia during stressful speaking tasks: A PET study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SCRIPT-DRIVEN IMAGERY; HUMAN AMYGDALA; FUNCTIONAL NEUROANATOMY; SYMPTOM PROVOCATION; BRAIN; FEAR; DISORDER; ANXIETY; RECOGNITION AB Objective: The central nervous system representation of social phobia (social anxiety disorder) is largely unknown. The aim of this study was to examine brain activity during symptom provocation in social phobics. Method: Positron emission tomography with the use of O-15 water was used to measure regional cerebral blood flow (rCBF) in 18 subjects with DSM-IV-defined social phobia and a nonphobic comparison group while they were speaking in front of an audience and in private. Heart rate and subjective anxiety were also recorded. Results: During public versus private speaking, subjective anxiety increased more in the social phobics than in the comparison group. increased anxiety was accompanied by enhanced rCBF in the amygdaloid complex in the social phobics relative to the comparison subjects. Cortically, brain blood flow decreased in the social phobics and increased in the comparison subjects more during public than private speaking in the orbitofrontal and insular cortices as well as in the temporal pole and increased less in the social phobics than in the comparison group in the parietal and secondary visual cortices. Furthermore, rCBF increased in the comparison group, but not in the social phobics, in the perirhinal and retrosplenial cortices. Conclusions: An rCBF pattern of relatively increased cortical rather than subcortical perfusion was observed in the nonphobic subjects, indicating that cortical evaluative processes were taxed by public performance. In contrast, the social phobia symptom profile was associated with increased subcortical activity. Thus, the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger-recognition system. C1 Uppsala Univ, Dept Psychol, SE-75142 Uppsala, Sweden. Uppsala Univ, Uppsala Univ PET Ctr, SE-75142 Uppsala, Sweden. Univ Uppsala Hosp, Dept Psychiat, S-75185 Uppsala, Sweden. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat Neuroimaging Grp, Boston, MA USA. RP Tillfors, M (reprint author), Uppsala Univ, Dept Psychol, Box 1225, SE-75142 Uppsala, Sweden. NR 59 TC 215 Z9 219 U1 1 U2 13 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2001 VL 158 IS 8 BP 1220 EP 1226 DI 10.1176/appi.ajp.158.8.1220 PG 7 WC Psychiatry SC Psychiatry GA 459JG UT WOS:000170246800009 PM 11481154 ER PT J AU Baer, JS Kivlahan, DR Blume, AW McKnight, P Marlatt, GA AF Baer, JS Kivlahan, DR Blume, AW McKnight, P Marlatt, GA TI Brief intervention for heavy-drinking college students: 4-year follow-up and natural history SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID ALCOHOL-USE; BINGE-DRINKING; CLINICAL-SIGNIFICANCE; YOUNG ADULTHOOD; SUBSTANCE USE; CONSEQUENCES; TRANSITION; DRINKERS; ABUSE AB Objectives. This study examined long-term response to an individual preventive intervention for highrisk college drinkers relative to the natural history of college drinking. Methods. A single-session, individualized preventive intervention was evaluated within a randomized controlled trial with college freshmen who reported drinking heavily while in high school. An additional group randomly selected from the entire screening pool provided a normative comparison. Participant self-report was assessed annually for 4 years. Results. High-risk controls showed secular trends for reduced drinking quantity and negative consequences without changes in drinking frequency. Those receiving the brief preventive intervention reported significant additional reductions, particularly with respect to negative consequences. Categorical individual change analyses show that remission is normative, and they suggest that participants receiving the brief intervention are more likely to improve and less likely to worsen regarding negative drinking consequences. Conclusions. Brief individual preventive interventions for high-risk college drinkers can achieve longterm benefits even in the context of maturational trends. C1 VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Baer, JS (reprint author), VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, S116-ATC,1660 S Columbian Way, Seattle, WA 98108 USA. FU NIAAA NIH HHS [F32 AA005591, R37 AA05591] NR 43 TC 264 Z9 264 U1 5 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2001 VL 91 IS 8 BP 1310 EP 1316 DI 10.2105/AJPH.91.8.1310 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BT UT WOS:000170345600038 PM 11499124 ER PT J AU Mullins, ME Chao, S Dong, H Slanetz, PJ AF Mullins, ME Chao, S Dong, H Slanetz, PJ TI Posttransplantation non-Hodgkin's lymphoma of the adrenal gland SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID ADENOMAS; CT C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Mullins, ME (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders House, Boston, MA 02114 USA. NR 4 TC 4 Z9 4 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2001 VL 177 IS 2 BP 336 EP 336 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454ZE UT WOS:000170001000013 PM 11461857 ER PT J AU Mullins, ME Stein, J Saini, SS Mueller, PR AF Mullins, ME Stein, J Saini, SS Mueller, PR TI Prevalence of incidental Bochdalek's hernia in a large adult population SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article; Proceedings Paper CT 85th Annual Meeting and Scientific-Assembly-of-the-Radiological-Society-of-North-America CY NOV 28-DEC 03, 1999 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer ID DIAPHRAGMATIC RUPTURE; CT AB OBJECTIVE. The purpose of this study was to determine the prevalence and characteristics of adult Bochdalek's hernia in a large patient population. MATERIALS AND METHODS. We retrospectively reviewed all abdominal CT scans obtained at our hospital in 1998, Patients in our study were identified through a keyword search of our database for "Bochdalek," "hernia," and "diaphragm." The individual patient studies identified were reviewed in a soft-copy format. We noted the location and side of the body on which the diaphragmatic hernia arose and the contents of the sac. We also performed a chart review for each patient included in the study, noting the patient's sex, age, and symptoms. RESULTS. Incidental Bochdalek's hernia was diagnosed in 22 patients (17 women, five men), which represents an incidence of 0.17% based on 13,138 abdominal CT reports we reviewed. The mean age of the patients was 66.6 years. None of the patients were symptomatic. Sixty-eight percent of the hernias were on the right side of the body, 18% were on the left side, and 14% were bilateral. Seventy-three percent contained only fat or omentum, whereas 27% had solid or enteric organ involvement including the spleen, small intestine, or large intestine. CONCLUSION, Bochdalek's hernia is not rare, and the incidence of Bochdalek's hernias that contain enteric tract is higher than previously reported. This incidence likely represents a conservative estimate because some Bochdalek's hernias may have been overlooked or unreported. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Mullins, ME (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders House, Boston, MA 02114 USA. NR 21 TC 73 Z9 82 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2001 VL 177 IS 2 BP 363 EP 366 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454ZE UT WOS:000170001000019 PM 11461863 ER PT J AU Livingston, EH Harwell, JD AF Livingston, EH Harwell, JD TI Peer review SO AMERICAN JOURNAL OF SURGERY LA English DT Editorial Material DE medical staff; privileges; National Practitioners Data Bank; Health Care Quality Improvement Act ID IMMUNITY AB Peer review is essential for ensuring quality medical care. In the 1980s a physician-plaintiff prevailed in lawsuit filed against peer reviewers who excluded the physician from a hospital's medical staff. The peer reviewers had acted to preserve their own economic interests. A multimillion-dollar verdict against the peer reviewers destroyed the community's only multispecialty practice and received national attention. Congress reacted by passing the Health Care Quality Improvement Act that granted sweeping, legal immunity for peer reviewers but also created the National Practitioner's Data Bank. The combination of the establishment of a public repository for physicians malpractice and medical staff privileging activity in combination with the near complete legal protection of peer reviewers has converted peer review from an evaluative to a punitive process. The peer review process and the laws that govern it should be reformed to regain its ability to improve and assure quality without being a, threat to physicians. (C) 2001 Excerpta Medica, Inc. All rights reserved. C1 VA Greater Los Angeles Hlth Care Syst, Dept Surg, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. RP Livingston, EH (reprint author), VA Greater Los Angeles Hlth Care Syst, Dept Surg, Box 95-6904, Los Angeles, CA 90095 USA. NR 15 TC 9 Z9 9 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD AUG PY 2001 VL 182 IS 2 BP 103 EP 109 DI 10.1016/S0002-9610(01)00679-1 PG 7 WC Surgery SC Surgery GA 477PA UT WOS:000171292400001 PM 11574078 ER PT J AU Cubilla, AL Piris, A Pfannl, R Rodriguez, I Aguero, F Young, RH AF Cubilla, AL Piris, A Pfannl, R Rodriguez, I Aguero, F Young, RH TI Anatomic levels: Important landmarks in penectomy specimens - A detailed anatomic and histologic study based on examination of 44 cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE penis; carcinoma; prognostic parameters; depth of invasion; anatomic landmarks ID SQUAMOUS-CELL CARCINOMA; PENIS; LYMPHADENECTOMY; SURVIVAL; SYSTEM; TUMOR; NODES AB The majority of squamous cell carcinomas of the penis arise from the glans, and the prognosis is related significantly to the depth of invasion of crucial anatomic landmarks. Accurate information related to this can only be obtained when specimens are carefully evaluated grossly. Most pathologists in developed countries encounter resected specimens of penile carcinoma infrequently, and gross evaluation is occasionally suboptimal, potentially preventing obtaining reliable prognostic information. The four distinct levels of the glans penis are the epithelium, lamina propria, corpus spongiosum, and corpus cavernosum. A simple method for pathologic, evaluation of the glans is presented. Noteworthy findings in our study of a South American population were that the distance from the lamina propria to tunica albuginea ranged from 7 to 13 to 6 min at the dorsal, central, and ventral areas of the corpus spongiosum, respectively. The most distal portion of the corpus cavernosum was located within the glans in 34 of 44 cases and in the body of the penis in only 10. The corpus spongiosum was thinner in the former cases. These anatomic variations may bear on prognosis. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Inst Patol & Invest, Asuncion, Paraguay. RP Young, RH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 11 TC 30 Z9 30 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2001 VL 25 IS 8 BP 1091 EP 1094 DI 10.1097/00000478-200108000-00016 PG 4 WC Pathology; Surgery SC Pathology; Surgery GA 457VM UT WOS:000170157600016 PM 11474296 ER PT J AU Ullrich, R Roeder, G Lorber, C Quezado, ZMN Kneifel, W Gasser, H Schlag, G Redl, H Germann, P AF Ullrich, R Roeder, G Lorber, C Quezado, ZMN Kneifel, W Gasser, H Schlag, G Redl, H Germann, P TI Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 12th Annual Congress of the European-Society-of-Intensive-Care-Medicine CY OCT 03-06, 1999 CL BERLIN, GERMANY SP European Soc Intens Care Med ID TUMOR-NECROSIS-FACTOR; CONTINUOUS ARTERIOVENOUS HEMOFILTRATION; SEPSIS; SHOCK; INHIBITION; ANTIBODY; FAILURE; THERAPY; VOLUME; MODEL AB Background: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor a, interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CVVH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury Methods. Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CVVH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter. Results. Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CVVH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animal at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterial oxygen tension, 268 +/- 33 vs. 176 +/- 67 mmHg, respectively, P < 0.01). In addition, treatment with CVVH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance. Conclusion: These results suggest that nonspecific blood purification with high-volume CVVH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature. C1 Univ Vienna, Vienna Gen Hosp, Dept Anesthesiol & Gen Crit Care Med, Vienna, Austria. Ludwig Boltzmann Inst Expt & Clin Traumatol, Vienna, Austria. Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. RP Ullrich, R (reprint author), Univ Vienna, Dept Anesthesiol & Gen Intens Care, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 NR 25 TC 25 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2001 VL 95 IS 2 BP 428 EP 436 DI 10.1097/00000542-200108000-00027 PG 9 WC Anesthesiology SC Anesthesiology GA 459EJ UT WOS:000170237800023 PM 11506117 ER PT J AU Raines, DE Claycomb, RJ Scheller, M Forman, SA AF Raines, DE Claycomb, RJ Scheller, M Forman, SA TI Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels SO ANESTHESIOLOGY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; INHALATIONAL GENERAL-ANESTHETICS; TORPEDO POSTSYNAPTIC MEMBRANES; INHALED ANESTHETICS; NEUROBLASTOMA-CELLS; GLYCINE RECEPTORS; DESENSITIZATION; KINETICS; ALCOHOLS; ISOFLURANE AB Background. Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonbalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated. alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and gamma -aminobutyric acid type A (GABA(A)) receptor. Methods. Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA, receptors (alpha (1)beta (2)gamma (21)) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A), receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. Results. Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. Conclusions. Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia, 32 Fruit St, Boston, MA 02114 USA. FU NIAAA NIH HHS [K21-AA00206]; NIGMS NIH HHS [R29-GM53481] NR 41 TC 40 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2001 VL 95 IS 2 BP 470 EP 477 DI 10.1097/00000542-200108000-00032 PG 8 WC Anesthesiology SC Anesthesiology GA 459EJ UT WOS:000170237800028 PM 11506122 ER PT J AU Cydulka, RK Emerman, CL Rowe, BH Clark, S Woodruff, PG Singh, AK Camargo, CA AF Cydulka, RK Emerman, CL Rowe, BH Clark, S Woodruff, PG Singh, AK Camargo, CA CA MARC Invest TI Differences between men and women in reporting of symptoms during an asthma exacerbation SO ANNALS OF EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT American-College-of-Chest-Physicians Annual Meeting CY NOV 10, 1998 CL TORONTO, CANADA SP Amer Coll Chest Physicians ID RESPIRATORY SYMPTOMS; AIRWAY-OBSTRUCTION; PULMONARY-FUNCTION; POPULATION SAMPLE; PERCEPTION; GENDER; AGE; SEX; BREATHLESSNESS; SEVERITY AB Study objective: Compared with men, women presenting to the emergency department with acute asthma are more likely to be admitted and to have a longer hospital stay. This study compares peak expiratory flow rate (PEFR) with reported symptom severity between men and women with acute asthma. The null hypothesis was that men and women report similar severity symptoms for similar levels of airway obstruction. Methods: This study combined data from 4 prospective cohort studies per-formed from 1996 to 1998 as part of the Multicenter Airway Research Collaboration. Using a standardized protocol, investigators at 64 EDs in 21 US states and 4 Canadian provinces provided 24-hour per day coverage for a median of 2 weeks. Results: Of the 1,291 patients with moderate to severe exacerbations (initial percentage of predicted PEFR < 80%), 62% were women. Women were more likely than men to report "severe" complaints in terms of symptom frequency, symptom intensity, and resulting activity limitations (all P < .05). Women with moderate exacerbations were especially likely to describe their exacerbation as causing "severe" activity limitations (sex-PEFR interaction, P = .05). Conclusion: Men are less likely than women to report severe asthma symptoms and activity limitations in the presence of airway obstruction. This finding supports use of objective measures of airway obstruction when managing patients with asthma so that those whose symptoms do not reflect the severity of their obstruction can be recognized and properly treated. It also reconfirms the need for increased research on differences between men and women in acute asthma. C1 Case Western Reserve Univ, Metrohlth Med Ctr, Dept Emergency Med, Cleveland, OH 44109 USA. Univ Alberta Hosp, Div Emergency Med, Edmonton, AB T6G 2B7, Canada. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. RP Cydulka, RK (reprint author), Case Western Reserve Univ, Metrohlth Med Ctr, Dept Emergency Med, 2500 MetroHlth Dr,Room S1-203, Cleveland, OH 44109 USA. NR 35 TC 41 Z9 42 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD AUG PY 2001 VL 38 IS 2 BP 123 EP 128 DI 10.1067/mem.2001.114305 PG 6 WC Emergency Medicine SC Emergency Medicine GA 458MB UT WOS:000170197200002 PM 11468605 ER PT J AU Hebert, JR Peterson, KE Hurley, TG Stoddard, AM Cohen, N Field, AE Sorensen, G AF Hebert, JR Peterson, KE Hurley, TG Stoddard, AM Cohen, N Field, AE Sorensen, G TI The effect of social desirability trait on self-reported dietary measures among multi-ethnic female health center employees SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE nutrition assessment; diet; food; questionnaires; social desirability trait; psychology; education; self-report measures ID DOUBLY-LABELED WATER; FOOD-FREQUENCY QUESTIONNAIRE; ENERGY-INTAKE; UNITED-STATES; VEGETABLE CONSUMPTION; CANCER PREVENTION; BASE-LINE; TREATWELL 5-A-DAY; NUTRIENT INTAKE; OBESE SUBJECTS AB PURPOSE: To evaluate the effect of social desirability trait, the tendency it) respond in a manner consistent with societal expectations, on self-reported fruit, vegetable, and macronutrient intake. METHODS: A 61-item food frequency questionnaire (FFQ), 7-item fruit and vegetable screener, and a single question on combined fruit and vegetable intake were completed by 132 female employees at five health centers in eastern Massachusetts. Intake of fruit and vegetables derived front all three methods and macronutrients from the FFQ were fit as dependent variables in multiple linear regression models (overall and by race/ ethnicity and education); independent variables included 3-day mean intakes derived from 24-hour recalls (24HR) and score on the 33-point Marlowe-Crowne Social Desirability scale (the regression coefficient for which reflects its effect on estimates of dietary intake based on the comparison method relative to 24HR). RESULTS: Results are based on the 93 women with complete data and FFQ-derived Caloric intake between 450 and 4500 kcal/day. In women with college education, FFQ-derived estimates of total caloric were associated with under- reporting by social desirability trait (e.g., the regression coefficient for total caloric intake was -23.6 kcal/day/point in that group versus 36.1 kcal/day/point in women with education less than college) (difference = 59.7 kcal/day/point, 95% confidence interval (CI) = 13.2, 106,2). Except for the single question on which women,vith college education tended to under-report (difference =.103 servings/day/point, 95% Cl 0.003, 0.203), there was no association of social desirability trait with self-reported fruit and vegetable intake. CONCLUSIONS: The effect of social desirability trait on FFQ reports of macronutrient intake appeared to differ by education, but not by ethnicity or race. The results of this study may have important implications for epidemiologic studies of diet and health in women. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Univ S Carolina, Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. Univ S Carolina, Sch Publ Hlth, Nutr Ctr, Columbia, SC 29208 USA. Harvard Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA USA. Univ Massachusetts, Dept Nutr, Amherst, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Hebert, JR (reprint author), Univ S Carolina, Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. FU NCI NIH HHS [5 RO1 CA59728]; NIDDK NIH HHS [DK46200] NR 86 TC 63 Z9 65 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2001 VL 11 IS 6 BP 417 EP 427 DI 10.1016/S1047-2797(01)00212-5 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 459WK UT WOS:000170274300008 PM 11454501 ER PT J AU Dellon, AL Dellon, ES Tassler, PL Ellefson, RD Hendrickson, M AF Dellon, AL Dellon, ES Tassler, PL Ellefson, RD Hendrickson, M TI Experimental model of pyridoxine (B-6) deficiency-induced neuropathy SO ANNALS OF PLASTIC SURGERY LA English DT Article ID CARPAL-TUNNEL SYNDROME; VITAMIN-B-6 DEFICIENCY; SENSORY NEUROPATHY; TRACK ANALYSIS; THERAPY; RAT AB A pyridoxine (B-6) dietary deficiency was studied in female adult Sprague-Dawley rats by hind-limb walking-track analysis. Serum levels of pyridoxine and three metabolites were quantified by high-pressure liquid chromatography with fluorescence measurement. Morphometric analysis of the sciatic and posterior tibia[ nerves (from within the tarsal tunnel) was performed after I year on a diet deficient in vitamin B-6. The B-6-deficient rats developed abnormal walking-track patterns by 8 months, and these track parameters were different from age- and sex-matched normal diet control rats at the p < 0.05 level. Adding B-6 at 10 parts per million to the diet then partially corrected these parameters, whereas the addition of 30 parts per million B-6 corrected the abnormal pattern completely. Serum pyridoxal concentration correlated with the functional parameters, dropping from a mean of 115 mg per liter to 39.5 mg per liter (p < 0.05), and correcting with the B-6 additive. Morphometric analysis demonstrated that the B-6-deficient nerve from the tarsal tunnel had a decreased nerve fiber density (p < 0.001), with a normal total myelinated nerve fiber number, and an increased axon-to-myelin ratio (p < 0.003). It is concluded that a diet totally deficient in vitamin B-6 results in a peripheral neuropathy. C1 Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Johns Hopkins Univ, Sch Med, Div Plast Surg & Neurosurg, Baltimore, MD USA. Dept Hyg & Publ Hlth, Burlington, VT USA. Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. Cleveland Clin, Cleveland, OH 44106 USA. RP Dellon, AL (reprint author), Suite 370,3333 N Calvert St, Baltimore, MD 21218 USA. NR 40 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD AUG PY 2001 VL 47 IS 2 BP 153 EP 160 DI 10.1097/00000637-200108000-00008 PG 8 WC Surgery SC Surgery GA 461BB UT WOS:000170344100009 PM 11506323 ER PT J AU Esnaola, NF Rubin, BP Baldini, EH Vasudevan, N Demetri, GD Fletcher, CDM Singer, S AF Esnaola, NF Rubin, BP Baldini, EH Vasudevan, N Demetri, GD Fletcher, CDM Singer, S TI Response to chemotherapy and predictors of survival in adult rhabdomyosarcoma SO ANNALS OF SURGERY LA English DT Article ID INTERGROUP RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; EXPERIENCE; SARCOMAS; THERAPY AB Objective To assess outcome and identify predictors of survival of adults with rhabdomyosarcoma. Summary Background Data The literature on adult rhabdomyosarcoma is limited. Few studies have identified predictors of long-term survival in this patient population. Methods Thirty-nine adults with rhabdomyosarcoma were treated between 1973 and 1996 and prospectively followed. Outcomes were assessed with respect to patient and tumor characteristics, local treatment, and response to chemotherapy. Results Twenty-six patients had localized/locoregional disease and 13 patients had metastatic disease at presentation. Twenty-one patients underwent attempted curative resection, 27 received radiotherapy, and 37 received chemotherapy. Median follow-up for surviving patients was 152 months. The overall 5- and 10-year survival rates were 31 % and 27%, respectively. Five-year survival rates for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 60%, 14%, and 0%, respectively. Patients with localized/locoregional disease at presentation had a 44% 5-year survival rate; there were no 5-year survivors among patients with metastatic disease. Patients who had a complete response to chemotherapy had a 5-year survival rate of 57%, compared with a rate of only 7% for poor responders. Metastatic disease at presentation and poor response to chemotherapy were independent predictors of death on multivariate analysis. Conclusions Age, location, nodal status, and histologic subtype do not appear be associated with survival in adults with rhabdomyosarcoma treated with multimodal therapy. Metastatic disease at presentation and poor response to chemotherapy are strongly associated with poor prognosis. Future systemic therapies should be targeted to patients with localized/locoregional disease and partial responders to conventional chemotherapy. C1 Brigham & Womens Hosp, Div Surg Oncol, Dept Surg Radiat Oncol & Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Singer, S (reprint author), Brigham & Womens Hosp, Div Surg Oncol, Dept Surg Radiat Oncol & Pathol, 75 Francis St, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA75720-01] NR 27 TC 52 Z9 55 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD AUG PY 2001 VL 234 IS 2 BP 215 EP 223 DI 10.1097/00000658-200108000-00012 PG 9 WC Surgery SC Surgery GA 457GR UT WOS:000170129200012 PM 11505068 ER PT J AU Vlahakes, GJ AF Vlahakes, GJ TI Influence of anterior mitral leaflet second-order chordae on leaflet dynamics and valve competence - Invited commentary SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Vlahakes, GJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,BUL 119, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2001 VL 72 IS 2 BP 541 EP 541 DI 10.1016/S0003-4975(01)02853-3 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 462UC UT WOS:000170437300057 ER PT J AU Fuchs, JR Nasseri, BA Vacanti, JP AF Fuchs, JR Nasseri, BA Vacanti, JP TI Tissue engineering: A 21st century solution to surgical reconstruction SO ANNALS OF THORACIC SURGERY LA English DT Article ID ESOPHAGEAL EPITHELIAL-CELLS; BIOENGINEERED CARDIAC GRAFTS; BIOPROSTHETIC HEART-VALVE; POLYGLYCOLIC ACID MESH; GROWN IN-VITRO; ARTIFICIAL ESOPHAGUS; BIODEGRADABLE POLYMERS; INFARCTED MYOCARDIUM; CELLULAR CARDIOMYOPLASTY; TRACHEAL RECONSTRUCTION AB Tissue engineering has emerged as a rapidly expanding approach to address the organ shortage problem. It is an "interdisciplinary field that applies the principles and methods of engineering and the life sciences toward the development of biological substitutes that can restore, maintain, or improve tissue function." Much progress has been made in the tissue engineering of structures relevant to cardiothoracic surgery, including heart valves, blood vessels, myocardium, esophagus, and trachea. (C) 2001 by The Society of Thoracic Surgeons. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Vacanti, JP (reprint author), Massachusetts Gen Hosp, Dept Surg, Warren 1157,55 Fruit St, Boston, MA 02114 USA. NR 98 TC 201 Z9 246 U1 2 U2 39 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2001 VL 72 IS 2 BP 577 EP 591 DI 10.1016/S0003-4975(01)02820-X PG 15 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 462UC UT WOS:000170437300066 PM 11515900 ER PT J AU Markus, R Huzaira, M Anderson, RR Gonzalez, S AF Markus, R Huzaira, M Anderson, RR Gonzalez, S TI A better potassium hydroxide preparation? In vivo diagnosis of tinea with confocal microscopy SO ARCHIVES OF DERMATOLOGY LA English DT Article ID SCANNING LASER MICROSCOPY; IN-VIVO; ROUTINE HISTOLOGY; HUMAN SKIN; ONYCHOMYCOSIS AB Background: Traditional diagnostic testing for dermatophyte infection currently requires skin scraping for light microscopy and/or fungal culture or skin biopsy. Immunofluorescent microscopy can also be used with calcofluor stain. All of these tests can be time-consuming to perform, require a waiting period for results, and are invasive. We investigated the use of a real-time, noninvasive, confocal microscope in visualizing dermatophyte hyphae in vivo. Observations: Confocal microscopic imaging of active tinea can clearly identify dermatophyte hyphae within the upper epidermis after potassium hydroxide application. The hyphae appear as bright linear branching objects not found in uninvolved skin. Conclusions: it is possible to immediately and painlessly image dermatophyte hyphae in active lesions of tinea by means of a confocal microscope. With further improvement, imaging devices may be available to physicians to instantly and noninvasively evaluate a variety of skin disorders in microscopic detail. C1 Harvard Univ, Dept Dermatol, Wellman Labs Photomed, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Harvard Univ, Dept Dermatol, Wellman Labs Photomed, Massachusetts Gen Hosp, Bartlett Hall 814,55 Blossom St, Boston, MA 02114 USA. NR 14 TC 24 Z9 28 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2001 VL 137 IS 8 BP 1076 EP 1078 PG 3 WC Dermatology SC Dermatology GA 461MD UT WOS:000170367300009 PM 11493101 ER PT J AU Kroumpouzos, G Margolis, RJ Cohen, LM AF Kroumpouzos, G Margolis, RJ Cohen, LM TI Crusted erythematous postauricular plaques - Localized bullous SLE. SO ARCHIVES OF DERMATOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS C1 Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. Tufts Univ, Sch Med, New England Med Ctr, Boston, MA 02111 USA. RP Kroumpouzos, G (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. OI Kroumpouzos, George/0000-0002-5915-4640 NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2001 VL 137 IS 8 BP 1095 EP + PG 2 WC Dermatology SC Dermatology GA 461MD UT WOS:000170367300024 PM 11493105 ER PT J AU Spencer, T Biederman, J Wilens, T Faraone, S Prince, J Gerard, K Doyle, R Parekh, A Kagan, J Bearman, SK AF Spencer, T Biederman, J Wilens, T Faraone, S Prince, J Gerard, K Doyle, R Parekh, A Kagan, J Bearman, SK TI Efficacy of a mixed amphetamine salts compound in adults with attention-deficit/hyperactivity disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the New-Clinical-Drug-Evaluation-Unit CY JUN 01-04, 1999 CL BOCA RATON, FLORIDA SP New Clin Drug Evaluat Unit ID DEFICIT HYPERACTIVITY DISORDER; MINIMAL BRAIN-DYSFUNCTION; SUSTAINED-RELEASE; STANDARD METHYLPHENIDATE; DOUBLE-BLIND; CONTROLLED TRIAL; CHILDREN; DEXTROAMPHETAMINE; PLACEBO; PEMOLINE AB Background: We report on a controlled trial of a mixed amphetamine salts compound (Adderall, dextroamphetamine sulfate, dextro-, levoamphetamine sulfate, dextroamphetamine aspartate, levoamphetamine aspartate, and dextroamphetamine saccharate) in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Methods: This was a 7-week, randomized, double-blind, placebo-controlled, crossover study of Adderall in 27 well-characterized adults satisfying full DSM-IV criteria for ADHD of childhood onset and persistent symptoms into adulthood. Medication was titrated up to 30 mg twice a day. Outcome measures included the ADHD Rating Scale and the Clinical Global Impression Score. Comorbid psychiatric disorders were assessed to test for potential effects on treatment outcome. Results: Treatment with Adderall at an average oral dose of 54 mg (administered in 2 daily doses) was effective and well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall (42% decrease on the ADHD Rating Scale, P < .001), and sufficiently robust to be detectable in a parallel groups comparison restricted to the first 3 weeks of the protocol (P < .001). The percentage of subjects who improved (reduction in the ADHD rating scale of greater than or equal to 30%) was significantly higher with Adderall. treatment than with a placebo (70% vs 7%; P=.001). Conclusions: Adderall was effective and well tolerated in the short-term treatment of adults with ADHD. More work is needed to evaluate the long-term effects of Adderall, or other amphetamine compounds, in the treatment of adults with ADHD. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit ACC725, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Spencer, T (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit ACC725, Fruit St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R29MH57511] NR 53 TC 163 Z9 166 U1 5 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2001 VL 58 IS 8 BP 775 EP 782 DI 10.1001/archpsyc.58.8.775 PG 8 WC Psychiatry SC Psychiatry GA 459JH UT WOS:000170246900009 PM 11483144 ER PT J AU Seddon, JM Rosner, B Sperduto, RD Yannuzzi, L Haller, JA Blair, NP Willett, W AF Seddon, JM Rosner, B Sperduto, RD Yannuzzi, L Haller, JA Blair, NP Willett, W TI Dietary fat and risk for advanced age-related macular degeneration SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; CORONARY HEART-DISEASE; MACULOPATHY; REPRODUCIBILITY; WOMEN AB Objective: To evaluate the relationship between intake of total and specific types of fat and risk for advanced age-related macular degeneration (AMD), the leading cause of irreversible blindness in adults. Design: A multicenter eye disease case-control study Setting: Five US clinical ophthalmology centers. Patients: Case subjects included 349 individuals (age range, 55-80 years) with the advanced, neovascular stage of AMD diagnosed within 1 year of their enrollment into the study who resided near a participating clinical center. Control subjects included 504 individuals without AMD but with other ocular diseases. Controls were from the same geographic areas as cases and were frequency-matched to cases by age and sex. Main Outcome Measures: Relative risk for AMD according to level of fat intake, controlling for cigarette smoking and other risk factors. Results: Higher vegetable fat consumption was associated with an elevated risk for AMD. After adjusting for age, sex, education, cigarette smoking, and other risk factors, the odds ratio (OR) was 2.22 (95% confidence interval [ CI] 1.32-3.74) for persons in the highest vs those in the lowest quintiles of intake (P for trend, .007). The risk for AMD was also significantly elevated for the highest vs lowest quintiles of intake of monounsaturated (OR, 1.71) and polyunsaturated (OR, 1.86) fats (Ps for trend, .03 and .03, respectively). Higher consumption of linoleic acid was also associated with a higher risk for AMD (P for trend, .02). Higher intake of omega -3 fatty acids was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an omega -6 fatty acid (P for trend, .05; P for continuous variable,.03). Similarly, higher frequency of fish intake tended to reduce risk for AMD when the diet was low in linoleic acid (P for trend, .05). Conversely, neither omega -3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake. Conclusion: Higher intake of specific types of fat-including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid-rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega -3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Epidemiol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NEI, Dept Epidemiol & Clin Res, Bethesda, MD 20892 USA. Manhattan Eye Ear & Throat Hosp, Dept Ophthalmol, New York, NY 10021 USA. Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. Univ Illinois, Chicago, IL USA. RP Seddon, JM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Epidemiol Unit, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY09972] NR 21 TC 222 Z9 234 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2001 VL 119 IS 8 BP 1191 EP 1199 PG 9 WC Ophthalmology SC Ophthalmology GA 460GD UT WOS:000170299100013 PM 11483088 ER PT J AU Sankar, PS Pasquale, LR Grosskreutz, CL AF Sankar, PS Pasquale, LR Grosskreutz, CL TI Uveal effusion and secondary angle-closure glaucoma associated with topiramate use SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article C1 Massachusetts Eye & Ear Infirm, Glaucoma Consultat Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Grosskreutz, CL (reprint author), Massachusetts Eye & Ear Infirm, Glaucoma Consultat Serv, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. NR 4 TC 52 Z9 58 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2001 VL 119 IS 8 BP 1210 EP 1211 PG 2 WC Ophthalmology SC Ophthalmology GA 460GD UT WOS:000170299100019 PM 11483094 ER PT J AU Spiegel, JH Deschler, DG Cheney, ML AF Spiegel, JH Deschler, DG Cheney, ML TI Microvascular transplantation and replantation of the rabbit submandibular gland SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID SALIVARY-GLAND; FLOW-RATES; DRY EYE; HEAD; RADIOPROTECTION; AMIFOSTINE; XEROSTOMIA; RADIATION AB Background: Xerostomia is a devastating complication of radiation therapy. Previous research has demonstrated that submandibular glands may be removed from the neck and transplanted using microvascular techniques, with good gland survival. However, microvascular transplantation and replantation has never been attempted on a composite tissue such as a salivary gland. Objective: To evaluate the ability of a rabbit submandibular gland to undergo 2 successive microvascular transplantations. Subjects and Design: Study rabbits underwent a midline neck incision with dissection of a submandibular gland to its arterial and venous pedicle. Microvascular techniques were then used to transplant the gland to the femoral system of the right groin. The incisions were reopened later under surgical conditions. The transferred gland was examined for survival and patency of its artery and vein. Healthy glands were dissected and transferred to a suitable artery and vein within the neck, where they were again reanastamosed using microvascular surgical techniques. After additional time, the gland was again examined for survival and pedicle patency, then removed and evaluated for histopathological evidence of survival. Results: Surgical technique evolved during the course of this work to avoid encountered pitfalls. After refining the technique, we have determined that the rabbit submandibular gland is able to mdthstandsuccessivemicrovascular transplantation and replantation with good likelihood of longterm survival, according to histopathological criterial. Conclusions: The rabbit submandibular gland is able to undergo microvascular transplantation and replantation with evidence of long-term survivability and preserved function. The body's natural response to surgery and tissue transplantation makes replantation a technical challenge; however, methods delineated herein alleviate many of the potential pitfalls. Extending these results to humans, patients who are to undergo radiation therapy could have a disease-free gland removed from the neck, transferred outside of the field of radiation, and then returned to the neck at the completion of radiation therapy. This may enable them to maintain salivary gland function and maintain oral cavity function and comfort. C1 Boston Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Facial Plast & Reconstruct Surg, Boston, MA 02118 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02115 USA. RP Spiegel, JH (reprint author), Boston Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Facial Plast & Reconstruct Surg, D-616,88 E Newton St, Boston, MA 02118 USA. NR 31 TC 10 Z9 10 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD AUG PY 2001 VL 127 IS 8 BP 991 EP 996 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 459JB UT WOS:000170246300015 PM 11493212 ER PT J AU Johnson, KL Nelson, JL Furst, DE McSweeney, PA Roberts, DJ Zhen, DK Bianchi, DW AF Johnson, KL Nelson, JL Furst, DE McSweeney, PA Roberts, DJ Zhen, DK Bianchi, DW TI Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID PREGNANCY; DISEASE; SKIN; DNA AB Objective. The realization that fetal cells pass into the maternal circulation and can survive for many years has raised the question of whether fetal microchimerism can cause subsequent disease in the mother. Available data suggest that fetal-maternal transfusion may be related to some autoimmune diseases, notably systemic sclerosis (SSc). The goal of the current work was to identify and quantify tissue-specific fetal microchimerism in women with SSc. Methods. We analyzed multiple tissue specimens obtained at autopsy from women with SSc as well as women who had died of causes unrelated to autoimmunity, using fluorescence in situ hybridization to detect the presence of male cells in women with sons. Tissues analyzed included adrenal gland, heart, intestine, kidney, liver, lung, lymph node, pancreas, parathyroid, skin, and spleen. Results. Male cells were observed in tissue from at least 1 site in each woman with SSc and were found most frequently in spleen sections. After spleen, male cells were observed most frequently in lymph node, lung, adrenal gland, and skin tissue. The only tissue type in which male cells were not seen in any patient was pancreatic tissue. Male cells were not observed in tissue from women who had died of causes unrelated to autoimmunity. Conclusion. The results of this study suggest that fetal cells migrate from the peripheral circulation into multiple organs in women with SSc. All of the women studied had previously given birth to sons, so it is likely that these cells are of fetal origin. While the relevance of this finding to the pathogenesis of SSc remains to be elucidated, the presence of fetal cells in internal organs suggests that they could play a role in disease pathogenesis and that they may preferentially sequester in the spleen. The presence of these male cells may also be a result of disease, possibly through the migration of terminally differentiated and/or progenitor cells to areas of tissue damage. C1 Tufts Univ, Sch Med, Dept Pediat, Div Genet, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Seattle, WA 98195 USA. Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Colorado, Denver, CO 80202 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bianchi, DW (reprint author), Tufts Univ, Sch Med, Dept Pediat, Div Genet, NEMC 394,750 Washington St, Boston, MA 02111 USA. FU NIAID NIH HHS [AI-41721]; NICHD NIH HHS [HD-07492, HD-43204] NR 14 TC 91 Z9 98 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2001 VL 44 IS 8 BP 1848 EP 1854 DI 10.1002/1529-0131(200108)44:8<1848::AID-ART323>3.0.CO;2-L PG 7 WC Rheumatology SC Rheumatology GA 498BZ UT WOS:000172491100019 PM 11508438 ER PT J AU Whittal, ML Otto, MW Hong, JJ AF Whittal, ML Otto, MW Hong, JJ TI Cognitive-behavior therapy for discontinuation of SSRI treatment of panic disorder: a case series SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article ID LONGITUDINAL COURSE; ALPRAZOLAM; AGORAPHOBIA; METAANALYSIS; WITHDRAWAL; EFFICACY AB In this report we describe the outcome of eight outpatients with panic disorder and agoraphobia who discontinued their treatment with a selective serotonin reuptake inhibitor (SSRI) in the context of a structured, group program of cognitive-behavior therapy. All patients successfully discontinued their SSRI medication while demonstrating clinical improvement. These results were maintained at 3-month follow-up. This case series suggests that manualized CBT for discontinuation of benzodiazepine treatment for panic disorder may be successfully applied to SSRI discontinuation as well. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ British Columbia Hosp, Anxiety Disorders Unit, Vancouver, BC V6T 2B5, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Whittal, ML (reprint author), Univ British Columbia Hosp, Anxiety Disorders Unit, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 32 TC 25 Z9 27 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD AUG PY 2001 VL 39 IS 8 BP 939 EP 945 DI 10.1016/S0005-7967(00)00067-X PG 7 WC Psychology, Clinical SC Psychology GA 456NK UT WOS:000170088800006 PM 11480834 ER PT J AU Brody, AL Saxena, S Mandelkern, MA Fairbanks, LA Ho, ML Baxter, LR AF Brody, AL Saxena, S Mandelkern, MA Fairbanks, LA Ho, ML Baxter, LR TI Brain metabolic changes associated with symptom factor improvement in major depressive disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE positron emission tomography; major depression; anxiety; psychomotor retardation; prefrontal cortex; anterior cingulate gyrus ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; GLUCOSE-METABOLISM; DOUBLE-BLIND; FUNCTIONAL NEUROANATOMY; PREFRONTAL CORTEX; MOOD DISORDERS; ANXIETY; PLACEBO; SADNESS AB Background: Symptoms of major depressive disorder (MDD) have been linked to regional brain function through imaging studies of symptom provocation in normal control subjects and baseline studies of subjects with MDD. We examined associations between change in depressive symptom factors and change in regional brain metabolism from before to after treatment of MDD. Methods: Thirty-nine outpatients with MDD underwent F-18-fluorodeoxyglucose positron emission tomography scanning before and after treatment with either paroxetine or interpersonal psychotherapy. Associations were determined between changes in regional brain metabolism and changes in four Hamilton Depression Rating Scale factors (anxiety/somatization [ANX], psychomotor retardation [PR], cognitive disturbance [COGN], and sleep disturbance and two corresponding Profile of Mood States subscales (tension [TENS] and fatigue [FATIG]). Results: Improvement in ANX, PR, TENS, and FATIG,factors was associated with decreasing ventral frontal lobe metabolism. Improvement in ANX and TENS was also associated with decreasing ventral anterior cingulate gyrus (AC) and anterior insula activity, whereas improvement in PR was associated with increasing dorsal AC activity. COGN improvement was associated with increasing dorsolateral prefrontal cortex metabolism. Conclusions: Brain regions that show significant relationships with symptom provocation in normal control subjects have similar relationships with MDD symptoms as they improve with treatment. (C) 2001 Society of Biological Psychiatry. C1 Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Med & Mol Pharmacol, Los Angeles, CA 90095 USA. Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. Univ Calif Irvine, Dept Phys, Irvine, CA USA. Univ Alabama, Sch Med, Dept Psychiat & Behav Neurobiol, Birmingham, AL USA. RP Brody, AL (reprint author), Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, 300 UCLA Med Plaza,Suite 2340, Los Angeles, CA 90095 USA. FU NIMH NIH HHS [R01 MH-53565] NR 48 TC 130 Z9 137 U1 4 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2001 VL 50 IS 3 BP 171 EP 178 DI 10.1016/S0006-3223(01)01117-9 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 463AJ UT WOS:000170454400003 PM 11513815 ER PT J AU Pastor-Soler, N Bagnis, C Sabolic, I Tyszkowski, R McKee, M Van Hoek, A Breton, S Brown, D AF Pastor-Soler, N Bagnis, C Sabolic, I Tyszkowski, R McKee, M Van Hoek, A Breton, S Brown, D TI Aquaporin 9 expression along the male reproductive tract SO BIOLOGY OF REPRODUCTION LA English DT Article DE epididymis; epithelial transport; male reproductive tract ID NEUTRAL SOLUTE CHANNEL; RAT CAUDA-EPIDIDYMIDIS; CHIP28 WATER CHANNEL; MOLECULAR CHARACTERIZATION; EFFERENT DUCTS; TRANSPORT; LOCALIZATION; SECRETION; VESICLES; KIDNEY AB Fluid movement across epithelia lining portions of the male reproductive tract is important for modulating the luminal environment in which sperm mature and reside, and for increasing sperm concentration. Some regions of the male reproductive tract express aquaporin (AQP) 1 and/or AQP2, but these transmembrane water channels are not detectable in the epididymis. Therefore, we used a specific antibody to map the cellular distribution of another AQP, AQP9 (which is permeable to water and to some solutes), in the male reproductive tract. AQP9 is enriched on the apical (but not basolateral) membrane of nonciliated cells in the efferent duct and principal cells of the epididymis (rat and human) and vas deferens, where it could play a role in fluid reabsorption. Western blotting revealed a strong 30-kDa band in brush-border membrane vesicles isolated from the epididymis. AQP9 is also expressed in epithelial cells of the prostate and coagulating gland where fluid transport across the epithelium is important for secretory activity. However, it was undetectable in the seminal vesicle, suggesting that an alternative fluid transport pathway may be present in this tissue. Intracellular vesicles in epithelial cells along the reproductive tract were generally poorly stained for AQP9. Furthermore, the apical membrane distribution of AQP9 was unaffected by microtubule disruption. These data suggest that AQP9 is a constitutively inserted apical membrane protein and that its cell-surface expression is not acutely regulated by vesicular trafficking. AQP9 was detectable in the epididymis and vas deferens of 1-wk postnatal rats, but its expression was comparable with adult rats only after 3-4 wk. AQP9 could provide a route via which apical fluid and solute transport occurs in several regions of the male reproductive tract. The heterogenous and segment-specific expression of AQP9 and other aquaporins along the male reproductive tract shown in this and in our previous studies suggests that fluid reabsorption and secretion in these tissues could be locally modulated by physiological regulation of AQP expression and/or function. C1 Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Renal Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Inst Med Res & Occupat Hlth, Unit Mol Toxicol, Zagreb 10001, Croatia. RP Brown, D (reprint author), Massachusetts Gen Hosp East, Program Membrane Biol Renal Unit, 149 13th St, Charlestown, MA 02129 USA. FU FIC NIH HHS [TW01057]; NICHD NIH HHS [HD08684]; NIDDK NIH HHS [DK55864, DK38452, DK43351, DK57521] NR 49 TC 98 Z9 104 U1 1 U2 3 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 2001 VL 65 IS 2 BP 384 EP 393 DI 10.1095/biolreprod65.2.384 PG 10 WC Reproductive Biology SC Reproductive Biology GA 458QH UT WOS:000170205700007 PM 11466204 ER PT J AU Ghia, P Transidico, P Veiga, JP Schaniel, C Sallusto, F Matsushima, K Sallan, SE Rolink, AG Mantovani, A Nadler, LM Cardoso, AA AF Ghia, P Transidico, P Veiga, JP Schaniel, C Sallusto, F Matsushima, K Sallan, SE Rolink, AG Mantovani, A Nadler, LM Cardoso, AA TI Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells SO BLOOD LA English DT Article ID MACROPHAGE-DERIVED CHEMOKINE; ACUTE LYMPHOBLASTIC-LEUKEMIA; DENDRITIC CELLS; ANTITUMOR IMMUNITY; CC-CHEMOKINE; ENDOTHELIAL-CELLS; GENE-EXPRESSION; SERIAL ANALYSIS; UP-REGULATION; CUTTING EDGE AB The use of tumor cells as vaccines in cancer immunotherapy is critically dependent on their capacity to initiate and amplify tumor-specific immunity. Optimal responses may require the modification of the tumor cells not only to increase their Immunogenicity but also to improve their ability to recruit effector cells to the tumor sites or sites of tumor antigen exposure. It has been reported that CD40 crosslinking of acute lymphoblastic leukemia (ALL) cells significantly increases their immunogenicity and allows the generation and expansion of autologous antileukemia cytotoxic T lymphocytes. This study demonstrates that the CD40 ligation of these tumor cells also induces the secretion of the CC-chemokines MDC and TARC. Supernatants from malignant cells cultured In the presence of sCD40L promote the migration of activated T cells that express CCR4, the common specific receptor for MDC and TARC. More importantly, the supernatants from CD40-immunogenicity and allows the generation and expansion of autologous antileukemia cytotoxic T lymphocytes. This study demonstrates that the CD40 ligation of these tumor cells also induces the secretion of the CC-chemokines MDC and TARC. Supernatants from malignant cells cultured In the presence of sCD40L promote the migration of activated T cells that express CCR4, the common specific receptor for MDC and TARC. More importantly, the supernatants from CD40-stimulated tumor cells also support the transendothelial migration of autologous CCR4(+) antileukemia T cells. Therefore, the results demonstrate that the delivery to leukemia cells of a single physiologic signal, that is, CD40 cross-linking, simultaneously improves tumor cell immunogenicity and induces potent chemoattraction for T cells. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol & Pediat Oncol, Boston, MA 02115 USA. Osped Mauriziano Umberto 1, Ist Ric Cura Canc, Candiolo, Italy. Univ Turin, Candiolo, Italy. Ist Ric Farmacol Mario Negri, Milan, Italy. Basel Inst Immunol, Basel, Switzerland. Tokyo Med Sch, Tokyo, Japan. RP Cardoso, AA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol & Pediat Oncol, Rm D-540B,44 Binney St, Boston, MA 02115 USA. RI Schaniel, Chrisoph/C-9655-2012; Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Mantovani, Alberto/0000-0001-5578-236X FU NCI NIH HHS [P01-CA66996, P01-CA68484] NR 55 TC 48 Z9 48 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 533 EP 540 DI 10.1182/blood.V98.3.533 PG 8 WC Hematology SC Hematology GA 456QY UT WOS:000170094800008 PM 11468146 ER PT J AU Stone, RM Berg, DT George, SL Dodge, RK Paciucci, PA Schulman, PP Lee, EJ Moore, JO Powell, BL Baer, MR Bloomfield, CD Schiffer, CA AF Stone, RM Berg, DT George, SL Dodge, RK Paciucci, PA Schulman, PP Lee, EJ Moore, JO Powell, BL Baer, MR Bloomfield, CD Schiffer, CA TI Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; ACUTE MYELOGENOUS LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; TREATMENT-OF-CANCER; SOUTHWEST-ONCOLOGY-GROUP; COOPERATIVE GROUP; PHASE-III; ELDERLY PATIENTS; CONSOLIDATION THERAPY; REMISSION INDUCTION AB The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/ mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/ mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. CALGB Stat Ctr, Durham, NC USA. Mt Sinai Sch Med, New York, NY USA. N Shore Univ Hosp, Manhasset, NY USA. Sinai Hosp, Baltimore, MD 21215 USA. Duke Univ, Med Ctr, Durham, NC USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, Rm D-840,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA47642, CA02599, CA03927, CA04326, CA04457, CA07968, CA08025, CA11028, CA11789, CA12449, CA16450, CA21060, CA26806, CA31809, CA31946, CA31983, CA32291, CA33601, CA35279, CA35406, CA35421, CA37135, CA45374, CA45400, CA45418, CA45564, CA45808, CA47545, CA47555, CA47559, CA47577, CA52784, CA54389, CA77440, CA77658] NR 39 TC 127 Z9 128 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 548 EP 553 DI 10.1182/blood.V98.3.548 PG 6 WC Hematology SC Hematology GA 456QY UT WOS:000170094800010 PM 11468148 ER PT J AU Anderson, JE Tefferi, A Craig, F Holmberg, L Chauncey, T Appelbaum, FR Guardiola, P Callander, N Freytes, C Gazitt, Y Razvillas, B Deeg, HJ AF Anderson, JE Tefferi, A Craig, F Holmberg, L Chauncey, T Appelbaum, FR Guardiola, P Callander, N Freytes, C Gazitt, Y Razvillas, B Deeg, HJ TI Myeloablation and autologous peripheral blood stem cell rescue results in hematologic and clinical responses in patients with myeloid metaplasia with myelofibrosis SO BLOOD LA English DT Article ID BONE-MARROW FIBROSIS; IDIOPATHIC MYELOFIBROSIS; MYELOPROLIFERATIVE DISORDERS; PROGENITOR CELLS; SECONDARY MYELOFIBROSIS; PROGNOSTIC FACTORS; SCORING SYSTEM; TRANSPLANTATION; PROLIFERATION; EXPERIENCE AB Current therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 X 10(6) (range 0 to 410 x 10(6)) CD34(+) cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to greater than or equal to 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival Is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin greater than or equal to 100 g/L [10 gm/dL] without transfusion for greater than or equal to 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 x 10(9)/L (100 000/muL) responded with a durable platelet count more than 100 x 10(9)/L (100 000/muL). Symptomatic splenomegaly improved In 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation In most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Hematol, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. Mayo Clin & Mayo Fdn, Div Hematol, Rochester, MN 55905 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Univ Washington, Sch Med, Seattle, WA USA. Seattle Vet Adm Hosp, Seattle, WA USA. Hop St Louis, Paris, France. RP Anderson, JE (reprint author), Katmai Oncol Grp, 3260 Providence Dr,Suite 526, Anchorage, AK 99508 USA. FU NCI NIH HHS [CA-18029, CA-87948]; NHLBI NIH HHS [HL-36444] NR 25 TC 50 Z9 54 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 586 EP 593 DI 10.1182/blood.V98.3.586 PG 8 WC Hematology SC Hematology GA 456QY UT WOS:000170094800016 PM 11468154 ER PT J AU Traver, D Miyamoto, T Christensen, J Iwasaki-Arai, J Akashi, K Weissman, IL AF Traver, D Miyamoto, T Christensen, J Iwasaki-Arai, J Akashi, K Weissman, IL TI Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; RESTRICTED TRANSCRIPTION FACTOR; COMMON MYELOID PROGENITOR; T-CELL; YOLK-SAC; IN-VITRO; C-MYB; GENE-EXPRESSION; DEFICIENT MICE; FACTOR GATA-1 AB Hematopoietic fate maps in the developing mouse embryo remain imprecise. Definitive, adult-type hematopoiesis first appears in the fetal liver, then progresses to the spleen and bone marrow. Clonogenic common lymphoid progenitors and clonogenic common myeloid progenitors (CMPs) in adult mouse bone marrow that give rise to all lymphoid and myeloid lineages, respectively, have recently been identified. Here it is shown that myelopoiesis in the fetal liver similarly proceeds through a CMP equivalent. Fetal liver CMPs give rise to megakaryocyte erythrocyte-restricted progenitors (MEPs) and granulocyte-monocyte-restricted progenitors (GMPs) that can also be prospectively isolated by cell surface phenotype. MEPs and GMPs generate mutually exclusive cell types in clonogenic colony assays and in transplantation experiments, suggesting that the lineage restriction observed within each progenitor subset is absolute under normal conditions. Purified progenitor populations were used to analyze expression profiles of various hematopoiesis-related genes. Expression patterns closely matched those of the adult counterpart populations. These results suggest that adult hematopoietic hierarchies are determined early in the development of the definitive immune system and suggest that the molecular mechanisms underlying cell fate decisions within the myeloerythroid lineages are conserved from embryo to adult. C1 Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Traver, D (reprint author), Childrens Hosp, Enders 650,320 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA42551]; NIAID NIH HHS [5T32 AI-07290] NR 74 TC 82 Z9 83 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 627 EP 635 DI 10.1182/blood.V98.3.627 PG 9 WC Hematology SC Hematology GA 456QY UT WOS:000170094800022 PM 11468160 ER PT J AU Baek, KH Mondoux, MA Jaster, R Fire-Levin, E D'Andrea, AD AF Baek, KH Mondoux, MA Jaster, R Fire-Levin, E D'Andrea, AD TI DUB-2A, a new member of the DUB subfamily of hematopoietic deubiquitinating enzymes SO BLOOD LA English DT Article ID UBIQUITIN-PROTEASOME PATHWAY; NUCLEAR-PORE COMPLEX; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL-ANALYSIS; CELL-CYCLE; C-CBL; PROTEIN; GENE; YEAST; DEGRADATION AB Protein ubiquitination Is an important regulator of cytokine-activated signal transduction pathways and hematopoietic cell growth. Protein ubiquitination is controlled by the coordinate action of ubiquitin-conjugating enzymes and deubiquitinating enzymes. Recently a novel family of genes encoding growth-regulatory deubiquitinating enzymes (DUB-1 and DUB-2) has been identified. DUBs are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli. By means of polymerase chain reaction amplification with degenerate primers for the DUB-2 complementary DNA, 3 murine bacterial artificial chromosome (BAC) clones that contain DUB gene sequences were isolated. One BAC contained a novel DUB gene (DUB-2A) with extensive homology to DUB-2. Like DUB-1 and DUB-2, the DUB-2A gene consists of 2 exons. The predicted DUB-2A protein is highly related to other DUBs throughout the primary amino acid sequence, with a hypervariable region at its C-terminus. In vitro, DUB-2A had functional deubiquitinating activity; mutation of its conserved amino acid residues abolished this activity. The 5 ' flanking sequence of the DUB-2A gene has a hematopoietic-specific functional enhancer sequence. It Is proposed that there are at least 3 members of the DUB subfamily (DUB-1, DUB-2, and DUB-2A) and that different hematopoietic cytokines induce specific DUB genes, thereby initiating a cytokine-specific growth response. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. OI Baek, Kwang-Hyun/0000-0001-7662-7190 FU NIDDK NIH HHS [R01 DK 43889, P01 DK 50654] NR 39 TC 34 Z9 35 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 636 EP 642 DI 10.1182/blood.V98.3.636 PG 7 WC Hematology SC Hematology GA 456QY UT WOS:000170094800023 PM 11468161 ER PT J AU Bennett, CM Kanki, JP Rhodes, J Liu, TX Paw, BH Kieran, MW Langenau, DM Delahaye-Brown, A Zon, LI Fleming, MD Look, AT AF Bennett, CM Kanki, JP Rhodes, J Liu, TX Paw, BH Kieran, MW Langenau, DM Delahaye-Brown, A Zon, LI Fleming, MD Look, AT TI Myelopoiesis in the zebrafish, Danio rerio SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DICENTRARCHUS-LABRAX L; HEAD-KIDNEY; CONGENITAL NEUTROPENIA; HEMATOPOIETIC LINEAGES; POSITIONAL CLONING; NEOPLASTIC-CELLS; GENE; CLOCHE; EXPRESSION AB Genome-wide chemical mutagenesis screens in the zebrafish (Danio rerio) have led to the identification of novel genes affecting vertebrate erythropoiesis. In determining if this approach could also be used to clarify the molecular genetics of myelopoiesis, it was found that the developmental hierarchy of myeloid precursors in the zebrafish kidney is similar to that in human bone marrow. Zebrafish neutrophils resembled human neutrophils, possessing segmented nuclei and myeloperoxidase-positive cytoplasmic granules. The zebrafish homologue of the human myeloperoxidase (MPO) gene, which is specific to cells of the neutrophil lineage, was cloned and used to synthesize antisense RNA probes for in situ hybridization analyses of zebrafish embryos. Granulocytic cells expressing zebrafish mpo were first evident at 18 hours after fertilization (hpf) in the posterior intermediate cell mass (ICM) and on the anterior yolk sac by 20 hpf. By 24 hpf, mpo-expressing cells were observed along the ICM and within the developing vascular system. Thus, the mpo gene should provide a useful molecular probe for identifying zebrafish mutants with defects in granulopoiesis. The expression of zebrafish homologues was also examined in 2 other mammalian hematopoietic genes, Pu.1, which appears to initiate a commitment step in normal mammalian myeloid development, and L-Plastin, a gene expressed by human monocytes and macrophages. The results demonstrate a high level of conservation of the spatio-temporal expression patterns of these genes between zebrafish and mammals. The morphologic and molecular genetic evidence presented here supports the zebrafish as an informative model system for the study of normal and aberrant human myelopoiesis. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Mayer 630,44 Binney St, Boston, MA 02115 USA. OI Kieran, Mark/0000-0003-2184-7692 FU NIDDK NIH HHS [DK 02593] NR 45 TC 255 Z9 262 U1 3 U2 25 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 643 EP 651 DI 10.1182/blood.V98.3.643 PG 9 WC Hematology SC Hematology GA 456QY UT WOS:000170094800024 PM 11468162 ER PT J AU Mitsiades, CS Treon, SP Mitsiades, N Shima, Y Richardson, P Schlossman, R Hideshima, T Anderson, KC AF Mitsiades, CS Treon, SP Mitsiades, N Shima, Y Richardson, P Schlossman, R Hideshima, T Anderson, KC TI TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications SO BLOOD LA English DT Article ID NF-KAPPA-B; TRAIL-MEDIATED APOPTOSIS; FADD-DEPENDENT APOPTOSIS; DEATH RECEPTOR GENE; CANCER-CELLS; MONOCLONAL-ANTIBODY; APO2 LIGAND; FAS LIGAND; IN-VIVO; EXPRESSION AB Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 an MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 tg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-Induced apoptosis. Nuclear factor (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM. C1 Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. NR 59 TC 297 Z9 320 U1 2 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2001 VL 98 IS 3 BP 795 EP 804 DI 10.1182/blood.V98.3.795 PG 10 WC Hematology SC Hematology GA 456QY UT WOS:000170094800043 PM 11468181 ER PT J AU Colleoni, M Gelber, RD Gelber, S Castiglione-Gertsch, M Coates, AS Goldhirsch, A AF Colleoni, M Gelber, RD Gelber, S Castiglione-Gertsch, M Coates, AS Goldhirsch, A TI How to improve timing and duration of adjuvant chemotherapy SO BREAST LA English DT Article; Proceedings Paper CT 7th International Conference on Adjuvant Therapy of Primary Breast Cancer CY FEB 21-24, 2001 CL ST GALLEN, SWITZERLAND SP UICC, SAK ID BREAST-CANCER PATIENTS; PRIMARY TUMOR REMOVAL; ESTROGEN-RECEPTOR; CELL-PROLIFERATION; GROWTH; IMPACT; WOMEN; INHIBITION; KINETICS; THERAPY AB The efficacy of adjuvant systemic therapy for early breast cancer depends on tumour, patient, and treatment-related features. Selection of treatment is based upon tumour characteristics such as oestrogen receptor (ER) and progesterone receptor (PgR) status, and patient characteristics such as age and menopausal status. Three retrospective analyses of the International Breast Cancer Study Group (IBCSG) database were performed to assess the influence of tumour-related features and patient characteristics on timing of adjuvant chemotherapy, on the efficacy of a short perioperative course of chemotherapy, and on the shorter rather than longer duration of chemotherapy. Timing: Early initiation (between 1 and 3 weeks from surgery) of adjuvant chemotherapy improved disease-free survival in patients whose tumours did not express ER. compared with typical timing to start of chemotherapy (between 4 and 6 weeks after surgery). Outcome was not related to start of chemotherapy for those patients whose tumours expressed ER. This analysis was conducted in premenopausal patients with node-positive disease. Perioperative therapy: A single course of adjuvant perioperative chemotherapy (PeCT) was particularly effective for postmenopausal patients with node-negative ER and PgR-negative breast cancer. Indeed the absence of expression of ER, PgR or both was the most important factor predicting improved outcome with PeCT among postmenopausal patients. No significant effect of PeCT was observed for premenopausal patients with similar characteristics of disease presentation. Duration of chemotherapy: Three courses of adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were as effective as six courses for an older cohort of premenopausal patients (age > 40 years), while younger patients (< 40 years old), or those at any age. but with tumours classified as ER-negative, six courses of the CMF appeared superior to three courses of the same regimen. Thus, information on endocrine responsiveness and menopausal status is important for focusing on best choice of timing and duration of adjuvant chemotherapy. (C) 2001 Harcourt Publishers Ltd. C1 European Inst Oncol, Dept Med, I-20141 Milan, Italy. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA USA. Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. IBCSG Coordinat Ctr, Bern, Switzerland. Australian Canc Soc, Sydney, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. RP Colleoni, M (reprint author), European Inst Oncol, Dept Med, Via Ripamonti 435, I-20141 Milan, Italy. NR 30 TC 3 Z9 3 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD AUG PY 2001 VL 10 SU 3 BP 101 EP 105 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 460ND UT WOS:000170312900018 ER PT J AU Bonetti, M Gelber, RD Goldhirsch, A Castiglione-Gertsch, M Coates, AS AF Bonetti, M Gelber, RD Goldhirsch, A Castiglione-Gertsch, M Coates, AS CA Int Breast Cancer Study Grp TI Features that predict responsiveness to chemotherapy and endocrine therapies SO BREAST LA English DT Article; Proceedings Paper CT 7th International Conference on Adjuvant Therapy of Primary Breast Cancer CY FEB 21-24, 2001 CL ST GALLEN, SWITZERLAND SP UICC, SAK ID BREAST-CANCER; TAMOXIFEN; SUBSETS AB Prognostic factors, characterizing the background level of risk of relapse, and predictive factors, characterizing the degree of responsiveness to a specific treatment, are both used to select adjuvant therapies for patients with early-stage breast cancer. Determining how best to utilize available factors is challenging. We review various prognostic and predictive factors and present examples to illustrate how these factors can be used to improve our understanding about selection of adjuvant treatments, re-evaluation of data from previous clinical trials and design of future studies. Steroid-hormone-receptor status of the primary tumour and patient age/menopausal status (primarily reflecting the robustness of ovarian function) are the key features that predict responsiveness to chemotherapy and endocrine therapies. Qualitative interactions between these factors, and effects of combining chemotherapy and endocrine therapies, may confound treatment comparison. The STEPP (Subpopulation Treatment Effect Pattern Plots) method, by investigating the patterns of treatment effects within randomized clinical trials or datasets from meta-analyses, will help to identify features that predict responsiveness to the treatments under study without the pitfalls of selective retrospective subset analysis. Subset analyses according to steroid-hormone-receptor status and patient age should now be considered as prospectively defined. Future clinical trials should be designed as tailored treatment investigations, with endocrine therapies being evaluated within populations of patients with endocrine-responsive tumours, and chemotherapy questions being addressed within populations of patients with endocrine non-responsive disease. (C) 2001 Harcourt Publishers Ltd. C1 Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Osped Civico, IBCSG, CH-6903 Lugano, Switzerland. European Inst Oncol, I-20141 Milan, Italy. IBCSG Coordinating Ctr, CH-3008 Bern, Switzerland. Australian Canc Soc, Sydney, NSW 2001, Australia. Univ Sydney, Sydney, NSW 2001, Australia. RP Gelber, RD (reprint author), Dana Farber Canc Inst, Dept Biostat Sci, 44 Binney St, Boston, MA 02115 USA. OI Bonetti, Marco/0000-0003-2304-4180 NR 15 TC 8 Z9 8 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD AUG PY 2001 VL 10 SU 3 BP 147 EP 157 PG 11 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 460ND UT WOS:000170312900024 ER PT J AU Coates, AS Hurny, C Peterson, HF Bernhard, J Castiglione-Gertsch, M Gelber, RD Goldhirsch, A AF Coates, AS Hurny, C Peterson, HF Bernhard, J Castiglione-Gertsch, M Gelber, RD Goldhirsch, A CA Int Breast Cancer Study Grp TI Quality of life scores predict outcome in metastatic but not in early breast cancer SO BREAST LA English DT Article; Proceedings Paper CT 7th International Conference on Adjuvant Therapy of Primary Breast Cancer CY FEB 21-24, 2001 CL ST GALLEN, SWITZERLAND SP UICC, SAK ID OF-LIFE; LUNG-CANCER; PSYCHOLOGICAL RESPONSE; PSYCHOSOCIAL TREATMENT; ADJUVANT THERAPY; PROGNOSTIC VALUE; RECEIVING END; SURVIVAL; CHEMOTHERAPY; POPULATION AB We compared the prognostic value of quality of life (QL) scores in the adjuvant setting and after relapse in two randomized trials of the International Breast Cancer Study Group (IBCSG). More than 2000 premenopausal and postmenopausal patients with node-positive breast cancer participating in randomized trials comparing adjuvant therapies completed QL assessments for physical wellbeing (PWB), mood, appetite and coping at study entry, at months 3 and 18 if they remained relapse-free, and at I month and at 6 months after relapse. Cox regression models were used to test the relationship between QL scores and disease-free survival (DFS) in the adjuvant setting, or overall survival in the case of post-relapse QL measurement. All models were stratified by language/country group and included other factors related to QL and/or outcome. DFS was not significantly predicted by QL scores at baseline or month 18, or by changes in QL score between baseline and months 3 or 18. In contrast, after relapse, QL scores were predictive for subsequent overall survival One month after relapse, better mood (P = 0.04) was associated with longer survival in premenopausal patients, and better appetite (P = 0.005) in postmenopausal patients. Six months after relapse, PWB (P = 0.03) and appetite (P = 0.03) were predictive for survival in premenopausal, and PWB ( P < 0.0001), mood (P = 0.002), appetite (P = 0.0001) and coping (P = 0.0001) in postmenopausal patients. Any prognostic significance of QL scores in the adjuvant setting is minimal or obscured by chemotherapy effects, but there is strong prognostic significance after disease relapse. The contrast suggests that patient perception of the severity of underlying illness may determine reported QL scores. (C) 2001 Harcourt Publishers Ltd. C1 Burgerspital, CH-9000 St Gallen, Switzerland. Univ Sydney, Australian Canc Soc, Sydney, NSW 2006, Australia. Univ Sydney, Australian New Zealand Breast Canc Trials Grp, Sydney, NSW 2006, Australia. Dana Farber Canc Inst, Int Breast Study Grp, Ctr Stat, Boston, MA USA. European Inst Oncol, Milan, Italy. IBCSG Coordinating Ctr, Bern, Switzerland. RP Hurny, C (reprint author), Burgerspital, Rorschacher Str 94, CH-9000 St Gallen, Switzerland. NR 33 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD AUG PY 2001 VL 10 SU 3 BP 164 EP 170 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 460ND UT WOS:000170312900027 ER PT J AU Herbst, RS Lynch, C Vasconcelles, M Teicher, BA Strauss, G Elias, A Anderson, I Zacarola, P Dang, NH Leong, T Salgia, R Skarin, AT AF Herbst, RS Lynch, C Vasconcelles, M Teicher, BA Strauss, G Elias, A Anderson, I Zacarola, P Dang, NH Leong, T Salgia, R Skarin, AT TI Gemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE gemcitabine; vinorelbine; non-small-cell lung cancer; preclinical studies; combination therapy ID PLUS VINORELBINE; CELL; NAVELBINE; CISPLATIN; AGENTS; REGIMEN; DRUGS AB Purpose: This study was designed to assess the efficacy of gemcitabine plus vinorelbine using the mouse Lewis lung carcinoma model and to translate this regimen to a phase I clinical study of these two agents in patients with advanced lung cancer. Materials and methods: Using the mouse Lewis lung cancer model, employing growth delay and isobologram analysis, we demonstrated that gemcitabine, in combination with vinorelbine, produced additive activity with little increased toxicity over a wide range of doses. At the highest dose level studied, antagonism was observed. Based on these results, we initiated a phase I study of this combination at the Dana Farber Cancer Institute (DFCI) in patients with untreated or once pretreated non-small-cell lung cancer (NSCLC) or once pretreated small-cell lung cancer (SCLC). Vinorelbine (given in an intravenous bolus) and gemcitabine (given in a 30-min infusion) were initially administered to patients at a dose of 15 mg/m(2) and 500 mg/m(2), respectively, on days 1, 8, and 15 of a 28-day cycle. Seven dose levels were subsequently explored over the course of the study. There was no intrapatient dose escalation. Results: From November 1996 to March 1998, 40 patients were enrolled: 32 had NSCLC, 5 had SCLC and 3 had mixed disease (both SCLC and NSCLC). The patients were evenly divided by gender, the median age was 58 years (range 38 to 73 years), and the median ECOG performance status was 1 (range 0 to 2). All patients had normal renal and hepatic function and none had previously received gemcitabine or vinorelbine. Toxic reactions included mild to moderate fatigue, nausea, constipation, and, most significantly, neutropenia and thrombocytopenia. Phlebitis was a major problem when central venous lines were not used with 15% grade 1/2 events. The day-15 dose was held in 43% of patients at the expanded dose. No true maximum tolerated dose was reached after completion of seven dose levels. Dose level 4 (22.5 mg/m(2) vinorelbine and 1000 mg/m(2) gemcitabine) was chosen for expansion and future study due to the potential increased ability of patients to receive the full doses on time. Conclusions: We conclude that this drug combination and dosage are feasible and have potential as either a front- or second-line chemotherapeutic regimen for advanced lung cancer, and phase II/III trials should be performed. However, hematologic toxicities, as found in this study, could probably be reduced with treatment on days 1 and 8 every 21 days, and current literature would suggest this to be the preferred schedule. C1 Brigham & Womens Hosp, Div Adult Oncol, Lowe Canc Ctr Thorac Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Biostat, Boston, MA 02115 USA. RP Skarin, AT (reprint author), Brigham & Womens Hosp, Div Adult Oncol, Lowe Canc Ctr Thorac Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 34 TC 22 Z9 23 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2001 VL 48 IS 2 BP 151 EP 159 DI 10.1007/s002800100282 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 466ZY UT WOS:000170677100009 PM 11561781 ER PT J AU Griffin, JD AF Griffin, JD TI Phosphatidyl inositol signaling by BCR/ABL: opportunities for drug development SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 16th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium CY OCT 27-28, 2000 CL NAGOYA, JAPAN SP Bristol Myers Squibb DE chronic myelogenous leukemia; signal transduction; BCR/ABL; oncogenes; leukemia; phosphatidyl inositol 3-kinase ID ABL TYROSINE KINASE; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL; SH2 DOMAIN; PHOSPHOINOSITIDE 3-KINASES; HEMATOPOIETIC-CELLS; ADAPTER PROTEIN; POSITIVE CELLS; LIFE-SPAN AB The t(9;22) translocation associated with chronic myelogenous leukemia (CML) fuses the c-ABL gene on chromosome 9 with the BCR gene on chromosome 22, resulting in the production of one or more of a family of chimeric oncoproteins, p190, p210, or p230 BCR/ABL. These proteins have activated ABL kinase activity and are located in the cytoplasm of CML cells, predominantly in the cytoskeleton. Recent studies have led to the identification of numerous potential substrates for BCR/ABL, including many proteins that normally function in signal transduction pathways downstream from hematopoietic growth factor receptors. BCR/ABL is autophosphorylated on tyrosine residues and attracts a variety of adapter proteins and other signaling proteins, setting up large signaling complexes that ultimately result in growth, viability, and adhesion signals. Using new in vitro and animal model systems, it is now becoming possible to link specific signaling pathways to biological abnormalities in CML cells. Furthermore, the relative importance of some BCR/ABL-activated pathways is becoming clear. In vivo studies in certain lines of transgenic mice suggest that the antiapoptotic effect of Bcr/Abl is more important than previously thought. Our current studies indicate important roles for phosphoinositide 3-kinase/Akt and for STAT molecules. As a result of these more detailed biochemical analyses of BCR/ABL function, new targets for future drug development have been identified. C1 Dana Farber Canc Inst, Leukemia Program, Boston, MA 02115 USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Leukemia Program, 44 Binney St, Boston, MA 02115 USA. NR 51 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2001 VL 48 SU 1 BP S11 EP S16 DI 10.1007/s002800100299 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 478FV UT WOS:000171333000003 PM 11587359 ER PT J AU Li, XG Stuckert, P Bosch, I Marks, JD Marasco, WA AF Li, XG Stuckert, P Bosch, I Marks, JD Marasco, WA TI Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells SO CANCER GENE THERAPY LA English DT Article DE ScFv; ErbB2; nonviral gene transfer; gene therapy; protamine; liposomes ID IN-VIVO; CATIONIC LIPOSOMES; DNA; RECEPTOR; TRANSFERRIN; PROTEIN; FV; ENDOCYTOSIS; EXPRESSION; EFFICIENT AB Targeted gene transfer by nonviral vectors can be achieved through incorporation of specific ligand(s) into the vectors. In this study, the effects of incorporation of an anti-ErbB2 single-chain antibody fragment (ScFv) into nonviral vectors for targeted gene delivery were investigated. The ML39 ScFv, selected from a human ScFv phage display library and affinity matured in vitro (K-d = 1 x 10(-9) M), was used as ligand specific for the extracellular domain of the tumor surface protein, ErbB2. Two approaches were taken: (a) development of a vector that is composed of a bifunctional fusion protein capable of binding DNA with the ErbB2-specific ML39 ScFv at its N-terminus and a truncated form of human protamine at its C-terminus, and (b) formulation and evaluation of delivery vectors consisting of three independent components including ML39 ScFv, protamine, and cationic lipids. We demonstrate that fusion proteins comprised of the ML39 ScFv and a truncated form of protamine, denoted as ScFv-P-S, can selectively deliver exogenous DNA into ErbB2(+) cells, with an 8- to 10-fold increase in expression levels of the luciferase reporter gene in ErbB2( +) cells as compared to ErbB2(-) cells. In addition, vectors formulated by appropriately mixing DNA, ScFv, protamine, and lipids in vitro could even more efficiently deliver the reporter gene into ErbB2( +) cells with approximately 5-fold increase in gene expression in ErbB2( +) cell as compared to ErbB2( -) cells. Expression and refolding of the ScFv fusion proteins, in addition to determination of optimal conditions for vector development using these approaches, are discussed. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Anesthesia & Pharmaceut Chem, San Francisco, CA 94110 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Marasco, WA (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,JFB 824, Boston, MA 02115 USA. NR 40 TC 45 Z9 62 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2001 VL 8 IS 8 BP 555 EP 565 DI 10.1038/sj.cgt.7700337 PG 11 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 465FN UT WOS:000170579100002 PM 11571533 ER PT J AU Yoon, SK Armentano, D Wands, JR Mohr, L AF Yoon, SK Armentano, D Wands, JR Mohr, L TI Adenovirus-mediated gene transfer to orthotopic hepatocellular carcinomas in athymic nude mice SO CANCER GENE THERAPY LA English DT Article DE hepatoma; adenoviral vectors; gene delivery; gene therapy ID IN-VIVO; RECOMBINANT ADENOVIRUS; IMMUNE-RESPONSES; SUICIDE GENE; MOUSE-LIVER; THERAPY; EXPRESSION; VECTORS; CANCER; TUMORS AB Gene therapy may become an option for the treatment of malignant tumors such as hepatocellular carcinoma (HCC), once safe and efficient vector systems have been established. Due to their stability in vivo, recombinant adenoviral vectors are promising vectors for gene delivery to HCC. To study the characteristics of gene delivery into HCCs by recombinant adenoviral vectors in vivo, we established an in situ HCC model in the livers of athymic nude mice by intrahepatic injection of human HCC cells. Recombinant adenovirus vectors expressing beta -galactosiclase (Ad2CMV beta gal) were injected via the tail vein of mice bearing HCC or directly into intrahepatic tumors. Levels of beta -galactosiclase expression in tumor tissue and surrounding normal liver were analyzed by histochemistry or for quantification by a chemi luminescence assay in tissue homogenates. Following tail vein injection, high levels of beta -galactosidase expression were found in the liver, but virtually no gene expression could be detected in the tumor tissue. In contrast, after direct injection of Ad2CM beta gal into intrahepatic HCCs, high levels of beta -galactosiclase expression were detected in the tumor tissue. However, single transdced hepatocytes scattered throughout the normal liver could also be identified. These results indicate that barriers such as the endothelial lining of the tumor vasculature impair the efficiency of adenoviral vectors for gene delivery into HCCs by intravenous administration, which can be overcome by direct injection into the tumor tissue. However, due to the observed transduction of disseminated hepatocytes following intratumoral administration, additional HCC-specific targeting to further enhance the safety of adenoviral vectors may be required. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Hepatol Lab, Boston, MA 02115 USA. Catholic Univ, Coll Med, Dept Internal Med, Seoul, South Korea. Genzyme Corp, Framingham, MA USA. Rhode Isl Hosp, Liver Res Ctr, Providence, RI 02903 USA. Univ Hosp, Dept Med 2, Freiburg, Germany. RP Mohr, L (reprint author), Univ Klin Freiburg, Abt Med 2, Hugstetterstr 55, D-79106 Freiburg, Germany. FU NCI NIH HHS [CA35711]; NIAAA NIH HHS [AA-08169] NR 43 TC 18 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2001 VL 8 IS 8 BP 573 EP 579 DI 10.1038/sj.cgt.7700345 PG 7 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 465FN UT WOS:000170579100004 PM 11571535 ER PT J AU Huang, M Batra, RK Kogai, T Lin, YQ Hershman, JM Lichtenstein, A Sharma, S Zhu, LX Brent, GA Dubinett, SM AF Huang, M Batra, RK Kogai, T Lin, YQ Hershman, JM Lichtenstein, A Sharma, S Zhu, LX Brent, GA Dubinett, SM TI Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer SO CANCER GENE THERAPY LA English DT Article DE gene therapy; NIS/TPO; lung cancer ID SODIUM/IODIDE SYMPORTER; NA+/I SYMPORTER; MESSENGER-RNA; THYROID-CELLS; TRANSPORT; THERAPY; TISSUE; TUMORS; ACID AB Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid-specific expression of the sodium iodide symporter (NIS) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently Causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer. C1 Univ Calif Los Angeles, Dept Med, Pulm Immunol & Gene Med Lab, Div Pulm & Crit Care Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Pulm Immunol & Gene Med Lab, Div Endocrinol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Pulm Immunol & Gene Med Lab, Div Hematol Oncol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Lung Canc Res Program, Los Angeles, CA 90024 USA. VA Greater Healthcare Syst, Los Angeles, CA 90073 USA. RP Huang, M (reprint author), W Los Angeles Healthcare Syst, Pulm Immunol & Gene Med Lab, Vet Adm, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NCI NIH HHS [R01 CA78654, R01 CA71818, P50 CA090388, IP50CA90388, R01 CA078654, R01 CA085686] NR 20 TC 87 Z9 102 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2001 VL 8 IS 8 BP 612 EP 618 DI 10.1038/sj.cgt.7700354 PG 7 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 465FN UT WOS:000170579100008 PM 11571539 ER PT J AU Porter, DA Krop, IE Nasser, S Sgroi, D Kaelin, CM Marks, JR Riggins, G Polyak, K AF Porter, DA Krop, IE Nasser, S Sgroi, D Kaelin, CM Marks, JR Riggins, G Polyak, K TI A SAGE (serial analysis of gene expression) view of breast tumor progression SO CANCER RESEARCH LA English DT Article ID MAMMARY EPITHELIAL-CELLS; MALIGNANT-CELLS; CANCER; PATTERNS; ESTROGEN AB To identify molecular alterations involved in the initiation and progression of breast carcinomas, we analyzed the global gene expression profiles of normal mammary epithelial cells and in situ, invasive, and metastatic breast carcinomas using serial analysis of gene expression (SAGE). We identified sets of genes expressed only or most abundantly in a specific stage of breast tumorigenesis or in a certain subtype of tumors through the pair-wise comparison and by hierarchical clustering analysis of these eight SAGE libraries (two/stage). On the basis of these comparisons, we made the following observations: Normal mammary epithelial cells showed the most distinct and least variable gene expression profiles. Many of the genes highly expressed in normal mammary epithelium and lost in carcinomas encoded secreted proteins, cytokines, and chemokines, implicating abnormal paracrine and autocrine signaling in the initiation of breast tumorigenesis. Very few genes were universally up-regulated in all tumors regardless of their stage and histological grade, indicating a high degree of diversity at the molecular level that likely reflects the clinical heterogeneity characteristic of breast carcinomas. Tumors of different histology type and stage had very distinct gene expression patterns. No genes seemed to be specific for metastatic or for in situ carcinomas. We found that the most dramatic and consistent phenotypic change occurred at the normal-to-in situ carcinoma transition. This observation, combined with the fact that many of the genes involved encode secreted, cell-nonautonomous factors, implies that the normal epithelium-to-ill situ carcinoma transition may be the most promising target for cancer prevention and treatment. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St,D740C, Boston, MA 02115 USA. NR 28 TC 177 Z9 186 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2001 VL 61 IS 15 BP 5697 EP 5702 PG 6 WC Oncology SC Oncology GA 458KZ UT WOS:000170194700004 PM 11479200 ER PT J AU Matsuzoe, D Hideshima, T Iwasaki, A Yoneda, S Kawahara, K Shirakusa, T Kimura, A AF Matsuzoe, D Hideshima, T Iwasaki, A Yoneda, S Kawahara, K Shirakusa, T Kimura, A TI Glutathione S-transferase mu 1 null genotype is associated with K-ras gene mutation in lung adenocarcinoma among smokers SO CARCINOGENESIS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ONCOGENE ACTIVATION; CHEMICAL CARCINOGENESIS; CLINICAL-SIGNIFICANCE; P53 MUTATIONS; DNA-ADDUCTS; CANCER; TUMORS; SMOKING; BENZOPYRENE AB Glutathione S-transferase mul (GSTM1) plays a role in the detoxification of benzo[a]pyrene (BP) diol epoxide in tobacco smoke. Individuals who genetically lack the GSTM1 gene are likely to have an increased risk of smoking-related lung cancers, however, the target oncogenes for mutation are unknown. To investigate the relation between GSTM1 genotype and K-ras gene mutation we examined 193 adenocarcinomas and 119 squamous cell carcinomas of lung. The GSTM1 genotype was determined by PCR and K-ras gene mutations at codons 12 and 13 were detected by dot-blot hybridization analysis using sequence-specific oligonucleotide probes. K-ras gene mutations were found in 29 of 312 (9.3%) tumors. All of them arose in patients who were habitual smokers. Mutations of the K-ras gene were detected in 6 of 100 (6%) and 15 of 93 (16.1%) adenocarcinoma cases with the GSTM1(+) and GSTM1(-) genotypes, respectively, and the difference was statistically significant. These findings suggest that the cause of K-ras gene mutation in smokers with lung adenocarcinoma may be in part an accumulation of BP diol epoxide which is not well detoxified in individuals with the GSTM1 null genotype. C1 Fukuoka Univ, Sch Med, Dept Surg 2, Jonanku, Fukuoka 8140180, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Pathogenesis, Chiyoda Ku, Tokyo 1010062, Japan. RP Matsuzoe, D (reprint author), Fukuoka Univ, Sch Med, Dept Surg 2, Jonanku, 7-45-1 Nanakuma, Fukuoka 8140180, Japan. NR 29 TC 11 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2001 VL 22 IS 8 BP 1327 EP 1330 DI 10.1093/carcin/22.8.1327 PG 4 WC Oncology SC Oncology GA 463HV UT WOS:000170471800029 PM 11470766 ER PT J AU Ito, Y Mishra, NC Yoshida, K Kharbanda, S Saxena, S Kufe, D AF Ito, Y Mishra, NC Yoshida, K Kharbanda, S Saxena, S Kufe, D TI Mitochondrial targeting of JNK/SAPK in the phorbol ester response of myeloid leukemia cells SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE terminal differentiation; TPA; protein kinase C beta; stress-activated protein kinase; mitochondria; Bcl-x(L) ID PROTEIN-KINASE-C; INTERNUCLEOSOMAL DNA FRAGMENTATION; SIGNAL-TRANSDUCTION PATHWAY; EARLY GROWTH RESPONSE-1; MONOCYTIC DIFFERENTIATION; CYTOCHROME-C; MACROPHAGE DIFFERENTIATION; GENE-EXPRESSION; JUN EXPRESSION; BCL-X(L) AB Treatment of human U-937 myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation of the stress-activated protein kinase (SAPK) and induction of terminal monocytic differentiation, The present studies demonstrate that TPA targets SAPK to mitochondria by a mechanism dependent on activation of protein kinase C (PKC) beta. Translocation of SAPK to mitochondria in response to TPA is associated with release of cytochrome c, caspase-3 activation and induction of apoptosis, The results show that IPA induces the association of SAPK with the mitochondrial anti-apoptotic Bcl-x(L) protein, Overexpression of Bcl-xL attenuated the apoptotic response to TPA treatment. Moreover, expression of Bcl-xL mutated at sites of SAPK phosphorylation (Thr-47, -115) was more effective than wildtype Bcl-xL in abrogating TPA-induced cytochrome c release and apoptosis, By contrast, expression of Bcl-xL had little effect on induction of the monocytic phenotype, These findings indicate that myeloid leukemia cells respond to TPA with targeting of SAPK to mitochondria and that this response contributes to terminal differentiation through the release of cytochrome c and induction of apoptosis. C1 Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. Lovelace Resp Res Inst, Albuquerque, NM 87115 USA. RP Kufe, D (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. FU NCI NIH HHS [CA42802] NR 34 TC 54 Z9 55 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 2001 VL 8 IS 8 BP 794 EP 800 DI 10.1038/sj.cdd.4400886 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 454YN UT WOS:000169999500004 PM 11526432 ER PT J AU Walss-Bass, C Prasad, V Kreisberg, JI Luduena, RF AF Walss-Bass, C Prasad, V Kreisberg, JI Luduena, RF TI Interaction of the beta(IV)-tubulin isotype with actin stress fibers in cultured rat kidney mesangial cells SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE actin stress-fibers; microtubules; depolymerization; tubulin isotypes ID MICROTUBULE-ASSOCIATED PROTEINS; BETA-TUBULIN; MONOCLONAL-ANTIBODY; CONNECTING CILIUM; FOCAL ADHESIONS; BOVINE BRAIN; ORGANIZATION; FILAMENTS; BINDING; PHOSPHORYLATION AB Microtubules and actin filaments are two of the major components of the cytoskeleton. There is accumulating evidence for interaction between the two networks. Both the alpha- and beta -subunits of tubulin exist as numerous isotypes, some of which have been highly conserved in evolution. In an effort to better understand the functional significance of tubulin isotypes, we used a double immunofluorescence labeling technique to investigate the interactions between the tubulin beta -isotypes and the actin stress fiber network in cultured rat kidney mesangial cells, smooth-muscle-like cells from the renal glomerulus. Removal of the soluble cytoplasmic and nucleoplasmic proteins by detergent extraction caused the microtubule network to disappear while the stress fiber network was still present. In these extracted cells, the beta (I)- and beta (II)-tubulin isotypes were no longer present in the cytoplasm while the beta (IV)-isotype co-localized with actin stress fibers. Co-localization between beta (IV)-tubulin and actin stress fibers was also observed when the microtubule network was disrupted by the anti-tubulin drug colchicine and also by microinjection of the beta (IV)-tubulin antibody. Our results suggest that the beta (IV) isotype of tubulin may be involved in interactions between microtubules and actin. Cell Motil. Cytoskeleton 49:200-207, 2001. (C) 2001 Wiley-Liss, Inc. C1 Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Surg, San Antonio, TX 78284 USA. Dept Vet Affairs, Res & Dev Serv, San Antonio, TX USA. RP Luduena, RF (reprint author), Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78284 USA. FU NCI NIH HHS [CA26376]; NIGMS NIH HHS [GM23476] NR 43 TC 10 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD AUG PY 2001 VL 49 IS 4 BP 200 EP 207 DI 10.1002/cm.1033 PG 8 WC Cell Biology SC Cell Biology GA 468VD UT WOS:000170778100003 PM 11746664 ER PT J AU Walss-Bass, C Kreisberg, JI Luduena, RF AF Walss-Bass, C Kreisberg, JI Luduena, RF TI Mechanism of localization of beta(II)-tubulin in the nuclei of cultured rat kidney mesangial cells SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE nuclear localization; tubulin isotypes; microinjection; nucleolus; mitosis ID SPINDLE POLE BODY; BETA-TUBULIN; SACCHAROMYCES-CEREVISIAE; BOVINE BRAIN; ISOTYPE; MITOSIS; PROTEIN; CYCLE; ORGANIZATION; MICROTUBULES AB Tubulin is an alpha beta heterodimer. Both the alpha and beta polypeptides exist as multiple isotypes. Although tubulin was generally thought to exist only in the cytoplasm, we have previously reported the presence of the beta (II) isotype of tubulin in the nuclei Of Cultured rat kidney mesangial cells, smooth-muscle-like cells that reside in the glomerular mesangium; nuclear beta (II) exists as an alpha beta (II) dimer, capable of binding to colchicine. but in non-microtubule form [Walss et al.. 1999: Cell Motil. Cytoskeleton 42:274-284]. We have now investigated the nature of the process by which alpha beta (II) enters the nuclei of these cells. By micro-injecting fluorescently labeled alpha beta (II) into mesangial cells, we found that alpha beta (II) was present in the nuclei of cells only if they were allowed to go through mitosis. In contrast. there were no circumstances in which microinjected fluorescently labeled alpha beta (II) or alpha beta (IV) dimers entered the nuclei. These findings. together with the absence of any nuclear localization signal in alpha beta (II) strongly favor the model that alpha beta (II), rather than being transported into the intact nucleus. co-assembles with the nucleus at the end of mitosis. Our results also indicate that the nuclear localization mechanism is specific for alpha beta (II). This result raises the possibility that alpha beta (II) may have a specific function that requires its presence in the nuclei of cultured rat kidney mesangial cells. Cell Motil. Cytoskeleton 49:208-217, 2001. (C) 2001 Wiley-Liss, Inc. C1 Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Dept Vet Affairs, Res & Dev Serv, San Antonio, TX USA. RP Luduena, RF (reprint author), Univ Texas, Hlth Sci Ctr, Dept Biochem, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NCI NIH HHS [CA26376]; NIGMS NIH HHS [GM23476] NR 50 TC 14 Z9 15 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD AUG PY 2001 VL 49 IS 4 BP 208 EP 217 DI 10.1002/cm.1034 PG 10 WC Cell Biology SC Cell Biology GA 468VD UT WOS:000170778100004 PM 11746665 ER PT J AU Ali, SH O'Donnell, AL Balu, D Pohl, MB Seyler, MJ Mohamed, S Mousa, S Dandona, P AF Ali, SH O'Donnell, AL Balu, D Pohl, MB Seyler, MJ Mohamed, S Mousa, S Dandona, P TI High levels of oestrogen receptor-alpha in tumorigenesis: inhibition of cell growth and angiogenic factors SO CELL PROLIFERATION LA English DT Article ID HUMAN-BREAST-CANCER; ESTROGEN-RECEPTOR; ENDOTHELIAL-CELLS; NUDE-MICE; PROGESTERONE; PROLIFERATION; EXPRESSION; FIBRINOGEN; ESTRADIOL AB We previously found that the stable overexpression of oestrogen receptor-alpha in the human endothelial cell line ECV304* inhibits its growth in vitro, and that this inhibition is possibly mediated through a down-regulation of the vasoactive agents endothelin-1 and vascular endothelial growth factor. Here we show an in vivo growth-inhibitory effect of oestrogen receptor-alpha overexpression in tumours initiated in nude mice from the same clone of ECV304. In addition, we show that this growth inhibition is accompanied by an alpha (v)beta (3)-mediated inhibition of cell migration in vitro, and a downregulation of the integrin alpha (v)beta (3) vascular endothelial growth factor and vascularization in vivo. The levels of vascular endothelial growth factor and integrin alpha (v)beta (3) through their effect on cell growth and migration, contribute to the process of angiogenesis and to the pathogenesis of atherosclerosis and cancer. The results shown here demonstrate that a higher level of oestrogen receptor-alpha in the cell, through its effect on certain angiogenic factors, may play a role in the control of angiogenesis. C1 Kaleida Hlth Syst, Diabet Endocrinol Ctr Western New York, Buffalo, NY USA. SUNY Coll Buffalo, Buffalo, NY USA. VA Med Ctr, Dept Med & Endocrinol, Buffalo, NY USA. VA Med Ctr, Dept Pathol, Buffalo, NY USA. Dupont Merck Pharmaceut Co, Gen Pharmacol, Wilmington, DE USA. RP Ali, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 27 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0960-7722 J9 CELL PROLIFERAT JI Cell Prolif. PD AUG PY 2001 VL 34 IS 4 BP 223 EP 231 DI 10.1046/j.0960-7722.2001.00207.x PG 9 WC Cell Biology SC Cell Biology GA 465AA UT WOS:000170564500003 PM 11529880 ER PT J AU Saito, H AF Saito, H TI Histidine phosphorylation and two-component signaling in eukaryotic cells SO CHEMICAL REVIEWS LA English DT Review ID ETHYLENE-RESPONSE PATHWAY; ACTIVATED PROTEIN-KINASE; SPORULATION TRANSCRIPTION FACTOR; YEAST SACCHAROMYCES-CEREVISIAE; SINGLE CYTOPLASMIC DOMAIN; OXIDATIVE STRESS-RESPONSE; HIS-ASP PHOSPHOTRANSFER; RECEPTOR GENE FAMILY; MAP KINASE; CANDIDA-ALBICANS C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Saito, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 142 TC 61 Z9 63 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD AUG PY 2001 VL 101 IS 8 BP 2497 EP 2509 DI 10.1021/cr000243+ PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 463UY UT WOS:000170496700016 PM 11749385 ER PT J AU Torre-Amione, G Durand, JB Nagueh, S Vooletich, MT Kobrin, I Pratt, C AF Torre-Amione, G Durand, JB Nagueh, S Vooletich, MT Kobrin, I Pratt, C TI A pilot safety trial of prolonged (48 h) infusion of the dual endothelin-receptor antagonist tezosentan in patients with advanced heart failure SO CHEST LA English DT Article DE endothelins; heart failure; pharmacologic therapy ID DOPPLER-ECHOCARDIOGRAPHY; THERAPY AB Study objectives: Tezosentan, an IV dual endothelin-receptor antagonist, has demonstrated beneficial hemodynamic effects in patients with advanced heart failure. In addition, no notable differences in safety and tolerability variables were detected between tezosentan-treated and Placebo-treated patients when infused over 4 to 6 h. The present study was conducted primarily to assess the safety and tolerability of tezosentan when administered over a prolonged, 48-h treatment period, and secondarily to investigate hemodynamic response. Design: This randomized, double-blind, active-controlled study of continual IV administration of two dosages of tezosentan (20 mg/h and 50 mg/h; n = 6 each) or dobutamine (5 mug/kg/min; n = 2) over 48 h in patients with advanced heart failure was conducted to assess tolerability, safety, and hemodynamic variables (Doppler echocardiography). Results: During tezosentan infusion, no episodes of hypotension requiring withdrawal of therapy occurred, and hemodynamic rebound was not observed after abrupt cessation of the infusion. There were no reports of worsening heart failure in tezosentan-treated patients up to 28 days following the infusion. The most common side effect during the infusion was headache (9 of 12 tezosentan-treated patients and both dobutamine-treated patients). Echocardiographic Doppler measurements suggested improvements in cardiac index, pulmonary, capillary wedge pressure, and relaxation properties as well as in diastolic and systolic function in all treatment groups. Conclusions: Prolonged, 48-h IV dual endothelin-receptor antagonism with tezosentan was well tolerated with no new safety concerns emerging. These data further support the potential role of tezosentan in the treatment of patients with acute heart failure. C1 Methodist Hosp, Winter Ctr Heart Failure Res, Houston, TX 77030 USA. Methodist Hosp, Eugene & Judith Campbell Labs Cardiac Transplanta, Houston, TX 77030 USA. Baylor Coll Med, VA Med Ctr, Houston, TX 77030 USA. Actel Ltd, Allschwil, Switzerland. RP Torre-Amione, G (reprint author), Baylor Coll Med, Texas Med Ctr, Cardiol Sect, 1 Baylor Plaza, Houston, TX 77030 USA. NR 23 TC 27 Z9 27 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2001 VL 120 IS 2 BP 460 EP 466 DI 10.1378/chest.120.2.460 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 462DM UT WOS:000170405500025 PM 11502644 ER PT J AU Lenner, R Padilla, ML Teirstein, AS Gass, A Schilero, GJ AF Lenner, R Padilla, ML Teirstein, AS Gass, A Schilero, GJ TI Pulmonary complications in cardiac transplant recipients SO CHEST LA English DT Article DE cardiac; complications; pulmonary; transplantation ID HEART-TRANSPLANTATION; CYTOMEGALOVIRUS-INFECTION; ASPERGILLOSIS; CYCLOSPORINE; TUBERCULOSIS; PREVALENCE; REJECTION; DIAGNOSIS; CAPACITY; THERAPY AB Background: The incidence of pulmonary complications in heart transplant recipients has not been extensively studied. We report pulmonary complications in 159 consecutive adult orthotopic heart transplantations (OHTs) performed in 157 patients. Materials and methods: Retrospective review of medical records. Results: Forty-seven of 159 recipients (29.9%) had 81 pulmonary complications. Pneumonia was the most common (n = 27), followed by bronchitis (n = 15), pleural effusion (n = 10), pneumothorax (n = 7), prolonged respiratory failure requiring tracheotomy (n = 7), and obstructive sleep apnea syndrome (n = 6). All patients with late-onset (> 6 months after transplantation) community-acquired bacteria] pneumonia presented with fever, cough, and a new lobar consolidation on the chest radiograph, and responded promptly to empiric antibiotics without undergoing an invasive diagnostic procedure. in contrast, early-onset nosocomial bacterial pneumonias carried a 33.3% mortality rate. A positive tuberculin skin test result was associated with a significantly higher rate of pulmonary complications (62.5% vs 26.8%, p = 0.007). Lung cancer and posttransplant lymphoproliferative disorder (PTLD) developed exclusively in 6 of the 61 patients (8.1%) who received induction immunosuppression with murine monoclonal antibody (OKT3). Conclusion: Pulmonary complications are common following heart transplantation, occurring in 29.9% of recipients, and are attributed to pneumonia of primarily bacterial origin in one half of cases. Late-onset community-acquired pneumonia carried an excellent prognosis following empiric antibiotic therapy, suggesting that in the appropriate clinical setting invasive diagnostic procedures are unnecessary. Analogous to reports in other solid-organ transplant recipients, induction therapy with OKT3 was associated with an increased incidence of lung cancer and PTLD. Overall, the development of pulmonary complications after OHT has prognostic significance given the higher mortality in this subset of patients. C1 Bronx Vet Adm Med Ctr, New York, NY USA. NYU, Mt Sinai Med Ctr, New York, NY USA. RP Lenner, R (reprint author), 515 E 72nd,Apt 10 L, New York, NY 10021 USA. NR 33 TC 40 Z9 44 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2001 VL 120 IS 2 BP 508 EP 513 DI 10.1378/chest.120.2.508 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 462DM UT WOS:000170405500032 PM 11502651 ER PT J AU Lara-Marquez, ML Moan, MJ Cartwright, S Listman, J Israel, E Perkins, DL Christiani, DC Finn, PW AF Lara-Marquez, ML Moan, MJ Cartwright, S Listman, J Israel, E Perkins, DL Christiani, DC Finn, PW TI Atopic asthma: differential activation phenotypes among memory T helper cells SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE asthma; CD45; T helper cells; IL-2R; MHC-class II ID LEUKOCYTE-COMMON ANTIGEN; LYMPHOCYTES-T; SUBSETS; CD45; IDENTIFICATION; EOSINOPHILS; EXPRESSION; CHALLENGE; RESPONSES; SEVERITY AB Background T cells have been implicated in the pathogenesis of atopic asthma. We have previously shown that memory T helper cells (CD4(+)CD45RO(+)) are preferentially activated relative to naive T helper cells (CD4(+)CD45RA(+)) after bronchial allergen challenge. However, specific T helper subpopulations that are activated in atopy and/or asthma remain undefined. Objective To determine the T helper subpopulations and activation phenotypes relevant to acute and stable asthma that may be common with or distinct from atopy. Methods Two groups of atopic asthmatics (ten acute and nine stable asthmatics) and two non-asthmatic groups (14 non-asthmatic atopics and eight normal non-atopic controls) were analysed. Ten acute asthmatics were assessed in the emergency room during an acute episode (FEV1 43.6% +/- 18.4). Nine stable asthmatics were assessed during a symptom-free period (FEV1 85% +/- 6). Using multiple colour flow cytometry we analysed T cell subpopulations and the expression of IL-2-receptor (IL-2R) and MHC-class II antigens (MHC III) on naive and memory T helper cells in the peripheral blood of asthmatic and non-asthmatic groups. Results Atopic asthmatics (acute and stable) had an increased percentage of memory T helper cells expressing IL-2R compared with normal non-atopics (mean SD 16.1 +/- 6%, 12.4 +/- 2% and 7.7 +/- 1.8%, P < 0.05) but not compared with non-asthmatic atopics (10 3.5%). Naive T helper cells had low expression of IL-2R and MHC II in all four groups. MHC If antigen expression was increased in memory T helper cells of asthmatics (acute and stable) compared with normal non-atopics (13.9 +/- 7.5, 10.6 +/- 5 and 4.9 +/- 2.5, P < 0.05) but not compared with non-asthmatic atopics (7.92 4). A novel finding was that IL-2R and the MHC II molecules were mainly expressed in nonoverlapping populations and coexpression was found predominantly on memory T helper cells. Asthmatics (acute and stable) had higher proportion of double positive memory T helper cells (IL-2R(+)MHC II+) compared with both non-asthmatic groups (P < 0.05). Conclusions We demonstrate a differential expression of IL-2R(+) and MCH II+ on CD45RO(+) T helper cells that would suggest that there are three subsets of activated memory T helper cells in asthmatics. Two non-overlapping IL-2R(+) or MHC II+ CD45RO(+) T helper cells and a third subpopulation of activated cells that coexpress IL-2R and MHC II (double positives). This latter subpopulation is significantly higher in asthmatics (acute or stable) compared with both non-asthmatic groups, suggesting a specific T helper activation phenotype distinct to atopic. asthmatics as compared with atopic non-asthmatics. C1 Brigham & Womens Hosp, Div Resp, Boston, MA 02115 USA. Beth Israel Hosp, Div Resp, Boston, MA USA. Massachusetts Gen Hosp, Div Pulm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Nephrol, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Emergency Med, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Finn, PW (reprint author), Brigham & Womens Hosp, Div Resp, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [T32 HL07633]; NIEHS NIH HHS [ES-00002, R01 ES06568] NR 27 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD AUG PY 2001 VL 31 IS 8 BP 1232 EP 1241 DI 10.1046/j.1365-2222.2001.01146.x PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 464XT UT WOS:000170559200010 PM 11529893 ER PT J AU Ledoux, WR Hillstrom, HJ AF Ledoux, WR Hillstrom, HJ TI Acceleration of the calcaneus at heel strike in neutrally aligned and pes planus feet SO CLINICAL BIOMECHANICS LA English DT Article DE acceleration; foot calcaneus; comfortable cadence; neutrally aligned; pes planus ID SOFT-TISSUE; WALKING; JOINTS; FOOT; INVIVO; TIBIA; BONE AB Objective. The purpose of this research was twofold: (1) to study the impulsive acceleration of the calcaneus at heel strike in subjects with neutrally aligned (i.e., normal) feet and (2) to explore how the acceleration may differ in subjects with pes planus (i.e., flat). feet. The component of the acceleration vector aligned with the long axis of the tibia was quantified. Design. Subjects with either foot type were instrumented and calcaneal acceleration was quantified during comfortable cadence locomotion. Background. Aberrant peak acceleration has been associated with osteoarthritis. while tibial acceleration has been quantified, calcaneal acceleration has not. Additionally, foot morphology, or foot type, has demonstrated an effect on foot function and thus there may. be differences in calcaneal acceleration between foot types. Methods. Six subjects with neutrally aligned feet and six with pes planus feet were selected via a clinical exam. Accelerometers were attached to the posterior aspect of the medial surface of the calcanei bilaterally and 10 walking trials were collected. Results. The average baseline-to-peak acceleration for the neutrally aligned and pes planus feet was 4.79 g (SD, 2.14 g) and 5.24 g (SD, 3.28 g),: respectively; the peak-to-peak acceleration was 5.03 g (SD, 2.74 g) and 6.75 g (SD, 3.89 g). There were no significant differences (P > 0.05) between foot types. Conclusions. The calcaneal acceleration at heel strike for neutrally aligned and pes planus feet was not sensitive to foot type. C1 VA Puget Sound Hlth Care Syst, Rehabil Res & Dev Ctr, Seattle, WA 98108 USA. Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. Temple Univ, Sch Podiat Med, Gait Study Ctr, Philadelphia, PA 19122 USA. RP Ledoux, WR (reprint author), VA Puget Sound Hlth Care Syst, Rehabil Res & Dev Ctr, MS 151,1660 S Columbian Way, Seattle, WA 98108 USA. RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 NR 19 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD AUG PY 2001 VL 16 IS 7 BP 608 EP 613 DI 10.1016/S0268-0033(01)00041-9 PG 6 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 467QD UT WOS:000170714500008 PM 11470303 ER PT J AU Chakravarti, A Delaney, MA Noll, E Black, PM Loffler, JS Muzikansky, A Dyson, NJ AF Chakravarti, A Delaney, MA Noll, E Black, PM Loffler, JS Muzikansky, A Dyson, NJ TI Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas SO CLINICAL CANCER RESEARCH LA English DT Article ID HIGH-GRADE ASTROCYTOMAS; BRAIN-TUMORS; TELOMERASE EXPRESSION; SECONDARY GLIOBLASTOMAS; CELL-PROLIFERATION; MALIGNANT GLIOMAS; DE-NOVO; P53; GENE; MUTATIONS AB Purpose: Analysis of tumor-derived genetic lesions has provided insights into molecular pathogenesis of human gliomas. Because these changes represent only one of several mechanisms that alter gene expression during tumorigenesis, it is likely that further information will be obtained from a careful analysis of important regulatory proteins present in these tumors. Experimental Design: We have quantified the levels of key cell cycle/signaling proteins in 94 prospectively collected, meticulously preserved, "snap frozen" glioma specimens and have compared these levels with histopathological data and patient outcome. Results: The results of these experiments confirm that the levels of wild-type tumor suppressor proteins, such as p53, pRB, PTEN, p14(ARF), and p16(INK4), are lost or severely reduced in most gliomas, and that epidermal growth factor receptor, human telomerase reverse transcriptase, and cyclin-dependent kinase 4 are overexpressed frequently and with a few exceptions, almost exclusively, in glioblastomas. In addition, we report frequent underexpression of E2F-1 (in 55% of gliomas) and cyclin E overexpression (in 26% of gliomas), which have not yet been reported on the genomic level. Several of these markers significantly correlated with histopathological grade, and the levels of five proteins showed significant association with patient outcome. In particular, overexpression of epidermal growth factor receptor, human telomerase reverse transcriptase, cyclin-dependent kinase 4, and cyclin E was largely restricted to glioblastomas and was significantly associated with reduced patient survivals. Conclusions: We conclude that the quantitation of cell cycle/signaling proteins from meticulously preserved glioma specimens provides further insights into the molecular pathogenesis of human gliomas and yields valuable prognostic information. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Oncol Mol Lab,Dept Radiat Oncol, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Biostat, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Oncol, Charlestown, MA 02129 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. RP Chakravarti, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Oncol Mol Lab,Dept Radiat Oncol, 13th St,Bldg 149,Room 7330, Charlestown, MA 02129 USA. FU NCI NIH HHS [R01 CA64402, 1K08 CA82163-01] NR 48 TC 85 Z9 90 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2001 VL 7 IS 8 BP 2387 EP 2395 PG 9 WC Oncology SC Oncology GA 460VB UT WOS:000170328300030 PM 11489817 ER PT J AU Seminara, S Crowley, WF AF Seminara, S Crowley, WF TI The genetics of IHH-a paradox SO CLINICAL ENDOCRINOLOGY LA English DT Editorial Material ID LINKED KALLMANN SYNDROME; HYPOGONADISM; MOLECULES; ADHESION C1 Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. RP Seminara, S (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Bartlett Hall Extens,Fruit St, Boston, MA 02114 USA. FU NICHD NIH HHS [R01 HD015788, P30 HD028138, U54 HD028138, U54 HD029164] NR 8 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD AUG PY 2001 VL 55 IS 2 BP 159 EP 160 DI 10.1046/j.1365-2265.2001.01305.x PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466WE UT WOS:000170668500002 PM 11531920 ER PT J AU Sami, N Bhol, KC Beutner, EH Plunkett, RW Leiferman, KM Foster, CS Ahmed, AR AF Sami, N Bhol, KC Beutner, EH Plunkett, RW Leiferman, KM Foster, CS Ahmed, AR TI Simultaneous presence of mucous membrane pemphigoid and pemphigus vulgaris: Molecular characterization of both autoantibodies SO CLINICAL IMMUNOLOGY LA English DT Article DE dual diagnosis; pemphigus; pemphigoid; indirect immunofluorescence; salt split skin; immunoblot analysis; IgG subclass ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; COEXISTENCE; ANTIBODIES; THERAPY; SCLERODERMA; MYASTHENIA; SUBCLASS; FEATURES AB There are several reports in the literature describing the coexistence of features of pemphigus vulgaris and pemphigoid in the same patient. We describe 15 patients with clinical, histological, and immunopathological features of mucous membrane (cicatricial) pemphigoid at the time of initial diagnosis. All 15 patients failed to respond clinically to conventional systemic agents over a mean period of 7.2 years. Hence, IVIg therapy was used. Prior to initiating Mg therapy, features of mucous membrane pemphigoid and pemphigus vulgaris were demonstrated by various serological tests. Different assays were performed to identify molecular characteristics of these two autoantibodies. Twenty-five healthy normal individuals, 22 patients with mucous membrane pemphigoid, 17 patients with pemphigus vulgaris, and 12 patients with pemphigus foliaceus served as controls for comparison of serological studies. On indirect immunofluorescence, using monkey esophagous as substrate, sera of all 15 patients had demonstrable levels of anti-intercellular cement substance (ICS) or anti-keratinocyte cell surface antibody. Sera of 14 patients on salt split skin bound to the epidermal side of the split, which was consistent with mucous membrane pemphigoid. Sera of all 15 patients demonstrated binding to a 205-kDa protein (human B4 integrin) and a 130-kDa protein (desmoglein 3) on immunoblot. In a sample of sera from each of the 6 patients with mucous membrane pemphigoid and pemphigus vulgaris, the anti-ICS antibody was of the IgG4 subclass. The IgG4 subclass is a characteristic feature associated with pathogenic autoantibodies in pemphigus vulgaris. Hence, in such patients, a dual diagnosis should be considered and confirmed by various serological assays. It is possible that the presence of two pathogenic autoantibodies in these patients could have contributed to the lack of response to conventional immunosuppressive therapy. (C) 2001 Academic Press. C1 Harvard Sch Dent Med, Dept Oral Med, Boston, MA 02115 USA. New England Baptist Hosp, Dept Med, Boston, MA 02115 USA. Beutner Labs, Buffalo, NY 14215 USA. Mayo Clin, Immunodermatol Lab, Rochester, MN 55905 USA. Mass Eye & Ear Infirm, Boston, MA 02114 USA. RP Sami, N (reprint author), Harvard Sch Dent Med, Dept Oral Med, Boston, MA 02115 USA. NR 65 TC 14 Z9 15 U1 2 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2001 VL 100 IS 2 BP 219 EP 227 DI 10.1006/clim.2001.5065 PG 9 WC Immunology SC Immunology GA 460JQ UT WOS:000170304800012 PM 11465951 ER PT J AU Fujino, Y Goddon, S Dolhnikoff, M Hess, D Amato, MBP Kacmarek, RM AF Fujino, Y Goddon, S Dolhnikoff, M Hess, D Amato, MBP Kacmarek, RM TI Repetitive high-pressure recruitment maneuvers required to maximally recruit lung in a sheep model of acute respiratory distress syndrome SO CRITICAL CARE MEDICINE LA English DT Article; Proceedings Paper CT International Conference of the American-Thoracic-Society CY APR 23-29, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Thoracic Soc DE acute respiratory distress syndrome; lung injury; recruitment maneuver; pulmonary mechanics; permissive hypercapnia ID END-EXPIRATORY PRESSURE; TIDAL VOLUME; MECHANICAL VENTILATION; INFLATION; INJURY; EXPRESSION; STRATEGY; FAILURE AB Objective: To compare the effects of two different recruitment maneuvers repeated multiple times on gas exchange lung injury, hemodynamic, and lung mechanics. Design: Randomized prospective comparison. Settings: Animal research laboratory. Subject. Nineteen fasted Hampshire sheep. Interventions: In 15 27-kg sheep with saline lavage lung injury, we compared the effects of two recruitment maneuvers: 40 cm H2O continuous positive airway pressure for 60 secs and 40 cm H2O positive end-expiratory pressure with 20 cm H2O pressure control, rate 10 breaths/min, inspiratory to expiratory ratio 1:1 for 2 mins. Each recruitment maneuver was repeated four times, every 30 mins after a 30-sec ventilator disconnection. An additional group received no recruitment maneuvers. Animals were assigned randomly to the three groups and ventilated with 20 cm H2O positive end-expiratory pressure, pressure control 15 cm H2O, rate 20 breaths/min, inspiratory to expiratory ratio 1:1, and FIO2 1.0 between recruitment maneuver periods. Measurements and Main Results. Significant and marked increases in PaO2 were observed in the pressure control recruitment maneuver group but only after the second recruitment maneuver. In both the control group and continuous positive airway pressure groups, PaO2 did not significantly increase after any recruitment maneuver compared with baseline injury. There was a significant decrease in cardiac output immediately after some continuous positive airway pressure recruitment maneuvers and a significant increase in mean pulmonary artery pressure in both continuous positive airway pressure and pressure control groups immediately after recruitment maneuvers, but these changes resolved within 10 mins. There were no marked histologic differences between groups and no volutrauma. Conclusion: In this model, maximal lung recruitment was obtained with 40 cm H2O positive end-expiratory pressure and 20 cm H2O pressure control applied repetitively every 30 mins for 2 mins without physiologic or histologic harm. Multiple recruitment maneuvers in some animals were required for maximum effect. C1 Harvard Univ, RRT, Sch Med, Massachusetts Gen Hosp,Resp Care Dept Lab, Boston, MA 02114 USA. Harvard Univ, Dept Anesthesia, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Sao Paulo, Fac Med, Dept Pathol, Sao Paulo, Brazil. Hosp Clin Sao Paulo, Dept Pulm Med, Sao Paulo, Brazil. RP Kacmarek, RM (reprint author), Harvard Univ, RRT, Sch Med, Massachusetts Gen Hosp,Resp Care Dept Lab, Ellison 401, Boston, MA 02114 USA. NR 26 TC 61 Z9 70 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2001 VL 29 IS 8 BP 1579 EP 1586 DI 10.1097/00003246-200108000-00014 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 465FZ UT WOS:000170580100014 PM 11505131 ER PT J AU Scherrer-Crosbie, M Streckenbach, SC Zapol, WM AF Scherrer-Crosbie, M Streckenbach, SC Zapol, WM TI Acute cor pulmonale in acute respiratory distress syndrome: A dreaded complication of the past? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE acute respiratory distress syndrome; right ventricular function; mechanical ventilation ID VENTILATION; FAILURE C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 8 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2001 VL 29 IS 8 BP 1641 EP 1642 DI 10.1097/00003246-200108000-00028 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 465FZ UT WOS:000170580100028 PM 11505150 ER PT J AU Whitcomb, DC Somogyi, L AF Whitcomb, DC Somogyi, L TI Lessons from hereditary pancreatitis SO CROATIAN MEDICAL JOURNAL LA English DT Article DE base sequence; cystic fibrosis transmembrane conductance regulator; hereditary diseases; membrane proteins; pancreatitis; trypsin inhibitors; trypsinogen ID CATIONIC TRYPSINOGEN GENE; CYSTIC-FIBROSIS GENE; MUTATIONS; ACTIVATION; INHIBITOR; MAPS AB For decades there has been slow progress in understanding pancreatic diseases, particularly acute and chronic pancreatitis. As a result, there were no significant advances in the management of these patients. Treatment was mostly directed towards symptomatic relief and management of complications. A simple clinical observation that multiple members of a large family are affected by acute and chronic pancreatitis, some at very young age and in the absence of any alcohol use, led physician-scientists of the Midwest Multicenter Pancreatic Study Group (investigators from the University of Cincinnati, University of Kentucky, and University of Pittsburgh) to investigate the genetic basis of hereditary pancreatitis. Using information from the human genome project, the hereditary pancreatitis gene was identified as the cationic trypsinogen gene (protease serine 1, PRSS1). This discovery has led to the identification of a number of other genes and their products playing role in the pathogenesis of acute and chronic pancreatitis. In the emerging picture of pathogenesis of acute and chronic pancreatitis, trypsin appears to play a central role. This newly acquired knowledge is setting the stage for new preventive and management strategies for hereditary and sporadic acute and chronic pancreatitis. C1 Univ Cincinnati, Pancreat Dis Ctr, Div Digest Dis, Cincinnati, OH 45267 USA. Univ Cincinnati, Dept Med, Cincinnati, OH 45267 USA. Cincinnati VA Med Ctr, Cincinnati, OH USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. Vet Affairs Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. RP Somogyi, L (reprint author), Univ Cincinnati, Pancreat Dis Ctr, Div Digest Dis, POB 670595, Cincinnati, OH 45267 USA. FU NIAAA NIH HHS [NIH AA20885]; NIDDK NIH HHS [NIH DK54709] NR 30 TC 4 Z9 4 U1 0 U2 0 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD AUG PY 2001 VL 42 IS 4 BP 484 EP 487 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 466GW UT WOS:000170637900021 PM 11471204 ER PT J AU Masland, RH AF Masland, RH TI Neuronal diversity in the retina SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID GANGLION-CELL TYPE; RECEPTIVE-FIELD MICROSTRUCTURE; AMACRINE CELLS; BIPOLAR CELLS; PRIMATE RETINA; CAT RETINA; MAMMALIAN RETINA; RABBIT RETINA; RAT RETINA; SPATIAL SCALE AB The listing of cell types present in the retina is nearing completion, the first time this can be said for any significantly complex sample of the central nervous system, Mammalian retinas contain similar to 55 separate neuronal types. The functions of 22 of them are known or can be strongly inferred. For these 22, in every instance, a cell defined as a 'type' by structural criteria carries out a distinct and individual physiological function. Electrophysiological experiments continue to reveal new features of the retina's handling of information, and there is every reason to believe that the remaining 33 types of cell will also have distinct physiological functions. Further subtleties clearly exist in both peripheral and central visual coding. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Masland, RH (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM masland@helix.mgh.harvard.edu NR 55 TC 181 Z9 185 U1 2 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD AUG PY 2001 VL 11 IS 4 BP 431 EP 436 DI 10.1016/S0959-4388(00)00230-0 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 467PX UT WOS:000170713900005 PM 11502388 ER PT J AU Chang, JH Gabison, EE Kato, T Azar, DT AF Chang, Jin-Hong Gabison, Eric E. Kato, Takuji Azar, Dimitri T. TI Corneal neovascularization SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Corneal neovascularization (NV) is a sight-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface. It has been shown in the field of cancer angiogenesis research that a balance exists between angiogenic factors (such as fibroblast growth factor and vascular endothelial growth factor) and anti-angiogenic molecules (such as angiostatin, endostatin, or pigment epithelium derived factor) in the cornea. Several inflammatory, infectious, degenerative, and traumatic disorders are associated with corneal NV, in which the balance is tilted towards angiogenesis. The pathogenesis of corneal NV may be influenced by matrix metalloproteinases and other proteolytic enzymes. New medical and surgical treatments, including angiostatic steroids, nonsteroidal inflammatory agents, argon laser photocoagulation, and photodynamic therapy have been effective in animal models to inhibit corneal NV and transiently restore corneal "angiogenic privilege." (C) 2001 Lippincott Williams & Wilkins, Inc. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM dazar@meei.harvard.edu FU NEI NIH HHS [EY10101] NR 101 TC 331 Z9 363 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 242 EP 249 DI 10.1097/00055735-200108000-00002 PG 8 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900002 PM 11507336 ER PT J AU Jain, S Azar, DT AF Jain, Sandeep Azar, Dimitri T. TI New lamellar keratoplasty techniques: posterior keratoplasty and deep lamellar keratoplasty SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Posterior keratoplasty is a new surgical technique that may be valuable in treating patients with corneal decompensation secondary to endothelial dysfunction. There are currently two approaches to posterior keratoplasty. In the first approach, a corneal flap is created using a microkeratome (similar to laser in situ keratomileusis flap), and posterior stromal tissue is excised (by trephination or excimer laser keratectomy). In the second approach, a deep stromal pocket is created across the cornea through a superior scleral incision. A custom-made flat trephine is inserted into the pocket to excise a posterior lamellar disc. Preliminary studies have shown the feasibility of performing these techniques in sighted human eyes. Despite potential advantages, further clinical studies are needed to determine whether these techniques reduce interface scarring, astigmatism and graft rejection, improve visual outcomes, or are potentially an alternative for penetrating keratoplasty. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Jain, Sandeep; Azar, Dimitri T.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv, Boston, MA USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Corneal & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM dazar@meei.harvard.edu NR 25 TC 19 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 262 EP 268 DI 10.1097/00055735-200108000-00005 PG 7 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900005 PM 11507339 ER PT J AU Sippel, KC Ma, JJK Foster, CS AF Sippel, Kimberly C. Ma, Joseph J. K. Foster, C. Stephen TI Amniotic membrane surgery SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Human amniotic membrane (AM) is composed of three layers: a single epithelial layer, a thick basement membrane, and an avascular stroma. Amniotic membrane has anti-adhesive properties and is felt to promote epithelialization and decrease inflammation, neovascularization, and fibrosis. Amniotic membrane transplantation (AMT) is currently being used for a continuously widening spectrum of ophthalmic indications. Amniotic membrane transplantation has been shown to be effective in the reconstruction of the corneal surface in the setting of persistent epithelial defects, sterile corneal ulcerations, and partial limbal stem cell (LSC) deficiency states, including those secondary to chemical or thermal burns. Amniotic membrane transplantation also has been used in conjunction with limbal stem cell transplantation (LSCT) both in a concurrent fashion as well as in preparation for LSCT. Amniotic membrane transplantation also has been used in place of conjunctival autografting after pterygium excision and to reconstruct the conjunctival surface after removal of conjunctival lesions. Most recently, ex vivo cultivation and expansion of limbal epithelial cells has been performed utilizing AM as a matrix. However, the superiority of AMT over other treatment modalities in many of these settings needs to be substantiated by controlled clinical trials. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Sippel, Kimberly C.; Ma, Joseph J. K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv, Boston, MA USA. [Foster, C. Stephen] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Immunol & Uveitis Serv, Boston, MA USA. RP Foster, CS (reprint author), Massachusetts Eye & Ear Infirm, Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. EM fosters@uveitis.org NR 121 TC 83 Z9 91 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 269 EP 281 DI 10.1097/00055735-200108000-00006 PG 13 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900006 PM 11507340 ER PT J AU Khan, B Dudenhoefer, EJ Dohlman, CH AF Khan, Bilal Dudenhoefer, Eric J. Dohlman, Claes H. TI Keratoprosthesis: an update SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Porous polytetrafluoroethylene and polyurethane skirt materials, as well as copolymers of poly (2-hydroxyethyl methacrylate), have shown promise in approaching the goal of a "biointegratable" keratoprosthesis. A novel fixation method that uses scleral haptics also has been introduced to increase stability. An all silicone device that can be sewn into position has been used successfully, temporarily, during vitreoretinal procedures. The prognosis of keratoprosthesis (KPro) procedures depends on the preoperative diagnosis: graft failure-noncicatrizing disease>ocular cicatricial pemphigoid>chemical burns>Stevens-Johnson syndrome. The likelihood of endophthalmitis after KPro surgery follows this scheme. Causative organisms tend to be gram-positive. Modified vitreoretinal techniques also have been developed, allowing successful treatment of posterior segment complications. The science of keratoprosthesis is advancing more rapidly than in previous years. However, use of KPro to address complicated corneal blindness worldwide remains limited. The authors conducted an English language literature review from January 1, 2000 to April 1, 2001 and describe advances of note in the field of keratoprosthesis design, materials, and medical and surgical management. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Khan, Bilal; Dudenhoefer, Eric J.; Dohlman, Claes H.] Harvard Univ, Cornea & External Dis Serv, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Med Sch, Boston, MA USA. RP Dohlman, CH (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. NR 17 TC 56 Z9 68 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 282 EP 287 DI 10.1097/00055735-200108000-00007 PG 6 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900007 PM 11507341 ER PT J AU Johnson, JD Azar, DT AF Johnson, Jeffrey D. Azar, Dimitri T. TI Surgically induced topographical abnormalities after LASIK: management of central islands, corneal ectasia, decentration, and irregular astigmatism SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Proper preoperative evaluation is critical for avoiding many postoperative complications associated with laser in-situ keratomileusis (LASIK). Proper nonsurgical management includes careful monitoring of patients during the recovery period using various testing procedures, including corneal topography. When surgical intervention is required, a stepwise approach often is used as a conservative treatment, allowing further treatment if necessary. Many complications after LASIK are amenable to further treatment. However, it often is advisable to monitor patients until improved instrumentation is developed. The authors review the etiology and management of several complications after LASIK by reviewing the literature and relaying their own clinical experiences. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Johnson, Jeffrey D.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv, Boston, MA USA. [Azar, Dimitri T.] Harvard Univ, Sch Med, Ophthalmol, Boston, MA USA. [Azar, Dimitri T.] Massachusetts Eye & Ear Infirm, Corneal & Refract Surg Serv, Boston, MA 02114 USA. [Azar, Dimitri T.] Massachusetts Eye & Ear Infirm, Ophthalmol, Boston, MA 02114 USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM dazar@meei.harvard.edu NR 30 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 309 EP 317 DI 10.1097/00055735-200108000-00012 PG 9 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900012 PM 11507346 ER PT J AU Ang, RT Dartt, DA Tsubota, K AF Ang, Robert T. Dartt, Darlene A. Tsubota, Kazuo TI Dry eye after refractive surgery SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Photorefractive keratectomy and laser in situ keratomileusis can induce or exacerbate dry eye after surgery. This manifests as an increase in degree and frequency of symptoms, corneal findings, such as superficial punctate keratopathy, and abnormal results of dry eye tests, such as the Schirmer test and tear break-up time. The cause mainly involves decreased corneal sensation, resulting in decreased feedback to the lacrimal gland and reduced tear production. Other causes may include increased evaporation, inflammation, or toxicity of medications. Dry eye may result infrequently in impaired wound healing and decreased optical quality of the cornea, but it is transient, lasting from a few weeks up to 1 year. Patients should be warned about this distressing complication. During a period of dry eye, artificial tears and punctal plugs are helpful in preventing or alleviating patient discomfort. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Ang, Robert T.] Harvard Univ, Cornea & Refract Surg Serv, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Dartt, Darlene A.] Harvard Univ, Schepens Eye Res Inst, Sch Med, Boston, MA USA. [Tsubota, Kazuo] Ichikawa Gen Hosp, Tokyo Dent Coll, Tokyo, Japan. RP Dartt, DA (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM dartt@vision.eri.harvard.edu NR 43 TC 63 Z9 67 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 318 EP 322 DI 10.1097/00055735-200108000-00013 PG 5 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900013 PM 11507347 ER PT J AU Azar, DT Ang, RT Lee, JB Kato, T Chen, CC Jain, S Gabison, E Abad, JC AF Azar, Dimitri T. Ang, Robert T. Lee, Jae-Bum Kato, Takuji Chen, Chun Chen Jain, Sandeep Gabison, Eric Abad, Juan-Carlos TI Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article AB Laser epithelial keratomileusis (LASEK) is a surgical technique that may be performed in patients with low myopia who are considering conventional photorefractive keratectomy (PRK), in patients with thin corneas, and in patients with professions or lifestyles that predispose them to trauma. Ethanol (18%) is applied for 25 seconds and a hinged epithelial flap is created. After laser ablation, the flap is repositioned over the ablated stroma. Our data showed that epithelial defects occurred in 63% eyes on Day 1. Postoperative pain was absent in 47%. Uncorrected visual acuity of 20/40 or better was achieved in all patients at 1 week. Data from several studies suggest that LASEK may reduce postoperative pain and corneal haze associated with PRK. LASEK offers the potential advantage of avoiding flap-related complications associated with laser in situ keratomileusis and decreasing postoperative pain and corneal scarring associated with PRK. Long-term studies are needed to confirm these potential advantages and to determine the safety, efficacy, and predictability of this surgical technique. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 [Azar, Dimitri T.; Ang, Robert T.; Lee, Jae-Bum; Kato, Takuji; Chen, Chun Chen; Jain, Sandeep; Gabison, Eric; Abad, Juan-Carlos] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv, Boston, MA USA. [Azar, Dimitri T.; Ang, Robert T.; Lee, Jae-Bum; Kato, Takuji; Chen, Chun Chen; Jain, Sandeep; Gabison, Eric] Schepens Eye Res Inst, Boston, MA USA. [Ang, Robert T.] Asian Eye Inst, Makati, Philippines. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM dazar@meei.harvard.edu NR 18 TC 99 Z9 109 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD AUG PY 2001 VL 12 IS 4 BP 323 EP 328 DI 10.1097/00055735-200108000-00014 PG 6 WC Ophthalmology SC Ophthalmology GA V40ZG UT WOS:000209515900014 PM 11507348 ER PT J AU Rottbauer, W Baker, K Wo, ZG Mohideen, MAPK Cantiello, HF Fishman, MC AF Rottbauer, W Baker, K Wo, ZG Mohideen, MAPK Cantiello, HF Fishman, MC TI Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha 1 subunit SO DEVELOPMENTAL CELL LA English DT Article ID GATED ION CHANNELS; MESSENGER-RNAS; CA2+ CHANNELS; DANIO-RERIO; ZEBRAFISH; IDENTIFICATION; EXPRESSION; ALPHA(1C); MUSCLE; CELLS AB The heart must function from the moment of its embryonic assembly, but the molecular underpinnings of the first heart beat are not known, nor whether function determines form at this early stage. Here, we find by positional cloning that the embryonic lethal island beat (isl) mutation in zebrafish disrupts the alpha1 C L-type calcium channel subunit (C-LTCC). The isl atrium is relatively normal in size, and individual cells contract chaotically, in a pattern resembling atrial fibrillation. The ventricle is completely silent. Unlike another mutation with a silent ventricle, isl fails to acquire the normal number of myocytes. Thus, calcium signaling via C-LTCC can regulate heart growth independently of contraction, and plays distinctive roles in fashioning both form and function of the two developing chambers. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. RP Fishman, MC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU NHLBI NIH HHS [1RO1HL63206, 5R01HL49579]; NIDDK NIH HHS [5R01DK55383] NR 46 TC 116 Z9 119 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG PY 2001 VL 1 IS 2 BP 265 EP 275 DI 10.1016/S1534-5807(01)00023-5 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546XH UT WOS:000175301300013 PM 11702785 ER PT J AU Duvivier-Kali, VF Omer, A Parent, RJ O'Neil, JJ Weir, GC AF Duvivier-Kali, VF Omer, A Parent, RJ O'Neil, JJ Weir, GC TI Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane SO DIABETES LA English DT Article ID RAT PANCREATIC-ISLETS; DIABETIC NOD MICE; MANNURONIC ACID; IN-VITRO; XENOGRAFTS; XENOTRANSPLANTATION; MICROENCAPSULATION; TRANSPLANTATION; SURVIVAL; CELLS AB We describe a new technique for microencapsulation with high-mannuronic acid (high-M) alginate crosslinked with BaCl2 without a traditional permselective component, which allows the production of biocompatible capsules that allow prolonged survival of syngeneic and allogeneic transplanted islets in diabetic BALB/c and NOD mice for >350 days. The normalization of the glycemia in the transplanted mice was associated with normal glucose profiles in response to intravenous glucose tolerance tests. After explantation of the capsules, all mice became hyperglycemic, demonstrating the efficacy of the encapsulated islets. The retrieved capsules were free of cellular overgrowth and islets responded to glucose stimulation with a 5- to 10-fold increase of insulin secretion. Transfer of splenocytes isolated from transplanted NOD mice to NOD/SCID mice adoptively transferred diabetes, indicating that NOD recipients maintained islet-specific autoimmunity. In conclusion, we have developed a simple technique for microencapsulation that prolongs islet survival without immunosuppression, providing complete protection against allorejection and the recurrence of autoimmune diabetes. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr,Dept Med, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Weir, GC (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr,Dept Med, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [R01 DK 50657] NR 29 TC 150 Z9 156 U1 2 U2 14 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2001 VL 50 IS 8 BP 1698 EP 1705 DI 10.2337/diabetes.50.8.1698 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456RU UT WOS:000170096700003 PM 11473027 ER PT J AU Cummings, DE Purnell, JQ Frayo, RS Schmidova, K Wisse, BE Weigle, DS AF Cummings, DE Purnell, JQ Frayo, RS Schmidova, K Wisse, BE Weigle, DS TI A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans SO DIABETES LA English DT Article ID GROWTH-HORMONE SECRETAGOGUE; ARCUATE NUCLEUS; ACYLATED PEPTIDE; GH SECRETAGOGUE; DIURNAL RHYTHM; LEPTIN; SECRETION; RATS; ADIPOSITY; STOMACH AB The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radio-immunoassay in plasma samples drawn 38 times throughout, a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans. C1 Univ Washington, VA Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98108 USA. Harborview Med Ctr, Seattle, WA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Cummings, DE (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Seattle Div, 1660 S Columbian Way,S-111 Endo, Seattle, WA 98108 USA. FU NCRR NIH HHS [MO1RR00037]; NIDDK NIH HHS [K23-DK-02689, P30DK17047, R01-DK-55460] NR 30 TC 1700 Z9 1752 U1 12 U2 85 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2001 VL 50 IS 8 BP 1714 EP 1719 DI 10.2337/diabetes.50.8.1714 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456RU UT WOS:000170096700005 PM 11473029 ER PT J AU Yu, LP Cuthbertson, DD Maclaren, N Jackson, R Palmer, JP Orban, T Eisenbarth, GS Krischer, JP AF Yu, LP Cuthbertson, DD Maclaren, N Jackson, R Palmer, JP Orban, T Eisenbarth, GS Krischer, JP CA DPT-1 Participating Investigators TI Expression of GAD65 and islet cell antibody (ICA512) autoantibodies among cytoplasmic ICA+ relatives is associated with eligibility for the Diabetes Prevention Trial Type 1 SO DIABETES LA English DT Article ID INSULIN AUTOANTIBODY; DECARBOXYLASE ANTIBODIES; POSITIVE RELATIVES; PREDICT IDDM; MELLITUS; POPULATION; WORKSHOP; STANDARDIZATION; PROGRESSION; SIBLINGS AB More than 71,000 relatives of type 1 diabetic patients have been screened for cytoplasmic islet cell antibodies (ICAs), GAD65 autoantibodies (GAAs), and ICA512 autoantibodies (ICA512AAs). Among those 71,148 relatives, 2,448 were cytoplasmic ICA+, and the remainder were ICA-. Of the ICA+ group, 1,229 (50.2%) were positive for GAAs and/or ICA512AAs. Among ICA- relatives, 1,897 (2.76%) were positive for GAAs and/or ICA512AAs. Given the large number of relatives positive for cytoplasmic ICA and negative for "biochemically" determined autoantibodies, and the converse, we analyzed the proportion of ICA+ relatives found eligible to participate in the intervention phase of Diabetes Prevention Trial-Type 1 (DPT-1). To be eligible for the parenteral insulin DPT-1 trial, a relative had to have first-phase insulin secretion below the 1st percentile of cut-points (for parents) or below the 10th percentile (for siblings and offspring). To be eligible for the oral insulin trial, a relative had to have first-phase insulin secretion above cut-points (> 1st percentile for parents, >10th percentile for siblings/offspring) and be positive for anti-insulin autoantibodies. For both trials, DQB1*0602 was an exclusion criteria, cytoplasmic ICA positivity had to be confirmed, and an oral glucose tolerance test had to result in nondiabetic levels. Of 572 relatives found to be eligible for trial entry, 442 (77.3%) were positive for GAAs and/or ICA512AAs, although overall only 50.2% of ICA+ relatives were positive for GAAs and/or ICA512AAs. The positive predictive value for trial eligibility for ICA+ relatives with GAAs or ICA512AAs who completed staging was 51.0%. In contrast, only 11.9% of ICA+ but GAA- and ICA512AA-relatives were found to be eligible by DPT criteria for trial entry. Positivity for biochemically determined autoantibodies among cytoplasmic antibody-positive relatives is associated with eligibility for the DPT-1 study. C1 Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Denver, CO 80262 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Cornell Univ, Weill Med Coll, Juvenile Diabet Program, New York, NY USA. Harvard Univ, Joslin Diabet Ctr, Boston, MA USA. Univ Washington, Seattle Vet Affairs Med Ct, Seattle, WA 98195 USA. RP Eisenbarth, GS (reprint author), Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, 4200 E 9th Ave,B-140, Denver, CO 80262 USA. FU NCRR NIH HHS [M01-RR-00069]; NIDDK NIH HHS [5R37-DK-32083-16]; PHS HHS [R01-A1-39213] NR 29 TC 38 Z9 39 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2001 VL 50 IS 8 BP 1735 EP 1740 DI 10.2337/diabetes.50.8.1735 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456RU UT WOS:000170096700008 PM 11473032 ER PT J AU Trief, PM Himes, CL Orendorff, R Weinstock, RS AF Trief, PM Himes, CL Orendorff, R Weinstock, RS TI The marital relationship and psychosocial adaptation and glycemic control of individuals with diabetes SO DIABETES CARE LA English DT Article ID HEALTH SURVEY SF-36; SOCIAL SUPPORT; CHRONIC ILLNESS; FAMILY; ADJUSTMENT; MELLITUS; QUALITY; MANAGEMENT; FRAMEWORK; ADHERENCE AB OBJECTIVE - To explore the relationship between marital relationship domains (i.e., intimacy and adjustment) and glycemic control and psychosocial adaptation to diabetes. RESEARCH DESIGN AND METHODS - A total of 78 insulin-treated adults with both type 1 and type 2 diabetes were assessed on a Single occasion. They completed two marital quality measures (Spanier Dyadic Adjustment Scale and Personal Assessment of Intimacy in Relationships Scale) and four quality-of-life measures (Diabetes Quality of Life Scale, Medical Outcomes Study Health Survey, Problem Areas in Diabetes Scale, and Positive and Negative Affect Scale). Glycemic control was assessed by HbA(1c). Demographic data (age, sex, type and duration of diabetes, years married, other medical conditions, family history, disability, and years of education) were gathered from the chart and questionnaires. RESULTS - Concerning psychosocial adaptation, both of the marital quality measures were predictors of aspects of adaptation. Better marital satisfaction was related to higher levels of diabetes-related satisfaction and less impact, as well as less diabetes-related distress and better general quality of life. Higher levels of marital intimacy were related to better diabetes-specific and general quality of life, Concerning glycemic control, there was a nonsignificant trend for marital adjustment scores to relate to HbA(1c) (P = 0.0568). CONCLUSIONS - For insulin-treated adults with diabetes, quality of marriage is associated with adaptation to diabetes and other aspects of health-related quality of life, The suggestive finding that marital adjustment may relate to glycemic control warrants further study. Future work should also explore the impact of couples-focused interventions on adaptation, adherence, and glycemic control. C1 SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. Syracuse Univ, Syracuse, NY USA. Joslin Diabet Ctr, Syracuse, NY USA. Vet Adm Med Ctr, Syracuse, NY 13210 USA. RP Trief, PM (reprint author), SUNY Upstate Med Univ, Dept Psychiat, 750 E Adams St, Syracuse, NY 13210 USA. NR 30 TC 64 Z9 67 U1 3 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2001 VL 24 IS 8 BP 1384 EP 1389 DI 10.2337/diacare.24.8.1384 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456HE UT WOS:000170076400013 PM 11473074 ER PT J AU Meigs, JB Jacques, PF Selhub, J Singer, DE Nathan, DM Rifai, N D'Agostino, RB Wilson, PWF AF Meigs, JB Jacques, PF Selhub, J Singer, DE Nathan, DM Rifai, N D'Agostino, RB Wilson, PWF TI Fasting plasma homocysteine levels in the insulin resistance syndrome - The Framingham Offspring Study SO DIABETES CARE LA English DT Article ID CORONARY HEART-DISEASE; DEPENDENT DIABETES-MELLITUS; GLOMERULAR-FILTRATION RATE; RISK FACTOR; VASCULAR-DISEASE; CARDIOVASCULAR-DISEASE; MICROBIOLOGICAL ASSAY; LACTOBACILLUS-CASEI; JAPANESE PATIENTS; SERUM CREATININE AB OBJECTIVE - insulin resistance, associated metabolic abnormalities, and elevated homocysteine levels are risk factors for cardiovascular disease (CVD). We examined relationships between homocysteine levels and features of insulin resistance syndrome (IRS). RESEARCH DESIGN AND METHODS - We measured clinical characteristics plasma levels of fasting homocysteine, folate, B vitamins, creatinine, and fasting and 2-h insulin and glucose levels after a 75-g oral glucose tolerance test in 2,214 subjects without CVD at the Fifth examination (1991-1995) of the Framingham Offspring Study. After excluding 203 subjects with diabetes, the remaining 2,011 subjects were categorized as having none, one, two, or all three of the phenotypes of IRS: impaired glucose tolerance, hypertension, and/or a central metabolic syndrome (two or more traits: obesity, dyslipidemia, or hyperinsulinemia), In addition, in 1,592 subjects attending the sixth examination (1995-1998), we measured the urine albumin/creatinine ratio (UACR). Age-, sex-, creatinine-, vitamin-, and UACR-adjusted mean. homocysteine levels or proportions with homocysteine > 14 mu mol/l in each phenotypic category and differences between categories were assessed with regression models. RESULTS - The mean age of the Subjects was 54 years (range 28-82) 55% were women, 12.3% had hyperinsulinemia, and 15.9% had two or more of the IRS phenotypes. Adjusted mean homocysteine levels were higher comparing those with hyperinsulinemia (9.8 mu mol/l) and those without (9.4 mu mol/l, P = 0.04) and were higher among subjects with two or more IRS phenotypes (9.9 mu mol/l) compared with those with I or no phenotype (9.3 mu mol/l, P = 0.003). Mean UACR levels were also higher among subjects with two or more IRS phenotypes (7.2 mg/g) compared with those with I or no phenotype (5.5 mg/g, P = 0.007). CONCLUSIONS - Hyperhomocysteinemia and abnormal urinary albumin excretion are both associated with hyperinsulinemia and may partially account for increased risk of CVD associated with insulin resistance. Because hyperhomocystememia and microalbuminuria also reflect endothelial injury, these observations also support the hypothesis that endothelial dysfunction is associated with expression of the IRS. C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Gen Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Diabet Unit, Boston, MA USA. Childrens Hosp, Med Ctr, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Consulting Unit, Boston, MA 02215 USA. Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NHLBI NIH HHS [N01-HC-38083] NR 73 TC 178 Z9 191 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2001 VL 24 IS 8 BP 1403 EP 1410 DI 10.2337/diacare.24.8.1403 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456HE UT WOS:000170076400016 PM 11473077 ER PT J AU Mukamal, KJ Nesto, RW Cohen, MC Muller, JE Maclure, M Sherwood, JB Mittleman, MA AF Mukamal, KJ Nesto, RW Cohen, MC Muller, JE Maclure, M Sherwood, JB Mittleman, MA TI Impact of diabetes on long-term survival after acute myocardial infarction - Comparability of risk with prior myocardial infarction SO DIABETES CARE LA English DT Article ID CORONARY HEART-DISEASE; THROMBOLYTIC THERAPY; 10-YEAR SURVIVAL; MORTALITY; MELLITUS; PROGNOSIS; TRIAL; POPULATIONS; MANAGEMENT; EXPERIENCE AB OBJECTIVE - To determine the effect of diabetes on long-term survival after acute myocardial infarction and to compare its effect with that of a previous myocardial infarction. RESEARCH DESIGN AND METHODS - In a prospective cohort study, we followed 1,935 patients hospitalized with a confirmed acute myocardial infarction at 45 U.S. medical centers between 1989 and 1993, as part of the Determinants of Myocardial Infarction Onset Study. Trained interviewers performed chart reviews and face-to-face interviews with all patients. We analyzed survival using Cox proportional hazards regression to control for potentially confounding factors. RESULTS - Of the 1,935 patients, 320 (17%) died during a mean follow-up of 3.7 years. A total of 399 patients (21%) had previously diagnosed diabetes. Diabetes was associated with markedly higher total mortality in unadjusted (hazard ratio [HR] 2.4 95% Cl 1.9-3.0) and adjusted (1.7; 1.3-2.1) analyses. The magnitude of the effect of diabetes was identical to that of a previous myocardial infarction. The effect of diabetes was not significantly modified by age, smoking, household income, use of thrombolytic therapy, type of hypoglycemic treatment, or duration of diabetes, but the risk associated with diabetes was higher among women than men (adjusted HRs 2.7 vs. 1.3, P = 0.01). CONCLUSIONS - Diabetes is associated with markedly increased mortality after acute myocardial infarction, particularly in women. The increase in risk is of the same magnitude as a previous myocardial infarction and provides further support for aggressive treatment of coronary risk factors among diabetic patients. C1 Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. Lahey Clin Med Ctr, Dept Cardiovasc Med, Burlington, MA 01803 USA. Maine Med Ctr, Div Cardiol, Portland, ME 04102 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, 330 Brookline Ave,LY-03, Boston, MA 02215 USA. FU NHLBI NIH HHS [R01HL41016]; NIAAA NIH HHS [K23AA00299] NR 39 TC 146 Z9 156 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2001 VL 24 IS 8 BP 1422 EP 1427 DI 10.2337/diacare.24.8.1422 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 456HE UT WOS:000170076400019 PM 11473080 ER PT J AU Benito, N Navarro, P Arribas, M Valverde, AM Mur, C Kahn, R AF Benito, N Navarro, P Arribas, M Valverde, AM Mur, C Kahn, R TI Brown adipose tissue-specific insulin receptor knockout mice fed on high fat diet show obesity and diabetes phenotype. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Univ Complutense, Fac Farm, Dept Bioquim & Biol Mol, E-28040 Madrid, Spain. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2001 VL 44 SU 1 MA 13 BP A6 EP A6 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467MA UT WOS:000170706200014 ER PT J AU Foley, JE Gatlin, M Dunn, FL Horton, ES AF Foley, JE Gatlin, M Dunn, FL Horton, ES TI Both nateglinide and metformin sustain HbA(1c) lowering over 52 weeks in drug-naive type 2 diabetes patients SO DIABETOLOGIA LA English DT Meeting Abstract C1 Novartis Pharmaceut, E Hanover, NJ USA. Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 2 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2001 VL 44 SU 1 MA 826 BP A215 EP A215 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467MA UT WOS:000170706200825 ER PT J AU Moses, A Clemmons, D Sommer, A Jacobson, W AF Moses, A Clemmons, D Sommer, A Jacobson, W TI IGF-1/BP3 (Somatokine) is well tolerated and is biologically active in patients with type 2 diabetes mellitus receiving insulin. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. Insmed Inc, Richmond, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2001 VL 44 SU 1 MA 909 BP A237 EP A237 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467MA UT WOS:000170706200909 ER PT J AU Valverde, AM Mar, C Arribas, M Navarro, P Kahn, CR Benito, M AF Valverde, AM Mar, C Arribas, M Navarro, P Kahn, CR Benito, M TI Increased insulin sensitivity in IGF-I receptor-deficient brown adipocytes. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Univ Complutense Madrid, Fac Farm, CSIC, Inst Bioquim,Ctr Mixto, E-28040 Madrid, Spain. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2001 VL 44 SU 1 MA 299 BP A79 EP A79 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467MA UT WOS:000170706200301 ER PT J AU van der Ven, NCW Weinger, K Yi, J Snoek, FJ AF van der Ven, NCW Weinger, K Yi, J Snoek, FJ TI The role of self-efficacy in self-management of type 1 diabetes: Development and validation of the Confidence In Diabetes Self-care scale (CIDS) in Dutch and US patients. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Joslin Diabet Ctr, Behav Res Sect, Boston, MA 02215 USA. Vrije Univ Amsterdam, Med Ctr, Dept Med Psychol, Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2001 VL 44 SU 1 MA 989 BP A258 EP A258 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467MA UT WOS:000170706200989 ER PT J AU Shito, M Balis, UJ Tompkins, RG Yarmush, ML Toner, M AF Shito, M Balis, UJ Tompkins, RG Yarmush, ML Toner, M TI A fulminant hepatic failure model in the rat - Involvement of interleukin-1 beta and tumor necrosis factor-alpha SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE D-galactosamine; cytokine; hepatocellular injury; animal model; bioartificial liver support systems ID ACUTE LIVER-FAILURE; BIOARTIFICIAL LIVER; TISSUE-INJURY; GALACTOSAMINE HEPATITIS; GENE-EXPRESSION; MICE; HEPATOTOXICITY; REGENERATION; EXPERIENCE; CELLS AB The development of a fulminant hepatic failure (FHF) model is necessary for evaluating the efficacy of extracorporeal liver support systems. Recognizing the multifaceted functions of the liver, including synthesis and degradation, we investigated blood chemistry, histological findings, and survival rate in D-galactosamine (Ga1N)-intoxicated rats. The pathophysiologic response of inflammatory cytokines, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), was also measured. Sprague-Dawley rats (200-300 g) were divided into two groups: Ga1N and saline injection. Rats were killed at 1, 3, 6, 12, 24, 36, 48, 72, and 168 hr after intraperitoneal injection of Ga1N (1.4 g/kg) or saline. In both groups, liver-specific markers, liver histology, and IL-I beta and TNF-alpha levels in blood and liver tissue were analyzed. In a second series of experiments, the survival rates were examined after two administrations of Ga1N at 1.0, 1.4 or 2.0 g/kg, at a 12-hr interval. In the Ga1N injection group, the liver-specific markers reached peak levels between 36 and 48 hr after injection. Histologically, hepatocellular necrosis was seen at 6-48 hr, followed by a regenerative phase occurring between 72 and 168 hr. IL-I beta and TNF-alpha levels in liver tissue peaked at 12 hr and 1 hr, respectively. The levels of these cytokines in blood, however, did not change significantly. The survival rates at day 7 for 1.0, 1.4 or 2.0 g/kg Ga1N injected twice were 77.8%, 16.7%, and 0%, respectively. These results suggest that single and double injection of Ga1N enable the development of reversible and irreversible FHF models. The results also indicate that IL-1 beta and TNF-alpha are useful markers of liver injury. C1 Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, Bigelow 1401,55 Fruit St, Boston, MA 02114 USA. NR 33 TC 37 Z9 49 U1 0 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2001 VL 46 IS 8 BP 1700 EP 1708 DI 10.1023/A:1010653504568 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 462EM UT WOS:000170407800017 PM 11508670 ER PT J AU Poulaki, V Mitsiades, CS Mitsiades, N AF Poulaki, V Mitsiades, CS Mitsiades, N TI The role of Fas and FasL as mediators of anticancer chemotherapy SO DRUG RESISTANCE UPDATES LA English DT Review ID DRUG-INDUCED APOPTOSIS; FAS/FAS LIGAND INTERACTIONS; CARCINOMA CELL-LINES; APO-1/FAS RECEPTOR/LIGAND SYSTEM; DOXORUBICIN-INDUCED APOPTOSIS; FLICE-INHIBITORY PROTEIN; EWINGS-SARCOMA FAMILY; BLADDER-CANCER CELLS; TUMOR-CELLS; DOWN-REGULATION AB Fas Ligand (FasL) is a member of the TNF superfamily that induces apoptosis in susceptible cells upon cross-linking of its own receptor, Fas (Apo-I/CD95). FasL-induced apoptosis contributes to immune homeostasis and cell-mediated cytotoxicity. Several groups have suggested that it also participates in the mechanism of action of DNA-damaging anticancer drugs. However, others have disputed this hypothesis, based largely on the inability of exogenously added anti-Fas/FasL reagents to attenuate drug-induced apoptosis in their studies. In this minireview, we discuss the most recent evidence for and against the involvement of FasL/Fas in the sensitivity and resistance to chemotherapy in a variety of models. In our own model of Ewing's sarcoma (ES), we have extensively investigated the involvement of the FasL/Fas pathway in doxorubicin (Dox)-induced apoptosis. We have generated clones of the Fas-sensitive, Dox-sensitive ES cell line SK-N-MC that were either Fas-resistant or FasL-deficient, and found that they were significantly resistant to Dox. Cleavage of FasL by MMP-7 (matrilysin) protected the parental SK-N-MC cells from Dox, whereas inhibition of MMP-7 activity increased their sensitivity. Transfection of a construct encoding soluble (decoy) Fas protected SK-N-MC cells from Dox. However, incubation with anti-Fas or anti-FasL neutralizing antibodies or exogenous addition of pre-synthesized recombinant soluble Fas decoy protein had no protective effect. This raises the possibility that the proposed Fas/FasL suicidal interaction may take place in an intracellular compartment and thus is not accessible to exogenously added reagents. Therefore, commercially available Fas/FasL neutralizing reagents may not be a reliable indicator of the involvement of the Fas pathway in anticancer-drug-induced apoptosis and experiments using these agents should be carefully re-evaluated. The combined use of MMP inhibitors with conventional, cytotoxic chemotherapy may hold therapeutic benefit. (C) 2001 Harcourt Publishers Ltd. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Poulaki, V (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, 325 Cambridge St, Boston, MA 02114 USA. NR 116 TC 54 Z9 59 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD AUG PY 2001 VL 4 IS 4 BP 233 EP 242 DI 10.1054/drup.2001.0210 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 545EZ UT WOS:000175204900003 PM 11991678 ER PT J AU Wisse, BE Frayo, RS Schwartz, MW Cummings, DE AF Wisse, BE Frayo, RS Schwartz, MW Cummings, DE TI Reversal of cancer anorexia by blockade of central melanocortin receptors in rats SO ENDOCRINOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; TUMOR-BEARING RATS; FOOD-INTAKE; MEGESTROL-ACETATE; NEUROPEPTIDE-Y; WEIGHT-LOSS; PROSTATE-CANCER; STIMULATES FOOD; BODY-WEIGHT; CACHEXIA AB Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 +/- 3% to 110 +/- 6% of preanorectic baseline and caused significant weight gain (13 +/- 5 vs. 5 +/- 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebroventricular ghrelin (10 mug) increased food intake, but the effect was blunted relative to that in controls. Intracerebroventricular injections of NPY (1 mug) also failed to reverse anorexia in tumor-bearing rats. Because SHU9119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is implicated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin pathways. C1 Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98108 USA. RP Cummings, DE (reprint author), Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, 1660 S Columbian Way,Endo 111, Seattle, WA 98108 USA. RI Schwartz, Michael/H-9950-2012 FU NIDDK NIH HHS [DK-35816, T32-DK-07247] NR 49 TC 164 Z9 166 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2001 VL 142 IS 8 BP 3292 EP 3301 DI 10.1210/en.142.8.3292 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 459ZC UT WOS:000170280500003 PM 11459770 ER PT J AU Kogai, T Hershman, JM Motomura, K Endo, T Onaya, T Brent, GA AF Kogai, T Hershman, JM Motomura, K Endo, T Onaya, T Brent, GA TI Differential regulation of the human sodium/iodide symporter gene promoter in papillary thyroid carcinoma cell lines and normal thyroid cells SO ENDOCRINOLOGY LA English DT Article ID SODIUM-IODIDE SYMPORTER; TRANSCRIPTION FACTOR-I; TUMOR-NECROSIS-FACTOR; HUMAN NA+/I SYMPORTER; FRTL-5 CELLS; FUNCTIONAL-CHARACTERIZATION; INCREASED EXPRESSION; HISTONE ACETYLATION; STIMULATING HORMONE; CULTURED-CELLS AB The absence of TSH-stimulated radioiodide uptake in differentiated thyroid cancer is associated with a high recurrence rate and reduced survival. We studied regulation of the sodium/iodide symporter gene in human papillary thyroid cancer cell lines (BHP) and primary human thyroid cells. BHP cells expressed very low levels of sodium/iodide symporter mRNA and did not concentrate iodide, but iodide uptake was restored to levels seen in FRTL-5 rat thyroid cells by stable transfection of a sodium/iodide symporter cDNA. Sodium/iodide symporter gene expression, therefore, was necessary and sufficient for iodide uptake in BHP cells. We cloned the human sodium/iodide symporter gene 5'-flanking region and analyzed progressive 5'-deletions in transient transfections. We identified a region, -596 to -268, essential to confer full promoter activity in primary normal human thyroid cells. Sodium/iodide symporter promoter activity in four BHP cell lines, however, was markedly reduced, consistent with downregulation of the endogenous sodium/iodide symporter gene. Nuclear extracts from BHP 2-7 cells had reduced or absent binding to regions of the sodium/iodide symporter promoter shown to be critical for expression, compared with nuclear extracts from FRTL-5 cells. Competition studies indicated that these nuclear proteins were not known thyroid transcription factors. Modifications of the sodium/iodide symporter promoter with demethylation or histone acetylation did not increase sodium/iodide symporter expression, and no deletions of the critical regulatory region were identified in the endogenous gene in BHP cells. Regulation of the sodium/iodide symporter 5'-flanking region in transient transfection paralleled endogenous sodium/iodide symporter expression. Reduced expression of potential novel nuclear factor(s) in these cell lines may contribute to reduced sodium/iodide symporter expression resulting in absence of iodide uptake in some papillary thyroid cancers. C1 Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Healthcare Syst, Div Endocrinol,Mol Endocrinol Lab, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90073 USA. Yamanashi Med Univ, Dept Internal Med 3, Yamanashi 4093898, Japan. RP Brent, GA (reprint author), Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Healthcare Syst, Div Endocrinol,Mol Endocrinol Lab, 11301 Wilshire Blvd,Bldg 114,Room 230, Los Angeles, CA 90073 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 55 TC 27 Z9 32 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2001 VL 142 IS 8 BP 3369 EP 3379 DI 10.1210/en.142.8.3369 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 459ZC UT WOS:000170280500013 PM 11459780 ER PT J AU Tortoriello, DV Sidis, Y Holtzman, DA Holmes, WE Schneyer, AL AF Tortoriello, DV Sidis, Y Holtzman, DA Holmes, WE Schneyer, AL TI Human follistatin-related protein: A structural homologue of follistatin with nuclear localization SO ENDOCRINOLOGY LA English DT Article ID ACTIVIN-BINDING PROTEIN; SUBCELLULAR-LOCALIZATION; SPERMATOGENIC CELLS; FOLLICULAR-FLUID; HEPARAN-SULFATE; II RECEPTORS; INHIBIN; RAT; IDENTIFICATION; ORGANOGENESIS AB Follistatin-related protein is a recently discovered glycoprotein that is highly homologous in both primary sequence and exon/intron domain structure to the activin-binding protein, follistatin. We explored their potential for functional redundancy by investigating the relative affinities and kinetics of their interactions with activin, bone morphogenic protein-6, and bone morphogenic protein-7 and by exploring their expression and distribution in human tissues and cells. Follistatin and follistatin-related protein mRNA were ubiquitous by Northern analyses, although their sites of peak distribution differed, with follistatin-related protein and follistatin predominating in the placenta and ovary, respectively. Follistatin-related protein, like follistatin, preferentially bound activin with high affinity and in an essentially irreversible fashion. Although follistatin-related protein, like follistatin, possesses a signal sequence and no known nuclear localization signals, its secretion was undetectable in most cell lines by RIA. Intriguingly, follistatin-related protein was identified as a nuclear protein in human granulosa cells and all human cell lines tested. Furthermore, Western analyses of CHO cells transfected with human follistatin-related protein revealed this protein to reside within the insoluble nuclear protein fraction. We conclude that despite its remarkably high level of similarity to follistatin with regard to structure and activin binding kinetics, follistatin-related protein is a nuclear as well as a secretory protein that may perform distinct intracellular actions. C1 Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02144 USA. Massachusetts Gen Hosp, Natl Ctr Infertil Res, Boston, MA 02144 USA. Millennium Pharmaceut, Cambridge, MA 02144 USA. Microbia Inc, Cambridge, MA 02139 USA. RP Tortoriello, DV (reprint author), Columbia Univ Coll Phys & Surg, Div Mol Genet, Ross Berrie Med Sci Pavil,1150 St Nicholas Ave, New York, NY 10032 USA. FU NICHD NIH HHS [HD-29164, HD-39777]; NIDDK NIH HHS [DK-55838] NR 32 TC 80 Z9 85 U1 1 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2001 VL 142 IS 8 BP 3426 EP 3434 DI 10.1210/en.142.8.3426 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 459ZC UT WOS:000170280500020 PM 11459787 ER PT J AU Sugimoto, Y Morita, R Amano, K Shah, PU Pascual-Castroviejo, I Khan, S Delgado-Escueta, AV Yamakawa, K AF Sugimoto, Y Morita, R Amano, K Shah, PU Pascual-Castroviejo, I Khan, S Delgado-Escueta, AV Yamakawa, K TI T-STAR gene: fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients SO EPILEPSY RESEARCH LA English DT Article DE T-STAR; genomic structure; chromosomal band 8q24; physical map ID RNA-BINDING PROTEIN; SIGNAL-TRANSDUCTION; CHROMOSOME 8Q24; FAMILY AB Childhood absence epilepsy (CAE) is one of the most common epilepsies in children. At least four phenotypic subcategories of CAE have been proposed. Among them, a subtype persisting with tonic-clonic seizures has been mapped to 8q24 (ECA I MIM 600131). By constructing a physical map for the 8q24 region, we recently narrowed the ECA1 locus to a 1.5-Mb region. In the present communication, we show that T-STAR gene is located within the ECA I region. T-STAR is a novel member of STAR (for signal transduction and activation of RNA) family, and is predicted to encode a spermatogenesis related RNA-binding protein. T-STAR is located within the markers D8S2049 and D8S1753 and its complete coding region spans nine exons. In addition to its known expression in testis, moderate level of transcripts for T-STAR gene was detected in brain, heart and is highly abundant in skeletal muscle. Mutational analysis for the T-SATR gene in CAE families did not show any sequence variation in the coding region, and this suggests that the T-STAR gene is not involved in the pathogenesis of persisting CAE. However, genomic organization of T-STAR gene characterized in the present report might help in understanding the biological functions of T-STAR as well as its suspected involvement in other disorders mapped on this region. (C) 2001 Elsevier Science B.V. All rights reserved. C1 RIKEN, Inst Phys & Chem Res, Brain Sci Inst, Neurogenet Lab, Wako, Saitama 3510198, Japan. KEM Hosp, Bombay, Maharashtra, India. Seth GS Med Coll, Bombay, Maharashtra, India. Univ Madrid, Hosp La Paz, Madrid, Spain. Riyadh Armed Forces Hosp, Dept Neurosci, Riyadh, Saudi Arabia. Univ Calif Los Angeles, Sch Med, Comprehens Epilepsy Program, Los Angeles, CA 90073 USA. W Los Angeles DVA Med Ctr, Los Angeles, CA 90073 USA. RP Yamakawa, K (reprint author), RIKEN, Inst Phys & Chem Res, Brain Sci Inst, Neurogenet Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. RI Yamakawa, Kazuhiro/N-5050-2015 NR 16 TC 6 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD AUG PY 2001 VL 46 IS 2 BP 139 EP 144 DI 10.1016/S0920-1211(01)00274-1 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 461PQ UT WOS:000170373000006 PM 11463515 ER PT J AU Swanton, BJ Iohom, G Wang, JH Redmond, HP Shorten, GD AF Swanton, BJ Iohom, G Wang, JH Redmond, HP Shorten, GD TI The effect of lidocaine on neutrophil respiratory burst during induction of general anaesthesia and tracheal intubation SO EUROPEAN JOURNAL OF ANAESTHESIOLOGY LA English DT Article DE anaesthetics, intravenous, thiopental, anaesthetics, local, amide, lidocaine; cell physiology, cell respiration, respiratory burst; immune system, leucocytes, granulocytes, neutrophils ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; BACTERIAL PEPTIDE FMLP; OXIDATIVE RESPONSE; IN-VITRO; ANESTHETIC AGENTS; NITROUS-OXIDE; LARYNGOSCOPY; ALFENTANIL; ENFLURANE; MIDAZOLAM AB Background and objective Respiratory burst is an essential component of the neutrophil's biocidal function. In vitro, sodium thiopental, isoflurane and lidocaine each inhibit neutrophil respiratory burst. The objectives of this study were (a) to determine the effect of a standard clinical induction/tracheal intubation sequence on neutrophil respiratory burst and (b) to determine the effect of intravenous lidocaine administration during induction of anaesthesia on neutrophil respiratory burst. Methods Twenty ASA I and II patients, aged 18-60 years, undergoing elective surgery were studied. After induction of anaesthesia [fentanyl (2 mug kg(-1)), thiopental (4-6 mg kg(-1)), isoflurane (end-tidal concentration 0.5-1.5%) in nitrous oxide (66%) and oxygen], patients randomly received either lidocaine 1.5 mg kg(-1) (group L) or 0.9% saline (group S) prior to tracheal intubation. Neutrophil respiratory burst was measured immediately prior to induction of anaesthesia, immediately before and 1 and 5 min after lidocaine/saline. Results Neutrophil respiratory burst decreased significantly after induction of anaesthesia in both groups [87.4 +/- 8.2% (group L) and 88.5 +/- 13.4% (group S) of preinduction level (P < 0.01 both groups)]. After intravenous lidocaine (but not saline) administration, neutrophil respiratory burst returned towards preinduction levels, both before (97.1 +/- 23.6%) and after (94.4 +/- 16.6%) tracheal intubation. Conclusion Induction of anaesthesia and tracheal intubation using thiopentone and isoflurane, inhibit neutrophil respiratory burst. This effect may be diminished by the administration of lidocaine. C1 Cork Univ Hosp, Dept Anaesthesia & Intens Care Med, Cork, Ireland. Cork Univ Hosp, Dept Surg, Cork, Ireland. RP Swanton, BJ (reprint author), Massachusetts Gen Hosp, Dept Anaesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 29 TC 5 Z9 6 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0265-0215 J9 EUR J ANAESTH JI Eur. J. Anaesth. PD AUG PY 2001 VL 18 IS 8 BP 524 EP 529 DI 10.1046/j.1365-2346.2001.00887.x PG 6 WC Anesthesiology SC Anesthesiology GA 462NA UT WOS:000170425100007 PM 11473559 ER PT J AU Meyer, M Hensbergen, PJ van der Raaij-Helmer, EMH Brandacher, G Margreiter, R Heufler, C Koch, F Narumi, S Werner, ER Colvin, R Luster, AD Tensen, CP Werner-Felmayer, G AF Meyer, M Hensbergen, PJ van der Raaij-Helmer, EMH Brandacher, G Margreiter, R Heufler, C Koch, F Narumi, S Werner, ER Colvin, R Luster, AD Tensen, CP Werner-Felmayer, G TI Cross reactivity of three T cell attracting murine chemokines stimulating the CXC chemokine receptor CXCR3 and their induction in cultured cells and during allograft rejection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE chemokine; CXCR3; interferon ID INDUCIBLE PROTEIN 10; ALPHA CHEMOATTRACTANT; I-TAC; EXPRESSION; GENE; BINDING; GAMMA; MIG; LYMPHOCYTES; CLONING AB Recent work identified the murine gene homologous to the human T cell attracting chemokine CXC receptor ligand 11 (CXCL11, also termed I-TAC, SCYB11, beta -R1, H174, IP-9). Here, the biological activity and expression patterns of murine CXCL11 relative to CXCL9 (MIG) and CXCL10 (IP-10/crg-2), the other two CXCR3 ligands, were assessed. Calcium mobilization and chemotaxis experiments demonstrated that murine CXCL11 stimulated murine CXCR3 at much lower doses than murine CXCL9 or murine CXCL10. Murine CXCL11 also evoked calcium mobilization in CHO cells transfected with human CXCR3 and was chemotactic for CXCR3-expressing human T lymphocytes as well as for 300-19 pre-B cells transfected with human or murine CXCR3. Moreover, murine CXCL11 blocked the chemotactic effect of human CXCL11 on human CXCR3 transfectants. Depending on cell type (macrophage-like cells RAW264.7, J774A.1, fetal F20 and adult dermal fibroblasts, immature and mature bone marrow-derived dendritic cells) and stimulus (interferons, LPS, IL-1 beta and TNF-alpha), an up to 10,000-fold increase of CXCL9, CXCL10 and CXCL11 mRNA levels, quantified by real-time PCR, was observed. In vivo, the three chemokines are constitutively expressed in various tissues from healthy BALB/c mice and were strongly up-regulated during rejection of allogeneic heart transplants. Chemokine mRNA levels exceeded those of CXCR3 and IFN-gamma which were induced with similar kinetics by several orders of magnitude. C1 Univ Innsbruck, Inst Med Chem & Biochem, A-6020 Innsbruck, Austria. Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. Univ Innsbruck Hosp, Dept Transplant Surg, A-6020 Innsbruck, Austria. Univ Innsbruck, Univ Hosp, Dept Dermatol, Innsbruck, Austria. Univ Tokyo, Sch Med, Dept Mol Prevent Med, Tokyo 113, Japan. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA USA. RP Werner-Felmayer, G (reprint author), Univ Innsbruck, Inst Med Chem & Biochem, Fritz Pregl Str 3, A-6020 Innsbruck, Austria. EM gabriele.werner-felmayer@uibk.ac.at RI Brandacher, Gerald/L-7540-2016 FU NCI NIH HHS [R01-CA69212] NR 25 TC 45 Z9 49 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2001 VL 31 IS 8 BP 2521 EP 2527 DI 10.1002/1521-4141(200108)31:8<2521::AID-IMMU2521>3.0.CO;2-Q PG 7 WC Immunology SC Immunology GA 465GD UT WOS:000170580500032 PM 11500837 ER PT J AU Fischman, AJ Bonab, AA Feifel, D Hoh, C Barkley, RA Lichio, R McGough, JJ Mishkin, F Tuite, P Madras, BK Lanser, ME AF Fischman, AJ Bonab, AA Feifel, D Hoh, C Barkley, RA Lichio, R McGough, JJ Mishkin, F Tuite, P Madras, BK Lanser, ME TI Binding potential for I-123 Altropane is increased in striatum of young ADHD patients: Results of a multicenter trial SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD AUG PY 2001 VL 28 IS 8 SU S MA OS286 BP 1035 EP 1035 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 464HZ UT WOS:000170528300286 ER PT J AU El Fakhri, G Kijewski, MF Hilson, JB Johnson, KA Zimmerman, RE Becker, JA Killiany, R Jones, K Albert, MS AF El Fakhri, G Kijewski, MF Hilson, JB Johnson, KA Zimmerman, RE Becker, JA Killiany, R Jones, K Albert, MS TI Quantitative SPECT and volumetric MRI for discrimination between normal controls and preclinical Alzheimer's disease SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Brandeis Univ, Waltham, MA 02254 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD AUG PY 2001 VL 28 IS 8 SU S MA OS382 BP 1059 EP 1059 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 464HZ UT WOS:000170528300382 ER PT J AU Barrow, SA Bonab, AA Livni, E Madras, BK Meltzer, P Fischman, AJ AF Barrow, SA Bonab, AA Livni, E Madras, BK Meltzer, P Fischman, AJ TI Measurement of dopamine transporter (DAT) density in human striatum by PET with 11C Altropane SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD AUG PY 2001 VL 28 IS 8 SU S MA PS239 BP 1137 EP 1137 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 464HZ UT WOS:000170528300680 ER PT J AU Barrow, SA Burker, M McCusker, CD Carter, EA Fischman, AJ AF Barrow, SA Burker, M McCusker, CD Carter, EA Fischman, AJ TI Effect of intra-gastric polyethylene glycol-electrolyte solution (GoLYTELY) on gastrointestinal distribution of 18FDG in rats SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. RI McCusker, Catherine/G-2795-2010 OI McCusker, Catherine/0000-0001-9580-3612 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD AUG PY 2001 VL 28 IS 8 SU S MA PS347 BP 1164 EP 1164 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 464HZ UT WOS:000170528300784 ER PT J AU Mouriaux, F Chahud, F Maurage, CA Malecaze, F Labalette, P AF Mouriaux, F Chahud, F Maurage, CA Malecaze, F Labalette, P TI Implication of stem cell factor in the proliferation of choroidal melanocytes SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE cell culture; choroidal; c-kit; melanocytes; proliferation; stem cell factor ID FACTOR RECEPTOR PROTOONCOGENE; HUMAN UVEAL MELANOCYTES; C-KIT GENE; GROWTH-FACTOR; MAST-CELL; HUMAN PIEBALDISM; TYROSINE KINASE; PROTO-ONCOGENE; HUMAN TISSUES; LUNG-CANCER AB The tyrosine kinase receptor c-kit and its ligand stem cell factor exert a broad range of biological activities during organogenesis. It also improves normal cell development including complex biological responses involved in the differentiation and proliferation of the melanocytes. Diffuse uveal melanocytic proliferation is a rare paraneoplasic syndrome, resulting in rapid bilateral visual loss due to proliferation of melanocytes within the choroid, We have therefore investigated whether the c-kit/stem cell factor pathway regulates the proliferation of choroidal melanocytes and also if such pathway plays a role in bilateral uveal melanocytic proliferation. Normal cultured melanocytes of the choroid and paraffin-embedded sections of melanocytic proliferation were studied. C-kit expression and effects of stem cell factor were measured. Western blot assays of cell extracts demonstrated that c-kit was expressed in choroidal melanocytes. Immunocytochemical analysis on cultured melanocytes showed a cytoplasmic distribution. Immunohistochemical analysis on melanocytic proliferation showed a strong cytoplasmic distribution in the pigmented spindle-shaped melanocytes localized in the multiple focal areas of choroidal thickening. The addition of stem cell factor did not change melanocyte morphologies and was mitogenic in the presence of bFGF, isobutyl-l-methylxanthine and cholera toxin. In contrast, stem cell factor was not able to produce any significant melanin. Activation of c-kit by its ligand may contribute to the proliferation of choroidal melanocytes. (C) 2001 Academic Press. C1 Ctr Hosp Reg & Univ Lille, Claude Hurlez Hosp, Div Ophthalmol, F-59037 Lille, France. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Ophthalmol, Boston, MA USA. Ctr Hosp Reg & Univ Lille, Calmette Hosp, Div Pathol, F-59037 Lille, France. CHRU, Purpan Hosp, Div Ophthalmol, F-31000 Toulouse, France. RP Mouriaux, F (reprint author), Ctr Hosp Reg & Univ Lille, Claude Hurlez Hosp, Div Ophthalmol, 2 Av O Lambret, F-59037 Lille, France. NR 42 TC 13 Z9 14 U1 1 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD AUG PY 2001 VL 73 IS 2 BP 151 EP 157 DI 10.1006/exer.2001.1017 PG 7 WC Ophthalmology SC Ophthalmology GA 454VH UT WOS:000169992100001 PM 11446765 ER PT J AU Edwards, IJ Rudel, LL Terry, JG Kemnitz, JW Weindruch, R Zaccaro, DJ Cefalu, WT AF Edwards, IJ Rudel, LL Terry, JG Kemnitz, JW Weindruch, R Zaccaro, DJ Cefalu, WT TI Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Lp(a); lipids; calorie restriction; atherosclerosis; aging ID DIETARY RESTRICTION; LP(A); ISOFORMS; DISEASE; SERUM AB Many age-associated pathophysiological changes are retarded by caloric restriction (CR). The present study has investigated the effect of CR on plasma lipoprotein (a) [Lp(a)], an independent risk factor for the age-associated process of atherosclerosis. Rhesus monkeys were fed a control diet (n = 19 males, 12 females) or subjected to CR (n = 20 males, 11 females fed 30% less calories) for >2 years. All female animals were premenopausal, Plasma Lp(a) levels in control animals were almost two fold higher for males than females (47 +/- 9 vs 25 +/- 5 mg/dl mean SEM, p = 0.05). CR resulted in a reduction in circulating Lp(a) in males to levels similar to those measured in calorie-restricted females, (27 +/- 5 vs. 24 +/- 4 mg/dl mean +/- SEM). For all animals, plasma Lp(a) was correlated with total cholesterol (r = 0.27, p = 0.03) and LDL cholesterol (r = 0.50, p = 0.0001) whether unadjusted or after adjustment for treatment, gender or group. These studies introduce a new mechanism whereby CR may have a beneficial effect on risk factors for the development of atherosclerosis in primates. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA. Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA. Univ Wisconsin, Dept Med, Madison, WI 53706 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53706 USA. William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53705 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. RP Edwards, IJ (reprint author), Wake Forest Univ, Sch Med, Dept Pathol, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. FU NCRR NIH HHS [RR00167]; NHLBI NIH HHS [HL49373]; NIA NIH HHS [AG14190, AG11915, AG10816, AG00578] NR 18 TC 19 Z9 19 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD AUG PY 2001 VL 36 IS 8 BP 1413 EP 1418 DI 10.1016/S0531-5565(01)00107-3 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 470BM UT WOS:000170850600014 PM 11602214 ER PT J AU Mitsiades, N Mitsiades, CS Poulaki, V Anderson, KC Treon, SP AF Mitsiades, N Mitsiades, CS Poulaki, V Anderson, KC Treon, SP TI Concepts in the use of TRAIL/Apo2L: an emerging biotherapy for myeloma and other neoplasias SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE Apo2 ligand; B-cells; caspase; FLIP; multiple myeloma; NF-kappa B; plasma cells; TNF-related apoptosis inducing ligand; TRAIL ID APOPTOSIS-INDUCING LIGAND; NF-KAPPA-B; TRAIL-INDUCED APOPTOSIS; FAS-MEDIATED APOPTOSIS; FADD-DEPENDENT APOPTOSIS; HUMAN-MELANOMA CELLS; DEATH RECEPTOR GENE; MULTIPLE-MYELOMA; APO2 LIGAND; IN-VIVO AB TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) is a member of the TNF superfamily of death ligands that selectively induces apoptosis in tumour cells of diverse origins. in this report, we have reviewed recent studies examining TRAIL/Apo2L-induced apoptosis in multiple myeloma (MM), a B-cell malignancy which, in spite of its initial sensitivity to steroids, cytotoxic and high-dose chemotherapy, remains incurable. Recently, we demonstrated that TRAILApo2L induces apoptosis of steroid- and chemotherapy-sensitive and resistant MM cell lines. Moreover, TRAIL/Apo2L selectively induced apoptosis of patient MM tumour cells while sparing nonmalignant bone marrow and peripheral blood mononuclear cells. In addition, TRAIL/Apo2L inhibited the growth of human plasmacytomas xenografted into mice. Importantly, TRAIL/Apo2L-induced apoptosis was unaffected by IL-6, a potent growth and survival factor for MM cells which, as we and others have previously shown, blocks various pro-apoptotic signals including Fas ligand, which like TRAIL/Apo2L is also a member of the TNF family of ligands. In view of the potential clinical application of TRAIL/Apo2L to the treatment of MM, we have attempted to discern intracellular mechanisms of action and resistance for TRAIL/Apo2L in MM, along with strategies to increase sensitivity and overcome resistance of MM cells to TRAIL/Apo2L. These studies demonstrated that doxorubicin, an agent which is commonly used to treat MM patients, upregulated the expression of the DR5 death-signalling TRAIL receptor and synergistically enhanced the pro-apoptotic effect of TRAIL on MM cells. Moreover, NF-kappaB inhibitors such as SN50 (a cell permeable inhibitor of NF-kappaB nuclear translocation) as well as the proteasome inhibitor PS-341, which is currently in Phase II clinical trials, also enhanced the pro-apoptotic activity of TRAIL/Apo2L in MM cells. Lastly, TRAIL/Apo2L-induced apoptosis in MM cells was dependent on caspase-8 activation and inhibited by the caspase regulatory proteins FLIP and cIAP2. These studies provide a framework for the use of TRAIL/Apo2L as a single agent or as part of combination therapy for the treatment of MM. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Res Lab, Boston, MA 02115 USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 93 TC 26 Z9 28 U1 1 U2 2 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD AUG PY 2001 VL 10 IS 8 BP 1521 EP 1530 DI 10.1517/13543784.10.8.1521 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 472ZB UT WOS:000171013900009 PM 11772267 ER PT J AU Borodic, GE Acquadro, M Johnson, EA AF Borodic, GE Acquadro, M Johnson, EA TI Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE blepharospasm; botulinum toxin; dystonia; facial pain; inflammation; Meige syndrome; migraine headache; movement disease; myofascial pain; tension headache; torticollis; trigeminal neuralgia; toxin formulation; toxin quality ID EXPERIMENTAL ALLERGIC CONJUNCTIVITIS; GUINEA-PIG CONJUNCTIVA; NERVE GROWTH-FACTOR; SUBSTANCE-P; A TOXIN; MYOFASCIAL PAIN; SPASMODIC TORTICOLLIS; TRIGEMINAL NEURALGIA; MAST-CELL; RHEUMATOID-ARTHRITIS AB Botulinum toxin (BTX) injections are a well-recognised therapeutic modality for the treatment of regional involuntary muscle disorders and recently BTX has been used for treatment of pain and inflammatory disorders. The primary purpose of this review is to discuss the mechanism of action of therapeutic BTX in light of both the traditional understanding of BTX pharmacological effects as well as new observations. The review will deal with clinical observations and relevant animal experimentation. The data and hypotheses presented are not only relevant to botulinum toxin technology but will certainly prove important in the basic mechanisms of some of the diseases where botulinum toxin has been successfully applied. BTX used clinically comprises botulinum neurotoxin (BoNT) complexed with non-toxic proteins. The non-toxic components of the BTX complexes stabilise the labile BoNT during purification and formulation as a therapeutic. The complex proteins may also have unrecognised clinical significance such as slowing diffusion in tissues or imparting stability. The mechanisms of BTX formulations acting on SNARE proteins are briefly reviewed providing a basis for BTX clinical applications. The potential for design of improved botulinum toxins and formulations is addressed. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia, Boston, MA 02114 USA. Univ Wisconsin, Dept Food Microbiol & Toxicol, Inst Food Res, Madison, WI 53706 USA. RP Borodic, GE (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. NR 92 TC 69 Z9 71 U1 1 U2 8 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD AUG PY 2001 VL 10 IS 8 BP 1531 EP 1544 DI 10.1517/13543784.10.8.1531 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 472ZB UT WOS:000171013900010 PM 11772268 ER PT J AU Chong, SY Lin, YC Czarneski, J Zhang, M Coffman, F Kashanchi, F Raveche, E AF Chong, SY Lin, YC Czarneski, J Zhang, M Coffman, F Kashanchi, F Raveche, E TI Cell cycle effects of IL-10 on malignant B-1 cells SO GENES AND IMMUNITY LA English DT Article DE interleukin 10; antisense oligonucleotides; p27; cell cycle ID CHRONIC LYMPHOCYTIC-LEUKEMIA; T-HELPER CELL; B-CELLS; DEPENDENT KINASE; POLYREACTIVE ANTIBODIES; MONOCLONAL-ANTIBODIES; CYTOKINE PRODUCTION; ANTISENSE IL-10; INTERLEUKIN-10; PROLIFERATION AB IL-10 is overexpressed in human chronic lymphocytic leukemia (CLL), and is an autocrine growth factor involved in the development of malignant B1 clones in NZB mice, a murine model for CLL. Antisense IL-10 oligonucleotide treatment induces apoptosis and cell cycle disruption in these cells both in vitro and in vivo, In addition, NZB IL-10 knock-out mice fail to develop the B-1 clones. Dampening of IL-10 protein production via antisense IL-10 oligonucleotide treatment is correlated with decreased p27/Kip1 protein expression which results in increased cyclin D2, cyclin E and cyclin A associated kinase activity, The action of the antisense oligonucleotides is through alterations in cell cycle regulation, resulting in accelerated cell cycle progression, a G2/M block which culminates in apoptosis induction in the malignant cells. This implies that the role of IL-10 as an autocrine growth factor in malignant B-1 cells lies in its ability to inhibit apoptosis induction through the maintenance of sustainable cell cycle progression in malignant cells. C1 UMDNJ, New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA. Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. George Washington Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC USA. RP Raveche, E (reprint author), Dept Pathol, UMDNJ MSB C512,185 S Orange Ave, Newark, NJ 07109 USA. FU NCI NIH HHS [CA71478] NR 52 TC 12 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD AUG PY 2001 VL 2 IS 5 BP 239 EP 247 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 465UA UT WOS:000170607300001 PM 11528515 ER PT J AU Arai, K Lee, K Berthiaume, F Tompkins, RG Yarmush, ML AF Arai, K Lee, K Berthiaume, F Tompkins, RG Yarmush, ML TI Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model SO HEPATOLOGY LA English DT Article ID FULMINANT HEPATIC-FAILURE; ISOLATED-PERFUSED LIVER; NITROGEN-METABOLISM; BRAIN EDEMA; CLINICAL-EXPERIENCE; CIRRHOTIC RATS; CEREBRAL EDEMA; ENCEPHALOPATHY; AMMONIA; PLASMA AB A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O-2/5% CO2- Control rats were fasted for 36 hours with no other treatment before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis, but no change in ammonia consumption compared with normal fasted rat livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to a-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med,Surg Serv, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med,Surg Serv, GRB 1401,55 Fruit St, Boston, MA 02114 USA. RI Lee, Kyongbum/D-9230-2013 FU NIDDK NIH HHS [R01 DK43371]; NIGMS NIH HHS [R01 GM58125] NR 69 TC 54 Z9 56 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2001 VL 34 IS 2 BP 360 EP 371 DI 10.1053/jhep.2001.26515 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 457VH UT WOS:000170157200018 PM 11481621 ER PT J AU Lauwers, GY Furman, J Michael, LE Balis, UJ Kubilis, PS AF Lauwers, GY Furman, J Michael, LE Balis, UJ Kubilis, PS TI Cytoskeletal and kinetic epithelial differences between NSAID gastropathy and Helicobacter pylori gastritis: an immunohistochemical determination SO HISTOPATHOLOGY LA English DT Article DE cytokeratin; gastropathy; Helicobacter pylori; immunohistochemistry; NSAID gastropathy; stomach ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INTESTINAL METAPLASIA; REFLUX GASTRITIS; MUCOSAL DAMAGE; EXPRESSION; CELLS; DIFFERENTIATION; CYTOKERATINS; STOMACH; CARCINOMAS AB Aims: Distinguishing histological features between non-steroidal anti-inflammatory drug (NSAID) gastropathy and Helicobacter pylori gastritis have been accepted. However, the molecular basis explaining these dissimilar histologies has not been elucidated. In an attempt to clarify this question we investigated the differences in the structural cytoskeleton and proliferative activity of these two gastropathies. Methods and results: We assessed the distribution of five cytokeratins (CK) (CK 7, 8, 18, 19 and 20) and Ki67 for the ability to distinguish NSAID from H. pylori gastropathies. In H. pylori gastritis, CK7, 8, 18 and 19 were expressed comparably to normal mucosa from the deep foveolae up to the tips of the glands. The detection of CK20, normally expressed in the upper foveolar region and surface, was decreased with only an epithelial surface reaction. In NSAID gastropathy, CK expression was increased in intensity, with normal distribution for CK8, 18 and 19. Modification of localization was noted for CK7 and 20, with labelling extending toward the deep foveolar region. Unlike H. pylori gastritis, no surface epithelial labelling with Ki67 was noted with NSAID gastropathy but downward elongation of the proliferative zone occurred instead. Conclusions: Contrasting cytostructural alterations and distinct proliferative patterns distinguish NSAID gastropathy from H. pylori gastritis, possibly reflecting different injury pathways. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Florida, Dept Pathol, Gainesville, FL 32611 USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Warren 256,55 Fruit St, Boston, MA 02114 USA. NR 31 TC 7 Z9 8 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0309-0167 J9 HISTOPATHOLOGY JI Histopathology PD AUG PY 2001 VL 39 IS 2 BP 133 EP 140 DI 10.1046/j.1365-2559.2001.01185.x PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 464YB UT WOS:000170560000004 PM 11493329 ER PT J AU Ulbert, I Karmos, G Heit, G Halgren, E AF Ulbert, I Karmos, G Heit, G Halgren, E TI Early discrimination of coherent versus incoherent motion by multiunit and synaptic activity in human putative MT+ SO HUMAN BRAIN MAPPING LA English DT Article DE cerebral cortex; neocortex; occipital lobe; visual cortex; electroencephalography; vision; evoked potentials; visual perception; motion perception ID SOURCE-DENSITY ANALYSIS; VISUAL-EVOKED-POTENTIALS; MACAQUE MONKEY; AREA-MT; CORTICAL CONNECTIONS; MST NEURONS; CEREBRAL-CORTEX; TEMPORAL AREA; RHESUS-MONKEY; FLOW AB A laminar probe was chronically implanted in human putative MT+. The area was specifically responsive to globally coherent visual motion, a crucial aspect of the perception of movement through space. The probe contained 23 microcontacts spaced every 175 mu in a linear array roughly perpendicular to the cortical surface. Current-source density (CSD) and multiunit activity (MUA) were recorded while viewing initially stationary random dot patterns that either moved incoherently or dilated from the central fixation. Onset of visual motion evoked large MUA/CSD activity, with coherent mo on evoking earlier and faster-rising MUA/CSD activity than incoherent, in both superficial and deep pyramidal layers. The selective response, peaking at approximate to 115 ms, was especially large in deep pyramids, providing evidence that information necessary for visual flow calculations is projected from MT+ at an early latency to distant structures. The early onset of differential MUA/CSD implies that the selectivity of this area does not depend on recurrent inhibition or other intrinsic circuitry to detect coherent motion. The initially greater increase of MUA to coherent stimuli was followed by a greater decrease beginning at approximate to 133 ms, apparently because of recurrent inhibition. This resulted in the total MUA being greater to incoherent than coherent stimuli, whereas total rectified CSD was overall greater to coherent than to incoherent stimuli. However, MUA distinguished stationary from moving stimuli more strongly than did CSD. Thus, while estimates of total cell firing (MUA), and of total synaptic activity (CSD) generally correspond to previously reported BOLD results, they may differ in important details. (C) 2001 Wiley-Liss, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Charlestown, MA 02129 USA. INSERM, E9926, F-13258 Marseille, France. Hungarian Acad Sci, Inst Psychol, Budapest, Hungary. Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. RP Halgren, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Rm 2301,Bldg 149,13th St, Charlestown, MA 02129 USA. RI Ulbert, Istvan/F-2213-2010 FU NINDS NIH HHS [NS 18741, R01 NS018741] NR 55 TC 30 Z9 30 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD AUG PY 2001 VL 13 IS 4 BP 226 EP 238 DI 10.1002/hbm.1035 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 458WQ UT WOS:000170218800004 PM 11410951 ER PT J AU Hedrich, K Kann, M Lanthaler, AJ Dalski, A Eskelson, C Landt, F Schwinger, E Vieregge, P Lang, AE Breakefield, XO Ozelius, LJ Pramstaller, PP Klein, C AF Hedrich, K Kann, M Lanthaler, AJ Dalski, A Eskelson, C Landt, F Schwinger, E Vieregge, P Lang, AE Breakefield, XO Ozelius, LJ Pramstaller, PP Klein, C TI The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; UBIQUITIN-PROTEIN LIGASE; HOMOZYGOUS DELETIONS; DISEASE; DIAGNOSIS; FAMILIES AB Early-onset parkinsonism (EOP) may be associated with different mutations in the Parkin gene, including exon deletions and duplications. To test for gene dosage alterations, we developed a new method of quantitative duplex PCR using the fluorescence resonance energy transfer technique on the LightCycler (Roche Diagnostics). In 21 patients with EOP, three mutations (a single base pair substitution in exon 3 and small deletions in exon 9) were detected by conventional mutational screening (single-strand conformation polymorphism and sequence analysis), while alterations of gene dosage were found in seven patients. We identified heterozygous and compound heterozygous deletions of exons 2, 3, 5 and 7. The latter was also found in the homozygous state. In addition, two heterozygous duplications of exon 4 were observed. Remarkably, two patients; carried more than two Parkin mutations. This is the first study systematically screening all 12 exons of Parkin by real-time, kinetic quantification and clearly shows that mutational analysis of the Parkin gene should include gene dosage studies. Furthermore, our method of quantitative PCR is easily applicable to any other gene to be screened for deletions or duplications of whole exons. C1 Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. Med Univ Lubeck, Dept Human Genet, D-23538 Lubeck, Germany. Reg Gen Hosp, Dept Hematol, I-39100 Bolzano, Italy. TIB MOLBIOL, D-10829 Berlin, Germany. Univ Toronto, Dept Med, Toronto, ON M5S 2S8, Canada. Toronto Western Hosp, Toronto, ON M5S 2S8, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02129 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02129 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Reg Gen Hosp, Dept Neurol, I-39100 Bolzano, Italy. RP Klein, C (reprint author), Med Univ Lubeck, Dept Neurol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. RI Pramstaller, Peter/C-2357-2008 NR 25 TC 113 Z9 122 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2001 VL 10 IS 16 BP 1649 EP 1656 DI 10.1093/hmg/10.16.1649 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 463BH UT WOS:000170456600005 PM 11487568 ER PT J AU Anstead, GM Chandrasekar, B Zhao, WG Yang, J Perez, LE Melby, PC AF Anstead, GM Chandrasekar, B Zhao, WG Yang, J Perez, LE Melby, PC TI Malnutrition alters the innate immune response and increases early visceralization following Leishmania donovani infection SO INFECTION AND IMMUNITY LA English DT Article ID PROTEIN-ENERGY MALNUTRITION; NITRIC-OXIDE SYNTHASE; ALVEOLAR MACROPHAGE FUNCTION; ARACHIDONIC-ACID METABOLISM; COLONY-STIMULATING FACTOR; CALORIE MALNUTRITION; PROSTAGLANDIN E-2; IFN-GAMMA; PERITONEAL-MACROPHAGES; TUMOR-METASTASIS AB Malnutrition is a risk factor for the development of visceral leishmaniasis. However, the immunological basis for this susceptibility is unknown. We have developed a mouse model to study the effect of malnutrition on innate immunity and early visceralization following Leishmania donovani infection. Three deficient diets were studied, including 6, 3, or 1% protein; these diets were also deficient in iron, zinc, and calories. The control diet contained 17% protein, was zinc and iron sufficient, and was provided ab libitum. Three days after infection with L. donovani promastigotes, the total extradermal (lymph nodes, liver, and spleen) and skin parasite burdens were equivalent in the malnourished (3% protein) and control mice, but in the malnourished group, a greater percentage (39.8 and 4.0%, respectively; P = 0.009) of the extradermal parasite burden was contained in the spleen and liver. The comparable levels of parasites in the footpads in the two diet groups and the higher lymph node parasite burdens in the well-nourished mice indicated that the higher visceral parasite burdens in the malnourished mice were not due to a deficit in local parasite killing but to a failure of lymph node barrier function. Lymph node cells from the malnourished, infected mice produced increased levels of prostaglandin E-2 (PGE(2)) and decreased levels of interleukin-10. Inducible nitric oxide synthase activity was significantly lower in the spleen and liver of the malnourished mice. Thus, malnutrition causes a failure of lymph node barrier function after L. donovani infection, which may be related to excessive production of PGE(2) and decreased levels of IL-10 and nitric oxide. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Dept Vet Affairs Med Ctr, Med Serv, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. RP Melby, PC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr,Mailcode 7881, San Antonio, TX 78229 USA. NR 74 TC 77 Z9 79 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2001 VL 69 IS 8 BP 4709 EP 4718 DI 10.1128/IAI.69.8.4709-4718.2001 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 456UP UT WOS:000170100900002 PM 11447142 ER PT J AU Melby, PC Yang, J Zhao, WG Perez, LE Cheng, J AF Melby, PC Yang, J Zhao, WG Perez, LE Cheng, J TI Leishmania donovani p36(LACK) DNA vaccine is highly immunogenic but not protective against experimental visceral leishmaniasis SO INFECTION AND IMMUNITY LA English DT Article ID CD4(+) T-CELLS; IMMUNE-RESPONSE; BALB/C MICE; CUTANEOUS LEISHMANIASIS; INFECTED MACROPHAGES; ANTIGEN LACK; TH1 TYPE; IMMUNIZATION; MURINE; RESISTANCE AB The acquisition of immunity following subclinical or resolved infection with the intracellular parasite Leishmania donovani suggests that vaccination could prevent visceral leishmaniasis (VL). The LACK (Leishmania homolog of receptors for activated C kinase) antigen is of interest as a vaccine candidate for the leishmaniases because of its immunopathogenic role in murine L. major infection. Immunization of mice with a truncated (24-kDa) version of the 36-kDa LACK antigen, delivered in either protein or DNA form, was found previously to protect against cutaneous L. major infection by redirecting the early T-cell response away from a pathogenic interleukin-4 (IL-4) response and toward a protective Th1 response. The amino acid sequence of the Leishmania p36(LACK) antigen is highly conserved, but the efficacy of this vaccine antigen in preventing disease caused by strains other than L. major has not been determined. We investigated the efficacy of a p36(LACK) DNA vaccine against VL because of the serious nature of this form of leishmaniasis and because it was unclear whether the LACK vaccine would be effective in a model where there was not a dominant pathogenic IL-4 response. We demonstrate here that although the LACK DNA vaccine induced a robust parasite-specific Th1 immune response (IFN-gamma but not IL-4 production) and primed for an in vivo T-cell response to inoculated parasites, it did not induce protection against cutaneous or systemic L. donovani challenge. Coadministration of IL-12 DNA with the vaccine did not enhance the strong vaccine-induced Th1 response or augment a protective effect. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Dept Vet Affairs Med Ctr, Med Serv, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. RP Melby, PC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr,Mailcode 7881, San Antonio, TX 78229 USA. NR 47 TC 109 Z9 114 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2001 VL 69 IS 8 BP 4719 EP 4725 DI 10.1128/IAI.69.8.4719-4725.2001 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 456UP UT WOS:000170100900003 PM 11447143 ER PT J AU Smith, DJ King, WF Barnes, LA Trantolo, D Wise, DL Taubman, MA AF Smith, DJ King, WF Barnes, LA Trantolo, D Wise, DL Taubman, MA TI Facilitated intranasal induction of mucosal and systemic immunity to mutans streptococcal glucosyltransferase peptide vaccines SO INFECTION AND IMMUNITY LA English DT Article ID HEAT-LABILE ENTEROTOXIN; SURFACE PROTEIN ANTIGEN; ACTIVE-SITE PEPTIDE; TOXIN-B-SUBUNIT; CHOLERA-TOXIN; ESCHERICHIA-COLI; SOBRINUS GLUCOSYLTRANSFERASE; SYNTHETIC PEPTIDES; IMMUNOLOGICAL CHARACTERISTICS; SUBSEQUENCE PEPTIDE AB Synthetic peptide vaccines which are derived from functional domains of Streptococcus mutans glucosyltransferases (GTF) have been shown to induce protective immunity in Sprague-Dawley rats after subcutaneous injection in the salivary gland region. Since mucosal induction of salivary immunity would be preferable in humans, we explored methods to induce mucosal antibody in the rat to the GTF peptide vaccines HDS and HDS-GLU after intranasal administration. Several methods of facilitation of the immune response were studied: the incorporation of peptides in bioadhesive poly(D,L-lactide-coglycolide) (PLGA) microparticles, the use of monoepitopic (HDS) or diepitopic (HDS-GLU) peptide constructs, or the use of mucosal adjuvants. Salivary immunoglobulin A (IgA) responses were not detected after intranasal administration of diepitopic HDS-GLU peptide constructs in alum or after incorporation into PLGA microparticles. However, significant primary and secondary salivary IgA and serum IgG antibody responses to HDS were induced in all rats when cholera holotoxin (CT) or a detoxified mutant Escherichia coli heat-labile enterotoxin (R192G LT) were intranasally administered with HDS peptide constructs in PLGA. Coadministration of LT with HDS resulted in predominantly IgG2a responses in the serum, while coadministration with CT resulted in significant IgG1 and IgG2a responses to HDS. Serum IgG antibody, which was induced to the HDS peptide construct by coadministration with these adjuvants, also bound intact mutans streptococcal GTF in an enzyme-linked immunosorbent assay and inhibited its enzymatic activity. Thus, immune responses which are potentially protective for dental caries can be induced to peptide-based GTF vaccines after mucosal administration if combined with the CT or LT R192G mucosal adjuvant. C1 Forsyth Inst, Dept Immunol, Boston, MA 02115 USA. Cambridge Sci Inc, Belmont, MA 02178 USA. RP Smith, DJ (reprint author), Forsyth Inst, Dept Immunol, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [R56 DE004733, DE-04733, DE-06153, R01 DE004733, R37 DE006153] NR 57 TC 21 Z9 22 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2001 VL 69 IS 8 BP 4767 EP 4773 DI 10.1128/IAI.69.8.4767-4773.2001 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 456UP UT WOS:000170100900009 PM 11447149 ER PT J AU Guerreiro, H Croda, J Flannery, B Mazel, M Matsunaga, J Reis, MG Levett, PN Ko, AI Haake, DA AF Guerreiro, H Croda, J Flannery, B Mazel, M Matsunaga, J Reis, MG Levett, PN Ko, AI Haake, DA TI Leptospiral proteins recognized during the humoral immune response to leptospirosis in humans SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; INTERROGANS SEROVAR COPENHAGENI; TWO-DIMENSIONAL ELECTROPHORESIS; IMMUNOGLOBULIN-M ANTIBODIES; LINKED-IMMUNOSORBENT-ASSAY; IMMOBILIZED PH GRADIENTS; PATHOGENIC LEPTOSPIRA; MAMMALIAN INFECTION; MOLECULAR ANALYSIS; SEQUENCE-ANALYSIS AB Leptospirosis is an emerging zoonosis caused by pathogenic spirochetes belonging to the genus Leptospira. An understanding of leptospiral protein expression regulation is needed to develop new immunoprotective and serodiagnostic strategies. We used the humoral immune response during human leptospirosis as a reporter of protein antigens expressed during infection. Qualitative and quantitative immunoblot analysis was performed using sera from 105 patients from Brazil and Barbados. Sera from patients with other diseases and healthy individuals were evaluated as controls. Seven proteins, p76, p62, p48, p45, p41, p37, and p32, were identified as targets of the humoral response during natural infection. In both acute and convalescent phases of illness, antibodies to lipopolysaccharide were predominantly immunoglobulin M (IgM) while antibodies to proteins were exclusively IgG. Anti-p32 reactivity had the greatest sensitivity and specificity: positive reactions were observed in 37 and 84% of acute- and convalescent-phase sera, respectively, while only 5% of community control individuals demonstrated positive reactions. Six immunodominant antigens were expressed by all pathogenic leptospiral strains tested; only p37 was inconsistently expressed. Two-dimensional immunoblots identified four of the seven infection-associated antigens as being previously characterized proteins: LipL32 (the major outer membrane lipoprotein), LipL41 (a surface-exposed outer membrane lipoprotein), and heat shock proteins GroEL and DnaK. Fractionation studies demonstrated LipL32 and LipL41 reactivity in the outer membrane fraction and GroEL and DnaK in the cytoplasmic fraction, while p37 appeared to be a soluble periplasmic protein. Most of the other immunodominant proteins, including p48 and p45, were localized to the inner membrane. These findings indicate that leptospiral proteins recognized during natural infection are potentially useful for serodiagnosis and may serve as targets for vaccine design. C1 Brazilian Minist Hlth, Oswaldo Cruz Fdn, Goncalo Moniz Res Ctr, BR-40295001 Salvador, BA, Brazil. Univ Fed Bahia, Sch Pharm, BR-40000 Salvador, BA, Brazil. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA 90095 USA. Univ W Indies, Sch Clin Med & Res, Bridgetown, Barbados. Cornell Univ, Weill Med Coll, Div Int Med & Infect Dis, New York, NY 10021 USA. RP Fdn Oswaldo Cruz MS, Ctr Pesquisas Goncalo Moniz, Rua Waldemar Falcao 121, BR-40295001 Salvador, BA, Brazil. EM aik2001@med.cornell.edu RI Ko, Albert/P-2343-2015 FU FIC NIH HHS [D43 TW000905, D43 TW000919, TW-00905, TW-00919]; NIAID NIH HHS [AI-34431, AI-01605, R01 AI034431, R21 AI034431, R21 AI034431-06, R29 AI034431] NR 47 TC 108 Z9 140 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2001 VL 69 IS 8 BP 4958 EP 4968 DI 10.1128/IAI.69.8.4958-4968.2001 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 456UP UT WOS:000170100900034 PM 11447174 ER PT J AU Santos, IKFD Costa, CHN Krieger, H Feitosa, MF Zurakowski, D Fardin, B Gomes, RBB Weiner, DL Harn, DA Ezekowitz, RAB Epstein, JE AF Santos, IKFD Costa, CHN Krieger, H Feitosa, MF Zurakowski, D Fardin, B Gomes, RBB Weiner, DL Harn, DA Ezekowitz, RAB Epstein, JE TI Mannan-binding lectin enhances susceptibility to visceral leishmaniasis SO INFECTION AND IMMUNITY LA English DT Article ID INNATE IMMUNITY; T-CELLS; PROTEIN; GENE; INTERLEUKIN-6; MACROPHAGES; ASSOCIATION; INFECTION; INDUCTION; VARIANTS AB Levels of the serum opsonin mannan-binding lectin (MBL) were directly correlated with the probability of developing visceral leishmaniasis. Monocytes infected with MBL-opsonized Leishmania chagasi promastigotes secreted higher levels of tumor necrosis factor alpha and interleukin-6 than cells infected with nonopsonized parasites. Our findings indicate that MBL can modulate the clinical outcome of infection with L. chagasi and the function of infected macrophages. C1 Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Childrens Hosp, Dept Biostat, Boston, MA 02115 USA. Childrens Hosp, Div Emergency Med, Boston, MA 02115 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Empresa Brasileira Pesquisa Agropecuaria, Ctr Nacl Pesquisa Recursos Genet & Biotecnol, BR-70770900 Brasilia, DF, Brazil. Univ Fed Piaui, Ctr Ciencias Saude, Dept Med Comunitaria, BR-64000 Teresina, PI, Brazil. Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, BR-05508900 Sao Paulo, Brazil. FIOCRUZ, Inst Oswaldo Cruz, Dept Genet, BR-21045900 Rio De Janeiro, Brazil. Massachusetts Gen Hosp, Lab Dev Immunol, Boston, MA 02114 USA. RP Epstein, JE (reprint author), USN, Med Res Ctr, Malaria Dept, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. RI de Miranda Santos, Isabel/B-7597-2012; de Miranda Santos, Isabel/D-5261-2016 OI de Miranda Santos, Isabel/0000-0002-0438-4430; FU NICHD NIH HHS [K12 HD000850, K12-HD00850] NR 32 TC 102 Z9 104 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2001 VL 69 IS 8 BP 5212 EP 5215 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 456UP UT WOS:000170100900070 PM 11447210 ER PT J AU Samandari, R Kleefield, S Hammel, J Mehta, M Crone, R AF Samandari, R Kleefield, S Hammel, J Mehta, M Crone, R TI Privately funded quality health care in India: a sustainable and equitable model SO INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE LA English DT Article DE delivery of health care; education; eye diseases; hospitals; India; medical; quality of health care; rural health services; voluntary ID CATARACT; BLINDNESS AB Objective. As the cost and degree of training necessary to provide state of the art health care has increased throughout the world, the present challenge in health care is to establish institutions that are financially sound and responsive to the dynamic needs of the communities in which they exist. As public funds have diminished, the role of the private sector in establishing innovative health care institutions has increased. Setting and study participants. This paper reviews the case of the LV Prasad Eye Institute (LVPEI), an ophthalmologic institute in Hyderabad, India, that is financially sound and medically vital. With an annual budget of US$3 Million, 180 000 patients are seen and 23 000 surgeries are performed at the Institute and its satellites each year. Main Measures. The Institute provides patient care at a ratio of 1:1 non-paying to paying patients through fee cross-subsidization. The Institute uses a combination of financial modalities, including donations, grants and fees to administer its non-patient care programs. Non-clinical programs of the Institute include a paramedical training program and a fellowship in ophthalmology, an internationally accredited eye bank for the preservation of corneal tissues, a rural out-reach and education program, a basic science and epidemiology program that directs health policy activities of the Institute and a rehabilitation program for patients with incurable visual deficits. To evaluate its effectiveness, LVPEI uses quality improvement measures, including patient surveys, post-operative outcomes studies and service utilization reviews. Conclusion. This case report of a privately-funded medical institution describes a successful model through which high-quality, equitable health care can be provided in a developing country. The LVPEI's active program of quality management, its academic commitment and programmatic relevance to the needs of its community should be modularized and replicated to establish equitable, efficient and effective health care institutions in the developing world. C1 Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. Harvard Med Int, Boston, MA USA. Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Samandari, R (reprint author), Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. NR 22 TC 8 Z9 8 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1353-4505 J9 INT J QUAL HEALTH C JI Int. J. Qual. Health Care PD AUG PY 2001 VL 13 IS 4 BP 283 EP 288 DI 10.1093/intqhc/13.4.283 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 471BT UT WOS:000170907500004 PM 11560347 ER PT J AU Yazdanpanah, Y Chene, G Losino, E Goldie, SJ Merchadou, LD Alfandari, S Seage, GR Sullivan, L Marimoutou, C Paltiel, AD Salamon, R Mouton, Y Freedberg, KA AF Yazdanpanah, Y Chene, G Losino, E Goldie, SJ Merchadou, LD Alfandari, S Seage, GR Sullivan, L Marimoutou, C Paltiel, AD Salamon, R Mouton, Y Freedberg, KA TI Incidence of primary opportunistic infections in two human immunodeficiency virus-infected French clinical cohorts SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE opportunistic infections; natural history; HIV; France; incidence rate ID MYCOBACTERIUM-AVIUM COMPLEX; PNEUMOCYSTIS-CARINII PNEUMONIA; HOSPITAL-BASED SURVEILLANCE; IMMUNE-DEFICIENCY-SYNDROME; SWISS HIV COHORT; ANTIRETROVIRAL THERAPY; PRIMARY PROPHYLAXIS; NATURAL-HISTORY; SYNDROME AIDS; CELL COUNTS AB Background Clinical guidelines for the prevention of opportunistic infections in human immunodeficiency virus (HIV)-infected individuals have been developed on the basis of natural history data collected in the USA. The objective of this study was to estimate the incidence of primary opportunistic infections in HIV-infected individuals in geographically distinct cohorts in France. Methods We conducted our study on 2664 HIV-infected patients from the Tourcoing AIDS Reference Centre and the hospital-based information system of the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine enrolled from January 1987 to September 1995 and followed through December 1995. We estimated: (1) CD4-adjusted incidence rates of seven primary opportunistic infections in the absence of prophylaxis for that specific infection or any antiretroviral drugs other than zidovudine; and (2) CD4 lymphocyte count decline. Results The highest incidence rates for all opportunistic infections studied occurred in patients with CD4 counts <200/ l. With CD4 counts <50/l, the most common opportunistic infections were toxoplasmic encephalitis (12.6 per 100 person-years) and Pneumocystis carinii pneumonia (11.4 per 100 person-years). Mycobacterium tuberculosis was the least common opportunistic infection (<5.0/100 person-years). Even with CD4 counts >300/mul, cases of Pneumocystis carinii pneumonia and toxoplasmic encephalitis were reported. The mean CD4 lymphocyte decline per month was 4.6 cells/mul. There was a significant association between MV risk behaviour and the incidence of cytomegalovirus infection, between calendar year and the incidence of Pneumocystis carinii pneumonia, toxoplasmic encephalitis and Candida esophagitis, and between geographical area and the incidence of Pneumocystis carinii pneumonia and cytomegalovirus infection. Conclusions Geographical differences exist in the incidence of HIV-related opportunistic infections. These results can be used to define local priorities for prophylaxis of opportunistic infections. C1 CHRU Lille, Serv Univ Malad Infect & Voyageur, Ctr Hosp Tourcoing, F-59208 Tourcoing, France. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Partners AIDS Res Ctr, Boston, MA 02114 USA. Univ Bordeaux 2, INSERM, U330, F-33076 Bordeaux, France. Boston Univ, Sch Med, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Yazdanpanah, Y (reprint author), CHRU Lille, Serv Univ Malad Infect & Voyageur, Ctr Hosp Tourcoing, 135 Rue President Coty,BP 619, F-59208 Tourcoing, France. RI chene, genevieve/H-8665-2014 FU NIAID NIH HHS [R01-AI42006, R01 AI042006]; PHS HHS [U64/CCU114927] NR 32 TC 47 Z9 49 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2001 VL 30 IS 4 BP 864 EP 871 DI 10.1093/ije/30.4.864 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 471RW UT WOS:000170943300041 PM 11511618 ER PT J AU Marin, DB Flynn, S Mare, M Lantz, M Hsu, MA Laurans, M Paredes, M Shreve, T Zaklad, GR Mohs, RC AF Marin, DB Flynn, S Mare, M Lantz, M Hsu, MA Laurans, M Paredes, M Shreve, T Zaklad, GR Mohs, RC TI Reliability and validity of a chronic care facility adaptation of the Clinical Dementia Rating scale SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article; Proceedings Paper CT 10th Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 02-05, 1997 CL ORLANDO, FLORIDA SP Amer Assoc Geriatr Psychiat DE Clinical Dementia Rating scale; Alzheimer's disease ID ALZHEIMERS-DISEASE; CONTROLLED TRIAL; ONSET AB Objective This study investigated the reliability and validity of a chronic care facility adaptation of the Clinical Dementia Rating scale (CDR-CC). Method Sixty-two residents in a chronic care facility participated in an inter-rater and I month test-retest reliability study. The instrument was validated against the Mini-Mental State Examination (MMSE). Results Inter-rater and 1 month test-retest reliability for the global CDR-CC score were excellent (intraclass correlation coefficients 0.99 and 0.92, respectively). The CDR-CC domain and global scores were negatively correlated with the MMSE. Conclusions The CDR-CC is a global assessment tool that reliably and validly measures cognitive and functional impairment in a chronic care setting. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Jewish Home & Hosp Aged, New York, NY USA. Pfizer Inc, Groton, CT 06340 USA. Yale Univ, Sch Med, New Haven, CT USA. Bronx Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY USA. RP Marin, DB (reprint author), CUNY, Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. FU NIA NIH HHS [AG02219] NR 17 TC 19 Z9 19 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD AUG PY 2001 VL 16 IS 8 BP 745 EP 750 DI 10.1002/gps.385.abs PG 6 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 469UQ UT WOS:000170834800001 PM 11536340 ER PT J AU Babbitt, JT Kharazi, AI Taylor, JMG Bonds, CB Zhuang, D Mirell, SG Frumkin, E Hahn, TJ AF Babbitt, JT Kharazi, AI Taylor, JMG Bonds, CB Zhuang, D Mirell, SG Frumkin, E Hahn, TJ TI Increased body weight in C57BL/6 female mice after exposure to ionizing radiation or 60 Hz magnetic fields SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; DOSE-RESPONSE; X-RAYS; RATS; IRRADIATION; CANCER; TUMORIGENESIS; RECEPTOR; LYMPHOMA; 50-HZ AB Purpose: The purpose of this investigation was to determine whether early treatment with ionizing radiation and/or chronic magnetic field (MF) exposure affected body weight in female mice. Materials and methods: Weanling C57BL/6 female mice were irradiated with four equal weekly cobalt-60 exposures (total cumulative closes: 3.0, 4.0, 5.1 Gy) and/or received chronic lifetime exposure to 1.4mT 60Hz circularly polarized MF or ambient MF. The body weights of 2280 mice were recorded at 35 age intervals, and analysis of variance was used to compare the mean differences from baseline weights between treatment groups and sham-exposed controls. Results: A highly statistically significant effect of ionizing radiation on body Weight was observed at 28 age intervals (p less than or equal to0.001), and for MF exposure at 10 age intervals (p less than or equal to0.001). During the young adult growth phase, mice exposed only to MF exhibited less than or equal to0.5g greater weight gain relative to sham-exposed controls (p=0.0001). The effect of ionizing radiation alone was inversely related to close, with the largest weight increases observed in all of the irradiated groups after 9-12 months (p=0.0001). Conclusions: Treatment with split-dose ionizing radiation at an early age and chronic exposure to a residential power frequency NIF were Found to produce small but significant increases in body weight. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90095 USA. St Vincents Med Ctr, Immunotherapy Lab, Los Angeles, CA 90057 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Merle Norman Cosmet, El Segundo, CA USA. Scirex Corp, San Diego, CA USA. VA Greater Los Angeles Healthcare Syst West Los A, Ctr Geriatr Res Educ & Clin, Los Angeles, CA 90073 USA. RP Babbitt, JT (reprint author), VA West Los Angeles Healthcare Ctr, GRECC 11G,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 32 TC 8 Z9 10 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD AUG PY 2001 VL 77 IS 8 BP 875 EP 882 DI 10.1080/09553000110055790 PG 8 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 471BV UT WOS:000170907700005 PM 11571021 ER PT J AU Auchter, RM Scholtens, D Adak, S Wagner, H Cella, DF Mehta, MP AF Auchter, RM Scholtens, D Adak, S Wagner, H Cella, DF Mehta, MP TI Quality of life assessment in advanced non-small-cell lung cancer patients undergoing an accelerated radiotherapy regimen: Report of ECOG study 4593 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 18-23, 1997 CL ORLANDO, FLORIDA SP Amer Soc Therapeut Radiol & Oncol DE radiotherapy; lung cancer; quality of life; QOL; hyperfractionation ID OF-LIFE; RADIATION-THERAPY; PHASE-II; MUCOSAL REACTIONS; NECK-CANCER; TRIAL; ONCOLOGY; PACLITAXEL; SURVIVAL; FRACTIONATION AB Purpose: To prospectively evaluate the quality of life (QOL) before, at completion, and after therapy for patients receiving an accelerated fractionation schedule of radiotherapy for advanced, unresectable non-small-cell lung cancer in a Phase II multi-institutional trial. Methods and Materials: The Functional Assessment of Cancer Therapy-Lung (FACT-L) patient questionnaire was use to score the QOL in patients enrolled in the Eastern Cooperative Oncology Group Phase II trial (ECOG 4593) of hyperfractionated accelerated radiotherapy in non-small-cell lung cancer. Radiotherapy (total dose 57.6 Gy in 36 fractions) was delivered during 15 days, with three radiation fractions given each treatment day. The protocol was activated in 1993, and 30 patients had accrued by November 1995. The FACT-L questionnaire was administered at study entry (baseline), on the last day of radiotherapy (assessment 2), and 4 weeks after therapy (assessment 3). The FACT-L includes scores for physical, functional, emotional, and social well-being (33 items), and a subscale of lung cancer symptoms (10 additional items). The summation of the physical, functional, and lung cancer symptom subscales (21 items) constitutes the Trial Outcome Index (TOI), considered the most clinically relevant outcome measure in lung cancer treatment trials. Results: The FACT-L completion rates at the designated study time points were as follows: baseline, 30 of 30 assessment 2, 29 (97%) of 30; and assessment 3, 24 (80%) of 30. At treatment completion, statistically significant declines in QOL scores were noted, compared with baseline for physical and functional well-being. Emotional well-being scores improved at both assessment 2 and assessment 3. The physical and functional scores returned approximately to baseline values at assessment 3. The change in TOI score was evaluated as a function of the clinical response to treatment, toxicity grade, and survival; no clear association was noted. A trend for the largest decrease in QOL was noted for patient groups with shorter survival times. The mean change in the TOI score from baseline to assessment 3 was -8.96 for patients surviving < 52 weeks vs. -0.95 for those surviving > 52 weeks. Conclusions: The FACT-L questionnaire can be successfully administered to non-small-cell lung cancer patients enrolled in a prospective Phase II trial of accelerated radiation fractionation. The decrement in physical and functional QOL during treatment returned to baseline level at 4 weeks after treatment. Emotional well-being improved at all time points. A trend was noted for shorter survival times in patients with the largest negative change in TOI score. These data suggest that the clinical use of hyperfractionated accelerated radiotherapy did not cause a significant, long-term decrease in the QOL of the treated patients, and that it is feasible to perform a QOL study of patients enrolled in such a trial. (C) 2001 Elsevier Science Inc. C1 Univ Wisconsin, Dept Human Oncol, Sch Med, Madison, WI 53792 USA. Dana Farber Canc Inst, ECOG Stat Ctr, Boston, MA 02115 USA. H Lee Moffitt Canc Ctr, Tampa, FL USA. Evanston Northwestern Healthcare, Evanston, IL USA. RP Mehta, MP (reprint author), Univ Wisconsin, Dept Human Oncol, Sch Med, 600 Highland Ave,K4-B100, Madison, WI 53792 USA. OI mehta, minesh/0000-0002-4812-5713 NR 27 TC 26 Z9 27 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2001 VL 50 IS 5 BP 1199 EP 1206 DI 10.1016/S0360-3016(01)01604-2 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 459TA UT WOS:000170266500012 PM 11483329 ER PT J AU Hagstrom, SA Adamian, M Scimeca, M Pawlyk, BS Yue, GH Li, TS AF Hagstrom, SA Adamian, M Scimeca, M Pawlyk, BS Yue, GH Li, TS TI A role for the tubby-like protein 1 in rhodopsin transport SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; RDS MUTANT MICE; RETINAL DEGENERATION; TRANSGENIC MICE; GENE FAMILY; IMMUNOCYTOCHEMICAL LOCALIZATION; MOLECULAR CHARACTERIZATION; INNER SEGMENT; MOUSE MODEL; OPSIN AB PURPOSE. To test the hypothesis that a lack of Tubby-like protein 1 (TULP1) function causes aberrant transport of nascent rhodopsin and to examine the functional relationship between the homologous proteins TULP1 and Tubby by studying mice carrying combined mutations. METHODS. Subcellular localization of TULP1 and rhodopsin in photoreceptors was determined by immunofluorescence and by postembedding immunoelectron microscopy. Mice carrying different tulp1/tubby, allele combinations were examined by histology, electroretinograms (ERGS), and immunofluorescence microscopy. RESULTS. TULP1 is distributed throughout the photoreceptor cytoplasm but is excluded from the outer segments and the nuclei. In the tulp1-/- mice, ectopic accumulation of rhodopsin occurs at an early age. Both the Vesicular profiles in the interphotoreceptor space and the inner segment plasma membranes are immunoreactive for rhodopsin. Mice doubly homozygous for null mutations in the tulp1 and tubby genes initially develop photoreceptors and express a battery of photoreceptor markers at age 14 days. Thereafter their photoreceptors undergo a fulminant degeneration that reaches completion by postnatal day 17. The disease phenotype in the double homozygote is much more severe than either single homozygote. Double heterozygotes are phenotypically normal. CONCLUSIONS. A lack of TULP1 function results in misrouting of nascent rhodopsin. TULP1 may be a component of the cellular machinery that targets nascent rhodopsin to the outer segments. Comparison of disease phenotypes in the single and double mutants suggests that TULP1 and Tubby are not functionally interchangeable in photoreceptors nor do they form an obligate functional complex. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. RP Li, TS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY10309] NR 41 TC 62 Z9 63 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2001 VL 42 IS 9 BP 1955 EP 1962 PG 8 WC Ophthalmology SC Ophthalmology GA 462XL UT WOS:000170445000002 PM 11481257 ER PT J AU Stechschulte, SU Joussen, AM von Recum, HA Poulaki, V Moromizato, Y Yuan, J D'Amato, RJ Kuo, C Adamis, AP AF Stechschulte, SU Joussen, AM von Recum, HA Poulaki, V Moromizato, Y Yuan, J D'Amato, RJ Kuo, C Adamis, AP TI Rapid ocular angiogenic control via naked DNA delivery to cornea SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GENE-TRANSFER; IN-VIVO; ARTERIAL GENE AB PURPOSE. To determine the efficacy and safety of naked plasmid gene therapy to the corneal stroma and epithelium. METHODS. Naked plasmid DNA was injected under pressure into the cornea of mice. The expression of genes coding for beta galactosidase (beta -gal), enhanced green fluorescent protein (EGFP), vascular endothelial growth factor (VEGF), and soluble Flt-1 (s-Flt) was recorded and measured with regard to dose, time course, and bioactivity. RESULTS. LacZ gene expression of the protein beta -gal was demonstrated as early as 1 hour, with expression persisting for 10 days. Plasmid-injected corneas remained clear and free of inflammation. EGFP was bicistronically expressed with VEGF to demonstrate the practicality of simultaneous in vivo analysis of gene expression and growth factor bioactivity. Corneal injection of a plasmid containing VEGF cDNA induced corneal and anterior chamber neovascularization. Moreover, corneal injection of plasmid containing the cDNA for the soluble form of the VEGF receptor Flt-1 effectively prevented corneal neovascularization. CONCLUSIONS. The cornea is readily accessible for gene therapy in the laboratory and in the clinic. The method described is safe, effective, titratable, and easily monitored. Naked DNA delivery to the cornea has the potential to alter the treatment of a wide variety of corneal and anterior segment diseases. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. Childrens Hosp, Boston, MA 02115 USA. RP Adamis, AP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. RI von Recum, Horst/F-5911-2012 OI von Recum, Horst/0000-0002-9323-8100 NR 13 TC 70 Z9 78 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2001 VL 42 IS 9 BP 1975 EP 1979 PG 5 WC Ophthalmology SC Ophthalmology GA 462XL UT WOS:000170445000005 PM 11481260 ER PT J AU Bohning, DE Lomarev, MP Denslow, S Nahas, Z Shastri, A George, MS AF Bohning, DE Lomarev, MP Denslow, S Nahas, Z Shastri, A George, MS TI Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI SO INVESTIGATIVE RADIOLOGY LA English DT Article DE vagus nerve stimulation; functional MRI; synchronization; epilepsy; depression ID REFRACTORY EPILEPSY; VAGAL-STIMULATION; FLOW; SYSTEM; SPECT AB RATIONALE AND OBJECTIVES. Left cervical vagus nerve stimulation (VNS) by use of an implanted neurocybernetic prosthesis (NCP) system is effective in treating epilepsy, with open data suggesting effectiveness in depression, yet the mechanisms of action are unknown. Our objective was to develop a methodology for performing VNS-synchronized functional magnetic resonance imaging (VNS-fMRI) and then to demonstrate its feasibility for studying VNS effects. METHODS. In nine patients implanted for treatment of intractable depression, a Macintosh computer was used to detect the signal from the implanted VNS stimulator and then to synchronize fMRI image acquisition with its regular firing. RESULTS. With our VNS-fMRI methodology, the blood oxygenation level-dependent response to VNS was shown in brain regions regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally, left temporal cortex, the hypothalamus, and the left amygdala. CONCLUSIONS. Vagus nerve stimulation pulses from an NCP system can be detected externally to determine its firing pattern, thus allowing VNS-fMRI studies of VNS-induced brain activity. C1 Med Univ S Carolina, Dept Radiol, Ctr Adv Imaging Res, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. Ralph H Johnson Vet Hosp, Charleston, SC USA. Inst Human Brain, St Petersburg, Russia. RP Bohning, DE (reprint author), Med Univ S Carolina, Dept Radiol, Ctr Adv Imaging Res, 171 Ashley Ave, Charleston, SC 29425 USA. NR 22 TC 60 Z9 61 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD AUG PY 2001 VL 36 IS 8 BP 470 EP 479 DI 10.1097/00004424-200108000-00006 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 468WA UT WOS:000170780100006 PM 11500598 ER PT J AU Mollica, RH Sarajlic, N Chernoff, M Lavelle, J Vukovic, IS Massagli, MP AF Mollica, RH Sarajlic, N Chernoff, M Lavelle, J Vukovic, IS Massagli, MP TI Longitudinal study of psychiatric symptoms, disability, mortality, and emigration among Bosnian refugees SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSION; PRIMARY-CARE; MYOCARDIAL-INFARCTION; MEDICAL OUTCOMES; MENTAL-HEALTH; OLDER ADULTS; FOLLOW-UP; TORTURE; TRAUMA AB Context Evidence is emerging that psychiatric disorders are common in populations affected by mass violence. Previously, we found associations among depression, posttraumatic stress disorder (PTSD), and disability in a Bosnian refugee cohort. Objective To investigate whether previously observed associations continue over, time and are associated with mortality emigration to another region. Design, Setting, and Participants Three-year follow-up study conducted in 1999 among 534 adult Bosnian refugees originally living in a refugee camp in Croatia. At follow-up, 376 (70.4%) remained living in the region, 39 (7.3%) were deceased, 114 (21.3%) had emigrated, and 5 (1%) were lost to follow-up. Those still living in the region and the families of the deceased were reinterviewed (77.7% of the original participants). Main Outcome Measures Depression and PTSD diagnoses, based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and measured by the Hopkins Symptom Checklist-25 and the Harvard Trauma Questionnaire, respectively; disability, measured by the Medical Outcomes Study Short-Form 20; and cause of death, determined by family interviews with review of death certificates, if available. Results In 1999, 45% of the original respondents who met the DSM-IV criteria for depression, PTSD, or both continued to have these disorders and 16% of respondents who were asymptomatic in 1996 developed 1 or both disorders. Forty-six percent of those who initially met disability criteria remained disabled. Log-linear analysis revealed that disability and psychiatric disorder were related at both times. Male sex, isolation from family, and older age were associated with increased mortality after adjusting for demographic characteristics, trauma history, and health status (for male sex, adjusted odds ratio [OR], 2.63; 95% confidence interval [CI], 1.17-5.92; living alone, OR, 2.40; 95% Cf, 1.07-5.38; and each 10-year increase in age, OR, 1.91; 95% Cl, 1.34-2.71). Depression was associated with higher mortality in unadjusted analysis but was not after statistical adjustment (unadjusted OR, 3.12; 95% Cl, 1.55-6.26; adjusted OR, 1.85; 95% Cl, 0.82-4.16). Posttraumatic stress disorder was not associated with mortality or emigration. Spending less than 12 months in the refugee camp (OR, 11.30 95% CI, 6.55-19.50), experiencing 6 or more trauma events (OR, 3.34 95% CI, 1.89-5.91), having higher education (OR, 1.90; 95% Cl, 1.10-3.29), and not having an observed handicap (OR, 0.11; 95% CI, 0.02-0.52) were associated with higher likelihood of emigration. Depression was not associated with emigration status. Conclusions Former Bosnian refugees who remained living in the region continued to exhibit psychiatric disorder and disability 3 years after initial assessment. Social isolation, male sex, and older age were associated with mortality. Healthier, better educated refugees were more likely to emigrate. Further research is necessary to understand the associations among depression, emigration status, and mortality over time. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Program Refugee Trauma, Boston, MA USA. Univ Zagreb, Sch Med, Zagreb 41001, Croatia. RP Mollica, RH (reprint author), Harvard Program Refugee Trauma, 8 Story St,3rd Floor, Cambridge, MA 02138 USA. FU NIMH NIH HHS [MH5780602] NR 53 TC 179 Z9 183 U1 2 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 1 PY 2001 VL 286 IS 5 BP 546 EP 554 DI 10.1001/jama.286.5.546 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 458HE UT WOS:000170188300017 PM 11476656 ER PT J AU Sasaki, H Lo, KM Chen, LB Auclair, D Nakashima, Y Moriyama, S Fukai, I Tam, C Loda, M Fujii, Y AF Sasaki, H Lo, KM Chen, LB Auclair, D Nakashima, Y Moriyama, S Fukai, I Tam, C Loda, M Fujii, Y TI Expression of Periostin, homologous with an insect cell adhesion molecule, as a prognostic marker in non-small cell lung cancers SO JAPANESE JOURNAL OF CANCER RESEARCH LA English DT Article DE periostin; RT-PCR; lung cancer; prognosis ID GROWTH-FACTOR-BETA; SEQUENCE-ANALYSIS; TUMOR-METASTASIS; GENE-EXPRESSION; FASCICLIN-I; PROTEIN; CLONING AB We used our palindromic polymerase chain reaction (PCR)-driven cDNA differential display technique to identify and isolate a gene, designated periostin, from cancer tissues and found it to be overexpressed in several human tumors. We attempted to determine the influence of periostin expression on clinical outcome in patients with non-small cell lung cancer (NSCLC) by reverse transcriptase (RT)-PCR analysis. Periostin gene was highly expressed at the tumor periphery of lung cancer tissue but not within the tumor by in situ RNA hybridization, suggesting that expression of periostin may be involved in the process of tumor invasion. Periostin transcripts were detected in 50 (49.0%) of the tumor samples, although some paired normal lung samples showed weak expression. There was no relationship between periostin gene expression and gender, N- or T-status. The NSCLC patients with periostin expression had significantly poorer survival than the patients without periostin expression (P=0.0338). C1 Nagoya City Univ, Sch Med, Dept Surg 2, Mizuho Ku, Nagoya, Aichi 4678601, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Sasaki, H (reprint author), Nagoya City Univ, Sch Med, Dept Surg 2, Mizuho Ku, 1 Kawasumi,Mizuho Cho, Nagoya, Aichi 4678601, Japan. NR 20 TC 57 Z9 59 U1 0 U2 0 PU BUSINESS CENTER ACADEMIC SOCIETIES JAPAN PI TOKYO PA 5-16-9 HONKOMAGOME, BUNKYO-KU, TOKYO, 113-8633, JAPAN SN 0910-5050 J9 JPN J CANCER RES JI Jpn. J. Cancer Res. PD AUG PY 2001 VL 92 IS 8 BP 869 EP 873 PG 5 WC Oncology SC Oncology GA 466TJ UT WOS:000170661600008 PM 11509119 ER PT J AU Gupta, NK Simon, JW Walton, DS Augsburger, JJ AF Gupta, NK Simon, JW Walton, DS Augsburger, JJ TI Bilateral ectopia lentis as a presenting feature of medulloepithelioma SO JOURNAL OF AAPOS LA English DT Article AB Ectopia lentis may be a feature of numerous systemic and ocular disorders. Kivela and Tarkkanen(1) described an 8-year-old girl with medulloepithelioma who presented with ectopia tends and a mass behind the temporal iris. Shields(2) reported 2 children with medulloepithelioma who had ectopia lentis associated with neovascular glaucoma. To date, there has been no report of a child with ectopia lentis as the only presentation of an intraocular tumor. We present 2 children with malignant medulloepitheliomas who presented in this fashion. C1 Albany Med Coll, Lions Eye Inst, Albany, NY 12208 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. Wills Eye Hosp & Res Inst, Dept Oncol, Philadelphia, PA USA. RP Simon, JW (reprint author), Albany Med Coll, Lions Eye Inst, 35 Hackett Blvd, Albany, NY 12208 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD AUG PY 2001 VL 5 IS 4 BP 255 EP 257 DI 10.1067/mpa.2001.116272 PG 3 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 464QK UT WOS:000170543100010 PM 11507586 ER PT J AU Bragdon, CR O'Connor, DO Lowenstein, JD Jasty, M Biggs, SA Harris, WH AF Bragdon, CR O'Connor, DO Lowenstein, JD Jasty, M Biggs, SA Harris, WH TI A new pin-on-disk wear testing method for simulating wear of polyethylene on cobalt-chrome alloy in total hip arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE polyethylene wear; pin-on-disk testing ID HYLAMER; MOTION AB Hip simulator studies show that the wear Of Ultra-high molecular weight polyethylene against a cobalt alloy head depends oil the wear path, especially the combination of a predominantly linear wear direction Oil Which is Superimposed motions in different directions. We postulated that Multidirectional motion was necessary to generate realistic wear rates in pin-on-disk testing. To assess this hypothesis, a new pin-on-disk tester was developed, capable of unidirectional ind bidirectional motion. Unidirectional motion produced no detectable wear. The rectangular motion produced wear rates, Surface morphologies, and wear particles consistent with human acetabular specimens. The results for 1 Hz and 2 Hz were similar. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Biomech Lab, Boston, MA 02114 USA. RP Harris, WH (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Biomech Lab, Jackson 1206, Boston, MA 02114 USA. NR 29 TC 40 Z9 41 U1 0 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD AUG PY 2001 VL 16 IS 5 BP 658 EP 665 DI 10.1054/arth.2001.23718 PG 8 WC Orthopedics SC Orthopedics GA 462EB UT WOS:000170406800016 PM 11503127 ER PT J AU Li, G Lopez, O Rubash, H AF Li, G Lopez, O Rubash, H TI Variability of a three-dimensional finite element model constructed using magnetic resonance images of a knee for joint contact stress analysis SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article ID ARTICULAR-CARTILAGE; PRESSURE DISTRIBUTION; 3-DIMENSIONAL MODEL; MATHEMATICAL-MODEL; HYALINE CARTILAGE; LIGAMENT FORCES; MR-IMAGES; THICKNESS; CONTRACTIONS; VALIDATION AB Magnetic resonance (MR) imaging has been widely used to evaluate the thickness and volume of articular cartilage both in vivo and in vitro. While morphological information on the cartilage can be obtained using MR images, image processing for extracting geometric boundaries of the cartilage may introduce variations in the thickness of the cartilage. To evaluate the variability of using MR images to construct finite element (FE) knee cartilage models, five investigators independently digitized the same set of MR images of a human knee. The topology of cartilage thickness was determined using a minimal distance algorithm. Less than 8 percent variation in cartilage thickness was observed from the digitized data. The effect of changes in cartilage thickness on contact stress analysis was then investigated using five FE models of the knee. One FE model (average FE model) was constructed using the mean values of the digitized contours of the cartilage, and the other four were constructed by varying the thickness of the average FE model by +/-5 percent and +/-10 percent, respectively. The results demonstrated that under axial tibial compressive loading (up to 1400 N), variations of cartilage thickness caused by digitization of MR images may result in a difference of approximately 10 percent in peak contact stresses (surface pressure, von Mises stress, and hydrostatic pressure) in the cartilage. A reduction of cartilage thickness caused increases of contact stresses, while an increase of cartilage thickness reduced contact stresses. Furthermore, the effect of variation of material properties of the cartilage on contact stress analysis was investigated. The peak contact stress increased almost linearly with the Young's modulus of the cartilage. The peak von Mises stress was dramatically reduced when the Poisson ratio was increased from 0.05 to 0.49 under an axial compressive load of 1400 N, while peak hydrostatic pressure was dramatically increased. Peak surface pressure was also increased with the Poisson ratio, but with a lower magnitude compared to von Mises stress and hydrostatic pressure. In conclusion, the imaging process may cause 10 percent variations in peak contact stress, and the predicted stress distribution is sensitive to the accuracy, of the material properties of the cartilage model, especially to the variation of Poisson's ratio. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp,Orthoped Biomech Lab, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Li, G (reprint author), 330 Brookline Ave,RN115, Boston, MA 02215 USA. NR 54 TC 98 Z9 107 U1 0 U2 5 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD AUG PY 2001 VL 123 IS 4 BP 341 EP 346 DI 10.1115/1.1385841 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 468NF UT WOS:000170763200006 PM 11563759 ER PT J AU Jupiter, JB Fernandez, DL AF Jupiter, JB Fernandez, DL TI Complications following distal radial fractures SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID COLLES FRACTURE; OSTEOTOMY C1 Massachusetts Gen Hosp, Orthopaed Hand Serv, Boston, MA 02114 USA. Univ Bern, Dept Orthopaed Surg, Lindenhof Hosp, CH-3012 Bern, Switzerland. RP Jupiter, JB (reprint author), Massachusetts Gen Hosp, Orthopaed Hand Serv, ACC 527,15 Parkman St, Boston, MA 02114 USA. NR 60 TC 7 Z9 9 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2001 VL 83A IS 8 BP 1244 EP 1265 PG 22 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 463CC UT WOS:000170458400015 ER PT J AU Rao, WLR Dogan, A Bowen, KK Dempsey, RJ AF Rao, WLR Dogan, A Bowen, KK Dempsey, RJ TI Ornithine decarboxylase knockdown exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE antisense knockdown; cerebral ischemia; infarct; middle cerebral artery occlusion; neuronal damage; ornithine decarboxylase ID TRANSGENIC MICE; ARTERY OCCLUSION; SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE; INFARCT VOLUME; MESSENGER-RNA; CELL-DEATH; OVERPRODUCING PUTRESCINE; POLYAMINE METABOLISM; ENERGY-METABOLISM; INJURY AB Transient cerebral ischemia leads to increased expression of ornithine decarboxylase (ODC). Contradicting studies attributed neuroprotective and neurotoxic roles to ODC after ischemia. Using antisense oligonucleotides (ODNs), the current study evaluated the functional role of ODC in the process of neuronal damage after transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats. Transient MCAO significantly increased the ODC immunoreactive protein levels and catalytic activity in the ipsilateral cortex. which were completely pre-vented by the infusion of antisense ODN specific for ODC. Transient MCAO in rats infused with ODC antisense ODN increased the infarct volume, motor deficits, and mortality compared with the sense or random ODN-infused controls. Results of the current study support a neuroprotective or recovery role, or both, for ODC after transient focal ischemia. C1 Univ Wisconsin, Dept Neurol Surg, Madison, WI 53792 USA. Univ Wisconsin, Cardiovasc Res Ctr, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Dempsey, RJ (reprint author), Univ Wisconsin, Dept Neurol Surg, H4-336 CSC,600 Highland Ave, Madison, WI 53792 USA. NR 51 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2001 VL 21 IS 8 BP 945 EP 954 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 459AQ UT WOS:000170228000007 ER PT J AU Dijkhuizen, RM Asahi, M Wu, O Rosen, BR Lo, EH AF Dijkhuizen, RM Asahi, M Wu, O Rosen, BR Lo, EH TI Delayed rt-PA treatment in a rat embolic stroke model: Diagnosis and prognosis of ischemic injury and hemorrhagic transformation with magnetic resonance imaging SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE brain ischemia; hemorrhage; MRI; rats; rt-PA; thrombolytic therapy ID TISSUE-PLASMINOGEN ACTIVATOR; APPARENT DIFFUSION-COEFFICIENT; FOCAL CEREBRAL-ISCHEMIA; THROMBOLYTIC THERAPY; INTRACEREBRAL HEMORRHAGE; EARLY REPERFUSION; CONTROLLED TRIAL; NEURONAL DEATH; PERFUSION; MRI AB The authors characterized effects of late recombinant tissue plasminogen activator (rt-PA) administration in a rat embolic stroke model with magnetic resonance imaging (MRI). to assess potential MRI correlates, or predictors, or both, of rt-PA-induced hemorrhage. Diffusion-, perfusion-, and postcontrast T-1-weighted MRI were performed between 4 and 9 hours and at 24 hours after embolic stroke in spontaneously hypertensive rats. Treatment with either rt-PA or saline was started 6 hours after stroke. A spectrophotometric hemoglobin assay quantified hemorrhage severity. Before treatment, relative cerebral blood flow index (rCBF(i)) and apparent diffusion coefficient (ADC) in the ischemic territory were 30% +/- 23% and 60% +/- 5% (of contralateral), respectively, which increased to 45% +/- 39% and 68% +/- 4% 2 hours after rt-PA. After 24 hours, rCBF(i) and ADC were 27% +/- 27% and 59 +/- 5%. Hemorrhage volume after 24 hours was significantly greater in rt-PA-treated animals than in controls (8.7 +/- 3.7 muL vs. 5.1 +/- 2.4 muL, P < 0.05). Before rt-PA administration, clear postcontrast T-1-weighted signal intensity enhancement was evident in areas of subsequent bleeding. These areas had lower rCBF(i), levels than regions without hemorrhage (23% +/- 22% vs. 36% +/- 29%, P < 0.05). In conclusion, late thrombolytic therapy does not necessarily lead to successful reperfusion. Hemorrhage emerged in areas with relatively low perfusion levels and early blood-brain barrier damage. Magnetic resonance imaging may be useful for quantifying effects of thrombolytic therapy and predicting risks of hemorrhagic transformation. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH NMR Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neuroprotect Res Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH NMR Ctr, 13th St,Bldg 149, Charlestown, MA 02129 USA. RI Dijkhuizen, Richard/A-6506-2008 FU NCI NIH HHS [P01-CA48729]; NCRR NIH HHS [P41-RR14075]; NHLBI NIH HHS [R01-HL39810]; NINDS NIH HHS [P50-NS10828, R01-NS37074, R01-NS38731, R29-NS32806] NR 35 TC 46 Z9 49 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2001 VL 21 IS 8 BP 964 EP 971 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 459AQ UT WOS:000170228000009 PM 11487732 ER PT J AU Grinspoon, S Gelato, M AF Grinspoon, S Gelato, M TI Editorial: The rational use of growth hormone in HIV-infected patients SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CONTROLLED TRIAL; LIPODYSTROPHY; SECRETION; IMPROVES; MASS; MEN C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. SUNY Stony Brook, Hlth Sci Ctr, Div Endocrinol, Stony Brook, NY 11794 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM sgrinspoon@partners.org NR 13 TC 8 Z9 9 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2001 VL 86 IS 8 BP 3478 EP 3479 DI 10.1210/jc.86.8.3478 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 462QA UT WOS:000170430200002 PM 11502766 ER PT J AU Huang, JS Wilkie, SJ Sullivan, MP Grinspoon, S AF Huang, JS Wilkie, SJ Sullivan, MP Grinspoon, S TI Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSTMENOPAUSAL WOMEN; MINERAL DENSITY; HYPOGONADAL MEN; ELDERLY WOMEN; MUSCLE MASS; BODY-MASS; THERAPY; REPLACEMENT; ESTROGENS; SERUM AB Women with acquired immune deficiency syndrome wasting are at an increased risk of osteopenia because of low weight, changes in body composition, and hormonal alterations. Although women comprise an increasing proportion of human immunodeficiency virus-infected patients, prior studies have not investigated bone loss in this expanding population of patients. In this study we investigated bone density, bone turnover, and hormonal parameters in 28 women with acquired immune deficiency syndrome wasting and relative androgen deficiency (defined as free testosterone less than or equal to3.0 pg/ml, weight less than or equal to 90% ideal body weight, weight loss greater than or equal to 10% from pre-illness maximum weight, or weight < 100% ideal body weight with weight loss greater than or equal to5% from preillness maximum weight). Total body (1.04 +/- 0.08 vs. 1.10 +/- 0.07 g/cm(2), human immunodeficiency virus-infected vs. control respectively; P < 0.01), anteroposterior lumbar spine (0.94 +/- 0. 12 vs. 1.03 +/- 0.09 g/cm(2); P = 0.005), lateral lumbar spine (0.71 +/- 0.14 vs. 0.79 +/- 0.09 g/cm(2); P = 0.02), and hip (Ward's triangle; 0.68 +/- 0.14 vs. 0.76 +/- 0.12 g/cm(2); P = 0.05) bone density were reduced in the human immunodeficiency virus-infected compared with control subjects. Serum N-telopeptide, a measure of bone resorption, was increased in human immunodeficiency virus-infected patients, compared with control subjects (14.6 +/- 5.8 vs. 11.3 +/- 3.8 nmol/liter bone collagen equivalents, human immunodeficiency virus-infected vs. control respectively; P = 0.03). Although body mass index was similar between the groups, muscle mass was significantly reduced in the human immunodeficiency virus-infected vs. control subjects (16 +/- 4 vs. 21 +/- 4 kg, human immunodeficiency virus-infected vs. control, respectively; P < 0.0001). In univariate regression analysis, muscle mass (r = 0.53; P = 0.004) and estrogen (r = 0.51; P = 0.008), but not free testosterone (r = -0.05, P = 0.81), were strongly associated with lumbar spine bone density in the human immunodeficiency virus-infected patients. The association between muscle mass and bone density remained significant, controlling for body mass index, hormonal status, and age (P = 0.048) in multivariate regression analysis. These data indicate that both hormonal and body composition factors contribute to reduced bone density in women with acquired immune deficiency syndrome wasting. Anabolic strategies to increase muscle mass may be useful to increase bone density among osteopenic women with acquired immune deficiency syndrome wasting. C1 Massachusetts Gen Hosp, Neuorendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. Childrens Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuorendocrine Unit, BUL 457B,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [MD1-RR-01066]; NIDDK NIH HHS [T32-DK07477, R01-DK-54167] NR 20 TC 37 Z9 37 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2001 VL 86 IS 8 BP 3533 EP 3539 DI 10.1210/jc.86.8.3533 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 462QA UT WOS:000170430200011 PM 11502775 ER PT J AU Leder, BZ Catlin, DH Longcope, C Ahrens, B Schoenfeld, DA Finkelstein, JS AF Leder, BZ Catlin, DH Longcope, C Ahrens, B Schoenfeld, DA Finkelstein, JS TI Metabolism of orally administered androstenedione in young men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SERUM TESTOSTERONE; STEROIDS AB Androstenedione is a steroid hormone and the major precursor to testosterone. It is available without prescription and taken with the expectation that it will be converted to testosterone endogenously and increase strength and athletic performance. The metabolism of orally administered testosterone has not been well studied. We randomly assigned 37 healthy men to receive 0, 100, or 300 mg oral androstenedione in a single daily dose for 7 d. Single 8-h urine collections were performed on the day before the start of the androstenedione administration and on d I and 7 to assess excretion rates of free and glucuronide-conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone. Serum testosterone glucuronide concentrations were measured by frequent blood sampling over 8 h on d 1 in 16 subjects (5 each in the 0 and 100 mg group and 6 in the 300 mg group). In the control group, mean (+/- SE) d I and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 3 +/- 1, 215 +/- 26, 175 +/- 26, and 0.4 +/- 0.1 mug/h, respectively. In the 100 mg group, mean d I and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 47 +/- 11, 3,836 +/- 458,4,306 +/- 458, and 1.6 +/- 0.2 mug/h, respectively. In the 300 mg group, mean d I and 7 excretion rates for testosterone, androsterone, etiocholanolone, and dihydrotestosterone were 115 +/- 39, 8,142 +/- 1,362, 10,070 +/- 1,999, and 7.7 +/- 1.5 mug/h, respectively. Urinary excretion rates of all metabolites were greater in both the 100 and 300 mg groups than in controls (P < 0.0001). Urinary excretion rates of testosterone (P = 0.007), androsterone (P = 0.009), etiocholanolone (P = 0.0005), and dihydrotestosterone (P < 0.0001) were greater in the subjects who received 300 mg androstenedione than in those who received 100 mg. In the treated groups, excretion of free testosterone accounted for less than 0.1% of the total excreted testosterone measured. Serum testosterone glucuronide levels increased significantly during frequent blood sampling in both the 100 and 300 mg groups compared with controls (P = 0.0005 for the 100 mg group; P < 0.0001 for the 300 mg group). The net mean changes in area under the curve for serum testosterone glucuronide were - 18 +/- 25%, 579 +/- 572%, and 1267 +/- 1675% in the groups receiving 0, 100, and 300 mg/d androstenedione, respectively. We conclude that the administration of both 100 and 300 mg androstenedione increases the excretion rates of conjugated testosterone, androsterone, etiocholanolone, and dihydrotestosterone and the serum levels of testosterone glucuronide in men. The magnitude of these increases is much greater than the changes observed in serum total testosterone concentrations. These findings demonstrate that orally administered androstenedione is largely metabolized to testosterone glucuronide and other androgen metabolites before release into the general circulation. C1 Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA 01655 USA. Univ Calif Los Angeles, Olymp Analyt Lab, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Olymp Analyt Lab, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. RP Leder, BZ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Bulfinch 327,Fruit St, Boston, MA 02114 USA. EM bleder@partners.org FU NCRR NIH HHS [RR-1066]; NIDDK NIH HHS [K24DK02759] NR 21 TC 24 Z9 25 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2001 VL 86 IS 8 BP 3654 EP 3658 DI 10.1210/jc.86.8.3654 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 462QA UT WOS:000170430200028 PM 11502792 ER PT J AU Rabeneck, L Cook, KF Wristers, K Souchek, J Menke, T Wray, NP AF Rabeneck, L Cook, KF Wristers, K Souchek, J Menke, T Wray, NP TI SODA (severity of dyspepsia assessment): A new effective outcome measure for dyspepsia-related health SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE dyspepsia; health status; quality of life; outcome measure ID HELICOBACTER-PYLORI INFECTION; NONULCER DYSPEPSIA; FUNCTIONAL DYSPEPSIA; DUODENAL-ULCER; WORKING PARTY; RATING-SCALES; SYMPTOMS; PAIN; QUESTIONNAIRE; MANAGEMENT AB The aim of this research was to develop and evaluate an instrument fur measuring dyspepsia-related health to serve as the primary outcome measure for randomized clinical trials. Building on our previous work we developed SODA (Severity of Dyspepsia Assessment), a multidimensional dyspepsia measure. We evaluated SODA by administering it at enrollment and seven follow-up visits to 98 patients with dyspepsia who were randomized to a 6-week course of omeprazole versus placebo and followed over 1 year. The mean age was 53 years, and six patients (6%) were women. Median Cronbach's alpha reliability estimates over the eight visits for the SODA Pain Intensity, Non-Pain Symptoms. and Satisfaction scales were 0.97, 0.90, and 0.92. respectively. The mean change scores for all three scales discriminated between patients who reported they were improved versus those who were unchanged, providing evidence of validity. The effect sizes for the Pain intensity (.98) and Satisfaction (.87) scales were large, providing evidence for responsiveness. The effect size for the Non-Pain Symptoms scale was small(.24). indicating lower responsiveness in this study sample. SODA is a new. effective instrument for measuring dyspepsia-related health. SODA is multidimensional and responsive to clinically meaningful change with demonstrated reliability and validity. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Dept Vet Affairs, VA Hlth Serv Res & Dev, HSR & D Field Program, Houston, TX USA. VA Rehabil R&D Ctr, Houston, TX USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. RP Rabeneck, L (reprint author), VA Med Ctr, 111D,2002 Holcombe Blvd, Houston, TX 77030 USA. FU NIDDK NIH HHS [R03 DK 52467] NR 66 TC 38 Z9 40 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 2001 VL 54 IS 8 BP 755 EP 765 DI 10.1016/S0895-4356(00)00365-6 PG 11 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 455GV UT WOS:000170019900001 PM 11470383 ER PT J AU Hassan, MM Zaghloul, AS El-Serag, HB Soliman, O Patt, YZ Chappell, CL Beasley, RP Hwang, LY AF Hassan, MM Zaghloul, AS El-Serag, HB Soliman, O Patt, YZ Chappell, CL Beasley, RP Hwang, LY TI The role of hepatitis C in hepatocellular carcinoma - A case control study among Egyptian patients SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE hepatitis C; hepatitis B; Schistosoma mansoni; epidemiology ID VIRUS-INFECTION; ANTIBODY-RESPONSE; HIGH PREVALENCE; BLOOD-DONORS; RISK-FACTORS; EPIDEMIOLOGY AB Background: Egypt has one of the highest prevalence rates of hepatitis C virus (HCV) infection in the world; however, the risk and attribution related to HCV in Egyptian patients with hepatocellular carcinoma (HCC) remains unknown. Goals: The current study was undertaken to estimate the risk of HCC in relation to HCV in Egypt. Study: Thirty-three patients with HCC and 35 healthy controls who had a similar socioeconomic status were prospectively enrolled at the University of Cairo National Cancer Institute. Results: Anti-HCV antibodies were present in 75.8% of the patients and in 42.9% of the controls (p = 0.01); hepatitis B surface antigen (HBsAg) was present in 15.2% of the patients and in 2.9% of the controls (p = 0.03). In addition, the sex- and age-adjusted odds ratio (OR) for anti-HCV antibodies was 5.1 (95% CI = 1.5-17.4) and for HBsAg was 13.2 (95% CI = 1.2-148.2). Concurrent Schistosoma mansoni and anti-HCV was associated with an OR of 10.3 (95% CI = 1.3-79.8), which was higher than that for anti-HCV (6.5; 95% CI = 1.6-26.6) and S. mansoni infection (0.2; 95% CI = 0.1-6.2) alone. Finally, we estimated the attributable fraction of HCC to HCV to be 64% in this study population and 48% in the general Egyptian population. Conclusions: Both HCV and hepatitis B virus infection increase the risk of HCC in Egyptian patients, whereas isolated Schistosoma infection does not. Because of the very high prevalence rate of HCV in the general Egyptian population, it accounts for most HCC cases in Egypt. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Oncol & Dig Dis, Houston, TX 77030 USA. Cairo Univ, Natl Canc Inst, Cairo, Egypt. Univ Texas, Sch Publ Hlth, Houston, TX 77025 USA. Houston Vet Adm Med Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. RP Hassan, MM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Oncol & Dig Dis, 1515 Holcombe Blvd,Box 78, Houston, TX 77030 USA. NR 22 TC 56 Z9 56 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD AUG PY 2001 VL 33 IS 2 BP 123 EP 126 DI 10.1097/00004836-200108000-00006 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 456HL UT WOS:000170077000006 PM 11468438 ER PT J AU Kim, JK Kim, YJ Fillmore, JJ Chen, Y Moore, I Lee, JS Yuan, MS Li, ZW Karin, M Perret, P Shoelson, SE Shulman, GI AF Kim, JK Kim, YJ Fillmore, JJ Chen, Y Moore, I Lee, JS Yuan, MS Li, ZW Karin, M Perret, P Shoelson, SE Shulman, GI TI Prevention of fat-induced insulin resistance by salicylate SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID KAPPA-B KINASE; NECROSIS-FACTOR-ALPHA; INDUCED TYROSINE PHOSPHORYLATION; SKELETAL-MUSCLE; RECEPTOR SUBSTRATE-1; GLYCOGEN-SYNTHESIS; GLUCOSE-TRANSPORT; TRANSCRIPTION FACTOR; 3T3-L1 ADIPOCYTES; ACID CYCLE AB Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-H-3]glucose infusion, and glucose uptake in individual tissues was estimated using [1-C-14]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes. C1 Yale Univ, Sch Med, Howard Hughes Med Inst, Boyer Ctr Mol Med, New Haven, CT 06536 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. RP Shulman, GI (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, Boyer Ctr Mol Med, 295 Congress Ave,BCMM 254C,Box 9812, New Haven, CT 06536 USA. RI Perret, Pascale/M-3911-2014 OI Perret, Pascale/0000-0003-0804-8247 FU NIDDK NIH HHS [R01 DK-45493, DK-51729, P30 DK-45735, P30 DK045735, R01 DK-59635, R01 DK040936, R01 DK051729, U24 DK-59635, U24 DK059635] NR 46 TC 474 Z9 503 U1 1 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2001 VL 108 IS 3 BP 437 EP 446 DI 10.1172/JCI11559 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 460PT UT WOS:000170318300015 PM 11489937 ER PT J AU Shen, Y Zelen, M AF Shen, Y Zelen, M TI Screening sensitivity and sojourn time from breast cancer early detection clinical trials: Mammograms and physical examinations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LEAD TIME; TUMOR PROGRESSION; PREDICTIVE VALUE; DEATH RATES; PROGRAMS; WOMEN; MORTALITY; STOCKHOLM; INTERVAL; MODELS AB Purpose: To estimate sensitivities of breast cancer screening modalities and preclinical duration of the disease from eight breast cancer screening clinical trials. Patients and Methods: Screening programs invariably lead to diagnosis of disease before signs or symptoms are present. Two key quantities of screening programs are the sensitivity of the disease detection modality and the mean sojourn time (MST). The observed screening histories in a periodically screened cohort make it possible to estimate these quantities of interest. We applied recently developed statistical methods to data from eight randomized breast cancer screening trials to estimate the sensitivities of early detection modalities and MST. Moreover, when a screening trial involved two screening modalities, our methods enabled the estimation of the individual sensitivity of each screening modality. Results: We analyzed breast cancer data from several screening trials and have relatively complete data from the Health insurance Plan (HIP), Edinburgh, and two Canadian studies. The screening sensitivity for mammography, physical examination, and MST were, respectively, HIP: 0.39, 0.47, and 2.5 years; Edinburgh: 0.63, 0.40, and 4.3 years; Canadian (age 40 to 49 at entry): 0.61, 0.59, and 1.9 years; Canadian (age 50 to 59 at entry): 0.66, 0.39, and 3.1 years. Conclusion: The public debate on early breast cancer detection is mainly centered on mammograms. However, the current study indicates that a physical examination is of comparable importance. Cautious interpretation of trial differences is required as a result of various experimental designs and the age dependency of screening sensitivity and MST. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Shen, Y (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd,Box 213, Houston, TX 77030 USA. OI Shen, Yu/0000-0002-3899-7868 FU NCI NIH HHS [CA79466, CA78607] NR 42 TC 77 Z9 77 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2001 VL 19 IS 15 BP 3490 EP 3499 PG 10 WC Oncology SC Oncology GA 459AV UT WOS:000170228400008 PM 11481355 ER PT J AU Roodman, GD AF Roodman, GD TI Biology of osteoclast activation in cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HORMONE-RELATED PROTEIN; HUMAN BREAST-CANCER; HUMAN MYELOMA CELLS; FORMATION IN-VITRO; MULTIPLE-MYELOMA; PARATHYROID-HORMONE; BONE-RESORPTION; INHIBITORY FACTOR; DIFFERENTIATION FACTOR; CARBONIC-ANHYDRASE AB Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells. Local bone destruction also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, including interleukin IL-6, receptor activator of NF-kappaB (RANK) ligand, parathyroid hormone-related protein (PTHrP), and macrophage inflammatory protein-l-alpha (MIP-1 alpha), have been implicated as factors that enhance osteoclast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteoclast formation through upregulation of RANK ligand. Enhanced RANK ligand expression also plays an important role in bone destruction in patients with myeloma. RANK ligand can act to enhance the effects of other factors produced by myeloma cells or in response to myeloma cells, such as MIP-1 alpha and/or IL-6, to induce osteoclast formation. Understanding of the molecular mechanisms responsible for osteoclast activation in osteolytic metastases should lead to development of novel therapeutic approaches for this highly morbid and potentially fatal complication of cancer. C1 Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. RP Roodman, GD (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NIA NIH HHS [AG13625]; NIAMS NIH HHS [AR44603]; NIDCR NIH HHS [DE12603] NR 71 TC 182 Z9 190 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2001 VL 19 IS 15 BP 3562 EP 3571 PG 10 WC Oncology SC Oncology GA 459AV UT WOS:000170228400017 PM 11481364 ER PT J AU Cohen, LS Viguera, AC Bouffard, SM Nonacs, RM Morabito, C Collins, MH Ablon, JS AF Cohen, LS Viguera, AC Bouffard, SM Nonacs, RM Morabito, C Collins, MH Ablon, JS TI Venlafaxine in the treatment of postpartum depression SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the New-Clinical-Drug-Evaluation-Unit-Program CY JUN 10-13, 1998 CL BOCA RATON, FLORIDA SP New Clin Drug Evaluat Unit Program ID POSTNATAL DEPRESSION; MAJOR DEPRESSION; INTERPERSONAL PSYCHOTHERAPY; MOOD DISORDERS; DOSE-RESPONSE; PREVALENCE; CHILDBIRTH; EFFICACY; ANXIETY; IMPACT AB Background: Although postpartum depression is a highly prevalent illness, antidepressant treatment studies of postpartum depression are sparse. Incomplete recognition and treatment of puerperal illness place women at risk for chronic depression and may have adverse effects on child development. Method: An 8-week. flexible-dose, open study of venlataxine (immediate released mean dose = 162.5 mg/day) was performed in a group of 15 women who met DSM-III-R criteria for major depressive disorder with onset within the first 3 months postpartum. Patients were assessed at baseline and every 2 weeks across the study. Measurements of outcome included the 17-item Hamilton Rating Scale for Depression (HAM-D), the Kellner Symptom Questionnaire. and the Clinical Global Impressions scale (CGI). Results: Despite baseline scores of depression that were particularly high, response to treatment was robust. Twelve of 15 patients experienced remission of major depression (HAM-D score less than or equal to 7 or CGI score less than or equal to 2). Dramatic decrease in anxiety paralleled the decrease in depression across the sample. Conclusion: Venlafaxine is effective in the treatment of postpartum major depression, Early identification of women who suffer from postpartum mood disturbance is critical to minimize the morbidity associated with untreated mood disturbance and the effect of depression on children and families. C1 Harvard Univ, Massachusetts Gen Hosp, Med Sch,Dept Psychiat, Perinatal & Reproduct Psychiat Clin Res Program, Boston, MA 02114 USA. RP Cohen, LS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Med Sch,Dept Psychiat, Perinatal & Reproduct Psychiat Clin Res Program, WAC 815,15 Parkman St, Boston, MA 02114 USA. NR 36 TC 64 Z9 64 U1 3 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2001 VL 62 IS 8 BP 592 EP 596 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 471EL UT WOS:000170914700003 PM 11561929 ER PT J AU Mulsant, BH Sweet, RA Rosen, J Pollock, BG Zubenko, GS Flynn, T Begley, AE Mazumdar, S Reynolds, CF AF Mulsant, BH Sweet, RA Rosen, J Pollock, BG Zubenko, GS Flynn, T Begley, AE Mazumdar, S Reynolds, CF TI A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the New-Clinical-Drug-Evaluation-Unit-Program CY JUN 10-13, 1998 CL BOCA RATON, FL SP New Clin Drug Evaluat Unit Program ID DELUSIONAL DEPRESSION; MAJOR DEPRESSION; RATING-SCALE; PHARMACOLOGICAL TREATMENT; NONDELUSIONAL DEPRESSION; BEHAVIORAL DISTURBANCES; REVERSIBLE DEMENTIA; ELDERLY PATIENTS; OLDER PATIENTS; FLUVOXAMINE AB Objective: To conduct the first randomized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression, Method: The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features (DSM-III-R criteria). Patients wt re started openly on nortriptyline treatment titrated to therapeutic levels. They were then randomly assigned under double-blind conditions to addition of perphenazine or placebo, Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression (HAM-D) and the Brief Psychiatric Rating Scale (BPRS); side effects were assessed with the Geriatric Movement Disorder Assessment. Results: Both treatments were well tolerated. Of the 36 randomly assigned patients. 2 (1 in each group) dropped out due to treatment-related adverse effects. Four additional patients dropped out for administrative reasons. Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine (N = 14) or placebo (N = 16) for at least 2 weeks (median = 9 weeks). There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D, the BPRS, its psychoticism subscale, or any side effects measure. Rates of response (defined as resolution of both depression and psychosis) did not differ significantly in the 2 groups (nortriptyline-plus-perphenazine group, 50% vs. nortriptyline-plus-placebo group. 44%,). Conclusion: When treating older patients with psychotic depression, the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy. This finding supports existing data suggesting that the pathophysiology (and thus the required treatment) of psychotic depression may be different early and late in life. C1 Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Intervent Res Ctr Study Late Life Mood Disorders, Pittsburgh, PA USA. VA Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Mulsant, BH (reprint author), Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM mulsantbh@msx.upmc.edu FU NIMH NIH HHS [MH-30915, MH-49786, MH-52247] NR 70 TC 50 Z9 53 U1 1 U2 4 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2001 VL 62 IS 8 BP 597 EP 604 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 471EL UT WOS:000170914700004 PM 11561930 ER PT J AU Henderson, DC Goff, DC Connolly, CE Borba, CP Hayden, D AF Henderson, DC Goff, DC Connolly, CE Borba, CP Hayden, D TI Risperidone added to clozapine: Impact on serum prolactin levels SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID REFRACTORY SCHIZOPHRENIA; PREMENOPAUSAL WOMEN; COMBINATION AB Background: Several years ago, we reported that the addition of risperidone to clozapine improved response in some patients with schizophrenia. Risperidone, in general, is well tolerated when administered as monotherapy, but has been linked to a persistent elevation of serum prolactin and associated symptoms. The goal of this study was to determine whether the addition of risperidone to clozapine results in an elevation of serum prolactin levels in patients with chronic schizophrenia or schizoaffective disorder. Method: Twenty patients on clozapine-risperidone combination therapy were matched for age and gender with 20 patients treated with clozapine monotherapy. Demographic information was gathered along with clozapine and risperidone dose and the length of time on risperidone. Serum prolactin levels were measured from a single blood sample, Results: The 2 groups did not differ in age, race, gender, diagnosis, age at clozapine initiation, age at onset, Abnormal Involuntary Movement Scale scores, or clozapine dose. The mean SD serum prolactin level was 8.42 +/- 4.17 ng/mL for clozapine monotherapy patients and 35.76 +/- 17.43 ng/mL for combination therapy patients. The 2 medication categories showed a significant difference in log prolactin values (t = -7.97, df = 38, p less than or equal to .0001). Sixteen combination therapy patients (80%) exhibited elevated prolactin levels (range for entire group, 9.7-69.8 ng/mL) while only 2 clozapine monotherapy patients (10%) exhibited prolactin elevation levels (range for entire group, 2.4-20.2 ng/mL, df = 1, p < .0001). Conclusion: The combination of risperidone and clozapine appears to result in a moderate elevation of serum prolactin levels. Additionally, controlled prospective studies are needed to clarify the risks of long-term elevations of serum prolactin level. C1 Massachusetts Gen Hosp, Schizophrenia Res Program, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biostat Program, Boston, MA 02114 USA. RP Henderson, DC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. NR 22 TC 26 Z9 27 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2001 VL 62 IS 8 BP 605 EP 608 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 471EL UT WOS:000170914700005 PM 11561931 ER PT J AU Altshuler, L Kiriakos, L Calcagno, J Goodman, R Gitlin, M Frye, M Mintz, J AF Altshuler, L Kiriakos, L Calcagno, J Goodman, R Gitlin, M Frye, M Mintz, J TI The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: A retrospective chart review SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID LITHIUM-CARBONATE; AFFECTIVE-ILLNESS; IMIPRAMINE; UNIPOLAR; COMBINATION; PREVENTION; MANIA AB Background: Current treatment guidelines recommend discontinuation of an antidepressant within 3 to 6 months after remission of depression in patients with bipolar illness. Yet few studies directly compare the impact of antidepressant discontinuation versus antidepressant continuation on the risk for depressive relapse in patients with bipolar disorder who have been successfully treated for a depressive episode. Method: In a retrospective chart review, patients with DSM-IV bipolar disorder who were treated for an index episode of depression by adding antidepressant medication to ongoing mood stabilizer medications were identified. The risk of depressive relapse in 25 subjects who stopped antidepressant medications after improvement was compared with the risk of depressive relapse in 19 subjects who continued antidepressants after improvement. Results: Termination of antidepressant medication significantly increased the risk of a depressive relapse. Antidepressant continuation was not significantly associated with an increased risk of mania. Conclusion: While this study may have been limited by the retrospective nature of the chart review, nonrandomized assignment of treatment. and reliance on unstructured progress notes, it suggests that antidepressant discontinuation may increase the risk of depressive relapse in some patients with bipolar disorder. Further research is needed to clarify whether maintenance antidepressant treatment may be warranted in some patients with bipolar disorder, especially in those with frequent recurrent depressive episodes. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. W Los Angeles Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. RP Altshuler, L (reprint author), VA Med Ctr, B116AA,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM LAltshuler@mednet.ucla.edu NR 16 TC 94 Z9 96 U1 1 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2001 VL 62 IS 8 BP 612 EP 616 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 471EL UT WOS:000170914700007 PM 11561933 ER PT J AU Lawrence, CG Nadel, ES Silvers, SM Brown, DFM Bontempo, L Peak, D Reisner, A Biddinger, P Legome, E Silvers, S Lyn, E Ledbetter, S AF Lawrence, CG Nadel, ES Silvers, SM Brown, DFM Bontempo, L Peak, D Reisner, A Biddinger, P Legome, E Silvers, S Lyn, E Ledbetter, S TI Acute change in mental status SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material ID ACUTE MASTOIDITIS; LATENT MASTOIDITIS C1 Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Emergency Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Lawrence, CG (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD AUG PY 2001 VL 21 IS 2 BP 179 EP 182 DI 10.1016/S0736-4679(01)00361-4 PG 4 WC Emergency Medicine SC Emergency Medicine GA 460UQ UT WOS:000170327300012 PM 11489409 ER PT J AU Vojta, CL Vojta, DD TenHave, TR Amaya, M Lavizzo-Mourey, R Asch, DA AF Vojta, CL Vojta, DD TenHave, TR Amaya, M Lavizzo-Mourey, R Asch, DA TI Risk screening in a Medicare/Medicaid population - Administrative data versus self report SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE geriatrics; risk screening; Medicaid; dual eligible; health maintenance organization ID MANAGED CARE; PREDICTIVE-VALIDITY; HOSPITAL ADMISSION; ENROLLEES; IMPACT; COSTS; TRIAL; PLAN AB OBJECTIVE: To compare the abilities of two validated indices, one survey-based and the other database-derived, to prospectively identify high-cost, dual-eligible Medicare/Medicaid members. DESIGN., A longitudinal cohort study. SETTING: A Medicaid health maintenance organization in Philadelphia, Pa. PARTICIPANTS: HMO enrollees (N = 558) 65 years and older eligible for both Medicare and Medicaid. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety six patients responded to a survey containing the Probability of Repeat Admission Questionnaire (Pra) between October and November 1998. Using readily available administrative data, we created an administrative proxy for the Pra. Choosing a cut point of 0.40 for both indices maximized sensitivity at 55% for the administrative proxy and 50% for the survey Pra. This classification yielded 103 high-risk patients by administrative proxy and 73 by survey Pra. High-cost patients averaged at least 2.3 times the resource utilization during the 6-month follow-up. Correlation between the two scores was 0.53, and the scales disagreed on high-cost risk in 78 patients (54 high-cost by administrative proxy only, and 24 high-cost by survey Pra only). These two discordant groups utilized intermediate levels of resources, $2,171 and $2,794, that were not statistically significantly different between the two groups (probability > chi (2) = .66). Receiver operating characteristic curve areas (0.68 for survey Pra and administrative proxy for respondents, and 0.67 by administrative proxy for nonrespondents) revealed similar overall discriminative abilities for the two instruments for costs. CONCLUSIONS: The Medicaid/Medicare dual-eligible population responded to the survey Pra at a rate of 53%, limiting its practical utility as a screening instrument. Using a cut point of 0.40, the administrative proxy performed as well as the survey Pra in this population and was equally applicable to nonrespondents. The time lag inherent in database screening limits its applicability for new patients, but combining database-driven and survey-based approaches holds promise for targeting patients who might benefit from case management intervention. C1 Univ Penn, Div Geriatr, Philadelphia, PA 19104 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Inst Aging, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Leonard Davis Inst Hlth Econ, Philadelphia, PA USA. Hlth Partners, Div Med Affairs, Philadelphia, PA USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Vojta, CL (reprint author), 226 Ralston House,3615 Chestnut St, Philadelphia, PA 19104 USA. NR 21 TC 14 Z9 14 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2001 VL 16 IS 8 BP 525 EP 530 DI 10.1046/j.1525-1497.2001.016008525.x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 469DH UT WOS:000170798100003 PM 11556928 ER PT J AU Abrahm, JL AF Abrahm, JL TI Experiencing cancer: Quality of life in treatment. SO JOURNAL OF HEALTH POLITICS POLICY AND LAW LA English DT Book Review C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Abrahm, JL (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 0361-6878 J9 J HEALTH POLIT POLIC JI J. Health Polit. Policy Law PD AUG PY 2001 VL 26 IS 4 BP 789 EP 794 DI 10.1215/03616878-26-4-789 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Medicine, Legal; Social Issues; Social Sciences, Biomedical SC Health Care Sciences & Services; Legal Medicine; Social Issues; Biomedical Social Sciences GA 463VQ UT WOS:000170498300009 ER PT J AU Homma, A Anzueto, A Peters, JI Susanto, I Sako, E Zabalgoitia, M Bryan, CL Levine, SM AF Homma, A Anzueto, A Peters, JI Susanto, I Sako, E Zabalgoitia, M Bryan, CL Levine, SM TI Pulmonary artery systolic pressures estimated by echocardiogram vs cardiac catheterization in patients awaiting lung transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; DOPPLER-ECHOCARDIOGRAPHY; TRICUSPID REGURGITATION; VENTRICULAR FUNCTION; SYSTEMIC-SCLEROSIS; HYPERTENSION; IMPROVEMENT; FIBROSIS; DISEASE; HEART AB Background: At many lung transplant centers, right heart catheterization and transthoracic echocardiogram are part of the routine pre-transplant evaluation to measure pulmonary pressures. Because decisions regarding single vs bilateral lung transplant procedures and the need for cardiopulmonary bypass are often made based on pulmonary artery systolic pressures, we sought to examine the relationship between estimated and measured pulmonary artery systolic pressures using echocardiogram and catheterization, respectively. Methods: We retrospectively reviewed all patients in our program who had measured pulmonary hypertension (n = 57). Patients with both echocardiogram-estimated and catheterization-measured pulmonary artery systolic pressures performed within 2 weeks of each other were included (n = 19). We analyzed results for correlation and linear regression in the entire group and in the patients with primary pulmonary hypertension (n = 8) and pulmonary fibrosis (n = 8). Results: In patients with primary pulmonary hypertension, pulmonary artery systolic pressure was 94 +/- 27 and 95 +/- 15 mm Hg by echocardiogram and catheterization, respectively, with r(2) = 0.11; in patients with pulmonary fibrosis, 57 +/- 23 and 58 +/- 12 mm Hg with r(2) = 0.22; and in the whole group, 76 +/- 29 and 75 +/- 23 mm Hg with r(2) = 0.50. Thirty-two additional patients had mean pulmonary artery systolic pressure = 48 +/- 16 turn Hg by catheterization but either had no evidence of tricuspid regurgitation by echocardiogram (n = 22) or the pulmonary artery systolic pressure could not be measured (n = 10). Conclusions: In patients with pulmonary hypertension awaiting transplant, pulmonary artery systolic pressures estimated by echocardiogram correspond but do not serve as an accurate predictive model of pulmonary artery systolic pressures measured by catheterization. Technical limitations of the echocardiogram. in this patient population often preclude estimating pulmonary artery systolic pressure. C1 Univ Texas, Hlth Sci Ctr, Div Pulm Crit Care Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Div Cardiol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Div Cardiothorac Surg, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Homma, A (reprint author), Audie L Murphy VA Hosp, Pulm Dis Sect 111E, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. NR 29 TC 52 Z9 57 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD AUG PY 2001 VL 20 IS 8 BP 833 EP 839 DI 10.1016/S1053-2498(01)00274-1 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 463JV UT WOS:000170466500005 PM 11502405 ER PT J AU Kurnick, JT Ramirez-Montagut, T Boyle, LA Andrews, DM Pandolfi, F Durda, PJ Butera, D Dunn, IS Benson, EM Gobin, SJP van den Elsen, PJ AF Kurnick, JT Ramirez-Montagut, T Boyle, LA Andrews, DM Pandolfi, F Durda, PJ Butera, D Dunn, IS Benson, EM Gobin, SJP van den Elsen, PJ TI A novel autocrine pathway of tumor escape from immune recognition: Melanoma cell lines produce a soluble protein that diminishes expression of the gene encoding the melanocyte lineage Melan-A/MART-1 antigen through down-modulation of its promoter SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IN-VITRO STIMULATION; MHC CLASS-I; INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; T-LYMPHOCYTES; HETEROGENEOUS EXPRESSION; DIFFERENTIAL EXPRESSION; CLINICAL RELEVANCE; PERIPHERAL-BLOOD; PEPTIDE AB We have observed that malignant melanoma cells produce a soluble protein factor(s), which down-regulates melanocyte lineage Melan-A/MART-1 Ag expression by melanoma cells with concomitant loss of recognition by Melan-A/MART-1-specific T cells. This down-modulation of Melan-A/MART-1 expression, which we refer to as "Ag silencing," is mediated via its minimal promoter, whereas the promoter for the restricting Ag-presenting HLA-A2 molecule is not affected. Significantly, this Ag silencing is reversible, as removal of factor-containing supernatants from Melan-A/MART-1-expressing cells results in up-regulation of the promoter for the gene encoding this Ag, and renewed expression of the protein. We have evaluated over 20 known factors, none of which accounts for the Ag-silencing activity of the melanoma cell culture supernatants. The existence of this autocrine pathway provides an additional novel explanation for melanoma tumor progression in vivo in the presence of CTL specific for this melanocyte lineage Ag. These observations may have important implications for Melan-A/MART-1-specific CTL-mediated immunotherapy of melanoma tumors. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. Catholic Univ, Chair Semeiot Med, Rome, Italy. Inst Clin Pathol & Med Res, Westmead, NSW, Australia. Dept Immunohematol & Blood Transfus, Div Mol Biol, Leiden, Netherlands. RP Kurnick, JT (reprint author), Massachusetts Gen Hosp, Dept Pathol, Blake 351,100 Blossom St, Boston, MA 02114 USA. NR 49 TC 43 Z9 43 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2001 VL 167 IS 3 BP 1204 EP 1211 PG 8 WC Immunology SC Immunology GA 471VM UT WOS:000170949400010 PM 11466335 ER PT J AU Baecher-Allan, C Brown, JA Freeman, GJ Hafler, DA AF Baecher-Allan, C Brown, JA Freeman, GJ Hafler, DA TI CD4+CD25(high) regulatory cells in human peripheral blood SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOLOGICAL SELF-TOLERANCE; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; IMMUNOREGULATORY T-CELLS; AUTOIMMUNE-DISEASES; INTESTINAL INFLAMMATION; INDUCED EXPRESSION; B7 FAMILY; IN-VITRO; INTERLEUKIN-10; ACTIVATION AB Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders. C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Lab Mol Immunol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Baecher-Allan, C (reprint author), Harvard Univ, Sch Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NCI NIH HHS [CA84500]; NIAID NIH HHS [AI39671, AI41584, P01 AI39671]; NINDS NIH HHS [P01 NS38037]; ONDIEH CDC HHS [R01 ND24247-10] NR 36 TC 1237 Z9 1358 U1 1 U2 37 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2001 VL 167 IS 3 BP 1245 EP 1253 PG 9 WC Immunology SC Immunology GA 471VM UT WOS:000170949400015 PM 11466340 ER PT J AU Zahedi, R MacFarlane, RC Wisnieski, JJ Davis, AE AF Zahedi, R MacFarlane, RC Wisnieski, JJ Davis, AE TI C1 inhibitor: Analysis of the role of amino acid residues within the reactive center loop in target protease recognition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEREDITARY ANGIONEUROTIC-EDEMA; SITE-DIRECTED MUTAGENESIS; ALPHA-1-PROTEINASE INHIBITOR; FUNCTIONAL-ANALYSIS; CRYSTAL-STRUCTURE; SYSTEM PROTEASES; ANTITHROMBIN-III; COMPLEMENT C1S; HAGEMAN-FACTOR; HINGE REGION AB Previous analysis of a naturally occurring C1 inhibitor P2 mutant (Ala (443)--> Val) indicated a role for P2 in specificity determination. To define this role and that of other reactive center loop residues, a number of different amino acids were introduced at P2, as well as at P6 (Ala(439)) and P8'/9' (Gln(452)Gln(453)). Ala(439)--> Val is a naturally occurring mutant observed in a patient with hereditary angioedema. Previous data suggested that Gln(452)Gln(453) might be a contact site for Cis. Reactivity of the inhibitors toward target (C1s, C1, kallikrein, beta factor XIIa, and plasmin) and nontarget proteases (alpha -thrombin and trypsin) were studied. Substitution of P2 with bulky or charged residues resulted in decreased reactivity with all target proteases. Substitution with residues with hydrophobic or polar side chains resulted in decreased reactivity with some proteases, but in unaltered or increased reactivity with others. Second order rate constants for the reaction with Cis were determined for the mutants with activities most similar to the wild-type protein. The three P2 mutants showed reductions in rate from 3.35 x 10(5) M(-1)s(-1) for the wild type to 1.61, and 0.63 x 10(5) for the Ser, Thr, and Val mutants, respectively. In contrast, the Ala(439)--> Val and the Gln(452)Gln(453)--> Ala mutants showed little difference in association rates with Cls, in comparison with the wild-type inhibitor. The data confirm the importance of P2 in specificity determination. However, the P6 position appears to be of little, if any, importance. Furthermore, it appears unlikely that Gln(452)Gln(453) comprise a portion of a protease contact site within the inhibitor. C1 Ctr Blood Res, Boston, MA 02115 USA. Case Western Reserve Univ, Vet Affairs Med Ctr, Dept Med, Cleveland, OH 44106 USA. RP Davis, AE (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NICHD NIH HHS [HD22082, HD33727] NR 47 TC 15 Z9 15 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2001 VL 167 IS 3 BP 1500 EP 1506 PG 7 WC Immunology SC Immunology GA 471VM UT WOS:000170949400045 PM 11466370 ER PT J AU Fischer, FR Luo, Y Luo, M Santambrogio, L Dorf, ME AF Fischer, FR Luo, Y Luo, M Santambrogio, L Dorf, ME TI RANTES-induced chemokine cascade in dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; C-C CHEMOKINE; RECEPTOR EXPRESSION; BETA-CHEMOKINE; T-CELLS; AUTOCRINE REGULATION; MESANGIAL CELLS; IDENTIFICATION; INFLAMMATION; LYMPHOCYTES AB Dendritic cells (DC) are the most potent APCs and the principal activators of naive T cells. We now report that chemokines can serve as activating agents for immature DC. Murine bone marrow-derived DC respond to the CC chemokine RANTES (10-100 ng/ml) by production of proinflammatory mediators. RANTES induces rapid expression of transcripts for the CXC chemokines KC and macrophage inflammatory protein (MIP)-2, the CC chemokines MIP-1 beta and MIP-1 alpha, and the cytokines TNF-alpha and IL-6. Synthesis of KC, IL-6, and TNF-alpha proteins were also demonstrated. After 4 h, autoinduction of RANTES transcripts was observed. These responses are chemokine specific. Although DC demonstrated weak responses to eotaxin, DC failed to respond to other chemokines including KC, MIP-2, stromal-derived factor-1 alpha, MIP-1 beta, MIP-1 alpha, monocyte chemoattractant protein-1, T cell activation gene 3, or thymus-derived chemotactic agent 4. In addition, RANTES treatment up-regulated expression of an orphan chemokine receptor termed Eo1. Chemokine induction was also observed after treatment of splenic DC and neonatal microglia with RANTES, but not after treatment of thymocytes or splenocytes depleted of adherent cells. TNF-alpha -treated DC lose responsiveness to RANTES. DC from mice deficient for CCR1, CCR3, and CCR5 respond to RANTES, indicating that none of these receptors are exclusively used to initiate the chemokine cascade. RANTES-mediated chemokine amplification in DC may prolong inflammatory responses and shape the microenvironment, potentially enhancing acquired and innate immune responses. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Dorf, ME (reprint author), Harvard Univ, Sch Med, Dept Pathol, Armenise Bldg D-530,200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA67416]; NINDS NIH HHS [NS37284] NR 36 TC 54 Z9 57 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2001 VL 167 IS 3 BP 1637 EP 1643 PG 7 WC Immunology SC Immunology GA 471VM UT WOS:000170949400062 PM 11466387 ER PT J AU Fleming, CM He, HZ Ciota, A Perkins, D Finn, PW AF Fleming, CM He, HZ Ciota, A Perkins, D Finn, PW TI Administration of pentoxifylline during allergen sensitization dissociates pulmonary allergic inflammation from airway hyperresponsiveness SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FACTOR-KAPPA-B; BROWN-NORWAY RATS; SELECTIVE PHOSPHODIESTERASE INHIBITORS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTIGEN-INDUCED EOSINOPHILIA; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE CELLS; GUINEA-PIGS; MURINE MODEL AB Asthma, a chronic inflammatory disease characterized by intermittent, reversible airflow obstruction and airway hyperresponsiveness (AHR), is classically characterized by an excess of Th2 cytokines (IL-13, IL-4) and depletion of Th1 cytokines (IFN-gamma, IL-12). Recent studies indicating an important role for Th1 immunity in the development of AHR with allergic inflammation suggest that Th1/Th2 balance may be important in determining the association of AHR with allergic inflammation. We hypothesized that administration of pentoxifylline (PTX), a phosphodiesterase inhibitor known to inhibit Th1 cytokine production, during allergen (OVA) sensitization and challenge would lead to attenuation of AHR in a murine model of allergic pulmonary inflammation. We found that PTX treatment led to attenuation of AHR when administered at the time of allergen sensitization without affecting other hallmarks of pulmonary allergic inflammation. Attenuation of AHR with PTX treatment was found in the presence of elevated bronchoalveolar lavage fluid levels of the Th2 cytokine IL-13 and decreased levels of the Th1 cytokine IFN-gamma. PTX treatment during allergen sensitization leads to a divergence of AHR and pulmonary inflammation following allergen challenge. C1 Brigham & Womens Hosp, Dept Med, Div Resp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. RP Finn, PW (reprint author), Brigham & Womens Hosp, Dept Med, Div Resp, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL6723]; NIAID NIH HHS [R01 AI45007] NR 88 TC 25 Z9 28 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2001 VL 167 IS 3 BP 1703 EP 1711 PG 9 WC Immunology SC Immunology GA 471VM UT WOS:000170949400069 PM 11466394 ER PT J AU Rodriguez, JA Valentine, JS Eggers, DK Roe, JA Brown, RH Hayward, LJ AF Rodriguez, JA Valentine, JS Eggers, DK Roe, JA Brown, RH Hayward, LJ TI Influence of familial ALS-associated mutations on the thermal stability of distinctly metallated species of human superoxide dismutase SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. Loyola Marymount Univ, Dept Chem & Biochem, Los Angeles, CA 90045 USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. RI Valentine, Joan/B-6665-2008 OI Valentine, Joan/0000-0002-7174-925X NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD AUG PY 2001 VL 86 IS 1 BP 403 EP 403 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 463FW UT WOS:000170467300775 ER PT J AU Gerlock, AA AF Gerlock, AA TI Relationship mutuality - Why is it important in batterers' rehabilitation? SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article ID ABUSE SCREENING-TEST; SELF-ESTEEM AB Batterers' rehabilitation takes more than just stopping all forms of abuse and violence To stop domestic violence batterers are expected to halt all forms of violence and abusive behaviors and work on building relationship equality. In this study, relationship mutuality, as measured by the Mutuality psychological Development Questionnaire (MPDQ), was one of six variables significantly related to batterers' completion of domestic violence rehabilitation. Completers were more likely to be young, employed have lower levels of stress and post traumatic stress, be,receiving monthly monitoring from the courts, and have higher levels of relationship mutuality In addition the greater the frequency and severity of fire abuse the lower the level of relationship mutuality as reported by the batterer. When compared with the reports of their victims, batterers continued to minimize both the psychological abuse and physical violence. C1 Univ Washington, Dept Vet Affairs, VA Puget Sound Hlth Care Syst, Washington, DC USA. RP Gerlock, AA (reprint author), Univ Washington, Dept Vet Affairs, VA Puget Sound Hlth Care Syst, Washington, DC USA. NR 38 TC 4 Z9 4 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD AUG PY 2001 VL 16 IS 8 BP 768 EP 783 DI 10.1177/088626001016008003 PG 16 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 451XB UT WOS:000169826900003 ER PT J AU Hawighorst, T Velasco, P Streit, M Detmar, M AF Hawighorst, T Velasco, P Streit, M Detmar, M TI Thrombospondin-1 overexpression in the skin of transgenic mice suppresses tumor development, growth and metastasis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 006 BP 390 EP 390 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300040 ER PT J AU Lange-Asschenfeldt, B Velasco, P Janes, L Brown, L Bohlen, P Detmar, M AF Lange-Asschenfeldt, B Velasco, P Janes, L Brown, L Bohlen, P Detmar, M TI Modulation of vascular endothelial growth factor activity during wound healing affects granulation tissue vascularization but not the rate of wound closure SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Dermatol, CBRC, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Imclone Syst, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 001 BP 390 EP 390 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300035 ER PT J AU Shirakata, Y Oura, H Yano, K Velasco, P Riccardi, L Streit, M Hashimoto, K Detmar, M AF Shirakata, Y Oura, H Yano, K Velasco, P Riccardi, L Streit, M Hashimoto, K Detmar, M TI Inverse regulation of the angiogenesis factor VEGF and the angiogenesis inhibitors thrombospondin-1 and TSP-2 in human epidermal keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, CBRC, Charlestown, MA USA. Massachusetts Gen Hosp, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Ehime Univ, Matsuyama, Ehime 790, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 010 BP 391 EP 391 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300045 ER PT J AU Streit, M Stephen, A Lange-Asschenfeldt, B Hawighorst, T Brown, L Vacanti, J Detmar, M AF Streit, M Stephen, A Lange-Asschenfeldt, B Hawighorst, T Brown, L Vacanti, J Detmar, M TI Systemic inhibition of cutaneous tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, CBRC, Charlestown, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 011 BP 391 EP 391 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300043 ER PT J AU Velasco, P Lange-Asschenfeldt, B Suri, C Yancopoulos, G Detmar, M AF Velasco, P Lange-Asschenfeldt, B Suri, C Yancopoulos, G Detmar, M TI Antipodal roles of vascular endothelial growth factor and angiopoietin-1 in the control of delayed-type hypersensitivity reactions elicited in the skin of transgenic mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Dermatol, CBRC, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 009 BP 391 EP 391 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300042 ER PT J AU Riccardi, L Streit, M Brown, L Detmar, M AF Riccardi, L Streit, M Brown, L Detmar, M TI The angiogenesis inhibitor thrombospondin-2 inhibits tumor growth and angiogenesis of human malignant melanomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, CBRC, Charlestown, MA USA. Massachusetts Gen Hosp, Charlestown, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 016 BP 392 EP 392 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300051 ER PT J AU Skobe, M Hawighorst, T Alitalo, K Jackson, D Detmar, M AF Skobe, M Hawighorst, T Alitalo, K Jackson, D Detmar, M TI Lymphangiogenesis in melanoma, squamous cell carcinoma and breast carcinoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Charlestown, MA USA. Massachusetts Gen Hosp, Charlestown, MA USA. Haartman Inst, Helsinki, Finland. John Radcliffe Hosp, Inst Mol Med, Oxford OX3 9DU, England. NR 0 TC 0 Z9 1 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 017 BP 392 EP 392 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300049 ER PT J AU Fuhlbrigge, R King, S Dimitroff, C Sackstein, R Kupper, T AF Fuhlbrigge, R King, S Dimitroff, C Sackstein, R Kupper, T TI Direct observation of E-selectin mediated rolling on cutaneous lymphocyte-associated antigen using a novel blot rolling assay SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 047 BP 397 EP 397 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300079 ER PT J AU Okuyama, R Nguyen, C Oh, H Tagami, H Dotto, G AF Okuyama, R Nguyen, C Oh, H Tagami, H Dotto, G TI Embryonic mouse keratinocytes: Low growth potential and high commitment towards terminal differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, CBRC, Charlestown, MA USA. Tohoku Univ, Sch Med, Sendai, Miyagi 980, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 077 BP 402 EP 402 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300109 ER PT J AU Li, W Henry, G Garner, W Woodley, D AF Li, W Henry, G Garner, W Woodley, D TI The active and passive roles of extracellular matrices and growth factors in control of human keratinocyte migration SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Div Dermatol, Los Angeles, CA 90033 USA. Univ So Calif, Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA 90033 USA. Univ So Calif, Dept Surg, Los Angeles, CA 90033 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 174 BP 418 EP 418 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300207 ER PT J AU Usui, M Mansbridge, J Gibran, N Muffley, L Smith, D Larsen, J Carter, W Olerud, J AF Usui, M Mansbridge, J Gibran, N Muffley, L Smith, D Larsen, J Carter, W Olerud, J TI Epidermal margins of chronic nonhealing ulcers lack K10 and K2e in contrast to normal acute human wounds SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ Washington, Seattle, WA 98195 USA. Adv Tissue Sci, La Jolla, CA USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 178 BP 419 EP 419 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300212 ER PT J AU Soma, T Dohrmann, C Dobens, L White, K Brissette, J Raftery, L AF Soma, T Dohrmann, C Dobens, L White, K Brissette, J Raftery, L TI Role of TGF-beta in the hair cycle I: Dissection of endogenous cellular responses SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RI Raftery, Laurel/H-1406-2012 OI Raftery, Laurel/0000-0003-4797-4163 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 220 BP 426 EP 426 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300254 ER PT J AU Reddy, V Kounga, K Kramer, C Park, J Baden, H Lerner, E AF Reddy, V Kounga, K Kramer, C Park, J Baden, H Lerner, E TI Overexpression of nitric oxide synthase in the skin of transgenic mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 237 BP 429 EP 429 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300269 ER PT J AU Lerner, E Kounga, K Reddy, V Suchdev, R Bello, Y AF Lerner, E Kounga, K Reddy, V Suchdev, R Bello, Y TI Characterization of substances from the itch inducing plant Macuna pruriens SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 296 BP 439 EP 439 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300331 ER PT J AU Weninger, W Crowley, M Manjunath, N von Andrian, U AF Weninger, W Crowley, M Manjunath, N von Andrian, U TI Migratory properties of naive, effector, and central memory CD8+T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 384 BP 453 EP 453 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300416 ER PT J AU Qureshi, A Letko, E Bhol, K Razzaque, M Foster, C Ahmed, A AF Qureshi, A Letko, E Bhol, K Razzaque, M Foster, C Ahmed, A TI An in vitro organ culture model for toxic epidermal necrolysis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Immunol & Uveitis Serv, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 464 BP 467 EP 467 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300498 ER PT J AU Yue, Z Li, W Nadelman, C Woodley, D AF Yue, Z Li, W Nadelman, C Woodley, D TI Rho family GTPases, Rac and Cdc42, play an important role in regulation of human keratinocyte migration on collagen SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Div Dermatol, Norris Canc Ctr, Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 486 BP 470 EP 470 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300517 ER PT J AU Henry, G Li, W Garner, W Woodley, D AF Henry, G Li, W Garner, W Woodley, D TI Human serum but not plasma promotes migration of human skin cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Div Dermatol, Los Angeles, CA USA. Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA. Univ So Calif, Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. Univ So Calif, Dept Surg, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 487 BP 471 EP 471 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300518 ER PT J AU Rheinwald, J Wu, J Tsao, H Guo, Z DeLuca, M Ramsey, M AF Rheinwald, J Wu, J Tsao, H Guo, Z DeLuca, M Ramsey, M TI Telomere-independent keratinocyte senescence enforced by coordinate induction of p16INK4A and p14ARF; Spontaneous and experimental abrogation of this mechanism in culture and in vivo SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. IDI, Rome, Italy. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 499 BP 473 EP 473 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300530 ER PT J AU Philips, N Burchill, D O'Donoghue, D Gonzalez, S AF Philips, N Burchill, D O'Donoghue, D Gonzalez, S TI Dermal fibroblasts convert benzene to non-phenolic compounds that are less toxic than the phenolic metabolites of benzene SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Georgian Court Coll, Lakewood, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 550 BP 481 EP 481 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300581 ER PT J AU Nghiem, P Park, P Kim, Y Vaziri, C Schreiber, S AF Nghiem, P Park, P Kim, Y Vaziri, C Schreiber, S TI ATR is required for a mitotic entry checkpoint that prevents premature chromatin condensation after UV exposure SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Boston Univ, Canc Res Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 595 BP 489 EP 489 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300625 ER PT J AU Trowers, A Kodish, E Kuerbitz, S Wood, G AF Trowers, A Kodish, E Kuerbitz, S Wood, G TI Three pediatric cases of CD30+cutaneous anaplastic large cell lymphomas (ALCLs) bearing the t(2;5)(p23;q35) translocation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH USA. Med Coll Ohio, Dept Pediat, Toledo, OH 43699 USA. Univ Wisconsin, Dept Med, Madison, WI USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 602 BP 490 EP 490 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300634 ER PT J AU Tachihara, R Farinelli, W Lee, P Anderson, R AF Tachihara, R Farinelli, W Lee, P Anderson, R TI Percutaneous drug delivery using Er : YAG laser SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 658 BP 499 EP 499 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300689 ER PT J AU Hussein, MR Tuthill, E Roggero, L Sudilovsky, C Wood, GO Sudilovsky AF Hussein, MR Tuthill, E Roggero, L Sudilovsky, C Wood, GO Sudilovsky TI Loss of heterozygosity at 1p36 and 9p22-21 regions in the human melanocytic skin lesions SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ Wisconsin, Dept Med, Madison, WI USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. Cleveland Clin Fdn, Dept Pathol, Cleveland, OH 44195 USA. Inst Histopatol, Dept Pathol, RA-2000 Rosario, Santa Fe, Argentina. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 782 BP 520 EP 520 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300814 ER PT J AU Talora, C Rangarajan, A Radtke, F Okuyama, R Dotto, P AF Talora, C Rangarajan, A Radtke, F Okuyama, R Dotto, P TI Notch1 functions as an essential determinant of keratinocyte exit from the cell cycle and entry into differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Dept Dermatol, CBRC, Charlestown, MA USA. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Lausanne, Ludwig Inst Canc Res, Epalinges, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 813 BP 525 EP 525 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300842 ER PT J AU Ellis, C Drake, L Prendergast, M Abramovits, W Boguniewicz, M Daniel, C Lebwohl, M Stevens, S Whitaker-Worth, D Tong, K AF Ellis, C Drake, L Prendergast, M Abramovits, W Boguniewicz, M Daniel, C Lebwohl, M Stevens, S Whitaker-Worth, D Tong, K TI Third-party payer cost of atopic dermatitis and eczema in the United States SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Fujisawa Healthcare Inc, Outcomes Res & Prod Econ, Deerfield, IL USA. Univ Texas, Hlth Sci Ctr, SW Med Sch, Dallas, TX USA. Natl Jewish Med & Res Grp, Denver, CO USA. Univ Mississippi, Jackson, MS 39216 USA. NYU, Mt Sinai Sch Med, New York, NY USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Quorum Consulting Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 852 BP 531 EP 531 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300882 ER PT J AU Choi, C Nghiem, P AF Choi, C Nghiem, P TI Tacrolimus ointment in the treatment of chronic cutaneous graft-versus-host disease: A case series of 18 patients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Dermatol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 872 BP 535 EP 535 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300904 ER PT J AU Tsao, H Goggins, W Finkelstein, D AF Tsao, H Goggins, W Finkelstein, D TI Evidence for an association between cutaneous melanoma and Non-Hodgkin's lymphoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Melanoma Ctr, Boston, MA 02114 USA. Hong Kong Baptist Univ, Dept Math, Hong Kong, Peoples R China. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 903 BP 540 EP 540 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300932 ER PT J AU Letko, E Miserocchi, E Christen, W Foster, C Ahmed, A AF Letko, E Miserocchi, E Christen, W Foster, C Ahmed, A TI A prospective nonrandomized comparison of efficacy and safety of intravenous immunoglobulin to conventional therapy in ocular cicatricial pemphigoid SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Immunol & Uveitis Serv, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2001 VL 117 IS 2 MA 912 BP 541 EP 541 PG 1 WC Dermatology SC Dermatology GA 466WC UT WOS:000170668300942 ER PT J AU Hofmann-Lehmann, R Rasmussen, RA Vlasak, J Smith, BA Baba, TW Liska, V Montefiori, DC McClure, HM Anderson, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Posner, MR Cavacini, LA Chou, TC Ruprecht, RM AF Hofmann-Lehmann, R Rasmussen, RA Vlasak, J Smith, BA Baba, TW Liska, V Montefiori, DC McClure, HM Anderson, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Posner, MR Cavacini, LA Chou, TC Ruprecht, RM TI Passive immunization against oral AIDS virus transmission: An approach to prevent mother-to-infant HIV-1 transmission? SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 18th Annual Symposium on Nonhuman Primate Models for AIDS CY OCT 04-07, 1999 CL MADISON, WISCONSIN DE neutralizing human anti-HIV monoclonal antibodies; primate model; rhesus monkeys; simian-human immunodeficiency virus (SHIV) ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; RHESUS-MONKEYS; SYNERGISTIC NEUTRALIZATION; CHILD TRANSMISSION; IMMUNE GLOBULIN; TYPE-1; INFECTION; MACAQUES; COMBINATIONS AB To develop immunoprophylaxis regimens against mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, we established a simian-human immunodeficiency virus (SHIV) model in neonatal macaques that mimics intrapartum mucosal virus exposure (T.W. Baba, J. Koch, E.S. Mittler et al.: AIDS Res Hum Retroviruses 10:351-357, 1994). We protected four neonates from oral SHIV-vpu(+) challenge by ante- and postpartum treatment with a synergistic triple combination of immunoglobulin (Ig) G1 human anti-HIV-1 neutralizing monoclonal antibodies (mAbs) (T.W. Baba, V. Liska, R. Hofmann-Lehmann et al.: Nature Med 6:200-206, 2000), which recognize the CD4-binding site of Env, a glycosylation-dependent gp120, or a linear gp41 epitope. Two neonates that received only postpartum mAbs were also protected from oral SHIV-vpu+ challenge, indicating that postpartum treatment alone is sufficient. Next, we evaluated a similar mAb combination against SHIV89.6P, which encodes env of primary HIV89.6. One of four mAb-treated neonates was protected from infection and two maintained normal CD4(+) T-cell counts. We conclude that the epitopes recognized by the three mAbs are important determinants for achieving protection. Combination immunoprophylaxis with synergistic mAbs seems promising to prevent maternal HIV-1 transmission in humans. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Duke Univ, Med Ctr, Durham, NC USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. Univ Texas, MD Anderson Canc Ctr, Bastrop, TX USA. Univ Agr, Vienna, Austria. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, 44 Binney St,JFB809, Boston, MA 02115 USA. RI Hofmann-Lehmann, Regina/C-6528-2009; Chou, Ting-Chao/B-4111-2009 OI Chou, Ting-Chao/0000-0002-3340-1594 FU NCRR NIH HHS [RR-00165]; NIAID NIH HHS [1 R21 AI46177, P01 AI48240, R01 AI26926, R01 AI34266, R21 AI46177]; NIDCR NIH HHS [R01 DE12937] NR 41 TC 27 Z9 27 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2001 VL 30 IS 4 BP 190 EP 196 DI 10.1034/j.1600-0684.2001.d01-52.x PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 475MG UT WOS:000171167600002 PM 11555137 ER PT J AU Cornelussen, RNM Gupta, S Knowlton, AA AF Cornelussen, RNM Gupta, S Knowlton, AA TI Regulation of prostaglandin A(1)-induced heat shock protein expression in isolated cardiomyocytes SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE heat shock factor; NF Kappa B; HSP32; HSP72; cardioprotection ID TRANSCRIPTION FACTOR; MOLECULAR CHAPERONES; NUCLEAR ACCUMULATION; SODIUM-SALICYLATE; ARACHIDONIC-ACID; CARDIAC MYOCYTES; STRESS PROTEINS; HEME OXYGENASE; HUMAN-CELLS; ACTIVATION AB R. N. M. CORNELUSSEN, S. GUPTA AND A. A. KNOWLTON. Regulation of Prostaglandin A(1)-induced Heat Shock Protein Expression in Isolated Cardiomyocytes. Journal of Molecular and Cellular Cardiology (2001) 33, 1447-1454. Prostaglandins of the A-type (PC;As) induce heat shock protein (HSP) synthesis in a wide variety of mammalian cells resulting in protection against cellular stresses. The effect of PGAs on HSP-induction in cardiac myocytes is unknown. Therefore, we investigated the effect of PGA, on HSP synthesis in adult rat cardiac myocytes. After 24h of treatment, HSP72 was significantly increased 2.9-, 5.6- and 50-fold by PGA, used at concentrations of 10, 20 or 40 mug/ml, respectively (P < 0.05), However, the PGA(1)-concentration of 40 mug/ml, was found to be cytotoxic as evidenced by the release of LDH. In addition to HSP72, HSP32 was significantly increased by PGA,. The HSP32 induction was more vigorous with a marked increase with only 4 mug/ml of PGA(1). No differences in the levels of HSP27, HSP60 or HSP90 were detected. When isolated cardiac myocytes were treated with PGA,, clear activation of heat shock factor (HSF) 1, one of the transcription factors for HSPs, was observed. In addition, another stress-induced transcription factor NF kappaB was also activated by PGA exposure. Despite the significant upregulation of both HSP72 and HSP32 cytoprotective properties against hypoxia and reo,reoxygenation were absent, In conclusion, these experiments show for the first time that PGA, induces differential expression of heat shock proteins in cardiac myocytes probably mediated through the activation of both HSF1 and NF kappaB. (C) 2001 Academic Press. C1 VA Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. RP VA Med Ctr, 151C,2002 Holcombe Blvd, Houston, TX 77030 USA. EM annek@bcm.tmc.edu FU NHLBI NIH HHS [HL58515, R01 HL058515] NR 47 TC 12 Z9 13 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD AUG PY 2001 VL 33 IS 8 BP 1447 EP 1454 DI 10.1006/jmcc.2001.1406 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 455JX UT WOS:000170024700007 PM 11448133 ER PT J AU Zhao, R Chen, Y Tan, WB Waly, M Sharma, A Stover, P Rosowsky, A Malewicz, B Deth, RC AF Zhao, R Chen, Y Tan, WB Waly, M Sharma, A Stover, P Rosowsky, A Malewicz, B Deth, RC TI Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE D4 dopamine receptors; folic acid metabolism; 5-methyltetrahydrofolate; phospholipid methylation; purine metabolism; schizophrenia ID 5-FORMYLTETRAHYDROFOLATE POLYGLUTAMATES; RECEPTOR; LEUCOVORIN; METABOLISM; ACID AB In a previous study we demonstrated the ability of dopamine (DA) to stimulate phospholipid methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) In which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [C-14]-labeled formate, Into phospholipids in cultured SH-SY5Y neuroblastoma cells. These Interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. P-31-NMR was also used to follow DA-induced changes in cell phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process. C1 Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA. Cornell Univ, Dept Nutr Sci, Ithaca, NY USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Univ Minnesota, Hormel Inst, LIPIDNMR Lab, Austin, MN 55912 USA. RP Deth, RC (reprint author), Northeastern Univ, Dept Pharmaceut Sci, 312 Mugar Hall,360 Huntington Ave, Boston, MA 02115 USA. NR 23 TC 12 Z9 12 U1 1 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2001 VL 78 IS 4 BP 788 EP 796 DI 10.1046/j.1471-4159.2001.00471.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 463TV UT WOS:000170494100013 PM 11520899 ER PT J AU Le, R Cruz, L Urbanc, B Knowles, RB Hsiao-Ashe, K Duff, K Irizarry, MC Stanley, HE Hyman, BT AF Le, R Cruz, L Urbanc, B Knowles, RB Hsiao-Ashe, K Duff, K Irizarry, MC Stanley, HE Hyman, BT TI Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: Implications for neural system disruption SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Alzheimer disease; modeling; neural networks; senile plaque; transgenic ID NEURONAL LOSS; MUTANT PRESENILIN-1; PRECURSOR PROTEIN; MICE; IMMUNIZATION; DEPOSITION; PATHOLOGY; MOUSE AB Neurites that pass through amyloid-beta deposits in Alzheimer disease (AD) undergo 3 changes: they develop phosphorylated tau immunoreactivity the density of SMI-32-positive dendrites diminishes and they also develop a marked alteration in their geometric features, changing from being nearly straight to being quite curvy. The extent to which the latter 2 phenomena are related to phosphorylated tau is unknown. We have now examined whether amyloid-beta deposits in APP695Sw transgenic mice, which have only rare phosphorylated tau containing neurites. develop these changes. We found that dendritic density is diminished within the boundaries of amyloid-beta plaques, with the greatest loss (about 80%, p < 0.001) within the boundaries of thioflavine S cores. Remaining dendrites within plaques develop substantial morphological alterations quantitatively similar to those seen in AD. A statistically significant but smaller degree of change in geometry was seen in the immediate vicinity around plaques, suggesting a propagation of cytoskeletal disruption from the center of the plaque outward. We examined the possible physiological consequences of this change in dendritic geometry using a standard cable-theory model. We found a predicted delay of several milliseconds in about one quarter of the dendrites passing through a thioflavine S plaque. These results are consistent with previous observations in AD, and suggest that thioflavine S-positive amyloid-beta deposits have a marked effect on dendritic microarchitecture in the cortex, even in the relative absence of phosphorylated tau alterations. C1 Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. Drew Univ, Dept Biol, Madison, NJ 07940 USA. Boston Univ, Dept Phys, Boston, MA 02215 USA. Boston Univ, Ctr Polymer Studies, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. RP Hyman, BT (reprint author), Alzheimer Dis Res Labs, 149 13th St,Room 6405, Charlestown, MA 02219 USA. RI Urbanc, Brigita/G-5839-2011; Cruz Cruz, Luis/B-2685-2013 OI Urbanc, Brigita/0000-0001-9159-7698; FU NIA NIH HHS [AG 15453, AG08487] NR 16 TC 67 Z9 67 U1 0 U2 1 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2001 VL 60 IS 8 BP 753 EP 758 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 458JX UT WOS:000170192200002 PM 11487049 ER PT J AU Sieving, PA Fowler, ML Bush, RA Machida, S Calvert, PD Green, DG Makino, CL McHenry, CL AF Sieving, PA Fowler, ML Bush, RA Machida, S Calvert, PD Green, DG Makino, CL McHenry, CL TI Constitutive "light" adaptation in rods from G90D rhodopsin: A mechanism for human congenital nightblindness without rod cell loss SO JOURNAL OF NEUROSCIENCE LA English DT Article DE constitutive activity; rhodopsin; light adaptation; retinal degeneration; rod photoreceptor; photoresponse; congenital nightblindness; transgenic mouse ID DOMINANT RETINITIS-PIGMENTOSA; STATIONARY NIGHT BLINDNESS; MONKEY MACACA-FASCICULARIS; SCHIFF-BASE COUNTERION; ISOLATED RAT RETINA; TRANSGENIC MICE; PHOTORECEPTOR DEGENERATION; MONOCLONAL-ANTIBODIES; BOVINE RHODOPSIN; OUTER SEGMENT AB A dominant form of human congenital nightblindness is caused by a gly90-->asp (G90D) mutation in rhodopsin. G90D has been shown to activate the phototransduction cascade in the absence of light in vitro. Such constitutive activity of G90D rhodopsin in vivo would desensitize rod photoreceptors and lead to nightblindness. In contrast, other rhodopsin mutations typically give rise to nightblindness by causing rod cell death. Thus, the proposed desensitization without rod degeneration would be a novel mechanism for this disorder. To explore this possibility, we induced mice to express G90D opsin in their rods and then examined rod function and morphology, after first crossing the transgenic animals with rhodopsin knock-out mice to obtain appropriate levels of opsin expression. The G90D mouse opsin bound the chromophore and formed a bleachable visual pigment with lambda (max) of 492 nm that supported rod photoresponses. (G+/-, R+/-) retinas, heterozygous for both G90D and wildtype (WT) rhodopsin, possessed normal numbers of photoreceptors and had a normal rhodopsin complement but exhibited considerable loss of rod sensitivity as measured electroretinographically. The rod photoresponses were desensitized, and the response time to peak was faster than in (R+/-) animals. An equivalent desensitization resulted by exposing WT retinas to a background light producing 82 photoisomerizations rod(-1) sec(-1), suggesting that G90D rods in darkness act as if they are partially "light-adapted." Adding a second G90D allele gave (G+/+, R+/-) animals that exhibited a further increase of equivalent background light level but had no rod cell loss by 24 weeks of age. (G+/+, R-/-) retinas that express only the mutant rhodopsin develop normal rod outer segments and show minimal rod cell loss even at 1 year of age. We conclude that G90D is constitutively active in mouse rods in vivo but that it does not cause significant rod degeneration. Instead, G90D desensitizes rods by a process equivalent to light adaptation. C1 Univ Michigan, Kellogg Eye Ctr, Ctr Retinal & Macular Degenerat, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Sieving, PA (reprint author), Univ Michigan, Kellogg Eye Ctr, Ctr Retinal & Macular Degenerat, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. FU NEI NIH HHS [EY07003, EY00379, EY06094] NR 73 TC 49 Z9 50 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 2001 VL 21 IS 15 BP 5449 EP 5460 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 456XW UT WOS:000170108900010 PM 11466416 ER PT J AU Dunah, AW Standaert, DG AF Dunah, AW Standaert, DG TI Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate receptor; NMDA receptor; dopamine receptor; subcellular compartment; receptor trafficking; tyrosine phosphorylation ID D-ASPARTATE RECEPTOR; MOTOR RESPONSE ALTERATIONS; PROTEIN-KINASE-A; RAT-BRAIN; PARKINSONS-DISEASE; TYROSINE PHOSPHORYLATION; 6-HYDROXYDOPAMINE MODEL; REGIONAL EXPRESSION; DOMAIN INTERACTION; SYNAPTIC VESICLES AB Recent work has shown substantial alterations in NMDA receptor subunit expression, assembly, and phosphorylation in the dopamine-depleted striatum of a rodent 6-hydroxydopamine model of Parkinson's disease. These modifications are hypothesized to result from the trafficking of NMDA receptors between subcellular compartments. Here we show that in rat striatal tissues the NR2A and NR2B subunits in the synaptosomal membrane, and not those in the light membrane and synaptic vesicle-enriched compartments, are tyrosine phosphorylated. The dopamine D1 receptor agonist SKF-82958 produces (1) an increase in NR1, NR2A, and NR2B proteins in the synaptosomal membrane fraction; (2) a decrease in NR1, NR2A, and NR2B proteins in the light membrane and synaptic vesicle-enriched fractions; and (3) an increase in the tyrosine phosphorylation of NR2A and NR2B in the synaptosomal membrane compartment. The protein phosphatase inhibitor pervanadate reproduces the alterations in subcellular distribution and phosphorylation, whereas the effects of the dopamine D1 receptor agonist are blocked by genistein, a protein tyrosine kinase inhibitor. Dopamine D1 receptor agonist treatment does not change the subcellular distribution of the AMPA receptor subunits GluR1 or GluR2/3 in the striatum and has no effect on cortical or cerebellar NMDA receptor subunits. These data reveal a rapid dopamine D1 receptor- and tyrosine kinase-dependent trafficking of striatal NMDA receptors between intracellular and postsynaptic sites. The subcellular trafficking of striatal NMDA receptors may play a significant role both in the pathogenesis of Parkinson's disease and in the development of adverse effects of chronic dopaminergic therapy in parkinsonian patients. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Standaert, DG (reprint author), Massachusetts Gen Hosp, CNY B114-2000, Charlestown, MA 02129 USA. OI Standaert, David/0000-0003-2921-8348 FU NINDS NIH HHS [NS34361] NR 69 TC 256 Z9 262 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 2001 VL 21 IS 15 BP 5546 EP 5558 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 456XW UT WOS:000170108900020 PM 11466426 ER PT J AU Sonis, ST AF Sonis, ST TI Differences between patients with or without the need for intensive care due to severe odontogenic infections - Discussion SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Editorial Material ID PROTEIN C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Oral Med Oral & Maxillofacial Surg & Dent, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Boston, MA 02115 USA. RP Sonis, ST (reprint author), Brigham & Womens Hosp, Boston, MA 02115 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2001 VL 59 IS 8 BP 872 EP 873 DI 10.1053/joms.2001.25018 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 458TX UT WOS:000170211600007 ER PT J AU Ferguson, WS Harris, MB Goorin, AM Gebhardt, MC Link, MP Shochat, SJ Siegal, GP Devidas, M Grier, HE AF Ferguson, WS Harris, MB Goorin, AM Gebhardt, MC Link, MP Shochat, SJ Siegal, GP Devidas, M Grier, HE TI Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group trial SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE metastatic osteosarcoma; carboplatin; phase II window ID HIGH-DOSE CARBOPLATIN; GERM-CELL TUMORS; ADVANCED OVARIAN-CANCER; PHASE-II TRIAL; OSTEOGENIC-SARCOMA; SIMULTANEOUS RESECTION; RANDOMIZED-TRIAL; LUNG-CANCER; NEOADJUVANT CHEMOTHERAPY; ADJUVANT CHEMOTHERAPY AB Purpose: Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy. Patients and Methods: Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m(2) per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. Results: One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases. Conclusions: Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal. C1 Childrens Oncol Grp 9573, Arcadia, CA 91066 USA. Rhode Isl Hosp, Providence, RI USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Hackensack Univ Med Ctr, Hackensack, NJ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Alabama Birmingham, Birmingham, AL USA. Childrens Oncol Grp, Res Data Ctr, Gainesville, FL USA. RP Ferguson, WS (reprint author), Childrens Oncol Grp 9573, POB 60012, Arcadia, CA 91066 USA. EM wferguson@lifespan.org RI Siegal, Gene/A-8653-2009 FU NCI NIH HHS [CA03161, CA07431, CA29691] NR 61 TC 36 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG-SEP PY 2001 VL 23 IS 6 BP 340 EP 348 DI 10.1097/00043426-200108000-00004 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 470RE UT WOS:000170884300005 PM 11563767 ER PT J AU Islam, S Masiakos, PT Doody, DP Schnitzer, JJ Ryan, DP AF Islam, S Masiakos, PT Doody, DP Schnitzer, JJ Ryan, DP TI Tracheal resection and reanastomosis in the neonatal period SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the Section-on-Surgery-of-the-American-Academy-of-Pediatrics CY OCT 28-NOV 01, 2000 CL CHICAGO, ILLINOIS SP Sect Surg Amer Acad Pediatrics DE tracheal stenosis; congenital; resection; neonatal ID UNILATERAL PULMONARY AGENESIS; STENOSIS; CHILDREN; INFANTS AB Background/Purpose: Severe congenital tracheal stenosis is rare. Most of these can be managed conservatively before elective repair. Focal tracheal stenosis has been treated with resection of the involved trachea and primary reanastomosis in older infants. The authors found no reports of repair of this lesion in neonates. Two patients are presented with severe respiratory failure on the first day of life that required extracorporeal life support (ECLS) who underwent successful tracheal resection and reanastomosis (TRR) during the first week of life. Methods: A retrospective review was conducted. Results: Both babies had severe pulmonary hypertension and carbon dioxide retention despite maximal therapy and were placed on ECLS shortly after transfer. One had an isolated stenosis of the upper trachea, and the other had agenesis of the right lung, esophageal atresia with tracheo-esophageal fistula, and a tracheal stenosis at the end of a short trachea with a long, narrow left bronchus. Both underwent diagnostic studies and had surgical repair while on ECLS at day 3 and 7 of life without bleeding complications. They were weaned off ECLS 1 and 8 days after surgery. One patient was extubated and did well. The other was extubated transiently, but required a tracheostomy because of left mainstem bronchomalacia. Both are alive and well at 18 and 38 months of age, with no narrowing of the repairs. Conclusion: In the setting of severe respiratory failure requiring ECLS support, TRR can be performed safely and successfully in the neonate with focal tracheal stenosis. J Pediatr Surg 36:1262-1265. Copyright (C) 2001 by W.B. Saunders Company. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. RP Ryan, DP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Surg, Warren 1124,55 Fruit St, Boston, MA 02114 USA. NR 14 TC 4 Z9 4 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD AUG PY 2001 VL 36 IS 8 BP 1262 EP 1265 DI 10.1053/jpsu.2001.25790 PG 4 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 457CV UT WOS:000170120300037 PM 11479872 ER PT J AU Sheridan, RL Schnitzer, JJ AF Sheridan, RL Schnitzer, JJ TI Management of the high-risk pediatric burn patient SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the Section-on-Surgery-of-the-American-Academy-of-Pediatrics CY OCT 28-NOV 01, 2000 CL CHICAGO, ILLINOIS SP Sect Surg Amer Acad Pediatrics DE burn injury in children; nitric oxide; respiratory support; inhalation thermal injury ID THERMAL-INJURY; PERMISSIVE HYPERCAPNIA; RESPIRATORY-FAILURE; INHALATION INJURY; CHILDREN; MORTALITY; RESUSCITATION; VENTILATION; CATHETERS; PNEUMONIA AB Background/Purpose: Inhalation injury, flame burn exceeding 30%, and age under 48 months all have been cited as independent risk factors for mortality; the combination of all 3 risk factors is unusual. The authors have experienced an overall reduction in mortality rate and chose to examine this high-risk group to define techniques useful in improving outcome in pediatric burns. Methods:A review was done of children with all 3 risk factors over a recent 9-year interval. All were treated with a system of care emphasizing precise fluid repletion, early wound excision and closure, and avoidance of injurious pulmonary inflating pressures and concentrations of oxygen. Data are expressed as mean +/- SD. Results: There were 26 children admitted with all 3 risk factors. Their average age was 2.1 +/- 1.1 years (range, 5 weeks to 3.7 years), and burn size was 61% +/- 21% (range, 30% to 98%) of the body surface. All required mechanical ventilation for an average of 28 +/- 4.5 days (range, 7 to 74 days). Two children underwent tracheostomy; all others were treated with protracted oral intubation. Inhaled nitric oxide (NO) was used in 3 children, all of whom were considered for extracorporeal membrane oxygenator (ECMO) support, although none went on to ECMO. Only 7 children (27%) never had any bacteremia. Ventilator-related pneumonia occurred in 8 children (31%). Total lengths of stay, including acute and rehabilitation hospitalizations, averaged 105 +/- 10 days (1.87 +/- 0.2; range, 0.66 to 4.8 days per percent burn). After exclusion of 1 child with a 98% third-and fourth-degree burn, pre-hospital cardiac arrest, and anoxic brain injury who had support withdrawn at 6 hours, all children survived to discharge; 23 followed up in our clinic currently are alive and well with no overt residual respiratory insufficiency. Conclusion: A high rate of survival can be expected in young children with large burns and inhalation injury. J Pediatr Surg 36:1308-1312. Copyright (C) 2001 by W.B. Saunders Company. C1 Shriners Burn Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Div Burns & Trauma, Boston, MA USA. Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Sheridan, RL (reprint author), Shriners Burn Inst, 51 Blossom St, Boston, MA 02114 USA. NR 29 TC 20 Z9 23 U1 4 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD AUG PY 2001 VL 36 IS 8 BP 1308 EP 1312 DI 10.1053/jpsu.2001.25805 PG 5 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 457CV UT WOS:000170120300048 PM 11479883 ER PT J AU Levine, BS Anderson, BJ Butler, DA Antisdel, JE Brackett, J Laffel, LMB AF Levine, BS Anderson, BJ Butler, DA Antisdel, JE Brackett, J Laffel, LMB TI Predictors of glycemic control and short-term adverse outcomes in youth with type 1 diabetes SO JOURNAL OF PEDIATRICS LA English DT Article; Proceedings Paper CT Joint Meeting of the Pediatric-Academic-Societies/American-Academy-of-Pediatrics CY MAY 12-16, 2000 CL BOSTON, MA SP Pediat Acad Soc, Amer Acad Pediat ID METABOLIC CONTROL; ADOLESCENTS; MELLITUS; CHILDREN; IDDM AB Objectives: To examine predictors of glycemic control and to assess how glycemic control affects the incidence of short-term adverse outcomes in a pediatric population with type 1 diabetes. Study design: Three hundred youth, aged 7 to 16 years, with type 1 diabetes who were receiving diabetes specialty care were followed up prospectively for 1 year. Treatment plans and frequency of adverse outcomes were ascertained by questionnaires and medical record review. Incidence rates of adverse outcomes were compared among 3 strata of the population, representing tertiles of baseline glycosylated hemoglobin (HbA1c). Results: Blood glucose monitoring frequency was the sole modifiable predictor of HbA1c (P <.0001). Overall incidence rate of hospitalization was 13 per 100 person-years, more than 3 times the rate in the general pediatric population and significantly higher in the upper HbA1c tertile compared with the other strata (P =.001). Rate of emergency department use was 29 per 100 person-years and did not differ significantly among tertiles. Incidence of severe hypoglycemia was 62 per 100 person-years and notably high even in those with poorest glycemic control. Conclusion: Despite improvements in diabetes care, the incidence of shortterm adverse events in children with type 1 diabetes remains high, particularly in those with poorest glycemic control. C1 Childrens Hosp, Joslin Diabet Ctr, Pediat & Adolescent Unit, Boston, MA 02115 USA. Childrens Hosp, Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Pediat & Adolescent Unit, 1 Joslin Pl, Boston, MA 02215 USA. FU AHRQ HHS [T32 HS00063]; NIDDK NIH HHS [T32 DK07260, DK46887] NR 24 TC 144 Z9 147 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2001 VL 139 IS 2 BP 197 EP 203 DI 10.1067/mpd.2001.116283 PG 7 WC Pediatrics SC Pediatrics GA 461JA UT WOS:000170360100007 PM 11487743 ER PT J AU Vargas, JE Allred, EN Leviton, A Holmes, LB AF Vargas, JE Allred, EN Leviton, A Holmes, LB TI Congenital microcephaly: Phenotypic features in a consecutive sample of newborn infants SO JOURNAL OF PEDIATRICS LA English DT Article ID INTRAUTERINE GROWTH-RETARDATION; HEAD CIRCUMFERENCE; BIRTH-WEIGHT; MALFORMATIONS; BIOSYNTHESIS AB Objective: We compared the prevalence of major and minor anomalies in a consecutive sample of newborn infants with congenital microcephaly with that among normocephalic infants. Study design: Head measurements from >19,000 liveborn infants at 1 hospital during the years 1991 and 1992 were reviewed. Infants whose head circumference was in the lowest quartile (n = 850) were remeasured by research assistants to identify all whose head circumference was 2 SD below the mean for gestational age; 106 infants with congenital microcephaly were identified. Infants with microcephaly (n = 65) and 294 infants in a control group were examined systematically for major malformations and minor physical features. Results: Four (6.2%) of the 65 infants examined either had a major malformation or were considered dysmorphic. One of the 4 had a specific multiple malformation syndrome, and 1 dysmorphic infant had a rare metabolic defect. Overall, the infants with microcephaly did not have a higher frequency of minor anomalies. However, there was a higher frequency of frontal bossing, small chin, and short nose with anteverted nares, which was associated with small body size rather than microcephaly. Conclusions: Congenital microcephaly is infrequently accompanied by major malformations and occurs rarely as part of a recognizable syndrome. C1 Massachusetts Gen Hosp, Serv Pediat, Genet & Teratol Unit, Boston, MA 02114 USA. Childrens Hosp, Div Genet, Boston, MA 02115 USA. Childrens Hosp, Neuroepidemiol Unit, Boston, MA 02115 USA. RP Holmes, LB (reprint author), Massachusetts Gen Hosp, Serv Pediat, Genet & Teratol Unit, Warren 801,55 Fruit St, Boston, MA 02114 USA. FU NINDS NIH HHS [R01NS26093] NR 16 TC 14 Z9 14 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2001 VL 139 IS 2 BP 210 EP 214 DI 10.1067/mpd.2001.115314 PG 5 WC Pediatrics SC Pediatrics GA 461JA UT WOS:000170360100009 PM 11487745 ER PT J AU Goodson, JM Shoher, I Imber, S Som, S Nathanson, D AF Goodson, JM Shoher, I Imber, S Som, S Nathanson, D TI Reduced dental plaque accumulation on composite gold alloy margins SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE composite; dental plaque; gold alloy; restoration ID GLASS-IONOMER RESTORATIONS; SURFACE FREE-ENERGY; ANTIBACTERIAL PROPERTIES; STREPTOCOCCAL ADHERENCE; PERIODONTITIS SUBJECTS; MUTANS STREPTOCOCCI; IN-VITRO; AMALGAM; ADHESION; THERAPY AB Restoration of tooth surfaces with materials that inhibit formation of heavy bacterial plaque accumulations could be important in the treatment of patients with existing oral disease or in reducing the likelihood for periodontal disease. Captek(R) is a dental gold composite material used to produce copings for ceramometal restorations that has been reported to inhibit plaque accumulation. In this study, the oral bacteria of nine periodontally healthy subjects with a total of 42 gold composite copings were sampled. Contralateral teeth with normal tooth surfaces were also sampled as controls. The quantitative presence of forty bacteria was determined in each sample by DNA:DNA hybridization. The results indicated that the porcelain/gold composite alloy coping surfaces had significantly fewer bacteria than the control normal tooth surfaces (71 % reduction). The percentage composition, however. did not differ significantly between surfaces. C1 Forsyth Inst, Boston, MA 02115 USA. Precious Chem Res Ctr, Tel Aviv, Israel. Tel Aviv Univ, Sch Dent Med, IL-69978 Tel Aviv, Israel. Boston Univ, Goldman Sch Dent Med, Boston, MA USA. RP Goodson, JM (reprint author), Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE11814] NR 56 TC 5 Z9 7 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0022-3484 J9 J PERIODONTAL RES JI J. Periodont. Res. PD AUG PY 2001 VL 36 IS 4 BP 252 EP 259 DI 10.1034/j.1600-0765.2001.036004252.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 462RL UT WOS:000170433500008 PM 11519699 ER PT J AU Rasmussen, DD Mitton, DR Larsen, SA Yellon, SM AF Rasmussen, DD Mitton, DR Larsen, SA Yellon, SM TI Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses SO JOURNAL OF PINEAL RESEARCH LA English DT Article DE aging; insulin; leptin; melatonin; novelty; visceral fat ID PLASMA LEPTIN; VISCERAL FAT; PINEAL-GLAND; BODY-WEIGHT; FOOD-INTAKE; AGED RATS; INSULIN AB Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague-Dawley rats. Addition of melatonin to the drinking water (0.2 mug/mL) produced nocturnal and diurnal plasma melatonin concentrations in middle-aged rats (12 months) equivalent to those of young adult (5 months) rats. Administration of this melatonin dosage every day for 10 wk starting at 10 months of age suppressed (P < 0.01) relative intra-abdominal fat. non-fasted plasma insulin and plasma leptin by 27, 39, and 51%, respectively (vs. vehicle-treated controls). In contrast, administration of melatonin for 10 wk starting at 3 months of age did not significantly alter (P > 0.10) any of these parameters. The melatonin administration stimulated (102%, P < 0.001) behavioral responsiveness of the middle-aged rats in a test of response to novelty, restoring youthful levels, but did not significantly alter behavioral responsiveness of the young rats. These results suggest that suppression of intra-abdominal adiposity and plasma leptin and insulin levels and stimulation of behavioral responsiveness in response to daily exogenous melatonin begins at middle age, coincident with and likely dependent upon the aging-associated decline in endogenous pineal melatonin secretion. These results further suggest that appropriate melatonin supplementation may potentially provide therapy or prophylaxis not only for the insulin resistance, increased intra-abdominal fat and resulting pathologies that occur with aging, but also for some aging-associated behavioral changes. C1 Univ Washington, Mental Illness Res Educ & Clin Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ Washington, Dept Behav Sci & Med, Seattle, WA 98195 USA. Loma Linda Univ, Dept Physiol, Loma Linda, CA 92350 USA. RP Rasmussen, DD (reprint author), VA Med Ctr, Res Serv 151, Amer Lake, Tacoma, WA 98493 USA. FU NIAAA NIH HHS [AA-10567] NR 18 TC 49 Z9 50 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0742-3098 J9 J PINEAL RES JI J. Pineal Res. PD AUG PY 2001 VL 31 IS 1 BP 89 EP 94 DI 10.1034/j.1600-079X.2001.310113.x PG 6 WC Endocrinology & Metabolism; Neurosciences; Physiology SC Endocrinology & Metabolism; Neurosciences & Neurology; Physiology GA 452UM UT WOS:000169878100013 PM 11485011 ER PT J AU Olmez, N Wang, GF Li, Y Zhang, HD Schumacher, HR AF Olmez, N Wang, GF Li, Y Zhang, HD Schumacher, HR TI Chlamydial nucleic acids in synovium in osteoarthritis: What are the implications? SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE polymerase chain reaction; Chlamydia trachomatis; Chlamydia pneumoniae; osteoarthritis; reactive arthritis ID POLYMERASE-CHAIN-REACTION; INFLAMMATORY JOINT DISEASES; TARGETING DNA-SEQUENCES; REITERS-SYNDROME; TRACHOMATIS DNA; RIBOSOMAL-RNA; UNDIFFERENTIATED ARTHRITIS; PNEUMONIAE DNA; FLUID; PREVALENCE AB Objective. To study whether there. is evidence of bacterial DNA in some osteoarthritic (OA) joint tissues, and the clinical implications of finding bacterial DNA in this relatively noninflammatory disease. Methods. Polymerase chain reaction (PCR) was used to detect DNA of Chlamydia trachomatis, Chlamydia pneumoniae, and other bacteria using panbacterial primers in synovial membranes and other articular tissues of 32 consecutive patients undergoing surgery for hip and knee OA. Patients were interviewed and examined postoperatively. Operative reports were reviewed and followup examinations were accomplished on all patients. Results. Nine of 32 patients with OA (28.1%) had evidence for bacterial DNA in joint tissues with at least one set of primers for Chlamydia: 7 for C. trachomatis (21.9%), 2 for C. pneumoniae (6.2%). Five of 32 (15.6%) patients had postoperative complications; 3 of these were in patients who showed amplified DNA of C. trachomatis in joints and one in a patient in whom we detected Escherichia coli. Conclusion. C. trachomatis and C. pneumoniae nucleic acids can be present in joints in some cases of apparently classical OA. Whether chlamydial or other difficult to culture bacterial presence is associated with complications is suggested, but remains to be determined. Simple presence of C. trachomatis by PCR does not define a clinical syndrome or disease course. C1 Univ Penn, Sch Med, Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Arthritis & Immunol Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Rheumatol, Dept Med, Philadelphia, PA 19104 USA. RP Schumacher, HR (reprint author), Univ Penn, Sch Med, Dept Vet Affairs Med Ctr, 151 K Univ & Woodland Ave, Philadelphia, PA 19104 USA. NR 40 TC 25 Z9 25 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2001 VL 28 IS 8 BP 1874 EP 1880 PG 7 WC Rheumatology SC Rheumatology GA 459MR UT WOS:000170254700023 PM 11508594 ER PT J AU Pangan, AL Robinson, D AF Pangan, AL Robinson, D TI Hemarthrosis as initial presentation of scurvy SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE scurvy; ascorbic acid deficiency; hemarthrosis ID ASCORBIC-ACID; MANIFESTATIONS; COLLAGEN AB Vitamin C deficiency or scurvy is a disease now rarely seen except for certain populations at risk. When it occurs, diagnosis can be difficult as it can mimic other disorders. Its manifestations are primarily due to an abnormality in collagen formation causing bleeding in the skin, joints, muscles, or gastrointestinal tract and dystrophic hair deformities. We describe a case of scurvy in a 43-year-old man who presented with new onset hemarthrosis with no history of bleeding disorder. He was found to have perifollicular hyperpigmentation and corkscrew hairs, highly suggestive of scurvy. He admitted to completely eliminating fruits and vegetables from his diet and his serum vitamin C level was markedly decreased. Treatment with daily vitamin C supplement led to relief of symptoms and resolution of skin changes. C1 Massachusetts Gen Hosp, Arthritis Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Robinson, D (reprint author), Massachusetts Gen Hosp, Arthritis Unit, 55 Fruit St, Boston, MA 02114 USA. NR 14 TC 14 Z9 14 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2001 VL 28 IS 8 BP 1923 EP 1925 PG 3 WC Rheumatology SC Rheumatology GA 459MR UT WOS:000170254700030 PM 11508601 ER PT J AU Biederman, J Birmaher, B Carlson, GA Chang, KD Fenton, WS Geller, B Hoagwood, KE Hyman, SE Kendler, KS Koretz, DS Kowatch, RA Kupfer, DJ Leibenluft, E Nakamura, RK Nottelmann, ED Stover, E Vitiello, B Weiblinger, G Weller, E AF Biederman, J Birmaher, B Carlson, GA Chang, KD Fenton, WS Geller, B Hoagwood, KE Hyman, SE Kendler, KS Koretz, DS Kowatch, RA Kupfer, DJ Leibenluft, E Nakamura, RK Nottelmann, ED Stover, E Vitiello, B Weiblinger, G Weller, E TI National Institute of Mental Health research roundtable on prepubertal bipolar disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar disorder; prepubertal; assessment; diagnosis ID DEFICIT HYPERACTIVITY DISORDER; PSYCHIATRIC SYNDROMES CHIPS; EARLY ADOLESCENT BIPOLARITY; CHILDRENS INTERVIEW; CONCURRENT VALIDITY; MANIC SYMPTOMS; MAJOR DEPRESSION; FAMILIAL SUBTYPE; YOUNG-CHILDREN; DOUBLE-BLIND AB Objective: A research roundtable meeting was convened at the National Institute of Mental Health on April 27, 2000, to discuss the existing controversial areas in the diagnosis of bipolar disorder in prepubertal children. Method: Invited clinicians and researchers with expertise on bipolar disorder in children were asked to share and discuss their perspectives on diagnostic issues for bipolar disorder in prepubertal children. Results: The group reached agreement that diagnosis of bipolar disorder in prepubertal children is possible with currently available psychiatric assessment instruments. In addition to phenotypes that fit DSM-IV criteria for bipolar I and bipolar II, participants agreed on the existence of other phenotypic possibilities that do not meet diagnostic criteria. Bipolar not otherwise specified (NOS) was recommended as a "working diagnosis" for the non-DSM-IV phenotype. Conclusions: Bipolar disorder exists and can be diagnosed in prepubertal children. In children who present with both the DSM-IV and non-DSM-IV phenotypes (i.e., those given a diagnosis of bipolar-NOS), assessment should include careful evaluation of all behaviors that are impairing. Moreover, these children should be monitored systematically to explore stability and change over time in diagnosis and impairment. C1 NIMH, Dev Psychopathol & Prevent Res Branch, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Child Psychiat Serv, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. Stanford Univ, Sch Med, Div Child & Adolescent Psychiat, Stanford, CA 94305 USA. Washington Univ, Sch Med, St Louis, MO 63130 USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. Univ Cincinnati, Med Ctr, Dept Psychiat, Cincinnati, OH 45267 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Nottelmann, ED (reprint author), NIMH, Dev Psychopathol & Prevent Res Branch, 6001 Execut Blvd,Room 6200,MSC9617, Bethesda, MD 20892 USA. NR 87 TC 11 Z9 15 U1 8 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2001 VL 40 IS 8 BP 871 EP 878 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 454RP UT WOS:000169985800008 ER PT J AU Saxe, G Stoddard, F Courtney, D Cunningham, K Chawla, N Sheridan, R King, D King, L AF Saxe, G Stoddard, F Courtney, D Cunningham, K Chawla, N Sheridan, R King, D King, L TI Relationship between acute morphine and the course of PTSD in children with burns SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE posttraumatic stress disorder; morphine; prevention ID POSTTRAUMATIC-STRESS-DISORDER; NORADRENALINE RELEASE; BRAIN-REGIONS; TRAUMATIC STRESS; LOCUS-CERULEUS; MEMORY; AMYGDALA; RAT; EPINEPHRINE; NEURONS AB Objective: To investigate the relationship between the dose of morphine administered during a child's hospitalization for an acute burn and the course of posttraumatic stress disorder (PTSD) symptoms over the 6-month period following discharge from the hospital. Method: Twenty-four children admitted to the hospital for an acute burn were assessed twice with the Child PTSD Reaction Index: while in the hospital and 6 months after discharge. The Colored Analogue Pain Scale was also administered during the hospitalization. All patients received morphine while in the hospital. The mean dose of morphine (mg/kg/day) was calculated for each subject through chart review. Results: The Pearson product moment correlation revealed a significant association between the dose of morphine received while in the hospital and a 8-month reduction in PTSD symptoms. Children receiving higher doses of morphine had a greater reduction in PTSD symptoms over 6 months. Conclusions: This study suggests the possibility that acute treatment with morphine can secondarily prevent PTSD. This result is discussed in terms of the possible effect of morphine on fear conditioning and the consolidation of traumatic memory. C1 Boston Univ, Sch Med, Dept Child & Adolescent Psychiat, Boston Med Ctr, Boston, MA 02118 USA. Shriners Burns Hosp, Boston, MA USA. Boston VA Med Ctr, Natl Ctr PTSD, Boston, MA USA. RP Saxe, G (reprint author), Boston Univ, Sch Med, Dept Child & Adolescent Psychiat, Boston Med Ctr, Dowling 1 N,1 Boston Med Ctr Pl, Boston, MA 02118 USA. OI Saxe, Glenn/0000-0002-4756-1169 FU NIMH NIH HHS [R01 MH57370] NR 46 TC 178 Z9 182 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2001 VL 40 IS 8 BP 915 EP 921 DI 10.1097/00004583-200108000-00013 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 454RP UT WOS:000169985800014 PM 11501691 ER PT J AU Friedlander, AH Altman, L AF Friedlander, AH Altman, L TI Carotid artery atheromas in postmenopausal women - Their prevalence on panoramic radiographs and their relationship to atherogenic risk factors SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; STROKE; ATHEROSCLEROSIS; POPULATION; LIPOPROTEIN; ENDARTERECTOMY; CHOLESTEROL; INHIBITION; THICKNESS; PLASMA AB Background. More than 60 percent of the deaths in the United States attributed to stroke occur in postmenopausal women. As estrogen levels decline, atherosclerotic lesions (that is, atheromas) develop in the region of the carotid bifurcation and have been implicated as the precipitating cause in the majority of these strokes. Atheromas often are calcified and have been detected on the panoramic radiographs of neurologically asymptomatic male veterans; however, similar studies have not been conducted among female veterans. Methods. The authors assessed panoramic radiographs and medical records of 52 neurologically asymptomatic female veterans (mean age, 70.4 years), with a history of amenorrhea of more than 12 months' duration, for atheromas and risk factors associated with atherosclerosis. Results. The radiographs of 16 subjects (31 percent) exhibited atheromas located in the neck about 2.0 centimeters inferior and posterior to the angle of the mandible. These findings were confirmed in all instances by the presence of atheromas on anteroposterior cervical spine radiographs. The medical histories of these subjects were heavily laden with atherogenic risk factors (hypertension, 94 percent. body mass index of 27 to 29.9 [characterized as overweight], 25 percent; body mass index of 30 or higher [characterized as obese], 25 percent; smoking more than 15 pack years, 38 percent; hyperlipidemia, 69 percent; type 2 diabetes mellitus, 21 percent). Hypertension was significantly associated with the presence of atheromas. Conclusions. Some neurologically asymptomatic women at high risk of developing stroke can be identified in the dental office via panoramic radiography. Women whose X-rays show calcified carotid artery atheromas are almost always hypertensive and have medical histories heavily laden with other atherogenic risk factors. Clinical Implications. Dentists should refer patients with such calcifications to an appropriate physician for further evaluation and treatment. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Med Ctr, Hosp Dent Serv, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Womens Hlth Clin, Sepulveda Div, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Friedlander, AH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 33 TC 33 Z9 34 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2001 VL 132 IS 8 BP 1130 EP 1136 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 464AT UT WOS:000170510700022 PM 11575022 ER PT J AU Karlawish, JHT Casarett, D Klocinski, J Clark, CM AF Karlawish, JHT Casarett, D Klocinski, J Clark, CM TI The relationship between caregivers' global ratings of Alzheimer's disease patients' quality of life, disease severity, and the caregiving experience SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Alzheimer's disease; caregiver burden; depression; quality of life AB OBJECTIVES: To compare caregivers' ratings of Alzheimer's disease (AD) patients' global quality of life (QOL) using direct assessments and substituted judgments, and to identify qualities of the patients and their caregivers that are associated with these QOL assessments. DESIGN: Cross-sectional interviews. SETTING: A university-based Memory Disorders Clinic. PARTICIPANTS: Forty primary caregivers of AD patients. MEASUREMENTS: Direct scaling of overall quality of life (poor, fair, good, very good, or excellent) and measures of dementia severity, the caregiving experience, and patient and caregiver demographics. RESULTS: The majority of patients had mild (n = 20) or moderate (n = 11) AD. Caregivers' direct assessments of patient QOL were poor (5%, n = 2), fair (28%, n = 11), good (40%, n = 16), very good (20%, n = 8), and excellent (8%, n = 3). Twenty-one (52.5%) of the caregivers rated the patient's QOL the same as they thought the patient would; 12 (30.0%) rated the patient's QOL worse; and seven (17.5%) rated the patient's QOL better. Agreement between the two ratings was fair to moderate. Bivariate analyses showed that lower ratings of caregivers' direct assessments of patient QOL were associated with decreasing ratings of patient mental health and increasing dementia severity, caregiver burden, and caregiver depression. Multivariate models showed burden to be the significant predictor of caregivers' rating of patient QOL and the subscale measuring the caregivers' distress at controlling patient behavior had the strongest association with QOL. Lower ratings of substituted judgment assessments of patient QOL were associated with lower caregiver ratings of the patient's mental health. CONCLUSIONS: Nearly one-half of the caregivers of patients with predominantly mild to moderate AD assess a patient's QOL differently than they believe the patient would. Dementia severity and the caregiver's experiences of depression and burden negatively affect caregivers' assessments of QOL. These results provide a compelling reason why clinicians should take the time to screen for and address caregiver depression and burden and problematic patient behaviors. C1 Inst Aging, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Sociol, Philadelphia, PA 19104 USA. Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. Alzheimers Dis Ctr, Philadelphia, PA USA. Ctr Bioeth, Philadelphia, PA USA. RP Karlawish, JHT (reprint author), Inst Aging, 3615 Chestnut St, Philadelphia, PA 19104 USA. FU NIA NIH HHS [K01-AG00931, P01-AG01024] NR 17 TC 86 Z9 88 U1 3 U2 6 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2001 VL 49 IS 8 BP 1066 EP 1070 DI 10.1046/j.1532-5415.2001.49210.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 466QR UT WOS:000170656700008 PM 11555068 ER PT J AU Sheridan, RL Weber, JM Pasternack, MS Tompkins, RG AF Sheridan, RL Weber, JM Pasternack, MS Tompkins, RG TI Antibiotic prophylaxis for group A streptococcal burn wound infection is not necessary SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article ID GROUP-A STREPTOCOCCUS; SHOCK-LIKE SYNDROME; TOXIC-SHOCK; INVASIVE GROUP; NOSOCOMIAL INFECTIONS; RHEUMATIC-FEVER; CHILDREN; PENICILLIN; MYOSITIS; DISEASE AB Background. Historically, group A beta-hemolytic streptococci (GAS) burn wound infection has been a major source of morbidity and mortality in burn patients and has prompted the prophylactic administration of antibiotics to children with burns. Wound monitoring, surveillance cultures, and early excision of deep wounds may have changed this. Our objective in this project was to determine the efficacy of routine antibiotic prophylaxis in the era of early excision and closure of deep burn wounds. Methods Two cohorts of burned children were compared: all children admitted during calendar years 1992 through 1994 (group 1) and during calendar years 1995 through 1997 (group 2). All group I children received routine GAS antibiotic prophylaxis. Only those group 2 children with documented positive admission or surveillance cultures for GAS were treated. Results. There were 511 children in group I and 406 children in group 2. They were well matched for age (4.7 +/- 0.21 years vs. 5.3 +/- 0.26 years, p = 0.06) and burn size (11.0% +/- 0.7% vs. 12.4% +/- 0.8%,p = 0.18). GAS species were recovered at admission or during hospitalization from 11 (2.6%) of group 1 children and 18 (4.4%) of group 2 children (p = 0.05), indicating a marginally higher rate of carriage in group 2. Nevertheless, in group I there were three (0.6%) who developed GAS wound infection and in group 2 there were four (0.98%,p = 0.71). The incidence of GAS infection in those patients with positive admission cultures was three (27%) of group I and four (22%) of group 2. No child developed fulminant GAS infection. Conclusion. Routine antibiotic prophylaxis of burn wounds in children in not effective in further reducing a low baseline incidence of GAS wound infection if admission screening by culture is used to identify those children who carry the organism and early excision of deep burns is practiced. C1 Shriners Burns Hosp, Boston, MA USA. Massachusetts Gen Hosp, Surg Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Infect Dis Unit, Pediat Med Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Sheridan, RL (reprint author), Shriners Burn Inst, 51 Blossom St, Boston, MA 02114 USA. NR 43 TC 6 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2001 VL 51 IS 2 BP 352 EP 355 DI 10.1097/00005373-200108000-00022 PG 4 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 463DW UT WOS:000170462400021 PM 11493799 ER PT J AU Prien, EL AF Prien, EL TI Bioavailability of oxalate from Oca (Oxalis tuberosa) - Editorial comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. RP Prien, EL (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2001 VL 166 IS 2 BP 422 EP 422 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 451KE UT WOS:000169800600005 ER PT J AU Talcott, JA Clark, JA Stark, PC Mitchell, SP AF Talcott, JA Clark, JA Stark, PC Mitchell, SP TI Long-term treatment related complications of brachytherapy for early prostate cancer: A survey of patients previously treated SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; quality of life; brachytherapy; impotence; urinary incontinence ID EXTERNAL-BEAM IRRADIATION; QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; INTERSTITIAL BRACHYTHERAPY; MEDICARE BENEFICIARIES; I-125 IMPLANTATION; RADIATION-THERAPY; CARCINOMA; OUTCOMES; MORBIDITY AB Purpose: We determined long-term symptoms in patients after brachytherapy (radioactive seed implantation) for early (nonmetastatic) prostate cancer. Materials and Methods: We performed a cross-sectional survey of 105 (80% of those contacted) men treated at least 2 years 9 months (median 5.2 years) previously with brachytherapy alone (72 patients) or brachytherapy plus external beam radiation therapy (33) at a pioneering referral center for ultrasound guided. brachytherapy. Results: Median patient age was 70 years at treatment and 75 years when surveyed. Bowel symptoms were uncommon (range 4% to 9%) unless patient had also received external beam radiation therapy. Urinary incontinence occurred in 45% of men, although leakage of more than a few drops, daily leakage and wearing absorptive pads occurred in 11%, 11% and 16%, respectively. Men who underwent documented transurethral prostatic resection were much more likely to report incontinence (83% versus 39%, p = 0.005) and those who underwent implantation less than 5 years earlier were less likely (33% versus 53%, respectively, p = 0.04). Complete impotence was common (50%) but impaired erections were more so (73%). Patients who received combined radiation treatment had more frequent erectile dysfunction, Conclusions: Long-term bowel symptoms are infrequent after brachytherapy alone. Urinary incontinence is common, although usually only a few drops and not daily. Erectile dysfunction, prevalent. in populations of older men, was found in most men. However, because our study design precluded documenting baseline symptoms before treatment and subsequent clinical interventions, the contribution of factors other than brachytherapy is unclear. The morbidity of patients receiving more recent brachytherapy may be less. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Talcott, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 41 TC 96 Z9 100 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2001 VL 166 IS 2 BP 494 EP 499 DI 10.1016/S0022-5347(05)65970-8 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 451KE UT WOS:000169800600020 PM 11458054 ER PT J AU Planz, B Wang, QF Kirley, SD Marberger, M McDougal, WS AF Planz, B Wang, QF Kirley, SD Marberger, M McDougal, WS TI Regulation of keratinocyte growth factor receptor and androgen receptor in epithelial cells of the human prostate SO JOURNAL OF UROLOGY LA English DT Article DE prostate; receptors; growth factor receptors; androgen; epithelium ID NEOPLASTIC HUMAN-PROSTATE; SEMINAL-VESICLE; BENIGN; EXPRESSION; MODEL; KGF; PROLIFERATION; HYPERPLASIA; CANCER; GENE AB Purpose: Stromal-epithelial interactions of growth factors and the androgen receptor may have implications for the pathophysiology of benign and neoplastic transformation of the human adult prostate. We investigated a possible interaction of keratinocyte growth factor with its receptor as well as with the androgen receptor signaling pathway in human prostatic epithelial cells. Materials and Methods: Human prostatic epithelial cells were obtained from explant primary culture, established in DU145 cell conditioned medium and maintained in keratinocyte serum-free medium with supplements. Epithelial cells were characterized by light and electron microscopy, and immunocytochemical study using epithelial and mesenchymal markers. Androgen receptor, keratinocyte growth factor receptor and keratinocyte growth factor messenger RNA expression was measured by polymerase chain reaction (PCR). The response to 0.01 to 10 nM. dihydrotestosterone, 10 muM. flutamide and 1 to 1,000 ng./ml. keratinocyte growth factor was tested by [H-3] thymidine assay. The difference in keratinocyte growth factor receptor and androgen receptor gene expression after treatment with and without keratinocyte growth factor and flutamide were determined by quantitative multiplex PCR and quantitated using densitometry analysis. Results: Immunocytochemical and electron microscopy characterization revealed typical epithelial differentiation. PCR showed keratinocyte growth factor receptor and androgen receptor expression in epithelial cultured cells but no keratinocyte growth factor expression. Epithelial cells showed a significant time and dose dependent stimulation of cell proliferation with keratinocyte growth factor and dihydrotestosterone (p <0.05). When combined with the antiandrogen flutamide the effect of 100 ng./ml. keratinocyte growth factor was significantly decreased (p <0.05). At 100 ng./ml. keratinocyte growth factor quantitative multiplex PCR revealed stimulated keratinocyte growth factor receptor and androgen receptor messenger RNA expression. Conclusions: These results show that keratinocyte growth factor up-regulates the keratinocyte growth factor and androgen receptors in the absence of androgen. Thus, the androgen signaling pathway may be activated by growth factors such as keratinocyte growth factor in an androgen deficient environment. C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Reprod Endocrinol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Vienna, Dept Urol, Vienna, Austria. RP Planz, B (reprint author), Massachusetts Gen Hosp, Dept Urol, Fruit St, Boston, MA 02114 USA. FU NICHD NIH HHS [HD29164] NR 32 TC 21 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2001 VL 166 IS 2 BP 678 EP 683 DI 10.1016/S0022-5347(05)66042-9 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 451KE UT WOS:000169800600103 PM 11458116 ER PT J AU Pickl, WF Pimentel-Muinos, FX Seed, B AF Pickl, WF Pimentel-Muinos, FX Seed, B TI Lipid rafts and pseudotyping SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; MURINE LEUKEMIA-VIRUS; GLYCOPROTEIN TRANSMEMBRANE SUBUNITS; HIV-1 ENVELOPE GLYCOPROTEIN; INFLUENZA-VIRUS; MEMBRANE DOMAINS; RETROVIRAL VECTOR; EPITHELIAL-CELLS; CYTOPLASMIC TAIL; HIGH-TITER AB Specific interactions between envelope and core proteins govern the membrane assembly of most enveloped viruses. Despite this, mixed infections lead to pseudotyping, the association of the viral cores of one virus with the envelopes of another. How does this occur? We show here that the detergent-insoluble lipid rafts of the plasma membrane function as a natural meeting point for the transmembrane and core components of a phylogenetically diverse collection of enveloped viruses. As a result, viral particles preferentially incorporate both the envelope components of other viruses as well as the extra- and intracellular constituents of host cell Lipid rafts, including gangliosides, glycosyl phosphatidylinositol-anchored surface proteins, and intracellular signal transduction molecules. Pharmacological disruption of lipid rafts interferes with virus production. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Seed, B (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RI Pickl, Winfried/E-5682-2011; Pimentel-Muinos, Felipe/K-4557-2014 OI Pimentel-Muinos, Felipe/0000-0002-0258-2855 NR 84 TC 129 Z9 132 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2001 VL 75 IS 15 BP 7175 EP 7183 DI 10.1128/JVI.75.15.7175-7183.2001 PG 9 WC Virology SC Virology GA 452QR UT WOS:000169870700047 PM 11435598 ER PT J AU Poggioli, GJ Dermody, TS Tyler, KL AF Poggioli, GJ Dermody, TS Tyler, KL TI Reovirus-induced sigma 1s-dependent G(2)/M phase cell cycle arrest is associated with inhibition of p34(cdc2) SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS TYPE-1 VPR; AUTOGRAPHA-CALIFORNICA NUCLEOPOLYHEDROVIRUS; ATTACHMENT PROTEIN SIGMA-1; MESSENGER-RNA; FISSION YEAST; CDC2 PROTEIN; DNA-DAMAGE; TRANSLATION PRODUCTS; TYROSINE PHOSPHATASE; ACTIVATES P34CDC2 AB Serotype 3 reoviruses inhibit cellular proliferation by inducing a G(2)/M phase cell cycle arrest. Reovirus-induced G(2)/M phase arrest requires the viral S1 gene-encoded sigma 1s nonstructural protein. The G(2)-to-M transition represents a cell cycle checkpoint that is regulated by the kinase p34(cd2). We now report that infection with serotype 3 reovirus strain Abney, but not serotype I reovirus strain Lang, is associated with inhibition and hyperphosphorylation of p34(cdc2). The als protein is necessary and sufficient for inhibitory phosphorylation of p34(cdc2), since a viral mutant lacking als fails to hyperphosphorylate p34(cdc2) and inducible expression of als is sufficient for p34(cdc2) hyperphosphorylation. These studies establish a mechanism by which reovirus can perturb cell cycle regulation. C1 Univ Colorado, Hlth Sci Ctr, Dept Neurol B 182, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Immunol, Denver, CO 80262 USA. Denver Vet Affairs Med Ctr, Neurol Serv, Denver, CO 80220 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Elizabeth B Lamb Ctr Pediat Res, Nashville, TN 37232 USA. RP Tyler, KL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Neurol B 182, 4200 E 9th Ave, Denver, CO 80262 USA. OI Tyler, Kenneth/0000-0003-3294-5888 FU NIA NIH HHS [AG14071]; NIAID NIH HHS [R37 AI038296, AI38296, R01 AI038296] NR 73 TC 36 Z9 37 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2001 VL 75 IS 16 BP 7429 EP 7434 DI 10.1128/JVI.75.16.7429-7434.2001 PG 6 WC Virology SC Virology GA 456QD UT WOS:000170093000021 PM 11462015 ER PT J AU Hofmann-Lehmann, R Vlasak, J Rasmussen, RA Smith, BA Baba, TW Liska, V Ferrantelli, F Montefiori, DC McClure, HM Anderson, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Cavacini, LA Posner, MR Chou, TC Andersen, J Ruprecht, RM AF Hofmann-Lehmann, R Vlasak, J Rasmussen, RA Smith, BA Baba, TW Liska, V Ferrantelli, F Montefiori, DC McClure, HM Anderson, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Cavacini, LA Posner, MR Chou, TC Andersen, J Ruprecht, RM TI Postnatal passive immunization of neonatal macaques with a triple combination of human monoclonal antibodies against oral simian-human immunodeficiency virus challenge SO JOURNAL OF VIROLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; HIV-1/SIV CHIMERIC VIRUS; CD4 BINDING-SITE; RHESUS-MONKEYS; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEINS; PRIMARY ISOLATE; IN-VIVO; SYNERGISTIC NEUTRALIZATION; GP120 GLYCOPROTEIN AB To develop prophylaxis against mother-to-child human immunodeficiency virus (HM transmission, we established a simian-human immunodeficiency virus (SHIV) infection model in neonatal macaques that mimics intrapartum mucosal virus exposure (T. W. Baba et al., AIDS Res. Hum. Retroviruses 10:351-357, 1994). Using this model, neonates were protected from mucosal SHIV-vpu(+) challenge by pre- and postnatal treatment with a combination of three human neutralizing monoclonal antibodies (MAbs), F105, 2G12, and 2F5 (Baba et al., Nat. Med. 6:200-206, 2000). In the present study, we used this MAb combination only postnatally, thereby significantly reducing the quantity of antibodies necessary and rendering their potential use in humans more practical. We protected two neonates with this regimen against oral SHIV-vpu(+) challenge, while four untreated control animals became persistently infected. Thus, synergistic MAbs protect when used as immunoprophylaxis without the prenatal dose. We then determined in vitro the optimal MAb combination against the more pathogenic SHIV89.6P, a chimeric virus encoding env of the primary HIV89.6. Remarkably, the most potent combination included IgG1b12, which alone does not neutralize SHIV89.6P. We administered the combination of MAbs IgG1b12, 2F5, and 2G12 postnatally to four neonates. One of the four infants remained uninfected after oral challenge with SHIV89.6P, and two infants had no or a delayed CD4(+) T-cell decline. In contrast, all control animals had dramatic drops in their CD4(+) T cells by 2 weeks postexposure. We conclude that our triple MAb combination partially protected against mucosal challenge with the highly pathogenic SHIV89.6P. Thus, combination immunoprophylaxis with passively administered synergistic human MAbs may play a role in the clinical prevention of mother-to-infant transmission of HIV type 1. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Tufts Univ, Sch Med, Div Newborn Med, Boston, MA 02111 USA. Duke Univ, Med Ctr, Dept Surg, AIDS Res Ctr, Durham, NC 27710 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. Univ Texas, MD Anderson Canc Ctr, Bastrop, TX 78602 USA. Agr Univ Vienna, Inst Appl Microbiol, A-1190 Vienna, Austria. Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Therapeut Program, New York, NY 10021 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. RI Hofmann-Lehmann, Regina/C-6528-2009; Chou, Ting-Chao/B-4111-2009; Ferrantelli, Flavia/J-7794-2016 OI Chou, Ting-Chao/0000-0002-3340-1594; Ferrantelli, Flavia/0000-0002-0768-1078 FU NCRR NIH HHS [RR00165, P51 RR000165]; NIAID NIH HHS [KO8-AI01327, R01 AI34266, AI26926, P01 AI048240, P01 AI48240, R21 AI46177, R01 AI026926, AI45320, N01 AI85343, R21 AI046177, R01 AI034266] NR 64 TC 129 Z9 130 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2001 VL 75 IS 16 BP 7470 EP 7480 DI 10.1128/JVI.75.16.7470-7480.2001 PG 11 WC Virology SC Virology GA 456QD UT WOS:000170093000025 PM 11462019 ER PT J AU Feliers, D Duraisamy, S Faulkner, JL Duch, J Lee, AV Abboud, HE Choudhury, GG Kasinath, BS AF Feliers, D Duraisamy, S Faulkner, JL Duch, J Lee, AV Abboud, HE Choudhury, GG Kasinath, BS TI Activation of renal signaling pathways in db/db mice with type 2 diabetes SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 60th Annual Meeting of the American-Diabetes-Association CY JUN 09-13, 2000 CL SAN ANTONIO, TEXAS SP Amer Diabet Assoc DE diabetic nephropathy; insulin receptor; phosphotidylinositol 3-kinase; MAP kinase; Akt; receptor signaling; renal cortex ID GROWTH-FACTOR-BETA; PROTEIN-KINASE-C; INSULIN-RESISTANCE; MESANGIAL CELLS; GENE-EXPRESSION; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-UPTAKE; MESSENGER-RNA; MAP KINASE; RATS AB Background. Altered regulation of signaling pathways may contribute to the pathogenesis of renal disease. We examined renal cortical signaling pathways in type 2 diabetes. Methods. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in the early phase of diabetic nephropathy associated with renal matrix expansion and albuminuria. Results. Tyrosine phosphorylation of renal cortical proteins was increased in diabetic mice. Renal cortical activities of phosphatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates. Akt (PKB), and ERK1/2-type mitogen-activated protein (MAP) kinase activities were significantly augmented sixfold (P < 0.01), twofold (P < 0.0003), and sevenfold (P < 0.001). respectively, in diabetic mice compared with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation. as PI 3-kinase activity associated with beta chain of the insulin receptor was increased nearly fourfold(P < 0.0235). Additionally. the kinase activity of the immunoprecipitated insulin receptor P chain was augmented in the diabetic renal cortex, and tyrosine phosphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunoprecipitates and Akt also were increased threefold (P < 0.05) and twofold (P < 0.0002), respectively. However, there was no change in the hepatic insulin receptor-associated PI 3-kinase activity. Additionally, the hepatic ERK1/2-type MAP kinase activity was inhibited by nearly 50% (P < 0.01). Conclusions. These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, and suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. GRECC, S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Kasinath, BS (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol, 7703 Floyd Curl Dr,Mail Code 7882, San Antonio, TX 78229 USA. FU NIDDK NIH HHS [GGC DK50190] NR 40 TC 70 Z9 70 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2001 VL 60 IS 2 BP 495 EP 504 DI 10.1046/j.1523-1755.2001.060002495.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 455AW UT WOS:000170006200030 PM 11473632 ER PT J AU Stone, ME AF Stone, ME TI Crazy visitation: A chronicle of illness and recovery. SO LIBRARY JOURNAL LA English DT Book Review C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BOWKER MAGAZINE GROUP CAHNERS MAGAZINE DIVISION PI NEW YORK PA 249 W 17TH ST, NEW YORK, NY 10011 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD AUG PY 2001 VL 126 IS 13 BP 148 EP 148 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 463MR UT WOS:000170480400301 ER PT J AU Bell, BA Chang, MN Weinstein, HJ AF Bell, BA Chang, MN Weinstein, HJ TI A phase II study of homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: A pediatric oncology group study SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE homoharringtonine; children; Phase II study; relapsed/refractory; acute myelogenous leukemia ID ACUTE MYELOID-LEUKEMIA; HARRINGTONINE; TRIAL; INDUCTION; CELLS; DRUG AB Background. Homoharringtonine (HHT) is a plant alkaloid that is derived from a Chinese evergreen tree. Its mechanism of action is thought to be by inhibition of protein, DNA, and RNA synthesis by inhibition of chain initiation. The treatment of acute myelogenous leukemia (AML) in children, has been hampered by few new effective agents developed in the past 30 years. Significant numbers of children still die of this disease. The purpose of this study is to evaluate the efficacy and toxicity of HHT for the therapy of refractory AML in children. Procedure. Patients entered the study and were treated with HHT 7mg/m(2)/day for 10 days. The cycles could be repeated every 21 days depending on recovery from myelosuppression. Results. Thirty-seven patients entered the study, with twenty-eight evaluable for response. Complete response was obtained in four and a partial response in one (response rate 5/28=18%). Significant toxicities included prolonged severe myelosuppression in all responsive patients and neuropathogenic pain in two patients. The median duration of response was 62 days with a range of 28-126 days. Conclusions. HHT has activity against chemotherapy resistant AML in children, with tolerable toxicity. This agent warrants further clinical evaluation in combination with other agents or perhaps biologic response modifiers which will hopefully lead to useful therapeutic options. Med Pediatr Oncol 2001;37:103-107. 2001 Wiley-Liss, Inc. C1 Univ Alberta, Cross Canc Ctr, Dept Pediat Hematol Oncol, Edmonton, AB, Canada. Emory Egleston Pediat Care Fdn, Atlanta, GA USA. POG Stat Off, Gainesville, FL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bell, BA (reprint author), Childrens Oncol Grp, POB 60012, Arcadia, CA 91066 USA. FU NCI NIH HHS [CA 20549, CA 69428, CA 35587, CA 69177, CA15089, CA 33603, CA 28476, CA 29139, CA 05587, CA30969, CA 03161, CA 32053, CA 11233, CA 28383, CA 25408] NR 17 TC 11 Z9 13 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD AUG PY 2001 VL 37 IS 2 BP 103 EP 107 DI 10.1002/mpo.1177 PG 5 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 460KQ UT WOS:000170307100004 PM 11496347 ER PT J AU Coyne, J Katz, IR AF Coyne, J Katz, IR TI Improving the primary care treatment of late life depression - Progress and opportunities SO MEDICAL CARE LA English DT Editorial Material ID TRIAL C1 Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Dept Family Practice & Community Med, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Katz, IR (reprint author), Univ Penn, Dept Psychiat, 3600 Market St,Room 758, Philadelphia, PA 19104 USA. FU NIMH NIH HHS [MH52129, MH59380] NR 14 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2001 VL 39 IS 8 BP 756 EP 759 DI 10.1097/00005650-200108000-00002 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 459EN UT WOS:000170238200002 PM 11468495 ER PT J AU Unutzer, J Katon, W Williams, JW Callahan, CM Harpole, L Hunkeler, EM Hoffing, M Arean, P Hegel, MT Schoenbaum, M Oishi, SM Langston, CA AF Unutzer, J Katon, W Williams, JW Callahan, CM Harpole, L Hunkeler, EM Hoffing, M Arean, P Hegel, MT Schoenbaum, M Oishi, SM Langston, CA TI Improving primary care for depression in late life - The design of a multicenter randomized trial SO MEDICAL CARE LA English DT Article; Proceedings Paper CT NIMH Conference on Mental Health Services Research CY AUG 18, 2000 CL WASHINGTON, D.C. SP NIMH DE depression; aging; primary care ID PROBLEM-SOLVING TREATMENT; MANAGED PRIMARY-CARE; PATIENTS AGED 65; MAJOR DEPRESSION; OLDER ADULTS; GERIATRIC DEPRESSION; COST-EFFECTIVENESS; CLINICAL-TRIALS; RELIABILITY; DISORDERS AB BACKGROUND. Late life depression can be successfully treated with antidepressant medications or psychotherapy, but few depressed older adults receive effective treatment. RESEARCH DESIGN. A randomized controlled trial of a disease management program for late life depression. SUBJECTS. Approximately 1,750 older adults with major depression or dysthymia are recruited from seven national study sites. INTERVENTION. Half of the subjects are randomly assigned to a collaborative care program where a depression clinical specialist supervised by a psychiatrist and a primary care expert supports the patient's regular primary care provider to treat depression. Intervention services are provided for 12 months using antidepressant medications and Problem Solving Treatment in Primary Care according to a stepped care protocol that varies intervention intensity according to clinical needs. The other half of the subjects are assigned to care as usual. EVALUATION. Subjects are independently assessed at baseline, 3 months, 6 months, 12 months, 18 months, and 24 months. The evaluation assesses the incremental cost-effectiveness of the intervention compared with care as usual. Specific outcomes examined include care for depression, depressive symptoms, health-related quality of life, satisfaction with depression care, health care costs, patient time costs, market and nonmarket productivity, and household income. CONCLUSIONS. The study blends methods from health services and clinical research in an effort to protect internal validity while maximizing the generalizability of results to diverse health care systems. We hope that this study will show the cost-effectiveness of a new model of care for late life depression that can be applied in a range of primary care settings. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Ctr Hlth Serv Res, Los Angeles, CA 90024 USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ Texas, Hlth Sci Ctr, S Texas Vet Hlth Care Syst, San Antonio, TX USA. Indiana Univ, Regenstrief Inst Hlth Care, Ctr Aging Res, Indianapolis, IN 46204 USA. Duke Univ, Med Ctr, Durham, NC USA. Kaiser Permanente No Calif, Div Res, Oakland, CA USA. Desert Med Grp, Palm Springs, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Dartmouth Coll Sch Med, Hanover, NH USA. RAND Corp, Santa Monica, CA USA. John A Hartford Fdn, New York, NY USA. RP Unutzer, J (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, Ctr Hlth Serv Res, 10920 Wilshire Blvd,Suite 300, Los Angeles, CA 90024 USA. RI Williams, Jr., John/A-3696-2008 OI Williams, Jr., John/0000-0002-5267-5558 NR 71 TC 168 Z9 168 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2001 VL 39 IS 8 BP 785 EP 799 DI 10.1097/00005650-200108000-00005 PG 15 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 459EN UT WOS:000170238200005 PM 11468498 ER PT J AU Gerrity, MS Williams, JW Dietrich, AJ Olson, AL AF Gerrity, MS Williams, JW Dietrich, AJ Olson, AL TI Identifying physicians likely to benefit from depression education SO MEDICAL CARE LA English DT Article DE depression; self-efficacy; continuing medical education; measurement ID PRIMARY-CARE PHYSICIANS; CONTINUING MEDICAL-EDUCATION; COMPETING DEMANDS; MANAGEMENT; DISORDERS; SYMPTOMS; OUTCOMES; PROGRAM; MODEL; TRIAL AB BACKGROUND. Few methods exist to identify physicians: who might benefit from depression education. OBJECTIVES. To develop a measure of physicians' confidence or self-efficacy in caring for depressed patients and assess it's reliability and validity. RESEARCH DESIGN. A national sample of primary care physicians were surveyed and exploratory factor analysis (EFA) was used to identify factors underlying physicians' responses to 26 items. We named the factors, selected items with factor loadings greater than or equal to0.50 for final scales, and tested a priori hypotheses about self-efficacy. SUBJECTS. 1) Random cross-sectional sample of family physicians, internists, obstetrician-gynecologists, and pediatricians (n = 5,369) and 2) 49 general internists and family physicians participating in a prepost evaluation of a depression workshop. RESULTS. In the national sample, 3,712 physicians were eligible and 2,104 responded. Forty-six percent were female, and 51% were family physicians and general internists. EFA identified 5 factors, the first of which was called Self-Efficacy (4 items, alpha = 0.86). More family physicians (64%) had confidence (self-efficacy) in caring for depressed patients compared with general internists (33%), obstetrician-gynecologists (16%), and pediatricians (6%) (P <0.001). Few physicians intended to change their care of depressed patients (10%) or take CME on depression (24%). Of the 49 physicians attending a depression workshop, 76% reported high self-efficacy after the workshop versus 50% before it (P = 0.013). CONCLUSIONS. This study supports the reliability and validity of the Self-Efficacy scale as one method to identify physicians who might benefit from interventions. New approaches are needed because physicians are unlikely to change. C1 Portland VAMC, Portland, OR 97207 USA. Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. San Antonio Vet Affairs Med Ctr, San Antonio, TX USA. Dartmouth Coll Sch Med, Dept Community & Family Med, Hanover, NH USA. Dartmouth Coll Sch Med, Dept Pediat, Hanover, NH USA. RP Gerrity, MS (reprint author), Portland VAMC, P3MED,3710 SW US Vet Hosp Rd,POB 1034, Portland, OR 97207 USA. RI Williams, Jr., John/A-3696-2008 OI Williams, Jr., John/0000-0002-5267-5558 NR 48 TC 24 Z9 24 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2001 VL 39 IS 8 BP 856 EP 866 DI 10.1097/00005650-200108000-00011 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 459EN UT WOS:000170238200011 PM 11468504 ER PT J AU Au, DH McDonell, MB Martin, DC Fihn, SD AF Au, DH McDonell, MB Martin, DC Fihn, SD TI Regional variations in health status SO MEDICAL CARE LA English DT Article DE health status; medical geography; comorbidity ID QUALITY-OF-LIFE; VETERANS HEALTH; PROBLEM DRINKING; AUDIT AB CONTEXT. Knowledge about variations in the health status of patients seeking primary care in different parts of the United States is limited. OBJECTIVE. To examine regional variations in the physical and mental health of patients receiving primary care in the largest integrated health care system in the United States which is operated by the Department of Veteran Affairs (VA). STUDY DESIGN AND SETTING. We performed a mailed, cross sectional survey of 54,844 patients who were enrolled in seven VA General Internal Medicine clinics. RESULTS. Among the 30,690 patients who returned an initial set of screening questionnaires, the prevalence of common chronic conditions varied by as much as 60% among the seven clinics. Moreover, patients' general health (measured by the SF-36) also varied significantly in a pattern that mirrored the observed differences in the prevalence of chronic conditions. After adjustment for important comorbid illnesses and sociodemographic factors, geographic site accounted for a small percentage of the explained variance in patient assessed health status. CONCLUSIONS. The substantial differences in the health of patients enrolled in different VA primary clinics have important implications for the evaluation of clinical performance and health outcomes. Most of these differences can be attributed to sociodemographic and comorbid factors. C1 VA Puget Sound Hlth Care Syst, Div Pulm & Crit Care Med, NW Hlth Serv Res & Dev Ctr Excellence, Seattle Div, Seattle, WA 98108 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Au, DH (reprint author), VA Puget Sound Hlth Care Syst, Div Pulm & Crit Care Med, NW Hlth Serv Res & Dev Ctr Excellence, Seattle Div, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 14 TC 33 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2001 VL 39 IS 8 BP 879 EP 888 DI 10.1097/00005650-200108000-00013 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 459EN UT WOS:000170238200013 PM 11468506 ER PT J AU Landon, BE Reschovsky, J Reed, M Blumenthal, D AF Landon, BE Reschovsky, J Reed, M Blumenthal, D TI Personal, organizational, and market level influences on physicians' practice patterns - Results of a national survey of primary care physicians SO MEDICAL CARE LA English DT Article DE managed care; physicians' practice patterns; physician behavior; clinical decision making ID ONCOLOGY PATIENTS; DIAGNOSTIC-TESTS; ASSISTED SUICIDE; REFERRAL RATES; HEART-DISEASE; MANAGED CARE; QUALITY; RECOMMENDATIONS; EXPERIENCES; EUTHANASIA AB BACKGROUND. One of the principal tenets of managed care is that physicians' clinical decisions can be influenced both to improve the quality and consistency of care and to decrease health care expenditures. Medical decision making, however, remains a complex phenomenon and the most important determinants of physicians' approaches to clinical decision making remain poorly understood. OBJECTIVES. To determine how clinical decisions are associated with individual characteristics, practice setting and organizational characteristics, attributes of the patient population under care, and the market environment. RESEARCH DESIGN. Cross-sectional, nationally representative survey of patient-care physicians. SUBJECTS. Primary care physicians who provide direct patient care at least 20 hours per week. MEASURES. Proportion of physicians who would order a referral, diagnostic test, or treatment for 5 clinical scenarios thought to be representative of discretionary medical decisions. RESULTS. Responses were received from 4,825 primary care physicians who cared for adult patients (Response Rate 65%). The distribution of results for each of the five clinical scenarios demonstrates significant variability both within and between physicians. No evidence was seen of a consistent practice style across the vignettes (eg, "aggressive" or "conservative"). The organizational setting of practice was the most consistent predictor of behavior across all the clinical scenarios, with the exception of back pain, which was minimally related to any of the environmental factors. When compared to physicians in solo practice, physicians in all other practice settings were less likely to order a test or referral or pursue treatment. Practice involvement with managed care and measures of financial influences and administrative strategies associated with managed care were minimally and inconsistently associated with reported physician behaviors. CONCLUSIONS. The ability of managed care to improve the quality and consistency of care while also controlling the costs of care depends on its ability to influence medical decisions. Our findings generally demonstrate that managed care has a weak influence on discretionary medical decisions and that the influence of managed care pales in comparison to personal and practice setting influences. C1 Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. Ctr Studying Hlth Syst Change, Washington, DC USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners HealthCare Syst,Inst Hlth Care Policy, Boston, MA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Landon, BE (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. NR 44 TC 69 Z9 69 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2001 VL 39 IS 8 BP 889 EP 905 DI 10.1097/00005650-200108000-00014 PG 17 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 459EN UT WOS:000170238200014 PM 11468507 ER PT J AU Oldham, M Sapareto, SA Li, XA Allen, J Sutlief, S Wong, OC Wong, JW AF Oldham, M Sapareto, SA Li, XA Allen, J Sutlief, S Wong, OC Wong, JW TI Practical aspects of in situ O-16 (gamma, n) O-15 activation using a conventional medical accelerator for the purpose of perfusion imaging SO MEDICAL PHYSICS LA English DT Article DE perfusion imaging; radiation therapy; in situ; O-15 activation ID TUMOR BLOOD-FLOW; RADIOTHERAPY; HYPOXIA AB We report investigations into the feasibility of generating radioactive oxygen (O-15, a positron emitter, with half-life 2.05 min) using a tuned Elekta SL25 accelerator, for the end purpose of imaging tumor perfusion. O-15 is produced by the "gamma, neutron," (gamma ,n) reaction between high-energy photons and normal oxygen (O-16) in the body. As most in vivo O-16 is bound in water molecules the O-15 radio-marker is produced in proportion to water content in tissue. Imaging the washout of the O-15 distribution using sensitive positron-emission-tomography (PET) technology can yield spatial information about blood perfusion in the tissue. The aim of this article was to determine the amount of O-15 activity that could be produced by the tuned medical accelerator. A further aim was to model the activation process using Monte Carlo and to investigate ways to optimize the amount of O-15 that could be generated. Increased activation was achieved by (i) tuning the beam to give higher-energy electrons incident on the target of the accelerator, (ii) increasing dose rate by removing the conventional filtration in the beam and reducing the source to object distance, and (iii) reducing low-energy photons by means of a carbon block absorber. The activity per-unit-dose produced by the tuned beam was measured by irradiating spheres of water to known doses and placing the spheres in a calibrated coincidence-counting apparatus. Peak energy of the tuned bremsstrahlung beam was estimated at 29 MeV, and generated activity up to 0.24 mu Ci/cc/3Gy in water. The measured amount of O-15 agreed to within 10% of the prediction from the Monte-Carlo-computed spectrum, indicating reasonable ability to model the activation process. The optimal thickness of the carbon absorber was found to be about 25 cm. The insertion of a carbon absorber improved spectral quality for activation purposes but at the cost of reduced dose rate. In conclusion, the viability of generating O-15 with an Elekta SL25 has been demonstrated. In conjunction with recent advances in high-sensitivity portable PET imaging devices, real potential exists for imaging in situ activated O-15 washout as a surrogate measurement of macroscopic tumor perfusion. (C) 2001 American Association of Physicists in Medicine. C1 William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI 48073 USA. Univ Arizona, Hlth Sci Ctr, Dept Radiat Oncol, Tucson, AZ 85724 USA. Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA. Elekta Oncol Syst Ltd, Crawley RH1 2RR, England. VA Puget Sound Hlth Care Syst, Dept Radiat Oncol, Seattle, WA 98108 USA. William Beaumont Hosp, Dept Nucl Med, Royal Oak, MI 48073 USA. William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI 48073 USA. RP Oldham, M (reprint author), William Beaumont Hosp, Dept Radiat Oncol, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. NR 26 TC 2 Z9 3 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2001 VL 28 IS 8 BP 1669 EP 1678 DI 10.1118/1.1386777 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 465ZR UT WOS:000170620300013 PM 11548936 ER PT J AU Kanehira, K Braylan, RC Lauwers, GY AF Kanehira, K Braylan, RC Lauwers, GY TI Early phase of intestinal mantle cell lymphoma: A report of two cases associated with advanced colonic adenocarcinoma SO MODERN PATHOLOGY LA English DT Article DE colon carcinoma; intestinal lymphoma; lymphomatous polyposis; mantle cell lymphoma ID POLYMERASE CHAIN-REACTION; GASTROINTESTINAL-TRACT; GENE REARRANGEMENT; MALIGNANT-LYMPHOMA; POLYPOSIS; DISEASE AB Intestinal mantle cell lymphoma characteristically produces multiple polyps, a finding reported as multiple lymphomatous polyposis. The early stages of intestinal mantle cell lymphoma before polyp formation and the pattern of initial lymph node invasion, however, have not been described. We recently encountered two cases of intestinal mantle cell lymphoma in their early development found incidentally associated with advanced colonic adenocarcinoma. We present herein the clinical, histopathological, immunohistochemical, and molecular genetic features of these two cases. In one case, a single polypoid mass was found with invasion limited to mucosa and submucosa of the terminal ileum and without lymph node compromise. In the second case, there were multiple mucosal aggregates of neoplastic cells without formation of polyps. Regional lymph nodes in the latter case showed either partial or complete involvement by lymphoma. In both cases, immunohistochemistry (CD20+, CD5+, cyclin D1+, CD10-, and CD23-), and demonstration of clonal immunoglobulin heavy chain and bcl-1 gene rearrangements by PCR analysis confirmed the diagnosis of mantle cell lymphoma. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Univ Florida, Coll Med, Dept Pathol & Lab Med, Gainesville, FL 32610 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St,Warren 256, Boston, MA 02114 USA. NR 22 TC 16 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2001 VL 14 IS 8 BP 811 EP 817 DI 10.1038/modpathol.3880395 PG 7 WC Pathology SC Pathology GA 463CW UT WOS:000170460100011 PM 11504842 ER PT J AU Nishiya, N Tachibana, K Shibanuma, M Mashimo, JI Nose, K AF Nishiya, N Tachibana, K Shibanuma, M Mashimo, JI Nose, K TI Hic-5-reduced cell spreading on fibronectin: Competitive effects between paxillin and Hic-5 through interaction with focal adhesion kinase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASE; EXTRACELLULAR-MATRIX; PHOSPHATASE-PEST; SH3 DOMAIN; V-CRK; SIGNAL-TRANSDUCTION; BINDING PROTEIN; TERMINAL DOMAIN; PTP-PEST; PHOSPHORYLATION AB Hic-5 is a paxillin homologue that is localized to focal adhesion complexes. Hic-5 and paxillin share structural homology and interacting factors such as focal adhesion kinase (FAK), Pyk2/CAK beta /RAFTK, and PTP-PEST. Here, we showed that Hic-5 inhibits integrin-mediated cell spreading on fibronectin in a competitive manner with paxillin in NIH 3T3 cells. The overexpression of Hic-5 sequestered FAK from paxillin, reduced tyrosine phosphorylation of paxillin and FAK, and prevented paxillin-Crk complex formation. In addition, Hic-5-mediated inhibition of spreading was not observed in mouse embryo fibroblasts (MEFs) derived from FAK(-/-) mice. The activity of c-Src following fibronectin stimulation was decreased by about 30% in Hic-5-expressing cells, and the effect of Hic-5 was restored by the overexpression of FAK and the constitutively active forms of Rho-family GTPases, Rac1 V12 and Cdc42 V12, but not RhoA V14. These observations suggested that Hic-5 inhibits cell spreading through competition with paxillin for FAK and subsequent prevention of downstream signal transduction. Moreover, expression of antisense Hic-5 increased spreading in primary MEFs. These results suggested that the counterbalance of paxillin and Hic-5 expression may be a novel mechanism regulating integrin-mediated signal transduction. C1 Showa Univ, Sch Pharmaceut Sci, Dept Microbiol, Shinagawa Ku, Tokyo, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Nose, K (reprint author), Showa Univ, Sch Pharmaceut Sci, Dept Microbiol, Shinagawa Ku, Hatanodai 1-5-8, Tokyo, Japan. NR 85 TC 71 Z9 74 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2001 VL 21 IS 16 BP 5332 EP 5345 DI 10.1128/MCB.21.16.5332-5345.2001 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 456UG UT WOS:000170100200006 PM 11463817 ER PT J AU Gadjeva, M Verschoor, A Jezak, H Caroll, M AF Gadjeva, M Verschoor, A Jezak, H Caroll, M TI Local C4 synthesis restores impaired immune response to T-dependent antigens SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2001 VL 38 IS 2-3 MA 37 BP 91 EP 91 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 470MG UT WOS:000170875300038 ER PT J AU Kuipers, S Aerts, PC Harmsen, M Takahashi, K Hament, JM van Dijk, H AF Kuipers, S Aerts, PC Harmsen, M Takahashi, K Hament, JM van Dijk, H TI The ancient complement system. IV. A novel strategy to quantify mannose-binding lectin (MBL) levels in serum and other body fluids SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Univ Utrecht, Med Ctr, Eijkman Winkler Inst, NL-3584 CX Utrecht, Netherlands. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2001 VL 38 IS 2-3 MA 70 BP 104 EP 104 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 470MG UT WOS:000170875300071 ER PT J AU Kuipers, S Harmsen, M Takahashi, K van Dijk, H AF Kuipers, S Harmsen, M Takahashi, K van Dijk, H TI The ancient complement system. III. MBL, clusterin, and vitronectin levels in breast milk SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Univ Utrecht, Med Ctr, Eijkman Winkler Inst, NL-3584 CH Utrecht, Netherlands. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2001 VL 38 IS 2-3 MA 69 BP 104 EP 104 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 470MG UT WOS:000170875300070 ER PT J AU Paul, E Pozdnyakova, OO Carroll, MC AF Paul, E Pozdnyakova, OO Carroll, MC TI B cell autoreactivity in C4 deficient mice SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Ctr Blood Res, Boston, MA 02115 USA. Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2001 VL 38 IS 2-3 MA 98 BP 115 EP 116 PG 2 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 470MG UT WOS:000170875300099 ER PT J AU Ogueta, SB Yao, F Marasco, WA AF Ogueta, SB Yao, F Marasco, WA TI Design and in vitro characterization of a single regulatory module for efficient control of gene expression in both plasmid DNA and a self-inactivating lentiviral vector SO MOLECULAR MEDICINE LA English DT Article ID RIBOSOME ENTRY SITE; MAMMALIAN-CELLS; TETRACYCLINE REPRESSOR; IN-VIVO; SYSTEM; TRANSLATION; RNA; TRANSCRIPTION; INITIATION; TRANSPORT AB Background: Regulation of transgene expression in target cells represents a critical and challenging aspect of gene therapy. Recently, a two-plasmid tetracycline-inducible system was developed in which the tetracycline repressor (tetR) alone, rather than the tetR-VP16 fusion derivative, was shown to function as a potent trans-modulator of a second plasmid that contains two tandem repeats of the tetracycline operator (tetO) inserted between the TATA box and the transcription start site of the hCMV major immediate-early promoter. A technological advance in this area would be the development of a single autoregulatory cassette that incorporates both of these components into nonviral and viral gene transfer vectors. For the latter, an inducible lentiviral vector that is capable of temporal and quantitative control of gene expression in either dividing or nondividing cells is highly desirable. Materials and Methods: A one-piece inducible (1Pi) autoregulatory cassette was constructed to provide IRES-mediated translation of the tetR as well as tight control over the tetO unit preventing transcription initiation of the first cistron in the absence of the tetracycline. To increase efficiency of tetR-mediated repression, a nuclear localization signal was incorporated at the 3' end of the tetR gene. Regulation of gene expression at the transcriptional and protein level was analyzed in transient transfection experiments using plasmid DNA. Construction of a self-inactivating lentiviral vector containing this 1Pi cassette allowed the study of its long-term effectiveness in primary human cells. Results: The 1Pi autoregulatory cassette when incorporated into plasmid DNA allows efficient control of the secretable hEGF as well as eGFP expression in a variety of cell types. Transient transfection studies demonstrated that the time course of repression is different for the 1Pi and two-plasmid system (2Pi). In the 2Pi system, greater repression is seen with the first 24-48 hr; however, by 72 hr, similar levels of repression with the 1Pi and 2Pi systems are obtained. This regulation is reached three times faster when the tetR is modified with a nuclear localization signal to direct nascent proteins into the nuclear compartment. In addition, stable transduction of human umbilical vein endothelial cells (HUVEC) with a self-inactivating lentiviral vector incorporating this single regulator cassette provided tetracycline-inducible control of gene expression that is not diminished over time and is completely reversible upon removal of tetracycline. Conclusions: These results suggest a model in which the 1Pi autoregulatory system reaches a steady state over time, the minimal amount of tetR produced by the basal activity of the CMV promoter and accumulated is adequate to replace the tetR that is lost over time. These studies also show that the inducible self-inactivating lentiviral vector can temporally and reversibly regulate transgene expression in HUVECs. The use of this transcriptional control unit in both nonviral and viral vector delivery systems will constitute an attractive technological advance for many gene therapy applications where temporal and quantitative control of gene expression is desired. The strengths and limitations of the 1Pi system are discussed. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Plast Surg,Lab Tissue Repair & Gene Transfer, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Marasco, WA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA06516]; NIAID NIH HHS [AI41954, AI28785] NR 35 TC 13 Z9 14 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD AUG PY 2001 VL 7 IS 8 BP 569 EP 579 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 477DJ UT WOS:000171267600008 PM 11591893 ER PT J AU Robbins, JR Monack, D McCallum, SJ Vegas, A Pham, E Goldberg, MB Theriot, JA AF Robbins, JR Monack, D McCallum, SJ Vegas, A Pham, E Goldberg, MB Theriot, JA TI The making of a gradient: IcsA (VirG) polarity in Shigella flexneri SO MOLECULAR MICROBIOLOGY LA English DT Article ID ACTIN-BASED MOTILITY; SURFACE PROTEIN ICSA; ESCHERICHIA-COLI; OUTER-MEMBRANE; UNIPOLAR LOCALIZATION; INTRACELLULAR MOVEMENT; INTERCELLULAR SPREAD; LARGE PLASMID; GROWTH-PHASE; CHAIN-LENGTH AB The generation and maintenance of subcellular organization in bacteria is critical for many cell processes and properties, including growth, structural integrity and, in pathogens, virulence. Here, we investigate the mechanisms by which the virulence protein IcsA (VirG) is distributed on the bacterial surface to promote efficient transmission of the bacterium Shigella flexneri from one host cell to another. The outer membrane protein IcsA recruits host factors that result in actin filament nucleation and, when concentrated at one bacterial pole, promote unidirectional actin-based motility of the pathogen. We show here that the focused polar gradient of IcsA is generated by its delivery exclusively to one pole followed by lateral diffusion through the outer membrane. The resulting gradient can be modified by altering the composition of the outer membrane either genetically or pharmacologically. The gradient can be reshaped further by the action of the protease IcsP (SopA), whose activity we show to be near uniform on the bacterial surface. Further, we report polar delivery of IcsA in Escherichia coli and Yersinia pseudotuberculosis, suggesting that the mechanism for polar delivery of some outer membrane proteins is conserved across species and that the virulence function of IcsA capitalizes on a more global mechanism for subcellular organization. C1 Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. Cornell Univ, Dept Biol, Ithaca, NY 14853 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. RP Theriot, JA (reprint author), Stanford Univ, Sch Med, Dept Biochem, 279 W Campus Dr, Stanford, CA 94305 USA. FU NIAID NIH HHS [R01 AI35817, R37 AI036929, R01 AI36929] NR 31 TC 67 Z9 67 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2001 VL 41 IS 4 BP 861 EP 872 DI 10.1046/j.1365-2958.2001.02552.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 471AJ UT WOS:000170904400008 PM 11532149 ER PT J AU Matikainen, T Perez, GI Jurisicova, A Pru, JK Schlezinger, JJ Ryu, HY Laine, J Sakai, T Korsmeyer, SJ Casper, RF Sherr, DH Tilly, JL AF Matikainen, T Perez, GI Jurisicova, A Pru, JK Schlezinger, JJ Ryu, HY Laine, J Sakai, T Korsmeyer, SJ Casper, RF Sherr, DH Tilly, JL TI Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals SO NATURE GENETICS LA English DT Article ID DIOXIN-RESPONSIVE ENHANCER; PROTEIN-DNA INTERACTIONS; LIGANDED AH RECEPTOR; OOCYTE APOPTOSIS; CELL-DEATH; MOUSE OOCYTES; IN-VITRO; BCL-2; DESTRUCTION; FOLLICLES AB Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Moreover, a primary route of human exposure to PAHs is tobacco smoke(1,2). Oocyte destruction and ovarian failure occur in PAH-treated mice(1,2), and cigarette smoking causes early menopause in women(1,3). In many cells, PAHs activate the aromatic hydrocarbon receptor (Ahr), a member of the Per-Arnt-Sim family of transcription factors(4,5). The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants. Here we show that an exposure of mice to PAHs induces the expression of Bax in oocytes(6), followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulate Bax and undergo apoptosis after PAH exposure in vivo. Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Boston Univ, Sch Med, Dept Environm Hlth, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Publ Hlth, Boston, MA 02118 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA 02115 USA. Kyoto Prefectural Univ, Sch Med, Dept Prevent Med, Kyoto 6028566, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Med, Boston, MA 02115 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RI Jurisicova, Andrea/E-4580-2013; Casper, Robert/E-3775-2013 OI Casper, Robert/0000-0002-6249-462X FU NIEHS NIH HHS [R01-ES08430] NR 30 TC 279 Z9 288 U1 2 U2 21 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2001 VL 28 IS 4 BP 355 EP 360 DI 10.1038/ng575 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 458CC UT WOS:000170174800016 PM 11455387 ER PT J AU Altfeld, M Walker, BD AF Altfeld, M Walker, BD TI Less is more? STI in acute and chronic HIV-1 infection SO NATURE MEDICINE LA English DT Editorial Material ID ACTIVE ANTIRETROVIRAL THERAPY; CYTOTOXIC T-LYMPHOCYTE; IMMUNODEFICIENCY-VIRUS-INFECTION; SUSTAINED VIRAL SUPPRESSION; TYPE-1 INFECTION; CELL RESPONSES; TREATMENT INTERRUPTION; IN-VIVO; VIREMIA; CD8(+) AB Emerging data has indicated that supervised treatment interruption (STI) of highly active antiretroviral therapy might significantly augment immune responses in HIV-1-infected patients and slow disease progression. Here the authors discuss the rationale behind STI and future directions for study. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. NR 54 TC 39 Z9 39 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2001 VL 7 IS 8 BP 881 EP 884 DI 10.1038/90901 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 485EK UT WOS:000171740400013 PM 11479610 ER PT J AU Klopp, J Marinkovic, K Clarke, J Chauvel, P Nenov, V Halgren, E AF Klopp, J Marinkovic, K Clarke, J Chauvel, P Nenov, V Halgren, E TI Timing and localization of movement-related spectral changes in the human peri-Rolandic cortex: Intracranial recordings SO NEUROIMAGE LA English DT Article DE event related spectral power; EEG; motor cortex; evoked rhythms; mu rhythm ID PRIMATE MOTOR CORTEX; MU-RHYTHM; SPATIOTEMPORAL STAGES; VOLUNTARY MOVEMENT; NEURONAL-ACTIVITY; VISUAL-SEARCH; FACE; DESYNCHRONIZATION; POTENTIALS; EEG AB Event-related spectral power (ERSP) was measured from intracranial EEG and used to characterize the time-course and localization of the Rolandic mu rhythms in 12 patients during the delayed recognition of words or faces (DR) and the discrimination of simple lateralized visual targets (LVD). On each trial, the subject decided whether to make manual response (Go) or not (NoGo). ERSP increased on both Go and NoGo trials in peri-Rolandic regions of all subjects with a peak latency of similar to 330-ms poststimulus and duration of 260 ms during the DR task. The peak of this ERSP increase preceded movement by similar to 300 ms. All subjects produced a subsequent movement specific ERSP decrease of peri-Rolandic mu rhythms (starting similar to 90 ms before the average reaction time) with an peak latency of similar to 800 ms and duration of similar to 520 ms. The LVD task produced bilateral movement-selective readiness potentials and reproduced the movement-specific late ERSP decreases seen in the DR task (strongest from 7-24 Hz). Furthermore, the LVD task demonstrated that the late movement-related ERSP decrease is larger for the contralateral hand. However, the LVD task did not consistently reproduce the early ERSP increase seen in the DR task. Movement-related ERSP decreases were widespread, occurring in pre- and post-Rolandic as well as primary-motor, supplemental motor, and cingulate cortical regions. Other cortical areas including frontal, temporal, and occipital regions did not show movement-related ERSP changes. Peri-Rolandic ERSP decreases in mu rhythms correlate with the generation of a motor command. The early increases in mu. may reflect a transient state of motor inhibition just prior to motor execution. (C) 2001 Academic Press. C1 Univ Calif Los Angeles, Brain Monitoring & Modeling Lab, Div Neurosurg, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA USA. INSERM, F-13258 Marseille, France. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. RP Klopp, J (reprint author), Univ Calif Los Angeles, Brain Monitoring & Modeling Lab, Div Neurosurg, Los Angeles, CA 90024 USA. OI Chauvel, Patrick/0000-0003-2161-6077 FU NINDS NIH HHS [NS18741, R01 NS018741] NR 47 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG PY 2001 VL 14 IS 2 BP 391 EP 405 DI 10.1006/nimg.2001.0828 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 459MG UT WOS:000170253700014 PM 11467913 ER PT J AU Thompson, WL Kosslyn, SM Sukel, KE Alpert, NM AF Thompson, WL Kosslyn, SM Sukel, KE Alpert, NM TI Mental imagery of high- and low-resolution gratings activates Area 17 SO NEUROIMAGE LA English DT Article DE Area 17; V1; activation; PET; gratings; resolution; mental imagery; neuroimaging ID POSITRON-EMISSION-TOMOGRAPHY; PRIMARY VISUAL-CORTEX; CEREBRAL BLOOD-FLOW; FUNCTIONAL-ANATOMY; STRIATE CORTEX; MACAQUE MONKEY; MINDS EYE; PET; DISSOCIATION; CEREBELLUM AB Some, but not all, previous neuroimaging studies of visual mental imagery have found that Area 17 (primary visual cortex) is activated when people visualize objects. The present study was designed to test the hypothesis that the necessary degree of resolution of the mental image is a determining factor in whether Area 17 is activated during imagery. Eight male subjects visualized and compared sets of stripes that required high or low resolution to resolve, while their brains were scanned using O-15(CO2) positron emission tomography (PET). When imagery in general (visualization of high- and low-resolution gratings stimuli combined) was compared to an auditory baseline condition where subjects did not visualize, Area 17 was activated. However, region of interest (ROI) and statistical parametric mapping (SPM) analyses revealed no difference between imagery conditions using high- and low-resolution stimuli. These results indicate that the resolution of the stimuli alone does not necessarily determine whether Area 17 will be activated during visual mental imagery. (R) 2001 Academic Press. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Thompson, WL (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. FU NIMH NIH HHS [R01 MH60734-01] NR 51 TC 36 Z9 40 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG PY 2001 VL 14 IS 2 BP 454 EP 464 DI 10.1006/nimg.2001.0803 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 459MG UT WOS:000170253700019 PM 11467918 ER PT J AU Friedman, J Standaert, DG AF Friedman, J Standaert, DG TI Dystonia and its disorders SO NEUROLOGIC CLINICS LA English DT Review ID DOPA-RESPONSIVE DYSTONIA; ACID DECARBOXYLASE DEFICIENCY; IDIOPATHIC TORSION DYSTONIA; HEREDITARY OPTIC NEUROPATHY; TYROSINE-HYDROXYLASE GENE; CYCLOHYDROLASE-I GENE; AUTOSOMAL-DOMINANT INHERITANCE; PARKINSONISM SYNDROME LOCUS; WILSONS-DISEASE; ONSET DYSTONIA AB Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The term dystonia does not signify a single disease, but instead describes a symptom and sign that may be part of many disorders with a variety of causes. Dystonia may be classified by age of onset, distribution of symptoms, or by etiology. An increasing number of genetic forms of dystonia have been recognized and the findings have advanced knowledge of underlying neural mechanisms of pathogenesis. Options for treatment of dystonia include pharmacological therapy, botulinum toxin injection, or neurosurgical procedures. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Standaert, DG (reprint author), Massachusetts Gen Hosp, Dept Neurol, CNY114-2004, Boston, MA 02114 USA. OI Standaert, David/0000-0003-2921-8348 FU NINDS NIH HHS [NS37409] NR 142 TC 23 Z9 23 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0733-8619 J9 NEUROL CLIN JI Neurol. Clin. PD AUG PY 2001 VL 19 IS 3 BP 681 EP + DI 10.1016/S0733-8619(05)70040-2 PG 26 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 473YM UT WOS:000171077100011 PM 11532649 ER PT J AU Bello, L Francolini, M Marthyn, P Zhang, JP Carroll, RS Nikas, DC Strasser, JF Villani, R Cheresh, DA Black, PM AF Bello, L Francolini, M Marthyn, P Zhang, JP Carroll, RS Nikas, DC Strasser, JF Villani, R Cheresh, DA Black, PM TI alpha v beta 3 and alpha v beta 5 integrin expression in glioma periphery SO NEUROSURGERY LA English DT Article DE alpha v beta 3; alpha v beta 5; glioma periphery; invasion; neoangiogenesis ID EXTRACELLULAR-MATRIX PROTEINS; GROWTH FACTOR-II; CELL-MIGRATION; ALPHA(V)BETA(3) INTEGRIN; BIOLOGICAL-ACTIVITY; TUMOR ANGIOGENESIS; IN-VITRO; INVASION; RECEPTORS; KINASE AB OBJECTIVE: This study analyzed the expression of integrins alphav beta3 and alphav beta5 in glioma tissue and focused on the periphery of high-grade gliomas. METHODS: The analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration). RESULTS: Our data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. alphav beta3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin alphav beta3. Cells demonstrating alphav beta3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some alphav beta3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with alphav beta3 in the same cells. alphav beta3 expression was more relevant in tumor astrocytes. alphav beta3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center. CONCLUSION: Our data support the role of integrins alphav beta3 and alphav beta5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin alphav beta3 in neoangiogenesis and cell migration in high-grade glioma periphery. C1 Univ Milan, Osped Maggiore Policlin, Inst Neurosurg, IRCCS, I-20122 Milan, Italy. Brigham & Womens Hosp, Childrens Hosp, Div Neurosurg, Boston, MA 02115 USA. Brigham & Womens Hosp, Childrens Hosp, Brain Tumor Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Milan, CNR, Ctr Cellular & Mol Pharmacol, Dept Pharmacol, Milan, Italy. Scripps Res Inst, Dept Immunol & Vasc Biol, La Jolla, CA 92037 USA. RP Bello, L (reprint author), Univ Milan, Osped Maggiore Policlin, Inst Neurosurg, IRCCS, Via Francesco Sforza 35, I-20122 Milan, Italy. NR 54 TC 208 Z9 224 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD AUG PY 2001 VL 49 IS 2 BP 380 EP 389 DI 10.1097/00006123-200108000-00022 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 457MQ UT WOS:000170141700069 PM 11504114 ER PT J AU D'Amico, AV AF D'Amico, AV TI Combined-modality staging for localized adenocarcinoma of the prostate SO ONCOLOGY-NEW YORK LA English DT Article ID SYSTEMATIC SEXTANT BIOPSIES; EXTERNAL-BEAM RADIATION; RADICAL PROSTATECTOMY; TRANSRECTAL ULTRASOUND; ADJUVANT THERAPY; EXTRACAPSULAR EXTENSION; CLINICAL-SIGNIFICANCE; ANTIGEN FAILURE; REPEAT SEXTANT; CANCER AB The goal of identifying a set of pretreatment risk-stratifying factors for patients with localized prostate cancer is to be able to individualize treatment and optimize patient selection for clinical trials. Low-risk patients are most likely to remain disease-free following local therapy, whereas high-risk patients are not. By identifying a high-risk group in which approximately two-thirds of the patients fail biochemically within 10 years following local therapy, the ability to detect a difference in outcome as a result of additional therapy (if any difference exists) is maximized. Specifically, small improvements in outcome associated with the use of novel therapies can be measured more quickly in the highrisk population because of the intrinsically higher failure and progression rates. Therefore, novel therapies should be studied first in high-risk populations using a prospective randomized trial design (ie, local therapy with or without novel therapy). If efficacy is established in the high-risk cohort, then testing could be considered in the low-risk population. This review will demonstrate the ability to risk stratify more than 90% of all patients with clinically localized prostate cancer into low- or high-risk groups for biochemical progression following local therapy using four readily available pretreatment clinical parameters. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Therapy, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Therapy, 75 Francis St,L-2 Level, Boston, MA 02115 USA. NR 47 TC 44 Z9 45 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2001 VL 15 IS 8 BP 1049 EP 1059 PG 11 WC Oncology SC Oncology GA 467JJ UT WOS:000170698400017 PM 11548976 ER PT J AU Hernandez-Quintela, E Samapunphong, S Khan, BF Gonzalez, B Lu, PCS Farah, SG Azar, DT AF Hernandez-Quintela, E Samapunphong, S Khan, BF Gonzalez, B Lu, PCS Farah, SG Azar, DT TI Posterior corneal surface changes after refractive surgery SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY NOV 08-11, 1998 CL NEW ORLEANS, LOUISIANA SP Amer Acad Ophthalmol ID IN-SITU KERATOMILEUSIS; PHOTOREFRACTIVE KERATECTOMY; IATROGENIC KERATECTASIA; TOPOGRAPHIC CHANGES; MYOPIC ASTIGMATISM; BED THICKNESS; LASER AB Objective: To determine the frequency of changes in posterior corneal surface after laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). Design: Nonrandomized, comparative trial. Participants: Ninety-five eyes (71 patients) that underwent PRK (n = 45) or LASIK (n = 50). Controls: Twenty nonsurgery eyes were used to validate the method of analysis of the posterior corneal curvature (PCC). Seventy nonsurgery eyes were used for comparisons. Methods: Float, apex-fixed best fit corneal curvature (ABC), and posterior elevation difference were evaluated in 20 elevation topography maps at 6 zone diameters (3-7 and 10 mm) and at two time points. Corneal elevation maps before and after PRK or LASIK were analyzed by the ABC and float methods and compared with a nonsurgery group. Main Outcome Measures: Posterior corneal curvature change (mm) was classified as flattening, steepening, or no change. Results. Flattening of more than 0.12 mm was found in 22.2% of eyes (n = 10) in the PRK group, a change of +/-0.12 mm was found in 53.3% of eyes (n = 24), and steepening of more than 0.12 mm was found in 24.4% of eyes (n = 11) using the float method and in 28.9% of eyes (n = 13), 35.6% of eyes (n = 16), and 35.6% eyes (n = 16), respectively, using the ABC method. In the LASIK group, the float method registered flattening in 20% of eyes (n = 10), no change in 52% of eyes (n = 26), and steepening in 28% of eyes (n = 14), whereas the ABC method registered flattening in 30% of eyes (n = 15), no change in 40% of eyes (n = 20), and steepening in 30% of eyes (n = 15). The nonsurgery group showed a similar change in PCC at two different time points similar to that of the PRK and the LASIK groups. Conclusions: The differences observed in the PCC after PRK or LASIK were not statistically significantly different from those observed over time in the nonsurgery control group. Ophthalmology 2001;108:1415-1422 (C) 2001 by the American Academy of Ophthalmology. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,External Dis Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Refract Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Corneal Serv, Boston, MA 02114 USA. RP Azar, DT (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Corneal Serv, 243 Charles St, Boston, MA 02114 USA. NR 18 TC 26 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2001 VL 108 IS 8 BP 1415 EP 1422 DI 10.1016/S0161-6420(01)00634-0 PG 8 WC Ophthalmology SC Ophthalmology GA 457JV UT WOS:000170134500028 PM 11470692 ER PT J AU Jain, S Ou, R Azar, DT AF Jain, S Ou, R Azar, DT TI Monovision outcomes in presbyopic individuals after refractive surgery SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY OCT 22, 2000 CL DALLAS, TEXAS SP Amer Acad Ophthalmol ID PHOTOREFRACTIVE KERATECTOMY; OCULAR DOMINANCE; SUCCESS AB Purpose: To characterize monovision outcomes and patient satisfaction with conventional monovision (dominant eye corrected for distance) and crossed monovision (dominant eye corrected for near) in presbyopic individuals after excimer laser photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). Design: Retrospective observational case series. Participants. One hundred forty-four consecutive patients, 45 years or older, who were treated with excimer laser refractive surgery between December 1995 and June 1998. Methods: Patients in whom the surgical outcome was monovision (MV) (distance vision spherical equivalent [SE] -0.50 to +0.50 diopter (D), near vision SE -3.75 to -1.00 D and anisometropia 1.00 D or greater), crossed MV (dominant eye corrected for near vision and the nondominant eye for distance vision) and full correction (bilateral SE -0.50 to +0.50) were identified. Data were abstracted and analyzed statistically. Main Outcome Measures: Preoperative and postoperative visual acuity and refraction. Patient satisfaction with monovision. Results. Forty-two patients had surgical outcome of MV. In MV patients, the average distance vision SE, near vision SE, and anisometropia were -0.04 +/-0.27 D, -1.95 +/-0.70 D, and 1.92 +/- .74 D, respectively. Patient satisfaction was 88% with MV. Twelve patients attained crossed MV. All patients with crossed MV were satisfied with their vision. Patient satisfaction with MV showed no relationship to gender, age at initial surgery, preoperative trial of monovision, laterality of treatment, type of monovision, or predictability of outcomes. Conclusions: Monovision may be a valuable option for presbyopic individuals considering refractive surgery. Crossed monovision can result in satisfactory visual outcomes. Ophthalmology 2001;108:1430-1433 (C) 2001 by the American Academy of Ophthalmology. C1 Massachusetts Eye & Ear Infirm, Corneal & Refract Surg Serv, Boston, MA 02114 USA. Schepens Eye Res Inst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Baylor Coll Med, Houston, TX 77030 USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Corneal & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY10101] NR 13 TC 77 Z9 87 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2001 VL 108 IS 8 BP 1430 EP 1433 DI 10.1016/S0161-6420(01)00647-9 PG 4 WC Ophthalmology SC Ophthalmology GA 457JV UT WOS:000170134500031 PM 11470695 ER PT J AU Li, HS Deng, XY Thompson, BS Zhang, JY Wood, PG Eagon, PK Whitcomb, DC AF Li, HS Deng, XY Thompson, BS Zhang, JY Wood, PG Eagon, PK Whitcomb, DC TI Chronic ethanol consumption induces gene expression of pancreatic monitor peptide, but not SPINK1/PSTI-56, in rats SO PANCREAS LA English DT Article DE pancreatic hypersecretion; ethanol consumption; monitor peptide; differential gene expression ID SECRETORY TRYPSIN-INHIBITOR; CHOLECYSTOKININ-RELEASING PEPTIDE; POLYMERASE CHAIN-REACTION; ENZYME SECRETION; MESSENGER-RNA; HEREDITARY PANCREATITIS; PLASMA CHOLECYSTOKININ; ALCOHOLIC PANCREATITIS; DIFFERENTIAL DISPLAY; EXOCRINE PANCREAS AB The primary factors that predispose humans to the development of alcoholic pancreatitis are unknown. One of the earliest observations in humans in whom this disease develops is pancreatic hypersecretion caused by unknown mechanisms. Messenger RNA (mRNA) differential display was performed in a rat model to investigate the molecular mechanisms associated with ethanol-induced pancreatic hypersecretion. Male Wistar rats were pair-fed Lieber-DeCarli diets with or without ethanol for 7 days or 4 weeks. Total RNA was extracted from the pancreas and its neurohormonal control sites. Differentially expressed complementary DNA (cDNA) tags were isolated, cloned, and sequenced. One 248-bp cDNA was consistently and strongly induced in the pancreata of rats fed ethanol for 4 weeks. The sequence was highly homologous to both rat pancreatic monitor peptide (MP) and pancreatic secretory trypsin inhibitor (PSTI-56), also known as serine protease inhibitor, Kazal type 1 (SPINK1). Confirmatory reverse-transcription-polymerase chain reaction showed that PSTI-56 expression remained unchanged, whereas MP mRNA levels were elevated more than four times in the pancreata of ethanol-fed rats. These results indicate that long-term ethanol ingestion increases MP mRNA levels in the rat pancreas. Because MP stimulates cholecystokinin release and cholecystokinin is an important stimulant of pancreatic secretion, the enhanced MP gene expression may contribute to pancreatic hypersecretion. Key Words: Pancreatic hypersecretion-Ethanol consumption-Monitor peptide-Differential gene expression. C1 Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Ctr Genom Sci, Pittsburgh, PA 15261 USA. VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol & Hepatol, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. FU NIAAA NIH HHS [R01 AA-10885] NR 47 TC 10 Z9 10 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 2001 VL 23 IS 2 BP 117 EP 124 DI 10.1097/00006676-200108000-00001 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 455LG UT WOS:000170027900001 PM 11484913 ER PT J AU Yip, I Go, VLW Hershman, JM Wang, HJ Elashoff, R DeShields, S Liu, Y Heber, D AF Yip, I Go, VLW Hershman, JM Wang, HJ Elashoff, R DeShields, S Liu, Y Heber, D TI Insulin-leptin-visceral fat relation during weight loss SO PANCREAS LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Pancreatic-Association CY 1999 CL CHICAGO, ILLINOIS SP Amer Pancreat Assoc DE insulin; leptin; visceral fat; sibutramine; body composition; obesity ID DEPENDENT DIABETES-MELLITUS; CORONARY HEART-DISEASE; SERUM LEPTIN; OBESE WOMEN; PLASMA LEPTIN; ENERGY-EXPENDITURE; GLUCOSE-TOLERANCE; BODY-WEIGHT; ADIPOSITY; MEN AB Introduction: The relation between insulin-leptin-visceral fat axis during weight loss has not been studied previously. Aims: To evaluate the insulin, leptin, and abdominal adiposity relation during weight loss in patients with upper body obesity. Methodology: Twenty volunteers (7 men, 13 women) with mean age 50.6 +/- 6.3 (SD) and upper body obesity (weight 105.4 +/- 12.3 kg, BMI 35.9 +/- 2.5 kg/m(2)) were recruited. Participants were enrolled in a one-arm clinical study using a calorie-deficient diet and an escalating dose regimen of sibutramine, starting with 5 mg daily and increasing in 5-mg increments to 20 mg per day. Body weight, insulin, leptin, glucose, lipids, abdominal computed tomography (CT), and total body electrical conductance (TOBEC) were measured serially at weeks 0, 4, 8, 12, and 24, Results: Eighteen patients completed the 6-month study: one man and one woman discontinued because of adverse events. With diet and sibutramine, body weight was significantly and continuously reduced throughout the 6-month study. There was a 16.0% (p = 0.0001) reduction in body weight (p < 0.001) and 22.5% (p = 0.0001) decrease in total body fat mass. Abdominal CT scans showed a 28.3% (p = 0.0001) reduction in total abdominal fat, a 26.0% (p = 0.0001) reduction in subcutaneous fat (p < 0.001), and a 31.0% (p = 0.0003) reduction in visceral fat (p < 0.001). There was a 32.0% (p = 0.0008) reduction in leptin levels and 37.9% (p = 0.0001) reduction in insulin levels between baseline and week 4, but no further significant reduction in leptin and insulin levels was observed for the duration of the study. There was a significant correlation between insulin and leptin concentrations throughout the study (p = 0.0001). Leptin was presented as a function of insulin measured at the same time. Significant associations between visceral abdominal fat, subcutaneous fat, and leptin were also observed. Conclusion: In this study, we found that leptin and insulin were related in weight loss. The data suggest that insulin may act as a strong regulator of leptin secretion during weight loss and that circulating leptin levels can be predicted by insulin level. Using sibutramine in conjunction with hypocaloric diet reduced body weight and decreased fat mass significantly. Visceral and subcutaneous abdominal fat depots were shown to decrease. Whether sibutramine exerts any selective reduction of visceral abdominal fat as opposed to total body fat mass will require further clinical investigation. C1 Univ Calif Los Angeles, Ctr Human Nutr, Sch Med, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Dept Med, Div Endocrinol, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Biomath, Los Angeles, CA 90024 USA. RP Yip, I (reprint author), Univ Calif Los Angeles, Ctr Human Nutr, Sch Med, Warren Hall,Rm 12-217,900 Vet Ave, Los Angeles, CA 90095 USA. FU NCI NIH HHS [5P01 CA42710]; NIDDK NIH HHS [3 T32 DK07688] NR 44 TC 9 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 2001 VL 23 IS 2 BP 197 EP 203 DI 10.1097/00006676-200108000-00010 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 455LG UT WOS:000170027900010 PM 11484922 ER PT J AU Neuzil, KM Dupont, WD Wright, PF Edwards, KM AF Neuzil, KM Dupont, WD Wright, PF Edwards, KM TI Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE influenza vaccine; clinical trial; pediatrics ID VIRUS-VACCINE; OTITIS-MEDIA; DAY-CARE; CHILDREN; PREVENTION; TRIVALENT; HOUSEHOLD; DISEASE; INFANTS; RATES AB Background. Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population. Methods. From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients. Results. During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes. Conclusions. Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old. C1 Univ Washington, Sch Med, Med Serv 111, Dept Med, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Prevent Med, Nashville, TN 37212 USA. RP Neuzil, KM (reprint author), Univ Washington, Sch Med, Med Serv 111, Dept Med, 1660 S Columbian Way, Seattle, WA 98108 USA. RI Dupont, William/I-4430-2012 FU NIAID NIH HHS [AI-52594] NR 31 TC 156 Z9 165 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2001 VL 20 IS 8 BP 733 EP 740 DI 10.1097/00006454-200108000-00004 PG 8 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 462TT UT WOS:000170436400004 PM 11734733 ER PT J AU Savidge, TC Lowe, DC Walker, WA AF Savidge, TC Lowe, DC Walker, WA TI Developmental regulation of intestinal epithelial hydrolase activity in human fetal jejunal xenografts maintained in severe-combined immunodeficient mice SO PEDIATRIC RESEARCH LA English DT Article ID ISOMALTASE GENE-EXPRESSION; ACID BETA-GALACTOSIDASE; RAT SMALL-INTESTINE; SUCRASE-ISOMALTASE; INVASIVE BACTERIA; MESSENGER-RNA; HUMAN FETUS; LACTASE; ISOGRAFTS; DIFFERENTIATION AB Intestinal epithelial brush border hydrolases are important and sensitive enzyme markers of gastrointestinal development and function. Little is know about the mechanisms that regulate the induction of these enzymes during human fetal development, as these events occur primarily in utero. The present work used ectopically grafted human fetal jejunal xenografts (median age, 13.3 wk of gestation), maintained in severe-combined immunodeficient mice, to study the differential expression of five different hydrolases after 10 wk of xenotransplantation. The spatio-temporal distribution of brush border alkaline phosphatase, aminopeptidase-N, alpha -glucosidase, lactase-phlorizin hydrolase, and dipeptidyl peptidase IV enzyme activities were measured quantitatively using scanning microdensitometry along the crypt-villus axes of fetal, xenograft, and pediatric (median age, 34 mo) biopsies. Ectopic grafting of fetal jejunum closely recapitulated the development of these enzymes in utero, with alkaline phosphatase, aminopeptidase-N, alpha -glucosidase, and dipeptidyl peptidase IV enzyme activities closely matching the spatiotemporal distribution and levels recorded in pediatric duodenal biopsies. Lactase-phlorizin hydrolase was the only enzyme not to reach values recorded in pediatric brush border membranes, although activities were significantly (5.6-fold) higher than in pretransplanted fetal bowel. Human jejunal xenografts therefore demonstrate an appropriate developmental induction of brush border hydrolase activity and may represent a useful model to study trans-acting factors that promote human epithelial differentiation and function in vivo. Characterization of such agents may be of potential therapeutic use in the treatment of diseases associated with gastrointestinal immaturity, notably necrotizing enterocolitis. C1 Massachusetts Gen Hosp, Dev Gastroenterol Lab, Combined Program Pediat Gastroenterol & Nutr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Babraham Inst, Dept Cellular Physiol, Cambridge CB2 4AT, England. RP Savidge, TC (reprint author), Massachusetts Gen Hosp, Dev Gastroenterol Lab, Combined Program Pediat Gastroenterol & Nutr, 114 16th St, Charlestown, MA 02129 USA. EM savidge@helix.mgh.harvard.edu FU NICHD NIH HHS [R01-HD31852, R37-HD12437]; NIDDK NIH HHS [P01-DK33506, P30-DK40561] NR 50 TC 13 Z9 13 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD AUG PY 2001 VL 50 IS 2 BP 196 EP 202 DI 10.1203/00006450-200108000-00006 PG 7 WC Pediatrics SC Pediatrics GA 456RV UT WOS:000170096800006 PM 11477203 ER PT J AU Takata, GS Chan, LS Shekelle, P Morton, SC Mason, W Marcy, SM AF Takata, GS Chan, LS Shekelle, P Morton, SC Mason, W Marcy, SM TI Evidence assessment of management of acute otitis media: I. The role of antibiotics in treatment of uncomplicated acute otitis media SO PEDIATRICS LA English DT Review DE otitis media; children; antibiotics ID RESISTANT STREPTOCOCCUS-PNEUMONIAE; CEFUROXIME AXETIL SUSPENSION; PLACEBO-CONTROLLED TRIAL; PRIMARY-CARE-NETWORK; DOUBLE-BLIND TRIAL; AMOXICILLIN-CLAVULANATE; TRIMETHOPRIM-SULFAMETHOXAZOLE; GENERAL-PRACTICE; CLINICAL-TRIAL; CO-AMOXICLAV AB Context. In 1995, >5 million episodes of acute otitis media (AOM) accounted for $3 billion in health care expenditures. Objectives. To synthesize the literature on the natural history of AOM, the effectiveness of antibiotic treatment in uncomplicated AOM, and the relative effectiveness of specific antibiotic regimens. Data Sources. Seven electronic databases for articles published between 1966 and March 1999 and reference lists in proceedings, published articles, reports, and guidelines. Study Selection. Two physicians independently assessed each article. Studies addressing AOM in children 4 weeks to 18 years old were included; those addressing children with immunodeficiencies or craniofacial abnormalities were excluded. Randomized, controlled trials (RCTs) were used to assess antibiotic effectiveness, and RCTs and cohort studies were used to assess the natural history of AOM. Among the 3491 citations identified, 80 (2.3%) met our inclusion criteria. Data Extraction. Two physicians independently abstracted data and assessed the quality of studies using a validated scale for RCTs and 8 quality components for cohort studies. Data Synthesis. Random-effects estimates of pooled absolute rate differences of outcomes were derived, and heterogeneity of both the rates and rate differences was assessed. Children with AOM not treated with antibiotics experienced a 1- to 7-day clinical failure rate of 19% (95% confidence interval: 0.10-0.28) and few suppurative complications. When patients were treated with amoxicillin, the 2- to 7-day clinical failure rate was reduced to 7%, a 12% (95% confidence interval: 0.04-0.20) reduction. Adverse effects, primarily gastrointestinal, were more common among children on cefixime than among those on ampicillin or amoxicillin. They were also more common among children on amoxicillin-clavulanate than among those on azithromycin. Conclusions. The majority of uncomplicated cases of AOM resolve spontaneously without apparent suppurative complications. Ampicillin or amoxicillin confers a limited therapeutic benefit. There is no evidence to support any particular antibiotic regimens as more effective at relieving symptoms. Certain antibiotics are more likely than others to cause diarrhea and other adverse events. C1 Childrens Hosp Los Angeles, Div Gen Pediat, Los Angeles, CA 90027 USA. Los Angeles Cty, Div Biostat & Outcomes Assessment, Los Angeles, CA USA. Univ So Calif, Ctr Pediat Hlth Outcomes Res, Dept Pediat, Los Angeles, CA USA. Univ So Calif, Greater Los Angeles Vet Affairs Healthcare Syst, Hlth Serv Res & Dev Serv, Los Angeles, CA USA. RAND Corp, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. RAND Corp, Stat Grp, Santa Monica, CA USA. Childrens Hosp, Div Infect Dis, Los Angeles, CA 90027 USA. So Calif Kaiser Permanente Hlth Care Program, Dept Pediat, Panorama City, CA USA. RP Takata, GS (reprint author), Childrens Hosp Los Angeles, Div Gen Pediat, 4650 Sunset Blvd,MS 76, Los Angeles, CA 90027 USA. FU PHS HHS [290-97-0001] NR 103 TC 72 Z9 75 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2001 VL 108 IS 2 BP 239 EP 247 DI 10.1542/peds.108.2.239 PG 9 WC Pediatrics SC Pediatrics GA 458TZ UT WOS:000170211800023 PM 11483783 ER PT J AU Chan, LS Takata, GS Shekelle, P Morton, SC Mason, W Marcy, SM AF Chan, LS Takata, GS Shekelle, P Morton, SC Mason, W Marcy, SM TI Evidence assessment of management of acute otitis media: II. Research gaps and priorities for future research SO PEDIATRICS LA English DT Article DE otitis media; children; future research ID READ CLINICAL JOURNALS; QUALITY; TRIALS; DIAGNOSIS AB Objectives. To report research gaps and priorities of future research identified during an evidence assessment process on the management of acute otitis media (AOM). Methods. A conceptual framework for management of AOM was developed to guide the evidence assessment. An 11-member technical expert panel guided the selection of key questions, prioritization of influencing factors, development of scope, definition of AOM, and search strategy through polling processes and conference calls. Quality of clinical trials was evaluated using established scales. Outcome measures were abstracted from each study. Results. A total of 3461 titles and abstracts were screened, and 760 full-length articles were reviewed. Of the 760 articles, 80 studies addressed the key questions. In defining AOM, 42 (52.5%) of the 80 studies included the middle-ear effusion component, only 2 (2.5%) included the rapid onset component, and 26 (32.5%) included the signs/symptoms of inflammation component. None of the 80 studies used all 3 components. Of the 74 controlled trials, 39 (53%) were of acceptable quality (Jadad score of 3 or higher). The technical experts did not agree in the ranking of the importance of the 41 influencing factors (Kendall's coefficient of concordance was 0.0022). Another poll also indicated diverse opinions of the experts on the importance of 7 key questions derived from the conceptual framework (Kendall coefficient of concordance is 0.21). Furthermore, our review found that the type and definition of outcome measure varied. Conclusions. Despite the large body of literature on AOM, its quality is uneven and its findings are not generalizable. Future research should try to answer all key questions and investigate all risk factors in well-designed, scientific studies. C1 USC, Los Angeles Cty Med Ctr, Div Biostat & Outcomes Assessment, Los Angeles, CA 90033 USA. USC, Dept Pediat, Ctr Pediat Hlth Outcomes Res, Los Angeles, CA 90033 USA. Childrens Hosp Los Angeles, Div Gen Pediat, Los Angeles, CA 90027 USA. Greater Los Angeles Vet Affair Healthcare Syst, Hlth Serv Res & Dev Serv, Los Angeles, CA USA. RAND Corp, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. Childrens Hosp Los Angeles, Div Infect Dis, Los Angeles, CA 90027 USA. So Calif Kaiser Permanente Hlth Care Program, Dept Pediat, Panorama City, CA USA. RP Chan, LS (reprint author), USC, Los Angeles Cty Med Ctr, Div Biostat & Outcomes Assessment, Room 12-900,1200 N State St, Los Angeles, CA 90033 USA. FU PHS HHS [290-97-0001] NR 19 TC 29 Z9 31 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2001 VL 108 IS 2 BP 248 EP 254 DI 10.1542/peds.108.2.248 PG 7 WC Pediatrics SC Pediatrics GA 458TZ UT WOS:000170211800024 PM 11483784 ER PT J AU Ferris, TGG Perrin, JM Manganello, JA Chang, YC Causino, N Blumenthal, D AF Ferris, TGG Perrin, JM Manganello, JA Chang, YC Causino, N Blumenthal, D TI Switching to gatekeeping: Changes in expenditures and utilization for children SO PEDIATRICS LA English DT Article DE managed care; child health services; primary care; chronic illness; gatekeeping; expenditures; utilization; child; quality; insurance; specialist ID SUPPLEMENTAL SECURITY INCOME; CARE; PATTERNS; ADOLESCENTS; CHOICE; PLAN AB Background. Gatekeeping has been a central strategy in the cost-containment initiatives of managed care organizations. Little empirical research describes the impact of switching into a gatekeeping plan on health care expenditures and utilization for children. Objective. To determine the likelihood of a parent with a chronically ill child enrolling in a health plan with gatekeeping, as well as the effects of gatekeeping on health care expenditures and utilization for children, especially those with chronic conditions. Design. We followed a cohort of 1839 children who either voluntarily switched to a gatekeeping plan or remained in an indemnity plan from 1991 through 1994. Study participants were children of employees of a large hospital. The gatekeeping plan was virtually identical to the previous indemnity plan except for lower monthly employee contribution and the requirement for a primary care physician to preapprove subspecialty referrals. We determined the likelihood of a household containing a child with a chronic condition enrolling in the gatekeeping plan, as well as mean annual total, subspecialty, and primary care expenditures and utilization for all children and children with chronic conditions. Results. Households switching to gatekeeping were less likely to have children with chronic illness (8% vs 15%). Total and subspecialty expenditures for all children decreased more in the gatekeeping group (53% and 59%, respectively) than in the indemnity group (11% and 6%, respectively). For children with chronic conditions, mean visits to subspecialists decreased 57% in the gatekeeping group but increased 31% in the indemnity group. Mean visits to primary care physicians decreased 23% in the gatekeeping group compared with 13% in indemnity group. Conclusion. Parents of children with a chronic condition were much less likely than other parents to switch to a gatekeeping plan. Switching to gatekeeping was associated with reduced visits to specialists but did not increase the involvement of primary care physicians in the management of children with chronic conditions. The implications of these findings for the health of children are unknown. C1 Massachusetts Gen Hosp Children, Inst Hlth Policy, Div Gen Med, Boston, MA USA. Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ferris, TGG (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NICHD NIH HHS [K12-HD00850] NR 26 TC 34 Z9 34 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2001 VL 108 IS 2 BP 283 EP 290 DI 10.1542/peds.108.2.283 PG 8 WC Pediatrics SC Pediatrics GA 458TZ UT WOS:000170211800029 PM 11483789 ER PT J AU Wittenberg, E Goldie, SJ Graham, JD AF Wittenberg, E Goldie, SJ Graham, JD TI Predictors of hazardous child seating behavior in fatal motor vehicle crashes: 1990 to 1998 SO PEDIATRICS LA English DT Article DE air bags; child seating; motor vehicles ID RESTRAINT USE; SAFETY AB Objective. Motor vehicle crashes are the leading cause of death in children ages 5 to 14. Children seated in the front seats of vehicles are at increased risk of death and injury in crashes, particularly in vehicles with passenger-side air bags. This study identifies factors associated with the seating of children in the front seats of vehicles involved in fatal crashes between 1990 and 1998. Methods. Using 1990 to 1998 data from the Fatal Analysis Reporting System, a US census of motor vehicle crashes involving a fatality, multivariable logistic regression was used to model the association between child seating behavior and vehicle, driver, and occupant characteristics. Results. The proportion of vehicles carrying children in the front declined from 42% to 31% over the 9-year period. Controlling for driver and vehicle characteristics, the risk of front-seating declined between 1990 and 1998, and this risk was smaller in vehicles carrying only younger children (less than or equal to6 years) than in those carrying older children. In the 3 years after the introduction of dual air bags into a significant proportion of the passenger fleet in late 1995, dual air bags were associated with fewer children being seated in the front seat. By the end of 1998, traveling in a vehicle with dual air bags and only children age 6 or younger was associated with a 95% lower chance of a child being seated in the front (odds ratio = 0.05; 95% confidence interval: 0.04-0.08). An important factor in safer seating position was the presence of multiple passengers, especially an older one, and children were at higher risk of front-seating when they traveled alone with the driver. Conclusions. The 1990s saw a decline in front-seating of children in vehicles involved in fatal crashes among all types of vehicles and drivers. Although this trend is encouraging, children ages 6 to 12 and children traveling alone with the driver remain at higher risk of being seated in the front. These traveling situations should be targeted for behavioral safety interventions to improve child motor vehicle safety. C1 Harvard Univ, Sch Publ Hlth, Ctr Risk Anal, Boston, MA 02115 USA. RP Wittenberg, E (reprint author), Dana Farber Canc Inst, 44 Binney St,454,S21-24, Boston, MA 02115 USA. NR 20 TC 5 Z9 5 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2001 VL 108 IS 2 BP 438 EP 442 DI 10.1542/peds.108.2.438 PG 5 WC Pediatrics SC Pediatrics GA 458TZ UT WOS:000170211800052 PM 11483812 ER PT J AU Goodman, E Adler, NE Kawachi, I Frazier, AL Huang, B Colditz, GA AF Goodman, E Adler, NE Kawachi, I Frazier, AL Huang, B Colditz, GA TI Adolescents' perceptions of social status: Development and evaluation of a new indicator SO PEDIATRICS LA English DT Article DE subjective social status; socioeconomic status; obesity; depression; adolescence ID SOCIOECONOMIC-STATUS; UNITED-STATES; HEALTH INEQUALITIES; YOUNG ADULTHOOD; US ADOLESCENTS; CHILD HEALTH; OBESITY; YOUTH; OVERWEIGHT; RISK AB Objective. Eliminating health disparities, including those that are a result of socioeconomic status (SES), is one of the overarching goals of Healthy People 2010. This article reports on the development of a new, adolescent-specific measure of subjective social status (SSS) and on initial exploratory analyses of the relationship of SSS to adolescents' physical and psychological health. Methods. A cross-sectional study of 10 843 adolescents and a subsample of 166 paired adolescent/mother dyads who participated in the Growing Up Today Study was conducted. The newly developed MacArthur Scale of Subjective Social Status (10-point scale) was used to measure SSS. Paternal education was the measure of SES. Indicators of psychological and physical health included depressive symptoms and obesity, respectively. Linear regression analyses determined the association of SSS to depressive symptoms, and logistic regression determined the association of SSS to overweight and obesity, controlling for sociodemographic factors and SES. Results. Mean society ladder ranking, a subjective measure of SES, was 7.2 +/-1.3. Mean community ladder ranking, a measure of perceived placement in the school community, was 7.6 +/-1.7. Reliability of the instrument was excellent: the intraclass correlation coefficient was 0.73 for the society ladder and 0.79 for the community ladder. Adolescents had higher society ladder rankings than their mothers ( mu (teen) = 7.2 +/-1.3 vs mu (mom) = 6.8 +/-1.2; P = .002). Older adolescents' perceptions of familial placement in society were more closely correlated with maternal subjective perceptions of placement than those of younger adolescents (Spearman's rho(teens) (<15 years) = 0.31 vs Spearman's rho(teens 15 years) = 0.45; P <.001 for both). SSS explained 9.9% of the variance in depressive symptoms and was independently associated with obesity (odds ratio(society) = 0.89, 95% confidence interval = 0.83, 0.95; odds ratio(community) = 0.91, 95% confidence interval = 0.87, 0.97). For both depressive symptoms and obesity, community ladder rankings were more strongly associated with health than were society ladder rankings in models that controlled for both domains of SSS. Conclusions. This new instrument can reliably measure SSS among adolescents. Social stratification as reflected by SSS is associated with adolescents' health. The findings suggest that as adolescents mature, SSS may undergo a developmental shift. Determining how these changes in SSS relate to health and how SSS functions prospectively with regard to health outcomes requires additional research. C1 Univ Cincinnati, Coll Med, Childrens Hosp Med Ctr, Div Adolescent Med, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Goodman, E (reprint author), Univ Cincinnati, Coll Med, Childrens Hosp Med Ctr, Div Adolescent Med, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM goodeO@chmcc.org RI Huang, bin/G-2468-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NIDDK NIH HHS [DK46834] NR 57 TC 173 Z9 176 U1 3 U2 56 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD AUG PY 2001 VL 108 IS 2 AR e31 DI 10.1542/peds.108.2.e31 PG 8 WC Pediatrics SC Pediatrics GA 458TZ UT WOS:000170211800012 PM 11483841 ER PT J AU Kuter, DJ Tillotson, GS AF Kuter, DJ Tillotson, GS TI Hematologic effects of antimicrobials: Focus on the oxazolidinone linezolid SO PHARMACOTHERAPY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA 02115 USA. NYU, Publ Hlth Res Inst, New York, NY USA. RP Kuter, DJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Hematol & Oncol, 100 Blossom St, Boston, MA 02115 USA. NR 11 TC 79 Z9 83 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2001 VL 21 IS 8 BP 1010 EP 1013 DI 10.1592/phco.21.11.1010.34517 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 470BB UT WOS:000170849600012 PM 11718489 ER PT J AU Yaremchuk, M AF Yaremchuk, M TI Morphometry of the orbital region: A soft-tissue study from adolescence to mid-adulthood - Discussion SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. RP Yaremchuk, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg, WACC-453, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD AUG PY 2001 VL 108 IS 2 BP 293 EP 293 DI 10.1097/00006534-200108000-00002 PG 1 WC Surgery SC Surgery GA 456RW UT WOS:000170096900002 ER PT J AU Panossian, A Ashiku, S Kirchhoff, CH Randolph, MA Yaremchuk, MJ AF Panossian, A Ashiku, S Kirchhoff, CH Randolph, MA Yaremchuk, MJ TI Effects of cell concentration and growth period on articular and ear chondrocyte transplants for tissue engineering SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article; Proceedings Paper CT 16th Annual Meeting of the Northeastern-Society-of-Plastic-Surgeons CY SEP 30-OCT 02, 1999 CL BURLINGTON, VERMONT SP NE Soc Plast Surgeons ID VESICOURETERAL REFLUX; CARTILAGE; POLYMER AB This study determined the effects of chondrocyte source, cell concentration, and growth period on cartilage production when isolated porcine cells are injected subcutaneously in a nude mouse model. Chondrocytes were isolated from both car and articular cartilage and were suspended in Ham's F-12 medium at concentrations of 10, 20,40, and 80 million cells per cubic centimeter. Using the nude mouse model, each concentration group was injected subcutaneously in 100-mul aliquots and was allowed to incubate for 6 weeks in vivo. In addition, cells suspended at a fixed concentration of 40 million cells per cubic centimeter were injected in 100-mul aliquots and were incubated for 1, 2, 3, 4, 5, 6, 9, and 12 weeks. Each concentration or time period studied contained a total of eight mice, with four samples harvested per mouse for a final sample size of 32 constructs. All neocartilage samples were analyzed by histologic characteristics, mass, glycosaminoglycan level, and DNA content. Control groups consisted of native porcine ear and articular cartilage. Specimen mass increased with increasing concentration and incubation time. Ear neocartilage was larger than articular neocartilage at each concentration and time period. At 40 million cells per cubic centimeter, both ear and articular chondrocytes produced optimal neocartilage, without limitations in growth. Specimen mass increased with incubation time up to 6 weeks in both ear and articular samples. No significant variations in glycosaminoglycan content were found in either articular or ear neocartilage, with respect to variable chondrocyte concentration or growth period. Although articular samples demonstrated no significant trends in DNA content over time, car specimens showed decreasing values through 6 weeks, inversely proportional to increase in specimen mass. Although both articular and ear sources of chondrocytes have been used in past tissue-engineering studies with success, this study indicates that a suspension of ear chondrocytes injected into a subcutaneous location will produce biochemical and histologic data with greater similarity to those of native cartilage. The authors believe that this phenomenon is attributable to the local environment in which isolated chondrocytes from different sources are introduced. The subcutaneous environment of native ear cartilage accommodates subcutaneously injected ear chondrocyte transplants better than articular transplants. Native structural and biochemical cues within the local environment are believed to guide the proliferation of the differentiated chondrocytes. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. RP Randolph, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg, WACC4,Suite 453,15 Parkman St, Boston, MA 02114 USA. FU NIAMS NIH HHS [R03 AR45059] NR 24 TC 39 Z9 43 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD AUG PY 2001 VL 108 IS 2 BP 392 EP 402 DI 10.1097/00006534-200108000-00018 PG 11 WC Surgery SC Surgery GA 456RW UT WOS:000170096900018 PM 11496181 ER PT J AU Abrahm, J AF Abrahm, J TI Pain management for dying patients - How to assess needs and provide pharmacologic relief SO POSTGRADUATE MEDICINE LA English DT Article ID CANCER AB Many patients have pain at the end of life, but their discomfort may be either unexpressed or met with skepticism by their physicians. A thorough assessment and tailored treatment plan can keep patients with even the most severe pain comfortable in their final days. In this article, Or Abrahm discusses the evaluation of pain of malignant and nonmalignant origin and a pharmacologic approach to relieving it. C1 Dana Farber Canc Inst, Div Adult Psychosocial Oncol, Pain & Palliat Care Program, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Abrahm, J (reprint author), Dana Farber Canc Inst, Div Adult Psychosocial Oncol, Pain & Palliat Care Program, 44 Binney St, Boston, MA 02115 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU MCGRAW HILL HEALTHCARE PUBLICATIONS PI MINNEAPOLIS PA 4530 WEST 77TH ST, MINNEAPOLIS, MN 55435-5000 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD AUG PY 2001 VL 110 IS 2 BP 99 EP + PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 462XQ UT WOS:000170445500009 PM 11787419 ER PT J AU Hunt, MK Lobb, R Delichatsios, HK Stone, C Emmons, K Gillman, MW AF Hunt, MK Lobb, R Delichatsios, HK Stone, C Emmons, K Gillman, MW TI Process evaluation of a clinical preventive nutrition intervention SO PREVENTIVE MEDICINE LA English DT Article DE nutrition education; preventive nutrition; physician counseling; process evaluation ID HEALTH PROMOTION PROGRAMS; PHYSICIANS; IMPLEMENTATION; RESIDENTS; CARE; EXPERIENCE; EDUCATION; SMOKING; PATIENT; TRIALS AB Background. We report process data on the feasibility of delivering a clinical preventive nutrition intervention that was effective in increasing participants' consumption of fruits and vegetables. We also examine relationships between process variables and study outcomes. Methods. We randomly assigned six practice sites in a managed care organization to a dietary intervention or control condition. We invited adults 18 years of age or older scheduled for routine health visits within the subsequent 2 months to participate. Of the 566 patients we contacted from the intervention sites, 230 (41%) enrolled. From the control sites, we contacted 617, and 274 (44%) enrolled. Intervention participants received a tailored letter providing feedback on their consumption of target foods together with recommendations for improvement, stage-matched nutrition education booklets, a diet-health endorsement from their primary care providers (PCPs), and two motivational counseling telephone calls. Of enrollees, 195 (85%) in the intervention group and 252 (92%) in the control group returned the final survey 3 months later. Results. Seventy-one percent of both participants and PCPs reported that the PCPs had discussed the relationship between diet and health at their visit. Fifty-seven percent of participants and 62% of PCPs reported that they discussed the complete diet-health endorsement, which included: (1) acknowledgment of the relationship between diet and health and (2) tailored study recommendations. The inclusion of both parts of the diet-health endorsement, but not the length of time spent, appeared to correlate with healthful outcomes. Conclusions. These process data suggest that the brief PCP diet-health endorsement contributed to the intervention effect on fruits and vegetables. (C) 2001 American Health Foundation and Academic Press. C1 Dana Farber Canc Inst, Ctr Commun Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. RP Emmons, K (reprint author), Dana Farber Canc Inst, Ctr Commun Based Res, 44 Binney St, Boston, MA 02115 USA. OI Lobb, Rebecca/0000-0003-3503-0675 NR 53 TC 14 Z9 14 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2001 VL 33 IS 2 BP 82 EP 90 DI 10.1006/pmed.2001.0863 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 462HQ UT WOS:000170415000003 PM 11493040 ER PT J AU Delichatsios, HK Hunt, MK Lobb, R Emmons, K Gillman, MW AF Delichatsios, HK Hunt, MK Lobb, R Emmons, K Gillman, MW TI EatSmart: Efficacy of a multifaceted preventive nutrition intervention in clinical practice SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-General-Internal Medicine CY MAY 04-06, 2000 CL BOSTON, MASSACHUSETTS SP Soc Gen Internal Med DE nutrition; tailoring; motivational interviews; randomized controlled trial; stage of change; fruits and vegetables ID WORCESTER-AREA TRIAL; PRIMARY-CARE PRACTITIONERS; CORONARY HEART-DISEASE; DIETARY-FAT; HYPERLIPIDEMIA WATCH; VEGETABLE CONSUMPTION; SERUM-CHOLESTEROL; PHYSICIANS; PROGRAM; RISK AB Background. We evaluated a multifaceted preventive nutrition intervention to improve dietary habits among adult primary care patients. Methods. We randomized six group practices in a managed care organization. Participants completed baseline and 3-month follow-up surveys. The intervention comprised (1) mailed personalized dietary recommendations and educational booklets focusing on fruits and vegetables, red meat, and dairy foods, tailored to patients' baseline intake and stage of readiness to change eating behaviors; (2) verbal endorsement by the primary care provider of the benefits of these recommendations; and (3) two motivational counseling sessions with telephone counselors to set dietary goals. Results. Among the 230 subjects in the intervention group and 274 in the control group, mean age was 54 years, 70% were female, and 91% were white and 7% African American. Eighty-nine percent of the participants completed the follow-up survey. We measured change in intake of foods using results from the baseline and follow-up food frequency questionnaires. Using an intention-to-treat analysis and adjusting for age, sex, race, and baseline intake, the change in fruit and vegetable intake in the intervention group was 0.6 (95% confidence interval 0.3, 0.8) servings/day higher than in the control group. There was no intervention effect on red meat and dairy products. Conclusions. Tailored clinical nutrition interventions that combine brief physician endorsement with practice supports may be effective in changing patients' eating behavior. (C) 2001 American Health Foundation and Academic Press. C1 Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. Harvard Univ, Harvard Pilgrim Hlth Care, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Delichatsios, HK (reprint author), MGH Beacon Hill Primary Care, 100 Charles River Plaza,5th Floor, Boston, MA 02114 USA. OI Lobb, Rebecca/0000-0003-3503-0675 NR 50 TC 38 Z9 40 U1 1 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2001 VL 33 IS 2 BP 91 EP 98 DI 10.1006/pmed.2001.0848 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 462HQ UT WOS:000170415000004 PM 11493041 ER PT J AU Cooper, RA Fitzgerald, SG Boninger, ML Brienza, DM Shapcott, N Cooper, R Flood, K AF Cooper, RA Fitzgerald, SG Boninger, ML Brienza, DM Shapcott, N Cooper, R Flood, K TI Telerehabilitation: Expanding access to rehabilitation expertise SO PROCEEDINGS OF THE IEEE LA English DT Review DE Internet; rehabilitation; smart-technology; videoconferencing ID VIRTUAL-REALITY; INFORMATION NEEDS; FACTORIZATION METHOD; CLINICAL QUESTIONS; PATIENT EDUCATION; FUNCTIONAL STATUS; SELF-CALIBRATION; VASCULAR-SURGERY; INTERNET; TECHNOLOGY AB The potential of modern telecommunications and computing technologies as tools in the delivery and evaluation of assistive technology (AT) has been discussed and has been termed telerehabilitation. The problems of providing AT in rural areas parallels the delivery of health care to rural areas where the proportion of people with chronic illnesses is higher and the means to pay for them is reduced. Large distances mean long travel times, increasing costs associated with any service delivered and consuming valuable tune skilled professionals could be rising to provide services elsewhere. The technology available for practicing telerehabilitation is significant and expanding at a rapid rate. Currently, plain old telephone systems (POTS) and broad-band videoconferencing equipment, Internet and World Wide Web, and embedded processor systems are most widely available. These technologies continue to evolve as well as emerging technologies such as wearable sensors that will have telerehabilitation applications. Issues of payment, safety, liability. and licensure need to be resolved, as legislation lags the development of new technologies. C1 VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Rehabil Hosp, Med Ctr, Pittsburgh, PA 15261 USA. RP Cooper, RA (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 120 TC 21 Z9 23 U1 2 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9219 J9 P IEEE JI Proc. IEEE PD AUG PY 2001 VL 89 IS 8 BP 1174 EP 1191 DI 10.1109/5.940286 PG 18 WC Engineering, Electrical & Electronic SC Engineering GA 462HG UT WOS:000170414200004 ER PT J AU Cannon, DS Kivlahan, DR Gresen, RC Baker, RR Blusewicz, MJ Burk, JP Cantrell, PJ Dubbert, PM LaGana, CM Nightingale, EJ Patterson, JE AF Cannon, DS Kivlahan, DR Gresen, RC Baker, RR Blusewicz, MJ Burk, JP Cantrell, PJ Dubbert, PM LaGana, CM Nightingale, EJ Patterson, JE TI The impact of the Veterans Health Administration (VHA) reorganization on psychology programs: A survey of VHA psychology leaders SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article ID CARE SYSTEM; HISTORY; FUTURE AB Because the Veterans Health Administration (VHA) is the nation's largest health care system and employer and trainer of psychologists, changes in VHA psychology have implications for the rest of the profession. A national survey of 127 VHA psychology leaders (91% response rate) documented that many psychologists now are managed by a psychiatrist, deliver more outpatient services, and do less personality testing. In the context of a 10% reduction in psychology staffing, morale is rated lower than 2 years earlier. Diversified professional roles are associated with higher status of psychology and management support for mental health programs. Psychologists need to understand and respond adaptively to the organizational and economic forces affecting their practice. C1 VA Salt Lake Hlth Care Syst, Mental Hlth Care Ctr 116OP, Mental Hlth Strateg Hlth Care Grp, Informat Sect, Salt Lake City, UT 84148 USA. VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. Univ Calif Davis, Sch Med, Davis, CA 95616 USA. Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32611 USA. Kansas City VA Med Ctr, Kansas City, MO USA. Univ Kansas, Med Ctr, Dept Psychiat, Kansas City, MO USA. Univ Missouri, Dept Counseling Psychol, Kansas City, MO 64110 USA. Univ Mississippi, Sch Med, University, MS 38677 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Cannon, DS (reprint author), VA Salt Lake Hlth Care Syst, Mental Hlth Care Ctr 116OP, Mental Hlth Strateg Hlth Care Grp, Informat Sect, 500 Foothill Blvd, Salt Lake City, UT 84148 USA. EM dale.cannon@med.va.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 EI 1939-1323 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD AUG PY 2001 VL 32 IS 4 BP 373 EP 379 DI 10.1037//0735-7028.32.4.373 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 470WE UT WOS:000170893500007 ER PT J AU Cabrera, AR McNally, RJ Savage, CR AF Cabrera, AR McNally, RJ Savage, CR TI Missing the forest for the trees? Deficient memory for linguistic gist in obsessive-compulsive disorder SO PSYCHOLOGICAL MEDICINE LA English DT Article ID IMPAIRMENT; CHECKERS AB Background. Patients with obsessive-compulsive disorder (OCD) exhibit recall deficits on word learning tasks, mediated by their failure to detect semantic connections among the words. Methods. In the present experiment, using methods devised by Bransford & Franks (1971), we tested whether this encoding problem impairs their extraction of gist from complex linguistic material. Results. Consistent with our hypothesis, OCD patients extracted less gist from related sentences than did healthy participants. The groups did not differ in recognition memory for individual sentences or in criterion for affirming previously encountered sentences as 'old', as evinced by signal detection indices of memory sensitivity (d ') and response bias (beta), or in recognition memory confidence. Conclusions. These data provide further evidence that OCD patients exhibit less reliance on organizational strategies than do healthy control participants. These data are consistent with neuropsychological research suggestive of prefrontal executive problems in OCD. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Cambridge, MA USA. RP McNally, RJ (reprint author), Harvard Univ, Dept Psychol, William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. NR 20 TC 45 Z9 46 U1 1 U2 13 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2001 VL 31 IS 6 BP 1089 EP 1094 PG 6 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 463YA UT WOS:000170503800013 PM 11513376 ER PT J AU Zimmerman, P Chin, E Laifer-Narin, S Ragavendra, N Grant, EG AF Zimmerman, P Chin, E Laifer-Narin, S Ragavendra, N Grant, EG TI Radial artery mapping for coronary artery bypass graft placement SO RADIOLOGY LA English DT Editorial Material DE arteries, extremities; arteries, grafts and prostheses; arteries, US; editorials ID CIRCULATION; HAND; DOPPLER; REMOVAL C1 W Los Angeles Vet Adm Med Ctr, Dept Radiol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Radiol Sci, Med Ctr, Los Angeles, CA 90024 USA. RP Zimmerman, P (reprint author), W Los Angeles Vet Adm Med Ctr, Dept Radiol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 12 TC 5 Z9 6 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2001 VL 220 IS 2 BP 299 EP 302 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454TW UT WOS:000169988700003 PM 11477229 ER PT J AU Zalis, ME Hahn, PF Arellano, RS Gazelle, GS Mueller, PR AF Zalis, ME Hahn, PF Arellano, RS Gazelle, GS Mueller, PR TI CT colonography with teleradiology: Effect of lossy wavelet compression on polyp detection - Initial observations SO RADIOLOGY LA English DT Article DE colon, abnormalities; colon, CT; colonoscopy ID COLORECTAL NEOPLASMS; VIRTUAL COLONOSCOPY AB PURPOSE: To assess the consequences of lossy compression on the diagnostic accuracy of CT colonography for detecting colonic polyps. MATERIALS AND METHODS: Helical CT images of cleansed colonic segments were evaluated. Source images were compressed to 1:1, 10:1, and 20:1 ratios with lossy wavelet compression. Two independent readers blinded to corresponding colonoscopic results analyzed 144 randomly ordered colonic segments in multiplanar and volume-rendered endoscopic views. Sensitivity, specificity, and receiver operating characteristic curves were generated for each compression ratio on the basis of expressed confidence in lesion presence. Similar analyses were performed to assess distention and bowel preparation adequacy and evaluation time required. RESULTS: Results based on video colonoscopy- confirmed lesions revealed 100% (four of four) sensitivity for lesions larger than 10 mm for compression ratios 1:1, 10:7, and 20:1 for both readers; sensitivities for all lesions smaller than 10 mm were 50%-78%, 38%-67%, and 38%-67% for respective ratios for both readers. Differences in diagnostic performance for each reader across ratios were not significant (P = .30-.99, McNemar test). The time required to evaluate and assess bower preparation and distention adequacy did not change significantly across ratios, CONCLUSION: On the basis of the patient sample, lossy compression of transverse source images to at least a 20:1 ratio did not adversely affect diagnostic performance or evaluation time for CT colonography. C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Decis Anal & Technol Assessment Grp, Dept Radiol, Boston, MA 02114 USA. Harvard Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Zalis, ME (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. NR 15 TC 20 Z9 20 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2001 VL 220 IS 2 BP 387 EP 392 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454TW UT WOS:000169988700015 PM 11477241 ER PT J AU Goldberg, SN Saldinger, PF Gazelle, GS Huertas, JC Stuart, KE Jacobs, T Kruskal, JB AF Goldberg, SN Saldinger, PF Gazelle, GS Huertas, JC Stuart, KE Jacobs, T Kruskal, JB TI Percutaneous tumor ablation: Increased necrosis with combined radio-frequency ablation and intratumoral doxorubicin injection in a rat breast tumor model SO RADIOLOGY LA English DT Article DE breast neoplasms, therapy; chemotherapy; hyperthermia; radiofrequency (RF) ablation ID RADIOFREQUENCY TISSUE ABLATION; THERMAL ABLATION; HEPATOCELLULAR-CARCINOMA; CLINICAL-EXPERIENCE; LIVER METASTASES; HEPATIC-TUMORS; HYPERTHERMIA; ELECTRODE; MALIGNANCY; CELL AB PURPOSE: To determine whether a combination of intratumoral doxorubicin injection and radio-frequency (RF) ablation increases tumor destruction compared with RF ablation alone in an animal tumor model. MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.2-1.5-cm-diameter nodules (n = 110) were implanted subcutaneously in 84 female Fischer rats. For initial experiments (n = 46), tumors were treated with (a) conventional, monopolar RF (250 mA +/-: 25 [SD] at 70 degreesC +/- 1 for 5 minutes) ablation alone; (b) direct intratumoral doxorubicin injection (volume, 250 muL total dose, 0.5 mg) alone; (c) combined therapy (doxorubicin injection immediately followed by RF ablation); (d) RF ablation and injection of 250 muL of distilled water; or (e) no treatment. In subsequent experiments, amount of doxorubicin (0.02-2.50 mg; n = 40 additional tumors) and timing of doxorubicin administration (2 days before to 2 days after RF ablation; n = 24 more tumors) were varied. Pathologic examination, including staining for mitochondrial enzyme activity and perfusion, was performed, and the resultant tumor destruction from each treatment was evaluated. RESULTS: Coagulation diameter was 6.7 mm +/- 0.6 for tumors treated with RF ablation alone and 6.9 mm +/- 0.7 for those treated with RF ablation and water (P = .52), while intratumoral doxorubicin injection alone produced only 2.0-3.0 mm of coagulation (P < .001). Increased coagulation was observed only with combined doxorubicin injection and RF therapy (P < .001). Coagulation was dependent on concentration and timing of doxorubicin administration, with greatest coagulation (11.5 mm +/- 1.1) observed for doxorubicin administered within 30 minutes of RF ablation. CONCLUSION: Adjuvant intratumoral doxorubicin injection increases coagulation in solid tumors compared with RF ablation alone. Increased tumor destruction is also seen when doxorubicin is administered after RF ablation, which suggests that RF ablation may sensitize tumors to chemotherapy. Such combination therapies may, therefore, offer improved methods for ablating solid tumors. C1 Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Surg Oncol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Goldberg, SN (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. NR 39 TC 56 Z9 60 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2001 VL 220 IS 2 BP 420 EP 427 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454TW UT WOS:000169988700020 PM 11477246 ER PT J AU Bosch, JL Lester, JS McMahon, PM Beinfeld, MT Halpern, EF Kaufman, JA Brewster, DC Gazelle, GS AF Bosch, JL Lester, JS McMahon, PM Beinfeld, MT Halpern, EF Kaufman, JA Brewster, DC Gazelle, GS TI Hospital costs for elective endovascular and surgical repairs of infrarenal abdominal aortic aneurysms SO RADIOLOGY LA English DT Article DE aneurysm, aortic; aorta, grafts and prostheses; aorta, interventional procedures; cost-effectiveness; economics, medical ID EXPERIENCE; TRIAL; MULTICENTER; GRAFTS AB PURPOSE: To determine and compare the average in-hospital costs of elective open surgical and endovascular repairs of infrarenal abdominal aortic aneurysms. MATERIALS AND METHODS: Total actual cost data for patients undergoing elective endovascular (n = 181) or open surgical (n = 273) repair of abdominal aortic aneurysms between 1997 and 1999 were retrieved. The mean total hospital cost (including stent-graft costs and excluding attending physician fees) and mean postoperative length of stay were calculated for each treatment group. Costs were expressed in 1999 U.S. dollars. RESULTS: Endovascular repair yielded a shorter postoperative length of stay than did open surgery (mean stay, 3.4 vs 8.0 days; P < .001) and a lower proportion of patients who were admitted to the intensive care unit for 1 full day or longer (2.8% vs 36.3%; P < .001). The mean total hospital cost was significantly higher for endovascular repair than for open surgery ($20,716 vs $18,484; P < .001). CONCLUSION: Hospital costs were higher for endovascular repair than for open surgical repair. However, endovascular repair was associated with a decreased length of stay and fewer intensive care unit admissions. The increased mean hospital cost for endovascular repair was smaller than one would expect, considering the higher costs of endovascular grafts, as compared with those for surgical grafts (approximately $6,400 according to literature data). C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Vasc Surg, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. Erasmus Univ, Dept Epidemiol & Biostat, Ctr Med, NL-3000 DR Rotterdam, Netherlands. RP Bosch, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 0 Emerson Pl,Suite 2H, Boston, MA 02114 USA. NR 22 TC 41 Z9 41 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2001 VL 220 IS 2 BP 492 EP 497 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 454TW UT WOS:000169988700032 PM 11477259 ER PT J AU Gallaher, CK Hough, S AF Gallaher, CK Hough, S TI Ethnicity and age issues: Attitudes affecting rehabilitation of individuals with spinal cord injury SO REHABILITATION PSYCHOLOGY LA English DT Article ID PREJUDICE AB The individual with spinal cord injury, fan-Lily, staff, and significant others bring attitudes regarding age and ethnicity into the rehabilitation team dynamic. Such preconceived attitudes may direct one's ability to be open to change and incorporate new information. The authors present 3 cases that highlight the bidirectional nature of bias challenges and the potential impact of bias issues on the hospital setting, staff, individual, family, and significant others. The bidirectional nature of bias challenges is illustrated with 2 cases of bias issues presented by individuals with spinal cord injury during hospitalization and with 1 case of bias impact on an individual health care provider. Interventions and strategies to maximize information sharing, education, and adjustment during hospitalization, discharge planning, and community living are discussed. Individuals may face increasing challenges in maximizing the derived benefit from both health care delivery and community services if personal bias plays a role in excluding qualified personnel from consideration. C1 Vet Affairs Boston Healthcare Syst, Spinal Cord Injury Serv, W Roxbury, MA 02132 USA. Vet Affairs Boston Healthcare Syst, Psychol Serv, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. RP Hough, S (reprint author), Vet Affairs Boston Healthcare Syst, Spinal Cord Injury Serv, W Roxbury Campus,1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 28 TC 8 Z9 8 U1 0 U2 3 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0090-5550 J9 REHABIL PSYCHOL JI Rehabil. Psychol. PD AUG PY 2001 VL 46 IS 3 BP 312 EP 321 DI 10.1037/0090-5550.46.3.312 PG 10 WC Psychology, Clinical; Rehabilitation SC Psychology; Rehabilitation GA 472DZ UT WOS:000170969400010 ER PT J AU Bigelow, CE Harkrider, CJ Conover, DL Foster, TH Georgakoudi, I Mitra, S Nichols, MG Rajadhyaksha, M AF Bigelow, CE Harkrider, CJ Conover, DL Foster, TH Georgakoudi, I Mitra, S Nichols, MG Rajadhyaksha, M TI Retrofitted confocal laser scanner for a commercial inverted fluorescence microscope SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article AB We describe the design and implementation of an inverted laser scanning confocal fluorescence microscope utilizing the commercial Nikon Diaphot TMD platform. An external confocal scanner was retrofitted through the video side port of the Diaphot. With 10x, 0.5 NA dry and 60x, 1.4 NA oil immersion objectives, the depth discrimination is 5.8 mum and 0.8 mum, respectively, as determined by derivatives of fluorescence edge responses measured in liquid samples of rhodamine 6G dissolved in DMSO. We present sample edge response curves and representative confocal fluorescence images of tumor cells in monolayer culture. (C) 2001 American Institute of Physics. C1 Univ Rochester, Inst Opt, Rochester, NY 14627 USA. Univ Rochester, Dept Radiol, Rochester, NY 14642 USA. Univ Rochester, Inst Opt, Dept Radiol, Rochester, NY 14642 USA. Univ Rochester, Dept Phys & Astron, Rochester, NY 14642 USA. Univ Rochester, Dept Biochem & Biophys, Rochester, NY 14642 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02114 USA. RP Bigelow, CE (reprint author), Opt Coating Lab Inc, 2789 Northpoint Pkwy, Santa Rosa, CA 95407 USA. OI Nichols, Michael/0000-0002-6565-6743 NR 7 TC 13 Z9 13 U1 0 U2 1 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD AUG PY 2001 VL 72 IS 8 BP 3407 EP 3410 DI 10.1063/1.1382637 PG 4 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 455UV UT WOS:000170046900036 ER PT J AU Brand, KP Catalano, PJ Hammitt, JK Rhomberg, L Evans, JS AF Brand, KP Catalano, PJ Hammitt, JK Rhomberg, L Evans, JS TI Limitations to empirical extrapolation studies: The case of BMD ratios SO RISK ANALYSIS LA English DT Article DE noncancer risk assessment; relative potency; experimental design; uncertainty analysis; calibration; censoring; Monte Carlo simulation ID ADVERSE-EFFECT LEVELS; NATIONAL TOXICOLOGY PROGRAM; DOSE-RESPONSE ASSESSMENT; RISK ASSESSMENT; TOXICITY DATA; DEVELOPMENTAL TOXICITY; ANIMAL CARCINOGENICITY; SELECTION; BIOASSAY; DESIGNS AB Extrapolation relationships are of keen interest to chemical risk assessment in which they play a prominent role in translating experimentally derived (usually in animals) toxicity estimates into estimates more relevant to human populations. A standard approach for characterizing each extrapolation relies on ratios of pre-existing toxicity estimates. Applications of this "ratio approach" have overlooked several sources of error. This article examines the case of ratios of benchmark doses, trying to better understand their informativeness. The approach involves mathematically modeling the process by which the ratios are generated in practice. Both closed form and simulation-based models of this "data-generating process" (DGP) are developed, paying special attention to the influence: of experimental design. The results show the potential for significant limits to informativeness, and revealing dependencies. Future applications of the ratio approach should take imprecision and bias into account. Bootstrap techniques are recommended for gauging imprecision, but more complicated techniques will be required for gauging bias (and capturing dependencies). Strategies for mitigating the errors are suggested. C1 Univ Ottawa, Fac Med, Ottawa, ON K1H 8M8, Canada. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Ctr Risk Anal, Boston, MA 02115 USA. Gradient Corp, Cambridge, MA 02138 USA. RP Brand, KP (reprint author), Univ Ottawa, Inst Populat Hlth, 451 Smyth Rd, Ottawa, ON K1H 8M8, Canada. NR 52 TC 7 Z9 7 U1 0 U2 3 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0272-4332 J9 RISK ANAL JI Risk Anal. PD AUG PY 2001 VL 21 IS 4 BP 625 EP 640 DI 10.1111/0272-4332.214140 PG 16 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 490PJ UT WOS:000172060000006 PM 11726017 ER PT J AU Young, RH AF Young, RH TI Guest editor's introduction - Ovarian tumors: Perplexing patterns, perspicacious pathologists SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Editorial Material ID CELL C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Young, RH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. NR 42 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 2001 VL 18 IS 3 BP 155 EP 160 PG 6 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 468NT UT WOS:000170764100002 PM 11554664 ER PT J AU Young, RH Scully, RE AF Young, RH Scully, RE TI Differential diagnosis of ovarian tumors based primarily on their patterns and cell types SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE ovarian tumors; ovarian tumor-like lesions; pathologic differential diagnosis; histologic patterns; cell types; immunohistochemistry ID IMMUNOHISTOCHEMICAL ANALYSIS; CARCINOMAS; INHIBIN; EXPRESSION; ORIGIN AB The differential diagnosis of ovarian tumors is reviewed based on their patterns and cell types. This approach, which differs from the standard textbook discussion of each neoplasm as an entity, has practical value as differential diagnosis depends largely on the pattern or patterns and cell type or types of tumors. Awareness of the broad range of lesions that may exhibit particular patterns or contain one or more cell types is crucial in formulating a differential diagnosis. The following patterns are considered: moderate-to-large-glandular and hollow-tubular; solid tubular and pseudotubular; cords and ribbons; insular; trabecular; slit-like and reticular spaces; microglandular and microfollicular; macrofollicular and pseudomacrofollicular; papillary; diffuse; fibromatous-thecomatous; and biphasic and pseudobiphasic. The following cell types are considered: small round cells; spindle cells; mucinous cells, comprising columnar, goblet cell and signet ring cell subtypes; clear cells; hobnail cells; oxyphil cells; and transitional cells. The morphologic diversity of ovarian tumors poses many challenges; knowledge of the occurrence and frequency of these patterns and cell types in various tumors and tumor-like lesions is of paramount diagnostic importance. A specific diagnosis can usually be made by evaluating routinely stained slides, but much less often, special staining, immunohistochemical staining or, very rarely, ultrastructural examination is also required. Finally, clinical data, operative findings, and gross features of the lesions may provide important, and at times decisive diagnostic clues. Copyright (C) 2001 by W.B. Saunders Company. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Young, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA 02114 USA. NR 36 TC 64 Z9 71 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 2001 VL 18 IS 3 BP 161 EP 235 PG 75 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 468NT UT WOS:000170764100003 PM 11554665 ER PT J AU Roodman, GD AF Roodman, GD TI Studies in Paget's disease and their relevance to oncology SO SEMINARS IN ONCOLOGY LA English DT Article; Proceedings Paper CT Roundtable Discussion Meeting Update on the Role of Bisphosphonates in Metastases CY DEC 05, 2000 CL SAN ANTONIO, TEXAS ID OSTEOCLAST DIFFERENTIATION FACTOR; BONE-MARROW CELLS; BREAST-CANCER; SKELETAL COMPLICATIONS; MULTIPLE-MYELOMA; DOUBLE-BLIND; IN-VITRO; INTERLEUKIN-6; EXPRESSION; PAMIDRONATE C1 Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med Hematol, San Antonio, TX USA. RP Roodman, GD (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. NR 31 TC 16 Z9 17 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 SU 11 BP 15 EP 21 DI 10.1053/sonc.2001.25442 PG 7 WC Oncology SC Oncology GA 470HX UT WOS:000170866500004 PM 11544571 ER PT J AU Sparano, JA Winer, EP AF Sparano, JA Winer, EP TI Liposomal anthracyclines for breast cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID STERICALLY STABILIZED LIPOSOMES; PHASE-II TRIAL; KAPOSIS-SARCOMA; POLYETHYLENE-GLYCOL; ENCAPSULATED DOXORUBICIN; CARCINOMA XENOGRAFTS; ANTITUMOR-ACTIVITY; IN-VITRO; PHARMACOKINETICS; THERAPY C1 Montefiore Med Ctr, Weiler Div, Dept Oncol, Bronx, NY 10461 USA. Dana Farber Canc Inst, Adult Oncol Dept, Boston, MA 02115 USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Weiler Div, Dept Oncol, 2 South,1825 Eastchester Rd, Bronx, NY 10461 USA. NR 55 TC 41 Z9 41 U1 3 U2 8 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 SU 12 BP 32 EP 40 DI 10.1053/sonc.2001.26436 PG 9 WC Oncology SC Oncology GA 472MW UT WOS:000170988800006 PM 11552228 ER PT J AU Oh, WK George, DJ Kaufman, DS Moss, K Smith, MR Richie, JP Kantoff, PW AF Oh, WK George, DJ Kaufman, DS Moss, K Smith, MR Richie, JP Kantoff, PW TI Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: A preliminary report SO SEMINARS IN ONCOLOGY LA English DT Review ID PHASE-I TRIAL; CHEMOTHERAPY; MITOXANTRONE; ESTRAMUSTINE; THERAPY; MEN C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Adult Oncol, Boston, MA 02114 USA. Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. RP Oh, WK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, Boston, MA 02115 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 20 TC 39 Z9 42 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 SU 15 BP 40 EP 44 DI 10.1016/S0093-7754(01)90153-8 PG 5 WC Oncology SC Oncology GA 480VM UT WOS:000171483500007 PM 11685727 ER PT J AU Beer, TM Hough, KM Garzotto, M Lowe, BA Henner, WD AF Beer, TM Hough, KM Garzotto, M Lowe, BA Henner, WD TI Weekly high-dose calcitriol and docetaxel in advanced prostate cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID VITAMIN-D-RECEPTOR; PHASE-II TRIAL; CELL-LINES; ORAL ESTRAMUSTINE; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; PLATINUM DRUGS; D ANALOGS; GROWTH; ETOPOSIDE C1 Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Beer, TM (reprint author), Oregon Hlth Sci Univ, Dept Med, Mail Code L586,3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. FU NCRR NIH HHS [3M01RR00334-33S2] NR 54 TC 52 Z9 53 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 SU 15 BP 49 EP 55 DI 10.1016/S0093-7754(01)90155-1 PG 7 WC Oncology SC Oncology GA 480VM UT WOS:000171483500009 PM 11685729 ER PT J AU Burstein, HJ Bunnell, CA Winer, EP AF Burstein, HJ Bunnell, CA Winer, EP TI New cytotoxic agents and schedules for advanced breast cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID PHASE-II TRIAL; FIRST-LINE CHEMOTHERAPY; LIPOSOME-ENCAPSULATED DOXORUBICIN; HIGH-DOSE CHEMOTHERAPY; HER2/NEU-OVEREXPRESSING METASTATIC BREAST; CONTINUOUS INTRAVENOUS-INFUSION; THYMIDYLATE SYNTHASE INHIBITOR; STEM-CELL TRANSPLANTATION; CLINICAL SCREENING GROUP; ORAL ETOPOSIDE C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [5T32 CA09172-24] NR 164 TC 20 Z9 20 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 BP 344 EP 358 DI 10.1053/sonc.2001.26146 PG 15 WC Oncology SC Oncology GA 461WQ UT WOS:000170387200005 PM 11498829 ER PT J AU Ang, P Garber, JE AF Ang, P Garber, JE TI Genetic susceptibility for breast cancer - Risk assessment and counseling SO SEMINARS IN ONCOLOGY LA English DT Review ID PEUTZ-JEGHERS-SYNDROME; PROGESTIN-REPLACEMENT THERAPY; EPITHELIAL OVARIAN-CANCER; POPULATION-BASED SAMPLE; ASHKENAZI JEWISH WOMEN; ORAL-CONTRACEPTIVE USE; SINGLE BRCA2 MUTATION; FAMILY-HISTORY; PROPHYLACTIC OOPHORECTOMY; ATAXIA-TELANGIECTASIA C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore. RP Garber, JE (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 131 TC 13 Z9 13 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2001 VL 28 IS 4 BP 419 EP 433 DI 10.0153/sonc.2001.26152 PG 15 WC Oncology SC Oncology GA 461WQ UT WOS:000170387200010 PM 11498834 ER PT J AU Littner, M Kushida, CA Hartse, K Anderson, WM Davila, D Johnson, SF Wise, MS Hirshkowitz, M Woodson, BT AF Littner, M Kushida, CA Hartse, K Anderson, WM Davila, D Johnson, SF Wise, MS Hirshkowitz, M Woodson, BT TI Practice parameters for the use of laser-assisted uvulopalatoplasty: An update for 2000 SO SLEEP LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; CARBON-DIOXIDE LASER; OUTPATIENT TREATMENT; UVULOPALATOPHARYNGOPLASTY; COMPLICATIONS; SURGERY; CO2-LASER; PALATE; UPPP AB Laser-assisted uvulopalatoplasty (LAUP) is an outpatient surgical procedure which is in use as a treatment for snoring. LAUP also has been used as a treatment for sleep-related breathing disorders, including obstructive sleep apnea. The Standards of Practice Committee of the American Academy of Sleep Medicine reviewed the available literature, and developed these practice parameters as a guide to the appropriate use of this surgery. Adequate controlled studies on the LAUP procedure for sleep-related breathing disorders were not found in peer-reviewed journals. This is consistent with findings in the original practice parameters on LAUP published in 1994. The following recommendations are based on the review of the literature: LAUP is not recommended for treatment of sleep-related breathing disorders. However, it does appear to be comparable to uvulopalatopharyngoplasty (UPPP) for treatment of snoring. Individuals who are candidates for LAUP as a treatment for snoring should undergo a polysomnographic or cardiorespiratory evaluation for sleep-related breathing disorders prior to LAUP and periodic postoperative evaluations for the development of same. Patients should be informed of the best available information of the risks, benefits, and complications of the procedure. C1 VA Greater Los Angeles Healthcare Syst, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Med, Sepulveda, CA USA. Stanford Univ, Ctr Excellence Sleep Disorders, Stanford, CA 94305 USA. Sleep Consultants Inc, Ft Worth, TX USA. Univ S Florida, Coll Med, Tampa, FL USA. Baptist Med Ctr, Little Rock, AR USA. St Patrick Hosp Sleep Ctr, Missoula, MT USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. Baylor Coll Med, Houston VAMC Sleep Disorders & Res, Houston, TX 77030 USA. Med Coll Wisconsin, Dept Otolaryngol & Commun Sci, Milwaukee, WI 53226 USA. RP Littner, M (reprint author), Amer Acad Sleep Med, Stand Practice Comm, 6301 Bandel Rd,Suite 101, Rochester, MN 55901 USA. NR 56 TC 61 Z9 63 U1 0 U2 1 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD AUG 1 PY 2001 VL 24 IS 5 BP 603 EP 619 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 454KU UT WOS:000169972400011 PM 11480657 ER PT J AU Dighton, J Mascarenhas, M Arbuckle-Keil, GA AF Dighton, J Mascarenhas, M Arbuckle-Keil, GA TI Changing resources: assessment of leaf litter carbohydrate resource change at a microbial scale of resolution SO SOIL BIOLOGY & BIOCHEMISTRY LA English DT Article DE leaf litter; decomposition; microscopic FT-IR; carbohydrates ID FT-IR SPECTROSCOPY; INFRARED-SPECTROSCOPY; SPECTRA; TISSUES AB Studies of chemical changes in leaf litter resources during decomposition have relied upon bulk litter analysis using wet chemistry. We introduce, here, the use of microscopic Fourier transform infrared spectroscopy (Fr-IR) to evaluate changes in the carbohydrate chemistry of leaf litters at the scale of resolution relevant to the study of microbes (mum) and the use of sequential, non-destructive sampling of the same point. We demonstrate some of the discriminatory power of the method and follow the effect of enzymatic degradation of leaf material which reflects changes in carbohydrate chemistry during natural decomposition and in the presence of a saprotrophic fungus. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Rutgers State Univ, Pinelands Field Stn, New Lisbon, NJ 08064 USA. Massachusetts Gen Hosp East, Pulm Res Lab, Charlestown, MA 02129 USA. Rutgers State Univ, Dept Chem, Camden, NJ 08102 USA. RP Dighton, J (reprint author), Rutgers State Univ, Pinelands Field Stn, 501 4 Mile Rd,POB 206, New Lisbon, NJ 08064 USA. NR 15 TC 13 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0038-0717 J9 SOIL BIOL BIOCHEM JI Soil Biol. Biochem. PD AUG PY 2001 VL 33 IS 10 BP 1429 EP 1432 DI 10.1016/S0038-0717(01)00047-5 PG 4 WC Soil Science SC Agriculture GA 464LJ UT WOS:000170533800015 ER PT J AU Keck, T Balcom, JH Antoniu, BA Lewandrowski, K Warshaw, AL Fernandez-del Castillo, C AF Keck, T Balcom, JH Antoniu, BA Lewandrowski, K Warshaw, AL Fernandez-del Castillo, C TI Regional effects of nafamostat, a novel potent protease and complement inhibitor, on severe necrotizing pancreatitis SO SURGERY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the Society-of-University-Surgeons CY FEB 08-10, 2001 CL CHICAGO, ILLINOIS SP Soc Univ Surgeons ID GABEXATE MESILATE; ACTIVATION; THERAPY; FUT-175; RATS; CELL AB Background. We evaluated the effect of the novel protease inhibitor nafamostat on rat necrotizing pancreatitis through different routes of administration. Methods. Three hours after the induction of severe pancreatitis, the rats received intravenous gabexate or intravenous or local mesenteric intra-arterial nafamostat. At 9 hours, ascites and bronchoalveolar lavage fluid were collected for the evaluation of capillary leakage (Evans blue extravasation). Pancreas and lung were excised for histologic features, myeloperoxidase, and trypsinogen activation peptide. Twenty-four hour survival was evaluated. Results. Only the intravenous infusion of nafamostat significantly reduced myeloperoxidase (11.7 +/-2.3 vs 18.3 +/-1.8 mU/mg; P<.05) and capillary leakage in lungs (Evans blue dye, 1.60.3 vs 2.6 +/-0.3; P<.05). Only intra-arterial infusion of nafamostat significantly diminished capillary peritoneal leakage (Evans blue dye, 3.60.9 vs 9.4 +/-0.4; P<.01). Typsinogen activation peptide levels were significantly reduced in all groups, but only intra-arterial infusion did so to baseline. Histologic inflammation in the pancreas was most significantly reduced after intra-arterial infusion (0.920.08 vs 2.91 +/-0.06; P<.05). No form of protease inhibition reduced mortality rates. Conclusions. The effects of protease inhibition depend on the route of administration. Nafamostat has maximal effects on the pancreas and peritoneal capillary leakage when delivered by way of local intraarterial infusion, and shows a greater reduction of lung leukocyte infiltration and capillary leakage by the intravenous route. Nafamostat is more effective than gabexate. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,WACC 336, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,WACC 336, 55 Fruit St, Boston, MA 02114 USA. NR 25 TC 24 Z9 25 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2001 VL 130 IS 2 BP 175 EP 181 DI 10.1067/msy.2001.115827 PG 7 WC Surgery SC Surgery GA 463FF UT WOS:000170465600008 PM 11490346 ER PT J AU Borges, LF AF Borges, LF TI Reoperation rates for acute graft extrusion and pseudarthrosis after one-level anterior corpectomy and fusion with and without plate instrumentation: Etiology and corrective management - Commentary SO SURGICAL NEUROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Borges, LF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-3019 J9 SURG NEUROL JI Surg. Neurol. PD AUG PY 2001 VL 56 IS 2 BP 81 EP 81 DI 10.1016/S0090-3019(01)00528-6 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 479VG UT WOS:000171423800005 ER PT J AU Munafo, M Rigotti, N Lancaster, T Stead, L Murphy, M AF Munafo, M Rigotti, N Lancaster, T Stead, L Murphy, M TI Interventions for smoking cessation in hospitalised patients: a systematic review SO THORAX LA English DT Review DE smoking cessation; inpatients ID ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CLINICAL-TRIAL; NICOTINE; DISEASE; REPLACEMENT; EFFICACY; PROGRAM AB Background-An admission to hospital provides an opportunity to help people stop smoking. Individuals may be more open to help at a time of perceived vulnerability, and may find it easier to quit in an environment where smoking is restricted or prohibited. Providing smoking cessation services during hospitalisation may help more people to attempt and sustain an attempt to quit. The purpose of this paper is to systematically review the effectiveness of interventions for smoking cessation in hospitalised patients. Methods-We searched the Cochrane Tobacco Addiction Group register, CINAHL, and the Smoking and Health database for studies of interventions for smoking cessation in hospitalised patients. Randomised and quasi-randomised trials of behavioural, pharmacological, or multicomponent interventions to help patients stop smoking conducted with hospitalised patients who were current smokers or recent quitters were included. Studies of patients admitted for psychiatric disorders or substance abuse, those that did not report abstinence rates, and those with follow up of less than 6 months were,excluded. Two of the authors extracted data independently for each paper, with assistance from others. Results-Intensive intervention (inpatient contact plus follow up for at least 1 month) was associated with a significantly higher cessation rate compared with controls (Peto odds ratio (OR) 1.82, 95% CI 1.49 to 2.22). Any contact during hospitalisation followed by minimal follow up failed to detect a statistically significant effect on cessation rate, but did not rule out a 30% increase in smoking cessation (Peto OR 1.09, 95% CI 0.91 to 1.31). There was insufficient evidence to judge the effect of interventions delivered only during the hospital stay. Although the interventions increased quit rates irrespective of whether nicotine replacement therapy (NRT) was used, the results for NRT were compatible with other data indicating that it increases quit rates. There was no strong evidence that clinical diagnosis affected the likelihood of quitting. Conclusions-High intensity behavioural interventions that include at least I month of follow up contact are effective in promoting smoking cessation in hospitalised patients. C1 Univ Oxford, ICRF Gen Practice Res Grp, Oxford OX3 7LF, England. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Munafo, M (reprint author), Univ Oxford, ICRF Gen Practice Res Grp, Oxford OX3 7LF, England. OI Munafo, Marcus/0000-0002-4049-993X NR 33 TC 35 Z9 38 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD AUG PY 2001 VL 56 IS 8 BP 656 EP 663 DI 10.1136/thorax.56.8.656 PG 8 WC Respiratory System SC Respiratory System GA 456XF UT WOS:000170107500014 PM 11462070 ER PT J AU Li, CZ Zhang, J Jiang, YP Gurewich, V Chen, YH Liu, JN AF Li, CZ Zhang, J Jiang, YP Gurewich, V Chen, YH Liu, JN TI Urokinase-type plasminogen activator up-regulates its own expression by endothelial cells and monocytes via the u-PAR pathway SO THROMBOSIS RESEARCH LA English DT Article DE urokinase; monocytes; endothelial cells; u-PAR; expression ID SINGLE-CHAIN UROKINASE; MOLECULAR-WEIGHT UROKINASE; SIGNAL-TRANSDUCTION; TISSUE-TYPE; 2-CHAIN UROKINASE; INTESTINAL-TRACT; GROWTH-FACTOR; RECEPTOR; BINDING; INHIBITOR AB Signal transduction by urokinase-type plasminogen activator (u-PA) bound to its cell receptor has been well established. In the present study, we found, for the first time to our knowledge, that u-PA promotes its own synthesis by endothelial cells and monocytes. This phenomenon was characterized and shown to involve the u-PA receptor (u-PAR) pathway. The finding may be of general importance, since most cells that express u-PAR also produce u-PA. Human umbilical vein endothelial cells (HUVECs), U937 monocytes, and human peripheral blood monocytes (PFMCs) were incubated with diisopropylfluorophosphate (DFP)-pretreated u-PA, the amino-terminal fragment (ATF) of u-PA, or the kringle domain. A threefold up-regulation of u-PA secretion and synthesis by u-PA or ATF was found. The predominant effect was expressed in HUVECs, in which u-PA mRNA was also up-regulated. The u-PA kringle domain had no effect on u-PA synthesis, leading to the conclusion that the EGF domain was responsible. This was also consistent with the additional finding that the u-PAR, to which the EGF domain binds, was necessary for the up-regulation. The results indicate that u-PA up-regulates itself via its EGF domain and u-PAR. The possibilities that the results were related to displacement of receptor-bound u-PA or the blocking of u-PA incorporation into the cells were excluded. A modest up-regulation of u-PAR was also associated with this phenomenon. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Vasc Res Lab, Boston, MA 02215 USA. Nanjing Univ, Inst Mol Med, Nanjing 10008, Peoples R China. RP Liu, JN (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Vasc Res Lab, 21-27 Burlington,BIDMC,POB 15709, Boston, MA 02215 USA. NR 39 TC 13 Z9 17 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD AUG 1 PY 2001 VL 103 IS 3 BP 221 EP 232 DI 10.1016/S0049-3848(01)00322-X PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 462KZ UT WOS:000170420400007 PM 11672584 ER PT J AU Hasirci, V Berthiaume, F Bondre, SP Gresser, JD Trantolo, DJ Toner, M Wise, DL AF Hasirci, V Berthiaume, F Bondre, SP Gresser, JD Trantolo, DJ Toner, M Wise, DL TI Expression of liver-specific functions by rat hepatocytes seeded in treated poly( lactic-co-glycolic) acid biodegradable foams SO TISSUE ENGINEERING LA English DT Article ID FULMINANT HEPATIC-FAILURE; BIOARTIFICIAL LIVER; SANDWICH CONFIGURATION; 3-DIMENSIONAL CULTURE; ASSIST DEVICE; COLLAGEN GEL; MAINTENANCE; SUPPORT; MATRIX; CELLS AB Techniques of liver replacement would benefit patients awaiting donor livers and may be a substitute for transplantation in patients whose livers can regenerate. Poly(lactic-co-glycolic acid) (PLGA) copolymers are biodegradable and have been shown to be useful as scaffolds for seeding and culturing various types of cells. In this study, foam disks were prepared from PLGA (lactic-to-glycolic mole ratio of 85:15) by lyophilization of benzene (5% w/v) solutions. These disks were then used as scaffolds for rat hepatocyte culture. Foams were coated with either a type I collagen gel (0.1% w/v), coated with gelatin (5% w/v), or treated with oxygen plasma (25 W, 90 s) to modify their surface chemistry and wettability. The disks were then seeded with rat hepatocytes (10(6)/mL) and cultured for a period of 2 weeks. All surface treatments resulted in increased hydrophilicity, the greatest being obtained by collagen treatment (contact angle, < 10), and a minimal decrease in void fraction (5%). DNA content after a 2-week culture period increased proportionally with the wettability of the treated foam surface. Urea synthesis in untreated foams averaged 15.3 +/- 62.3 mug/h/ mg DNA, which was significantly higher than that for controls, whereas gelatin and collagen treated foams exhibited urea synthetic rates below the control levels at all times. The DNA content decreased significantly by about 50% between days 1 and 12. PLGA foams, treated and untreated, represent a promising scaffold for scaling up hepatocyte cultures. C1 Cambridge Sci Inc, Cambridge, MA 02138 USA. Middle E Tech Univ, Biotechnol Res Ctr, Dept Biol Sci, TR-06531 Ankara, Turkey. Northeastern Univ, Dept Chem Engn, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Ctr Engn Med, Boston, MA USA. RP Trantolo, DJ (reprint author), Cambridge Sci Inc, 180 Fawcett St, Cambridge, MA 02138 USA. NR 51 TC 50 Z9 53 U1 3 U2 8 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD AUG PY 2001 VL 7 IS 4 BP 385 EP 394 DI 10.1089/10763270152436445 PG 10 WC Cell & Tissue Engineering SC Cell Biology GA 459EL UT WOS:000170238000003 PM 11506728 ER PT J AU Ruprecht, RM Hofmann-Lehmann, R Smith-Franklin, BA Rasmussen, RA Liska, V Vlasak, J Xu, W Baba, TW Chenine, AL Cavacini, LA Posner, MR Katinger, H Stiegler, G Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Montefiori, DC McClure, HM AF Ruprecht, RM Hofmann-Lehmann, R Smith-Franklin, BA Rasmussen, RA Liska, V Vlasak, J Xu, W Baba, TW Chenine, AL Cavacini, LA Posner, MR Katinger, H Stiegler, G Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Montefiori, DC McClure, HM TI Protection of neonatal macaques against experimental SHIV infection by human neutralizing monoclonal antibodies SO TRANSFUSION CLINIQUE ET BIOLOGIQUE LA English DT Article DE neutralizing monoclonal antibodies against HIV oral transmission; passive immunization; rhesus monkeys; simian-human immunodeficiency virus ID HUMAN-IMMUNODEFICIENCY-VIRUS; COMPLEMENT-MEDIATED LYSIS; SYNERGISTIC NEUTRALIZATION; RHESUS-MONKEYS; IN-VIVO; ENVELOPE GLYCOPROTEIN; HIV-1 INFECTION; TYPE-1; COMBINATIONS; TRANSMISSION AB Neonatal macaques were completely protected against oral challenge with SHIV-vpu(+), a simian-human immunodeficiency virus that encodes the envelope gene of a laboratory-adapted HIV strain, by pre- and post-natal treatment with a triple combination of human neutralizing monoclonal antibodies (mAbs). The mAbs were directed either against the CD4 binding site, a glycosylation-dependent gp120 epitope, or against a linear epitope on gp41. This triple combination was highly synergistic in vitro and neutralized primary HIV completely. Subsequently, oral challenge was performed with pathogenic SHIV89.6P, an animal-passaged variant of a chimeric virus that encodes the envelope gene of the primary, dual-tropic HIV89.6. Only post-natal treatment with a similar triple mAb combination was used. One out of 4 mAb-treated infants was completely protected from infection. In the other 3 treated animals, there was a tendency towards lower peak viral RNA loads compared with untreated controls. Two out of 4 mAb-treated infants maintained normal CD4(+) T-cell numbers, in contrast to all controls that had steep declines at 2 weeks post-challenge. We conclude that the triple mAb combination significantly protected the neonates, even against mucosal challenge with pathogenic SHIV89.6P. Passively administered synergistic human mAbs may play a role in preventing mother-infant transmission of HIV, both against intrapartum transmission as well as against infection through breast milk. As passive immunization is a tool to assess correlates of immune protection, we conclude that the epitopes recognized by the mAbs in our combinations are important for AIDS vaccine development. Future passive immunization studies may reveal other important conserved epitopes. (C) 2001 Editions scientifiques et medicales Elsevier SAS. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Tufts Univ, Sch Med, Div Newborn Med, Dept Pediat, Boston, MA 02111 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Inst Appl Microbiol, A-1190 Vienna, Austria. Univ Texas, MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX 78602 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30329 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Hofmann-Lehmann, Regina/C-6528-2009 FU NCRR NIH HHS [RR-00165]; NIAID NIH HHS [R21 AI46177, R01 AI34266, R01 AI26926, P01 AI48240] NR 38 TC 34 Z9 35 U1 1 U2 6 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1246-7820 J9 TRANSFUS CLIN BIOL JI Transfu. Clin. Biol. PD AUG PY 2001 VL 8 IS 4 BP 350 EP 358 DI 10.1016/S1246-7820(01)00187-2 PG 9 WC Hematology; Immunology SC Hematology; Immunology GA 479RT UT WOS:000171417900003 PM 11642027 ER PT J AU Aronson, AJ Glaspy, JA Reddy, ST Reese, D Heber, D Bagga, D AF Aronson, AJ Glaspy, JA Reddy, ST Reese, D Heber, D Bagga, D TI Modulation of omega-3/omega-6 polyunsaturated ratios with dietary fish oils in men with prostate cancer SO UROLOGY LA English DT Article ID FATTY-ACIDS; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; CARCINOMA-CELLS; MESSENGER-RNA; IN-VITRO; EXPRESSION; RISK; CYCLOOXYGENASE-2; CONSUMPTION; GROWTH AB Objectives. The results of epidemiologic and animal studies support the role of a low-fat diet supplemented with omega-3 fatty acids contained in fish oil in preventing the development and progression of prostate cancer. As a first step in studying the role of a low-fat, fish oil-supplemented (LF/FOS) diet in a clinical setting, we conducted a prospective study in men with untreated prostate cancer to evaluate whether a 3-month dietary intervention affects the ratio of omega-3 to omega-6 fatty acids in plasma and gluteal fat, In addition, we evaluated the feasibility of studying cyclooxygenase-2 (COX-2) expression in serial prostate needle biopsy specimens before and after the diet. Methods. Nine men with untreated prostate cancer consumed an LF/FOS diet for 3 months. Plasma, gluteal adipose tissue, and prostate needle biopsy specimens were obtained from each patient before and after the intervention. The fatty acid compositions of the plasma and gluteal adipose tissue were determined by gas-liquid chromatography, and the COX-2 expression in the prostatic tissue specimens was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Results. Short-term intervention with an LF/FOS diet caused a significant increase in the omega-3/omega-6 fatty acid ratio in plasma (P = 0.002) and gluteal adipose tissue (P = 0.002) in men with prostate cancer. The COX-2 expression in prostatic tissue was quantitated by RT-PCR in 7 of 9 patients, and COX-2 expression decreased in 4 of these 7 patients. Conclusions. A short-term dietary intervention in men with prostate cancer leads to a significant increase in the omega-3/omega-6 fatty acid ratios in plasma and adipose tissue. The potential for this diet to prevent the development and progression of prostate cancer by way of altered COX-2 expression and prostaglandin production in prostatic tissue requires further study. UROLOGY 58: 283-288, 2001. (C) 2001, Elsevier Science Inc. C1 Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Div Cardiol, Los Angeles, CA 90024 USA. Univ Calif San Francisco, Dept Med, Urol Oncol Program, Ctr Comprehens Canc, San Francisco, CA USA. Univ Calif Los Angeles, Sch Med, Ctr Human Nutr, Los Angeles, CA USA. RP Aronson, AJ (reprint author), Univ Calif Los Angeles, Sch Med, Dept Urol, 66-124 Ctr Hlth Sci,Box 951738, Los Angeles, CA 90095 USA. NR 29 TC 20 Z9 22 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD AUG PY 2001 VL 58 IS 2 BP 283 EP 288 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 460GW UT WOS:000170300700041 ER PT J AU Teranishi, K Alwayn, I Buhler, L Gollackner, B Knosalla, C Correa, L Sachs, D Katopodis, A Awwad, M Cooper, D AF Teranishi, K Alwayn, I Buhler, L Gollackner, B Knosalla, C Correa, L Sachs, D Katopodis, A Awwad, M Cooper, D TI Depletion of natural antibody in baboons by continuous infusion of Gal type 2 and type 6 oligosaccharides SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Novartis Pharma, Basel, Switzerland. Immerge BioTherapeut, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 18 BP 4 EP 5 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800011 ER PT J AU Cretin-Buhler, N Hanson, K Iacomini, J AF Cretin-Buhler, N Hanson, K Iacomini, J TI Immunoglobulin transgenic and knock-in mice expressing anti-alpha Gal reactive antibodies SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 21 BP 5 EP 5 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800014 ER PT J AU Teranishi, K Manez, R Awwad, M Cooper, D AF Teranishi, K Manez, R Awwad, M Cooper, D TI Anti-Gal alpha 1-3Gal IgM and IgG antibody levels in sera of humans and old world non-human primates SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Cambridge, MA 02138 USA. Univ A Coruna, Hlth Inst, La Coruna, Spain. Juan Canalejo Med Ctr, La Coruna, Spain. Immerge BioTherapeut, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 39 BP 12 EP 12 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800032 ER PT J AU Teranishi, K Bracy, J Kurilla-Mahon, B Zhu, S Patience, C Sachs, D Cooper, D Down, J Iacomini, J AF Teranishi, K Bracy, J Kurilla-Mahon, B Zhu, S Patience, C Sachs, D Cooper, D Down, J Iacomini, J TI Exploratory studies of efficiency of gene transduction in baboons and rhesus monkeys SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Cambridge, MA 02138 USA. Biotransplant Inc, Charlestown, MA USA. Immerge BioTherapeut, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 41 BP 12 EP 13 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800034 ER PT J AU Mueller, NJ Barth, RN Yamamoto, S LaMattina, J Kumagai, N Kitamura, H Awwad, M Cooper, DKC Sachs, DH Yamada, K AF Mueller, NJ Barth, RN Yamamoto, S LaMattina, J Kumagai, N Kitamura, H Awwad, M Cooper, DKC Sachs, DH Yamada, K TI Species specificity of baboon and porcine-derived cytomegalovirus (CMV) infection in pig-to-primate xenotransplantation: molecular assays SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, ID Div, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Immerge BioTherapeut, Charlestown, MA USA. RI Barth, Rolf/B-2542-2014; LaMattina, John/B-2976-2014; Mueller, Nicolas/B-6864-2013 OI LaMattina, John/0000-0001-7016-0382; Mueller, Nicolas/0000-0002-1059-3191 NR 0 TC 5 Z9 5 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 50 BP 15 EP 16 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800042 ER PT J AU Gollackner, B Goh, SK Daniel, S Buhler, L DeAngelis, H Awaad, M Cooper, D Robson, S AF Gollackner, B Goh, SK Daniel, S Buhler, L DeAngelis, H Awaad, M Cooper, D Robson, S TI Porcine endothelial cell tissue factor (TF)-induction by baboon xenoreactive antibodies in vitro: evidence for pathogenic role of non-Gal elicited antibodies SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Immerge BioTherapeut, Charlestown, MA USA. Beth Israel Deaconess Hosp, Ctr Immunobiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 64 BP 21 EP 21 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800056 ER PT J AU Iacomini, J AF Iacomini, J TI Tolerance to alpha-Gal epitopes SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 74 BP 23 EP 24 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800064 ER PT J AU Yamamoto, S Barth, RN LaMattina, JC Kumagai, N Kitamura, H Correa, L Awwad, M Sykes, M Cooper, DKC Sachs, DH AF Yamamoto, S Barth, RN LaMattina, JC Kumagai, N Kitamura, H Correa, L Awwad, M Sykes, M Cooper, DKC Sachs, DH TI Role of T cell depletion in rejection responses of pig-to-primate thymokidney xenotransplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. Immerge BioTherapeut, Charlestown, MA USA. RI Barth, Rolf/B-2542-2014; LaMattina, John/B-2976-2014 OI LaMattina, John/0000-0001-7016-0382 NR 0 TC 3 Z9 4 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 76 BP 24 EP 25 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800066 ER PT J AU Barth, RN Mueller, N Yamamoto, S LaMattina, J Kumagai, N Kitamura, H Moran, S Awwad, M Cooper, DKC Sachs, DH AF Barth, RN Mueller, N Yamamoto, S LaMattina, J Kumagai, N Kitamura, H Moran, S Awwad, M Cooper, DKC Sachs, DH TI Cytomegalovirus (CMV) infection in pig-to-primate xenotransplantation: clinical manifestations SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA USA. RI Barth, Rolf/B-2542-2014; LaMattina, John/B-2976-2014; Mueller, Nicolas/B-6864-2013 OI LaMattina, John/0000-0001-7016-0382; Mueller, Nicolas/0000-0002-1059-3191 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 106 BP 35 EP 36 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800096 ER PT J AU Koulmanda, M Qipo, A Smith, RN Auchincloss, H AF Koulmanda, M Qipo, A Smith, RN Auchincloss, H TI Autoimmune destruction versus xenograft rejection of islet transplants in non-obese diabetic (NOD) mice SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, HMS, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 121 BP 38 EP 38 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800104 ER PT J AU Wu, A Barth, RN Yamamoto, S Kumagai, N Huck, J Awwad, M Sykes, M Cooper, DKC Sachs, DH Yamada, K AF Wu, A Barth, RN Yamamoto, S Kumagai, N Huck, J Awwad, M Sykes, M Cooper, DKC Sachs, DH Yamada, K TI Avoidance of humoral sensitization after thymic tissue Xenotransplantation in a pig-to-baboon model SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, HMS, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Immerge BioTherapeut, Charlestown, MA USA. RI Barth, Rolf/B-2542-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 127 BP 40 EP 41 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800110 ER PT J AU Abe, M Qi, J Sykes, M Yang, YG AF Abe, M Qi, J Sykes, M Yang, YG TI Tolerance induction across a highly disparate xenogeneic barrier by bone marrow transplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 145 BP 46 EP 46 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800125 ER PT J AU Bracy, J Chase, CM Russel, PS Colvin, RB Iacomini, J AF Bracy, J Chase, CM Russel, PS Colvin, RB Iacomini, J TI Induction of molecular chimerism by gene therapy prevents antibody mediated heart transplant rejection SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 146 BP 47 EP 47 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800126 ER PT J AU Barth, RN Yamamoto, S LaMattina, JC Kumagai, N Kitamura, H DeAngelis, H Awwad, M Sykes, M Cooper, DKC Sachs, DH AF Barth, RN Yamamoto, S LaMattina, JC Kumagai, N Kitamura, H DeAngelis, H Awwad, M Sykes, M Cooper, DKC Sachs, DH TI Xenogeneic thymokidney transplantation in a pig-to-baboon model: T cell reconstitution and induction of donor-specific T cell unresponsiveness SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Immerge BioTherapeut, Charlestown, MA USA. RI Barth, Rolf/B-2542-2014; LaMattina, John/B-2976-2014 OI LaMattina, John/0000-0001-7016-0382 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 150 BP 48 EP 48 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800130 ER PT J AU Buhler, L Kurilla-Mahon, B Chang, Q Alwayn, I Appel, J Awwad, M Sachs, DH White-Scharf, ME Cooper, DKC Down, JD AF Buhler, L Kurilla-Mahon, B Chang, Q Alwayn, I Appel, J Awwad, M Sachs, DH White-Scharf, ME Cooper, DKC Down, JD TI Factors influencing engraftment of porcine hematopoietic progenitor cells in non-human primates SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. BioTransplant Inc, Charlestown, MA USA. Immerge BioTherapeut Inc, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 149 BP 48 EP 48 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800129 ER PT J AU Buhler, L Deng, S Koulmanda, M O'Neil, J Awwad, M Sachs, DH Weir, G Squifflet, JP Cooper, DKC Morel, P AF Buhler, L Deng, S Koulmanda, M O'Neil, J Awwad, M Sachs, DH Weir, G Squifflet, JP Cooper, DKC Morel, P TI Adult porcine islet transplantation in non-human primates treated with no or conventional immunosuppression or a non-myeloablative regimen and CD154 blockade SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Univ Hosp Geneva, Geneva, Switzerland. Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. Immerge BioTherapeut, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 155 BP 50 EP 50 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800135 ER PT J AU Gollackner, B Knosalla, C Teranishi, K Kawai, T Buhler, L Mauiyyedi, S Barth, R Sachs, D Awaad, M Cooper, D AF Gollackner, B Knosalla, C Teranishi, K Kawai, T Buhler, L Mauiyyedi, S Barth, R Sachs, D Awaad, M Cooper, D TI Synthetic Gal oligosaccharides (BSA-Gal) prevent kidney graft rejection but cause liver necrosis when combined with cyclophosphamide in a pig-to-baboon model SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Transplantat, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Immerge BioTherapeut Inc, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 161 BP 52 EP 53 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800141 ER PT J AU Knosalla, C Gollackner, B Teranishi, K Buhler, L Mauiyyedi, S Yamamoto, S Barth, RN Awwad, M Sachs, DH Cooper, DKC AF Knosalla, C Gollackner, B Teranishi, K Buhler, L Mauiyyedi, S Yamamoto, S Barth, RN Awwad, M Sachs, DH Cooper, DKC TI Organ-specific differences in pig kidney and heart transplantation in baboons: absence of DIC after heart transplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Immerge BioTherapeut Inc, Boston, MA USA. RI Barth, Rolf/B-2542-2014 NR 0 TC 1 Z9 1 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 172 BP 56 EP 57 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800151 ER PT J AU Teranishi, K Robson, S Romano, E Cooper, D Apitz, R AF Teranishi, K Robson, S Romano, E Cooper, D Apitz, R TI Suppression of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoene SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Ctr Immunol, Boston, MA USA. Inst Venezolano Invest Cient, Caracas, Venezuela. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 300 BP 62 EP 62 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800162 ER PT J AU Teranishi, K Treter, S Awwad, M Cooper, D AF Teranishi, K Treter, S Awwad, M Cooper, D TI Methotrexate is an ineffective immunosuppressive agent in baboons SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Immerge BioTherapeut, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 410 BP 80 EP 80 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800214 ER PT J AU Buhler, L Zhu, A Cooper, DKC AF Buhler, L Zhu, A Cooper, DKC TI Induced anti-pig antibodies in baboons: absence of antibodies directed to non-Gal carbohydrate determinants SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 430 BP 88 EP 88 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800234 ER PT J AU Cretin-Buhler, N Bracy, J Hanson, K Iacomini, J AF Cretin-Buhler, N Bracy, J Hanson, K Iacomini, J TI The role of T cell help in the generation of alpha Gal reactive antibodies SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 434 BP 89 EP 89 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800238 ER PT J AU Gollackner, B Ryan, D Knosalla, C Alwayn, I Harper, D Correa, L Mauiyyedi, S Awaad, M Cooper, D AF Gollackner, B Ryan, D Knosalla, C Alwayn, I Harper, D Correa, L Mauiyyedi, S Awaad, M Cooper, D TI An investigation of arsenic trioxide (As2O3) in the suppression of anti-Gal antibody in baboons SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. Immerge Biotherapeut Inc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 448 BP 94 EP 94 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800252 ER PT J AU Bracy, J Kaye, J Hanson, K Iacomini, J AF Bracy, J Kaye, J Hanson, K Iacomini, J TI Engraftment of transduced bone marrow cells expressing alpha Gal in presensitized hosts SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Tansplantat Biol Res Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 546 BP 112 EP 112 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800306 ER PT J AU McMorrow, IM LeGuern, C AF McMorrow, IM LeGuern, C TI A molecular switch for T cell silencing SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 552 BP 114 EP 114 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800312 ER PT J AU Kawahara, T Ohdan, H Zhao, G Sykes, M AF Kawahara, T Ohdan, H Zhao, G Sykes, M TI Early and late mechanisms of anti-Gal-producing B cell tolerance induced by mixed chimerism SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Hiroshima Univ, Dept Surg 2, Hiroshima, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 556 BP 115 EP 116 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800316 ER PT J AU Benatuil, L Fernandez, AZ Apitz-Castro, R Cooper, DKC Romano, E AF Benatuil, L Fernandez, AZ Apitz-Castro, R Cooper, DKC Romano, E TI Pig peripheral blood mononuclear cells are a major factor in the development of the thrombotic microangiopathy that complicates procedures designed to induce chimerism in pig-to-baboon xenotransplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 IVIC, Ctr Med Expt, Caracas, Venezuela. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 602 BP 117 EP 117 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800319 ER PT J AU Appel, JZ Newman, D Awwad, M Gray, HSK Down, JD Cooper, DKC Robson, SC AF Appel, JZ Newman, D Awwad, M Gray, HSK Down, JD Cooper, DKC Robson, SC TI Activation of human endothelial cells by mobilized porcine leukocytes in vitro: implications for mixed chimerism in xenotransplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Immerge BioTherapeut Inc, Charlestown, MA USA. BioTransplant Inc, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 611 BP 120 EP 120 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800328 ER PT J AU Gollackner, B Huck, J Knosalla, C Teranishi, K Buhler, L Correa, L Robson, S Sachs, D Cooper, D AF Gollackner, B Huck, J Knosalla, C Teranishi, K Buhler, L Correa, L Robson, S Sachs, D Cooper, D TI Unexpected changes in lipid metabolism after kidney and heart transplantation in the pig-to-baboon model SO XENOTRANSPLANTATION LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Hosp, Ctr Immunobiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 SU 1 MA 639 BP 130 EP 130 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 477XD UT WOS:000171308800355 ER PT J AU Alwayn, IPJ Xu, YX Basker, M Wu, C Buhler, L Lambrigts, D Treter, S Harper, D Kitamura, H Vitetta, ES Abraham, S Awwad, M White-Scharf, ME Sachs, DH Thall, A Cooper, DKC AF Alwayn, IPJ Xu, YX Basker, M Wu, C Buhler, L Lambrigts, D Treter, S Harper, D Kitamura, H Vitetta, ES Abraham, S Awwad, M White-Scharf, ME Sachs, DH Thall, A Cooper, DKC TI Effects of specific anti-B and/or anti-plasma cell immunotherapy on antibody production in baboons: depletion of CD20-and CD22-positive B cells does not result in significantly decreased production of anti-alpha Gal antibody SO XENOTRANSPLANTATION LA English DT Article ID COMBINED IMMUNODEFICIENT MICE; DISSEMINATED DAUDI LYMPHOMA; PORCINE BONE-MARROW; MONOCLONAL-ANTIBODY; ANTI-GAL-ALPHA-1-3GAL ANTIBODY; ANTI-CD22 IMMUNOTOXIN; IMMUNOAFFINITY COLUMN; TOLERANCE INDUCTION; NATURAL ANTIBODIES; IN-VITRO AB Anti-Gal alpha1-3Gal antibodies (anti alpha Gal Ab) are a major barrier to clinical xenotransplantation as they are believed to initiate both hyperacute and acute humoral rejection. Extracorporeal immunoadsorption (EIA) with alpha Gal oligosaccharide columns temporarily depletes anti-alpha Gal Ab, but their return is ultimately associated with graft destruction. We therefore assessed the ability of two immunotoxins (IT) and two monoclonal antibodies (mAb) to deplete B and/or plasma cells both in vitro and in vivo in baboons, and to observe the rate of return of anti alpha Gal Ab following EIA. The effects of the mouse anti-human IT anti-CD22-ricin A (proportional to CD22-IT, directed against a B cell determinant) and anti-CD38-ricin A (proportional to CD38-IT, B and plasma cell determinant) and the mouse anti-human anti-CD38 mAb (proportional to CD38 mAb) and mouse/human chimeric anti-human anti-CD20 (alpha CD20 mAb, Rituximab, B cell determinant) on B and plasma cell depletion and anti alpha Gal Ab production were assessed both in vitro and in vivo in baboons (n=9) that had previously undergone splenectomy. For comparison, two baboons received nonmyeloablative whole body irradiation (WBI) (300 cGy), and one received myeloablative WBI (900 cGy). Depletion of B cells was monitored by flow cytometry of blood, bone marrow (BM) and lymph nodes (LNG, staining with anti-CD20 and/or anti-CD22 mAbs, and by histology of LN. EIA was carried out after the therapy and anti alpha Gal Ab levels were measured daily. In vitro proportional to CD22-IT inhibited protein synthesis in the human Daudi B cell line more effectively than proportional to CD38-IT. Upon differentiation of B cells into plasma cells, however, less inhibition of protein synthesis after proportional to CD22-IT treatment was observed. Depleting CD20-positive cells in vitro from a baboon spleen cell population already depleted of granulocytes, monocytes, and T cells led to a relative enrichment of CD20-negative cells, that is plasma cells, and consequently resulted in a significant increase in anti alpha Gal Ab production by the remaining cells, whereas depleting CD38-positive cells resulted in a significant decrease in anti alpha Gal Ab production. In vivo, WBI (300 or 900 cGy) resulted in 100% B cell depletion in blood and BM,> 80% depletion in LN, with substantial recovery of B cells after 21 days and only transient reduction in anti alpha Gal Ab after EIA. proportional to CD22-IT depleted B cells by > 97% in blood and BM, and by 60% in LN, but a rebound of B cells was observed after 14 and 62 days in LN and blood, respectively. At 7 days, serum anti alpha Gal IgG and IgM Ab levels were reduced by a maximum of 40-45% followed by a rebound to levels up to 12-fold that of baseline anti alpha Gal Ab by day 83 in one baboon. The results obtained with proportional to CD38-IT were inconclusive. This may have been, in part, due to inadequate conjugation of the toxin. Cell coating was 100% with proportional to CD38 mAb, but no changes in anti alpha Gal Ab production were observed. proportional to CD20 mAb resulted in 100% depletion of B cells in blood and BM and 80% in LN, with recovery of B cells starting at day 42. Adding 150cGy WBI at this time led to 100% depletion of B cells in the BM and LN. Although B cell depletion in blood and BM persisted for >3 months, the reduction of serum anti alpha Gal IgG or IgM Ab levels was not sustained beyond 2 days. proportional to CD20 mAb+WBI totally and efficiently depleted CD20- and CD22-positive B cells in blood, BM, and LN for >3 months in vivo, but there was no sustained clinically significant reduction in serum anti alpha Gal Ab. The majority of antibody secretors are CD38-positive cells, but targeting these cells in vitro or in vivo with alpha CD38-IT was not very effective. These observations suggest that CD20-and CD22-positive B cells are not the major source of anti alpha Gal Ab production. Future efforts will be directed towards suppression of plasma cell function. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. BioTransplant Inc, Boston, MA USA. Univ Texas, SW Med Ctr, Ctr Canc Immunobiol, Dallas, TX 75235 USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH East,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 49 TC 43 Z9 44 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 IS 3 BP 157 EP 171 DI 10.1034/j.1399-3089.2001.008003157.x PG 15 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 456NP UT WOS:000170089200008 PM 11472623 ER PT J AU Rosenzweig, M Yamada, K Harper, DM Hempel, DM Johnson, RP AF Rosenzweig, M Yamada, K Harper, DM Hempel, DM Johnson, RP TI T-cell differentiation of human and non-human primate CD34(+) hematopoietic progenitor cells using porcine thymic stroma SO XENOTRANSPLANTATION LA English DT Article DE porcine; T-cell differentiation; thymus; xenogeneic ID IMMUNODEFICIENCY-VIRUS-INFECTION; IN-VITRO; ANTIRETROVIRAL THERAPY; THYMOCYTE DEPLETION; POSITIVE SELECTION; BONE-MARROW; MOUSE; MHC; GRAFTS; HIV-1 AB Transplantation of swine thymic tissue has been proposed as an approach to reconstitute the immune system of HIV-infected individuals. This is an attractive strategy because miniature swine are readily available as donors and porcine tissue is resistant to infection with HIV-1. Demonstration that porcine thymus tissue supports primate T-cell differentiation is critical to the ultimate utility of this approach. Using a thymic stroma culture system we have previously described [Rosenzweig M, Marks DF, Zhu H et al. In vitro T lymphopoiesis of human and rhesus CD34+ progenitor cells. Blood 1996; 87: 4040], we demonstrate that porcine thymus tissue is able to promote the in vitro T-lymphocyte differentiation of both human and non-human primate hematopoietic progenitor cells. CD34(+) hematopoietic progenitors differentiated into both double positive (CD4(+)CD8(+)) and single positive thymocytes expressing CD4 or CD8 alone. A polyclonal T-cell repertoire was evident. In addition, the T cells responded appropriately to mitogen and were permissive to infection with simian immunodeficiency virus (SIV). These data demonstrate the ability of porcine thymus to support T-cell differentiation of both human and non-human hematopoietic progenitor cells and support in vivo studies of transplantation of swine thymic tissue as a strategy for immune reconstitution in AIDS. C1 Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Immunol, Southborough, MA 01772 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Rosenzweig, M (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Immunol, 1 Pine Hill Dr,POB 9102, Southborough, MA 01772 USA. NR 29 TC 2 Z9 2 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2001 VL 8 IS 3 BP 185 EP 192 DI 10.1111/j.1399-3089.2001.00106.x PG 8 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 456NP UT WOS:000170089200011 PM 11472626 ER PT J AU Pellman, D AF Pellman, D TI Polarizing attachments: connecting microtubules to the membrane and kinetochore. SO YEAST LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD AUG PY 2001 VL 18 SU 1 BP S13 EP S13 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 462WE UT WOS:000170442100008 ER PT J AU Nghiem, P Park, PK Kim, YS Vaziri, C Schreiber, SL AF Nghiem, P Park, PK Kim, YS Vaziri, C Schreiber, SL TI ATR inhibition selectively sensitizes G(1) checkpoint-deficient cells to lethal premature chromatin condensation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DNA-DAMAGE CHECKPOINT; PIK-RELATED KINASES; CYCLE CHECKPOINTS; MAMMALIAN-CELLS; PROTEIN-KINASE; REPLICATION; PHOSPHORYLATION; CAFFEINE; EXPRESSION; MITOSIS AB Premature chromatin condensation (PCC) is a hallmark of mammalian cells that begin mitosis before completing DNA replication. This lethal event is prevented by a highly conserved checkpoint involving an unknown, caffeine-sensitive mediator. Here, we have examined the possible involvement of the caffeine-sensitive ATM and ATR protein kinases in this check point. We show that caffeine's ability to inhibit ATR (but not ATM) causes PCC, that ATR (but not ATM) prevents PCC, and that ATR prevents PCC via Chk-1 regulation. Moreover, mimicking cancer cell phenotypes by disrupting normal Gt checkpoints sensitizes cells to PCC by ATR inhibition plus tow-dose DNA damage. Notably, loss of p53 function potently sensitizes cells to PCC caused by ATR inhibition by a small molecule. We present a molecular model for how ATR prevents PCC and suggest that ATR represents an attractive therapeutic target for selectively killing cancer cells by premature chromatin condensation. C1 Harvard Univ, Howard Hughes Med Inst, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Cutaneous Oncol Unit, Boston, MA 02115 USA. Boston Univ, Canc Res Ctr, Boston, MA 02118 USA. RP Schreiber, SL (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X FU NIAMS NIH HHS [K08-AR0208703]; NIGMS NIH HHS [GM-52067] NR 27 TC 203 Z9 203 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 31 PY 2001 VL 98 IS 16 BP 9092 EP 9097 DI 10.1073/pnas.161281798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458VV UT WOS:000170216900033 PM 11481475 ER PT J AU Wyatt, LW Chung, CY Carlsen, B Iida-Klein, A Rudkin, GH Ishida, K Yamaguchi, DT Miller, TA AF Wyatt, LW Chung, CY Carlsen, B Iida-Klein, A Rudkin, GH Ishida, K Yamaguchi, DT Miller, TA TI Bone morphogenetic protein-2 (BMP-2) and transforming growth factor-beta 1 (TGF-beta 1) alter connexin 43 phosphorylation in MC3T3-E1 Cells SO BMC CELL BIOLOGY LA English DT Article ID GAP JUNCTIONAL COMMUNICATION; INTER-CELLULAR COMMUNICATION; INTERCELLULAR COMMUNICATION; OSTEOBLASTIC CELLS; INVITRO; DIFFERENTIATION; CALVARIA; DEFECTS AB Background: Bone morphogenetic proteins (BMPs) and transforming growth factor-betas (TGF-betas) are important regulators of bone repair and regeneration. BMP-2 and TGF-beta1 have been shown to inhibit gap junctional intercellular communication (GJIC) in MC3T3-E1 cells. Connexin 43 ( Cx43) has been shown to mediate GJIC in osteoblasts and it is the predominant gap junctional protein expressed in these murine osteoblast-like cells. We examined the expression, phosphorylation, and subcellular localization of Cx43 after treatment with BMP-2 or TGF-beta1 to investigate a possible mechanism for the inhibition of GJIC. Results: Northern blot analysis revealed no detectable change in the expression of Cx43 mRNA. Western blot analysis demonstrated no significant change in the expression of total Cx43 protein. However, significantly higher ratios of unphosphorylated vs. phosphorylated forms of Cx43 were detected after BMP-2 or TGF-beta1 treatment. Immunofluorescence and cell protein fractionation revealed no detectable change in the localization of Cx43 between the cytosol and plasma membrane. Conclusions: BMP-2 and TGF-beta1 do not alter expression of Cx43 at the mRNA or protein level. BMP-2 and TGF-beta1 may inhibit GJIC by decreasing the phosphorylated form of Cx43 in MC3T3-E1 cells. C1 VA Greater Los Angeles Healthcare Syst, Plast Surg Sect, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, GRECC, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90024 USA. RP Miller, TA (reprint author), VA Greater Los Angeles Healthcare Syst, Plast Surg Sect, Los Angeles, CA 90073 USA. FU NIA NIH HHS [F32-AG05708-01, F32 AG005708] NR 30 TC 11 Z9 13 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUL 30 PY 2001 VL 2 AR 14 DI 10.1186/1471-2121-2-14 PG 6 WC Cell Biology SC Cell Biology GA 501NF UT WOS:000172690200001 PM 11504560 ER PT J AU Johnson, DC AF Johnson, DC TI A role for phosphodiesterase type-4 inhibitors in COPD? SO LANCET LA English DT Editorial Material ID OBSTRUCTIVE PULMONARY-DISEASE; TRIAL C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Johnson, DC (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. NR 15 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 28 PY 2001 VL 358 IS 9278 BP 256 EP 257 DI 10.1016/S0140-6736(01)05493-9 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 457AF UT WOS:000170114400004 PM 11498207 ER PT J AU Cole, BF Gelber, RD Gelber, S Coates, AS Goldhirsch, A AF Cole, BF Gelber, RD Gelber, S Coates, AS Goldhirsch, A TI Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis SO LANCET LA English DT Article ID ADJUVANT CHEMOTHERAPY; METAANALYSIS; LIFE AB Background Overview analysis involving 18 000 women with breast cancer in 47 randomised trials showed that prolonged chemotherapy significantly reduces the risk of relapse and death compared with no chemotherapy. Here we express the size of the benefit in terms of quality-adjusted survival time gained. Methods We used the Q-TWIST method (Quality-adjusted Time Without Symptoms of disease and Toxicity of treatment) to provide treatment comparisons within 10 years' follow-up, incorporating differences in quality of life associated with times patients spend with chemotherapy toxic effects, after relapse, and without symptoms of relapse or toxicity. Findings Within 10 years' follow-up the benefit of increased relapse-free and overall survival for younger women (<50 years old) who received polychemotherapy balanced the burdens in terms of acute toxic side-effects, especially among women enrolled in trials that did not include tamoxifen. Overall, chemotherapy-treated younger women gained an average of 10.3 months of relapse-free survival and 5.4 months of overall survival within 10 years (p<0.0001 for both) compared with the no-chemotherapy group. Polychemotherapy provided more quality-adjusted time than control across nearly all values of utility weights for time spent undergoing chemotherapy and time after relapse. The range of benefit was from -0.6 to 10.3 months. For older women (50-69 years) overall, polychemotherapy also provided significant benefit compared with no chemotherapy but, compared with younger women, the size of benefit was less and the range of utility-weight values favouring polychemotherapy was smaller. Average gains for older women treated with polychemotherapy (with or without tamoxifen) were 6.8 months of relapse-free survival (p<0.0001) and 2.9 months of overall survival (p=0.0001) within 10 years. The range of quality-adjusted benefit was -3.1 to 6.8 months. For older women with oestrogen-receptor-poor tumours who did not receive tamoxifen (9% of the total), the benefit of polychemotherapy was significant and similar to that observed for younger women. Interpretation The benefits of adjuvant chemotherapy within 10 years outweigh the burdens especially for younger women (<50 years old) and among older women (50-69 years) to a lesser degree. Additional studies to compare the quality-adjusted survival of chemotherapy plus endocrine therapy versus endocrine therapy alone are required for younger patients with tumours that express steroid-hormone receptors. C1 Dartmouth Coll, Sch Med, Dartmouth Hitchcock Med Ctr, Lebanon, NH 03756 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Frontier Sci & Technol Res Fdn, Boston, MA USA. Australian Canc Soc, Sydney, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. European Inst Oncol, Milan, Italy. RP Cole, BF (reprint author), Dartmouth Coll, Sch Med, Dartmouth Hitchcock Med Ctr, 7927 Rubin Bldg, Lebanon, NH 03756 USA. FU NCI NIH HHS [CA-06516, CA-75362] NR 21 TC 86 Z9 88 U1 0 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 28 PY 2001 VL 358 IS 9278 BP 277 EP 286 DI 10.1016/S0140-6736(01)05483-6 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 457AF UT WOS:000170114400011 PM 11498214 ER PT J AU Grammatikakis, N Jaronczyk, K Siganou, A Vultur, A Brownell, HL Benzaquen, M Rausch, C Lapointe, R Gjoerup, O Roberts, TM Raptis, L AF Grammatikakis, N Jaronczyk, K Siganou, A Vultur, A Brownell, HL Benzaquen, M Rausch, C Lapointe, R Gjoerup, O Roberts, TM Raptis, L TI Simian virus 40 large tumor antigen modulates the Raf signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LARGE T-ANTIGEN; SV40 LARGE T; SIMIAN-VIRUS-40 LARGE-T; FULL NEOPLASTIC TRANSFORMATION; J-DOMAIN; DNA-REPLICATION; GENE ACTIVITY; INTACT-CELLS; POLYOMAVIRUS; ACTIVATION AB The large tumor antigen of simian virus 40 (SVLT) is a potent oncogene. Although inactivation of the p53 and pRb tumor suppressors has been causally linked to the transforming properties of SVLT, its exact mechanism of action remains undefined. Previous data indicated that Ras is activated in SVLT-expressing cells. In this report we show that SVLT also increases Raf kinase activity in both insect and mammalian cells, thus identifying the Raf kinase as an additional target of SVLT. Our results further show that SVLT was still able to activate Raf in cells where Ras levels had been drastically reduced through expression of an antisense construct, indicating that SVLT may activate Raf at least partly by a mechanism that is independent of its stimulatory effect on Ras. C1 Queens Univ, Dept Microbiol & Immunol, Kingston, ON K7L 3N6, Canada. Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. Queens Univ, Dept Pathol, Kingston, ON K7L 3N6, Canada. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Raptis, L (reprint author), Queens Univ, Dept Microbiol & Immunol, Botterell Hall,Rm 715, Kingston, ON K7L 3N6, Canada. NR 36 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 27 PY 2001 VL 276 IS 30 BP 27840 EP 27845 DI 10.1074/jbc.M101987200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 456QH UT WOS:000170093400015 PM 11382757 ER PT J AU Huggins, GS Bacani, CJ Boltax, J Aikawa, R Leiden, JM AF Huggins, GS Bacani, CJ Boltax, J Aikawa, R Leiden, JM TI Friend of GATA 2 physically interacts with chicken ovalbumin upstream promoter-TF2 (COUP-TF2) and COUP-TF3 and represses COUP-TF2-dependent activation of the atrial natriuretic factor promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ZINC-FINGER PROTEIN; NUCLEAR ORPHAN RECEPTORS; LIGAND-BINDING DOMAIN; HEART TUBE FORMATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; VENTRAL MORPHOGENESIS; TERMINAL DOMAIN; N-COR; FOG-2 AB Friend of GATA (FOG)-2 is a multi-zinc finger transcriptional corepressor protein that binds specifically to GATA4. Gene targeting studies have demonstrated that FOG-2 is required for normal cardiac morphogenesis, including the development of the coronary vasculature, left ventricular compact zone, and heart valves. To better understand the molecular mechanisms by which FOG-2 regulates these cardiac developmental programs, we screened a mouse day 11 embryo library using a yeast two-hybrid interaction trap with the fifth and sixth zinc fingers of FOG-2 as bait. Using this approach, we isolated clones encoding the orphan nuclear receptors chicken ovalbumin upstream promoter-transcription factor (COUP-TF) 2 and COUP-TF3. COUP-TF2-null embryos die during embryonic development with defective angiogenesis and cardiac defects, a pattern that partly resembles the FOG-2-null phenotype. The interaction between COUP-TF2 and FOG-2 in mammalian cells was confirmed by co-immunoprecipitation of these proteins from transfected COS-7 cells. The sites of binding interaction between COUP-TF2 and FOG-2 were mapped to zinc fingers 5 and 6 and fingers 7 and 8 of FOG-2 and to the carboxyl terminus of the COUP-TF proteins. Binding to COUP-TF2 was specific because FOG-2 did not interact with the ligand-binding domains of retinoid X receptor alpha, glucocorticoid receptor, and peroxisome proliferating antigen receptor gamma, which are related to the COUP-TF proteins. Full-length FOG-2 markedly enhanced transcriptional repression by GAL4-COUP-TF2(117-414), but not by a COUP-TF2 repression domain mutant. Moreover, FOG-2 repressed COUP-TF2dependent synergistic activation of the atrial natriuretic factor promoter by both GATA4 and the FOG-2-independent mutant GATA4-E215K. Taken together, these findings suggest that FOG-2 functions as a corepressor for both GATA and COUP-TF proteins. C1 Harvard Univ, Sch Publ Hlth, Cardiovasc Biol Lab, Boston, MA 02115 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Abbott Labs, Abbott Pk, IL 60064 USA. RP Huggins, GS (reprint author), Harvard Univ, Sch Publ Hlth, Cardiovasc Biol Lab, 677 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [K08 HL03667-01A1, R01 HL054592, R01 HL54592-06] NR 46 TC 37 Z9 42 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 27 PY 2001 VL 276 IS 30 BP 28029 EP 28036 DI 10.1074/jbc.M103577200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 456QH UT WOS:000170093400039 PM 11382775 ER PT J AU Malkin, D Chilton-MacNeill, S Meister, LA Sexsmith, E Diller, L Garcea, RL AF Malkin, D Chilton-MacNeill, S Meister, LA Sexsmith, E Diller, L Garcea, RL TI Tissue-specific expression of SV40 in tumors associated with the Li-Fraumeni syndrome SO ONCOGENE LA English DT Article DE Li-Fraumeni syndrome; p53; SV40 polyomavirus; tumor initiation ID GERMLINE P53 MUTATIONS; WILD-TYPE P53; T-ANTIGEN; TRANSGENIC MICE; CHOROID-PLEXUS; BRAIN-TUMORS; CANCER; GENE; FAMILIES; SIMIAN-VIRUS-40 AB Inactivation of wild-type p53 tumor suppressor function is the primary mechanism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with germline p53 mutations. Tumors derived from LFS patients frequently retain the normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA tumor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS families, each of whom presented with multiple malignant neoplasms. Patient 1 developed an embryonal rhabdomyosarcoma (RMS) and a choroid plexus carcinoma (CPC), while patient 2 developed a CPC and subsequently presented with both an osteosarcoma (OS) and renal cell carcinoma (RCC). We utilized DNA sequence analysis and immunohistochemistry to determine p53 gene status in the germline and tumors, as well as evidence for SV40 T-antigen oncoprotein expression. Each patient harbored a heterozygous germline p53 mutation at codons 175 and 273, respectively. In patient 1, the normal p53 gene was lost while the mutant p53 allele was reduced to homozygosity in the RMS. Both normal and mutant genes were maintained in the CPC. In patient 2, normal and mutant p53 alleles were retained in both the CPC and RCC. Both specific PCR and immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addition to chromosomal alterations, epigenetic mechanisms may disrupt p53 function during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the normal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetically susceptible individuals. C1 Univ Toronto, Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. Joe DiMaggio Childrens Hosp, Div Pediat Hematol, Hollywood, FL USA. Dana Farber Canc Inst, Dept Pediat, Div Oncol, Boston, MA 02115 USA. Univ Colorado, Sch Med, Childrens Hosp, Dept Pediat,Sect Hematol Oncol, Denver, CO 80218 USA. RP Malkin, D (reprint author), Univ Toronto, Hosp Sick Children, Dept Pediat, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. NR 36 TC 44 Z9 45 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 27 PY 2001 VL 20 IS 33 BP 4441 EP 4449 DI 10.1038/sj.onc.1204583 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 456GN UT WOS:000170074900001 PM 11494139 ER PT J AU Hideshima, T Chauhan, D Schlossman, R Richardson, P Anderson, KC AF Hideshima, T Chauhan, D Schlossman, R Richardson, P Anderson, KC TI The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications SO ONCOGENE LA English DT Article DE TNF alpha; multiple myeloma; adhesion molecule; IL-6; NF-kappa B ID NF-KAPPA-B; MARROW STROMAL CELLS; ADHESION MOLECULES; INDUCED APOPTOSIS; PLASMA-CELLS; TNF-ALPHA; INTERLEUKIN-6; THALIDOMIDE; ACTIVATION; EXPRESSION AB In this study we demonstrate that tumor necrosis factor alpha (TNF alpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNF alpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNF alpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNF alpha -induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNF alpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU PHS HHS [P01 78378] NR 39 TC 250 Z9 266 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 27 PY 2001 VL 20 IS 33 BP 4519 EP 4527 DI 10.1038/sj.onc.1204623 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 456GN UT WOS:000170074900009 PM 11494147 ER PT J AU Kawai, T Sogawa, H Koulmanda, M Smith, RN O'Neil, JJ Wee, SL Boskovic, S Sykes, M Colvin, RB Sachs, DH Auchincloss, H Cosimi, AB Ko, DSC AF Kawai, T Sogawa, H Koulmanda, M Smith, RN O'Neil, JJ Wee, SL Boskovic, S Sykes, M Colvin, RB Sachs, DH Auchincloss, H Cosimi, AB Ko, DSC TI Long-term islet allograft function in the absence of chronic immunosuppression: A case report of a nonhuman primate previously made tolerant to a renal allograft from the same donor SO TRANSPLANTATION LA English DT Article ID MIXED ALLOGENEIC CHIMERISM; CYNOMOLGUS MONKEYS; INDUCTION; TRANSPLANTATION; SURVIVAL; REGIMEN AB Development of mixed chimerism by donor bone marrow transplantation (DBMT) has led to long-term tolerance of solid organ allografts in nonhuman primates. As an initial attempt to extend this approach to cellular transplant, islet transplant from the same donor was attempted in the recipient previously made tolerant to a kidney allograft. Methods. After the conditioning with ATG, total body irradiation, thymic irradiation, and splenectomy, DBMT was performed followed by 4 weeks of cyclosporine. Kidney transplantation and native nephrectomies were subsequently performed on day 89. After 2.8 years of DBMT, diabetes was induced by streptozocin (STZ) and islets from bone marrow and kidney donor were transplanted without immunosuppression. Results. After DBMT, the recipient developed chimerism and no evidence of kidney rejection for more than 1000 days. STZ induced diabetes was reversed after the islet transplantation. Islet biopsies demonstrated insulin staining without rejection. Although the recipient became diabetic 300 days after islet transplantation, viable transplanted islets were found in the liver and under the kidney capsule without any evidence of rejection. Conclusion. Tolerance with a nonmyeloablative conditioning can allow successful pancreatic islet transplantation without immunosuppression. Because no histological evidence of rejection was identified, recurrent diabetes is presumed to be inadequate islet mass. C1 Massachusetts Gen Hosp, Transplantat Unit, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Transplantat Unit, Dept Surg, White 510,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [P0I-HL18646]; NIAID NIH HHS [R01 AI037692, R01 AI037692-09, R0I AI37692-05] NR 10 TC 28 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 27 PY 2001 VL 72 IS 2 BP 351 EP 354 DI 10.1097/00007890-200107270-00036 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 461AK UT WOS:000170342600036 PM 11477369 ER PT J AU Llevadot, J Giugliano, RP Antman, EM AF Llevadot, J Giugliano, RP Antman, EM TI Bolus fibrinolytic therapy in acute myocardial infarction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR; RECOMBINANT STAPHYLOKINASE VARIANTS; DOSE-RANGING TRIAL; THROMBOLYTIC THERAPY; INTRACRANIAL HEMORRHAGE; T-PA; ALTERED IMMUNOREACTIVITY; CORONARY THROMBOLYSIS; THROMBIN INHIBITION; PLATELET ACTIVATION AB Context New bolus fibrinolytics derived from the human tissue-type plasminogen activator (tPA) have emerged as a means of dissolution of occlusive thrombosis associated with acute myocardial infarction. Objective To review the new bolus fibrinolytic drugs derived from tPA, reteplase, lanoteplase, and tenecteplase, Data Sources The MEDLINE, EMBASE, and Current Contents databases were searched for articles from 1983 to 2001, using the index terms pharmacokinetics, pharmacodynamics, plasminogen activator, reteplase, lanoteplase, and tenecteplase. Additional data sources included bibliographies of articles identified on MEDLINE, EMBASE, and Current Content, inquiry of experts and pharmaceutical companies, and preliminary data presented at recent national and international cardiology conferences. Study Selection We selected for review studies that evaluated the pharmacokinetics and pharmacodynamics of reteplase, lanoteplase, and tenecteplase, and assessed the effects of these bolus fibrinolytic drugs on the angiographic and immediate and long-term outcomes of patients, Of 138 articles identified, 38 were analyzed. Data Extraction Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting. Data Synthesis Tenecteplase and reteplase are comparable with accelerated infusion recombinant tPA in terms of efficacy and safety but more convenient because they are administered by bolus injection. Lanoteplase and heparin bolus plus infusion is as effective as tPA with regard to mortality, but the rate of intracranial hemorrhage is significantly higher. Conclusion Given the ease of administration and the similar outcomes compared with accelerated infusion recombinant tPA, it is likely that a key component of contemporary reperfusion will include a bolus fibrinolytic. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 333 Longwood Ave,Suite 402, Boston, MA 02115 USA. NR 71 TC 45 Z9 48 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 25 PY 2001 VL 286 IS 4 BP 442 EP 449 DI 10.1001/jama.286.4.442 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 456DZ UT WOS:000170069000016 PM 11466123 ER PT J AU Kuhlencordt, PJ Gyurko, R Han, F Scherrer-Crosbie, M Aretz, TH Hajjar, R Picard, MH Huang, PL AF Kuhlencordt, PJ Gyurko, R Han, F Scherrer-Crosbie, M Aretz, TH Hajjar, R Picard, MH Huang, PL TI Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice SO CIRCULATION LA English DT Article DE arteriosclerosis; nitric oxide synthase; coronary disease; aneurysm; hypertension ID APOE-DEFICIENT MICE; SMOOTH-MUSCLE; SUPEROXIDE GENERATION; FLUID-MECHANICS; IN-VITRO; GENE; ACETYLCHOLINE; ATHEROGENESIS; HYPERTENSION; ENDOTHELIUM AB Background-To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. Methods and Results-After 16 weeks of "Western-type" diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. Conclusions-eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Huang, PL (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, 149 E 13th St, Charlestown, MA 02129 USA. OI Picard, Michael/0000-0002-9264-3243 NR 34 TC 345 Z9 358 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 24 PY 2001 VL 104 IS 4 BP 448 EP 454 DI 10.1161/hc2901.091399 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 457BA UT WOS:000170116200015 PM 11468208 ER PT J AU Radant, A Tsuang, D Peskind, ER McFall, M Raskind, W AF Radant, A Tsuang, D Peskind, ER McFall, M Raskind, W TI Biological markers and diagnostic accuracy in the genetics of posttraumatic stress disorder SO PSYCHIATRY RESEARCH LA English DT Review DE startle reaction; hippocampus; comorbidity; heritability; hypothalamic hormones ID FAMILIAL ALZHEIMERS-DISEASE; URINARY CORTISOL EXCRETION; CORTICOTROPIN-RELEASING HORMONE; GLUCOCORTICOID RECEPTOR NUMBER; JUVENILE MYOCLONIC EPILEPSY; NATIONAL COMORBIDITY SURVEY; CHILDHOOD SEXUAL ABUSE; HIPPOCAMPAL VOLUME; VIETNAM VETERANS; RISK-FACTORS AB Family End twin studies suggest a substantial genetic contribution to the etiology of posttraumatic stress disorder (PTSD). Identification of the nature of this genetic contribution should enhance understanding of the pathophysiology of PTSD and suggest improved therapeutic strategies for its treatment. However, a broadly defined phenotype, specific requirement for an environmental exposure and high frequency of comorbid psychiatric illness all complicate genetic studies of PTSD, It is likely that genetic heterogeneity, incomplete penetrance, pleiotropy and the involvement of more than one gene all constitute formidable obstacles to the genetic analysis of PTSD. One way to circumvent these problems is to perform genetic analysis of traits associated with PTSD, rather than PTSD itself, an approach that has been fruitful for other diseases with complex modes of inheritance. Hypothalamic-pituitary-adrenal axis hypofunction, physiologic markers of increased arousal, and increased acoustic startle response are all potential PTSD-associated traits that might be susceptible to genetic analysis. However, the capacity of these traits to distinguish PTSD from non-PTSD patients and their familial pattern must be better defined before they can be employed in genetic studies. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 VA Med Ctr, Puget Sound Hlth Care Syst, Mental Hlth Serv,VA Puget Sound, Vet Affairs NE Network MIRECC, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Biobehav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. RP Radant, A (reprint author), VA Med Ctr, Puget Sound Hlth Care Syst, Mental Hlth Serv,VA Puget Sound, Vet Affairs NE Network MIRECC, 116-MHC,1660 S Columbian Way, Seattle, WA 98108 USA. RI Tsuang, Debby/L-7234-2016 OI Tsuang, Debby/0000-0002-4716-1894 NR 102 TC 27 Z9 27 U1 4 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 24 PY 2001 VL 102 IS 3 BP 203 EP 215 DI 10.1016/S0165-1781(01)00252-9 PG 13 WC Psychiatry SC Psychiatry GA 452JZ UT WOS:000169855700001 PM 11440771 ER PT J AU Yaffe, K Barnes, D Nevitt, M Lui, LY Covinsky, K AF Yaffe, K Barnes, D Nevitt, M Lui, LY Covinsky, K TI A prospective study of physical activity and cognitive decline in elderly women - Women who walk SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID AEROBIC EXERCISE; OLDER ADULTS; RISK-FACTORS; DEMENTIA; MEN; AGE; FRACTURE; DISEASE AB Background: Several studies have suggested that physical activity is positively associated with cognitive function in elderly persons. Evidence about this association has been limited by the cross-sectional design of most studies and by the frequent lack of adjustment for potential confounding variables. We determined whether physical activity is associated with cognitive decline in a prospective study of older women. Methods: We studied 5925 predominantly white community-dwelling women (aged greater than or equal to 65 years) who were recruited at 4 clinical centers and were without baseline cognitive impairment or physical limitations. We measured cognitive performance using a modified Mini-Mental State Examination at baseline and 6 to 8 years later. Physical activity was measured by self-reported blocks (1 block approximate to 160 m) walked per week and by total kilocalories (energy) expended per week in recreation, blocks walked, and stairs climbed. Cognitive decline was defined as a 3-point decline or greater on repeated modified Mini-Mental State Examination. Results: Women with a greater physical activity level at baseline were less likely to experience cognitive de dine during the 6 to 8 years of follow-up: cognitive decline occurred in 17%, 18%, 22%, and 24% of those in the highest, third, second, and lowest quartile of blocks walked per week (P < .001 for trend). Almost identical results were obtained by quartile of total kilocalories expended per week. After adjustment for age, educational level, comorbid conditions, smoking status, estrogen use, and functional limitation, women in the highest quartile remained less likely than women in the lowest quartile to develop cognitive decline (for blocks walked: odds ratio, 0.66 [95% confidence interval, 0.54-0.82]; for total kilocalories: odds ratio, 0.74 [95% confidence interval, 0.60-0.90]). Conclusions: Women with higher levels of baseline physical activity were less likely to develop cognitive decline. This association was not explained by differences in baseline function or health status. This finding supports the hypothesis that physical activity prevents cognitive decline in older community-dwelling women. C1 Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Univ Calif Berkeley, Dept Publ Hlth & Epidemiol, Berkeley, CA 94720 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Campus Box 111G,4150 Clement St, San Francisco, CA 94121 USA. FU NIA NIH HHS [AG05407, AG05394, K23-AG00888]; NIADDK NIH HHS [AM35584]; NIAMS NIH HHS [AR35582, AR35583] NR 30 TC 389 Z9 405 U1 1 U2 32 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2001 VL 161 IS 14 BP 1703 EP 1708 DI 10.1001/archinte.161.14.1703 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 453MY UT WOS:000169920700001 PM 11485502 ER PT J AU Hu, FB Stampfer, MJ Solomon, CG Liu, SM Willett, WC Speizer, FE Nathan, DM Manson, JE AF Hu, FB Stampfer, MJ Solomon, CG Liu, SM Willett, WC Speizer, FE Nathan, DM Manson, JE TI The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women - 20 years of follow-up SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; SEX-DIFFERENCES; CHOLESTEROL; RISK; PROGNOSIS; ONSET AB Background: Few data are available on the long-term impact of type 2 diabetes mellitus on total mortality and fatal coronary heart disease (CHD) in women. Methods: We examined prospectively the impact of type 2 diabetes and history of prior CHD on mortality from all causes and CHD among 121046 women aged 30 to 55 years with type 2 diabetes in the Nurses' Health Study who were followed up for 20 years from 1976 to 1996. Results: During 20 years of follow-up, we documented 8464 deaths from all causes, including 1239 fatal CHD events. Compared with women with no diabetes or CHD at baseline, age-adjusted relative risks (RRs) of overall mortality were 3.39 (95% confidence interval [CI], 3.08-3.73) for women with a history of diabetes and no CHD at baseline, 3.00 (95% CI, 2.50-3.60) for women with a history of CHD and no diabetes at baseline, and 6.84 (95% CI, 4.71-9.95) for women with both conditions at base- line. The corresponding age-adjusted RRs of fatal CHD across these 4 groups were 1.0, 8.70, 10.6, and 24.8, respectively. Multivariate adjustment for body mass index and other coronary risk factors only modestly attenuated the RRs. Compared with nondiabetic persons, the multivariate RRs of fatal CHD across categories of diabetes duration (less than or equal to5, 6-10, 11-15, 16-25, > 25 years) were 2.75,.3.63, 5.51, 6.38, and 11.9 (P < .001 for trend), respectively. The combination of prior CHD and a long duration of clinical diabetes tie, > 15 years) was associated with a 30-fold (95% CI, 20.7-43.5) increased risk of fatal CHD. Conclusions: Our data indicate that among women, history of diabetes is associated with dramatically increased risks of death from all causes and fatal CHD. :The combination of diabetes and prior CHD identifies particularly high-risk women. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Womens Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Diabet, Massachusetts Gen Hosp, Boston, MA USA. RP Hu, FB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Channing Lab, 665 Huntington Ave, Boston, MA 02115 USA. RI Liu, Simin/I-3689-2014 OI Liu, Simin/0000-0003-2098-3844 FU NCI NIH HHS [CA40356]; NHLBI NIH HHS [HL34594, HL24074] NR 27 TC 296 Z9 307 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2001 VL 161 IS 14 BP 1717 EP 1723 DI 10.1001/archinte.161.14.1717 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 453MY UT WOS:000169920700003 PM 11485504 ER PT J AU Shekelle, P Eccles, MP Grimshaw, JM Woolf, SH AF Shekelle, P Eccles, MP Grimshaw, JM Woolf, SH TI When should clinical guidelines be updated? SO BRITISH MEDICAL JOURNAL LA English DT Article C1 Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90073 USA. Univ Newcastle Upon Tyne, Ctr Hlth Serv Res, Newcastle Upon Tyne NE2 4AA, Tyne & Wear, England. Univ Aberdeen, Hlth Serv Res Unit, Aberdeen AB25 2ZD, Scotland. Virginia Commonwealth Univ, Dept Family Practice, Fairfax, VA 22033 USA. RP Shekelle, P (reprint author), RAND Corp, 1700 Main St,POB 2138,M-26, Santa Monica, CA 90407 USA. RI Grimshaw, Jeremy/D-8726-2013; OI Grimshaw, Jeremy/0000-0001-8015-8243 NR 10 TC 110 Z9 117 U1 1 U2 3 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUL 21 PY 2001 VL 323 IS 7305 BP 155 EP 157 DI 10.1136/bmj.323.7305.155 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 456WR UT WOS:000170106200024 PM 11463690 ER PT J AU Tsiodras, S Gold, HS Sakoulas, G Eliopoulos, GM Wennersten, C Venkataraman, L Moellering, RC Ferraro, MJ AF Tsiodras, S Gold, HS Sakoulas, G Eliopoulos, GM Wennersten, C Venkataraman, L Moellering, RC Ferraro, MJ TI Linezolid resistance in a clinical isolate of Staphylococcus aureus SO LANCET LA English DT Article ID OXAZOLIDINONE AB The new oxazolidinone antimicrobial, linezolid, has been approved for the treatment of infections caused by various gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Although instances of linezolid resistance in VRE have been reported, resistance has not been encountered among clinical isolates of S aureus. We have characterised an MRSA isolate resistant to linezolid that was recovered from a patient treated with this agent for dialysis-associated peritonitis. C1 Massachusetts Gen Hosp, Dept Pathol, Clin Microbiol Labs, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ferraro, MJ (reprint author), Massachusetts Gen Hosp, Dept Pathol, Clin Microbiol Labs, Gray B-526, Boston, MA 02114 USA. OI Tsiodras, Sotirios/0000-0002-0463-4321 NR 5 TC 616 Z9 654 U1 2 U2 33 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 21 PY 2001 VL 358 IS 9277 BP 207 EP 208 DI 10.1016/S0140-6736(01)05410-1 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 454HL UT WOS:000169967100015 PM 11476839 ER PT J AU Singh, JP Larson, MG O'Donnell, CJ Levy, D AF Singh, JP Larson, MG O'Donnell, CJ Levy, D TI Genetic factors contribute to the variance in frequency domain measures of heart rate variability SO AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL LA English DT Review DE heart rate variability; genetics ID RESPIRATORY SINUS ARRHYTHMIA; HERITABILITY; MORTALITY; LOCUS; RISK AB Power spectral analysis of heart rate variability (HRV) provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HRV only partially explain its variability in the population. The purpose of this study was to estimate the contribution of genetic factors to the variance in HRV measures and assess the heritability of HRV. Subjects who underwent Halter recordings at a routine examination were eligible, excluding subjects with congestive heart failure, coronary artery disease, diabetes mellitus and those taking cardioactive medications. We analyzed the low-frequency power (LF), high-frequency power (HF), LF/HF ratio,. very low-frequency power (VLF) and total power (TP). Heritability analysis was done by studying correlations between siblings (n = 682, in 291 sibships, 517 pairs) and between spouse pairs (n = 206 pairs). Adjustments were made for sex, age, systolic and diastolic blood pressure, heart rate, coffee and alcohol intake. SAS procedure MIXED was used to estimate and test significance of correlation within sibling pairs and within spouse pairs. Results from separate models were combined to estimate the components of variance of each phenotype, i.e. variance attributable to measured covariates, additive genetic effects (heritability) and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21-0.26) compared to spouses (0.01-0.19)The measured covariates in general accounted for 13-40% of the total phenotypic variance, whereas genes accounted for 13-23% of the variation among HRV measures. Genetic factors contribute towards a substantial proportion of the variance in heart rate and HRV. Recognition of the genetic determinants of HRV may provide additional insight into the pathophysiology of the autonomic nervous system and offer clues toward its modulation. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Boston, MA 02114 USA. NHLBI, Framingham Heart Study, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Beth Israel Hosp, Div Cardiol, Boston, MA USA. Beth Israel Hosp, Div Clin Epidemiol, Boston, MA USA. RP Singh, JP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Bullfinch Basement 001, Boston, MA 02114 USA. NR 23 TC 25 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-0702 J9 AUTON NEUROSCI-BASIC JI Auton. Neurosci-Basic Clin. PD JUL 20 PY 2001 VL 90 IS 1-2 SI SI BP 122 EP 126 DI 10.1016/S1566-0702(01)00277-6 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 450YW UT WOS:000169773300018 PM 11485278 ER PT J AU Segev, DL Hoshiya, Y Stephen, AE Hoshiya, M Tran, TT MacLaughlin, DT Donahoe, PK Maheswaran, S AF Segev, DL Hoshiya, Y Stephen, AE Hoshiya, M Tran, TT MacLaughlin, DT Donahoe, PK Maheswaran, S TI Mullerian inhibiting substance regulates NF kappa B signaling and growth of mammary epithelial cells in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER; II RECEPTOR; FEMALE RATS; EXPRESSION; GLAND; APOPTOSIS; HORMONE; SURVIVAL; PUBERTY; ONSET AB Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro through interference with cell cycle progression and induction of apoptosis, a process associated with NF kappaB activation and up-regulation of one of its important target genes, IEX-1S (Segev, D. L., Ha, T., Tran, T. T., Kenneally, M., Harkin, P., Jung, M., MacLaughlin, D. T., Donahoe, P. K., and Maheswaran, S. (2000) J. Biol. Chem. 275, 28371-28379). Here we demonstrate that MIS activates the NF kappaB signaling cascade, induces IEX-1S mRNA, and inhibits the growth of MCF10A, an immortalized human breast epithelial cell line with characteristics of normal cells. In vivo an inverse correlation was found to exist between various stages of mammary growth and MIS type II receptor expression. Receptor mRNA significantly diminished during puberty, when the ductal system branches and invades the adipose stroma and during the expansive growth at lactation, but it was up-regulated during involution, a time of regression and apoptosis. Peripartum variations in MIS type II receptor expression correlated with NF kappaB activation and IEX-1S mRNA expression. Administration of MIS to female mice induced NF kappaB DNA binding and IEX-1S mRNA expression in the breast. Furthermore, exposure to MIS in vivo increased apoptosis in the mouse mammary ductal epithelium. Thus, MIS may function as an endogenous hormonal regulator of NF kappaB signaling and growth in the breast. C1 Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Maheswaran, S (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, WRN1024,55 Fruit St, Boston, MA 02114 USA. FU NCI NIH HHS [CA17393, T32 CA-71345-04, F32 CA77945-01A1]; NICHD NIH HHS [HD32112] NR 34 TC 44 Z9 47 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 20 PY 2001 VL 276 IS 29 BP 26799 EP 26806 DI 10.1074/jbc.M103092200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 454HJ UT WOS:000169966900011 PM 11356848 ER PT J AU Gerszten, RE Friedrich, EB Matsui, T Hung, RR Li, L Force, T Rosenzweig, A AF Gerszten, RE Friedrich, EB Matsui, T Hung, RR Li, L Force, T Rosenzweig, A TI Role of phosphoinositide 3-kinase in monocyte recruitment under flow conditions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE; NEUTROPHIL MIGRATION; SIGNAL-TRANSDUCTION; T-LYMPHOCYTES; BETA-GAMMA; IN-VITRO; CELLS; ACTIVATION; ADHESION; CHEMOKINES AB Chemokines such as the monocyte chemol attractant protein-1. MCP-1) convert monocyte rolling to firm arrest under physiological flow conditions via integrin activation and simultaneously activate phosphoinositide 3-kinase (PI3K). Here we used adenoviral gene transfer and biochemical inhibitors to manipulate PI3K-dependent pathways in human monocytes. In in vitro lipid kinase assays from purified human monocytes, we showed that MCP-1 activates the "classical" PI3K alpha pathway and not PI3K gamma, a PI3K isoform thought to be activated only by the py complex of heterotrimeric G proteins. The activity of PI3K alpha in purified human monocytes was evident within 30 s. MCP-1-induced monocyte arrest was significantly inhibited both by wortmannin (n = 4;p < 0.01) and LY294002 (n = 4;p< 0.01) with restoration of the rolling phenotype (p < 0.05 for both inhibitors, compared with rolling of control monocytes after MCP-1 treatment). To test the hypothesis that activation of PI3K is sufficient to induce monocyte adhesion, we transduced the monocytic THP-1 cell line with a recombinant adenovirus (Ad) carrying a constitutively active mutant of PI3K (Ad.BD110). me examined the ability of these cells to adhere to human vascular endothelium (HUVEC) transduced with adenoviruses carrying E-selectin, intercellular adhesion molecule-1 (ICAM-1), and VCAM-1, Under flow conditions, ICAM-1- and VCAM-1-dependent firm adhesion of Ad.BD110-transduced THP-1 cells was enhanced compared with THP-1 cells infected with control Ad (n = 4;p < 0.01 for both),Adhesion augmented by constitutive PI3K activation was entirely abrogated by pretreatment with wortmannin (n = 3;p < 0.01). In contrast, a constitutively active Akt construct had no effect on THP-1 adhesion (n = 3;p = NS). We conclude that PI3K activation is necessary and sufficient to enhance monocytic adhesion under physiological now conditions, BD110-expressing TRP-1 cells should provide a useful tool for identifying the signaling pathways downstream of PI3K that are necessary for monocyte recruitment relevant to a variety of human vascular pathologies. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Program Cardiovasc Gene Therapy, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. Tufts Univ, Sch Med, New England Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, E 8307 149 13th St, Charlestown, MA 02129 USA. OI Force, Thomas/0000-0002-0450-8659 FU NHLBI NIH HHS [HL59521, HL65584, HL54202, HL03348, HL61688]; NIAID NIH HHS [AI40970]; NIDDK NIH HHS [DK50282] NR 22 TC 55 Z9 55 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 20 PY 2001 VL 276 IS 29 BP 26846 EP 26851 DI 10.1074/jbc.M011235200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 454HJ UT WOS:000169966900017 PM 11278864 ER PT J AU Grewal, JS Luttrell, LM Raymond, JR AF Grewal, JS Luttrell, LM Raymond, JR TI G protein-coupled receptors desensitize and down-regulate epidermal growth factor receptors in renal mesangial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOGENIC SIGNAL TRANSDUCTION; TYROSINE KINASE-ACTIVITY; FLUID-PHASE ENDOCYTOSIS; SMOOTH-MUSCLE CELLS; EGF RECEPTOR; ANGIOTENSIN-II; BETA(2)-ADRENERGIC RECEPTOR; MEDIATED ENDOCYTOSIS; PHOSPHOLIPASE-C; PHORBOL ESTER AB Different types of plasma membrane receptors engage in various forms of cross-talk. We used cultures of rat renal mesangial cells to study the regulation of EGF receptors (EGFRs) by various endogenous G protein-coupled receptors (GPCRs). GPCRs (5-hydroxytryptamine(2A) lysophosphatidic acid, angiotensin AT(1), bradykinin B-2) were shown to transactivate EGFRs through a protein kinase C-dependent pathway. This transactivation resulted in the initiation of multiple cellular signals (phosphorylation of the EGFRs and ERK and activation of cAMP-responsive element-binding protein (CREB), NF-kappaB, and E2F), as well as subsequent rapid down-regulation of cell-surface EGFRs and internalization and desensitization of the EGFRs without change in the total cellular complement of EGFRs. Internalization of the EGFRs and the down-regulation of cell-surface receptors in mesangial cells were blocked by pharmacological inhibitors of clathrin-mediated endocytosis and in HEK293 cells by transfection of cDNA constructs that encode dominant negative beta -arrestin-1 or dynamin. Whereas all of the effects of GPCRs on EGFRs were dependent to a great extent on protein kinase C, those initiated by EGF were not. These studies demonstrate that GPCRs can induce multiple signals through protein kinase C-dependent transactivation of EGFRs. Moreover, GPCRs induce profound desensitization of EGFRs by a process associated with the loss of cell-surface EGFRs through clathrin-mediated endocytosis. C1 Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. Ralph H Johnson Vet Affairs Med Ctr, Med Specialty Serv, Charleston, SC 29401 USA. Duke Univ, Med Ctr, Div Endocrinol, Dept Med, Durham, NC 27710 USA. Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Durham, NC 27710 USA. RP Raymond, JR (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, Rm 829,Clin Sci Bldg,171 Ashley Ave, Charleston, SC 29425 USA. FU NIDDK NIH HHS [DK55524, DK52448, DK54720] NR 81 TC 44 Z9 46 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 20 PY 2001 VL 276 IS 29 BP 27335 EP 27344 DI 10.1074/jbc.M103578200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 454HJ UT WOS:000169966900081 PM 11371570 ER PT J AU Jongsma, H Pettersson, LME Zhang, YZ Reimer, MK Kanje, M Waldenstrom, A Sundler, F Danielsen, N AF Jongsma, H Pettersson, LME Zhang, YZ Reimer, MK Kanje, M Waldenstrom, A Sundler, F Danielsen, N TI Markedly reduced chronic nociceptive response in mice lacking the PAC(I) receptor SO NEUROREPORT LA English DT Article DE dorsal root ganglion; formalin test; inflammation; mechanical von Frey; neuropeptides; PACAP; pain measurements; sciatic nerve injury; sensory thresholds; thermal laser ID CYCLASE-ACTIVATING POLYPEPTIDE; PROTEIN-KINASE-C; FORMALIN TEST; SENSORY NEURONS; NERVE INJURY; SUBSTANCE-P; SPINAL-CORD; RAT; PACAP; EXPRESSION AB The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been proposed to have a role in nociception. Here we have used the formalin test, thermal laser stimulation and mechanical von Prey stimulation to investigate possible alteration of PAC(1)(-/-) mice nociceptive behaviour. Our finding, that PAC(1)(-/-) mice have a substantial, 75% decrease in nociceptive response during the late phase, provides clear evidence that the specific PACAP-recepror PAC(1) is involved in the mediation of nociceptive responses during chronic conditions such as inflammation. PAC(1)(-/-) mice had small or no changes in the response to mechanical and thermal laser stimulation. This suggests a limited, if any, involvement of PAC(1) in nociception after short-lasting stimuli. Injury-induced changes in DRG neuropeptide expression were more pronounced in PAC(1)(-/-) mice, implying neuroregulatory functions of PAC(1). NeuroReport 12:2215-2219 (C) 2001 Lippincott Williams & Wilkins. C1 Univ Lund, BMC F10, Dept Physiol Sci, SE-22184 Lund, Sweden. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Paediat Oncol, Boston, MA 02115 USA. Univ Lund, Dept Anim Physiol, SE-22362 Lund, Sweden. RP Jongsma, H (reprint author), Univ Lund, BMC F10, Dept Physiol Sci, SE-22184 Lund, Sweden. NR 25 TC 43 Z9 45 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 20 PY 2001 VL 12 IS 10 BP 2215 EP 2219 DI 10.1097/00001756-200107200-00034 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 451NY UT WOS:000169809200035 PM 11447337 ER PT J AU Zuccato, C Ciammola, A Rigamonti, D Leavitt, BR Goffredo, D Conti, L MacDonald, ME Friedlander, RM Silani, V Hayden, MR Timmusk, T Sipione, S Cattaneo, E AF Zuccato, C Ciammola, A Rigamonti, D Leavitt, BR Goffredo, D Conti, L MacDonald, ME Friedlander, RM Silani, V Hayden, MR Timmusk, T Sipione, S Cattaneo, E TI Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease SO SCIENCE LA English DT Article ID NEUROTROPHIC FACTOR; MOUSE MODEL; CELLULAR-LOCALIZATION; TARGETED DISRUPTION; GABAERGIC NEURONS; TRANSGENIC MICE; MESSENGER-RNA; RAT-BRAIN; IN-VITRO; EXPRESSION AB Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, Loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is Lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This Leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD. C1 Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy. Univ Milan, Ctr Excellance Neurodegenerat Dis, I-20133 Milan, Italy. Univ Milan, IRCCS Osped Maggiore, Sch Med, Ctr Dino Ferrari,Dept Neurol Sci, I-20133 Milan, Italy. Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. Univ Helsinki, Inst Biotechnol, Program Mol Neurosci, Helsinki, Finland. Uppsala Univ, Ctr Biomed, Dept Dev Neurosci, Uppsala, Sweden. RP Cattaneo, E (reprint author), Univ Milan, Dept Pharmacol Sci, Via Balzaretti 9, I-20133 Milan, Italy. RI Leavitt, Blair/G-1934-2012; Conti, Luciano/H-4184-2012; Friedlander, Robert/A-2845-2016; Hayden, Michael/D-8581-2011; OI Conti, Luciano/0000-0002-2050-9846; Friedlander, Robert/0000-0003-4423-9219; Hayden, Michael/0000-0001-5159-1419; ZUCCATO, CHIARA/0000-0003-1771-3392; Silani, Vincenzo/0000-0002-7698-3854; CATTANEO, ELENA/0000-0002-0755-4917 FU Telethon [E.0840] NR 37 TC 734 Z9 752 U1 6 U2 45 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 20 PY 2001 VL 293 IS 5529 BP 493 EP 498 DI 10.1126/science.1059581 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 454HG UT WOS:000169966700048 PM 11408619 ER PT J AU Haverson, K Saalmuller, A Alvarez, B Alonso, F Bailey, M Bianchi, ATJ Boersma, WJA Chen, Z Davis, WC Dominguez, J Engelhardt, H Ezquerra, A Grosmaire, LS Hamilton, MJ Hollemweguer, E Huang, CA Khanna, KV Kuebart, G Lackovic, G Ledbetter, JA Lee, R Llanes, D Lunney, JK McCullough, KC Molitor, T Nielsen, J Niewold, TA Pescovitz, MD de la Lastra, JP Rehakova, Z Salmon, H Schnitzlein, WM Seebach, J Simon, A Sinkora, J Sinkora, M Stokes, CR Summerfield, A Sver, L Thacker, E Valpotic, I Yang, H Zuckermann, FA Zwart, R AF Haverson, K Saalmuller, A Alvarez, B Alonso, F Bailey, M Bianchi, ATJ Boersma, WJA Chen, Z Davis, WC Dominguez, J Engelhardt, H Ezquerra, A Grosmaire, LS Hamilton, MJ Hollemweguer, E Huang, CA Khanna, KV Kuebart, G Lackovic, G Ledbetter, JA Lee, R Llanes, D Lunney, JK McCullough, KC Molitor, T Nielsen, J Niewold, TA Pescovitz, MD de la Lastra, JP Rehakova, Z Salmon, H Schnitzlein, WM Seebach, J Simon, A Sinkora, J Sinkora, M Stokes, CR Summerfield, A Sver, L Thacker, E Valpotic, I Yang, H Zuckermann, FA Zwart, R TI Overview of the Third International Workshop on Swine Leukocyte Differentiation Antigens SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE swine; pig; porcine; cluster of differentiation (CD); antigens; monoclonal antibodies (mAb) ID CYTOLYTIC T-LYMPHOCYTES; PORCINE B-CELLS; MONOCLONAL-ANTIBODIES; CD WORKSHOP; EXPRESSION; ACTIVATION; ADHESION; SUBSETS; DEFINE; PHAGOCYTOSIS AB The aim of the Third International Workshop on Swine Leukocyte Differentiation Antigens (CD workshop), supported by the Veterinary Immunology Committee (VIC) of the International Union of Immunological Societies (IUIS), was to standardize the assignment of monoclonal antibodies (mAb) reactive with porcine leukocyte differentiation antigens and to define new antibody clusters, using nomenclature in accordance with human and ruminant CD nomenclature, as agreed at the summary meeting of the Second International Swine CD Workshop in Davis, 1995: only mAb with proven reactivity for the orthologous porcine gene product or cross-reactivity for the human gene products, were given the full CD nomenclature, all other allocations were prefixed with 'w'. As in previous workshops, the overall organization was entrusted to the chair and first author, with support by the chair of the previous workshop and second author. In addition to the existing 26 pig leukocyte CD/SWC determinants established in previous workshops, this workshop established/confirmed another I I CDs for pig leukocytes, identified by a total of 21 mAb: CD11R1 (2 mAb), CD11R2 (I mAb), CD11R3 (4 mAb), wCD40 (I mAb), wCD46 (4 mAb), wCD47 (3 mAb), wCD49d (I mAb), CD61 (I mAb), wCD92 (I mAb), wCD93 (I mAb) and CD163 (2 mAb). (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Bristol, Div Mol & Cellular Biol, Langford BS40 5DU, England. Fed Res Ctr Virus Dis Anim, D-72001 Tubingen, Germany. INIA, SGIT, Dept Sanidad Anim, Madrid 28130, Spain. DLO, Inst Anim Sci & Hlth, NL-8200 AB Lelystad, Netherlands. Pharmingen, San Diego, CA 92121 USA. Washington State Univ, Coll Vet Med, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. Univ Guelph, Dept Anim & Poultry Sci, Guelph, ON N1G 2W1, Canada. Bristol Myers Squibb Co, Seattle, WA 98121 USA. Massachusetts Gen Hosp, TBRC, Boston, MA 02129 USA. Univ Minnesota, Coll Vet Med, St Paul, MN 55108 USA. Univ Zagreb, Fac Vet, Dept Biol, HR-10000 Zagreb, Croatia. Univ Queensland, Dept Parasitol, St Lucia, Qld 4067, Australia. Fac Vet Cordoba, Dept Genet, Unidad Mixta Marcadores Genet Mol, Cordoba 14005, Spain. RP Haverson, K (reprint author), Univ Bristol, Div Mol & Cellular Biol, Langford BS40 5DU, England. RI salmon, henri/B-2605-2010; Ezquerra, Angel/I-3440-2012; Sinkora, Marek/H-2523-2014; Perez de la Lastra, Jose/F-9184-2013; Dominguez, Javier/I-1210-2015; OI Perez de la Lastra, Jose/0000-0003-4663-5565; Ezquerra, Angel/0000-0002-1824-5087; Summerfield, Artur/0000-0001-8292-4634 NR 56 TC 43 Z9 43 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD JUL 20 PY 2001 VL 80 IS 1-2 SI SI BP 5 EP 23 DI 10.1016/S0165-2427(01)00290-2 PG 19 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 456NQ UT WOS:000170089300002 PM 11445215 ER PT J AU Haverson, K Saalmuller, A Chen, Z Huang, CA Simon, A Seebach, J Boersma, WJA Zwart, R Niewold, TA Thacker, E Llanes, D de la Lastra, JMP Engelhardt, H Ezquerra, A Alonso, F Dominguez, J Ledbetter, JA Grosmaire, L Lee, R Nielsen, J Salmon, H Valpotic, I Sver, L Lackovic, G Summerfield, A Khanna, KV AF Haverson, K Saalmuller, A Chen, Z Huang, CA Simon, A Seebach, J Boersma, WJA Zwart, R Niewold, TA Thacker, E Llanes, D de la Lastra, JMP Engelhardt, H Ezquerra, A Alonso, F Dominguez, J Ledbetter, JA Grosmaire, L Lee, R Nielsen, J Salmon, H Valpotic, I Sver, L Lackovic, G Summerfield, A Khanna, KV TI Summary of the first round analyses of the Third International Workshop on Swine Leukocyte Differentiation Antigens SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE swine; cluster of differentiation (CD) antigens; monoclonal antibodies (mAb); flow cytometry; clustering analysis ID MONOCLONAL-ANTIBODIES; CELLS AB The reactivity of 155 monoclonal antibodies submitted to the Third International Workshop on Swine Leukocyte Differentiation Antigens, together with 41 internal standards, was analysed by flow cytometry on 29 different pig cell targets as well as two human cell targets as a means of establishing suitable panels of monoclonal antibodies for more detailed clustering analyses by the various subsections of the workshop. Results were collected either without further gating, with gating based on FS/SS characteristics or with gating based on the co-expression of a reference antibody in two-colour flow cytometry. The CD or SWC reactivity of the internal standards had been established in previous workshops. Data sets were subsequently analysed by statistical clustering using the Leucocyte Typing Database IV software. The resulting 18 cluster groups were allocated to the appropriate second round sections of the workshop, after reviewing the overall cellular reactivity of each cluster as well as the specificity of known standards which clustered in a group. (C) 2001 Elsevier Science BN. All rights reserved. C1 Univ Bristol, Div Mol & Cellular Biol, Langford BS40 5DU, England. Fed Res Ctr Virus Dis Anim, Tubingen, Germany. Pharmingen, San Diego, CA USA. Massachusetts Gen Hosp, Transplant Biol Res Ctr, Boston, MA USA. DLO, ID, Lelystad, Netherlands. Iowa State Univ, Vet Med Res Inst, Ames, IA USA. Univ Cordoba, Dept Genet, Cordoba, Spain. Univ Guelph, Dept Anim & Poultry Sci, Guelph, ON N1G 2W1, Canada. CIS, INIA, Madrid, Spain. Bristol Myers Squibb Co, Seattle, WA 98121 USA. Univ Melbourne, Sch Vet Sci, Ctr Anim Biotechnol, Melbourne, Vic, Australia. Minist Agr, State Vet Inst Virus Res, Lindholm, Kalvehave, Denmark. INRA, F-37380 Nouzilly, France. Univ Zagreb, Fac Vet, Dept Biol, Zagreb 41000, Croatia. Inst Viruskrankheiten & Immunprophylaxe, Mittelhausern, Switzerland. Univ Minnesota, Coll Vet Med, St Paul, MN USA. RP Haverson, K (reprint author), Univ Bristol, Div Mol & Cellular Biol, Langford BS40 5DU, England. RI salmon, henri/B-2605-2010; Ezquerra, Angel/I-3440-2012; Perez de la Lastra, Jose/F-9184-2013; Dominguez, Javier/I-1210-2015; OI Perez de la Lastra, Jose/0000-0003-4663-5565; Ezquerra, Angel/0000-0002-1824-5087; Summerfield, Artur/0000-0001-8292-4634 NR 8 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD JUL 20 PY 2001 VL 80 IS 1-2 SI SI BP 25 EP 34 DI 10.1016/S0165-2427(01)00291-4 PG 10 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 456NQ UT WOS:000170089300003 PM 11445216 ER PT J AU Sinkora, J Rehakova, Z Haverson, K Sinkora, M Dominguez, J Huang, CA AF Sinkora, J Rehakova, Z Haverson, K Sinkora, M Dominguez, J Huang, CA TI Monoclonal antibodies putatively recognising activation and differentiation antigens SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE pig; cluster of differentiation (CD) antigens; monoclonal antibody (mAb); CD25; SLA II; haematopoiesis; lymphopoiesis ID PORCINE PERIPHERAL-BLOOD; POSITIVE T-CELLS; B-CELLS; PSEUDORABIES VIRUS; MINIATURE SWINE; LYMPHOCYTES; EXPRESSION; PIGS; ONTOGENY; TISSUES AB In the activation/maturation section, 46 monoclonal antibodies (mAbs) were analysed using freshly isolated as well as mitogen activated and recall antigen re-stimulated cells. A total of 10 internal standards as well as 6 antibodies with established reactivity for human cells, reported to cross-react with porcine leukocytes, were included in the panel. The standard antibodies were anti-CD25, CD44, CD45, SLA II, SWC1, SWC2, SWC7 and SWC8 reagents. The test panel contained antibodies with putative reactivity to CD25, SLA II and other mAbs directed against ill-defined targets. Single and double colour surface staining was performed in the attempt to group the mAbs tested into clusters of differentiation. Five new anti-class II reagents, two directed to SLA-DQ and three to SLA-DR, could be added to the previously established ones. One new anti-CD25 as well as two new antibodies with SWC7 and SWC8 specifities, respectively, could also be added to the previously established ones. The identity of the two latter antibodies was also confirmed in other sections of this workshop (B-cell section for SWC7 antibodies and myeloid section for the SWC8 antibodies). The antibody JM2F12, in our hands, has shown strong similarities to the cross-reactive anti human-CD49f reagent. No other clusters were identified, as all remaining antibodies behaved in a different way on different target leukocyte populations. The second purpose of the section was fulfilled: interesting staining profiles of several antibodies on differentiating lymphocytes were recorded and are discussed here. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Inst Microbiol, Dept Immunol & Gnotobiol, Novy Hradek, Czech Republic. Div Mol & Cellular Biol, Bristol, Avon, England. INIA, SGIT, Dept Sanidad Anim, Madrid 28130, Spain. Massachusetts Gen Hosp, TBRC, Boston, MA 02129 USA. RP Sinkora, J (reprint author), Inst Microbiol, Dept Immunol & Gnotobiol, Novy Hradek, Czech Republic. RI Sinkora, Marek/H-2523-2014; Dominguez, Javier/I-1210-2015 NR 23 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD JUL 20 PY 2001 VL 80 IS 1-2 SI SI BP 143 EP 164 DI 10.1016/S0165-2427(01)00283-5 PG 22 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 456NQ UT WOS:000170089300012 PM 11445225 ER PT J AU Goulder, PJR Brander, C Tang, YH Tremblay, C Colbert, RA Addo, MM Rosenberg, ES Nguyen, T Allen, R Trocha, A Altfeld, M He, SQ Bunce, M Funkhouser, R Pelton, SI Burchett, SK McIntosh, K Korber, BTM Walker, BD AF Goulder, PJR Brander, C Tang, YH Tremblay, C Colbert, RA Addo, MM Rosenberg, ES Nguyen, T Allen, R Trocha, A Altfeld, M He, SQ Bunce, M Funkhouser, R Pelton, SI Burchett, SK McIntosh, K Korber, BTM Walker, BD TI Evolution and transmission of stable CTL escape mutations in HIV infection SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; VIREMIA; IMMUNODOMINANT; PROGRESSION; SUPPRESSION; RESPONSES; VARIANTS; CHILDREN; DISEASE AB Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs)(1-3); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection(4). In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression(4-6). In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div AIDS, Boston, MA 02114 USA. Childrens Hosp, Med Ctr, William S Rowe Div Rheumatol, Boston, MA 02115 USA. Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. Churchill Hosp, Oxford Transplant Ctr, Oxford OX3 7LJ, England. Univ Calif Los Alamos Natl Lab, Los Alamos, NM 87545 USA. Boston Univ, Med Ctr, Sect Pediat Infect Dis, Boston, MA 02118 USA. RP Goulder, PJR (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. OI Allen, Rachel/0000-0001-9834-8475; Korber, Bette/0000-0002-2026-5757 NR 30 TC 414 Z9 428 U1 1 U2 12 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 19 PY 2001 VL 412 IS 6844 BP 334 EP 338 DI 10.1038/35085576 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 453LW UT WOS:000169918200047 PM 11460164 ER PT J AU Breakefield, XO Kamm, C Hanson, PI AF Breakefield, XO Kamm, C Hanson, PI TI TorsinA: Movement at many levels SO NEURON LA English DT Review ID ELEGANS EMBRYOS; DYSTONIA; PROTEIN; OOC-3 AB TorsinA is the causative protein in the human neurologic disease early onset torsin dystonia, a movement disorder involving dysfunction in the basal ganglia without apparent neurodegeneration. Most cases result from a dominantly acting three-base pair deletion in the TOR1A gene causing loss of a glutamic acid near the carboxyl terminus of torsinA. Torsins are members of the AAA+ superfamily of ATPases and are present in all multicellular organisms. Initial studies suggest that torsinA is an ER protein involved in chaperone functions and/or membrane movement. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurogenet Unit, Boston, MA 02129 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Breakefield, XO (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurogenet Unit, Boston, MA 02129 USA. RI Hanson, Phyllis/E-9420-2012 NR 21 TC 87 Z9 90 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 19 PY 2001 VL 31 IS 1 BP 9 EP 12 DI 10.1016/S0896-6273(01)00350-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 456UR UT WOS:000170101100005 PM 11498045 ER PT J AU Chen, ZF Rebelo, S White, F Malmberg, AB Baba, H Lima, D Woolf, CJ Basbaum, AI Anderson, DJ AF Chen, ZF Rebelo, S White, F Malmberg, AB Baba, H Lima, D Woolf, CJ Basbaum, AI Anderson, DJ TI The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord SO NEURON LA English DT Article ID SUBSTANTIA-GELATINOSA NEURONS; NERVOUS-SYSTEM; DIFFERENTIAL EXPRESSION; ODORANT RECEPTORS; GENE-EXPRESSION; SEMAPHORIN-III; MOTOR-NEURONS; MUTANT MICE; IN-VIVO; NF-L AB Cutaneous sensory neurons that detect noxious stimuli project to the dorsal horn of the spinal cord, while those innervating muscle stretch receptors project to the ventral horn. DRG11, a paired homeodomain transcription factor, is expressed in both the developing dorsal horn and in sensory neurons, but not in the ventral spinal cord. Mouse embryos deficient in DRG11 display abnormalities in the spatio-temporal patterning of cutaneous sensory afferent fiber projections to the dorsal, but not the ventral spinal cord, as well as defects in dorsal horn morphogenesis. These early developmental abnormalities lead, in adults, to significantly attenuated sensitivity to noxious stimuli. In contrast, locomotion and sensori-motor functions appear normal. Drg11 is thus required for the formation of spatio-temporally appropriate projections from nociceptive sensory neurons to their central targets in the dorsal horn of the spinal cord. C1 CALTECH, Div Biol 216 76, Pasadena, CA 91125 USA. CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, WM Keck Fdn, Ctr Integrat Neurosci, San Francisco, CA 94143 USA. Univ Porto, Inst Histol & Embriol, P-4100 Porto, Portugal. Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. Yale Univ, Sch Med, PVA EPVA Neurosci Res Ctr, New Haven, CT 06510 USA. Vet Adm Med Ctr, Rehabil Res Ctr, W Haven, CT 06516 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02129 USA. RP Anderson, DJ (reprint author), CALTECH, Div Biol 216 76, Pasadena, CA 91125 USA. RI Rebelo, Sandra/B-5587-2008; White, Fletcher/F-2895-2012; White, Fletcher/F-3203-2015; OI White, Fletcher/0000-0002-8408-9262; Rebelo, Sandra/0000-0002-5358-5204; Lima, Deolinda/0000-0002-5723-0777 FU NINDS NIH HHS [NS38253-01, NS 14627] NR 71 TC 96 Z9 98 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 19 PY 2001 VL 31 IS 1 BP 59 EP 73 DI 10.1016/S0896-6273(01)00341-5 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 456UR UT WOS:000170101100011 PM 11498051 ER PT J AU Sala, C Piech, V Wilson, NR Passafaro, M Liu, GS Sheng, M AF Sala, C Piech, V Wilson, NR Passafaro, M Liu, GS Sheng, M TI Regulation of dendritic spine morphology and synaptic function by Shank and Homer SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; METABOTROPIC GLUTAMATE RECEPTORS; POSTSYNAPTIC DENSITY PROTEINS; HIPPOCAMPAL-NEURONS; BINDING-PROTEIN; MULTIDOMAIN PROTEINS; EXCITATORY SYNAPSES; DENTATE GYRUS; SMALL GTPASES; FAMILY AB The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. MIT, Dept Brain & Cognit Sci, RIKEN MIT Neurosci Res Ctr, Ctr Learning & Memory, Cambridge, MA 02139 USA. RP Sheng, M (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. RI Sala, Carlo/A-2493-2009 OI Sala, Carlo/0000-0003-0662-9523 NR 50 TC 416 Z9 431 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 19 PY 2001 VL 31 IS 1 BP 115 EP 130 DI 10.1016/S0896-6273(01)00339-7 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 456UR UT WOS:000170101100015 PM 11498055 ER PT J AU Rexrode, KM Buring, JE Glynn, RJ Stampfer, MJ Youngman, LD Gaziano, JM AF Rexrode, KM Buring, JE Glynn, RJ Stampfer, MJ Youngman, LD Gaziano, JM TI Analgesic use and renal function in men SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NONNARCOTIC ANALGESICS; COLORECTAL-CANCER; FAILURE; DISEASE; RISK; ASPIRIN; ACETAMINOPHEN; ABUSE AB Context Several case-control studies suggest an association between analgesic use and increased risk of chronic renal disease, but few cohort studies have examined this association. Objective To determine whether analgesic use is associated with risk of renal dysfunction. Design and Setting Cohort study of analgesic use data from the Physicians' Health Study, which lasted 14 years from September 1982 to December 1995 with annual follow-up. Participants A total of 11 032 initially healthy men who provided blood samples and self-report of analgesic use. Main Outcome Measures Elevated creatinine level defined as 1.5 mg/dL (133 mu mol/L) or higher and a reduced creatinine clearance defined as 55 mL/min (0.9 mL/s) or less, and self-reported use of acetaminophen, aspirin, and other nonsteroidal antiinflammatory drugs (never [<12 pills]; 12-1499 pills; 1500-2499 pills; and 2500 pills). Results PI total of 460 men had elevated creatinine levels (4.2%) and 1258 had reduced creatinine clearance (11.4%). Mean creatinine levels and creatinine clearances were similar among men who did not use analgesics and those who did, even at total intakes of 2500 or more pills. In multivariable analyses adjusted for age; body mass index; history of hypertension, elevated cholesterol, and diabetes; occurrence of cardiovascular disease; physical activity; and use of other analgesics, the relative risks of elevated creatinine level associated with intake of 2500 or more pills were 0.83 (95% confidence interval [CI], 0.50-1.39, P for trend =.05) for acetaminophen, 0.98 (95% CI, 0.53-1.81; P for trend =.96) for aspirin, and 1.07 (95% CI, 0.71-1.64; P for trend =.86) for other nonsteroidal anti-inflammatory drugs. Ho association was observed be tween analgesic use and reduced creatinine clearance. Conclusions Moderate analgesic use in this cohort study of initially healthy men was not associated with increased risk of renal dysfunction. C1 Brigham & Womens Hosp, Dept Med, Div Prevent Med, Channing Lab, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. US FDA, Res Off, Laurel, MD USA. Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. VA Boston Healthcare Syst, Boston, MA USA. RP Gaziano, JM (reprint author), Brigham & Womens Hosp, Dept Med, Div Prevent Med, Channing Lab, 900 Commonwealth Ave, Boston, MA 02215 USA. OI Rexrode, Kathryn/0000-0003-3387-8429 FU NCI NIH HHS [CA-34944, CA-40360]; NHLBI NIH HHS [HL-26490, HL-34595] NR 27 TC 60 Z9 62 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 18 PY 2001 VL 286 IS 3 BP 315 EP 321 DI 10.1001/jama.286.3.315 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 452QA UT WOS:000169869200022 PM 11466097 ER PT J AU Matsui, T Tao, JZ del Monte, F Lee, KH Li, L Picard, M Force, TL Franke, TF Hajjar, RJ Rosenzweig, A AF Matsui, T Tao, JZ del Monte, F Lee, KH Li, L Picard, M Force, TL Franke, TF Hajjar, RJ Rosenzweig, A TI Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo SO CIRCULATION LA English DT Article DE apoptosis; signal transduction; gene therapy; ischemia ID ADENOVIRAL GENE-TRANSFER; GROWTH-FACTOR-I; PROTEIN-KINASE AKT; PHOSPHATIDYLINOSITOL 3-KINASE; VENTRICULAR-FUNCTION; MYOCARDIAL-ISCHEMIA; CELL-SURVIVAL; HEART-FAILURE; INSULIN; PHOSPHORYLATION AB Background - The serine-threonine kinase Akt is activated by Several ligand-receptor systems previously shown to be cardioprotective, Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear. Methods and Results - We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (P <0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (+dP/dt and -dP/dt), Akt activation restored regional wall thickening and +dP/dt and -dP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro, myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening, Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment. Conclusions Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes, Akt may represent an important nodal target for therapy in ischemic and other heart disease. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Program Cardiovasc Gene Therapy,CVRC, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Nucl Med, Seoul, South Korea. Columbia Univ, Dept Pharmacol, New York, NY USA. RP Rosenzweig, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Program Cardiovasc Gene Therapy,CVRC, 149 13th St,Room 4214, Charlestown, MA 02129 USA. EM rosenzweig@helix.mgh.harvard.edu RI Lee, Kyun Han/C-9648-2011; OI Force, Thomas/0000-0002-0450-8659; Picard, Michael/0000-0002-9264-3243 FU NHLBI NIH HHS [HL-59521, HL-04250, HL-50361, HL-57623, HL-61557] NR 31 TC 454 Z9 479 U1 1 U2 28 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 17 PY 2001 VL 104 IS 3 BP 330 EP 335 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 455AH UT WOS:000170005000018 PM 11457753 ER PT J AU Xia, F Taghian, DG DeFrank, JS Zeng, ZC Willers, H Iliakis, G Powell, SN AF Xia, F Taghian, DG DeFrank, JS Zeng, ZC Willers, H Iliakis, G Powell, SN TI Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOUBLE-STRAND BREAK; CANCER SUSCEPTIBILITY GENE; DNA-DAMAGE RESPONSE; V(D)J RECOMBINATION; MAMMALIAN-CELLS; IONIZING-RADIATION; ATAXIA-TELANGIECTASIA; CHECKPOINT CONTROL; REPAIR DEFICIENCY; HIGH-FREQUENCY AB Carriers of BRCA2 germline mutations are at high risk to develop early-onset breast cancer. The underlying mechanisms of how BRCA2 inactivation predisposes to malignant transformation have not been established. Here, we provide direct functional evidence that human BRCA2 promotes homologous recombination (HR), which comprises one major pathway of DNA double-strand break repair. We found that up-regulated HR after transfection of wildtype (wt) BRCA2 into a human tumor line with mutant BRCA2 was linked to increased radioresistance. In addition, BRCA2-mediated enhancement of HR depended on the interaction with Rad51. In contrast to the tumor suppressor BRCA1, which is involved in multiple DNA repair pathways, BRCA2 status had no impact on the other principal double-strand break repair pathway, nonhomologous end joining. Thus, there exists a specific regulation of HR by BRCA2, which may function to maintain genomic integrity and suppress tumor development in proliferating cells. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Lab Mol & Cellular Radiat BIol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Div Expt Radiat Oncol,Dept Radiat Oncol, Philadelphia, PA 19107 USA. RP Powell, SN (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Lab Mol & Cellular Radiat BIol, 149 13th St, Charlestown, MA 02129 USA. RI Xia, Fen/G-3708-2013 NR 62 TC 155 Z9 157 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 17 PY 2001 VL 98 IS 15 BP 8644 EP 8649 DI 10.1073/pnas.151253498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 454HK UT WOS:000169967000079 PM 11447276 ER PT J AU Kennedy, BK Liu, OW Dick, FA Dyson, N Harlow, E Vidal, M AF Kennedy, BK Liu, OW Dick, FA Dyson, N Harlow, E Vidal, M TI Histone deacetylase-dependent transcriptional repression by pRB in yeast occurs independently of interaction through the LXCXE binding cleft SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-CYCLE ARREST; RETINOBLASTOMA GENE-PRODUCT; SACCHAROMYCES-CEREVISIAE; PROMYELOCYTIC LEUKEMIA; REVERSE 2-HYBRID; PROTEIN-PROTEIN; COMPLEX; ACTIVATION; DOMAIN; SITE AB We have developed a yeast model system to address transcriptional repression by the retinoblastoma protein (pRB). When fused to the DNA-binding domain of Gal4p (DB-pRB), pRB can repress transcription of reporter genes containing Gal4p binding sites: the histone deacetylase activity encoded by yeast RPD3 is required for DB-pRB repression. Mutation of the LXCXE binding cleft in pRB, a region reported to be required for histone deacetylase recruitment, does not interfere with pRB-mediated repression. From these findings based on yeast experiments, we surmise that the small pocket region of pRB must contain an additional domain that confers histone deacetylase-dependent transcriptional repression. This hypothesis was verified by experiments examining pRB-dependent histone deacetylase association in mammalian cells. In addition to RPD3, repression by pRB in yeast requires MS/1, an ortholog of RbAp48, hut not SIN3 or SAP30. By comparing the genetic requirements of DB-pRB repression in yeast to those of other DB-repressor fusions, we can suggest a mechanism by which pRB recruits histone deacetylase activity. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Kennedy, BK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 51 TC 23 Z9 23 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 17 PY 2001 VL 98 IS 15 BP 8720 EP 8725 DI 10.1073/pnas.151240898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 454HK UT WOS:000169967000092 PM 11447271 ER PT J AU Jooss, K Gjata, B Danos, O von Boehmer, H Sarukhan, A AF Jooss, K Gjata, B Danos, O von Boehmer, H Sarukhan, A TI Regulatory function of in vivo anergized CD4(+) T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECOMBINANT ADENOASSOCIATED VIRUS; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; IN-VIVO; SELF-TOLERANCE; INTESTINAL INFLAMMATION; REQUIRES PRESENTATION; DENDRITIC CELLS; B-CELLS; IL-10; EXPRESSION AB It has been suggested that anergic T cells may not be only inert cells but may rather play an active role, for example by regulating immune responses. We have previously reported the existence of "anergic" IL-10-producing CD4(+) T cells generated in vivo by continuous antigenic stimulation. Using a gene transfer system where the antigen recognized by such T cells is expressed in skeletal muscle by two different DNA viral vectors, we show that these cells not only remain tolerant toward their cognate antigen but also can suppress the immune response of naive T cells against the immunogenic adenoviral proteins. Furthermore, they can completely inhibit tissue destruction that takes place as a result of an immune response. The system presented here is unique in that the T cells have been anergized in vivo, their antigen specificity and functional status are known, and the amount, form, and timing of antigen expression can be manipulated. This model will therefore permit us to carefully dissect the mechanisms by which these anergic T cells regulate the priming and/or effector function of naive T cells. C1 INSERM, Inst Necker, F-345 Paris, France. Genethon III, F-91002 Evry, France. Harvard Univ, Dana Farber Canc Ctr, Boston, MA 02115 USA. RP Sarukhan, A (reprint author), INSERM, Inst Necker, F-345 Paris, France. NR 46 TC 51 Z9 52 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 17 PY 2001 VL 98 IS 15 BP 8738 EP 8743 DI 10.1073/pnas.151088898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 454HK UT WOS:000169967000095 PM 11438696 ER PT J AU Sheehan, J Templer, M Gregory, M Hanumanthaiah, R Troyer, D Phan, T Thankavel, B Jagadeeswaran, P AF Sheehan, J Templer, M Gregory, M Hanumanthaiah, R Troyer, D Phan, T Thankavel, B Jagadeeswaran, P TI Demonstration of the extrinsic coagulation pathway in teleostei: Identification of zebrafish coagulation factor VII SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TISSUE FACTOR; BLOOD-COAGULATION; GENOME EVOLUTION; SWISS-MODEL; FACTOR XA; HEMOSTASIS; PROTHROMBIN; DUPLICATIONS; MOLECULES; INHIBITOR AB It is not known whether the mammalian mechanism of coagulation initiation is conserved in fish. Identification of factor VII is critical in providing evidence for such a mechanism. A cDNA was cloned from a zebrafish (teleost) library that predicted a protein with sequence similarity to human factor VII. Factor VII was shown to be present in zebrafish blood and liver by Western blot analysis and immunohistochemistry. Immunodepletion of factor VII from zebrafish plasma selectively inhibited thromboplastin-triggered thrombin generation. Heterologous expression of zebrafish factor VII demonstrated a secreted protein (50 kDa) that reconstituted thromboplastin-triggered thrombin generation in immunodepleted zebrafish plasma. These results suggest conservation of the extrinsic coagulation pathway between zebrafish and humans and add credence to the zebrafish as a model for mammalian hemostasis. The structure of zebrafish factor VIIa predicted by homology modeling was consistent with the overall three-dimensional structure of human factor VIIa. However, amino acid disparities were found in the epidermal growth factor-2/serine protease regions that are present in the human tissue factor-factor VIIa contact surface, suggesting a structural basis for the species specificity of this interaction. In addition, zebrafish factor VII demonstrates that the Gla-EGF-EGF-SP domain structure, which is common to coagulation factors VII, IX, X, and protein C, was present before the radiation of the teleosts from the tetrapods. Identification of zebrafish factor VII significantly narrows the evolutionary window for development of the vertebrate coagulation cascade and provides insight into the structural basis for species specificity in the tissue factor-factor VIIa interaction. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, S Texas Vet Hlth Care Syst, Audie Murphy Div, San Antonio, TX 78229 USA. RP Jagadeeswaran, P (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NHLBI NIH HHS [R01 HL063792, HL63792]; NIGMS NIH HHS [GM 53373] NR 36 TC 50 Z9 50 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 17 PY 2001 VL 98 IS 15 BP 8768 EP 8773 DI 10.1073/pnas.131109398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 454HK UT WOS:000169967000100 PM 11459993 ER PT J AU Turenne, GA Price, BD AF Turenne, GA Price, BD TI Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity SO BMC CELL BIOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; DAMAGE-INDUCED PHOSPHORYLATION; DNA-DAMAGE; MDM2; ATM; INHIBITION; APOPTOSIS; SURVIVAL; PATHWAY; DEGRADATION AB Background: The p53 protein is activated by genotoxic stress, oncogene expression and during senescence, p53 transcriptionally activates genes involved in growth arrest and apoptosis. p53 activation is regulated by post-translational modification, including phosphorylation of the N-terminal transactivation domain. Here, we have examined how Glycogen Synthase Kinase (GSK3), a protein kinase involved in tumorigenesis, differentiation and apoptosis, phosphorylates and regulates p53. Results: The 2 isoforms of GSK3, GSK3 alpha and GSK3 beta, phosphorylate the sequence Ser-X-X-X-Ser(P) when the C-terminal serine residue is already phosphorylated. Several p53 kinases were examined for their ability to create GSK3 phosphorylation sites on the p53 protein. Our results demonstrate that phosphorylation of serine 37 of p53 by DNA-PK creates a site for GSK3 phosphorylation at serine 33 in vitro. GSK3 alpha did not phosphorylate p53 under any condition. GSK3 beta increased the transcriptional activity of the p53 protein in vivo. Mutation of either serine 33 or serine 37 of p53 to alanine blocked the ability of GSK3 beta to regulate p53 transcriptional activity. GSK3 beta is therefore able to regulate p53 function in vivo. p53's transcriptional activity is commonly increased by DNA damage. However, GSK3 beta kinase activity was inhibited in response to DNA damage, suggesting that GSK3 beta regulation of p53 is not involved in the p53-DNA damage response. Conclusions: GSK3 beta can regulate p53's transcriptional activity by phosphorylating serine 33. However, GSK3 beta does not appear to be part of the p53-DNA damage response pathway. Instead, GSK3 beta may provide the link between p53 and non-DNA damage mechanisms for p53 activation. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Price, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, D810A,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA64585, R01 CA064585] NR 50 TC 78 Z9 78 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUL 16 PY 2001 VL 2 AR 12 DI 10.1186/1471-2121-2-12 PG 9 WC Cell Biology SC Cell Biology GA 501ND UT WOS:000172690000001 PM 11483158 ER PT J AU Carter, BL Malone, DC Billups, SJ Valuck, RJ Barnette, DJ Sintek, CD Ellis, S Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Dombrowski, R Geraets, DR Amato, M AF Carter, BL Malone, DC Billups, SJ Valuck, RJ Barnette, DJ Sintek, CD Ellis, S Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Dombrowski, R Geraets, DR Amato, M TI Interpreting the findings of the IMPROVE study SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE administration; clinical pharmacists; clinical pharmacy; clinical studies; costs; databases; department of veterans affairs; economics; interventions; managed care systems; methodology; outcomes; patient care; pharmaceutical care; pharmaceutical services; pharmacy, institutional, hospital; primary care; quality of life; toxicity ID AFFAIRS MEDICAL-CENTERS; HEALTH SURVEY SF-36; CLINICAL PHARMACISTS; PHARMACEUTICAL CARE; VETERANS; INTERVENTIONS; SELECTION; VALIDITY; SCORE AB Various findings of the Impact of Managed Pharmaceutical Care on Resource Utilization and Outcomes in Veterans Affairs Medical Centers (IMPROVE) study are reviewed. Suggestions for future methodologies that will enhance this study are discussed. The IMPROVE study is one of the largest pharmaceutical care st though it was an intervention study that examined global outcomes following management by pharmacists, it was designed as an effectiveness study. Several new practice and research methods were developed, including a method to identify patients at high risk for drug-related problems utilizing pharmacy databases, a method to identify chronic diseases using pharmacy databases, a method to evaluate the structure and process for delivering pharmaceutical care in Veterans Affairs medical centers (VAMCs), and guidelines for providing care to patients in the IMPROVE study. Nine VAMCs participated in the study, and 1054 patients were randomized to either an intervention group (n = 523) or a control group (n = 531). Pharmacists documented a total of 1855 contacts with the intervention group patients and made 3048 therapy-specific interventions over the 12-month study period. There was no meaningful difference in patient satisfaction or quality of life in the two groups. Selected disease-specific indicators found an improved rate of measurement of hemoglobin A(1c) tests and better control of total and low-density-lipoprotein (LDL) cholesterol levels in the intervention group compared with the control group. Total health care costs increased in both groups over the 12-month period. The mean increase in costs in the intervention group was $1020. which was lower than the control group's value of $1313. The lessons learned from the IMPROVE study suggest to future investigators how to study and measure the effects of clinical pharmacy services on patient outcome. C1 Univ Iowa, Coll Pharm, Div Clin & Adm Pharm, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Family Med, Iowa City, IA 52242 USA. Univ Arizona, Coll Pharm, Dept Pharm Practice, Tucson, AZ 85721 USA. Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharm Practice, Boulder, CO 80309 USA. Univ N Carolina, Sch Pharm, Dept Pharm Practice, Chapel Hill, NC USA. Univ N Carolina, Sch Pharm, Dept Family Med, Chapel Hill, NC USA. Denver Vet Affairs Med Ctr, Denver, CO USA. James A Haley Vet Hosp, Tampa Bay, FL USA. Idaho State Univ, Coll Pharm, Pocatello, ID 83209 USA. Boise Vet Affairs Med Ctr, Boise, ID USA. Vet Affairs Sierra Nevada Hlth Syst, Reno, NV USA. Univ Nevada, Reno, NV 89557 USA. John L McClellan Mem Vet Hosp, Little Rock, AR USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. Iowa City Vet Affairs Med Ctr, Iowa City, IA USA. Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. RP Carter, BL (reprint author), Univ Iowa, Coll Pharm, Div Clin & Adm Pharm, S 532,Pharm Bldg, Iowa City, IA 52242 USA. NR 20 TC 23 Z9 25 U1 1 U2 4 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUL 15 PY 2001 VL 58 IS 14 BP 1330 EP 1337 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 454AE UT WOS:000169949600016 PM 11471481 ER PT J AU Hunninghake, GW Zimmerman, MB Schwartz, DA King, TE Lynch, J Hegele, R Waldron, J Colby, T Muller, N Lynch, D Galvin, J Gross, B Hogg, J Toews, G Helmers, R Cooper, JAD Baughman, R Strange, C Millard, M AF Hunninghake, GW Zimmerman, MB Schwartz, DA King, TE Lynch, J Hegele, R Waldron, J Colby, T Muller, N Lynch, D Galvin, J Gross, B Hogg, J Toews, G Helmers, R Cooper, JAD Baughman, R Strange, C Millard, M TI Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID DESQUAMATIVE INTERSTITIAL PNEUMONIA; THIN-SECTION CT; COMPUTED-TOMOGRAPHY; OBSERVER VARIATION; ALVEOLITIS; DISEASE; PROGNOSIS; ACCURACY AB It not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF. C1 Univ Iowa, Dept Med, Iowa City, IA 52242 USA. Univ Iowa, Dept Biostat, Iowa City, IA 52242 USA. Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. Vet Affairs Med Ctr, Iowa City, IA 52242 USA. Univ Colorado, Dept Med, Denver, CO 80202 USA. Univ Colorado, Dept Radiol, Denver, CO 80202 USA. Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. Mayo Clin Scottsdale, Dept Med, Scottsdale, AZ USA. Mayo Clin Scottsdale, Dept Pathol, Scottsdale, AZ USA. Birmingham VAMC, Dept Med, Birmingham, AL USA. Univ Alabama, Sch Med, Birmingham, AL 35294 USA. Univ Cincinnati, Dept Med, Cincinnati, OH 45221 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Baylor Univ, Med Ctr, Dept Med, Houston, TX 77030 USA. Univ British Columbia, Dept Med, Vancouver, BC V6T 1W5, Canada. Univ British Columbia, Dept Pathol, Vancouver, BC V6T 1W5, Canada. Univ Arkansas, Dept Pathol, Little Rock, AR 72204 USA. RP Hunninghake, GW (reprint author), Univ Iowa, Coll Med, Dept Internal Med, C33-Gh, Iowa City, IA 52242 USA. OI Strange, Charlie/0000-0002-8109-8067 NR 30 TC 298 Z9 320 U1 1 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2001 VL 164 IS 2 BP 193 EP 196 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 459WW UT WOS:000170275300005 PM 11463586 ER PT J AU Eisner, MD Thompson, T Hudson, LD Luce, JM Hayden, D Schoenfeld, D Matthay, MA AF Eisner, MD Thompson, T Hudson, LD Luce, JM Hayden, D Schoenfeld, D Matthay, MA CA Acute Respiratory Distress Synd TI Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; mechanical ventilators; acute lung injury ID QUALITY-OF-LIFE; SYNDROME ARDS; MORTALITY; SURVIVORS; RABBITS; PULMONARY; PNEUMONIA; SEVERITY; TRIAL AB In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a recent ARDS Network randomized controlled trial demonstrated that a low tidal volume (VT) mechanical ventilation strategy (6 ml/kg) reduced mortality by 22% compared with traditional mechanical ventilation (12 ml/kg). In this study, we examined the relative efficacy Of low VT mechanical ventilation among 902 patients with different clinical risk factors for AWARDS who participated in ARDS Network randomized controlled trials. The clinical risk factor for ALI/ARDS was associated with substantial variation in mortality. The risk of death (before discharge home with unassisted breathing) was highest in patients with sepsis (43%); intermediate in subjects with pneumonia (36%), aspiration (37%), and other risk factors (35%); and lowest in those with trauma (11%) (p < 0.0001). Despite these differences in mortality, there was no evidence that the efficacy of the low VT strategy varied by clinical risk factor (p = 0.76, for interaction between ventilator group and risk factor). There was also no evidence of differential efficacy Of low VT ventilation in the other study outcomes: proportion of patients achieving unassisted breathing (p = 0.59), ventilator-free days (p = 0.58), or development of nonpulmonary organ failure (p = 0.44). Controlling for demographic and clinical covariates did not appreciably affect these results. After reclassifying the clinical risk factors as pulmonary versus nonpulmonary predisposing conditions and infection-related versus non-infection-related conditions, there was still no evidence that the efficacy Of low VT ventilation differed among clinical risk factor subgroups. In conclusion, we found no evidence that the efficacy of the low VT ventilation strategy differed among clinical risk factor subgroups for ALI/ARDS. C1 Univ San Francisco, Div Environm & Occupat Med, Dept Med, San Francisco, CA 94117 USA. Univ San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94117 USA. Harvard Univ, Massachusetts Gen Hosp, ARDS Network Clin Coordinating Ctr, Cambridge, MA 02138 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Eisner, MD (reprint author), Univ San Francisco, Div Environm & Occupat Med, Dept Med, 350 Parnassus Ave,Suite 609, San Francisco, CA 94117 USA. FU NHLBI NIH HHS [K23 HL04201, N01-HR 46054, N01-HR 46055, N01-HR 46056, N01-HR 46057, N01-HR 46058, N01-HR 46059, N01-HR 46060, N01-HR 46061, N01-HR 46062, N01-HR 46063, N01-HR 46064] NR 34 TC 177 Z9 195 U1 1 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2001 VL 164 IS 2 BP 231 EP 236 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 459WW UT WOS:000170275300012 PM 11463593 ER PT J AU Wirshing, DA Pierre, JM Eyeler, J Weinbach, J Wirshing, WC AF Wirshing, DA Pierre, JM Eyeler, J Weinbach, J Wirshing, WC TI Risperidone-associated new-onset diabetes SO BIOLOGICAL PSYCHIATRY LA English DT Article DE risperidone; diabetes; obesity; schizophrenia; serotonin; weight ID MELLITUS; ANTIPSYCHOTICS; SCHIZOPHRENIA; DEPRESSION AB Background: Weight gain, and its associated complications such as the development of diabetes, is becoming increasingly recognized as an important potential side effect of the novel antipsychotic drugs. Methods: Two retrospective cases are described in which patients with schizophrenia developed diabetes while taking the antipsychotic medication risperidone. Results: Both patients had preexisting risk factors for diabetes and developed insulin resistance in the context of weight gain. Both cases necessitated medical intervention and one patient requires ongoing treatment with insulin. Conclusions: Although the exact mechanism of antipsychotic induced diabetes remains obscure, weight gain appears to be a significant risk factor. Careful monitoring of weight and fasting glucoses is recommended for any patient taking novel antipsychotic medications. (C) 2001 Society of Biological Psychiatry. C1 VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Sch Med, Los Angeles, CA USA. RP Wirshing, DA (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Psychiat, 11301 Wilshire Blvd,Bldg 210,Room 15,B151H, Los Angeles, CA 90073 USA. NR 10 TC 53 Z9 57 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2001 VL 50 IS 2 BP 148 EP 149 DI 10.1016/S0006-3223(01)01087-3 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 459KL UT WOS:000170249500010 PM 11526997 ER PT J AU Ni, H Ramakrishnan, V Ruggeri, ZM Papalia, JM Phillips, DR Wagner, DD AF Ni, H Ramakrishnan, V Ruggeri, ZM Papalia, JM Phillips, DR Wagner, DD TI Increased thrombogenesis and embolus formation in mice lacking glycoprotein V SO BLOOD LA English DT Article ID VON-WILLEBRAND-FACTOR; PLATELET THROMBUS FORMATION; BERNARD-SOULIER-SYNDROME; ALPHA-THROMBIN; BINDING-SITE; IB-ALPHA; SIGNALING PROTEIN; A1 DOMAIN; COMPLEX; FLOW AB The glycoprotein (GP) Ib-V-IX complex plays a critical role in initiating platelet adhesion to von Willebrand factor (VWF) at the site of vascular injury. The complex also forms a high-affinity binding site for thrombin, Using an intravital microscopy mouse model, it was previously established that vWF plays a critical role in mediating platelet adhesion and thrombus formation following mesenteric arteriolar injury induced by ferric chloride. Further characterization of this model showed that these thrombotic events were also thrombin dependent. Using this vWF-and thrombin-dependent model, this study shows that GP V gene deficiency significantly accelerates both platelet adhesion and thrombus formation in mice following arteriolar injury. The time required for vessel occlusion in GP V-deficient (GP V-/-) mice was significantly shorter than that in wild-type mice. Interestingly, large emboli were also produced in GP V-/- mice, but not in wild-type mice, causing frequent downstream occlusion. However, when the 2 genotypes were compared in the in vitro perfusion chamber where thrombin was inhibited by heparin, no significant differences were found in either initial single-platelet adhesion or thrombus volume. These results demonstrate that GP V-/- mice have accelerated thrombus growth in response to vascular injury and suggest that this is caused by enhanced thrombin-induced platelet activation rather than enhanced binding of GPIb-V-IX to vWF, Absence of GP V also compromises thrombus stability. (C) 2001 by The American Society of Hematology. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. COR Therapeut, San Francisco, CA USA. Scripps Res Inst, La Jolla, CA USA. RP Wagner, DD (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. OI Ni, Heyu/0000-0002-7621-2945 FU NHLBI NIH HHS [HL 31950, HL 42846, P01 HL56949, R37 HL41002] NR 35 TC 38 Z9 39 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2001 VL 98 IS 2 BP 368 EP 373 DI 10.1182/blood.V98.2.368 PG 6 WC Hematology SC Hematology GA 450AY UT WOS:000169720400016 PM 11435305 ER PT J AU Podar, K Tai, YT Davies, FE Lentzsch, S Sattler, M Hideshima, T Lin, BK Gupta, D Shima, Y Chauhan, D Mitsiades, C Raje, N Richardson, P Anderson, KC AF Podar, K Tai, YT Davies, FE Lentzsch, S Sattler, M Hideshima, T Lin, BK Gupta, D Shima, Y Chauhan, D Mitsiades, C Raje, N Richardson, P Anderson, KC TI Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration SO BLOOD LA English DT Article ID PROTEIN-KINASE CASCADE; RECEPTOR MESSENGER-RNA; MARROW STROMAL CELLS; KAPOSIS-SARCOMA; FACTOR VEGF; PERMEABILITY FACTOR; SPLICE VARIANTS; TYROSINE KINASE; KAPPA-B; ANGIOGENESIS AB Multiple myeloma (MM) remains incurable, with a median survival of 3 to 4 years. This study shows direct effects of vascular endothelial growth factor (VEGF) upon NIM and plasma cell leukemia (PCL) cells. The results indicate that VEGF triggers tumor cell proliferation via a protein kinase C (PKC)-independent Raf-1-MEK-extracellular signal-regulated protein kinase pathway and migration via a PKC-dependent pathway. These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM. (C) 2001 by The American Society of Hematology. C1 Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. FU PHS HHS [P0-1 78378] NR 59 TC 296 Z9 311 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2001 VL 98 IS 2 BP 428 EP 435 DI 10.1182/blood.V98.2.428 PG 8 WC Hematology SC Hematology GA 450AY UT WOS:000169720400024 PM 11435313 ER PT J AU Bartlett, NL Petroni, GR Parker, BA Wagner, ND Gockerman, JP Omura, GA Canellos, GP Cooper, MR Johnson, JL Peterson, BA AF Bartlett, NL Petroni, GR Parker, BA Wagner, ND Gockerman, JP Omura, GA Canellos, GP Cooper, MR Johnson, JL Peterson, BA TI Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma - Cancer and Leukemia Group B Studies 8852 and 8854 SO CANCER LA English DT Article DE non-Hodgkin lymphoma, cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide; granulocyte-colony stimulating factor; dose escalation ID NON-HODGKINS-LYMPHOMA; AGGRESSIVE LYMPHOMAS; PROMACE-CYTABOM; PHASE-II; TRIAL; TRANSPLANTATION; REGIMEN; THERAPY; CHOEP AB BACKGROUND. To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS. Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III-IV or bulky Stage II disease, and an ECOG performance status of 0-1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3-4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS. The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1-3 with doxorubicin 50 mg/m2 on Day 1, vincristine 1.4 mg/m(2) [maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1-5. With the addition of C-CSF at 200 mug/m(2) on Days 5-19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m2 on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 mug/m(2) to 400 mug/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%Cl], 23-39) and 48% (95%Cl, 40-57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%Cl, 17-52) and 51% (95%Cl, 33-70), respectively. CONCLUSIONS. Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP. (C) 2001 American Cancer Society. C1 Washington Univ, Sch Med, Barnard Canc Ctr, St Louis, MO 63110 USA. Stat Ctr, Canc & Leukemia Grp B, Durham, NC USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Alabama, Birmingham, AL USA. Dana Farber Partners Canc Care, Boston, MA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Minnesota, Minneapolis, MN 55455 USA. RP Bartlett, NL (reprint author), Washington Univ, Sch Med, Barnard Canc Ctr, 660 S Euclid,Box 8056, St Louis, MO 63110 USA. FU NCI NIH HHS [CA31946, CA33601, CA45418] NR 19 TC 20 Z9 20 U1 0 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2001 VL 92 IS 2 BP 207 EP 217 DI 10.1002/1097-0142(20010715)92:2<207::AID-CNCR1311>3.0.CO;2-D PG 11 WC Oncology SC Oncology GA 453XR UT WOS:000169943900001 PM 11466671 ER PT J AU Colevas, AD Amrein, PC Gomolin, H Barton, JJ Read, RR Adak, S Benner, S Costello, R Posner, MR AF Colevas, AD Amrein, PC Gomolin, H Barton, JJ Read, RR Adak, S Benner, S Costello, R Posner, MR TI A Phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck SO CANCER LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 19-23, 2000 CL NEW ORLEANS, LOUISIANA SP Amer Soc Clin Oncol DE uracil; ftorafur; tegafur; head and neck; squamous cell carcinoma; clinical trial; Phase II ID SOUTHWEST-ONCOLOGY-GROUP; ADVANCED COLORECTAL-CANCER; 5-FLUOROURACIL INFUSION; FLUOROURACIL; RECURRENT; CISPLATIN; METHOTREXATE; CHEMOTHERAPY; COMBINATION; PACLITAXEL AB BACKGROUND. The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/ LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS. Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS. One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10-37%). CONCLUSIONS, UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN. (C) 2001 American Cancer Society. C1 Dana Farber Canc Inst, Dept Adult Oncol, Head & Neck Oncol Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, Boston, MA USA. Harvard Vanguard Med Associates, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Wallingford, CT 06492 USA. RP Colevas, AD (reprint author), 44 Binney St, Boston, MA 02115 USA. NR 36 TC 11 Z9 11 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2001 VL 92 IS 2 BP 326 EP 331 DI 10.1002/1097-0142(20010715)92:2<326::AID-CNCR1326>3.0.CO;2-W PG 6 WC Oncology SC Oncology GA 453XR UT WOS:000169943900016 PM 11466686 ER PT J AU Pardo, FS Leon, S Carroll, R Black, P Atkin, L AF Pardo, FS Leon, S Carroll, R Black, P Atkin, L TI Pituitary tumorigenesis and hPit-1 cells SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID GROWTH-FACTOR; TUMORS; ADENOMAS; HORMONE; GENE AB Despite decades of clinical data verifying the success of therapeutic approaches to human pituitary tumors. a significant number of tumors progress and can be life-threatening. The development of better therapeutic strategies for pituitary tumors is complicated by the relative scarcity of human pituitary material for basic experimentation Human pituitary tissue was used to derive cell cultures. and a cell line, hPIT-1. Molecular and functional analyses were used to further characterize the cells as human pituitary explants in vitro. Functional analyses of the cell cultures indicated that the cells were tumorigenic and of human folliculostellate origin, hPit-1 cells revealed numerous abnormalities of ploidy. Molecular analyses indicated the absence of expression of the following pituitary hormones or hormone subunits by this culture: growth hormone, prolactin, ACTH, FSH beta, LH beta, TH beta, and p-glycoprotein. By contrast. the cells expressed uniformly high levels of human follistatin mRNA. Finally, the cells are moderately tumorigenic in immune-deficient mice. Although the precise molecular genetic mechanisms for tumorigenesis in thr established cell culture: art: unknown. the cells serve as a future resource in the study of pituitary tumor initiation, progression, and response to therapy. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Mol Tumor Radiat Biol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. UCSD Radiat Oncol, Oncol Mol Lab, San Diego, CA 92093 USA. RP Pardo, FS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Mol Tumor Radiat Biol, Boston, MA 02114 USA. NR 23 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JUL 15 PY 2001 VL 128 IS 2 BP 148 EP 153 DI 10.1016/S0165-4608(01)00406-X PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 455JT UT WOS:000170024300010 PM 11463454 ER PT J AU Ichikawa, T Chiocca, EA AF Ichikawa, T Chiocca, EA TI Comparative analyses of transgene delivery and expression in tumors inoculated with a replication-conditional or -defective viral vector SO CANCER RESEARCH LA English DT Article ID THYMIDINE KINASE GENE; SIMPLEX VIRUS TYPE-1; IONIZING-RADIATION; ONCOLYTIC VIRUS; CANCER-THERAPY; RECURRENT HEAD; GLIOMA-CELLS; NECK-CANCER; PHASE-I; BRAIN AB Viral vectors for cancer can be classified into those that do not replicate (replication-defective vectors) and those that selectively replicate in neoplastic cells (replication-conditional or oncolytic vectors). Both of these can deliver anticancer cDNAs for therapeutic purposes, Opposite hypotheses can be made regarding the advantages of each vector type with regard to anatomic transgene expression. For the former vector, because cDNA delivery occurs in neoplastic cells that have the ability to migrate into the tumor mass, relatively extensive anatomic and temporal expression of anticancer functions may occur. For the latter vector, active viral replication may permit anatomically and temporally extensive delivery of the foreign cDNA into the tumor mass. Herein, we performed a simple comparative analysis to test which of these hypotheses is valid. Direct inoculation of s.c. tumors with a replication-conditional or a replication-defective viral vector, each of which expressed lacZ cDNA, was performed. Tumors were excised and analyzed for anatomic delivery of beta -galactosidase and for neoplastic viral titers. We find that lacZ cDNA expression is observed in approximately 40% of the tumor area 3, 7, and 14 days after injection with the replication-conditional vector, whereas approximately 10% of the tumor area expresses the transgene 3 days after injection with the replication-defective vector, with a rapid decline in expression thereafter, Titers of the replication-conditional virus remain stable within injected tumors for the 14 days of the assay (approximately 1:1,000 of the initial injection dose), whereas titers of the replication-defective vector decrease rapidly after injection (to a value of 1:100,000 of the initial injection dose). Taken in conjunction, these studies show that transgene delivery and expression in tumors last longer and are found throughout an anatomically more extensive area after injection with replication-conditional gene therapy vectors than after injection with replication-defective gene therapy vectors. C1 Massachusetts Gen Hosp, Mol Neurooncol Lab, Neurosurg Serv, Charlestown, MA 02129 USA. RP Chiocca, EA (reprint author), Massachusetts Gen Hosp, Mol Neurooncol Lab, Neurosurg Serv, East Bldg CNY6,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [P01 CA692460] NR 23 TC 40 Z9 40 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2001 VL 61 IS 14 BP 5336 EP 5339 PG 4 WC Oncology SC Oncology GA 451YN UT WOS:000169830500002 PM 11454670 ER PT J AU Rebbeck, TR Wang, YT Kantoff, PW Krithivas, K Neuhausen, SL Godwin, AK Daly, MB Narod, SA Brunet, JS Vesprini, D Garber, JE Lynch, HT Weber, BL Brown, M AF Rebbeck, TR Wang, YT Kantoff, PW Krithivas, K Neuhausen, SL Godwin, AK Daly, MB Narod, SA Brunet, JS Vesprini, D Garber, JE Lynch, HT Weber, BL Brown, M TI Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history SO CANCER RESEARCH LA English DT Article ID ANDROGEN-RECEPTOR; MUTATION CARRIERS; OVARIAN-CANCER; CAG REPEAT; ESTROGEN; GENE; AGE; LENGTH; WOMEN AB Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance, We studied the effect of alleles at the A1B1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations, We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at A1B1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had A1B1 alleles no shorter than 28 or 29 or more A1B1 polyglutamine repeats (OR, 1.62; 95% CI, 2.02-10.56 and OR. 6.97: 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through A1B1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk. C1 Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med & Genet, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Canc, Boston, MA 02215 USA. Univ Utah, Dept Genet Epidemiol, Salt Lake City, UT 84108 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Womens Coll Hosp, Toronto, ON M5G 1N8, Canada. Creighton Univ, Dept Prevent Med, Omaha, NE 68179 USA. RP Rebbeck, TR (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, 904 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. RI Myles, Brown/B-6906-2008; OI Brown, Myles/0000-0002-8213-1658 FU NCI NIH HHS [CA55914, CA57601, CA70328, CA73730, CA74415, N01-CN-6700]; NIEHS NIH HHS [ES08030] NR 26 TC 91 Z9 93 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2001 VL 61 IS 14 BP 5420 EP 5424 PG 5 WC Oncology SC Oncology GA 451YN UT WOS:000169830500018 PM 11454686 ER PT J AU Nakamura, H Mullen, JT Chandrasekhar, S Pawlik, TM Yoon, SS Tanabe, KK AF Nakamura, H Mullen, JT Chandrasekhar, S Pawlik, TM Yoon, SS Tanabe, KK TI Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil SO CANCER RESEARCH LA English DT Article ID GENE-THERAPY; LIVER METASTASES; COLON-CARCINOMA; VIRAL MUTANT; TUMORS; COMPETENT; CANCER; VECTOR; ENHANCEMENT; GROWTH AB Infection of tumor cells by herpes simplex virus 1 (HSV-1) results in cell destruction and production of progeny virion in a process referred to as viral oncolysis, In this study, an HSV-I mutant (HSV1yCD) was engineered such that the viral ribonucleotide reductase gene is disrupted by sequences encoding yeast cytosine deaminase, which efficiently metabolizes the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), HSV1yCD-infected cells convert 5-FC to 5-FU, which enhances cytotoxicity without significantly reducing viral replication and oncolysis, Oncolysis by a replicating HSV-1 mutant combined with therapeutic transgene delivery represents a new paradigm; HSV1yCD-infected cells are destroyed by viral replication, and uninfected cells are subjected to bystander killing from both progeny virion and extracellular diffusion of 5-FU, In contrast, HSV1yCD-mediated bioactivation of another prodrug, ganciclovir, impairs viral replication, HSV1yCD administered into the portal venous system replicates preferentially in liver metastases rather than normal liver. The anti-neoplastic activity of HSV1yCD combined with systemic 5-FC administration is greater than that achieved with HSV-1 replication alone, Combination oncolysis and prodrug bioactivation leads to significant prolongation of survival in mice with diffuse liver metastases. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. RP Tanabe, KK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Cox Bldg,Room 626,100 Blossom St, Boston, MA 02114 USA. FU NCI NIH HHS [CA71345, CA76183]; NIDDK NIH HHS [DK43352]; NIGMS NIH HHS [GM07035] NR 25 TC 75 Z9 82 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2001 VL 61 IS 14 BP 5447 EP 5452 PG 6 WC Oncology SC Oncology GA 451YN UT WOS:000169830500022 PM 11454690 ER PT J AU Dominguez, I Green, JBA AF Dominguez, I Green, JBA TI Missing links in GSK3 regulation SO DEVELOPMENTAL BIOLOGY LA English DT Review ID GLYCOGEN-SYNTHASE KINASE-3; PROTEIN PHOSPHATASE 2A; WNT SIGNAL-TRANSDUCTION; EARLY XENOPUS EMBRYOS; APC TUMOR-SUPPRESSOR; MAMMARY EPITHELIAL-CELLS; EPIDERMAL GROWTH-FACTOR; BETA-CATENIN STABILITY; DORSAL-VENTRAL AXIS; NEGATIVE REGULATOR C1 Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Dominguez, I (reprint author), Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. RI Green, Jeremy/F-3630-2010; OI Green, Jeremy/0000-0002-6102-2620; Dominguez, Maria Isabel/0000-0001-9617-4141 NR 105 TC 52 Z9 54 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2001 VL 235 IS 2 BP 303 EP 313 DI 10.1006/dbio.2001.0317 PG 11 WC Developmental Biology SC Developmental Biology GA 455UT UT WOS:000170046700001 PM 11437438 ER PT J AU Maytin, EV Ubeda, M Lin, JC Habener, JF AF Maytin, EV Ubeda, M Lin, JC Habener, JF TI Stress-inducible transcription factor CHOP/gadd153 induces apoptosis in mammalian cells via p38 kinase-dependent and -independent mechanisms SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE apoptosis; programmed cell death; transcription factor; stress-inducible genes; stress response; green fluorescent protein ID FACTOR CHOP GADD153; BINDING-PROTEIN; FACTORS C/EBP; DNA DAMAGE; EPIDERMAL-KERATINOCYTES; ENDOPLASMIC-RETICULUM; MYXOID LIPOSARCOMA; GENE-TRANSCRIPTION; SODIUM-BUTYRATE; ACTIVATION AB CHOP/gadd153 is a transcription factor induced by cellular stresses such as UV light, genotoxic agents, and protein misfolding in the endoplasmic reticulum. The fact that these stresses induce CHOP expression, and at the same time cause cellular apoptosis, suggests that CHOP may be directly involved in apoptosis, However, evidence has been circumstantial. Here, we show that CHOP can directly induce apoptosis. A GFP-tagged CHOP vector, ectopically overexpressed in several cell types (3T3 fibroblasts, keratinocytes, and HeLa cells), caused apoptosis as defined by morphology, DNA fragmentation, and FAGS analysis. Apoptosis was quantified using a rapid fluorescence assay that measures the signal from cells collected in culture supernatants. The apoptosis-modulating effects of p38 kinase, previously shown to phosphorylate CHOP, were also examined. Simultaneous overexpression of CHOP and p38 significantly augmented apoptosis, However, although p38 kinase clearly modulated the activity of full-length CHOP, it was not absolutely required. Deletion mapping experiments showed that the bZIP region of CHOP stimulates apoptosis to nearly the same extent as wild-type CHOP, Thus, while the amino-terminal region of CHOP serves an important modulatory role (i.e., regulation by p38), the underlying apoptosis-inducing activity of CHOP resides within the bZIP region of the molecule. (C) 2001 Academic Press. C1 Cleveland Clin Fdn, Lerner Res Inst ND20, Dept Biomed Engn, Lab Mol Dermatol, Cleveland, OH 44195 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Mol Endocrinol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Maytin, EV (reprint author), Cleveland Clin Fdn, Lerner Res Inst ND20, Dept Biomed Engn, Lab Mol Dermatol, 9500 Euclid Ave, Cleveland, OH 44195 USA. FU PHS HHS [R01, R29] NR 44 TC 163 Z9 168 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUL 15 PY 2001 VL 267 IS 2 BP 193 EP 204 DI 10.1006/excr.2001.5248 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 452CY UT WOS:000169840600005 PM 11426938 ER PT J AU Lei, EP Krebber, H Silver, PA AF Lei, EP Krebber, H Silver, PA TI Messenger RNAs are recruited for nuclear export during transcription SO GENES & DEVELOPMENT LA English DT Article DE transcription; mRNA export; chromatin IP; RNA polymerase II; Npl3; Yra1 ID C-TERMINAL DOMAIN; CAP-BINDING COMPLEX; POLYMERASE-II; IN-VIVO; SACCHAROMYCES-CEREVISIAE; NUCLEOCYTOPLASMIC TRANSPORT; PORE COMPLEX; LARGE SUBUNIT; PROTEIN; YEAST AB following transcription and processing, eukaryotic mRNAs are exported from the nucleus to the cytoplasm for translation. Here we present evidence that mRNAs are targeted for nuclear export cotranscriptionally. Combined mutations in the Saccharomyces cerevisiae hnRNP Npl3 and TATA-binding protein (TBP) block mRNA export, implying that cotranscriptional recruitment of Npl3 is required for efficient export of mRNA. furthermore, Npl3 can be found in a complex with RNA Pol II, indicating that Npl3 associates with the transcription machinery. Finally, Npl3 is recruited to genes in a transcription dependent manner as determined by chromatin immunoprecipitation. Another mRNA export factor, Yra1, also associates with chromatin cotranscriptionally but appears to be recruited at a later step. Taken together, our results suggest that export factors are recruited to the sites of transcription to promote efficient mRNA export. C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM pamela_silver@dfci.harvard.edu NR 61 TC 158 Z9 160 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2001 VL 15 IS 14 BP 1771 EP 1782 DI 10.1101/gad.892401 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 455GW UT WOS:000170020000005 PM 11459827 ER PT J AU Hodgson, DC Goumnerova, LC Loeffler, JS Dutton, S Black, PM Alexander, E Xu, RH Kooy, H Silver, B Tarbell, NJ AF Hodgson, DC Goumnerova, LC Loeffler, JS Dutton, S Black, PM Alexander, E Xu, RH Kooy, H Silver, B Tarbell, NJ TI Radiosurgery in the management of pediatric brain tumors SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE radiosurgery; brain neoplasms; pediatrics ID GAMMA-KNIFE RADIOSURGERY; STEREOTAXIC RADIOSURGERY; PROGNOSTIC FACTORS; LINEAR-ACCELERATOR; ARTERIOVENOUS-MALFORMATIONS; GLIOBLASTOMA-MULTIFORME; MALIGNANT GLIOMAS; RADIATION-THERAPY; RESIDUAL TUMOR; CHILDREN AB Objective: To describe the outcome of pediatric brain tumor patients following stereotactic radiosurgery (SRS), and factors associated with progression-free survival. Methods: We reviewed the outcome of 90 children treated with SRS for recurrent (n = 62) or residual (n = 28) brain tumors over a 10 year period. Median follow-up from SRS was 24 months for all patients and 55.5 months for the 34 patients currently alive. Results: The median progression-free survival (PFS) for all patients was 13 months. Median PFS according to tumor histology was medulloblastoma = 11 months, ependymoma 8.5 months, glioblastoma and anaplastic astrocytoma = 12 months. Median PFS in patients treated to a single lesion was 15.4 months. No patient undergoing SRS to more than 1 lesion survived disease free beyond 2 years. After adjusting for histology and other clinical factors, SRS for tumor recurrence (RR = 2.49) and the presence of > 1 lesion (RR = 2.3) were associated with a significantly increased rate of progression (p < 0.05). Three-year actuarial local control (LC) was as follows: medulloblastoma = 57%, ependymoma = 29%, anaplastic astrocytoma/glioblastoma = 60%, other histologies = 56%. Nineteen patients with radionecrosis and progressive neurologic symptoms underwent reoperation after an interval of 0.6-62 months following SRS. Pathology revealed necrosis with no evidence of tumor in 9 of these cases. Conclusion: SRS can be given safely to selected children with brain tumors. SRS appears to reduce the proportion of first failures occurring locally and is associated with better outcome when given as a part of initial management. Some patients with unresectable relapsed disease can be salvaged with SRS. SRS to multiple lesions does not appear to be curative. Serious neurologic symptoms requiring reoperation is infrequently caused by radionecrosis alone. (C) 2001 Elsevier Science Inc. C1 Univ Toronto, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Longwood Radiat Oncol Ctr, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Tarbell, NJ (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St,Bulfinch 360, Boston, MA 02114 USA. NR 29 TC 48 Z9 51 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2001 VL 50 IS 4 BP 929 EP 935 DI 10.1016/S0360-3016(01)01518-8 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 448EZ UT WOS:000169615100011 PM 11429220 ER PT J AU Ng, AK Kuntz, KM Mauch, PM Weeks, JC AF Ng, AK Kuntz, KM Mauch, PM Weeks, JC TI Costs and effectiveness of staging and treatment options in early-stage Hodgkin's disease SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Hodgkin's disease; cost-effectiveness analysis; costs; patient preferences; utilities ID BONE-MARROW TRANSPLANTATION; EXTENDED-FIELD RADIOTHERAPY; RADIATION-THERAPY SALVAGE; SOUTHWEST-ONCOLOGY-GROUP; HIGH-DOSE THERAPY; COMBINATION CHEMOTHERAPY; PROGNOSTIC FACTORS; FOLLOW-UP; TREATMENT STRATEGIES; FAVORABLE-PROGNOSIS AB Purpose: Using a cost-effectiveness analysis, to weigh the costs and benefits of the different staging and treatment options in early-stage Hodgkin's disease. Methods: We constructed a decision-analytic model for a hypothetical cohort of 25-year-old patients with early-stage Hodgkin's disease. Markov models were used to simulate the lifetime costs and prognosis of each staging and treatment strategy. Baseline probabilities and cost estimates were derived from published studies and bills of relevant patient cohorts. Results: Among the six management strategies considered, the incremental cost-effectiveness ratio of laparotomy and tailored treatment compared with mantle and para-aortic-splenic radiation therapy in all clinical stage I-II patients was $24,100/quality-adjusted life year, while that of the strategy of combined modality therapy in all clinical stage I-II patients compared with laparotomy was $61,700/quality-adjusted life year. All the remaining strategies were dominated by one of these three strategies. Sensitivity analysis showed that the cost-effectiveness ratios were driven predominantly by the effectiveness rather than the cost of each strategy. In particular, the analysis was heavily influenced by the utility of the post-laparotomy health state. Conclusions: In considering the various alternative management strategies in early-stage Hodgkin's disease, even very small gains in effectiveness were enough to justify the additional costs of more expensive treatment options. (C) 2001 Elsevier Science Inc. C1 Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Weeks, JC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 454 Brookline Ave, Boston, MA 02115 USA. NR 65 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2001 VL 50 IS 4 BP 979 EP 989 DI 10.1016/S0360-3016(01)01546-2 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 448EZ UT WOS:000169615100017 PM 11429226 ER PT J AU Shapiro, CL Manola, J Leboff, M AF Shapiro, CL Manola, J Leboff, M TI Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MINERAL DENSITY; CLODRONATE; MENOPAUSE; REDUCTION AB Purpose: We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in ct prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy. patients and Methods: Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starling chemotherapy (baseline), and 6 and 12 months after starling chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone greater than or equal to 30 MIU/mL at the la-month evaluation. Results: Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was -4.0 (range, -10.4 to +1.0; P = .0001) and -3.7 (range, -10.1 to 9.2; P = .0001), respectively In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function, Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure, Conclusion: Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine, This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated, (C) 2001 by American Society of Clinical Oncology. C1 Ohio State Univ, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA. Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Shapiro, CL (reprint author), Ohio State Univ, Arthur G James Canc Hosp, Starling Loving Hall B421,320 W 10th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [R29 CA60050-06] NR 16 TC 226 Z9 236 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 15 PY 2001 VL 19 IS 14 BP 3306 EP 3311 PG 6 WC Oncology SC Oncology GA 452DB UT WOS:000169840900002 PM 11454877 ER PT J AU Henri, S Vremec, D Kamath, A Waithman, J Williams, S Benoist, C Burnham, K Saeland, S Handman, E Shortman, K AF Henri, S Vremec, D Kamath, A Waithman, J Williams, S Benoist, C Burnham, K Saeland, S Handman, E Shortman, K TI The dendritic cell populations of mouse lymph nodes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-II EXPRESSION; LANGERHANS CELLS; IN-VIVO; CD8 EXPRESSION; MICE LACKING; T-CELL; SPLEEN; PHENOTYPE; THYMUS; MATURATION AB The dendritic cells (DC) of mouse lymph nodes (LN) were isolated, analyzed for surface markers, and compared with those of spleen. Low to moderate staining of LN DC for CD4 and low staining for CD8 was shown to be attributable to pickup of these markers from T cells. Excluding this artifact, five LN DC subsets could be delineated. They included the three populations found in spleen (CD4(+)8(-)DEC-205(-), CD4(-)8(-)DEC-205(-), CD4(-)8(+)DEC-205(+)), although the CD4-expressing DC were of low incidence. LN DC included two additional populations, characterized by relatively low expression of CD8 but moderate or high expression of DEC-205. Both appeared among the DC migrating out of skin into LN, but only one was restricted to skin-draining LN and was identified as the mature form of epidermal Langerhans cells (LC). The putative LC-derived DC displayed the following properties: large size; high levels of class II MHC, which persisted to some extent even in CIITA null mice; expression of very high levels of DEC-205 and of CD40; expression of many myeloid surface markers; and no expression of CD4 and only low to moderate expression of CD8. The putative LC-derived DC among skin emigrants and in LN also showed strong intracellular staining of langerin. C1 Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. Scripps Clin, La Jolla, CA 92037 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Oklahoma State Univ, Stillwater, OK 74078 USA. Schering Plough Corp, Lab Immunol Res, Dardilly, France. RP Henri, S (reprint author), PO Royal Melbourne Hosp, Walter & Eliza Inst Med Res, Melbourne, Vic 3050, Australia. RI Henri, Sandrine/O-3045-2016 NR 33 TC 330 Z9 341 U1 1 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2001 VL 167 IS 2 BP 741 EP 748 PG 8 WC Immunology SC Immunology GA 471VL UT WOS:000170949300018 PM 11441078 ER PT J AU Brander, C O'Connor, P Suscovich, T Jones, NG Lee, Y Kedes, D Ganem, D Martin, J Osmond, D Southwood, S Sette, A Walker, BD Scadden, DT AF Brander, C O'Connor, P Suscovich, T Jones, NG Lee, Y Kedes, D Ganem, D Martin, J Osmond, D Southwood, S Sette, A Walker, BD Scadden, DT TI Definition of an optimal cytotoxic T lymphocyte epitope in the latently expressed Kaposi's sarcoma-associated herpesvirus kaposin protein SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DENDRITIC CELLS; SEXUAL TRANSMISSION; IMMUNE-RESPONSES; HODGKINS-DISEASE; HOMOSEXUAL MEN; MHC MOLECULES; IN-VITRO; INFECTION; IDENTIFICATION AB Cytotoxic T lymphocytes (CTL) recognize and kill virus-infected cells and contribute to immunologic control of viral replication. For many herpesviruses (e.g., Epstein-Barr and cytomegalovirus), virus-specific CTL responses can be readily detected in infected persons, but CTL responses against Kaposi's sarcoma-associated herpesvirus (KSHV) appear to be weak and remain poorly characterized. Using a human leukocyte antigen (HLA) binding motif-based epitope prediction algorithm, we identified 37 HLA-A*0201 binding peptides from 8 KSHV open-reading frames (ORFs). After in vitro stimulation of peripheral blood mononuclear cells from KSHV-infected persons, CTL responses against 1 peptide in the KSHV kaposin protein (ORF K12) were detected in 2 HLA-A*0201-positive subjects. The optimal CTL epitope was identified by HLA restriction analysis and peptide titration assays. These data describe a latent phase viral gene product targeted by CTL that may be relevant for KSHV immunopathogenesis. C1 Massachusetts Gen Hosp, Ctr AIDS Res, Boston, MA 02129 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Virginia Hlth Syst, Myles H Thaler Ctr AIDS Res, Dept Microbiol, Charlottesville, VA USA. Univ Virginia Hlth Syst, Myles H Thaler Ctr AIDS Res, Dept Med, Charlottesville, VA USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Microbiol & Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Epimmune, San Diego, CA USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr AIDS Res, 149 13th St,Rm 5212, Boston, MA 02129 USA. FU NCI NIH HHS [CA-78378, CA-78124, CA-73580]; NIAID NIH HHS [AI-42851] NR 42 TC 40 Z9 42 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2001 VL 184 IS 2 BP 119 EP 126 DI 10.1086/322003 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 447DM UT WOS:000169554500001 PM 11424007 ER PT J AU Morris, EJ Keramaris, E Rideout, HJ Slack, RS Dyson, NJ Stefanis, L Park, DS AF Morris, EJ Keramaris, E Rideout, HJ Slack, RS Dyson, NJ Stefanis, L Park, DS TI Cyclin-dependent kinases and P53 pathways are activated independently and mediate bax activation in neurons after DNA damage SO JOURNAL OF NEUROSCIENCE LA English DT Article DE apoptosis; p53; CDK; neuronal; cell cycle; Bax ID CEREBELLAR GRANULE NEURONS; TROPHIC FACTOR DEPRIVATION; KILLS POSTMITOTIC NEURONS; TRANSCRIPTION FACTOR E2F1; ALZHEIMERS-DISEASE BRAIN; PROGRAMMED CELL-DEATH; SYMPATHETIC NEURONS; CYTOSINE-ARABINOSIDE; INDUCED APOPTOSIS; C-JUN AB DNA damage has been implicated as one important initiator of cell death in neuropathological conditions such as stroke. Accordingly, it is important to understand the signaling processes that control neuronal death induced by this stimulus. Previous evidence has shown that the death of embryonic cortical neurons treated with the DNA-damaging agent camptothecin is dependent on the tumor suppressor p53 and cyclin-dependent kinase (CDK) activity and that the inhibition of either pathway alone leads to enhanced and prolonged survival. We presently show that p53 and CDKs are activated independently on parallel pathways. An increase in p53 protein levels, nuclear localization, and DNA binding that result from DNA damage are not affected by the inhibition of CDK activity. Conversely, no decrease in retinoblastoma protein (pRb) phosphorylation was observed in p53-deficient neurons that were treated with camptothecin. However, either p53 deficiency or the inhibition of CDK activity alone inhibited Bax translocation, cytochrome c release, and caspase-3-like activation. Taken together, our results indicate that p53 and CDK are activated independently and then act in concert to control Bax-mediated apoptosis. C1 Univ Ottawa, Neurosci Res Inst, Ottawa, ON K1H 8M5, Canada. Columbia Univ, New York, NY 10032 USA. Massachusetts Gen Hosp, Ctr Canc, Mol Oncol Lab, Charlestown, MA 02129 USA. RP Park, DS (reprint author), Univ Ottawa, Neurosci Res Inst, Ottawa, ON K1H 8M5, Canada. NR 64 TC 83 Z9 85 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 15 PY 2001 VL 21 IS 14 BP 5017 EP 5026 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 449NR UT WOS:000169692800011 PM 11438577 ER PT J AU Katchanov, J Harms, C Gertz, K Hauck, L Waeber, C Hirt, L Priller, J von Harsdorf, R Bruck, W Hojrtnagl, H Dirnagl, U Bhide, PG Endres, M AF Katchanov, J Harms, C Gertz, K Hauck, L Waeber, C Hirt, L Priller, J von Harsdorf, R Bruck, W Hojrtnagl, H Dirnagl, U Bhide, PG Endres, M TI Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cell cycle; cerebral ischemia; cyclin-dependent kinases; delayed neuronal cell death; p16 (INK4a); p27(Kip1) ID ALZHEIMERS-DISEASE; DENTATE GYRUS; SYMPATHETIC NEURONS; POSTMITOTIC NEURONS; CORTICAL-NEURONS; PROMOTE SURVIVAL; PC12 CELLS; IN-VIVO; BRAIN; NEUROGENESIS AB After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number (similar to1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms. C1 Humboldt Univ, Charite, Neurol Klin & Poliklin, D-10098 Berlin, Germany. Humboldt Univ, Charite, Inst Pharmacol & Toxicol, D-10098 Berlin, Germany. Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. Franz Volhard Clin, D-13125 Berlin, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Struct & Neurovasc Regulat Lab, Charlestown, MA 02129 USA. Humboldt Univ, Virchow Hosp, Charite, Dept Neuropathol, D-13353 Berlin, Germany. RP Endres, M (reprint author), Humboldt Univ, Charite, Neurol Klin & Poliklin, Schumannstr 20-21, D-10098 Berlin, Germany. RI Waeber, Christian/A-8333-2009; Gertz, Karen/J-1603-2015; Hirt, Lorenz/G-3553-2010; OI Waeber, Christian/0000-0001-6078-0027; Hirt, Lorenz/0000-0002-2921-5000; Harms, Christoph/0000-0002-2063-2860; Dirnagl, Ulrich/0000-0003-0755-6119 FU NINDS NIH HHS [NS 32657] NR 63 TC 164 Z9 185 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 15 PY 2001 VL 21 IS 14 BP 5045 EP 5053 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 449NR UT WOS:000169692800014 PM 11438580 ER PT J AU Chang, BH Waternaux, C Lipsitz, S AF Chang, BH Waternaux, C Lipsitz, S TI Meta-analysis of binary data: which within study variance estimate to use? SO STATISTICS IN MEDICINE LA English DT Article ID METAANALYSIS AB We applied a mixed effects model to investigate between- and within-study variation in improvement rates of 180 schizophrenia outcome studies. The between-study variation was explained by the fixed study characteristics and an additional random study effect. Both rate difference and logit models were used. For a binary proportion outcome p(i) with sample size n(i) in the ith study, ((p) over cap (i)(1 - (p) over cap (i))n(i))(-1) is the usual estimate of the within-study variance sigma (2)(i) in the logit model, where (p) over cap (i) is the sample mean of the binary outcome for subjects in study i. This estimate can be highly correlated with logit((p) over cap (i)). we used ((p) over bar (i)(1 - (p) over bar )n(i))(-1) as an alternative estimate of sigma (2)(i), where (p) over bar is the weighted mean of (p) over cap (i)'s. We estimated regression coefficients (beta) of the fixed effects and the variance (tau (2)) of the random study effect using a quasi-likelihood estimating equations approach. Using the schizophrenia meta-analysis data, we demonstrated how the choice of the estimate of sigma (2)(i) affects the resulting estimates of beta and tau (2). We also conducted a simulation study to evaluate the performance of the two estimates of sigma (2)(i) in different conditions, where the conditions vary by number of studies and study size. Using the schizophrenia meta-analysis data, the estimates of beta and tau (2) were quite different when different estimates of sigma (2)(i) were used in the logit model. The simulation study showed that the estimates of beta and tau (2) were less biased, and the 95 per cent CI coverage was closer to 95 per cent when the estimate of sigma (2)(i) was ((p) over bar (1 - (p) over bar )n(i))(-1) rather than ((p) over cap (i)(1 - (p) over cap (i))n(i))(-1). Finally, we showed that a simple regression analysis is not appropriate unless tau (2) is much larger than sigma (2)(i), or a robust variance is used. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Boston Univ, SPH, Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. New York State Psychiat Inst, Div Biostat, New York, NY 10032 USA. Dana Farber Canc Inst, Div Biostat, Boston, MA 02115 USA. RP Chang, BH (reprint author), Boston Univ, SPH, Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, 200 Springs Rd,Bldg 70, Bedford, MA 01730 USA. NR 7 TC 20 Z9 20 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUL 15 PY 2001 VL 20 IS 13 BP 1947 EP 1956 DI 10.1002/sim.823.abs PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 446VB UT WOS:000169533900005 PM 11427951 ER PT J AU Theruvath, TP Saidman, SL Mauiyyedi, S Delmonico, FL Williams, WW Tolkoff-Rubin, N Collins, AB Colvin, RB Cosimi, AB Pascual, M AF Theruvath, TP Saidman, SL Mauiyyedi, S Delmonico, FL Williams, WW Tolkoff-Rubin, N Collins, AB Colvin, RB Cosimi, AB Pascual, M TI Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection SO TRANSPLANTATION LA English DT Article ID PERITUBULAR CAPILLARIES; KIDNEY-TRANSPLANTATION; DYSFUNCTION; COMBINATION; NEPHROPATHY; PROGRESSION; IMMUNITY; RESCUE; HLA AB Background. In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC), Since rescue therapy with tacrolimus and mycophenolate mofetil has been fouled to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'. Methods. Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d dec posits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1), Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. Results. At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl), DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128, Rescue therapy was associated with a rapid and sustained decrease in antibody titers In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC, Conclusion. These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil, Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplantat Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Pascual, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Unit, Box MZ 70, Boston, MA 02114 USA. NR 35 TC 108 Z9 116 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2001 VL 72 IS 1 BP 77 EP 83 DI 10.1097/00007890-200107150-00016 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 453ZZ UT WOS:000169949100016 PM 11468538 ER PT J AU Fuchimoto, Y Gleit, ZL Huang, CA Kitamura, H Schwarze, ML Menard, MT Mawulawde, K Madsen, JC Sachs, DH AF Fuchimoto, Y Gleit, ZL Huang, CA Kitamura, H Schwarze, ML Menard, MT Mawulawde, K Madsen, JC Sachs, DH TI Skin-specific alloantigens in miniature swine SO TRANSPLANTATION LA English DT Article ID LARGE-ANIMAL-MODEL; MIXED CHIMERISM; LONG-TERM; TOLERANCE; ALLOGRAFTS AB Background. The acceptance of skin allografts has historically been among the most challenging problems in the field of transplantation, attributed, at least in part, to the existence of antigens expressed by skin but not by other tissues. Many studies have suggested the existence of skin-specific antigens in rodents, but data in large-animal models are more limited. Methods. We have recently developed protocols for attaining stable mixed hematopoietic chimerism in miniature swine, using MHC-matched donors and recipients, We have now assessed tolerance to donor-derived skin and cardiac allografts in these chimeric animals, Results. Skin-graft rejection was seen in four of six animals receiving skin grafts taken from the respective hematopoietic donors, In the other two animals, donor-derived skin grafts survived indefinitely. No cardiac-allograft rejection was observed in mixed-chimeric animals that received heart transplants from their hematopoietic donors, even in animals that had already rejected skin allografts from the same donors. In all animals assessed, in vitro hyporesponsiveness to donor hematopoietic cells persisted. Conclusion, These findings support the concept that skin expresses immunogenic alloantigens that either are not expressed or are not immunogenic in cardiac or hematopoietic tissue. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp East, Transplantat Biol Res Ctr, Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NCI NIH HHS [1RO1 CA79989-01A1]; NHLBI NIH HHS [1RO1 HL63430-01]; NIAID NIH HHS [1F32AI-10306] NR 15 TC 31 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2001 VL 72 IS 1 BP 122 EP 126 DI 10.1097/00007890-200107150-00024 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 453ZZ UT WOS:000169949100024 PM 11468546 ER PT J AU McBride, AE Silver, PA AF McBride, AE Silver, PA TI State of the Arg: Protein methylation at arginine comes of age SO CELL LA English DT Review ID N-METHYLTRANSFERASE; SUBSTRATE-SPECIFICITY; BINDING; OLIGOMERIZATION; DOMAIN; PRMT3 C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Dept Canc Biol,Dana Farber Canc Inst, Boston, MA 02115 USA. RP McBride, AE (reprint author), Bowdoin Coll, Dept Biol, Brunswick, ME 04011 USA. NR 20 TC 331 Z9 338 U1 3 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 13 PY 2001 VL 106 IS 1 BP 5 EP 8 DI 10.1016/S0092-8674(01)00423-8 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 452QM UT WOS:000169870300002 PM 11461695 ER PT J AU Grishok, A Pasquinelli, AE Conte, D Li, N Parrish, S Ha, I Baillie, DL Fire, A Ruvkun, G Mello, CC AF Grishok, A Pasquinelli, AE Conte, D Li, N Parrish, S Ha, I Baillie, DL Fire, A Ruvkun, G Mello, CC TI Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C-elegans developmental timing SO CELL LA English DT Article ID DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; CELL-DIFFERENTIATION; MESSENGER-RNA; LIN-4 RNA; PROTEINS; TRANSCRIPTION; TRANSLATION; HELICASE; SEQUENCE AB RNAi is a gene-silencing phenomenon triggered by double-stranded (ds) RNA and involves the generation of 21 to 26 nt RNA segments that guide mRNA destruction. In Caenorhabditis elegans, lin-4 and let-7 encode small temporal RNAs (stRNAs) of 22 nt that regulate stage-specific development. Here we show that inactivation of genes related to RNAi pathway genes, a homolog of Drosophila Dicer (dcr-1), and two homologs of rde-1 (alg-1 and alg-2), cause heterochronic phenotypes similar to lin-4 and let-7 mutations. Further we show that dcr-1, alg-1, and alg-2 are necessary for the maturation and activity of the lin-4 and let-7 stRNAs. Our findings suggest that a common processing machinery generates guide RNAs that mediate both RNAi and endogenous gene regulation. C1 Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Johns Hopkins Univ, Biol Grad Program, Baltimore, MD 21218 USA. Simon Fraser Univ, Inst Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. Carnegie Inst Washington, Baltimore, MD 21210 USA. Hanwha Chem R&D Inst, Daejun 305345, South Korea. RP Mello, CC (reprint author), Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. FU NIGMS NIH HHS [R01 GM037706, GM07321, GM37706, GM58800] NR 42 TC 1142 Z9 1241 U1 9 U2 87 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 13 PY 2001 VL 106 IS 1 BP 23 EP 34 DI 10.1016/S0092-8674(01)00431-7 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 452QM UT WOS:000169870300006 PM 11461699 ER PT J AU Mao, CG Xu, RJ Szulc, ZM Bielawska, A Galadari, SH Obeid, LM AF Mao, CG Xu, RJ Szulc, ZM Bielawska, A Galadari, SH Obeid, LM TI Cloning and characterization of a novel human alkaline ceramidase - A mammalian enzyme that hydrolyzes phytoceramide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EUKARYOTIC STRESS-RESPONSE; SACCHAROMYCES-CEREVISIAE; MOLECULAR-CLONING; PSEUDOMONAS-AERUGINOSA; NEUTRAL CERAMIDASE; ANCHORED PROTEINS; FUMONISIN B-1; CELL-GROWTH; SPHINGOLIPIDS; INHIBITION AB Ceramidases are enzymes involved in regulating cellular levels of ceramides, sphingoid bases, and their phosphates, Based on sequence homology to the yeast alkaline ceramidases YPC1p (Mao, C,, Xu, R,, Bielawska, A., and Obeid, L, M, (2000) J. Biol, Chem. 275, 6876-6884) and YDC1p (Mao, C,, Xu, R,, Bielawska, A., Szulc, Z, M,, and Obeid, L, RI. (2000) J. Biol Chem, 275, 31369-31378), we report the identification and cloning of a cDNA encoding for a novel human alkaline ceramidase (aPHC) that hydrolyzes phytoceramide selectively, Northern blot analysis showed that aPHC was ubiquitously expressed, with the highest expression in placenta. Green fluorescent protein tagging showed that it was localized in both the Golgi apparatus and endoplasmic reticulum. Overexpression of aPHC in mammalian cells elevated in vitro ceramidase activity toward N-4-nitrobenz-2-oxa-1,3-diazole-C-12-phytoceramide. Its expression in a yeast mutant strain devoid of any ceramidase activity restored the ceramidase activity and caused an increase in the hydrolysis of phytoceramide in yeast cells, thus leading to the decreased biosynthesis of sphingolipids. These data collectively suggest that, similar to the yeast phytoceramidase YPC1p, aPHC has phytoceramidase activity both in vitro and in cells; hence, it is a functional homolog of the yeast phytoceramidase YPC1p, However, in contrast to YPC1p, aPHC exhibited no reverse activity of ceramidase either in vitro or in cells. Biochemical characterization showed that aPHC had a pH optimum of 9.5, was activated by Ca2+, but was inhibited by Zn2+ and sphingosine, Substrate specificity showed that aPHC hydrolyzed phytoceramide preferentially, Together, these data demonstrate that aPHC is a novel human alkaline phytoceramidase, the first mammalian alkaline ceramidase to be identified as being specific for the hydrolysis of phytoceramide. C1 Med Univ S Carolina, Ralph H Johnson Vet Affairs Hosp, Div Gen Internal Med, Charleston, SC 29425 USA. United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Biochem, Abu Dhabi, U Arab Emirates. RP Mao, CG (reprint author), Dept Med, 114 Doughty St,Rm 605 STB,POB 250779, Charleston, SC 29425 USA. OI obeid, lina/0000-0002-0734-0847 NR 44 TC 96 Z9 98 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2001 VL 276 IS 28 BP 26577 EP 26588 DI 10.1074/jbc.M102818200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 451VP UT WOS:000169823300122 PM 11356846 ER PT J AU Reddien, PW Cameron, S Horvitz, HR AF Reddien, PW Cameron, S Horvitz, HR TI Phagocytosis promotes programmed cell death in C-elegans SO NATURE LA English DT Article ID CAENORHABDITIS-ELEGANS; APOPTOTIC CELLS; PROTEIN CED-9; GENE; ENGULFMENT; ENCODES; NEMATODE; MACROPHAGES; ACTIVATION; MIGRATION AB In the nematode Caenorhabditis elegans programmed cell death requires the killer genes egl-1, ced-4 and ced-3 (refs 1 and 2), and the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 (refs 3-5). Here we show that engulfment promotes programmed cell death. Mutations that cause partial loss of function of killer genes allow the survival of some cells that are programmed to die, and mutations in engulfment genes enhance the frequency of this cell survival. Furthermore, mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die. Engulfment genes probably act in engulfing cells to promote death, as the expression in engulfing cells of ced-1, which encodes a receptor that recognizes cell corpses(6), rescues the cell-killing defects of ced-1 mutants. We propose that engulfing cells act to ensure that cells triggered to undergo programmed cell death by the CED-3 caspase(7) die rather than recover after the initial stages of death. C1 MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA 02115 USA. RP Horvitz, HR (reprint author), MIT, Howard Hughes Med Inst, Dept Biol, 68-425,77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 30 TC 231 Z9 250 U1 1 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 12 PY 2001 VL 412 IS 6843 BP 198 EP 202 DI 10.1038/35084096 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 451AJ UT WOS:000169778700056 PM 11449278 ER PT J AU Karlsson, M Reue, K Xia, YR Lusis, AJ Langin, D Tornqvist, H Holm, C AF Karlsson, M Reue, K Xia, YR Lusis, AJ Langin, D Tornqvist, H Holm, C TI Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene SO GENE LA English DT Article DE monoglyceride lipase; gene structure; 5 ' leader sequences; 3 ' untranslated region; human cDNA sequence ID HORMONE-SENSITIVE LIPASE; PURIFICATION; EXPRESSION; TISSUE AB Monoglyceride lipase (MGL) functions together with hormone-sensitive lipase to hydrolyze intracellular triglyceride stores of adipocytes and other cells to fatty acids and glycerol. In addition, MGL presumably complements lipoprotein lipase in completing the hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides. Cosmid clones containing the mouse MGL gene were isolated from a genomic library using the coding region of the mouse MGL cDNA as probe. Characterization of the clones obtained revealed that the mouse gene contains the coding sequence for MGL on seven exons, including a large terminal exon of approximately 2.6 kb containing the stop codon and the complete 3 ' untranslated region. Two different 5 ' leader sequences, diverging 21 bp upstream of the predicted translation initiation codon, were isolated from a mouse adipocyte cDNA library. Western blot analysis of different mouse tissues revealed protein size heterogeneities. The amino acid sequence derived from human MGL cDNA clones showed 84% identity with mouse MGL. The mouse MGL gene was mapped to chromosome 6 in a region with known homology to human chromosome 3q21. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Lund Univ, BMC, Dept Cell & Mol Biol, S-22184 Lund, Sweden. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Microbiol & Mol Genet, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Toulouse 3, Hop Rangueil, Fac Med, Inst Louis Bugnard,INSERM,Unite 317, F-31403 Toulouse 4, France. Novo Nordisk AS, Diabet Biol, DK-2880 Bagsvaerd, Denmark. RP Holm, C (reprint author), Lund Univ, BMC, Dept Cell & Mol Biol, C11, S-22184 Lund, Sweden. FU NHLBI NIH HHS [HL 28481] NR 15 TC 55 Z9 58 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUL 11 PY 2001 VL 272 IS 1-2 BP 11 EP 18 DI 10.1016/S0378-1119(01)00559-5 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 467WR UT WOS:000170727200002 PM 11470505 ER PT J AU Hermankova, M Ray, SC Ruff, C Powell-Davis, M Ingersoll, R D'Aquila, RT Quinn, TC Siliciano, RF Persaud, D AF Hermankova, M Ray, SC Ruff, C Powell-Davis, M Ingersoll, R D'Aquila, RT Quinn, TC Siliciano, RF Persaud, D TI HIV-1 drug resistance profiles in children and adults with viral load of < 50 copies/mL receiving combination therapy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE; LATENT RESERVOIR; GENOTYPIC RESISTANCE; PROTEASE INHIBITOR; CONFERS RESISTANCE; INFECTED PATIENTS; PLASMA VIREMIA; IN-VIVO AB Context The continued release of human immunodeficiency virus type 1 (HIV-1) into plasma at very low levels during highly active antiretroviral therapy (HAART) can be detected using specialized techniques, but the nature and significance of this low-level viremia, especially as related to acquisition of drug resistance mutations, are unclear. Objective To determine genetic resistance profiles of low-level plasma HIV-1 in patients with prolonged viral suppression (<50 copies/mL of plasma HIV-1 RNA) while receiving HAART. Design and Setting Cross-sectional study conducted at a US academic hospital from November 1999 to February 2001 using a novel method for amplification of low levels of viral genomes in plasma. Patients Eighteen HIV-1-infected patients (7 children and 11 adults), enrolled in a longitudinal study of HIV-1 reservoirs, who had suppression of viral replication while receiving protease inhibitor-containing combination therapy. Two patients (1 adult and 1 child) with less optimal suppression of viral replication were included to assess virus predominating when plasma HIV-1 RNA levels are low but detectable (<1000 copies/mL). Follow-up analyses were conducted in 3 patients. Main Outcome Measure Detection of drug resistance mutations in clones amplified from low-level plasma virus. Results Viral sequences were amplified from 8 of the 18 patients with simultaneous plasma HIV-1 measurements of less than 50 copies/mL and from 2 patients with 231 and 50 copies/mL. Clones from 3 treatment-naive patients with less than 50 copies/mL of plasma HIV-1 RNA showed continued release, for as long as 42 months, of wild-type drug-sensitive virus. The 7 patients with prior nonsuppressive therapy, with viral loads below 50 copies/mL and during "blips" to 231 and 64 copies/mL, had only resistance mutations consistent with pre-HAART therapy (although reverse transcriptase inhibitor mutations may have continued to occur), New HAART-related mutations were seen in a control patient with prior viral load levels of about 400 to 1000 copies/mL. For phylogenetic analysis, sequences were available for both resting CD4(+) T cells and plasma HIV for 7 of 10 patients and showed patient-specific clustering of sequences and a close relationship between virus in the plasma and the latent reservoir. Conclusions Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia to less than 50 copies/mL of HIV-1 RNA may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART-selected mutations reflecting partial resistance to therapy. Low-level viremia below 50 copies/mL may represent less of a concern regarding impending drug failure of current HAART regimens, However, the archival drug-resistant virus may be relevant regarding future treatment strategies. C1 Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Genet, Baltimore, MD USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, 600 N Wolfe St,256 Pk Bldg, Baltimore, MD 21287 USA. RI Quinn, Thomas/A-2494-2010; Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU NIAID NIH HHS [AI29193, AI43222]; NICHD NIH HHS [P30HD27799] NR 47 TC 162 Z9 166 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 11 PY 2001 VL 286 IS 2 BP 196 EP 207 DI 10.1001/jama.286.2.196 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 451JJ UT WOS:000169798700025 PM 11448283 ER PT J AU Pelish, HE Westwood, NJ Feng, Y Kirchhausen, T Shair, MD AF Pelish, HE Westwood, NJ Feng, Y Kirchhausen, T Shair, MD TI Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HYPERVALENT IODINE(III) REAGENT; PHENOLIC COUPLING REACTION; AMARYLLIDACEAE ALKALOIDS; GOLGI PROTEINS; BREFELDIN-A; IDENTIFICATION; LIBRARY; CELLS; ANALOGS; AGENTS C1 Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Inst Chem & Cell Biol, Boston, MA 02115 USA. RP Shair, MD (reprint author), Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. NR 27 TC 187 Z9 192 U1 2 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 11 PY 2001 VL 123 IS 27 BP 6740 EP 6741 DI 10.1021/ja016093h PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 452AQ UT WOS:000169835300049 PM 11439080 ER PT J AU Jobling, MF Huang, XD Stewart, LR Barnham, KJ Curtain, C Volitakis, I Perugini, M White, AR Cherny, RA Masters, CL Barrow, CJ Collins, SJ Bush, AI Cappai, R AF Jobling, MF Huang, XD Stewart, LR Barnham, KJ Curtain, C Volitakis, I Perugini, M White, AR Cherny, RA Masters, CL Barrow, CJ Collins, SJ Bush, AI Cappai, R TI Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126 SO BIOCHEMISTRY LA English DT Article ID BETA-AMYLOID PEPTIDES; ALZHEIMER A-BETA; PROTEIN-PEPTIDES; ALPHA-HELIX; IN-VITRO; DISEASE; FRAGMENT; RESIDUES-106-126; AFFINITY; REGION AB The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible spongiform encephalopathies, A peptide encompassing residues 106-126 of human PrP (PrP106-126) is neurotoxic in vitro due its adoption of an amyloidogenic fibril structure. The Alzheimer's disease amyloid beta peptide (A beta) also undergoes fibrillogenesis to become neurotoxic. A beta aggregation and toxicity is highly sensitive to copper, zinc, or iron ions. We show that PrP106-126 aggregation, as assessed by turbidometry, is abolished in Chelex-100-treated buffer, ICP-MS analysis showed that the Chelex-100 treatment had reduced Cu2+ and Zn2+ levels approximately 3-fold. Restoring Cu2+ and Zn2+ to their original levels restored aggregation. Circular dichroism showed that the Chelex-100 treatment reduced the aggregated beta -sheet content of the peptide. Electron paramagnetic resonance spectroscopy identified a 2N1S1O coordination to the Cu2+ atom, suggesting histidine 111 and methionine 109 or 112 are involved. Nuclear magnetic resonance confirmed Cu2+ and Zn2+ binding to His-111 and weaker binding to Met-112, An N-terminally acetylated PrP106-126 peptide did not bind Cu2+ implicating the free amino group in metal binding. Mutagenesis of either His-111, Met-109, or Met-111 abolished PrP106-126 neurotoxicity and its ability to form fibrils. Therefore, Cu2+ and/or Zn2+ binding is critical for PrP106-126 aggregation and neurotoxicity. C1 Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. Mental Hlth Res Inst, Parkville, Vic 3052, Australia. Univ Melbourne, Sch Chem, Melbourne, Vic 3010, Australia. Massachusetts Gen Hosp East, Genet & Aging Unit, Lab Oxidat Biol, Charlestown, MA 02129 USA. Biomol Res Inst, Parkville, Vic 3052, Australia. Monash Univ, Sch Phys, Clayton, Vic 3168, Australia. Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia. RP Cappai, R (reprint author), Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. RI Bush, Ashley/A-1186-2007; White, Anthony/P-5596-2016; OI Bush, Ashley/0000-0001-8259-9069; White, Anthony/0000-0003-1802-9891; Curtain, Cyril/0000-0001-6955-320X; Cappai, Roberto/0000-0002-9505-8496 NR 54 TC 216 Z9 223 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 10 PY 2001 VL 40 IS 27 BP 8073 EP 8084 DI 10.1021/bi0029088 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 451ZV UT WOS:000169833400014 PM 11434776 ER PT J AU Feng, DL Lindpaintner, K Larson, MG O'Donnell, CJ Lipinska, I Sutherland, PA Mittleman, M Muller, JE D'Agostino, RB Levy, D Tofler, GH AF Feng, DL Lindpaintner, K Larson, MG O'Donnell, CJ Lipinska, I Sutherland, PA Mittleman, M Muller, JE D'Agostino, RB Levy, D Tofler, GH TI Platelet glycoprotein IIIa Pl(A) polymorphism, fibrinogen, and platelet aggregability - The Framingham heart study SO CIRCULATION LA English DT Article DE platelets; genetics; glycoproteins; fibrinogen ID CORONARY-ARTERY DISEASE; MYOCARDIAL-INFARCTION; RISK; ASSOCIATION; THROMBOSIS; RECEPTOR; BINDING; GPIIIA; AGGREGATION; STROKE AB Background-Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor fur cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with PP genotype in modulating platelet aggregability, Methods and Results-Glycoprotein ma PIA genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Barn method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation respectively) but not for the Pl(A2)-positive genotype (P >0.90). Conclusion-Higher fibrinogen levels were associated with increased platelet aggregability, However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding PIA genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Inst Prevent Cardiovasc Dis, Boston, MA 02215 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Boston Univ, Dept Math, Stat & Consulting Unit, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. Royal N Shore Hosp, Sydney, NSW, Australia. RP Feng, DL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 55th Fruit St,Bulfinch 106, Boston, MA 02114 USA. FU NHLBI NIH HHS [K04-HL-03138-01, R01-HL48157] NR 33 TC 44 Z9 47 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 10 PY 2001 VL 104 IS 2 BP 140 EP 144 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 453BJ UT WOS:000169896600015 PM 11447076 ER PT J AU Khaw, BA da Silva, J Vural, I Narula, J Torchilin, V AF Khaw, BA da Silva, J Vural, I Narula, J Torchilin, V TI Intracytoplasmic gene delivery for in vitro transfection with cytoskeleton-specific immunoliposomes SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE in vitro gene transfection; cell culture; transient hypoxia; immunoliposomes; antimyosin; luciferase; beta-galactosidase ID LIPOSOME-MEDIATED TRANSFECTION; PLASMID DNA; CATIONIC LIPIDS; IN-VITRO; THERAPY; LUNG; TOXICITY; CELLS; CYTOTOXICITY; LOCALIZATION AB A novel and highly efficient method of in vitro gene transfection has been developed. This method employs direct intracytoplasmic gene delivery into embryonic cardiocytes using neutral cytoskeletal-antigen specific immunoliposomes (CSIL). These immunoliposomes target cardiocytes specifically under reversible hypoxic conditions. Two independent reporter genes, pGL2 and pSV-beta -galactosidase, were used! to verify CSIL-transfection (CSIL-fection). The efficiency of CSIL-fection with firefly luciferase pGL2 vector was 30+ times greater than controls consisting of hypoxic cardiocytes treated with plain liposomes (PL) or normoxic cardiocytes treated with CSIL, PL or naked DNA. CSIL-fection was also compared to cationic liposome transfection. Net cationic liposome transfection appeared to be more efficient than CSIL-fection for pGL2 vectors. However, a smaller number of viable cells was observed in the cationic liposome treated cultures than in the CSIL treated cultures. Therefore, to determine whether more cells were transfected with cationic liposomes or CSIL, pSV-beta -galactosidase vector was used. CSIL-fection with pSV-beta -galactosidase vector produced at least 40 times more transfected cells than those transfected with cationic liposomes. No transfection with pSV-beta -galactosidase vectors was obtained with IgG-liposome, PL or naked DNA treatments. Targeted enhanced efficiency of transfection by this novel method could have practical therapeutic applications in the genetic modification of cells ex vivo that could then be reimplanted into patients for gene therapy. (C) 2001 Elsevier Science BY All rights reserved. C1 Northeastern Univ, Dept Pharmaceut Sci, Ctr Cardiovasc Targeting, Bouve Coll Hlth Sci, Boston, MA 02115 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Med Coll Penn & Hahnemann Univ, Philadelphia, PA USA. RP Khaw, BA (reprint author), Northeastern Univ, Dept Pharmaceut Sci, Ctr Cardiovasc Targeting, Bouve Coll Hlth Sci, Mugar Bldg,Rm 205, Boston, MA 02115 USA. NR 32 TC 26 Z9 27 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 10 PY 2001 VL 75 IS 1-2 BP 199 EP 210 DI 10.1016/S0168-3659(01)00364-9 PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 456VT UT WOS:000170103800019 PM 11451510 ER PT J AU Fernandez, M Raskind, W Matsushita, M Wolff, J Lipe, H Bird, T AF Fernandez, M Raskind, W Matsushita, M Wolff, J Lipe, H Bird, T TI Hereditary benign chorea - Clinical and genetic features of a distinct disease SO NEUROLOGY LA English DT Article ID GTP CYCLOHYDROLASE-I; LINKAGE ANALYSIS; RESPONSIVE DYSTONIA; CHROMOSOME 14Q; MUTATIONS; MAPS AB Objective To describe a second family with benign hereditary chorea (BCH, OMIM 118700) and suggestive Linkage to chromosome 14q. BGH is an autosomal dominant disorder of early onset that differs from Huntington disease in being nondementing and nonprogressive without other neurologic signs. There has been controversy regarding the existence of BCH as a discrete disorder. Background: A single kindred was recently reported with Linkage of BCH to a 20.6-KcM region on chromosome 14q. Methods In a four-generation family with BCH, linkage was evaluated to markers in a 23-KcM region between D14S49 and D14S66 that contains the putative BCH locus. Results: A multipoint nonparametric Iod score of 3.01 is consistent with linkage of disease in this family to the 14q BCH locus. A recombination event in one affected individual enabled the critical region to be narrowed to 6.93 KcM flanked by D14S1068 and D14S1064. This region contains two candidate genes: glial maturation factor beta and guanosine triphosphate cyclohydrolase I (GCH1). Survival motor neuron (SMN) interacting protein-1 is eliminated as a candidate gene because it Lies outside the critical region. No sequence alteration was identified in the coding region of GCH1 in an affected individual. Conclusion: These data provide further evidence that BCH is a distinct entity, narrow the location of BCH to a 6.93-KcM region on chromosome 14q, and exclude SMN interacting protein-1 as a candidate gene. C1 Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. Univ Washington, Sch Med, Dept Psychiat, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Geriatr & Mental Illness Res Serv, VISN 20, Seattle, WA USA. RP Bird, T (reprint author), Univ Washington, Vet Affairs Med Ctr, Geriatr Res Serv, S-182-GRECC,1660 S Columbian Way, Seattle, WA 98108 USA. FU NIA NIH HHS [1 T32 AG00258-01A1] NR 20 TC 15 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 10 PY 2001 VL 57 IS 1 BP 106 EP 110 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 449TD UT WOS:000169702500019 PM 11445636 ER PT J AU Huang, JN Park, I Ellingson, E Littlepage, LE Pellman, D AF Huang, JN Park, I Ellingson, E Littlepage, LE Pellman, D TI Activity of the ApC(Cdh1) form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p SO JOURNAL OF CELL BIOLOGY LA English DT Article DE cell cycle; cyclin-dependent kinases; mitosis; S phase; ubiquitin ID CELL-CYCLE REGULATION; SACCHAROMYCES-CEREVISIAE; PHOSPHATASE CDC14; DNA-REPLICATION; MITOTIC SPINDLE; BUDDING YEAST; APC; PROTEOLYSIS; PHOSPHORYLATION; MITOSIS AB Cell cycle progression is driven by waves of cyclin expression coupled with regulated protein degradation. An essential step for initiating mitosis is the inactivation of proteolysis mediated by the anaphase-promoting complex/cyclosome (APC/C) bound to its regulator Cdh1p/Hct1p. Yeast APC(Cdh1) was Proposed previously to be inactivated at Start by G1 cyclin/cyclin-dependent kinase (CDK). Here, we demonstrate that in a normal cell cycle APC(Cdh1) is inactivated in a graded manner and is not extinguished until S phase. Complete inactivation of APC(Cdh1) requires S phase cyclins. Further, persistent APC(Cdh1) activity throughout G1 helps to ensure the proper timing of Cdc20p expression. This suggests that S phase cyclins have an important role in allowing the accumulation of mitotic cyclins and further suggests a regulatory loop among S phase cyclins, APC(Cdh1), and APC(Cdh1). C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat Hematol, Boston, MA 02115 USA. Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Houston, TX 77030 USA. RP Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Rm M612A,44 Binney St, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU NICHD NIH HHS [P30 HD27823-10, K08 HD01203]; NIGMS NIH HHS [R01 GM55772] NR 48 TC 80 Z9 83 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 9 PY 2001 VL 154 IS 1 BP 85 EP 94 DI 10.1083/jcb.200102007 PG 10 WC Cell Biology SC Cell Biology GA 452FB UT WOS:000169845900014 PM 11448992 ER EF