FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Crowson, AN Mihm, MC Nash, J Magro, CM AF Crowson, AN Mihm, MC Nash, J Magro, CM TI The cutaneous manifestations of Crohn's disease in sites discontiguous from the involved gastrointestinal tract: A clinicopathological study of 28 patients. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Cent Med Labs, Winnipeg, MB, Canada. Reg Med Lab, Tulsa, OK USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 377 BP 67A EP 67A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400385 ER PT J AU Granter, SR McKee, PH Calonje, E Mihm, MC Busam, K AF Granter, SR McKee, PH Calonje, E Mihm, MC Busam, K TI Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: A clinicopathologic study of 10 cases on the spectrum of so-called "malignant blue nevus" SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dept Pathol, Div Dermatopathol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Div Dermatopathol, Boston, MA 02114 USA. St Thomas Hosp, St Johns Inst Dermatol, Dept Dermatopathol, London, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 382 BP 67A EP 67A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400390 ER PT J AU Harris, K Duncan, L Tanabe, K Flotte, T AF Harris, K Duncan, L Tanabe, K Flotte, T TI Sentinel lymph nodes: Relative counts as an indication of melanoma metastasis SO MODERN PATHOLOGY 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 NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 384 BP 68A EP 68A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400392 ER PT J AU North, PE Waner, M Mizeracki, A Nicholas, R Kincannon, I Gibson, D Mihm, MC AF North, PE Waner, M Mizeracki, A Nicholas, R Kincannon, I Gibson, D Mihm, MC TI Placental antigens expressed by juvenile hemangioma (JH) are not present in other benign vascular proliferations SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 AR Childrens Hosp, Little Rock, AR USA. Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 403 BP 71A EP 71A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400744 ER PT J AU Faquin, WC Pitman, MB Barcus, ME Nasser, SM Pilch, BZ Glyptis, T Powers, CN AF Faquin, WC Pitman, MB Barcus, ME Nasser, SM Pilch, BZ Glyptis, T Powers, CN TI Measurement of DNA topoisomerase II alpha expression differentiates benign from malignant Hurthle cell neoplasms of the thyroid. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 430 BP 75A EP 75A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400437 ER PT J AU Gallagher, LA Pilch, BZ Gaz, RD Randolph, GW Faquin, WC AF Gallagher, LA Pilch, BZ Gaz, RD Randolph, GW Faquin, WC TI Histologic and clinicopathologic features of 31 medullary and microcarcinomas and their precursors. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 433 BP 76A EP 76A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400440 ER PT J AU Rosenberg, AE Nielsen, GP Lauwers, GY Yantiss, RK AF Rosenberg, AE Nielsen, GP Lauwers, GY Yantiss, RK TI Reactive nodular fibrous pseudotumor of the gastrointestinal tract: A clinicopathological study of four cases. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 542 BP 94A EP 94A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400549 ER PT J AU Yantiss, RK Farraye, FA Chang, HK Compton, CC Odze, RD AF Yantiss, RK Farraye, FA Chang, HK Compton, CC Odze, RD TI Prognostic significance of acinar cell differentiation in pancreatic endocrine tumors (PET). SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 572 BP 99A EP 99A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400579 ER PT J AU Amin, MB Young, RH Scully, RE AF Amin, MB Young, RH Scully, RE TI Large cell hyalinizing Sertoli cell tumor of the testis: A distinctive estrogenic tumor of boys with Peutz-Jeghers syndrome (PJS): A report of six cases. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Emory Univ Hosp, Atlanta, GA 30322 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 580 BP 100A EP 100A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400587 ER PT J AU Hatzianastassiou, DK Young, RH Srigley, JR Ulbright, TM AF Hatzianastassiou, DK Young, RH Srigley, JR Ulbright, TM TI Unusual patterns of differentiation in Leydig cell tumors of the testis. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Indiana Univ, Indianapolis, IN 46204 USA. Army Gen Hosp 401, Athens, Greece. Massachusetts Gen Hosp, Boston, MA 02114 USA. McMaster Univ, Hamilton, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 639 BP 110A EP 110A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400646 ER PT J AU Henley, JD Young, RH Ulbright, TM AF Henley, JD Young, RH Ulbright, TM TI Clear cell sex cord-stromal tumours of the testis: A mimicker of seminoma SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Indiana Univ Hosp, Dept Pathol, Indianapolis, IN 46202 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 640 BP 110A EP 110A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400647 ER PT J AU Krishnan, B Smith, V Lechago, J Chen, Z Truong, L AF Krishnan, B Smith, V Lechago, J Chen, Z Truong, L TI Mast cells in renal epithelial neoplasm's (REN), identification and significance. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Methodist Hosp, Dept Pathol, VA Med Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 662 BP 114A EP 114A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400669 ER PT J AU Kukoski, R Macri, E Renshaw, AA Hoffman, M Loda, M Datta, MW AF Kukoski, R Macri, E Renshaw, AA Hoffman, M Loda, M Datta, MW TI Functional sequestration of p27 by cyclin D2 leads to cyclin activation in testicular germ cell tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. Baptist Hosp, Dept Pathol, Miami, FL USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Urol, Boston, MA USA. Dana Farber Canc Inst, Div Tumor Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 665 BP 115A EP 115A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400672 ER PT J AU McGregor, DK Ayala, G Krishnan, B Truong, L AF McGregor, DK Ayala, G Krishnan, B Truong, L TI Diagnosing primary and metastatic renal cell carcinoma (RCC), the use of the renal cell carcinoma marker (RMa). SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. Methodist Hosp, Houston, TX 77030 USA. VA Med Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 678 BP 117A EP 117A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400685 ER PT J AU McKenney, JK Amin, MB Srigley, JR Ro, JY Jimenez, R Grignon, DJ Young, RH AF McKenney, JK Amin, MB Srigley, JR Ro, JY Jimenez, R Grignon, DJ Young, RH TI Adenoid basal proliferations of the prostate other than usual basal cell hyperplasia: A study of 23 cases with a proposed classification. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Emory Univ, Atlanta, GA 30322 USA. Credit Valley Hosp, Mississauga, ON, Canada. Wayne State Univ, Detroit, MI USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 680 BP 117A EP 117A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400687 ER PT J AU Oliva, E Amin, MB Jimenez, R Young, RH AF Oliva, E Amin, MB Jimenez, R Young, RH TI Clear cell carcinoma (CCC) of the urinary bladder: A report of thirteen cases with emphasis on its histogenesis SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Emory Univ Hosp, Dept Pathol, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 691 BP 119A EP 119A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400698 ER PT J AU Osipov, V Keating, JT Faul, P Loda, M Datta, MW AF Osipov, V Keating, JT Faul, P Loda, M Datta, MW TI The expression of p27 and VHL in renal tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 693 BP 119A EP 119A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400700 ER PT J AU Piris, A Velazquez, EF Cubilla, AL AF Piris, A Velazquez, EF Cubilla, AL TI Continuous sequence of Squamous Hyperplasia and low grade invasive squamous cell carcinoma (SCC) of the penis suggests a causal link. A report of 30 cases. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Inst Patol & Invest, Asuncion, Paraguay. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 699 BP 120A EP 120A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400706 ER PT J AU Tamboli, P Amin, MB Eble, JN Young, RH AF Tamboli, P Amin, MB Eble, JN Young, RH TI Histologic spectrum of glandular neoplasms of the urachus, with special emphasis on low-grade tumors. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Emory Univ, Atlanta, GA 30322 USA. Indiana Univ Hosp, Indianapolis, IN 46202 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 722 BP 124A EP 124A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400729 ER PT J AU Velazquez, EF Piris, A Cubilla, AL AF Velazquez, EF Piris, A Cubilla, AL TI High grade Squamous Intraepithelial lesion (HGSIL) of the penis: Morphological subtypes correlates with homologous variants of invasive squamous cell carcinoma (SCC). A report of 126 cases. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Inst Patol & Invest, Asuncion, Paraguay. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 736 BP 126A EP 126A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400743 ER PT J AU Velazquez, EF Piris, A Cubilla, AL AF Velazquez, EF Piris, A Cubilla, AL TI Correlation of lichen sclerosus (LS) with histological types of penile squamous cell carcinoma (SCC) and giant condylomas. A study of 61 cases. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Inst Patol & Invest, Asuncion, Paraguay. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 737 BP 127A EP 127A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400746 ER PT J AU Weinstein, M Signoretti, S Loda, M AF Weinstein, M Signoretti, S Loda, M TI Diagnostic utility of p63 staining of prostate needle biopsies. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 742 BP 127A EP 127A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400751 ER PT J AU Wu, CL Chakravarti, A Delaney, M Zietman, AL Shipley, WU Hammond, EH AF Wu, CL Chakravarti, A Delaney, M Zietman, AL Shipley, WU Hammond, EH TI Loss of p16 protein expression correlates with Gleason scores and distant metastasis of prostate cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Univ Utah, Sch Med, Latter Day St Hosp, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 745 BP 128A EP 128A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400754 ER PT J AU Wu, CL Cheng, L AF Wu, CL Cheng, L TI Quantification of spermine in intact human prostate specimens SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 744 BP 128A EP 128A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400753 ER PT J AU Baergen, RN Rutgers, JL Young, RH AF Baergen, RN Rutgers, JL Young, RH TI Extrauterine lesions of intermediate trophoblast (ELIT). SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Cornell Univ, Weill Med Coll, New York, NY USA. Univ Calif Irvine, Long Beach Mem Med Ctr, Long Beach, CA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 774 BP 133A EP 133A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400783 ER PT J AU Bell, DA Mok, S AF Bell, DA Mok, S TI P53 and c-erbB2 overexpression in microscopic ovarian carcinomas. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 775 BP 133A EP 133A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400784 ER PT J AU Fan, MJ Sung, R Oliva, E Young, RH Scully, RE AF Fan, MJ Sung, R Oliva, E Young, RH Scully, RE TI Morphologic spectrum and differential diagnosis of 63 ovarian smooth muscle tumors SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 794 BP 136A EP 136A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400803 ER PT J AU Fan, MJ Sung, R Oliva, E Young, RH Scully, RE AF Fan, MJ Sung, R Oliva, E Young, RH Scully, RE TI Spindle cell ovarian smooth muscle tumors: A study of 53 cases evaluating prognostic criteria SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 795 BP 136A EP 136A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400804 ER PT J AU Murray, SK Young, RH Scully, RE AF Murray, SK Young, RH Scully, RE TI Uterine endometrioid carcinoma with small non-villous papillae: An analysis of 26 cases of a favorable-prognosis tumor to be distinguished from serous carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 826 BP 141A EP 141A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400835 ER PT J AU Oliva, E Amin, MB Murray, SK Young, RH Scully, RE AF Oliva, E Amin, MB Murray, SK Young, RH Scully, RE TI Endometrial stromal and smooth muscle tumors of the uterus; Do they have distinctive immunohistochemical profiles? SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Emory Univ Hosp, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 831 BP 142A EP 142A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400840 ER PT J AU Pitman, MB Cibas, E Powers, CN Frable, WJ AF Pitman, MB Cibas, E Powers, CN Frable, WJ TI Consequences of eliminating ASCUS SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 838 BP 143A EP 143A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400847 ER PT J AU Krane, JF McKeon, F Faquin, WC AF Krane, JF McKeon, F Faquin, WC TI Expression of p63, a p53 homologue, in normal and neoplastic salivary gland (SG) SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 881 BP 151A EP 151A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400890 ER PT J AU de Leval, L Braaten, KM Harris, NL AF de Leval, L Braaten, KM Harris, NL TI Primary large B-cell lymphoma of bone: A B-cell neoplasm with a predominantly germinal-center (GC)-like immunophenotype. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 939 BP 160A EP 160A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400948 ER PT J AU Dong, HY Shahsafaei, A Dorfman, DM AF Dong, HY Shahsafaei, A Dorfman, DM TI CD27 and CD148 are expressed in B cell lymphomas derived from both memory and native B cells. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 943 BP 161A EP 161A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400952 ER PT J AU Du, MQ Liu, H Diss, TC Hamoudi, RA Cabecadas, J Dong, HY Harris, N Isaacson, PG AF Du, MQ Liu, H Diss, TC Hamoudi, RA Cabecadas, J Dong, HY Harris, N Isaacson, PG TI KSHV positive germinotropic lymphoma: A new KSHV associated lymphoproliferative disorder SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 UCL Royal Free & Univ Coll Med Sch, London, England. Canc Res Inst, Gene Cloning Ctr, Sutton, Surrey, England. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 946 BP 161A EP 161A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622400955 ER PT J AU Lauwers, GY Terris, B Batts, KP Chang, Y Yamabe, H Belghiti, J Nagorney, DM Flejou, JF Yamaoka, Y Vauthey, JN AF Lauwers, GY Terris, B Batts, KP Chang, Y Yamabe, H Belghiti, J Nagorney, DM Flejou, JF Yamaoka, Y Vauthey, JN TI Prognostic histologic determinants of resected hepatocellular carcinomas SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Hop Beaujon, Paris, France. Mayo Clin, Rochester, MN USA. Kyoto Univ, Kyoto, Japan. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 1169 BP 199A EP 199A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622401178 ER PT J AU Wu, CL Kirley, S Zukerberg, LR AF Wu, CL Kirley, S Zukerberg, LR TI Cables is a novel cell cycle regulatory protein SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 1253 BP 213A EP 213A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622401262 ER PT J AU Quade, BJ Lemyre, E Bruns, GAP Gusella, JF Korf, BR Herrick, SR Ligon, AH Lewis, J Maas, RL Michelson, AM Morton, CC AF Quade, BJ Lemyre, E Bruns, GAP Gusella, JF Korf, BR Herrick, SR Ligon, AH Lewis, J Maas, RL Michelson, AM Morton, CC TI Developmental Genome Anatomy Project: Two breakpoints localized in large insert genomic clones. SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Charlestown, MA USA. Childrens Hosp, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 1265 BP 215A EP 215A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622401274 ER PT J AU Matsubara, O Imazeki, N Okochi, Y Ozeki, Y Mark, EJ AF Matsubara, O Imazeki, N Okochi, Y Ozeki, Y Mark, EJ TI Vascular endothelial growth factor and thrombospondin-1 in diffuse alveolar damage and advanced pulmonary fibrosis SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Natl Def Med Coll, Tokorozawa, Saitama 359, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 1318 BP 223A EP 223A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622401327 ER PT J AU Lindeman, N Waltregny, D Signoretti, S Loda, M AF Lindeman, N Waltregny, D Signoretti, S Loda, M TI Rapid immunostaining of frozen sections: a tool for laser capture microdissection and quantitative RT-PCR SO MODERN PATHOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2001 VL 14 IS 1 MA 1378 BP 233A EP 233A PG 1 WC Pathology SC Pathology GA 396EB UT WOS:000166622401387 ER PT J AU Tsou, R Isik, FF AF Tsou, R Isik, FF TI Integrin activation is required for VEGF and FGF receptor protein presence on human microvascular endothelial cells SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE integrins; extracellular matrix; growth factor receptors; microvascular; endothelial cell; angiogenesis ID FIBROBLAST GROWTH-FACTOR; EXTRACELLULAR-MATRIX; MESSENGER-RNA; ANGIOGENESIS; EXPRESSION; ALPHA(V)BETA(3); MODULATION; ADHESION; INVITRO; INVIVO AB Endothelial cell proliferation and migration is initiated by growth factors including FGF and VEGF that bind to specific transmembrane receptor tyrosine kinases. Mechanisms that regulate in vivo expression of fibroblast growth factor receptors (FGFR) and vascular endothelial growth factor receptors (VEGFR) are not well understood. Since it is well known that different matrices influence the proliferation and migration of endothelial cells in culture, we hypothesized that changes in the extracellular matrix environment can regulate growth factor receptors on endothelial cells. We cultured human microvascular endothelial cells on different matrices (vitronectin, laminin, fibronectin, fibrin, and collagen IV) and examined for the presence of growth factor receptors (FGFR-1, FGFR-2, VEGFR-1, and VEGFR-2). We show that vitronectin increased the presence of all four growth factor receptors and most notably, VEGFR-1. In contrast, fibrin decreased all four receptors, especially FGFR-1 and FGFR-2. Inhibiting phosphotyrosine signaling abolished immunostaining for all four receptors, regardless of the matrix, but was not dependent on activating the Fyn-Shc pathway. Cells plated on vitronectin in the presence of blocking antibodies to integrins alpha (v)beta (3) and alpha (v)beta (5) similarly decreased presence of these growth factor receptors. Our data suggests a possible mechanism of how matrix-integrin interactions regulate endothelial cell responsiveness to growth factors and anchorage-dependent cell growth. C1 Univ Washington, Med Ctr, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA USA. RP Tsou, R (reprint author), Univ Washington, Med Ctr, Box 356410,1959 NE Pacific St, Seattle, WA 98195 USA. FU NIGMS NIH HHS [R01 GM57426] NR 46 TC 37 Z9 38 U1 0 U2 8 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PY 2001 VL 224 IS 1-2 BP 81 EP 89 DI 10.1023/A:1011947301849 PG 9 WC Cell Biology SC Cell Biology GA 475EG UT WOS:000171148800009 PM 11693202 ER PT J AU Tsuruzoe, K Emkey, R Kriauciunas, KM Ueki, K Kahn, CR AF Tsuruzoe, K Emkey, R Kriauciunas, KM Ueki, K Kahn, CR TI Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FACTOR-I-RECEPTOR; PROTEIN-TYROSINE-PHOSPHATASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOTYROSINE PROTEIN; TISSUE EXPRESSION; ADIPOSE-CELLS; SHC PROTEINS; KINASE-B; GROWTH; GENE AB To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system, Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. In these cell lines, IGF-1 caused the rapid tyrosine phosphorylation of all four IRS proteins. However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells, This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. IRS-3 expression in WT cells also caused an increase in IGF-1-induced mitogen-activated protein kinase phosphorylation and egr-1 expression (similar to1.8- and similar to2.4-fold with respect to WT). In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. C1 Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr,Res Div, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr,Res Div, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK33201, DK36836, DK55545, P30 DK036836, R01 DK033201, R01 DK055545] NR 48 TC 60 Z9 66 U1 0 U2 4 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 JAN PY 2001 VL 21 IS 1 BP 26 EP 38 DI 10.1128/MCB.21.1.26-38.2001 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382VD UT WOS:000165847300003 PM 11113178 ER PT J AU Li, YJ Higgins, RR Pak, BJ Shivdasani, RA Ney, PA Archer, M Ben-David, Y AF Li, YJ Higgins, RR Pak, BJ Shivdasani, RA Ney, PA Archer, M Ben-David, Y TI p45(NFE2) is a negative regulator of erythroid proliferation which contributes to the progression of Friend virus-induced erythroleukemias SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR NF-E2; MURINE LEUKEMIA-VIRUS; MULV-INDUCED-ERYTHROLEUKEMIAS; HUMAN FERROCHELATASE GENE; LEUCINE ZIPPER PROTEIN; CELLULAR P53 GENE; F-MULV; CONTROL REGION; MICE LACKING; EXPRESSION AB In previous studies, we identified a common site of retroviral integration designated Fli-2 in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia cell lines. Insertion of F-MuLV at the Fli-2 locus, which was associated with the loss of the second allele, resulted in the inactivation of the erythroid cell- and megakaryocyte-specific gene p45(NFE2). Frequent disruption of p45(NFE2) due to proviral insertion suggests a role for this transcription factor in the progression of Friend virus-induced erythroleukemias. To assess this possibility, erythroleukemia was induced by F-MuLV in p45(NFE2) mutant mice. Since p45(NFE2) homozygous mice mostly die at birth, erythroleukemia was induced in +/- and +/+ mice. We demonstrate that +/- mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/- mice were significantly larger than those of +/+ mice. Of the 37 tumors generated from the +/- and +/+ mice, 10 gave rise to cell lines, all of which were derived from +/- mice. Establishment in culture was associated with the loss of the remaining wild-type p45(NFE2) allele in 9 of 10 of these cell lines. The loss of a functional p45(NFE2) in these cell lines was associated with a marked reduction in globin gene expression. Expression of wild-type p45(NFE2) in the nonproducer erythroleukemic cells resulted in reduced cell growth and restored the expression of globin genes. Similarly, the expression of p45(NFE2) in these cells also slows tumor growth in vivo. These results indicate that p45(NFE2) functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia. C1 Sunnybrook & Womens Coll Hlth Sci Ctr, Div Canc Biol Res, Toronto, ON M4N 3M5, Canada. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON M4N 3M5, Canada. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. RP Ben-David, Y (reprint author), Sunnybrook & Womens Coll Hlth Sci Ctr, Div Canc Biol Res, 2075 Bayview Ave,S Wing,Room S216, Toronto, ON M4N 3M5, Canada. FU NCI NIH HHS [R01 CA084214-02, CA21762, R01 CA084214, R01 CA084214-01, R01 CA084214-03, R01 CA084214-04, R01 CA084214-05]; NIDDK NIH HHS [R01 DK053469, R01 DK053469-01A2, R01 DK053469-02, R01 DK053469-03, R01 DK053469-04, R01 DK53469] NR 35 TC 19 Z9 19 U1 0 U2 1 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 JAN PY 2001 VL 21 IS 1 BP 73 EP 80 DI 10.1128/MCB.21.1.73-80.2001 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382VD UT WOS:000165847300007 PM 11113182 ER PT J AU Dufresne, SD Bjorbaek, C El-Haschimi, K Zhao, Y Aschenbach, WG Moller, DE Goodyear, LJ AF Dufresne, SD Bjorbaek, C El-Haschimi, K Zhao, Y Aschenbach, WG Moller, DE Goodyear, LJ TI Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; COFFIN-LOWRY SYNDROME; PHOSPHORYLATION SITES; SYNTHASE KINASE-3; IN-VIVO; INSULIN; IDENTIFICATION; GROWTH; MECHANISM; EXERCISE AB The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. RSK2 knockout (KO) mice weigh 10% less and are 14% shorter than wild-type (WT) mice. They also have impaired learning and coordination. Hindlimb skeletal muscles were obtained from mice 10, 15, or 30 min after insulin injection or immediately after strenuous treadmill exercise for 60 min. While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. This occurred despite 27% lower ERK2 protein expression in skeletal muscle of KO mice. KO mice had 18% less muscle glycogen in the fasted basal state, and insulin increased glycogen synthase activity more in KO than WT mice. The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals, c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2.5-fold) and exercise (15-fold). In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Merck Res Labs, Dept Mol Endocrinol, Rahway, NJ 07065 USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIAMS NIH HHS [AR-42238, R01 AR042238] NR 40 TC 95 Z9 102 U1 0 U2 2 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 JAN PY 2001 VL 21 IS 1 BP 81 EP 87 DI 10.1128/MCB.21.1.81-87.2001 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382VD UT WOS:000165847300008 PM 11113183 ER PT J AU Zhang, SL DuBois, W Ramsay, ES Bliskovski, V Morse, HC Taddesse-Heath, L Vass, WC DePinho, RA Mock, BA AF Zhang, SL DuBois, W Ramsay, ES Bliskovski, V Morse, HC Taddesse-Heath, L Vass, WC DePinho, RA Mock, BA TI Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; CELL-CYCLE ARREST; TUMOR SUPPRESSION; MULTIPLE-MYELOMA; INK4A LOCUS; MURINE PLASMACYTOMAS; INTESTINAL NEOPLASIA; MAJOR MODIFIER; STABILIZES P53; GENE AB The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that included Cdkn2a, which encodes p16(INK4a) and p19(ARF), and the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45), In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval, Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19(ARF) alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene. C1 NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Mock, BA (reprint author), NCI, Genet Lab, NIH, Bldg 37,Rm 2B-08,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 NR 47 TC 68 Z9 68 U1 0 U2 0 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 JAN PY 2001 VL 21 IS 1 BP 310 EP 318 DI 10.1128/MCB.21.1.310-318.2001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382VD UT WOS:000165847300030 PM 11113205 ER PT J AU Fasshauer, M Klein, J Kriauciunas, KM Ueki, K Benito, M Kahn, CR AF Fasshauer, M Klein, J Kriauciunas, KM Ueki, K Benito, M Kahn, CR TI Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ENHANCER-BINDING-PROTEIN; PPAR-GAMMA; GLUCOSE-UPTAKE; ECTOPIC EXPRESSION; ADIPOSE-TISSUE; C/EBP-ALPHA; CELLS; ADIPOGENESIS; GENE; KINASE AB The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin, To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPAR gamma), CCAAT/enhancer-binding protein alpha (C/EBP alpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4, The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPAR gamma, or C/EBP alpha but not the thiazolidinedione troglitazone, Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS3. Akt phosphorylation was reduced in parallel with the total PI 3-kinase activity. Inhibition of PI 3-kinase with LY294002 blocked differentiation of mild-type cells, Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPAR gamma and C/EBP alpha. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Univ Leipzig, Dept Internal Med 3, D-04103 Leipzig, Germany. Med Univ Lubeck, Dept Internal Med 1, D-23538 Lubeck, Germany. Univ Complutense, Fac Farm, E-28040 Madrid, Spain. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK 33201, DK 36836, DK 5545, P30 DK036836, R01 DK033201] NR 39 TC 113 Z9 118 U1 0 U2 6 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 JAN PY 2001 VL 21 IS 1 BP 319 EP 329 DI 10.1128/MCB.21.1.319-329.2001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382VD UT WOS:000165847300031 PM 11113206 ER PT J AU Wen, RR Wang, DM McKay, C Bunting, KD Marine, JC Vanin, EF Zambetti, GP Korsmeyer, SJ Ihle, JN Cleveland, JL AF Wen, RR Wang, DM McKay, C Bunting, KD Marine, JC Vanin, EF Zambetti, GP Korsmeyer, SJ Ihle, JN Cleveland, JL TI Jak3 selectively regulates Bax and Bcl-2 expression to promote T-cell development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RECEPTOR-DEFICIENT MICE; DEFECTIVE LYMPHOID DEVELOPMENT; INTERLEUKIN-7 RECEPTOR; TARGETED DISRUPTION; GAMMA-CHAIN; P53-DEPENDENT APOPTOSIS; ERYTHROPOIETIN RECEPTOR; JAK3-DEFICIENT MICE; HEMATOPOIETIC-CELLS; V(D)J RECOMBINATION AB Jak3-deficient mice display vastly reduced numbers of lymphoid cells. Thymocytes and peripheral T cells from Jak3-deficient mice have a high apoptotic index, suggesting that Jak3 provides survival signals. Here we report that Jak3 regulates T lymphopoiesis at least in part through its selective regulation of Bax and Bcl-2. Jak3-deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wildtype littermates. Notably, up-regulation of Bax in Jak3-deficient T cells is physiologically relevant, as Jak3 Bax double-null mice have marked increases in thymocyte and peripheral T-cell numbers. Rescue of T lymphopoiesis by Bax loss was selective, as mice deficient in Jak3 plus p53 or in Jak3 plus Fas remained lymphopenic. However, Bax loss failed to restore proper ratios of peripheral CD4/CD8 T cells, which are abnormally high in Jak3-null mice. Transplantation into Jak3-deficient mice of Jak3-null bone marrow transduced with a Bcl-2-expressing retrovirus also improved peripheral T-cell numbers and restored the ratio of peripheral CD4/CD8 T cells to wild-type levels. The data support the concepts that Jak kinases regulate cell survival through their selective and cell context-dependent regulation of pro- and antiapoptotic Bcl-2 family proteins and that Bax and Bcl-2 play distinct roles in T-cell development. C1 St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Expt Hematol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA. Univ Tennessee, Dept Biochem, Memphis, TN 38163 USA. Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Cleveland, JL (reprint author), St Jude Childrens Res Hosp, Dept Biochem, 332 N Lauderdale St, Memphis, TN 38105 USA. RI Marine, Jean Christophe/J-2237-2015; Marine, Jean-Christophe/K-3292-2016 OI Marine, Jean-Christophe/0000-0003-2433-9837 FU NCI NIH HHS [R01 CA076379, CA76379, P30 CA021765, R01 CA063230]; NHLBI NIH HHS [P01 HL053749]; NIDDK NIH HHS [DK42932, DK44158, R01 DK042932, R01 DK044158] NR 67 TC 53 Z9 54 U1 0 U2 1 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 JAN PY 2001 VL 21 IS 2 BP 678 EP 689 DI 10.1128/MCB.21.2.678-689.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 386YZ UT WOS:000166094500028 PM 11134353 ER PT J AU Yu, XX Du, XX Moreno, CS Green, RE Ogris, E Feng, Q Chou, L McQuoid, MJ Pallas, DC AF Yu, XX Du, XX Moreno, CS Green, RE Ogris, E Feng, Q Chou, L McQuoid, MJ Pallas, DC TI Methylation of the protein phosphatase 2A catalytic subunit is essential for association of B alpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SMALL-T-ANTIGEN; TERMINAL LEUCINE RESIDUE; OKADAIC ACID; MICROCYSTIN-LR; BOVINE BRAIN; CELLS; METHYLTRANSFERASE; FORMS; BINDING; TYPE-2A AB Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-terminal leucine 309 are two important mechanisms by which protein phosphatase 2A (PP2A) can be regulated. In this study, both genetic and biochemical approaches were used to investigate regulation of regulatory subunit binding by C subunit methylation. Monoclonal antibodies selectively recognizing unmethylated C subunit were used to quantitate the methylation status of wild-type and mutant C subunits. Analysis of 13 C subunit mutants showed that both carboxyterminal and active site residues are important for maintaining methylation in vivo. Severe impairment of methylation invariably led to a dramatic decrease in B alpha subunit binding but not of striatin, SG2NA, or polyomavirus middle tumor antigen (MT) binding. In fact, most unmethylated C subunit mutants showed enhanced binding to striatin and SG2NA. Certain carboxy-terminal mutations decreased B alpha subunit binding without greatly affecting methylation, indicating that B alpha subunit binding is not required for a high steady-state level of C subunit methylation. Demethylation of PP2A in cell lysates with recombinant PP2A methylesterase greatly decreased the amount of C subunit that could be coimmunoprecipitated via the B alpha subunit but not the amount that could be coimmunoprecipitated with A alpha subunit or MT. When C subunit methylation levels were greatly reduced in vivo, B alpha subunits were found complexed exclusively to methylated C subunits, whereas striatin and SG2NA in the same cells bound both methylated and unmethylated C subunits. Thus, C subunit methylation is critical for assembly of PP2A heterotrimers containing B alpha subunit but not for formation of heterotrimers containing MT, striatin, or SG2NA. These findings suggest that methylation may be able to selectively regulate the association of certain regulatory subunits with the A/C heterodimer. C1 Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Winship Canc Ctr, Atlanta, GA 30322 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Cellular & Mol Biol, Boston, MA 02115 USA. RP Pallas, DC (reprint author), Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. RI Moreno, Carlos/B-3863-2009 OI Moreno, Carlos/0000-0002-5582-0028 FU NCI NIH HHS [R01 CA057327] NR 52 TC 97 Z9 99 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN PY 2001 VL 12 IS 1 BP 185 EP 199 PG 15 WC Cell Biology SC Cell Biology GA 391JX UT WOS:000166353800015 PM 11160832 ER PT J AU Biswas, DK Cruz, A Pettit, N Mutter, GL Pardee, AB AF Biswas, DK Cruz, A Pettit, N Mutter, GL Pardee, AB TI A therapeutic target for hormone-independent estrogen receptor-positive breast cancers SO MOLECULAR MEDICINE LA English DT Article ID POSTMENOPAUSAL WOMEN; RESPONSIVE ELEMENT; CELLS; ACTIVATION; PROLIFERATION; PREVENTION; EXPRESSION; TAMOXIFEN; MECHANISM; DELIVERY AB Background: The action of the steroid hormone estradiol (E2) is mediated via interaction with a specific receptor (ER) that initiates a series of events downstream, leading to the modulation of hormone-responsive genes and cell proliferation. Antihormones also bind, but do not confer the active configuration to ER, thereby, blocking the transmission of E2-ER-initiated signals for cell proliferation. Although these compounds qualify for successful therapy of ER-positive [ER (+)] breast cancer patients, only a fraction of patients responds to antihormone treatment. In this study, the functional status of ER is determined to identify alternative targets for therapy of antihormone-resistant ER (+) breast cancers. Method: The interaction of ER with a specific DNA sequence, designated as E2 response element (ERE), was targeted to assess the functional state of ER. ER-ERE complex formation was measured by electrophoretic mobility shift assay (EMSA) and by a newly developed technique, based on the preferential binding of DNA-protein complex to a nitrocellulose membrane (NMBA) that measures both total and functional fraction of ER. Results: The NMBA assay identified functional variants of ER among ER (+) breast cancer cell lines and breast tumor biopsy specimens. ER of (21PT) cells did not bind E2 and these cells were tamoxifen (TAM) resistant. However 21PT cells were sensitive to a calmodulin (CaM) antagonist, W7, that blocked ERE-ER complex formation. Conclusions: ER variants of the 21PT type were detected among breast cancer biopsy specimens, emphasizing the significance of an alternative therapeutic target for TAM-resistant ER (+) human breast cancers with compounds such as W7. C1 Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Biswas, DK (reprint author), Dana Farber Canc Inst, Div Canc Biol, 44 Binney St, Boston, MA 02115 USA. RI Mutter, George/C-5819-2009 FU NCI NIH HHS [CA61253-07] NR 32 TC 8 Z9 8 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 JAN PY 2001 VL 7 IS 1 BP 59 EP 67 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 397VM UT WOS:000166718500007 PM 11474128 ER PT J AU Watnick, PI Lauriano, CM Klose, KE Croal, L Kolter, R AF Watnick, PI Lauriano, CM Klose, KE Croal, L Kolter, R TI The absence of a flagellum leads to altered colony morphology, biofilm development and virulence in Vibrio cholerae O139 SO MOLECULAR MICROBIOLOGY LA English DT Article ID MANNOSE-SENSITIVE HEMAGGLUTININ; SWARMER CELL-DIFFERENTIATION; ALTERNATIVE SIGMA-FACTOR; PSEUDOMONAS-AERUGINOSA; TWITCHING MOTILITY; EL-TOR; ESCHERICHIA-COLI; GENE-EXPRESSION; OUTER-MEMBRANE; EXOPOLYSACCHARIDE PRODUCTION AB Throughout most of history, epidemic and pandemic cholera was caused by Vibrio cholerae of the serogroup O1. In 1992, however, a V. cholerae strain of the serogroup O139 emerged as a new agent of epidemic cholera. Interestingly, V. cholerae O139 forms biofilms on abiotic surfaces more rapidly than V. cholerae O1 biotype El Tor, perhaps because regulation of exopolysaccharide synthesis in V. cholerae O139 differs from that in O1 El Tor. Here, we show that all flagellar mutants of V. cholerae O139 have a rugose colony morphology that is dependent on the vps genes. This suggests that the absence of the flagellar structure constitutes a signal to increase exopolysaccharide synthesis. Furthermore, although exopolysaccharide production is required for the development of a three-dimensional biofilm, inappropriate exopolysaccharide production leads to inefficient colonization of the infant mouse intestinal epithelium by flagellar mutants. Thus, precise regulation of exopolysaccharide synthesis is an important factor in the survival of V. cholerae O139 in both aquatic environments and the mammalian intestine. C1 Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02111 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA. RP Kolter, R (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, 200 Longwood Ave, Boston, MA 02111 USA. FU NIAID NIH HHS [AI43486, K08 AI001588, K08 AI001588-01, K08 AI01588, R01 AI043486]; NIGMS NIH HHS [GM58213, R01 GM058213] NR 60 TC 168 Z9 178 U1 2 U2 13 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 JAN PY 2001 VL 39 IS 2 BP 223 EP 235 DI 10.1046/j.1365-2958.2001.02195.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 395JL UT WOS:000166577200002 PM 11136445 ER PT J AU Handforth, A Krahl, SE AF Handforth, A Krahl, SE TI Suppression of harmaline-induced tremor in rats by vagus nerve stimulation SO MOVEMENT DISORDERS LA English DT Article DE tremor; vagus nerve stimulation; harmaline ID POSITRON EMISSION TOMOGRAPHY; VAGAL; CEREBELLUM; SEIZURES; SYSTEM; REPRESENTATION; INHIBITION; CAT AB We studied whether vagus nerve stimulation could suppress tremor in the harmaline tremor model in the rat. Animals were chronically implanted with helical leads around the left vagus nerve and a disk-shaped electrode positioned subcutaneously in the dorsal neck. Harmaline-induced tremor was recorded on a physiograph while each animal received a sequence of five 20-minute trials. Each trial consisted of five minutes of pre-stimulation baseline, five minutes of vagus nerve stimulation, and ten minutes of post-stimulation, Vague nerve stimulation significantly suppressed harmaline-induced tremor. The suppressive effect was present within the first minute of stimulation and was reproducible across the five trials of the study. The results of this study suggest that the central generator or expression of tremor in the harmaline animal model can be suppressed by vagus nerve stimulation. C1 VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Neurol & Res Serv W127, Los Angeles, CA 90073 USA. RP Handforth, A (reprint author), VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Neurol & Res Serv W127, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 22 TC 19 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN PY 2001 VL 16 IS 1 BP 84 EP 88 DI 10.1002/1531-8257(200101)16:1<84::AID-MDS1010>3.0.CO;2-S PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 398NQ UT WOS:000166762900012 PM 11215598 ER PT J AU Lance, JW Adams, RD AF Lance, JW Adams, RD TI Negative myoclonus in posthypoxic patients: Historical note SO MOVEMENT DISORDERS LA English DT Article C1 Prince Wales Hosp, Inst Neurol Sci, Sydney, NSW, Australia. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Lance, JW (reprint author), Wales Med Ctr, Suite 5A,66 High St, Randwick, NSW 2031, Australia. NR 6 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN PY 2001 VL 16 IS 1 BP 162 EP 163 DI 10.1002/1531-8257(200101)16:1<162::AID-MDS1029>3.0.CO;2-9 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 398NQ UT WOS:000166762900028 PM 11215580 ER PT S AU Bacskai, BJ Kajdasz, ST Christie, RH Zipfel, WR Williams, RM Kasischke, KA Webb, WW Hyman, BT AF Bacskai, BJ Kajdasz, ST Christie, RH Zipfel, WR Williams, RM Kasischke, KA Webb, WW Hyman, BT BE Periasamy, A So, PTC TI Chronic imaging of amyloid plaques in the live mouse brain using multiphoton microscopy SO MULTIPHOTON MICROSCOPY IN THE BIOMEDICAL SCIENCES SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Multiphoton Microscopy in the Biomedical Sciences CY JAN 21-23, 2001 CL SAN JOSE, CA SP SPIE, Bio Rad Labs Inc, Carl Zeiss Inc, Coherent Laser Grp, Chroma Technol Corp, Nikon Instruments Inc, Omega Opt Inc, Spectra Phys Lasers DE in vivo; imaging; 2-photon; multiphoton; Alzheimer's; amyloid-beta ID ALZHEIMER-DISEASE; TRANSGENIC MICE; PRECURSOR PROTEIN; NEURONAL LOSS; BETA; ABNORMALITIES; IMMUNIZATION AB Transgenic mice expressing the human Amyloid Precursor Protein (APP) develop amyloid plaques as they age. These plaques resemble those found in the human disease. Multiphoton laser scanning microscopy combined with a novel surgical approach was used to measure amyloid plaque dynamics chronically in the cortex of living transgenic mice. Thioflavine S (thioS) was used as a fluorescent marker of amyloid deposits. Multiphoton excitation allowed visualization of amyloid plaques up to 200 micrometers deep into the brain. The surgical site could be imaged repeatedly without overt damage to the tissue, and individual plaques within this volume could be reliably identified over periods of several days to several months. On average, plaque sizes remained constant over time, supporting a model of rapid deposition, followed by relative stability. Alternative reporters for in vivo histology include thiazine red, and FITC-labeled amyloid-beta peptide. We also present examples of multi-color imaging using Hoechst dyes and FITC-labeled tomato lectin. These approaches allow us to observe cell nuclei or microglia simultaneously with amyloid-beta deposits in vivo. Chronic imaging of a variety of reporters in these transgenic mice should provide insight into the dynamics of amyloid-beta activity in the brain. C1 Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RI Zipfel, Warren/B-4059-2016 OI Zipfel, Warren/0000-0003-2640-329X NR 17 TC 2 Z9 2 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3940-1 J9 PROC SPIE PY 2001 VL 4262 BP 125 EP 133 DI 10.1117/12.424546 PG 9 WC Engineering, Biomedical; Microscopy; Optics SC Engineering; Microscopy; Optics GA BS31Y UT WOS:000169435900016 ER PT S AU Brown, EB Campbell, RB Tsuzuki, Y Fukumura, D Jain, RK AF Brown, EB Campbell, RB Tsuzuki, Y Fukumura, D Jain, RK BE Periasamy, A So, PTC TI Measurement of physiological parameters in tumors in vivo using MPLSM SO MULTIPHOTON MICROSCOPY IN THE BIOMEDICAL SCIENCES SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Multiphoton Microscopy in the Biomedical Sciences CY JAN 21-23, 2001 CL SAN JOSE, CA SP SPIE, Bio Rad Labs Inc, Carl Zeiss Inc, Coherent Laser Grp, Chroma Technol Corp, Nikon Instruments Inc, Omega Opt Inc, Spectra Phys Lasers DE two photon; multiphoton; in vivo; cancer; tumor; angiogenesis; permeability ID HUMAN ADENOCARCINOMA LS174T; VASCULAR-PERMEABILITY; HIPPOCAMPAL SPINES; BLOOD-FLOW; SCID MICE; ANGIOGENESIS; GROWTH; MECHANISMS; DIFFUSION; DELIVERY AB Conventional epifluorescence microscopy coupled with chronic animal window models has provided stunning insight into tumor pathophysiology, including gene expression, angiogenesis, interstitial transport, and drug delivery. However, the findings to date have been limited to the tumor surface (< 150 microns). This is an important drawback because the internal architecture of tumors is known to be heterogeneous, with a collagenous tumor/host interface, highly vascularized outer regions, and poorly vascularized inner necrotic regions. Here we present the first application of the multiphoton laser-scanning microscope (MPLSM) to monitoring drug delivery in tumors, phenotypic tumor cell. behavior, and tumor-induced gene promoter activity in vivo. Furthermore, we show that the MPLSM can be used in living tumors to quantify physiological parameters such as vascular density, blood flow velocity, leukocyte/endothelial interactions, and single vessel permeability. These measurements are performed with high three-dimensional resolution up to depths of several hundred microns, thus providing novel insights into the internal milieu of tumors. These findings will allow the development of drug therapeutic strategies that not only affect the tumor surface, but also internal regions. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. RP Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. NR 23 TC 2 Z9 2 U1 1 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3940-1 J9 PROC SPIE PY 2001 VL 4262 BP 134 EP 145 DI 10.1117/12.424547 PG 12 WC Engineering, Biomedical; Microscopy; Optics SC Engineering; Microscopy; Optics GA BS31Y UT WOS:000169435900017 ER PT J AU Limaye, AM Modi, JN AF Limaye, AM Modi, JN TI Air pollution: Health hazards and policies SO NATIONAL MEDICAL JOURNAL OF INDIA LA English DT Editorial Material ID HOSPITAL ADMISSIONS; DAILY MORTALITY; UTAH VALLEY; CHILDREN; CITIES C1 Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ALL INDIA INST MEDICAL SCIENCES PI NEW DELHI PA ANSARI NAGAR, NEW DELHI 110 029, INDIA SN 0970-258X J9 NATL MED J INDIA JI Natl. Med. J. India PD JAN-FEB PY 2001 VL 14 IS 1 BP 4 EP 7 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 408PY UT WOS:000167337900002 PM 11242698 ER PT J AU Raveh, T Droguett, G Horwitz, MS DePinho, RA Kimchi, A AF Raveh, T Droguett, G Horwitz, MS DePinho, RA Kimchi, A TI DAP kinase activates a p19(ARF)/p53-mediated apoptotic checkpoint to suppress oncogenic transformation SO NATURE CELL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR; TRANSCRIPTIONAL ACTIVATION; DEATH DOMAIN; CELL-DEATH; P53; GROWTH; GENE; DNA; HYPERMETHYLATION; IMMORTALIZATION AB DAP kinase is a pro-apoptotic calcium-regulated serine/threonine kinase, whose expression is frequently lost in human tumours, Here we show that DAP kinase counteracts oncogene-induced transformation by activating a p19(ARF)/p53-dependent apoptotic checkpoint. Ectopic expression of DAP kinase suppressed oncogenic transformation of primary embryonic fibroblasts by activating p53 in a p19(ARF)-dependent manner. Consequently, the fibroblasts underwent apoptosis, characterized by caspase activation and DNA fragmentation. In response to c-Myc or E2F-1, the endogenous DAP kinase protein was upregulated. Furthermore, functional or genetic inactivation of the endogenous DAP kinase reduced the extent of induction of p19(ARF)/p53 and weakened the subsequent apoptotic responses to c-Myc or E2F-1. These results establish a role for DAP kinase in an early apoptotic checkpoint designed to eliminate pre-malignant cells during cancer development. C1 Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. Harvard Univ, Sch Med, Dept Med Genet, Boston, MA 02115 USA. Dana Farber Canc Inst, Dep Adult Oncol, Boston, MA 02115 USA. EM lvkimchi@weizmann.weizmann.ac.il NR 38 TC 253 Z9 266 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JAN PY 2001 VL 3 IS 1 BP 1 EP 7 PG 7 WC Cell Biology SC Cell Biology GA 387XD UT WOS:000166146400013 PM 11146619 ER PT J AU He, L Gunn, TM Bouley, DM Lu, XY Watson, SJ Schlossman, SF Duke-Cohan, JS Barsh, GS AF He, L Gunn, TM Bouley, DM Lu, XY Watson, SJ Schlossman, SF Duke-Cohan, JS Barsh, GS TI A biochemical function for attractin in agouti-induced pigmentation and obesity SO NATURE GENETICS LA English DT Article ID STIMULATING-HORMONE-RECEPTOR; YELLOW A(Y) MUTATION; MELANOCORTIN RECEPTORS; TRANSGENIC MICE; COAT COLOR; NERVOUS-SYSTEM; IN-VITRO; PROTEIN; MOUSE; EXPRESSION AB Agouti protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (A(y)) mice, and causes obesity by mimicking agouti-related protein (Agrp), found primarily in the hypothalamus. Mouse attractin (Atrn) is a widely expressed transmembrane protein whose loss of function in mahogany (Atrn(mg-3J)/Atrn(mg-3J)) mutant mice blocks the pleiotropic effects of A(y). Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for agouti protein, but not Agrp, in vitro and in vivo. Additional histopathologic abnormalities in Atrn(mg-3J)/Atrn(mg-3J) mice and cross-species genomic comparisons indicate that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective. C1 Stanford Univ, Sch Med, Dept Pediat & Genet, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA. Univ Michigan, Sch Med, Mental Hlth Res Inst, Ann Arbor, MI USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA USA. RP Barsh, GS (reprint author), Stanford Univ, Sch Med, Dept Pediat & Genet, Stanford, CA 94305 USA. RI Lu, Xin-Yun/M-8657-2016; OI Gunn, Teresa/0000-0003-2688-6420; Duke-Cohan, Jonathan/0000-0002-9478-9609 FU NIDDK NIH HHS [DK-48506]; NIMH NIH HHS [MH42251] NR 50 TC 97 Z9 103 U1 1 U2 4 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 JAN PY 2001 VL 27 IS 1 BP 40 EP 47 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 388NP UT WOS:000166187900013 PM 11137996 ER PT J AU Peterfy, M Phan, J Xu, P Reue, K AF Peterfy, M Phan, J Xu, P Reue, K TI Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin SO NATURE GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCUS; SERUM LEPTIN LEVELS; MUTANT MOUSE; INSULIN-RESISTANCE; DIABETES-MELLITUS; ADIPOSE-TISSUE; MICE; REVEALS; GENOME; MAP AB Mice carrying mutations in the fatty liver dystrophy (fld) gene have features of human lipodystrophy(1), a genetically heterogeneous group of disorders characterized by loss of body fat, fatty liver hypertriglyceridemia and insulin resistance(2-4). Through positional cloning, we have isolated the gene responsible and characterized two independent mutant alleles, fld and fld(2J). The gene (Lpin1) encodes a novel nuclear protein which we have named lipin. Consistent with the observed reduction of adipose tissue mass in fld and fld(2J) mice, wild-type Lpin1 mRNA is expressed at high levels in adipose tissue and is induced during differentiation of 3T3-L1 pre-adipocytes. Our results indicate that lipin is required for normal adipose tissue development, and provide a candidate gene for human lipodystrophy. Lipin defines a novel family of nuclear proteins containing at least three members in mammalian species, and homologs in distantly related organisms from human to yeast. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Reue, K (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. FU NHLBI NIH HHS [HL24841] NR 26 TC 327 Z9 341 U1 4 U2 7 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 JAN PY 2001 VL 27 IS 1 BP 121 EP 124 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 388NP UT WOS:000166187900029 PM 11138012 ER PT J AU Moore, KJ Rosen, ED Fitzgerald, ML Randow, F Andersson, LP Altshuler, D Milstone, DS Mortensen, RM Spiegelman, BM Freeman, MW AF Moore, KJ Rosen, ED Fitzgerald, ML Randow, F Andersson, LP Altshuler, D Milstone, DS Mortensen, RM Spiegelman, BM Freeman, MW TI The role of PPAR-gamma in macrophage differentiation and cholesterol uptake SO NATURE MEDICINE LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; LOW-DENSITY-LIPOPROTEIN; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); SCAVENGER RECEPTORS; AFFINITY LIGAND; GENE-EXPRESSION; RETINOIC ACID; OXIDIZED LDL; HUMAN CD36; IN-VITRO AB Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), the transcription factor target of the anti-diabetic thiazolidinedione (TZD) drugs, is reported to mediate macrophage differentiation and inflammatory responses. Using PPAR-gamma -deficient stem cells, we demonstrate that PPAR-gamma is neither essential for myeloid development, nor for such mature macrophage functions as phagocytosis and inflammatory cytokine production. PPAR-gamma is required for basal expression of CD36, but not for expression of the other major scavenger receptor responsible for uptake of modified lipoproteins, SR-A. In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation. C1 Massachusetts Gen Hosp, Dept Med, Lipid Metab Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. MIT, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02139 USA. Brigham & Womens Hosp, Dept Pathol, Div Vasc Res, Boston, MA 02115 USA. Univ Michigan, Dept Physiol, Div Endocrine, Ann Arbor, MI 48109 USA. RP Freeman, MW (reprint author), Massachusetts Gen Hosp, Dept Med, Lipid Metab Unit, Boston, MA 02114 USA. RI Altshuler, David/A-4476-2009; OI Altshuler, David/0000-0002-7250-4107; Moore, kathryn/0000-0003-2505-2547 FU NHLBI NIH HHS [HL5409, HL45098, HL56985]; NIDDK NIH HHS [DK50305] NR 47 TC 344 Z9 359 U1 0 U2 7 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 JAN PY 2001 VL 7 IS 1 BP 41 EP 47 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 389MX UT WOS:000166243100033 PM 11135614 ER PT J AU Woolf, CJ AF Woolf, CJ TI Turbocharging neurons for growth: accelerating regeneration in the adult CNS SO NATURE NEUROSCIENCE LA English DT Editorial Material ID PRIMARY SENSORY NEURONS; ROOT GANGLION NEURONS; AXON REGENERATION; GAP-43 EXPRESSION; INJURY; PROTEINS; AXOTOMY AB Mature central neurons lose their capacity for axon growth, but overexpression of growth-associated proteins restores this potential, which may support spinal cord regeneration. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 149 13th St, Charlestown, MA 02129 USA. NR 15 TC 11 Z9 11 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JAN PY 2001 VL 4 IS 1 BP 7 EP 9 DI 10.1038/82921 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 405UB UT WOS:000167178000004 PM 11135634 ER PT J AU Brown, SP Masland, RH AF Brown, SP Masland, RH TI Spatial scale and cellular substrate of contrast adaptation by retinal ganglion cells SO NATURE NEUROSCIENCE LA English DT Article ID STARBURST AMACRINE CELLS; RECEPTIVE-FIELD PROPERTIES; MACAQUE MONKEY RETINA; RABBIT RETINA; BIPOLAR CELLS; GAIN-CONTROL; GABA(C) RECEPTORS; PRIMATE RETINA; VISUAL-CORTEX; MORPHOLOGY AB Human visual perception and many visual system neurons adapt to the luminance and contrast of the stimulus. Here we describe a form of contrast adaptation that occurs in the retina. This adaptation had a local scale smaller than the dendritic or receptive fields of single ganglion cells and was insensitive to pharmacological manipulation of amacrine cell function. These results implicate the bipolar cell pathway as a site of contrast adaptation. The time required for contrast adaptation varied with stimulus size, ranging from approximately 100 ms for the smallest stimuli, to seconds for stimuli the size of the receptive field. The differing scales and time courses of these effects suggest that:multiple types of contrast adaptation are used in viewing natural scenes. C1 Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Masland, RH (reprint author), Harvard Univ, Sch Med, Program Neurosci, Goldenson 228, Boston, MA 02115 USA. RI Brown, Solange/H-1615-2012 NR 50 TC 89 Z9 93 U1 1 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JAN PY 2001 VL 4 IS 1 BP 44 EP 51 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 405UB UT WOS:000167178000013 PM 11135644 ER PT J AU Walhout, AJM Vidal, M AF Walhout, AJM Vidal, M TI Protein interaction maps for model organisms SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID REVERSE 2-HYBRID SYSTEM; CAENORHABDITIS-ELEGANS; SACCHAROMYCES-CEREVISIAE; C-ELEGANS; YEAST GENOME; DNA; GENES; CELL; ASSOCIATION; PREDICTION AB Until recently. classical genetics and biochemistry were the main techniques used to investigate how organisms develop, reproduce, behave and age. But with the availability of complete genome sequences new approaches are emerging. Complete sets of proteins 'proteomes' - can be predicted from genome sequences and used to characterize protein functions globally. For example. through the large-scale identification of physical protein-protein interactions, comprehensive protein interaction maps are being generated. And these maps might help us to understand the processes that control the biology of living organisms. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu OI Walhout, Marian/0000-0001-5587-3608 NR 77 TC 95 Z9 97 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JAN PY 2001 VL 2 IS 1 BP 55 EP 62 DI 10.1038/35048107 PG 8 WC Cell Biology SC Cell Biology GA 386HU UT WOS:000166055800019 PM 11413466 ER PT J AU Cole, GM Frautschy, SA AF Cole, GM Frautschy, SA TI Church baptizes Joseph and Perry. Eccentric views absolved SO NEUROBIOLOGY OF AGING LA English DT Editorial Material ID ALZHEIMERS-DISEASE; DEPOSITION; INFLAMMATION; PHENOTYPE C1 Univ Calif Los Angeles, Dept Med, Greater Los Angeles VAMC, N Hills, CA 91343 USA. Univ Calif Los Angeles, Dept Neurol, Greater Los Angeles VAMC, N Hills, CA 91343 USA. RP Cole, GM (reprint author), Univ Calif Los Angeles, Dept Med, Greater Los Angeles VAMC, GRECC 11E,16111 Plummer St, N Hills, CA 91343 USA. FU NIA NIH HHS [R01 AG013741, P50 AG016570] NR 22 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN-FEB PY 2001 VL 22 IS 1 BP 147 EP 150 DI 10.1016/S0197-4580(00)00214-1 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 397ZK UT WOS:000166728900020 PM 11164288 ER PT J AU Boas, DA Gaudette, T Strangman, G Cheng, XF Marota, JJA Mandeville, JB AF Boas, DA Gaudette, T Strangman, G Cheng, XF Marota, JJA Mandeville, JB TI The accuracy of near infrared spectroscopy and imaging during focal changes in cerebral hemodynamics SO NEUROIMAGE LA English DT Article ID TISSUE OPTICAL-PROPERTIES; SENSORY STIMULATION; BRAIN; DIFFUSION; OXYGENATION; TOMOGRAPHY; INFANTS; TIME; ILLUMINATION; REFLECTANCE AB Near infrared spectroscopy (NIRS) can detect changes in the concentrations of oxy-hemoglobin ([HbO]) and deoxy-hemoglobin ([Hb]) in tissue based upon differential absorption at multiple wavelengths. The common analysis of; NIRS data rises the modified Beer-Lambert law, which is an empirical formulation that assumes global concentration changes. We used simulations to examine the errors that result when this analysis is applied to focal hemodynamic changes, and we performed simultaneous NIRS measurements during a motor task in adult humans and a neonate to evaluate the dependence of the measured changes on detector-probe geometry. For both simulations and in vivo measurements, the wide range of NIRS results was compared to an imaging analysis, diffuse optical tomography (DOT). The results demonstrate that relative changes in [HbO] and [Hb] cannot, in general, be quantified with NIRS. In contrast to that method, DOT analysis was shown to accurately quantify simulated changes in chromophore concentrations. These results and the general principles suggest that DOT can accurately measure changes in [Hb] and [HbO], but NIRS cannot accurately determine even relative focal changes in these chromophore concentrations. For the standard NIRS analysis to become more accurate for focal changes, it must account for the position of the focal change relative to the source and detector as web as the wavelength dependent optical properties of the medium. (C) 2001 Academic Press. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Charlestown, MA 02129 USA. Tufts Univ, Ctr Electroopt Technol, Medford, MA 02155 USA. RP Boas, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Charlestown, MA 02129 USA. FU NINDS NIH HHS [1 N29 NS38842 A01, F32-NS10567] NR 36 TC 263 Z9 268 U1 9 U2 41 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 JAN PY 2001 VL 13 IS 1 BP 76 EP 90 DI 10.1006/nimg.2000.0674 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 391VC UT WOS:000166376000008 PM 11133311 ER PT J AU Man, HY Lin, JW Ju, WH Ahmadian, G Liu, LD Becker, LE Sheng, M Wang, YT AF Man, HY Lin, JW Ju, WH Ahmadian, G Liu, LD Becker, LE Sheng, M Wang, YT TI Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization (vol 25, pg 649, 2000) SO NEURON LA English DT Correction C1 Hosp Sick Children, Programme Brain & Behav, Toronto, ON M5G 1X8, Canada. Hosp Sick Children, Div Pathol, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1L5, Canada. 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. RP Man, HY (reprint author), Hosp Sick Children, Programme Brain & Behav, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. RI Wang, Yu Tian/J-8255-2015 OI Wang, Yu Tian/0000-0001-8592-0698 NR 1 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN PY 2001 VL 29 IS 1 BP U18 EP U18 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 397NX UT WOS:000166702700029 ER PT S AU Maynard, KI Ayoub, IA Shen, CC AF Maynard, KI Ayoub, IA Shen, CC BE Slikker, W Trembly, B TI Delayed multidose treatment with nicotinamide extends the degree and duration of neuroprotection by reducing infarction and improving behavioral scores up to two weeks following transient focal cerebral ischemia in Wistar rats SO NEUROPROTECTIVE AGENTS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 5th International Conference on Neuroprotective Agents CY SEP 17-21, 2000 CL LAKE TAHOE, NEVADA SP Natl Ctr Toxicol Res /FDA, Cent Arkansas Chapter Sigma Xi DE middle cerebral artery occlusion; stroke; niacin; neuroprotection; rats ID ARTERY OCCLUSION; VOLUME; NAD(+); GROWTH; MODEL AB A single, delayed dose of nicotinamide (NAm) was shown to be protective against focal cerebral ischemia in rats, but the protection was limited to three to seven days following stroke. The investigation reported here was conducted to examine if the use of multiple doses of NAm, administered after the onset of focal cerebral ischemia, would extend the duration of neuroprotection compared with a single dose treatment regimen. Male Wistar rats were subjected to transient focal cerebral ischemia by occluding the right middle cerebral artery (MCAo) for two hours. Following MCAo, motor and sensory behavioral tests were performed daily and the cerebral infarct volumes were measured at two weeks after sacrifice. Each animal was placed into one of four groups that received either normal saline alone (Group S), one (Group A), two (Group B), or three (Group C doses of NAm (500 mg/kg). Each animal, therefore, received three treatments over two weeks, with the first dose administered intravenously two hours after the onset of MCAo. Single and multiple doses of NAm reduced the infarction (p < 0.01) and improved (p < 0.05) the neurologic sensory and motor behavior when compared with the saline-treated animals up to two weeks after stroke. Moreover, animals that received multiple doses of NAm recuperated full motor function not different from normal, preoperative motor behavior. Delayed treatment with NAm given as multiple doses, therefore, further enhances the extent and duration of neuroprotection by significantly reducing cerebral infarct volumes, improving neurologic behavioral scores, and confers a complete motor recovery up to two weeks from the onset of focal cerebral ischemia in Wistar rats. C1 Massachusetts Gen Hosp, Neurophysiol Lab, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Maynard, KI (reprint author), Massachusetts Gen Hosp, Neurophysiol Lab, Neurosurg Serv, 55 Fruit St,EDR 414, Boston, MA 02114 USA. NR 30 TC 27 Z9 29 U1 0 U2 5 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-352-1 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 939 BP 416 EP 424 PG 9 WC Multidisciplinary Sciences; Clinical Neurology SC Science & Technology - Other Topics; Neurosciences & Neurology GA BT12V UT WOS:000172028600049 PM 11462797 ER PT J AU Filley, CM Price, BH Nell, V Antoinette, T Morgan, AS Bresnahan, JF Pincus, JH Gelbort, MM Weissberg, M Kelly, JP AF Filley, CM Price, BH Nell, V Antoinette, T Morgan, AS Bresnahan, JF Pincus, JH Gelbort, MM Weissberg, M Kelly, JP TI Toward an understanding of violence: Neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conference consensus statement SO NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY LA English DT Review ID TEMPORAL-LOBE EPILEPSY; SLEEP-RELATED VIOLENCE; CLOSED-HEAD-INJURY; ANTISOCIAL-BEHAVIOR; SUBSTANCE-ABUSE; MENTAL-DISORDER; MICE LACKING; BRAIN-INJURY; PERSONALITY-DISORDER; UNITED-STATES AB Objective: Violence is a global problem that poses a major challenge to individuals and society. This document is a consensus statement on neurobehavioral aspects of violence as one approach to its understanding and control. Background: This consensus group was convened under the auspices of the Aspen Neurobehavioral Conference, an annual consensus conference devoted to the understanding of issues related to mind and brain. The conference is supported by the Brain Injury Association and by individual philanthropic contributions. Participants were selected by conference organizers to represent leading opinion in neurology, neuropsychology, psychiatry, trauma surgery, nursing, evolutionary psychology, medical ethics, and law. Methods: A literature review of the role of the brain in violent behavior was conducted and combined with expert opinion from the group. The major goal was to survey this field so as to identify major areas of interest that could be targeted for further research. Additional review was secured from the other attendees at the Aspen Neurobehavioral Conference. Results: The group met in the spring of 1998 and 1999 for two 5-day sessions, between which individual assignments were carried out. The consensus statement was prepared after the second meeting, and agrement on the statement was reached by participants after final review of the document. Conclusions: Violence can result from brain dysfunction, although social and evolutionary factors also contribute. Study of the neurobehavioral aspects of violence, particularly frontal lobe dysfunction, altered serotonin metabolism, and the influence of heredity, promises to lead to a deeper understanding of the causes and solution of this urgent problem. C1 Univ Colorado, Sch Med, Denver, CO 80262 USA. Denver Vet Affairs Med Ctr, Denver, CO USA. McLean Hosp, Belmont, MA 02178 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. Univ S Africa, Inst Social & Hlth Sci, Greenside, South Africa. WHO, Collaborating Ctr Injury & Violence Prevent, Greenside, South Africa. Greenery Rehabil Ctr, Canonsburg, PA USA. St Francis Hosp & Med Ctr, Hartford, CT 06105 USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Rehabil Inst Chicago, Chicago, IL 60611 USA. Northwestern Mem Hosp, Chicago, IL USA. Georgetown Univ Hosp, Washington, DC 20007 USA. RP Filley, CM (reprint author), Univ Colorado, Hlth Sci Ctr, Behav Neurol Sect, 4200 E 9th Ave,B-183, Denver, CO 80262 USA. NR 110 TC 68 Z9 70 U1 8 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-878X J9 NEUROPSY NEUROPSY BE JI Neuropsychiatr. Neuropsychol. Behav. Neurol. PD JAN PY 2001 VL 14 IS 1 BP 1 EP 14 PG 14 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 405WP UT WOS:000167183800001 PM 11234904 ER PT J AU Ochsner, KN Kosslyn, SM Cosgrove, GR Cassem, EH Price, BH Nierenberg, AA Rauch, SL AF Ochsner, KN Kosslyn, SM Cosgrove, GR Cassem, EH Price, BH Nierenberg, AA Rauch, SL TI Deficits in visual cognition and attention following bilateral anterior cingulotomy SO NEUROPSYCHOLOGIA LA English DT Article DE anterior cingulate; executive control; attention; mental imagery; neurosurgical treatment of psychiatric illness ID GUIDED STEREOTAXIC CINGULOTOMY; CINGULATE CORTEX; INTERFERENCE TASK; COUNTING STROOP; ERROR-DETECTION; PERFORMANCE; SELECTION; PARADIGM; SYSTEM; PAIN AB A series of eight tests of visual cognitive abilities was used to examine pre- to post-operative performance changes in a patient receiving bilateral anterior cingulotomy. Compared with a set of eight matched control participants, post-operatively, the patient exhibited deficits in (a) the ability to sequence novel cognitive operations required to generate multipart images or rotate perceptual stimuli; (b) the ability to search for, select, and compare images of objects when the instructions did not specify precisely which objects should be visualized: and, (c) the ability to select a controlled and unpracticed response over an automatic one. Other imagery and cognitive tasks Mere not affected. Results are consistent with the hypothesis that anterior cingulate cortex is a component of an executive control system. One of the anterior cingulate's roles may be to monitor on-line processing and signal the motivational significance of current actions or cognitions. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. McLean Hosp, Dept Neurol, Belmont, MA 02178 USA. RP Ochsner, KN (reprint author), Stanford Univ, Dept Psychol, Bldg 420, Stanford, CA 94305 USA. FU ACF HHS [AF-99999]; PHS HHS [R01-99-11111] NR 55 TC 80 Z9 81 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PY 2001 VL 39 IS 3 BP 219 EP 230 DI 10.1016/S0028-3932(00)00114-7 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 397HK UT WOS:000166687100001 PM 11163601 ER PT J AU Baldessarini, RJ Campbell, A Webb, NL Swindell, CS Flood, JG Shashoua, VE Kula, NS Hemamalini, S Bradley, MO AF Baldessarini, RJ Campbell, A Webb, NL Swindell, CS Flood, JG Shashoua, VE Kula, NS Hemamalini, S Bradley, MO TI Fatty acid derivatives of clozapine: Prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE blood-brain barrier; clozapine; docosahexaenoic acid; dopamine; fatty acids; linoleic acid; myristic acid; oleic acid; palmitic acid ID BLOOD-BRAIN-BARRIER; DOUBLE-BLIND; CHRONIC-SCHIZOPHRENIA; ANTIPSYCHOTICS; METABOLITES; DOPAMINE; RECEPTOR; GROWTH; RETINA; SERUM AB Stable amides of clozapine derived from fatty acids prominent in cerebral tissue might enhance the central activity of clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity. Amide derivatives of clozapine were prepared from structurally varied fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by dopamine agonist apomorphine and to induce catalepsy. Their duration-of-action and potency were compared to free clozapine, and concentrations of clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at dopamine receptors and other potential drug-target sites. Clozapine-N-amides of linoleic, myristic, oleic, and palmitic acids had moderate initial central depressant activity but by 6 h,failed to inhibit arousal induced by apomorphine. However, the docosahexaenoic acid (DHA) derivative was ovally bioavailable, 10-times more potent (ED50 5.0 mu mol/kg) than clozapine itself and very long-acting (greater than or equal to 24 h) against apomorphine, and did not induce catalepsy. DHA itself was inactive behaviorally. Clozapine showed expected dopamine receptor affinities, but DHA-clozapine was inactive at these and other potential target sites. After systemic administration of DHA-clozapine, serum levels of free clozapine were very low, and brain concentrations somewhat lower than after administering clozapine. DHA-clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after oral administration or injection without inducing catalepsy, and it markedly reduced peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of free, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety. (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Harvard Univ, Sch Med, Consolidated Dept Psychiat, Boston, MA USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. Protarga Inc, Conshohocken, PA USA. Massachusetts Gen Hosp, Clin Chem Lab, Boston, MA 02114 USA. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr, Neuropharmacol Lab, 115 Mill St, Belmont, MA 02478 USA. FU NIH HHS [NH47370]; NIMH NIH HHS [MH34006] NR 34 TC 10 Z9 10 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2001 VL 24 IS 1 BP 55 EP 65 DI 10.1016/S0893-133X(00)00173-1 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 379RP UT WOS:000165656500007 PM 11106876 ER PT J AU Cramer, SC Nelles, G Schaechter, JD Kaplan, JD Finklestein, SR Rosen, BR AF Cramer, SC Nelles, G Schaechter, JD Kaplan, JD Finklestein, SR Rosen, BR TI A functional MRI study of three motor tasks in the evaluation of stroke recovery SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE stroke; motor recovery; functional MRI ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; POSTSTROKE HEMIPARESIS; INFARCTION; REORGANIZATION; ACTIVATION; CORTEX; BRAIN; RATS; EVOLUTION AB Functional brain imaging studies have provided insights into the processes related to motor recovery after stroke. The comparative value of different motor activation tasks for probing these processes has received limited study. We hypothesized that different hand motor tasks would activate the brain differently in controls, and that this would affect control-patient comparisons. Functional magnetic resonance imaging (MRI) was used to evaluate nine control subjects and seven patients with good recovery after a left hemisphere hemiparetic stroke. The volume of activated brain in bilateral sensorimotor cortex and four other motor regions was compared during each of three tasks performed by the right hand: index finger tapping, four-finger tapping, and squeezing. In control subjects, activation in left sensorimotor cortex was found to be significantly larger during squeezing as compared with index-finger tapping. Men comparing control subjects with stroke patients, patients showed a larger volume of activation in right sensorimotor cortex during index-finger tapping but not with four-finger tapping or squeezing. In addition, patients also showed a trend toward larger activation volume than controls within left supplementary motor area during index-finger tapping but not during the other tasks. Motion artifact was more common with squeezing than with the tapping tasks. The choice of hand motor tasks used during brain mapping can influence findings in control subjects as well as the differences identified between controls and stroke patients. The results may be useful for future studies of motor recovery after stroke. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH NMR Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Neurol, Spauling Rehabil Hosp, Boston, MA 02115 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Clin Investigator Training Program,Pfizer Inc, Boston, MA 02115 USA. RP Cramer, SC (reprint author), Univ Washington, Dept Neurol, 1959 NE Pacific St,Box 356465, Seattle, WA 98195 USA. NR 34 TC 60 Z9 64 U1 0 U2 1 PU DEMOS MEDICAL PUBLISHING PI NEW YORK PA 386 PARK AVE SOUTH, STE 201, NEW YORK, NY 10016 USA SN 0888-4390 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PY 2001 VL 15 IS 1 BP 1 EP 8 DI 10.1177/154596830101500101 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 466BH UT WOS:000170624100001 PM 11527274 ER PT J AU Cooper, RA Baldini, FD Boninger, ML Cooper, R AF Cooper, RA Baldini, FD Boninger, ML Cooper, R TI Physiological responses to two wheelchair-racing exercise protocols SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE wheelchair racing; exercise; fitness; spinal cord injury; fitness ID DISABILITIES; RACERS AB Objective: This study investigated the blood lactate accumulation during two wheelchair-racing protocols. During exercise, energy is required, which causes metabolism to increase and blood lactate to accumulate. Proper training can reduce the amount of blood lactate accumulation and increase tolerance to blood lactate accumulation during aerobic exercise. Methods: Eleven male wheelchair elite track athletes with a spinal Cord injury were tested to determine their blood lactate response to speed and resistance workouts. A computer,monitored wheelchair dynamometer was used during all exercise tests. The order of the test (e.g., speed or resistance workout) was randomized. Blood pressure and blood samples were taken immediately before and after completion of each exercise test. Results: The difference between the blood lactate concentrations before and after testing were 8.56 +/- 4.42, and 11.67 +/- 4.69 mM for the resistance and speed tests, respectively. Conclusions: Our results showed that the blood lactate responses were significantly different for the resistance and speed workouts. C1 VA Pittsburgh Healthcare Syst, Human Engn Res Labs 151R1, Pittsburgh, PA 15206 USA. Calif State Univ Sacramento, Dept Hlth & Phys Educ, Sacramento, CA 95819 USA. Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Cooper, R (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs 151R1, 7180 Highland Dr, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 16 TC 2 Z9 2 U1 1 U2 3 PU DEMOS MEDICAL PUBLISHING PI NEW YORK PA 386 PARK AVE SOUTH, STE 201, NEW YORK, NY 10016 USA SN 0888-4390 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PY 2001 VL 15 IS 3 BP 191 EP 195 DI 10.1177/154596830101500306 PG 5 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 533BG UT WOS:000174509100006 PM 11944740 ER PT J AU Lu, C Peng, YW Shang, J Pawlyk, BS Yu, F Li, T AF Lu, C Peng, YW Shang, J Pawlyk, BS Yu, F Li, T TI The mammalian retinal degeneration B2 gene is not required for photoreceptor function and survival SO NEUROSCIENCE LA English DT Article DE retinitis pigmentosa; retinal degeneration; phosphatidylinositol transfer protein; hippocampus; mossy fiber; amacrine cell ID PHOSPHATIDYLINOSITOL TRANSFER PROTEIN; PHOSPHOLIPID TRANSFER PROTEIN; DROSOPHILA-MELANOGASTER; RAT RETINA; HOMOLOG; MOUSE; RDGB; EXPRESSION; MUTANTS; CLONING AB The retinal degeneration B (rdgB) gene in Drosophila is essential for photoreceptor function and survival. The rdgB mutant fly exhibits an abnormal electroretinogram and a light-dependent photoreceptor degeneration. The function of RdgB is not fully understood, but the presence of a phosphatidylinositol transfer protein domain suggests a possible role in phosphatidylinositol metabolism and signaling. Two mammalian homologs, M-RdgB1 and M-RdgB2. are known. While M-RdgB1 is widely expressed, M-RdgB2 is found primarily in the retina and the dentate gyrus. Functional conservation between the Drosophila and mammalian RdgBs was demonstrated by the ability of both M-RdgBs to rescue the photoreceptor phenotype in rdgB mutant flies through transgenic expression. To investigate the role of M-RdgB2 in the mammalian retina, we disrupted the m-rdgB2 gene in mice by gene targeting. The homozygous knockout mice are fertile and apparently healthy. By light microscopy, immunocytochemistry and electroretinograms, mice up to 18 months of age showed normal photoreceptor function and survival. The inner retinal neurons were also examined by immunolabeling with a number of cell-specific markers and no apparent defects were found in the major cell populations. We conclude that M-rdgB2 is not essential for phototransduction and photoreceptor survival. Thus, m-rdgB2 is not a candidate gene for human retinal degenerations. Whether M-rdgB2 has a role in visual processing in the inner retina, or whether it is required for hippocampal function, remains to be determined. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. Duke Univ, Sch Med, Dept Ophthalmol, Durham, NC 27710 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. RP Li, T (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, 243 Charles St, Boston, MA 02114 USA. EM tli@meei.harvard.edu FU NEI NIH HHS [P30EY05722, EY10309, EY11498] NR 31 TC 32 Z9 32 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PY 2001 VL 107 IS 1 BP 35 EP 41 DI 10.1016/S0306-4522(01)00337-2 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 496LK UT WOS:000172396900004 PM 11744244 ER PT J AU Elibol, B Soylemezoglu, F Unal, I Fujii, M Hirt, L Huang, PL Moskowitz, MA Dalkara, T AF Elibol, B Soylemezoglu, F Unal, I Fujii, M Hirt, L Huang, PL Moskowitz, MA Dalkara, T TI Nitric oxide is involved in ischemia-induced apoptosis in brain: A study in neuronal nitric oxide synthase null mice SO NEUROSCIENCE LA English DT Article DE Bcl-2; Bax; caspases; actin; knockout mice; focal cerebral ischemia ID FOCAL CEREBRAL-ISCHEMIA; PROGRAMMED CELL-DEATH; ARTERY OCCLUSION; CASPASE ACTIVATION; DNA FRAGMENTATION; HYPOXIA-ISCHEMIA; GLOBAL-ISCHEMIA; RAT; ACTIN; BAX AB Nitric oxide can promote or inhibit apoptosis depending on the cell type and coexisting metabolic or experimental conditions. We examined the impact of nitric oxide on development of apoptosis 6, 24, and 72 h after permanent middle cerebral artery occlusion in mutant mice that lack the ability to generate nitric oxide from neuronal nitric oxide synthase. Adjacent coronal sections passing through the anterior commissure were stained with hematoxylin and eosin or terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Immunoblotting was used to identify changes in the anti- and proapoptotic proteins Bcl-2 and Bax, respectively. Activation of caspases was assessed by appearance of actin cleavage products using a novel antiserum directed against 32-kDa actin fragment (fractin). In the neuronal nitric oxide synthase mutant mouse, infarct size and TUNEL positive apoptotic neurons were reduced compared to the wild-type controls. At 6 h, Bcl-2 levels in the ischemic hemisphere were increased in mutants but decreased in the wild-type strain. Bax levels did not change significantly. Caspase-mediated actin cleavage appeared in the ischemic hemisphere at this time point, and was significantly less in mutant brains at 72 h compared to the wild-type. The reduction in the number of TUNEL and fractin positive apoptotic cells appears far greater than anticipated based on the smaller lesion size in mutant mice. Hence, from these data we suggest that a deficiency in neuronal nitric oxide production slows the development of apoptotic cell death after ischemic injury and is associated with preserved Bcl-2 levels and delayed activation of effector caspases. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA 02129 USA. Univ Hacettepe, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey. Univ Hacettepe, Inst Neurol Sci & Psychiat, TR-06100 Ankara, Turkey. Univ Hacettepe, Fac Med, Dept Pathol, TR-06100 Ankara, Turkey. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02129 USA. RP Moskowitz, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, 149 13th St,Room 6403, Boston, MA 02129 USA. RI Moskowitz, Michael/D-9916-2011; Hirt, Lorenz/G-3553-2010 OI Hirt, Lorenz/0000-0002-2921-5000 FU NINDS NIH HHS [101NS37141-01, NS10828] NR 52 TC 43 Z9 45 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PY 2001 VL 105 IS 1 BP 79 EP 86 DI 10.1016/S0306-4522(01)00159-2 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 464BQ UT WOS:000170513200008 PM 11483302 ER PT J AU McLean, PJ Kawamata, H Hyman, BT AF McLean, PJ Kawamata, H Hyman, BT TI alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons SO NEUROSCIENCE LA English DT Article DE Parkinson's disease; aggregation; Lewy body; alpha-synuclein; synphilin-1 ID PARKINSONS-DISEASE; LEWY BODIES; IN-VITRO; MUTATION; MUTANT; PATHOGENESIS; DEGRADATION; AGGREGATION; SYNPHILIN-1; FILAMENTS AB alpha -Synuclein accumulates in the brains of sporadic Parkinsons disease patients as a major component of Lewy bodies, and mutations in alpha -synuclein are associated with familial forms of Parkinson's disease. The pathogenic mechanisms that precede and promote the aggregation of a-synuclein into Lewy bodies in neurons remain to be determined. Here, we constructed a series of alpha -synuclein-enhanced green fluorescent protein (alpha -synucleinEGFP. SynEGFP) fusion proteins to address whether the Parkinson's disease-associated mutations alter the subcellular distribution of, alpha -synuclein, and to use as a tool for experimental manipulations to induce aggregate formation. When transiected into mouse cultured primary neurons, the 49-kDa alpha -synucleinEGFP fusion proteins are partially truncated to a similar to 27-kDa form. This nonfluorescent carboxy-terminally modified fusion protein spontaneously forms inclusions in the neuronal cytoplasm. A marked increase in the accumulation of inclusions is detected following treatment with each of three proteasome inhibitors, n-acetyl-leu-leu-norleucinal, lactacystin and MG132. Interestingly, Ala30Pro a-synucleinEGFP does not form the cytoplasmic inclusions that are characteristic of wild-type and AlaS3Thr alpha -synucleinEGFP. supporting the idea that the Ala30Pro alpha -syyncceen protein conformation differs from wild-type alpha -synuclein. Similar inclusions are formed if alpha -synuclein carboxy-terminus is modified by the addition of a V5/6xHistidine epitope tag. By contrast, overexpression of unmodified alpha -synuclein does not lead to aggregate formation. Furthermore, synphilin-1, an alpha -synnuclein interacting protein also found in Lewy bodies, colocalizes with the carboxy-terminally truncated alpha -synuclein fusion protein in discrete cytoplasmic inclusions. Our finding that manipulations of the carboxy-terminus of alpha -synuclein lead to inclusion formation may provide a model for studies of the pathogenic mechanisms of alpha -synuclein aggregation in Lewy bodies. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp East, Dept Neurol, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp East, Dept Neurol, Alzheimers Dis Res Unit, Rm 6405,149 13th St, Charlestown, MA 02129 USA. NR 23 TC 146 Z9 152 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PY 2001 VL 104 IS 3 BP 901 EP 912 DI 10.1016/S0306-4522(01)00113-0 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 453TT UT WOS:000169933100027 PM 11440819 ER PT J AU Van Brederode, JFM Rho, JM Cerne, R Tempel, BL Spain, WJ AF Van Brederode, JFM Rho, JM Cerne, R Tempel, BL Spain, WJ TI Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice SO NEUROSCIENCE LA English DT Article DE Kv1.1; knockout; potassium channel; seizure; epilepsy ID POTASSIUM CHANNEL GENE; EPISODIC ATAXIA; MYOKYMIA SYNDROME; INCREASED NUMBER; K+ CHANNELS; MOUSE-BRAIN; KV1.1; RECEPTORS; EXCITABILITY; LOCALIZATION AB Mice lacking the potassium channel subunit KCNA1 exhibit a severe epileptic phenotype beginning at an early postnatal age. The precise cellular physiological substrates for these seizures are unclear, as is the site of origin. Since KCNA1 mRNA in normal mice is expressed in the neocortex, we asked whether neurons in the neocortex of three to four week-old Kcnal-null mutants exhibit evidence of hyperexcitability. Layer V pyramidal neurons were directly visualized in brain slices with infrared differential-interference contrast microscopy and evaluated with cellular electrophysiological techniques. There were no significant differences in intrinsic membrane properties and action potential shape between Kcnal-null and wild-type mice, consistent with previous findings in hippocampal slice recordings. However, the frequency of spontaneous post-synaptic currents was significantly higher in Kcnal-null compared to wild-type mice. The frequency of spontaneous inhibitory post-synaptic currents and miniature (action-potential-independent) inhibitory post-synaptic currents was also significantly higher in Kcnal-null compared to wild-type mice. However, the frequency of spontaneous and miniature excitatory post-synaptic currents was not different in these two groups of animals. Comparison of the amplitude and kinetics of miniature inhibitory and excitatory post-synaptic currents revealed differences in amplitude, rise time and half-width between Kcnal-null and wild-type mice. Our data indicate that the inhibitory drive onto layer V pyramidal neurons is increased in Kcnal knockout mice, either directly through an increased spontaneous release of GABA from presynaptic terminals contacting layer V pyramidal neurons, or an enhanced excitatory synaptic input to inhibitory interneurons. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved. C1 Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Pediat, Seattle, WA 98195 USA. Univ Washington, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. Univ Washington, VM Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Neurol Res Labs 151, Seattle, WA 98108 USA. RP Van Brederode, JFM (reprint author), Univ Washington, Dept Neurol, Seattle, WA 98195 USA. FU BLRD VA [I01 BX000386]; NIDCD NIH HHS [DC03805]; NINDS NIH HHS [NS 34769, K08 NS 01974] NR 33 TC 19 Z9 19 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PY 2001 VL 103 IS 4 BP 921 EP 929 DI 10.1016/S0306-4522(01)00041-0 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 423NK UT WOS:000168182200007 PM 11301201 ER PT B AU Schellenberg, GD D'Souza, I Poorkaj, P Bird, TD AF Schellenberg, GD D'Souza, I Poorkaj, P Bird, TD BE Tanaka, C McGeer, PL Ihara, Y TI Tau and neurodegenerative disease: genetics and pathogenetic mechanisms SO NEUROSCIENTIFIC BASIS OF DEMENTIA LA English DT Proceedings Paper CT International Symposium on Dementia CY SEP 11-13, 1999 CL KOBE, JAPAN ID MULTIPLE-SYSTEM TAUOPATHY; AUTOSOMAL-DOMINANT PARKINSONISM; FAMILIAL PRESENILE-DEMENTIA; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; NEUROFIBRILLARY TANGLES; PROTEIN-TAU; FUNCTIONAL IMPLICATIONS; FTDP-17 MUTATIONS; MESSENGER-RNAS C1 Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. RP Schellenberg, GD (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. NR 51 TC 0 Z9 0 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND BN 3-7643-6205-7 PY 2001 BP 71 EP 79 PG 9 WC Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA BR76Q UT WOS:000167470700008 ER PT J AU Hoh, BL Carter, BS Budzik, RF Putman, CM Ogilvy, CS AF Hoh, BL Carter, BS Budzik, RF Putman, CM Ogilvy, CS TI Results after surgical and endovascular treatment of paraclinoid aneurysms by a combined neurovascular team SO NEUROSURGERY LA English DT Article DE endovascular; guglielmi detachable coil; internal carotid artery; ophthalmic aneurysm; outcome; paraclinoid aneurysm; surgery ID CAROTID-OPHTHALMIC ANEURYSMS; RETROGRADE SUCTION DECOMPRESSION; EXTRACRANIAL-INTRACRANIAL ANASTOMOSIS; GUGLIELMI DETACHABLE COILS; ANTERIOR CLINOID PROCESS; ARTERY ANEURYSMS; CEREBRAL ANEURYSMS; BALLOON OCCLUSION; GIANT ANEURYSMS; BYPASS AB OBJECTIVE: Advances in surgical and endovascular techniques have improved treatment for paraclinoid aneurysms. A combined surgical and endovascular team can formulate individualized treatment strategies for patients with paraclinoid aneurysms. Patients who are considered to be at high surgical risk can be treated endovascularly to minimize morbidity. We reviewed the clinical and radiographic outcomes of 238 paraclinoid aneurysms treated by our combined surgical and endovascular unit. METHODS: From 1991 to 1999, the neurovascular team treated 238 paraclinoid aneurysms in 216 patients at the Massachusetts General Hospital. The modality of treatment for each aneurysm was chosen based on anatomic and clinical risk factors, with endovascular treatment offered to patients considered to have higher surgical risks. One hundred eighty aneurysms were treated by direct surgery, 57 were treated by endovascular occlusion, and one was treated by surgical extracranial-intracranial bypass and endovascular internal carotid artery balloon occlusion. Locations were transitional, 12 (5%); carotid cave, 11 (5%); ophthalmic, 131 (55%); posterior carotid wall, 38 (16%); and superior hypophyseal 46 (19%). Lesions contained completely within the cavernous sinus were excluded from this analysis. RESULTS: Using the Glasgow Outcome Scale (GOS), overall clinical outcomes were excellent or good (GOS 5 or 4), 86%; fair (GOS 3), 7%; poor (GOS 2), 4%; and death (GOS 1), 3%. Among the surgically treated patients, 90% experienced excellent or good outcomes (GOS 5 or 4), 6% had fair outcomes (GOS 3), 2% had poor outcomes (GOS 2), and 3% died (GOS 1). Among the endovascularly treated patients, 74% had excellent or good outcomes (GOS 5 or 4), 12% had fair outcomes (GOS 3), 10% had poor outcomes (GOS 2), and 4% died (GOS 1). The overall major and minor complication rate from surgery was 29%, with a 6% surgery-related permanent morbidity rate and a mortality rate of 0%. The overall major and minor complication rate from endovascular treatment was 21%, with a 3% endovascular-related permanent morbidity rate and a 2% mortality rate. Visual outcomes for patients who presented with visual symptoms were as follows: improved, 69%; no change, 25%; worsened, 6%; and new visual deficits, 3%. In general, angiographic efficacy was lower in the endovascular treatment group. CONCLUSION: A combined team approach of direct surgery and endovascular coiling can lead to good outcomes in the treatment for paraclinoid aneurysms, including high-risk lesions that might not have been treated in previous surgical series. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brain Aneurysm AVM Ctr,Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Intervent Neuroradiol Serv, Boston, MA 02114 USA. RP Ogilvy, CS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brain Aneurysm AVM Ctr,Neurosurg Serv, VBK-710,Fruit St, Boston, MA 02114 USA. NR 65 TC 88 Z9 93 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD JAN PY 2001 VL 48 IS 1 BP 78 EP 89 DI 10.1097/00006123-200101000-00014 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 388FE UT WOS:000166166100030 PM 11152364 ER PT J AU Marteinsdottir, I Furmark, T Tillfors, M Agren, H Hartvig, P Fredrikson, M Langstrom, B Fischer, H Antoni, G Hagberg, G AF Marteinsdottir, I Furmark, T Tillfors, M Agren, H Hartvig, P Fredrikson, M Langstrom, B Fischer, H Antoni, G Hagberg, G TI Presynaptic serotonin imaging in social phobia using [3-C-11]-5-hydroxy-L-tryptophan and PET SO NORDIC JOURNAL OF PSYCHIATRY LA English DT Meeting Abstract C1 Fdn Santa Lucia IRCCS, Lab Funct Neuroimaging, Rome, Italy. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Neuroimaging Res Grp, Boston, MA 02114 USA. Uppsala Univ, PET Ctr, Uppsala, Sweden. Huddinge Univ Hosp, Div Psychiat, Dept NEUROTEC, Karolinska Inst, Stockholm, Sweden. Uppsala Univ, Dept Psychol, Uppsala, Sweden. Uppsala Univ, Dept Neurosci, Uppsala, Sweden. NR 0 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-9488 J9 NORD J PSYCHIAT JI Nord. J. Psychiatr. PY 2001 VL 55 IS 2 BP 98 EP 98 PG 1 WC Psychiatry SC Psychiatry GA 434KL UT WOS:000168813600072 ER PT S AU Leaf, A Kang, JX AF Leaf, A Kang, JX BE Simopoulos, AP Pavlou, KN TI Omega-3 fatty acids and cardiovascular disease SO NUTRITION AND FITNESS: DIET, GENES, PHYSICAL ACTIVITY AND HEALTH SE WORLD REVIEW OF NUTRITION AND DIETETICS LA English DT Proceedings Paper CT 4th International Conference on Nutrition and Fitness CY MAY 25-29, 2000 CL INT OLYMP ACAD, ATHENS, GREECE SP FAO, Minist Culture, Hellen Minist Hlth, Hellen Minist Educ, Ctr Genet, Nutr & Hlth, Stavros S Niarchos Fdn HO INT OLYMP ACAD ID RAT CARDIAC MYOCYTES; COD-LIVER OIL; FISH OIL; EICOSAPENTAENOIC ACID; PLATELET-FUNCTION; LONG-CHAIN; VENTRICULAR-FIBRILLATION; DIETARY SUPPLEMENTATION; NONHUMAN-PRIMATES; PREVENTION C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Leaf, A (reprint author), Massachusetts Gen Hosp, E 149,13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [R01 HL62284]; NIDDK NIH HHS [R01 DK 38165] NR 56 TC 11 Z9 11 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0084-2230 BN 3-8055-7210-7 J9 WORLD REV NUTR DIET JI World Rev.Nutr.Diet. PY 2001 VL 89 BP 161 EP 172 PG 12 WC Nutrition & Dietetics; Sport Sciences SC Nutrition & Dietetics; Sport Sciences GA BS86M UT WOS:000171273700015 PM 11530733 ER PT S AU Kennedy, JS AF Kennedy, JS BE Suskind, RM Tontisirin, K TI Stress, nutrition, and the immune response SO NUTRITION, IMMUNITY AND INFECTION IN INFANTS AND CHILDREN SE Nestle Nutrition Institute Workshop Series LA English DT Proceedings Paper CT 45th Nestle Nutrition Workshop on Nutrition, Immunity, and Infection in Infants and Children CY 1999 CL BANGKOK, THAILAND SP Mahidol Univ, WHO ID PROTEIN-ENERGY MALNUTRITION; SELENIUM-DEFICIENT MICE; CELL-MEDIATED-IMMUNITY; RESPIRATORY-TRACT INFECTIONS; VITAMIN-A SUPPLEMENTATION; CD4(+) T-CELLS; COXSACKIEVIRUS B3; PHYSICAL-ACTIVITY; MEASLES-VIRUS; CALORIE MALNUTRITION C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Kennedy, JS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dana 516,44 Binney St, Boston, MA 02115 USA. NR 113 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0742-2806 BN 0-7817-3079-1 J9 NESTLE NUTR WORKS SE PY 2001 VL 45 BP 173 EP 200 PG 28 WC Immunology; Infectious Diseases; Nutrition & Dietetics; Pediatrics SC Immunology; Infectious Diseases; Nutrition & Dietetics; Pediatrics GA BV44T UT WOS:000179009200009 ER PT J AU McElrath, TF Robinson, JN Ecker, JL Ringer, SA Norwitz, ER AF McElrath, TF Robinson, JN Ecker, JL Ringer, SA Norwitz, ER TI Neonatal outcome of infants born at 23 weeks' gestation SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID LOW-BIRTH-WEIGHT; SURVIVAL; AGE; VIABILITY AB Objective: To determine the neonatal outcome in accurately dated 23-week deliveries. Methods: We reviewed the records of consecutive births between 23 0/7 and 23 6/7 weeks at Brigham & Women's Hospital, Boston, Massachusetts, from January 1995 to December 1999. Women were excluded if they presented for elective termination or had known fetal death or poor dating criteria. Neonatal records were abstracted for mortality and short-term morbidity, including the respiratory distress syndrome (RDS), intraventricular hemorrhage, chronic lung disease, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity. Survival was defined as discharge from neonatal intensive care. Results: Thirty-three singleton pregnancies met criteria for inclusion, 11 of whom survived to discharge (survival rate 0.33; 95% CI 0.18, 0.52). More advanced gestational age was associated with increased likelihood of survival: 0 of 12 at 23 0/7 to 23 2/7 weeks, 4 of 10 at 23 3/7 to 23 4/7 weeks, and 7 of 11 at 23 5/7 to 23 6/7 weeks (P = .02). All 11 survivors developed RDS and chronic lung disease. One of II survivors had necrotizing enterocolitis, and 2 of 11 had severe retinopathy of prematurity. One survivor had periventricular leukomalacia on head ultrasonography, compared with 7 of the nonsurvivors who had head ultrasonography (P = .03). One survivor developed severe intraventricular hemorrhage (grade 3 or 4) compared with 8 of the 12 at-risk nonsurvivors who had head ultrasonography (P = .01). Conclusion: About one third of infants delivered at 23 weeks' gestation survived to be discharged from neonatal intensive care. More advanced gestational age was associated with increased likelihood of survival. No neonates survived free of substantial morbidity. (Obstet Gynecol 2001;97:49 -52. (C) 2001 by The American College of Obstetricians and Gynecologists.) C1 Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Newborn Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol, Boston, MA USA. RP McElrath, TF (reprint author), Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. NR 19 TC 24 Z9 24 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2001 VL 97 IS 1 BP 49 EP 52 DI 10.1016/S0029-7844(00)01086-3 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391TT UT WOS:000166372100010 PM 11152906 ER PT J AU Sandusky, H Cilluffo, M Braun, J Gordon, LK AF Sandusky, H Cilluffo, M Braun, J Gordon, LK TI Ocular pANCA antigens are expressed in nonpigmented ciliary body epithelium and are conserved in multiple mammalian species SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE uveitis; pANCA; phylogeny; autoimmunity ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; INFLAMMATORY BOWEL-DISEASE; ULCERATIVE-COLITIS; ANTERIOR UVEITIS; CELLS; AUTOIMMUNITY; SPONDYLOARTHROPATHY; IDENTIFICATION; AUTOANTIBODIES; RETRIEVAL AB Purpose: pANCA marker autoantibody is expressed by a subset of patients with anterior uveitis. A recombinantly isolated pANCA monoclonal antibody, Fab 5-3, identifies ocular expression of corresponding pANCA antigens in human ciliary body and retina. In this study, Fab 5-3 was used to explore pANCA antigen expression in ocular tissues of multiple mammalian species and identify the ciliary body cell type expressing the pANCA antigen. Methods: Ocular tissues were obtained from several mammalian species and evaluated for expression of the pANCA (Fab 5-3) antigen(s) using immunohistochemistry and Western analysis of tissue extracts. Additionally, primary cultures of nonpigmented and pigmented rabbit ciliary body epithelium were analyzed for pANCA expression using immunofluorescence and Western analysis. Results: Ocular pANCA (Fab 5-3) antigen expression was observed by immunohistochemistry only in the cytoplasm of retinal ganglion cells and ciliary body epithelium. Retinal antigen expression was conserved in all species examined. Ciliary body expression was observed in human, rabbit, rat, and mouse, but not in pig or cow. Antigen expression in the rabbit ciliary body was restricted to the nonpigmented layer as defined in primary cultures of nonpigmented and pigmented ciliary body epithelium. Immunoreactive proteins in both the human and rabbit included a 32-33 kDa doublet (histone HI), and novel 80 and 100kDa proteins. Conclusions: This study identifies ocular pANCA antigen expression in multiple mammalian species localized to the retinal ganglion cell layer and the non-pigmented ciliary body epithelium. The present study also establishes novel 80 and 100 kDa proteins which may correspond to the cytoplasmic antigens detected in situ and can be further characterized biochemically and immunologically using small animal model systems. C1 Univ Calif Los Angeles, Dept Ophthalmol, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Physiol Sci, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Dept Surg, Los Angeles, CA 90073 USA. RP Gordon, LK (reprint author), Jules Stein Eye Inst, 100 Stein Plaza, Los Angeles, CA 90095 USA. FU NCI NIH HHS [P01-CA12800]; NEI NIH HHS [KO8-EY00360, R01-EY06969]; NIDDK NIH HHS [P01-DK46763] NR 28 TC 12 Z9 12 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PY 2001 VL 9 IS 1 BP 25 EP 34 DI 10.1076/ocii.9.1.25.3981 PG 10 WC Ophthalmology SC Ophthalmology GA 412QQ UT WOS:000167566200003 PM 11262665 ER PT J AU Feifel, H Strack, S AF Feifel, H Strack, S TI Thanatologists view death: A 15-year perspective SO OMEGA-JOURNAL OF DEATH AND DYING LA English DT Article; Proceedings Paper CT 25th Meeting of the International Work Group on Death, Dying, and Bereavement CY SEP 26, 1999 CL DENVER, COLORADO SP Int Work Grp Death Dying & Bereavement ID DYING PATIENTS; AIDS AB This study examined the death attitudes of a number of prominent thanatologists over a 15-year span. In 1973, 40 (30 men, 10 women) invited participants at a conference on death and dying were surveyed concerning their attitudes toward dying and death using Feifel's Death Attitudes Questionnaire, a Death Semantic Differential Test, and a Death Metaphors Test. Fifteen years later, 25 (62.5 percent) of these individuals again gave their responses to the three measures. Analyses were limited to basic group comparisons because the original raw data were unavailable. Respondents were primarily behavioral scientists (64 percent), but sizeable minorities were from medicine/nursing (24 percent) and religion/philosophy (12 percent). They were about equally divided in the religious (45 percent) versus non-religious (55 percent) categories, and rated themselves as being fairly satisfied with themselves and life in general. Almost two-thirds reported some fear of death (64 percent at both time points), and only 20 percent indicated that the idea of their own death was "easy to accept." Most (60-64 percent) reported a fear of the personal consequences of death, including pain and an inability to have experiences or complete projects, with the next most pervasive fear (36-40 percent) being the consequences to loved ones, including pain, loss, and financial difficulties. Concerning what occurs after death, about half of the respondents (48-52 percent) indicated that death is the end of existence, another 24-30 percent were uncertain and 16-17 percent believed in the continued existence of a soul. Death attitudes were remarkably stable over the 15-year interval. The major difference found was a lessening of death fear from 1973 to 1988 (p < .002), that subjects attributed primarily to their ongoing conversations about death and dying (56 percent), and the deaths of family and friends (32 percent). C1 US Dept Vet Affairs, Ctr Ambulatory Care, Los Angeles, CA 90012 USA. Univ So Calif, Sch Med, Los Angeles, CA 90089 USA. RP Strack, S (reprint author), US Dept Vet Affairs, Ctr Ambulatory Care, 351 E Temple St, Los Angeles, CA 90012 USA. NR 31 TC 2 Z9 2 U1 0 U2 0 PU BAYWOOD PUBL CO INC PI AMITYVILLE PA 26 AUSTIN AVE, AMITYVILLE, NY 11701 USA SN 0030-2228 J9 OMEGA-J DEATH DYING JI Omega-J. Death Dying PY 2001 VL 43 IS 2 BP 97 EP 111 PG 15 WC Psychology, Multidisciplinary; Social Sciences, Biomedical SC Psychology; Biomedical Social Sciences GA 511RC UT WOS:000173278500002 ER PT J AU Boerner, K Silverman, PR AF Boerner, K Silverman, PR TI Gender specific coping patterns in widowed parents with dependent children SO OMEGA-JOURNAL OF DEATH AND DYING LA English DT Article ID GRIEF; DEATH AB This article looks at how the gender of the surviving parent affects the coping styles of bereaved family's with dependent children. Interview data from five father- and five mother-headed bereaved families from the MGH/Harvard Child Bereavement Study were subjected to an in-depth analysis. The findings suggest differences in parental coping patterns that seemed to be gender specific. Mothers in this sub-sample tended to adjust their own priorities to their children's needs, recognizing their children's needs for continuity in daily family life. For mothers there was more continuity between their past and their present roles. Family life was more disrupted by the death in father-headed households and fathers' efforts to establish new family routines did not always achieve their goal. Fathers, in this sub-sample, recognized the importance of continuity for their children by the second year after the death. However, they did not always make needed changes in their coping styles to meet these needs. Coping styles that fathers used seemed more parent-centered using an administrative approach to managing the household; mothers were more child-centered and had a more nurturing approach in dealing with their children. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Boerner, K (reprint author), Arlene R Gordon Res Inst, 111 E 59th St, New York, NY 10022 USA. NR 35 TC 9 Z9 9 U1 1 U2 2 PU BAYWOOD PUBL CO INC PI AMITYVILLE PA 26 AUSTIN AVE, AMITYVILLE, NY 11701 USA SN 0030-2228 J9 OMEGA-J DEATH DYING JI Omega-J. Death Dying PY 2001 VL 43 IS 3 BP 201 EP 216 DI 10.2190/GD5J-47U3-VR9P-Q63W PG 16 WC Psychology, Multidisciplinary; Social Sciences, Biomedical SC Psychology; Biomedical Social Sciences GA 521EU UT WOS:000173826900002 ER PT J AU Waxman, S Anderson, KC AF Waxman, S Anderson, KC TI History of the development of arsenic derivatives in cancer therapy SO ONCOLOGIST LA English DT Article; Proceedings Paper CT Scientific Roundtable on Arsenic Trioxide: Scientific and Clinical Progress CY JUL 19, 2000 CL NEW YORK, NEW YORK DE arsenic trioxide; acute promyelocytic leukemia; apoptosis ID ACUTE PROMYELOCYTIC LEUKEMIA; CLINICALLY ACHIEVABLE CONCENTRATIONS; TRIOXIDE INDUCES APOPTOSIS; GROWTH-INHIBITION; CELL-LINES; MALIGNANT LYMPHOCYTES; HODGKINS-DISEASE; RAR-ALPHA; IN-VITRO; MELARSOPROL AB Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation acid cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease. C1 CUNY Mt Sinai Sch Med, Rochelle Belfer Chemotherapy Fdn Lab, New York, NY 10029 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol,Kraft Family Blood Donor Ctr, Boston, MA 02115 USA. RP Waxman, S (reprint author), CUNY Mt Sinai Sch Med, Rochelle Belfer Chemotherapy Fdn Lab, 1 Gustave L Levy Pl, New York, NY 10029 USA. NR 48 TC 171 Z9 183 U1 4 U2 15 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 SU 2 BP 3 EP 10 DI 10.1634/theoncologist.6-suppl_2-3 PG 8 WC Oncology SC Oncology GA 543TL UT WOS:000175117200002 PM 11331434 ER PT J AU Demetri, GD AF Demetri, GD TI Targeted approaches for the treatment of thrombocytopenia SO ONCOLOGIST LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Hematology CY DEC 01, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Hematol DE c-Mpl; thrombocytopenia; thrombopoietin; thrombopoiesis; platelet transfusion ID RECOMBINANT HUMAN INTERLEUKIN-11; CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA; PLACEBO-CONTROLLED TRIAL; RHIL-11 GROWTH-FACTOR; PHASE-I TRIAL; C-MPL LIGAND; BREAST-CANCER; MEGAKARYOCYTE GROWTH; HUMAN THROMBOPOIETIN; BONE-MARROW AB Molecular targeting of novel therapies has the promise of inducing very specific biologic effects. In clinical hematology and oncology, molecular targeting of specific cell surface receptors with erythropoietin, G-CSF, or GM-CSF has been used to stimulate erythropoiesis and granulopoiesis, respectively. Although anemia and neutropenia can be corrected with targeted therapy, safe and effective treatment of thrombocytopenia remains an unmet medical need. While platelet transfusions still represent the standard of care for severe thrombocytopenia, there are several negative aspects associated with their use, including issues of availability, transient effectiveness, costs, adverse effects, negative perception by patients, and infection considerations. Despite extensive investigations of cytokines which act primarily on primitive levels of hematopoiesis, pharmacologic interventions to date have failed to elevate platelet counts in a reliable, highly effective, and well-tolerated fashion. Recombinant human interleukin-11 has been approved by the U.S. Food and Drug Administration for the treatment of chemotherapy-induced thrombocytopenia but has only modest efficacy and significant side effects. The identification of c-Mp1 as the thrombopoietin receptor has opened new avenues for the therapeutic manipulation of thrombopoiesis. The development of specific c-Mp1 ligands, including recombinant human thrombopoietin (rHuTPO), has allowed investigators to target this receptor for the treatment of chemotherapy-induced thrombocytopenia and other medical disorders characterized by extremely low platelet counts. As a potent stimulator of platelet production, rHuTPO has the potential to reduce the need for platelet transfusions and their attendant complications. C1 Dana Farber Canc Inst, Sarcoma Ctr, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Sarcoma Ctr, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. NR 57 TC 32 Z9 32 U1 0 U2 1 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 SU 5 BP 15 EP 23 PG 9 WC Oncology SC Oncology GA 543TN UT WOS:000175117400004 PM 11700388 ER PT J AU Jonasch, E Haluska, FG AF Jonasch, E Haluska, FG TI Interferon in oncological practice: Review of interferon biology, clinical applications, and toxicities SO ONCOLOGIST LA English DT Review DE interferon; cancer; clinical applications; toxicity; management ID CHRONIC MYELOGENOUS LEUKEMIA; RENAL-CELL CARCINOMA; PHASE-II TRIAL; LEUKOCYTE-A INTERFERON; METASTATIC MALIGNANT-MELANOMA; CHRONIC MYELOID-LEUKEMIA; PROSPECTIVE RANDOMIZED TRIAL; LOW-DOSE CYTARABINE; RESECTED CUTANEOUS MELANOMA; BONE-MARROW TRANSPLANTATION AB For the past 40 years, various forms of interferon (IFN) have been evaluated as therapy in a number of malignant and non-malignant diseases. With the advent of gene cloning, large quantities of pure IFN became available for clinical study. This paper reviews the biology, pharmacology, and clinical applications of IFN formulations most commonly used in oncology. It then reviews the most common side effects seen in patients treated with IFN, and makes recommendations for the management of IFN-induced toxicity. The major oncological indications for IFN include melanoma, renal cell carcinoma, AIDS-related Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, and chronic myelogenous leukemia. Unfortunately, IFN therapy is associated with significant toxicity, which can be divided into constitutional, neuropsychiatric, hematologic, and hepatic effects. These toxicities have a major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient. Careful attention to all aspects of patient care can result in improved tolerability of this difficult but promising therapy. Conclusion: a better understanding of IFN biology, indications, side effect profiles, and toxicity management will aid in optimizing its use in the treatment of patients with cancer. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jonasch, E (reprint author), Div Hematol Oncol, 55 Fruit St, Boston, MA 02114 USA. NR 164 TC 288 Z9 317 U1 2 U2 13 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 1 BP 34 EP 55 DI 10.1634/theoncologist.6-1-34 PG 22 WC Oncology SC Oncology GA 528MN UT WOS:000174247700007 PM 11161227 ER PT J AU Penson, RT Svendsen, SS Chabner, BA Lynch, TJ Levinson, W AF Penson, RT Svendsen, SS Chabner, BA Lynch, TJ Levinson, W TI Medical mistakes: A workshop on personal perspectives SO ONCOLOGIST LA English DT Article DE errors; accidents; psychosocial; stress; systems; guilt ID ADVERSE EVENTS; HOSPITALIZED-PATIENTS; SOCIOECONOMIC-STATUS; MALPRACTICE CLAIMS; CARE; PHYSICIANS; EMERGENCY; ERRORS; COMMUNICATION; DOCTORS AB Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center at MGH. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families. and their caregivers, and gain insight and support from fellow staff members. Medical errors are difficult to discuss. Significant medical errors occur in approximately 3% of hospitalizations. Two-thirds are preventable. Despite an entrenched belief that doctors should be infallible, errors are inevitable. Dr. Wendy Levinson of the University of Chicago facilitated a discussion of the impact medical errors have on staff. Staff broke into small groups to share their personal experience and then discussed common themes: the sense of shame and guilt, the punitive culture, guidelines for disclosure to patients and colleagues, and changes in medical practice that can prevent future mistakes. Auditing and improving systems has led to considerable improvements in the field of aviation safety. However, in medicine people are more important than the process. While we should never cease to aim for the very best in delivered care, we must acknowledge how prone we all are to mistakes and that we can learn from and prevent errors. Openly sharing experiences in a confidential setting, such as the Schwartz Rounds, helps defuse feelings of guilt and challenges the culture of shame and isolation that often surrounds medical errors. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. Univ Chicago, Pritzker Sch Med, Div Biol Sci, Chicago, IL 60637 USA. RP Penson, RT (reprint author), Cox 809,100 Blossom St, Boston, MA 02114 USA. NR 34 TC 18 Z9 18 U1 6 U2 14 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 1 BP 92 EP 99 DI 10.1634/theoncologist.6-1-92 PG 8 WC Oncology SC Oncology GA 528MN UT WOS:000174247700012 PM 11161232 ER PT J AU Penson, RT Seiden, MV Chabner, BA Lynch, TJ AF Penson, RT Seiden, MV Chabner, BA Lynch, TJ TI Caring for colleagues SO ONCOLOGIST LA English DT Article DE physicians; psychosocial; collusion; conflict; confidentiality ID PATIENT AB Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Caring for colleagues who develop cancer is a privilege woven with an extra dimension - caregiver-patient issues. As well as stretching the usual need for a supportive relationship, when one of the health care team develops cancer it particularly provokes concerns about our own mortality. The case is presented of a well-known physician who developed a second cancer and has been cared for at the NIGH Cancer Center. Staff discuss her care as it has been effected by her status as a colleague. They perceived unique barriers to optimal care such as assumptions about the patient's level of medical knowledge, and technical, informational, emotional, and hierarchical issues that may obstruct the development of a trusting relationship between caregivers and the physician/patient. Emotional stress may prevent the sharing of an accurate prognosis. In the case under consideration, the patient had a frank and open attitude to her cancer yet her caregivers were concerned about continual breeches of patient confidentiality. Despite the many potential problems inherent when the caregiver becomes the patient, this case discussion was a poignant reminder of the unique challenges of every experience with cancer and the weighty privilege of being involved with patient care. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. RP Penson, RT (reprint author), Cox 809,100 Blossom St, Boston, MA 02114 USA. NR 13 TC 3 Z9 4 U1 1 U2 4 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 2 BP 197 EP 204 DI 10.1634/theoncologist.6-2-197 PG 8 WC Oncology SC Oncology GA 528MP UT WOS:000174247800014 PM 11306731 ER PT J AU Penson, RT Yusuf, RZ Chabner, BA Lafrancesca, JP McElhinny, M Axelrad, AS Lynch, TJ AF Penson, RT Yusuf, RZ Chabner, BA Lafrancesca, JP McElhinny, M Axelrad, AS Lynch, TJ TI Losing god SO ONCOLOGIST LA English DT Article DE physicians; spiritual; psychosocial; faith; conflict; crisis ID PHYSICIANS; BELIEFS; CARE AB Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (NIGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers; reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Nebulous language, distrust, and dogma confound spiritual aspects of cancer care. However, existential well being is an important determinant of quality of life: finding meaning and purpose make suffering more tolerable. The case presented is of a patient who experienced "losing God" as a Hodgkin's disease survivor with metastatic prostate cancer and severe coronary artery disease. His caregivers were able to provide the sense of community in which fie could re-establish his faith. Health care providers do not have to be religious in order to help patients to deal with a spiritual crisis. The clinical skills of compassion need to be deployed to diagnose and respond to spiritual suffering. Acknowledging and addressing anger or guilt, common sources of suffering, are essential to adjustment. Simply being there for the patient and being open to their hurt can help resolve their spiritual crisis, a responsibility that is shared by the whole health care team. C1 Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. RP Penson, RT (reprint author), Cox 809,100 Blossom St, Boston, MA 02114 USA. NR 43 TC 6 Z9 6 U1 3 U2 7 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 3 BP 286 EP 297 DI 10.1634/theoncologist.6-3-286 PG 12 WC Oncology SC Oncology GA 528NQ UT WOS:000174250200010 PM 11423676 ER PT J AU Evans, TL Lynch, TJ AF Evans, TL Lynch, TJ TI Lung cancer SO ONCOLOGIST LA English DT Article DE non-small cell lung cancer; metastatic disease; treatment; stage IIIBNSCLC ID PHASE-III; TRIAL; CHEMOTHERAPY; CONCURRENT; CISPLATIN; RADIOTHERAPY; VINORELBINE; PACLITAXEL; VINDESINE; SURVIVAL AB Is any one combination therapy for metastatic non-small cell lung cancer (NSCLC) superior to other regimens for metastatic NSCLC? The answer is "probably no." More than 4,000 patients with advanced NSCLC participated in randomized trials presented at the 37th Annual Meeting of the American Society of Clinical Oncology. TAX326 was the only study in which the investigational arm (cisplatin/docetaxel) showed a statistically significant difference in survival compared with the reference standard (cisplatin/vinorelbine). We did learn, however, that what we administer may make some difference: cisplatin might be superior to carboplatin, and patients treated with nonplatinum chemotherapy regimens have a trend toward poorer survival than those who receive platinum doublets. Although there is still no clear best regimen for advanced NSCLC, we may now know how much chemotherapy to give: a randomized study presented found that four cycles produces as much survival benefit as treating until progression. The most significant abstracts presented at this year's lung cancer session involved the use of novel agents with unique mechanisms of action. The median survival in the large, randomized trials of chemotherapy in advanced NSCLC remains a bleak 9 months. ISIS 3521, an antisense oligonucleotide that targets protein kinase C, was found to produce a near doubling of survival when combined with carboplatin and paclitaxel. OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, was shown to have impressive single agent activity in the second-line treatment of lung cancer. The future of lung cancer therapy will involve combining these novel agents with active chemotherapy regimens in an effort to improve outcome. While we appear to have reached a plateau in what we can accomplish with various combinations of cytotoxic chemotherapy in metastatic NSCLC, in locally-advanced disease new chemotherapy combinations can achieve remarkable results when combined with radiation therapy. The Southwest Oncology Group presented unprecedented phase 11 data on the use of cisplatin and etoposide with concurrent radiation therapy followed by consolidation docetaxel in patients with stage IIIB NSCLC. C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Lynch, TJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, 100 Blossom St,Room 201 Cox, Boston, MA 02114 USA. NR 19 TC 10 Z9 11 U1 0 U2 0 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 5 BP 407 EP 414 DI 10.1634/theoncologist.6-5-407 PG 8 WC Oncology SC Oncology GA 529VJ UT WOS:000174321200004 PM 11675518 ER PT J AU Penson, RT Castro, CM Seiden, MV Chabner, BA Lynch, TJ AF Penson, RT Castro, CM Seiden, MV Chabner, BA Lynch, TJ TI Complementary, alternative, integrative, or unconventional medicine? SO ONCOLOGIST LA English DT Article DE holistic; chemotherapy; ovarian cancer ID BREAST-CANCER; CLINICAL-TRIALS; UNITED-STATES; THERAPIES; ONCOLOGY; ABC; WOMEN; METAANALYSIS; PREVALENCE; REMEDIES AB Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Interest in complementary and alternative medicine (CAM) has grown exponentially in the past decade, fueled by Internet marketing, dissatisfaction with mainstream medicine, and a desire for patients to be actively involved in their health care. There is a large discordance between physician estimates and reported prevalence of CAM use. Many patients do not disclose their practices mainly because they believe CAM falls outside the rubric of conventional medicine or because physicians do not ask. Concern about drug interactions and adverse effects are compounded by a lack of Food and Drug Administration regulation. Physicians need to be informed about CAM and be attuned to the psychosocial needs of patients. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. RP Penson, RT (reprint author), Cox 809,100 Blossom St, Boston, MA 02114 USA. NR 60 TC 17 Z9 18 U1 4 U2 8 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2001 VL 6 IS 5 BP 463 EP 473 DI 10.1634/theoncologist.6-5-463 PG 11 WC Oncology SC Oncology GA 529VJ UT WOS:000174321200012 PM 11675526 ER PT J AU Vogel, CL Cobleigh, MA Tripathy, D Gutheil, JC Harris, LN Fehrenbacher, L Slamon, DJ Murphy, M Novotny, WF Burchmore, M Shak, S Stewart, SJ AF Vogel, CL Cobleigh, MA Tripathy, D Gutheil, JC Harris, LN Fehrenbacher, L Slamon, DJ Murphy, M Novotny, WF Burchmore, M Shak, S Stewart, SJ TI First-line Herceptin (R) monotherapy in metastatic breast cancer SO ONCOLOGY LA English DT Article; Proceedings Paper CT Symposium on Optimising the Role of Herceptin in Breast Cancer CY JUN 19-21, 2000 CL MONTE CARLO, MONACO DE first-line therapy; FISH; HER2 positive; Herceptin((R)); IHC 3+; metastatic breast cancer; monotherapy ID ANTI-HER2 MONOCLONAL-ANTIBODY; TRASTUZUMAB HERCEPTIN; PHASE-II; CELLS; OVEREXPRESSION; CHEMOTHERAPY; HER2/NEU; THERAPY; GROWTH AB The pivotal phase II and III Herceptin (R) trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg im. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for greater than or equal to6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase Ill combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients. Copyright (C) 2001 S. Karger AG, Basel. C1 Univ Miami, Sch Med, Comprehens Canc Res Grp Inc, Miami, FL 33152 USA. Columbia Canc Res Network Florida, Miami, FL USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Calif San Francisco, Mt Zion Canc Ctr, San Francisco, CA USA. Vical Inc, San Diego, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Kaiser Permanente, Vallejo, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Genentech Inc, S San Francisco, CA 94080 USA. RP Vogel, CL (reprint author), S Point Med Ctr, 600 S Pine Isl Rd Ste 104, Plantation, FL 33324 USA. NR 25 TC 109 Z9 115 U1 2 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2001 VL 61 SU 2 BP 37 EP 42 DI 10.1159/000055400 PG 6 WC Oncology SC Oncology GA 490TA UT WOS:000172066100006 PM 11694786 ER PT J AU Winer, EP Burstein, HJ AF Winer, EP Burstein, HJ TI New combinations with Herceptin((R)) in metastatic breast cancer SO ONCOLOGY LA English DT Article; Proceedings Paper CT Symposium on Optimising the Role of Herceptin in Breast Cancer CY JUN 19-21, 2000 CL MONTE CARLO, MONACO DE Herceptin((R)); trastuzumab; HER2; vinorelbine; biological therapy; combination therapy; metastatic breast cancer ID RECEPTOR-ENHANCED CHEMOSENSITIVITY; ANTI-HER2 MONOCLONAL-ANTIBODY; FIRST-LINE CHEMOTHERAPY; QUALITY-OF-LIFE; PHASE-II; TRASTUZUMAB HERCEPTIN; OVARIAN-CANCER; VINORELBINE; THERAPY; CISPLATIN AB Preclinical data indicate that trastuzumab (Herceptin (C)) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective (overall response rate 75%) and well tolerated, with the major side effects being typical of single-agent vinorelbine. Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer. Copyright (C) 2001 S. Karger AG, Basel. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, 44 Binney St,D 1214, Boston, MA 02115 USA. NR 40 TC 32 Z9 32 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2001 VL 61 SU 2 BP 50 EP 57 DI 10.1159/000055402 PG 8 WC Oncology SC Oncology GA 490TA UT WOS:000172066100008 PM 11694788 ER PT J AU Janne, PA Rodriguez-Thompson, D Metcalf, DR Swanson, SJ Greisman, HA Wilkins-Haug, L Johnson, BE AF Janne, PA Rodriguez-Thompson, D Metcalf, DR Swanson, SJ Greisman, HA Wilkins-Haug, L Johnson, BE TI Chemotherapy for a patient with advanced non-small-cell lung cancer during pregnancy: A case report and a review of chemotherapy treatment during pregnancy SO ONCOLOGY LA English DT Article DE lung neoplasm; carcinoma; non-small-cell lung cancer; pregnancy; antineoplastic agents; cisplatin; vinca alkaloids ID EPITHELIAL OVARIAN-CARCINOMA; COMPLICATING PREGNANCY; PLACENTAL METASTASIS; BREAST-CANCER; CISPLATIN; PNEUMOTHORAX; VINORELBINE; MANAGEMENT; ANESTHESIA; THERAPY AB Background. Lung cancer is the most common cause of cancer death in women in the USA. Lung cancer arising during pregnancy is rare and has been reported only 15 times since the 1950s. However, the use of chemotherapy for lung cancer during pregnancy has not previously been reported. Methods:The history, treatment and outcome of a patient with stage IV non-small-cell lung carcinoma (NSCLC) diagnosed during pregnancy is presented. Previous published reports on lung cancer were retrieved by a literature search of Medline and Cancerlit. Results: A 31-year-old woman was diagnosed as having stage IV NSCLC with bilateral pulmonary involvement when 26 weeks pregnant. Her shortness of breath progressed to dyspnea at rest on 100% inspired oxygen. Therefore, she was treated with systemic chemotherapy using cisplatin and vinorelbine. Despite this treatment, her oxygenation declined further over the next 4 days and thus the baby was delivered via cesarean section after 27 weeks of gestation. Four cycles of vinorelbine and cisplatin have now been administered. Following this treatment, the patient has experienced a significant clinical improvement and no longer requires supplemental oxygen. No chemotherapy-related adverse effects have been noted in the baby. In the 15 previously reported patients with concurrent lung cancer and pregnancy, chemotherapy administration during pregnancy has not been described. Conclusions: Treatment of lung cancer with chemotherapy during pregnancy should be considered on an individual basis with regard to the stage of the cancer and the maturity of the fetus. To our knowledge, the case presented here is the first report of a woman receiving chemotherapy for lung cancer while pregnant. Copyright (C) 2001 S. Karger AG, Basel. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Thorac Surg, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, D1234,44 Binney St, Boston, MA 02115 USA. NR 67 TC 25 Z9 27 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2001 VL 61 IS 3 BP 175 EP 183 DI 10.1159/000055371 PG 9 WC Oncology SC Oncology GA 480AQ UT WOS:000171438600001 PM 11574771 ER PT J AU Shin, SW Breathnach, OS Linnoila, RI Williams, J Gillespie, JW Kelly, MJ Johnson, BE AF Shin, SW Breathnach, OS Linnoila, RI Williams, J Gillespie, JW Kelly, MJ Johnson, BE TI Genetic changes in contralateral bronchioloalveolar carcinomas of the lung SO ONCOLOGY LA English DT Article DE bronchioloalveolar carcinoma; clonality; loss of heterozygosity; p53; K-ras ID SQUAMOUS-CELL CARCINOMA; ORIGIN; CANCER; TUMORS; HETEROZYGOSITY; ADENOCARCINOMA; RECURRENCE; MUTATIONS; FEATURES; HEAD AB Objective: The pattern of metastases and recurrence of bronchioloalveolar carcinoma (BAC) differs from adenocarcinoma of the lung, occurring more frequently within the lung without extrapulmonary involvement. Analyses of genetic differences of contralateral BACs may help to explain these clinical differences. Methods: We compared paired tumors from 5 patients with contralateral metachronous BACs for loss of heterozygosity (LOH) on 6 chromosomal arms (2q, 3p, 5q, 9p, 13q and 17p) and mutational analysis of p53 and K-ras. Results: Two patients, patients 1 and 2, had discordant patterns of LOH on 2 and 3 of the chromosome arms, respectively. in addition, patient 2 had a detectable K-ras mutation in his initial tumor but not in his second. These results suggest that in patients 1 and 2, the contralateral tumors were clonally unrelated. Patient 3 had no mutations in the K-ras or p53 gene and no LOH on any of the 5 informative chromosome arms. Patient 4 had LOH of 9p and mutated K-ras in both the fi rst and the second tu mor, with a mutation in the p53 gene in the first but not in the second tumor. Patient 5 had LOH of 17p and the same p53 mutations in both the first and the second tumor, with a mutation of K-ras in the first tumor but not in the second. Conclusions: The preponderance of evidence suggests that in patients 3, 4 and 5, the paired tumors were clonally related. The different patterns of LOH and mutations in clinically similar contralateral metachronous BACs provide evidence of genetic heterogeneity in the tumors of this patient group. Copyright (C) 2001 S. Karger AG, Basel. C1 Natl Canc Inst, Div Clin Sci, Med Branch, Bethesda, MD USA. Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. NCI, Div Clin Sci, Expt Pathol Branch, Bethesda, MD USA. Natl Naval Med Ctr, Dept Pathol, Bethesda, MD USA. NCI, Div Clin Sci, Pathol Lab, Bethesda, MD USA. Duke Univ, Dept Hematol Oncol, Durham, NC USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Room 1234,44 Binney St, Boston, MA 02115 USA. OI Kelley, Michael/0000-0001-9523-6080 NR 24 TC 8 Z9 8 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2001 VL 60 IS 1 BP 81 EP 87 DI 10.1159/000055301 PG 7 WC Oncology SC Oncology GA 390BX UT WOS:000166275200013 PM 11150913 ER PT S AU Dunn, AK Bolay, H Maskowitz, M Boas, DA AF Dunn, AK Bolay, H Maskowitz, M Boas, DA BE Farkas, DL Leif, RC TI Spatially-resolved cerebral blood flow imaging using laser speckle SO OPTICAL DIAGNOSITICS OF LIVING CELLS IV SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Diagnostics of Living Cells IV CY JAN 24-25, 2001 CL SAN JOSE, CA SP SPIE DE laser speckle; cerebral blood flow; brain function ID DOPPLER AB Cerebral blood flow measurements are crucial for studying neuronal activity and cerebrovascular responses. Most optical techniques for monitoring real time blood flow rely on laser Doppler measurements which are limited to a localized region in space (point measurements). We have used the time-varying speckle pattern produced by coherent light scattered from moving particles to provide real time, two-dimensional maps of capillary blood flow dynamics. The speckle images of relative blood flow during cortical spreading depression showed a 2-3 mm area of increased blood flow propagating with a velocity of 3.5 mm/min. The speckle technique therefore, provides a relatively simple method of obtaining spatially resolved cerebral blood flow changes in the exposed cortex with high temporal resolution (milliseconds). C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Charlestown, MA 02129 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM adunn@nmr.mgh.harvard.edu RI Dunn, Andrew/I-9527-2014 NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3938-X J9 PROC SPIE PY 2001 VL 4260 BP 16 EP 19 DI 10.1117/12.426780 PG 4 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BS45W UT WOS:000169896100003 ER PT S AU Zhang, Q Brukilacchio, TJ Gaudett, T Wang, L Li, A Boas, DA AF Zhang, Q Brukilacchio, TJ Gaudett, T Wang, L Li, A Boas, DA BE Chance, B Alfano, RR Tromberg, BJ Tamura, M SevickMuraca, EM TI Experimental comparison of using continuous-wave and frequency-domain diffuse optical imaging systems to detect heterogeneities SO OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE IV SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Tomography and Spectroscopy of Tissue IV CY JAN 21-23, 2001 CL SAN JOSE, CA SP SPIE DE optical imaging; continuous wave; frequency domain; sensitivity; noise model; instrumentation; phantom experiment ID SPECTROSCOPY; NOISE AB Continuous-Wave (CW) and Frequency-Domain (RF) methods of diffuse optical imaging are compared to identify the optimal approach for a clinical system. The CW Imager features fast imaging with 9 frequency-encoded sources and 16 detectors. The homodyne RF imager has 40 sources modulated at a frequency of 70MHz and 9 detectors. Both systems incorporate two wavelengths. The features and characterization of both systems are discussed and compared. A versatile phantom box design is presented that offered flexibility in experimental design and facilitated optimization of probe geometry. A 3-D absorption image reconstruction phantom experiment is carried out to test the performance of the RF system. Noise models are set up and experimentally verified, and a signal-to-noise ratio (SNR) analysis is presented. The heterogeneity detection sensitivity of the CW method and the RF method are compared, using both simulation and phantom experiments. The comparison results are discussed in the context of the most suitable approach to the design of a clinical breast cancer detection system. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, 13th St Bldg 149, Charlestown, MA 02129 USA. NR 16 TC 9 Z9 9 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3928-2 J9 PROC SPIE PY 2001 VL 4250 BP 219 EP 238 DI 10.1117/12.434493 PG 20 WC Engineering, Biomedical; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Engineering; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA BS86R UT WOS:000171276400027 ER PT S AU Wang, L Zhang, Q Brukilacchio, TJ Boas, DA AF Wang, L Zhang, Q Brukilacchio, TJ Boas, DA BE Chance, B Alfano, RR Tromberg, BJ Tamura, M SevickMuraca, EM TI Optimizing single projection linear tomographic optical breast imaging SO OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE IV SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Tomography and Spectroscopy of Tissue IV CY JAN 21-23, 2001 CL SAN JOSE, CA SP SPIE DE optical imaging; image reconstruction; truncated singular value decomposition (TSVD) AB Optimization of the systems and reconstruction techniques is important for good optical breast imaging. Quantitative and objective assessments of the quality of the reconstructed image and the detection sensitivity are required to optimize single projection optical imaging. In this paper, the detection sensitivity was estimated by the contrast to noise ratio, and the quality of an image is evaluated using, resolution, image noise, positional error, and quantitative accuracy. The expressions of these evaluating parameters were set up and analyzed by simulation. Using the quantitative assessment parameters we developed, we present a sensitivity and accuracy analysis of the Truncated Singular Value Decomposition (TSVD) method applied to optical breast imaging in transmission mode. The results indicate that the higher spatial resolution and improved quantitative accuracy obtained by decreasing the TSVD regularization parameter (i.e. the number of singular values used in the matrix inversion) must be balanced against the concomitant increase in image noise. Other parameters needs to be optimized including probe geometry, voxel size were also analyzed. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, 13th St Bldg 149, Charlestown, MA 02129 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3928-2 J9 PROC SPIE PY 2001 VL 4250 BP 391 EP 406 DI 10.1117/12.434519 PG 16 WC Engineering, Biomedical; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Engineering; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA BS86R UT WOS:000171276400047 ER PT S AU Brukilacchio, T Zhang, Q Gaudett, T Wang, L Li, A Boas, D AF Brukilacchio, T Zhang, Q Gaudett, T Wang, L Li, A Boas, D BE Chance, B Alfano, RR Tromberg, BJ Tamura, M SevickMuraca, EM TI Characterization of the point spread function for diffuse optical tomographic imaging and the effect of noise on resolution SO OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE IV SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Tomography and Spectroscopy of Tissue IV CY JAN 21-23, 2001 CL SAN JOSE, CA SP SPIE DE diffuse optical tomography; point spread function (PSF); breast cancer detection; near infrared; mammography; Tikhonov regularization; truncated singular value decomposition (TSVD); resolution; noise; spectroscopic imaging AB Diffuse optical tomographic imaging has broad application to the field of clinical diagnosis of diseased tissue states. In particular, there has been considerable interest in applying diffuse optical imaging to breast cancer detection. We explore the effects of such parameters as regularization, source-to-source and detector-to-detector spacing, voxel size and source modulation frequency on characteristics of the point spread function (PSF) of the reconstructed image. An understanding of these effects is critical to the optimization of diffuse optical tomographic imaging techniques. We also present a figure of merit that can be used to compare various reconstruction techniques and parameters when considering the effects of noise on quantitative accuracy and resolution. In all cases we look at heterogeneities with changes in absorption only and limit the analysis to the linear approximation of the diffusion equation. We show that the resolution and quantitative accuracy are fundamentally limited by the degree of regularization required to achieve images of acceptable contrast in the presence of representative noise levels. All simulations are based on Tikhonov regularization and truncated singular value decomposition (TSVD) reconstruction techniques for which we have generally achieved best results. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, 13th St Bldg 149, Charlestown, MA 02129 USA. EM tbruk@nmr.mgh.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3928-2 J9 PROC SPIE PY 2001 VL 4250 BP 489 EP 507 DI 10.1117/12.434509 PG 19 WC Engineering, Biomedical; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Engineering; Optics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA BS86R UT WOS:000171276400059 ER PT J AU Carey, JW Dodson, TB AF Carey, JW Dodson, TB TI Hospital course of HIV-positive patients with odontogenic infections SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS-RELATED COMPLEX; IMMUNE-DEFICIENCY SYNDROME; PNEUMOCOCCAL BACTEREMIA; BACTERIAL-INFECTIONS; RISK; COMPLICATIONS; NEUTROPENIA; PNEUMONIA; DISEASE AB Objective, The study purpose was to compare and contrast the hospital course of patients who are human immunodeficiency virus-positive (HIV+) and human immunodeficiency virus-negative (HIV-) who were admitted to manage their odontogenic infection. Study design. We used a retrospective case-control study design and a sample derived from patients admitted for management of their odontogenic infections. Cases and controls were defined as patients who were HIV+ or HIV-, respectively. HIV status was determined by patient self-report. Outcome variables included admission temperature (degrees Celsius) and white blood cell count, number of fascial spaces infected, days with temperature >38 degreesC, need for intensive care, and length of hospital stay. Results. The study sample consisted of 60 patients (10 HIV+ cases and 50 HIV- controls matched for age and sex) with a mean age of 32.8 +/- 6.6 years and was predominately male (78%). Significant differences existed between patients who were HIV+ and those who were HIV- for the following variables: admission white blood cell count, number of days with maximum temperature >38.0 degreesC, and use of the intensive care unit. Conclusions. The study results suggest that patients who are HIV+ who are admitted for management of odontogenic infection have a significantly more intense hospital course than those who are HIV-. However, the overall length of hospital stay is not significantly different. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02421 USA. Emory Univ, Sch Med, Dept Surg, Div Oral & Maxillofacial Surg, Atlanta, GA 30322 USA. RP Dodson, TB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren 1201, Boston, MA 02421 USA. RI Andrade, Hugo/M-6631-2013 OI Andrade, Hugo/0000-0001-6781-6125 NR 32 TC 5 Z9 5 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 JAN PY 2001 VL 91 IS 1 BP 23 EP 27 DI 10.1067/moe.2001.111410 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 395RG UT WOS:000166594600007 PM 11174567 ER PT J AU Greenspan, SL Cheng, S Miller, PD Orwoll, ES AF Greenspan, SL Cheng, S Miller, PD Orwoll, ES CA QUS-2 PMA Trials Grp TI Clinical performance of a highly portable, scanning calcaneal ultrasonometer SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE bone mineral density; calcaneus; fracture; osteoporosis; ultrasound ID BONE-MINERAL DENSITY; BAND ULTRASOUND ATTENUATION; X-RAY ABSORPTIOMETRY; SITE-SPECIFIC ANALYSIS; PREDICT HIP FRACTURE; QUANTITATIVE ULTRASOUND; ELDERLY WOMEN; OSTEOPOROTIC FRACTURES; PERIMENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN AB The aim of this study was to establish a normative database, assess precision, and evaluate the ability to identify women with low bone mass and to discriminate women with fracture from those without for a highly portable, scanning calcaneal ultrasonometer: the QUS-2, Fourteen hundred and one Caucasian women were recruited for the study. Among them were 794 healthy women 25-84 years of age evenly distributed per 10-year period to establish a normative database. Of these, 171 aged 25-34 years were defined as the young normal group for the purpose of T-score determination. Precision was assessed within 1 day (short-term) and over a 16-week period (long-term) in 79 women aged 25-84 years. Five hundred twenty-eight women ranging from 50 to 84 years of age with or without prevalent fractures of the spine, hip or forearm were measured to compare the QUS-2 with bone mineral density (BMD) of the hip and spine. Mean calcaneal broadband ultrasound attenuation (BUA) was constant in healthy women from 25 to 54 years of age and decreased with increasing age thereafter. Short-term precision, with and without repositioning of the heel, and long-term precision yielded comparable results (BUA SDs of 2.1-2.4 dB/MHz, coefficients of variations (CVs) of 2.5-2.9%). Calcaneal BUA was significantly correlated with BMD of the total hip (TH), femoral neck (FN) and lumbar spine (LS) in 698 women (r = 0.6-0.7, all p <0.0001). A similar relationship was observed for LS BMD compared with either TH or FN BMD (r = 0.7, p <0.0001). Prevalence of osteoporosis in our population (WHO criteria) was 20%, 17%, 21%, and 24% for BUA, BMD of the TH, FN and LS, respectively. Age-adjusted values for a 1 SD reduction in calcaneal BUA and TH and FN BMD predicted prevalent fractures of the spine, forearm, and hip with significant (p <0.05) odds ratios of 2.3, 2.0 and 2.1, respectively. Areas under the receiver operating characteristic curves for age-adjusted bone mass values predicting prevalent fracture were 0.62 for BUA, 0.59 for TH BMD, 0.60 for FN BMD, and 0.57 for LS BMD; all statistically equivalent. We conclude that the QUS-2 calcaneal ultrasonometer exhibits reproducible clinical performance that is similar to BMD of the spine and hip in identifying women with low bone mass and discriminating women with fracture from those without. C1 Univ Pittsburgh, Med Ctr, Div Endocrinol & Metab, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Med Ctr, Div Geriatr Med, Pittsburgh, PA 15213 USA. Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. Univ Colorado, Hlth Sci Ctr, Dept Med, Lakewood, CO USA. Colorado Ctr Bone Res, Lakewood, CO USA. Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. RP Greenspan, SL (reprint author), Univ Pittsburgh, Med Ctr, Div Endocrinol & Metab, 1110 Kaufmann Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. OI Orwoll, Eric/0000-0002-8520-7355 NR 48 TC 36 Z9 37 U1 0 U2 1 PU SPRINGER-VERLAG LONDON LTD PI GODALMING PA SWEETAPPLE HOUSE CATTESHALL ROAD, GODALMING GU7 3DJ, SURREY, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PY 2001 VL 12 IS 5 BP 391 EP 398 DI 10.1007/s001980170108 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 446JD UT WOS:000169509400010 PM 11444088 ER PT J AU Melton, LJ Orwoll, ES Wasnich, RD AF Melton, LJ Orwoll, ES Wasnich, RD TI Does bone density predict fractures comparably in men and women? SO OSTEOPOROSIS INTERNATIONAL LA English DT Review ID MINERAL DENSITY; HIP FRACTURE; OSTEOPOROTIC FRACTURES; FOREARM FRACTURE; FEMORAL-NECK; OLDER MEN; US ADULTS; RISK; DENSITOMETRY; STRENGTH C1 Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, Rochester, MN 55905 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. Hawaii Osteoporosis Ctr, Honolulu, HI USA. RP Melton, LJ (reprint author), Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, 200 1st St SW, Rochester, MN 55905 USA. OI Orwoll, Eric/0000-0002-8520-7355 FU NIAMS NIH HHS [AR 27065] NR 33 TC 41 Z9 44 U1 0 U2 0 PU SPRINGER-VERLAG LONDON LTD PI GODALMING PA SWEETAPPLE HOUSE CATTESHALL ROAD, GODALMING GU7 3DJ, SURREY, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PY 2001 VL 12 IS 9 BP 707 EP 709 DI 10.1007/s001980170044 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 481HE UT WOS:000171513200001 PM 11605734 ER PT J AU Harthorne, JW AF Harthorne, JW TI A stretched-thin doctor draws the line SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Harthorne, JW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU FUTURA PUBL CO PI ARMONK PA 135 BEDFORD RD, PO BOX 418, ARMONK, NY 10504-0418 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD JAN PY 2001 VL 24 IS 1 BP 111 EP 111 DI 10.1046/j.1460-9592.2001.00111.x PG 1 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 402DD UT WOS:000166970000020 ER PT J AU Keck, T Campo-Ruiz, V Warshaw, AL Anderson, RR Castillo, CFD Gonzalez, S AF Keck, T Campo-Ruiz, V Warshaw, AL Anderson, RR Castillo, CFD Gonzalez, S TI Evaluation of morphology and microcirculation of the pancreas by ex vivo and in vivo reflectance confocal microscopy SO PANCREATOLOGY LA English DT Article DE confocal microscopy; in vivo; pancreas; microcirculation; leukocyte-endothelial interaction; angioarchitecture; angiogenesis ID LASER-SCANNING MICROSCOPY; CROSS-LINKED HEMOGLOBIN; IN-VIVO; NECROTIZING PANCREATITIS; HEMORRHAGIC-SHOCK; RAT PANCREAS; HUMAN SKIN; ISCHEMIA; INJURY; MICROVASCULATURE AB Background. Near-infrared reflectance confocal microscopy (CM) provides non-invasive real-time images of thin virtual horizontal tissue sections with high resolution and contrast. Aim: Aim of the study was to characterize morphology, microcirculation and leukocyte-endothelial interaction (LEI) in normal pancreas by in vivo and ex vivo CM. Methods: For CM we used water immersion objective lenses of high numerical aperture and near-infrared wavelengths. Experimentally measured lateral optical resolution is 0.5-1 mum and the axial resolution is 3-5 mum. The maximum depth of resolution was 300-400 mum. For ex vivo imaging, freshly excised pancreatic tissue from rats was studied by reflectance CM and conventional histopathology. For in vivo CM, the pancreatic head was exteriorized on a specially constructed stage for imaging the microcirculation and LEI. Images were obtained in real time at rates of 30 frames/s and later analyzed off-line to evaluate LEI and functional capillary density (FCD). Results. CM allowed high resolution visualization of normal pancreas acinar cells, ducts, islets, capillaries and LEI in postcapillary venules. Histological images and optical sections from ex vivo CM can be correlated. Cellular morphology is better analyzed by conventional histology, but angioarchitecture and connective tissue structure are better evaluated by CM. FCD (265.7 +/- 16.6 cm(-1)) and LEI (rolling leukocytes 5.3 +/- 1.6/ 100 mum/sticking leukocytes 1.5 +/- 0.9/100 mum) were evaluated by in vivo CM in the normal pancreas. Conclusions: CM findings in tissues ex vivo correlate with those of classical histology but add informative details of connective tissue structure and angioarchitecture. Potential future applications for in vivo CM include real-time analysis of microcirculation, leukocyte-endothelial interaction and angiostructure in inflammatory and malignant pancreatic diseases. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Wellman Labs Photomed, Boston, MA 02115 USA. RP Warshaw, AL (reprint author), Massachusetts Gen Hosp, Dept Surg, WHT 506,55 Fruit St, Boston, MA 02114 USA. RI Smaga, Ivan/E-3628-2016 OI Smaga, Ivan/0000-0002-9000-3832 NR 44 TC 13 Z9 13 U1 0 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 1 BP 48 EP 57 DI 10.1159/000055792 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502XD UT WOS:000172767300009 PM 12120268 ER PT J AU Rossi, L Pfutzer, RH Parvin, S Ali, L Sattar, S Kahn, AKA Gyr, N Whitcomb, DC AF Rossi, L Pfutzer, RH Parvin, S Ali, L Sattar, S Kahn, AKA Gyr, N Whitcomb, DC TI SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh - A preliminary report SO PANCREATOLOGY LA English DT Article DE pancreatitis; serine protease inhibitor, Kazal type 1; pancreatic secretory trypsin inhibitor; tropical pancreatitis; mutation ID CATIONIC TRYPSINOGEN GENE; HEREDITARY PANCREATITIS; INHIBITOR AB Background/Aims: Tropical pancreatitis (TP) refers to a severe type of idiopathic chronic pancreatitis that develops in children in tropical regions of Africa and southern Asia. Phenotypically TP is subdivided into fibrocalculous pancreatic diabetes (FCPD) and tropical calcific pancreatitis without diabetes mellitus (TCP). Recently an association was identified between idiopathic pancreatitis in the USA and Europe and mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene (previously termed pancreatic secretory trypsin inhibitor, PSTI). Our aim was to determine if either form of TP has a genetic basis. Methods:We studied 8 well-characterized patients from Bangladesh with FCPD, 4 with TCP and 4 controls without pancreatic disease. The entire SPINK1 gene was sequenced in these patients. Results: We detected two disease-associated SPINK1 mutations (N34S/IVS1-37T >C and IVS3 + 2T >C) in 6 of 8 patients from Bangladesh with FCPD but not in 4 patients with TCP (p < 0.03) or 4 controls (p < 0.03). Conclusions: We conclude that SPINK1 mutations are associated with FCPD in Bangladesh. Since SPINK1 mutations in Europeans and North Americans are associated with idiopathic chronic pancreatitis that is phenotypically different from FCPD, we further conclude that mutated SPINK1 markedly increases the risk of developing a variety of pancreatic diseases possibly through a chronic elevation of active trypsin within the pancreas. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Univ Pittsburgh, Ctr Genom Sci, Pittsburgh, PA 15101 USA. Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Dept Med, Pittsburgh, PA 15101 USA. Bangladesh Inst Res & Rehabil Diabet Endocrine &, Dhaka, Bangladesh. Univ Basel Hosp, Dept Med, CH-4031 Basel, Switzerland. VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Ctr Genom Sci, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15101 USA. FU NIDDK NIH HHS [DK54709] NR 15 TC 66 Z9 68 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 3 BP 242 EP 245 DI 10.1159/000055818 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502XF UT WOS:000172767500009 PM 12120202 ER PT J AU Pfutzer, RH Whitcomb, DC AF Pfutzer, RH Whitcomb, DC TI SPINK1 mutations am associated with multiple phenotypes SO PANCREATOLOGY LA English DT Article; Proceedings Paper CT 3rd International Symposium on Inherited Diseases of the Pancreas CY APR 05-07, 2001 CL MILAN, ITALY SP European Inst Oncol DE serine protease; hereditary pancreatitis; tropical pancreatitis; idiopathic pancreatitis; chronic pancreatitis ID CATIONIC TRYPSINOGEN GENE; CLEAVAGE SITE MUTATION; CHRONIC-PANCREATITIS; HEREDITARY PANCREATITIS; RISK; BANGLADESH; INHIBITOR; CANCER; MAPS AB Mutations in the gene encoding for the pancreatic secretory trypsin inhibitor or serine protease inhibitor, Kazal type I (SPINK1) have been associated with different entities of chronic pancreatitis. While there is no doubt about the involvement of SPINK1 mutations in pancreatic inflammatory disease, much controversy has arisen regarding which alterations are associated with disease and what type of disease model should be applied when the SPINK1 gene is examined. This article presents the existing data on SPINK1 mutations in idiopathic chronic pancreatitis, familial pancreatitis, hereditary pancreatitis and tropical pancreatitis. The possible role of SPINK1 mutations and polymorphisms in pancreatic disease is discussed. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Ctr Genomic Sci, Pittsburgh, PA 15261 USA. Univ Heidelberg Hosp, Dept Med 2, D-68135 Mannheim, Germany. VA Pittsburgh Hlth Care Syst, Div Gastroenterol, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Dept Med, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. NR 23 TC 25 Z9 25 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 5 BP 457 EP 460 DI 10.1159/000055847 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502XH UT WOS:000172767700009 PM 12120224 ER PT J AU Whitcomb, DC AF Whitcomb, DC TI Hereditary pancreatitis: A model for understanding the genetic basis of acute and chronic pancreatitis SO PANCREATOLOGY LA English DT Article; Proceedings Paper CT Meeting of the International-Association-of-Pancreatology/American-Pancreatic-Associati on CY 2000 CL CHICAGO, ILLINOIS SP Int Assoc Pancreatol, Amer Pancreat Assoc DE pancreatitis; genetics; hereditary ID CATIONIC TRYPSINOGEN GENE; CYSTIC-FIBROSIS GENE; AUTOIMMUNE PANCREATITIS; MUTATIONS; ACTIVATION; INHIBITOR; MAPS AB Progress in understanding pancreatic diseases has been limited by a number of factors. Primary problems include the absence of good animal models, and difficulty in understanding the origin of pancreatic disease since the disease is usually manifest by the progressive destruction of the gland itself. Beginning in 1995, our laboratory, with the support of the Midwest Multicenter Pancreatic Study Group, began investigating the genetic basis of hereditary pancreatitis. Utilization of information becoming available through the human genome project allowed us to map and identify the hereditary pancreatitis gene as cationic trypsinogen (PRSS1). Molecular modeling, and subsequent experimental evidence, has solved key elements of the mysteries surrounding the origin of acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. The availability of new genetic information and genomic tools should produce a revolution in our understanding of pancreatic diseases. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Univ Pittsburgh, Med Ctr,Dept Med, Ctr Genom Sci, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Med Ctr,Dept Med, Ctr Genom Sci, Div Gastroenterol Hepatol & Nutr, Mezzanine Level,C Wing,PUH,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NIAAA NIH HHS [AA20885]; NIDDK NIH HHS [DK54709] NR 32 TC 20 Z9 22 U1 0 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 6 BP 565 EP 570 DI 10.1159/000055864 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 503GE UT WOS:000172790100002 PM 12120237 ER PT J AU Brugge, WR AF Brugge, WR TI Role of endoscopic ultrasound in the diagnosis of cystic lesions of the pancreas SO PANCREATOLOGY LA English DT Article; Proceedings Paper CT Meeting of the International-Association-of-Pancreatology/American-Pancreatic-Associati on CY 2000 CL CHICAGO, ILLINOIS SP Int Assoc Pancreatol, Amer Pancreat Assoc DE pancreatic cyst; cystadenoma; endoscopic ultrasound; tumor markers ID PAPILLARY-MUCINOUS TUMORS; SEROUS CYSTADENOMA; FLUID ANALYSIS; NEOPLASMS; PSEUDOCYSTS; EXPRESSION; EMPHASIS; FEATURES; CA-72-4; BENIGN AB Endoscopic ultrasound (EUS) is an ideal imaging technique for pancreatic cystic lesions. Ultrasound is, exquisitely sensitive for detecting and characterizing cysts arising in solid organs, and when the transducer is placed on an endoscope, high resolution imaging of the pancreas is achieved. Linear EUS can also guide needle aspiration of pancreatic cystic lesions and through the use of aspiration cytology, cystic tumors of the pancreas can be diagnosed. Since cytology is a relatively insensitive test, cyst fluid tumor markers such as CEA have been employed to improve the sensitivity for the detection of malignancy. Cyst fluid CEA values are uniformly low in serous cystadenomas, higher in mucinous lesions, and markedly elevated in mucinous cystadenocarcinomas. Through the use of these techniques, the ability to detect and diagnose early malignancies of the pancreas will be greatly enhanced. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Massachusetts Gen Hosp, GI Unit Blake 452C, Boston, MA 02114 USA. RP Brugge, WR (reprint author), Massachusetts Gen Hosp, GI Unit Blake 452C, Boston, MA 02114 USA. NR 17 TC 37 Z9 39 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 6 BP 637 EP 640 DI 10.1159/000055874 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 503GE UT WOS:000172790100012 PM 12120247 ER PT J AU Fernandez-del Castillo, C Warshaw, AL AF Fernandez-del Castillo, C Warshaw, AL TI Cystic neoplasms of the pancreas SO PANCREATOLOGY LA English DT Article; Proceedings Paper CT Meeting of the International-Association-of-Pancreatology/American-Pancreatic-Associati on CY 2000 CL CHICAGO, ILLINOIS SP Int Assoc Pancreatol, Amer Pancreat Assoc DE cystic neoplasms; mucinous cystadenomas; cystadenocarcinomas; serous cystadenomas; intraductal papillary mucinous tumors ID K-RAS MUTATIONS; DIFFERENTIAL-DIAGNOSIS; FLUID ANALYSIS; MUCINOUS CYSTADENOCARCINOMA; MICROCYSTIC ADENOMA; SEROUS CYSTADENOMA; TUMORS; LESIONS; EXPRESSION; BENIGN AB Cystic tumors of the pancreas have become increasingly prevalent. In large series, more than 90% of pancreatic cystic neoplasms are accounted for by mucinous cystadenomas and cystadenocarcinomas, serous cystadenomas, and intraductal papillary mucinous tumors. Differentiating cystic neoplasms from pseudocysts can almost always be accomplished by clinical and radiological means, but in doubtful cases, when observation is contemplated, or when it is important to determine preoperatively the type of cystic neoplasm, cyst fluid analysis is useful. This can be readily obtained by endoscopic ultrasound, and analysis of enzymes, viscosity, cytology and a variety of tumor markers allows for a better differential diagnosis. Copyright (C) 2001 S. Karger AG, Basel and IAP. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Warshaw, AL (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,WHT 506, Boston, MA 02114 USA. NR 23 TC 28 Z9 30 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PY 2001 VL 1 IS 6 BP 641 EP 647 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 503GE UT WOS:000172790100013 PM 12120248 ER PT J AU Isacson, O van Horne, C Schumacher, JM Brownell, AL AF Isacson, O van Horne, C Schumacher, JM Brownell, AL TI Improved surgical cell therapy in Parkinson's disease - Physiological basis and new transplantation methodology SO PARKINSON'S DISEASE SE ADVANCES IN NEUROLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; MPTP-INDUCED PARKINSONISM; PRIMATE MODEL; STRIATAL REINNERVATION; NEUROCHEMICAL ANALYSIS; DOPAMINE TRANSPORTER; MESENCEPHALIC TISSUE; GRAFT-SURVIVAL; BASAL GANGLIA; NIGRAL GRAFTS C1 Harvard Univ, McLean Hosp, Sch Med, Dept Neurol, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Neuroregenerat Labs, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Sch Med, Dept Neurol, Belmont, MA 02478 USA. FU NINDS NIH HHS [P50 NS39793] NR 61 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0091-3952 J9 ADV NEUROL JI Adv.Neurol. PY 2001 VL 86 BP 447 EP 454 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA BT75D UT WOS:000173954800047 PM 11554007 ER PT J AU Field, AE Camargo, CA Taylor, CB Berkey, CS Roberts, SB Colditz, GA AF Field, AE Camargo, CA Taylor, CB Berkey, CS Roberts, SB Colditz, GA TI Peer, parent, and media influences on the development of weight concerns and frequent dieting among preadolescent and adolescent girls and boys SO PEDIATRICS LA English DT Article DE dieting; adolescents; parents; peers; media ID MIDDLE SCHOOL GIRLS; EATING DISORDERS; BODILY ATTRACTIVENESS; DIETARY RESTRAINT; POTENTIAL RISK; LOSS BEHAVIORS; THIN STANDARD; OVERWEIGHT; CHILDREN; WOMEN AB Objective. To assess prospectively the influence of peers, parents, and the media on the development of weight concerns and frequent dieting. Design. Prospective cohort study. Setting. Questionnaires mailed annually to participants throughout the United States. Participants. One-year follow-up of 6770 girls and 5287 boys who completed questionnaires in 1996 and 1997 and were between 9 and 14 years of age in 1996. Main Outcome Measure. Onset of high levels of concern with weight and dieting frequently to control weight. Results. During 1 year of follow-up, 6% of girls and 2% of boys became highly concerned with weight and 2% of girls and 1% of boys became constant dieters. Peer influence was negligible. Independent of age and body mass index, both girls (odds ratio [OR]): 1.9; 95% confidence interval [CI]: 1.1-3.1) and boys (OR: 2.7; 95% CI: 1.1-6.4) who were making a lot of effort to look like same-sex figures in the media were more likely than their peers to become very concerned with their weight. Moreover, both girls (OR: 2.3; 95% CI: 1.1-5.0) and boys (OR: 2.6; 95% CI: 1.1-6.0) who reported that their thinness/lack of fat was important to their father were more likely than their peers to become constant dieters. Conclusions. Our results suggest that parents and the media influence the development of weight concerns and weight control practices among preadolescents and adolescents. However, there are gender differences in the relative importance of these influences. C1 Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. Tufts Univ, Energy Metab Lab, USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Field, AE (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NHLBI NIH HHS [R 29 HL 57871-01]; NIDDK NIH HHS [DK 46200, DK-46834] NR 42 TC 284 Z9 292 U1 12 U2 84 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 JAN PY 2001 VL 107 IS 1 BP 54 EP 60 DI 10.1542/peds.107.1.54 PG 7 WC Pediatrics SC Pediatrics GA 387YL UT WOS:000166150600022 PM 11134434 ER PT J AU Ferris, TG Dougherty, D Blumenthal, D Perrin, JM AF Ferris, TG Dougherty, D Blumenthal, D Perrin, JM TI A report card on quality improvement for children's health care SO PEDIATRICS LA English DT Review DE child; adolescent; quality; quality improvement; CQI; TQM; guidelines; benchmark; review ID CLINICAL-PRACTICE GUIDELINES; RANDOMIZED CONTROLLED TRIAL; FOLLOW-UP; IMMUNIZATION RATES; PATIENT OUTCOMES; PHYSICIAN PERFORMANCE; PARENT SATISFACTION; PEDIATRIC EMERGENCY; DISEASE MANAGEMENT; ASTHMA AB Objective. Improving the quality of health care is a national priority. Nonetheless, no systematic effort has assessed the status of quality improvement (QI) initiatives for children or reviewed past research in child health care QI. This assessment is necessary to establish priorities for QI programs and research. Methods. To assess the status of QI initiatives and research, we reviewed the literature and interviewed experts experienced in QI for child health services. We defined QI as activities intended to close the gap between desired processes and outcomes of care and what is actually delivered. We classified reports published between 1985 and 1997 by publication characteristics, study design, clinical problem addressed, site of intervention, the QI method(s) used, and explicit association with a continuous quality improvement program. Results. We reviewed 68 reports meeting our definition of QI. More than half (48) were published after 1994. The reviewed reports included controlled evaluations in 36% of all identified interventions, and 3% of the reports were associated with continuous quality improvement. QI methods demonstrating some effectiveness included reminder systems for office-based preventive services and inpatient pathways for complex care. Reportedly successful QI initiatives more commonly described improvement in administrative measures such as rate of hospitalization or length of stay rather than functional status or quality of life. Interviews found that barriers to QI for children were similar to those for adults, but were compounded by difficulties in measuring child health outcomes, limited resources among public organizations and small provider groups, and relative lack of competition for pediatric tertiary care providers. Research and dissemination of QI for children were seen as less well developed than for adults. Conclusions. Attempts to improve the quality of child health services have been increasing, and the evidence we reviewed suggests that it is possible to improve the quality of care for children. Nonetheless, numerous gaps remain in the understanding of QI for children, and widespread improvement in the quality of health services for children faces significant barriers. C1 Massachusetts Gen Med Sch, Inst Hlth Policy, Boston, MA USA. Massachusetts Gen Med Sch, Ctr Child & Adolescent Hlth Policy, Boston, MA USA. Agcy Hlth Care Res & Qual, Silver Spring, MD USA. RP Ferris, TG (reprint author), Massachusetts Gen Hosp, Partners Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NICHD NIH HHS [K12-HD00850] NR 112 TC 46 Z9 47 U1 6 U2 12 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 JAN PY 2001 VL 107 IS 1 BP 143 EP 155 DI 10.1542/peds.107.1.143 PG 13 WC Pediatrics SC Pediatrics GA 387YL UT WOS:000166150600036 PM 11134448 ER PT J AU Cantiello, HF AF Cantiello, HF TI Role of actin filament organization in CFTR activation SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference on the Secretion Defect in Cystic Fibrosis CY MAY, 1999 CL CHALKIDIKI, GREECE DE actin filament; CFTR; cytochalasin D ID NA+ CHANNEL; SODIUM-CHANNEL; F-ACTIN; PROTEIN; MECHANISM; GELSOLIN; CELLS; POLYMERIZATION; MEMBRANE; CYTOSKELETON AB The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion-selective channel whose dysfunction leads to the onset of cystic fibrosis. CFTR activation is normally elicited by stimulation of the cAMP pathway, which effects protein kinase A activation. However, previous studies from our laboratory indicate that the actin cytoskeleton is also required for a proper CFTR function. In this report, the regulatory role of actin filament organization in the activation of CFTR was explored. Maneuvers to modify the steady-state organization of actin filaments elicit the activation of CFTR in the absence of a functional cAMP pathway. Partial disruption of the actin cytoskeleton of CFTR-expressing cells with cytochalasin D (CD) induced CFTR activation in the absence of an activated PKA. Similar findings were obtained by intracellular dialysis with the actin-severing protein gelsolin. However, extended treatment with CD leading to the collapse of the actin cytoskeleton rendered CFTR completely insensitive to direct PKA activation. cAMP activation of CFTR was also found to be dysfunctional in cells lacking the actin-crosslinking protein ABP-280, which was recovered after dialysis of the cells with filamin, a homologue of ABP-280. The present data indicate that an organized actin network is required for the proper cAMP-dependent activation of CFTR. The possibility is also explored that actin must be directly associated with CFTR to elicit its activation, further suggesting that this channel protein may bind actin as well. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. RP Cantiello, HF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Charlestown, MA 02129 USA. NR 36 TC 19 Z9 19 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PY 2001 VL 443 SU 1 BP S75 EP S80 PG 6 WC Physiology SC Physiology GA 500GT UT WOS:000172618800016 PM 11845308 ER PT J AU Cantiello, HF AF Cantiello, HF TI Electrodiffusional ATP movement through CFTR and other ABC transporters SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference on the Secretion Defect in Cystic Fibrosis CY MAY, 1999 CL CHALKIDIKI, GREECE DE ATP-binding cassette (ATP) transporters; CFTR; Pgp; traffic; ATPases ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PURIFIED P-GLYCOPROTEIN; CYSTIC-FIBROSIS GENES; MULTIDRUG-RESISTANCE; CHLORIDE CHANNEL; MEMBRANE; CELLS; EXPRESSION; CANCER; BIOCHEMISTRY AB The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the superfamily of ATP-binding cassette (ABC) transporters, also known as traffic ATPases. Recent studies from our laboratory determined that various members of the ABC family of transport proteins mediate the electrodiffusional movement of the nucleotide ATR In this report, evidence for the movement of cellular nucleotides by the ABC transporter CFTR and related molecules, including P-glycoproteins (Pgp), is reviewed. The wild-type mdr1 gene product, Pgp, enables the spontaneous release of cellular ATP. However, single amino acid substitutions in both nucleotide-binding sites render a dysfunctional Pgp, whose function can only be reversed by voltage activation. This report includes data indicating that reconstitution of highly purified CFTR from human epithelial origin enables the permeation of both Cl and ATR The relevance of the ABC domains in ATP transport is also explored, and the hypothesis is forwarded that improper ATP transport by a dysfunctional CFTR is a relevant factor in cystic fibrosis. C1 Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. RP Cantiello, HF (reprint author), Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. NR 37 TC 25 Z9 25 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PY 2001 VL 443 SU 1 BP S22 EP S27 PG 6 WC Physiology SC Physiology GA 500GT UT WOS:000172618800006 PM 11845298 ER PT J AU Trzcinska, M Pimentel, P Stellar, JR Hanson, RN Choi, SW Elmaleh, DR Zhang, J Prakash, KRC Tamiz, AP Kozikowski, AP Johnson, KM Smith, MP Babich, JW AF Trzcinska, M Pimentel, P Stellar, JR Hanson, RN Choi, SW Elmaleh, DR Zhang, J Prakash, KRC Tamiz, AP Kozikowski, AP Johnson, KM Smith, MP Babich, JW TI Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE anticocaine behavioral screen; brain stimulation reward; GBR analogue; piperidine; piperazine; phenyltropane; reward threshold; WIN analogue ID DOPAMINE UPTAKE INHIBITORS; MAZINDOL BINDING-SITES; SELF-STIMULATION; TROPANE ANALOGS; D-AMPHETAMINE; ABUSE; ADDICTION; GBR-12909; RATS; POTENT AB Six novel monoamine reuptake inhibitors were screened for their intrinsic effects on brain stimulation reward (BSR), as well as for their potential to reduce cocaine-induced reward-enhancement in that paradigm. Two of the compounds, nocaine-3B and 5-ara-74A (disubstituted piperidines) significantly reduced locus of rise (LOR), threshold measure of reward, at some doses. One compound, 1-RV-96A (a hybrid of the GBR and WIN-like agents) significantly reduced reward (increased LOR), but only at the highest dose tested. No effect of dose was found for MC9-20 (a GBR-like acyclic analogue of the N-bisarylmethoxyethyl-N ' -phenylpropyl piperazine). nocaine-250B or 4-ara-42C (disubstituted piperidines). When cocaine (10 m/kg, ip) and selected, hedonically neutral doses of novel compounds were combined, the following findings were obtained: MC9-20 (2.5 mg/kg, ip) showed a significant increase in cocaine-induced reward enhancement (0.2 log units or 53%). In contrast, nocaine-250B and 1-RV-96A (both at 10 mg/kg, ip) demonstrated a significant reduction (0.13 log units or 41%) in cocaine-induced reward enhancement (P<.01 and P<.05, respectively). as measured by changes in LOR. There were no differences in the maximum behavioral output (MAX) at either dose of each of the six drugs, or when selected doses were combined with cocaine. These results indicate that nocaine-250B and I-RV-96A constitute two potential anticocaine compounds worthy of further behavioral and biochemical evaluation. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. Northeastern Univ, Neurosci Program, Boston, MA 02115 USA. Northeastern Univ, Dept Chem, Boston, MA 02115 USA. Biostream Inc, Cambridge, MA 02142 USA. Univ Texas, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA. Georgetown Univ, Med Ctr, Drug Discovery Program, Washington, DC 20007 USA. Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. RP Trzcinska, M (reprint author), Northeastern Univ, Dept Psychol, 125 NI Hall, Boston, MA 02115 USA. RI Johnson, Kenneth/E-7944-2014 FU NIDA NIH HHS [DA 10548, DA 11548] NR 59 TC 3 Z9 3 U1 2 U2 3 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 JAN PY 2001 VL 68 IS 1 BP 171 EP 180 DI 10.1016/S0091-3057(00)00454-8 PG 10 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 419DW UT WOS:000167934900022 PM 11274722 ER PT J AU Krengli, M Orecchia, R Liebsch, NJ Munzenrider, JE AF Krengli, M Orecchia, R Liebsch, NJ Munzenrider, JE TI Potentiality of proton beam in radiotherapy SO PHYSICA MEDICA LA English DT Article; Proceedings Paper CT International Conference on Ocular Pathologies Therapy with Proton Beams CY OCT 12-13, 2000 CL CATANIA, ITALY SP INFN Lab Nazl Sud, Inst Sci Europeo, LNS, Univ Catania, AIFM, Cent Siciliano Fis Nucl & Struttura Mat DE proton beam; uveal melanoma; skull base tumors; radiotherapy AB The clinical use of protontherapy began in 1954 at Uppsala University in Sweden and in 1961 at Harvard Cyclotron Laboratory (HCL) in Boston, USA. The proton beam has physical and radiobiologic characteristic,, which differ from those of conventional radiotherapy. The main advantage is due to the Bragg peak that can be modulated and spread Out in order to obtain the best coverage of the target volume. The RBE for protons does not substantially differ from that of photon,, and the value of 1.1 is generally accepted in clinical practice. After a few decades experience, the main clinical indications remain proximity of the target area to critical structures, low tumour radiosensitivity necessitating high doses, and a high benefit to cost ratio. For the tumors that meet these criteria, such as uveal melanomas and chondrosarcomas and chordomas of the base of skull and spinal region, protontherapy may be superior to photon beam therapy. For other malignancies, including tumors of the brain. head and neck. prostate. as well as soft tissue sarcomas, where improved local control is likely to result in higher rates of definitive cure. preliminary results are promisising but large comparative treatment studies are still needed. C1 Univ Piemonte Orientale, Div Radioterapia, Novara, Italy. Univ Milan, Ist Europeo Oncol, Div Radioterapia, Milan, Italy. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ISTITUTI EDITORIALI E POLGRAFICI INTERNAZIONALI PI PISA PA CASELLA POSTALE N 1, SUCCURSALE N 8, 56123 PISA, ITALY SN 1120-1797 J9 PHYS MEDICA JI Phys. Medica PY 2001 VL 17 SU 3 BP 10 EP 12 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 489GB UT WOS:000171982700005 ER PT J AU Kausch, AP Owen, TP Zachwieja, SJ Flynn, AR Sheen, J AF Kausch, AP Owen, TP Zachwieja, SJ Flynn, AR Sheen, J TI Mesophyll-specific, light and metabolic regulation of the C(4)PPCZm1 promoter in transgenic maize SO PLANT MOLECULAR BIOLOGY LA English DT Article DE beta-glucuronidase; phosphoenolpyruvate carboxylase gene; PPCZm1; promoter; transgenic plants; Zea mays L. ID PHOTOSYNTHETIC GENE-EXPRESSION; PHOSPHOENOLPYRUVATE CARBOXYLASE GENE; LARGE SUBUNIT GENE; DIFFERENTIAL EXPRESSION; C-4 PHOTOSYNTHESIS; HIGHER-PLANTS; BUNDLE SHEATH; ZEA-MAYS; LEAVES; CELLS AB To play an essential role in C-4 photosynthesis, the maize C-4 phosphoenolpyruvate carboxylase gene (PPCZm1) acquired many new expression features, such as leaf specificity, mesophyll specificity, light inducibility and high activity, that distinguish the unique C-4 PPC from numerous non-C-4 PPC genes in maize. We present here the first investigation of the developmental, cell-specific, light and metabolic regulation of the homologous C-4 PPCZm1 promoter in stable transgenic maize plants. We demonstrate that the 1.7 kb of the 5'-flanking region of the PPCZm1 gene is sufficient to direct the C-4-specific expression patterns of beta -glucuronidase (GUS) activity, as a reporter, in stable transformed maize plants. In light-grown shoots, GUS expression was strongest in all developing and mature mesophyll cells in the leaf, collar and sheath. GUS activity was also detected in mesophyll cells in the outer husks of ear shoots and in the outer glumes of staminate spikelets. We did not observe histological localization of GUS activity in light- or dark-grown callus, roots, silk, developing or mature kernels, the shoot apex, prop roots, or pollen. In addition, we used the stable expressing transformants to conduct and quantify physiological induction studies. Our results indicate that the expression of the C-4 PPCZm1-GUS fusion gene is mesophyll-specific and influenced by development, light, glucose, acetate and chloroplast biogenesis in transgenic maize plants. These studies suggest that the adoption of DNA regulatory elements for C-4-specific gene expression is a crucial step in C-4 gene evolution. C1 Univ Rhode Isl, Dept Plant Sci, Kingston, RI 02892 USA. Connecticut Coll, Dept Bot, New London, CT 06320 USA. DeKalb Genet Corp, Mystic, CT 06355 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Kausch, AP (reprint author), Univ Rhode Isl, Dept Plant Sci, Kingston, RI 02892 USA. NR 38 TC 43 Z9 45 U1 0 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-4412 J9 PLANT MOL BIOL JI Plant Mol.Biol. PD JAN PY 2001 VL 45 IS 1 BP 1 EP 15 DI 10.1023/A:1006487326533 PG 15 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 399FL UT WOS:000166800900001 PM 11247600 ER PT J AU May, JW Ganchi, PA AF May, JW Ganchi, PA TI Treatment of difficult TRAM flap hernias using intraperitoneal synthetic mesh application - Discussion SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material ID ABDOMINAL-WALL; PROSTHETIC MESH; REPAIR; GROIN; NERVE; GIANT C1 Massachusetts Gen Hosp, Wang Ambulatory Care Ctr, Boston, MA 02114 USA. RP May, JW (reprint author), Massachusetts Gen Hosp, Wang Ambulatory Care Ctr, Suite 453,15 Parkman St, Boston, MA 02114 USA. NR 14 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 JAN PY 2001 VL 107 IS 1 BP 63 EP 66 DI 10.1097/00006534-200101000-00010 PG 4 WC Surgery SC Surgery GA 387BJ UT WOS:000166100000010 ER PT J AU Butler, PEM Gonzalez, S Randolph, MA Kim, J Kollias, N Yaremchuk, MJ AF Butler, PEM Gonzalez, S Randolph, MA Kim, J Kollias, N Yaremchuk, MJ TI Quantitative and qualitative effects of chemical peeling on photo-aged skin: An experimental study SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material ID TRICHLOROACETIC-ACID; HAIRLESS MOUSE; ANIMAL-MODEL; PHENOL PEEL; DERMABRASION; COLLAGEN; WRINKLES; UPDATE AB Chemical peel reverses the visible stigmata of photo aping in human skin. The qualitative and, in particular, the quantitative changes in the dermis that effect this transformation are unclear. This study used a recognized photo-aged animal model, the Skh:HR-1 hairless mouse, to quantify and qualify the changes that occurred in collagen and glycosaminoglycan content after chemical peel. One hundred Skh:HR-1 hairless mice were photo-aged by use of chronic ultraviolet B irradiation for 14 weeks. After irradiation the animals were randomly distributed into five groups of 20 mice each: group 1, control; group 2, 50% glycolic acid peel; group 3, 30% trichloroacetic acid peel; group 4, 50% trichloroacetic acid peel; group 5, phenol peel (Baker-Gordon formula). The respective peeling agent was applied to the dorsal skin of each animal while it was fully anesthetized. Punch biopsies were taken at several times after peel for histological and biochemical analysis. Glycosaminoglycan content was assessed at 14, 28, and 60 days using a colorimetric assay. Collagen content per unit volume increased initially 3 days after the procedure in all chemical peel groups, declining on day 7, and peaking again on day 28. Significant elevations (p < 0.84) were seen in the 30% trichloroacetic acid, 50% trichloroacetic acid, and phenol peels on days 3 and 28 in comparison with controls. This increase in collagen content was not maintained and returned to control values bu 60 days. Glycosaminoglycan content per unit volume was elevated initially after peel with significant elevation (p < 0.02) in the 50% trichloroacetic acid and phenol groups on days 14 and 28. This increase in glycosaminoglycan content was not maintained beyond 28 days and declined to control Values by day 60 in all groups. Histological examination demonstrated an increase in dermal thickness in the 50% trichloroacetic acid and phenol groups in comparison with controls by day 60. Under polarized Light all chemical peel groups at day 60 demonstrated a reorganization of collagen in the reticular and papillary dermis. The elastotic masses that are pathognomonic of photo aging were present in the control group but were absent in the peer groups and demonstrated a reorganization of the elastic fibers in the dermis. This effect was deeper in the dermis in the deeper peel groups (50% trichloroacetic acid and phenol peel). The beneficial effects of chemical peel were due to a combination of two findings; a reorganization in dermal structural elements and an increase in dermal volume. These effects were more pronounced in the deeper peer groups. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg,Wellman Labs Photomed, Boston, MA 02114 USA. RP Yaremchuk, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg,Wellman Labs Photomed, WACC Suite 453, Boston, MA 02114 USA. NR 50 TC 24 Z9 27 U1 2 U2 9 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 JAN PY 2001 VL 107 IS 1 BP 222 EP 228 DI 10.1097/00006534-200101000-00036 PG 7 WC Surgery SC Surgery GA 387BJ UT WOS:000166100000035 PM 11176627 ER PT S AU Hancock, KE Davis, KA Voigt, HF AF Hancock, KE Davis, KA Voigt, HF GP IEEE IEEE IEEE TI Computer simulations of dorsal cochlear nucleus neural circuitry SO PROCEEDINGS OF THE 23RD ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-4: BUILDING NEW BRIDGES AT THE FRONTIERS OF ENGINEERING AND MEDICINE SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 23rd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY OCT 25-28, 2001 CL ISTANBUL, TURKEY SP Natl Sci Fdn, TUBITAK, Sci & Tech Res Ctr Turkey, ISIK Univ, COMNET, EREL Techno Grp, GUZEL SANATLAR Printinghouse, JOHNSON&JOHNSON Med, PFIZER, SIEMENS Med, TURKCELL Iletism Hizmetler A S, ALSTOM Elect Ltd Co, GANTEK Technol & SUN Microsyst, TURCOM Co Grp DE cochlear nucleus; hearing; computational modeling; parameter estimation ID CROSS-CORRELATION ANALYSIS; INHIBITORY INTERACTIONS; RESPONSE PROPERTIES; IV UNITS; NEURONS; BAND; CAT; MODEL; NOISE AB The dorsal cochlear nucleus (DCN) is part of the first stage of auditory processing in the central nervous system. Experimental evidence has provided a conceptual model for a portion of the DCN neural circuit that serves as a basis for the computational model described in this paper. The model consists of four neural populations arranged tonotopically. The pattern of convergence from one population to another and the strengths of those connections are important model parameters. Lumped parameter electrical circuit models are used to model the membrane potential of individual cells. Synapses are simulated by activating variable conductances in postsynaptic cells according to spike activity in presynaptic cells. The level of detail incorporated in the model is a good compromise between biophysical accuracy and the computational tractability required to simulate relatively large networks. Results are shown demonstrating the ability of the model to replicate features of DCN cross-correlation functions and to simulate DCN response properties with quantitative accuracy. The model is a useful tool for exploring hypotheses regarding DCN structure and function. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Hancock, KE (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RI Voigt, Herbert/I-2068-2015 OI Voigt, Herbert/0000-0002-0476-6594 NR 17 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-7211-5 J9 P ANN INT IEEE EMBS PY 2001 VL 23 BP 666 EP 669 PN 1-4 PG 4 WC Cardiac & Cardiovascular Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Neurosciences SC Cardiovascular System & Cardiology; Computer Science; Engineering; Neurosciences & Neurology GA BV41G UT WOS:000178871900191 ER PT S AU Yarmush, ML Tompkins, RG Toner, M AF Yarmush, ML Tompkins, RG Toner, M GP IEEE IEEE IEEE TI Hepatic tissue engineering SO PROCEEDINGS OF THE 23RD ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-4: BUILDING NEW BRIDGES AT THE FRONTIERS OF ENGINEERING AND MEDICINE SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 23rd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY OCT 25-28, 2001 CL ISTANBUL, TURKEY SP Natl Sci Fdn, TUBITAK, Sci & Tech Res Ctr Turkey, ISIK Univ, COMNET, EREL Techno Grp, GUZEL SANATLAR Printinghouse, JOHNSON&JOHNSON Med, PFIZER, SIEMENS Med, TURKCELL Iletism Hizmetler A S, ALSTOM Elect Ltd Co, GANTEK Technol & SUN Microsyst, TURCOM Co Grp C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Cambridge, MA 02138 USA. RP Yarmush, ML (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-7211-5 J9 P ANN INT IEEE EMBS PY 2001 VL 23 BP 4062 EP 4062 PN 1-4 PG 1 WC Cardiac & Cardiovascular Systems; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Neurosciences SC Cardiovascular System & Cardiology; Computer Science; Engineering; Neurosciences & Neurology GA BV41G UT WOS:000178871901122 ER PT B AU Suit, H Hall, EJ AF Suit, H Hall, EJ BE Kogelnik, HD Lukas, P Sedlmayer, F TI Treatment volume vs target volume SO PROGRESS IN RADIO-ONCOLOGY VII, PROCEEDINGS LA English DT Proceedings Paper CT 7th International Meeting on Progress in Radio-Oncology (ICRO/OGRO 7) CY MAY 15-19, 2002 CL SALZBURG, AUSTRIA SP Austrian Int Club Radio Oncol, Austrian Soc Radiooncol Radiobiol & Med RadioPhys ID ATOMIC-BOMB SURVIVORS; RADIATION ONCOGENESIS; CANCER; RADIOTHERAPY; RISK; THERAPY; PHOTON; BEAMS C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. RP Suit, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2515-2 PY 2001 BP 185 EP 195 AR UNSP C515F0090 PG 5 WC Oncology SC Oncology GA BU78B UT WOS:000176997100024 ER PT B AU Bortfeld, T Thieke, C Kufer, KH Trinkaus, H AF Bortfeld, T Thieke, C Kufer, KH Trinkaus, H BE Kogelnik, HD Lukas, P Sedlmayer, F TI New approaches in intensity-modulated radiotherapy - A new optimization paradigm SO PROGRESS IN RADIO-ONCOLOGY VII, PROCEEDINGS LA English DT Proceedings Paper CT 7th International Meeting on Progress in Radio-Oncology (ICRO/OGRO 7) CY MAY 15-19, 2002 CL SALZBURG, AUSTRIA SP Austrian Int Club Radio Oncol, Austrian Soc Radiooncol Radiobiol & Med RadioPhys AB Intensity modulated radiotherapy (IMRT) is in clinical use in many hospitals around the world, while it is still under active development. The general goal of current INMT developments is to make the procedure more efficient and more accurate. This presentation focuses on developments in optimized IMRT planning. Current optimization techniques grade treatment plans by assigning a single number to them, which is a measure of the quality of the plan. It is quite obvious that characterizing something as complex as a treatment plan by a single number is extremely difficult. We propose a different strategy, in which IMRT optimization is tackled using a so-called multi-criteria approach. The dose distributions in the relevant critical structures and in the target volume are controlled separately and interactively. A prototype implementation of this concept demonstrates its benefits: it allows to find clinically better dose distributions in a shorter amount of time. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Bortfeld, T (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2515-2 PY 2001 BP 251 EP 258 PG 4 WC Oncology SC Oncology GA BU78B UT WOS:000176997100035 ER PT B AU Willett, C AF Willett, C BE Kogelnik, HD Lukas, P Sedlmayer, F TI Intraoperative radiation therapy SO PROGRESS IN RADIO-ONCOLOGY VII, PROCEEDINGS LA English DT Proceedings Paper CT 7th International Meeting on Progress in Radio-Oncology (ICRO/OGRO 7) CY MAY 15-19, 2002 CL SALZBURG, AUSTRIA SP Austrian Int Club Radio Oncol, Austrian Soc Radiooncol Radiobiol & Med RadioPhys ID IRRADIATION; RADIOTHERAPY; TOLERANCE; IORT AB The modern use of intraoperative radiation therapy (IORT) was initiated by the studies of Abe and colleagues at the University of Kyoto. This work stimulated significant laboratory and clinical investigation into the use of IORT throughout Japan, Europe, and the United States. Because of this experience, single high doses of irradiation can be safely delivered to a tumor volume in appropriate clinical situations. Most importantly, this high dose of additional radiation treatment yields improved local control of selected tumors. Treatment programs of external beam radiation therapy, surgical resection, and IORT for patients with locally advanced primary and recurrent rectal carcinoma and retroperitoneal sarcoma has yielded excellent local control and higher survival rates. The future of IORT will be in the successful integration of this therapy into multimodality treatment programs of chemotherapy, external beam irradiation, and surgery for locally advanced malignancies. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Willett, C (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2515-2 PY 2001 BP 297 EP 305 PG 5 WC Oncology SC Oncology GA BU78B UT WOS:000176997100041 ER PT J AU Liberman, RP Eckman, TA Marder, SR AF Liberman, RP Eckman, TA Marder, SR TI Training in social problem solving among persons with schizophrenia SO PSYCHIATRIC SERVICES LA English DT Article ID SKILLS AB The specificity of the different curricula used for training persons with schizophrenia in the wide spectrum of skills they need is both a strength and a limitation. By separately teaching skills for each domain of community adaptation, clinicians using behavioral learning principles have overcome most symptomatic and cognitive barriers to learning. It is axiomatic in behavior therapy that "you get what you teach"; hence it has been necessary to adopt arduous training in many areas to bring about improvements in social functioning (1). Although social skills training has yielded excellent acquisition and durability of skills, generalization to other domains of functioning has to be carefully programmed. One way to promote generalization is to teach persons with schizophrenia a general social problem-solving method. In the modules for training social and independent living skills produced by Liberman's UCLA group, problem solving is embedded in two of the eight learning activities for each skill area, which may account for the durability and generalization of skills reported in recent studies of the modules (2-4). Information about the modules for teaching social and independent living skills is available on the Web site of Psychiatric Rehabilitation Consultants at www.psychrehab.com. C1 Univ Calif Los Angeles, Ctr Res Treatment & Rehabil Psychosis, Los Angeles, CA USA. Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RP Liberman, RP (reprint author), W Los Angeles Vet Affairs Med Ctr, 116AR,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIMH NIH HHS [MH-30911, MH-41573] NR 9 TC 13 Z9 13 U1 0 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD JAN PY 2001 VL 52 IS 1 BP 31 EP 33 DI 10.1176/appi.ps.52.1.31 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 387PW UT WOS:000166131800006 PM 11141525 ER PT J AU Berman, SM Phan, H Mandelkern, M Zaidel, E AF Berman, SM Phan, H Mandelkern, M Zaidel, E TI Lateralized brain activations for word and accent detection SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Irvine, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2001 VL 38 SU 1 BP S25 EP S25 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 473AX UT WOS:000171018100100 ER PT J AU Berman, SM Derbyshire, SW Naliboff, BD Mandelkern, M Mayer, EA AF Berman, SM Derbyshire, SW Naliboff, BD Mandelkern, M Mayer, EA TI Regional brain changes in response to rectal balloon inflation in irritable bowel syndrome SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Irvine, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2001 VL 38 SU 1 BP S25 EP S25 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 473AX UT WOS:000171018100099 ER PT J AU Steinhauer, SR Kasparek, A Condray, R Siegle, GJ AF Steinhauer, SR Kasparek, A Condray, R Siegle, GJ TI Pathways contributing to pupillary dilation during sustained processing SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2001 VL 38 SU 1 BP S91 EP S91 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 473AX UT WOS:000171018100365 ER PT J AU Woodward, SH Kimble, MO Kaloupek, DG Kaufman, M Forti, A Stegman, WK Stewart, LP AF Woodward, SH Kimble, MO Kaloupek, DG Kaufman, M Forti, A Stegman, WK Stewart, LP TI Novelty P3 is highly sensitive to depression in PTSD SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Natl Ctr PTSD, Palo Alto, CA USA. Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. Natl Ctr PTSD, Boston, MA USA. Vet Adm Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2001 VL 38 SU 1 BP S101 EP S101 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 473AX UT WOS:000171018100405 ER PT J AU Freudenreich, O Murray, GB AF Freudenreich, O Murray, GB TI Anxiety and position-dependent neurologic findings due to autonomic dysreflexia SO PSYCHOSOMATICS LA English DT Article ID PANIC DISORDER C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Freudenreich, O (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Warren 605, Boston, MA 02114 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JAN-FEB PY 2001 VL 42 IS 1 BP 81 EP 82 DI 10.1176/appi.psy.42.1.81 PG 2 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 391RN UT WOS:000166369100014 PM 11161127 ER PT S AU Suit, H Spiro, I AF Suit, H Spiro, I BE Meyer, JL TI Radiation in the multidisciplinary management of desmoid tumors SO RADIATION THERAPY OF BENIGN DISEASES: CURRENT INDICATIONS AND TECHNIQUES SE FRONTIERS OF RADIATION THERAPY AND ONCOLOGY LA English DT Article; Proceedings Paper CT 33rd San Francisco Cancer Symposium CY APR 03-04, 1999 CL SAN FRANCISCO, CALIFORNIA ID FAMILIAL ADENOMATOUS POLYPOSIS; NONCYTOTOXIC DRUG-THERAPY; AGGRESSIVE FIBROMATOSIS; COMBINATION CHEMOTHERAPY; ADJUVANT RADIOTHERAPY; SOFT-TISSUE; TAMOXIFEN; TRISOMY-20; DISEASE; CARCINOMA C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Suit, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. NR 54 TC 8 Z9 10 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0071-9676 BN 3-8055-7063-5 J9 FRONT RADIAT THER ON JI Front.Radiat.Ther.Oncol. PY 2001 VL 35 BP 107 EP 119 PG 13 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA BS87V UT WOS:000171311600012 PM 11351941 ER PT J AU Weber, AL AF Weber, AL TI History of head and neck radiology: Past, present, and future SO RADIOLOGY LA English DT Article DE head and neck; neck, abnormalities; neck, radiography; skull, abnormalities; skull, radiography ID AXIAL SCANNING TOMOGRAPHY; AMERICA; CT AB Head and neck radiology has evolved during the century since the discovery of the x ray in 1895 by Wilhelm Conrad Roentgen. In the first few decades, conventional radiography was the diagnostic modality for evaluation of head and neck diseases. Special radiographic projections were designed to demonstrate abnormal processes in the paranasal sinuses, temporal bones, base of the skull, and neck. Barium examination with fluoroscopy was used for assessment of the pharynx and esophagus. Linear tomography, introduced in 1932, allowed the acquisition of sections that depicted abnormalities that were not clearly defined at conventional radiography. Linear tomography was further enhanced with the introduction of thin-section polytomography, especially of the temporal bone, in 1954. Computed tomography in 1972 and magnetic resonance imaging in 1982 improved our diagnostic capabilities by enabling location and characterization of tumors, cysts, and inflammatory processes in the head and neck and aiding in earlier diagnosis and treatment. Teaching of residents and fellows by an expanding staff of head and neck radiologists developed. The formation of the American Society of Head and Neck Radiology in 1977 provided a forum for postgraduate education and scientific exchange. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. RP Weber, AL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Radiol, 243 Charles St, Boston, MA 02114 USA. NR 90 TC 13 Z9 15 U1 1 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 JAN PY 2001 VL 218 IS 1 BP 15 EP 24 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 412TW UT WOS:000167571300008 PM 11152774 ER PT J AU Saini, S Sharma, R Levine, LA Barmson, RT Jordan, PF Thrall, JH AF Saini, S Sharma, R Levine, LA Barmson, RT Jordan, PF Thrall, JH TI Technical cost of CT examinations SO RADIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting and Scientific Assembly of the Radiological-Society-of-North-America (RSNA) CY NOV 29-DEC 06, 1998 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE computed tomography (CT), utilization; cost-effectiveness; economics, medical; radiology and radiologists, socioeconomic issues AB PURPOSE: To measure the technical cost of different categories of computed tomographic (CT) examinations. MATERIALS AND METHODS: For fiscal year 1997, the technical costs of performing CT examinations in a tertiary care academic medical center were measured. Costs were divided into labor and nonlabor categories. Indirect departmental costs were fully allocated according to activity-based methods. Hospital overhead casts were set at 85% of the departmental budget. Physician costs, including those related to image interpretation were not included. The technical cost of CT was determined on a per technical relative value unit (RVU) basis and on a per examination basis. For the latter, the technical cost of nonenhanced CT, contrast material-enhanced diagnostic ST, and interventional CF procedures were determined. RESULTS: In fiscal year 1997, 45,599 examinations (22,158 [48.6%] abdominal and/or pelvic, 12,115 [26.6%] head and neck, 6,572 [14.4%] thoracic, 1,593 [3.5%] interventional, and 3,161 [6.9%] other) were performed with five CT scanners for a technical RVU output of 254,461. Of 45,599 examinations, 31,007 (68%) were performed with intravenously administered contrast medium. Overall labor costs were $1,744,653, and nonlabor costs were $2,912,282. The cost of a hypothetical CT examination with a mean technical RVU of 5.58 was $189. The overall cost per examination was $150 for nonenhanced CT, $237 for contrast-enhanced CT, and $462 for interventional CT. CONCLUSION: Although CT is based on sophisticated technology, the mean technical cost of a diagnostic CT examination is less than $200. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Saini, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 7 TC 21 Z9 21 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 JAN PY 2001 VL 218 IS 1 BP 172 EP 175 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 412TW UT WOS:000167571300029 PM 11152797 ER PT J AU Fan, CM Rafferty, EA Geller, SC Kaufman, JA Brewster, DC Cambria, RP Waltman, AC AF Fan, CM Rafferty, EA Geller, SC Kaufman, JA Brewster, DC Cambria, RP Waltman, AC TI Endovascular stent-graft in abdominal aortic aneurysms: The relationship between patent vessels that arise from the aneurysmal sac and early endoleak SO RADIOLOGY 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 DE aneurysms, aortic; aneurysm, therapy; computed tomography (CT), angiography; stents and prostheses ID ENDOLUMINAL AAA REPAIR; LUMBAR ARTERIES; EMBOLIZATION; CLASSIFICATION; REGISTRY; PRESSURE AB PURPOSE: To determine the association of patent sac branch vessels (lumbar and inferior mesenteric arteries [IMAs]) with early endoleak rate after stent-graft repair of abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: Pre- and postoperative computed tomographic (CT) angiograms in 158 patients who underwent stent-graft AAA repair were retrospectively reviewed to determine the preoperative patency of IMAs and other sac branch vessels (feeders) and presence or absence of immediate postoperative endoleak. Relationships of early endoleak rate with total branch vessel, IMA, and lumbar artery patency and graft type were evaluated. RESULTS: There was a significant association between patency of sac feeders and rate of early endoleak, especially type 2. As total patent feeders increased from zero to three to four to six, total endoleak rate increased from 6% (one of 17) to 35% (30 of 86); type 2 endoleak rate, from 0% to 5%. IMA patency was significantly associated with total early endoleak rate. Increasing lumbar artery patency also was associated with significantly higher total and type 2 endoleak rates: With zero to three lumbar arteries, the total endoleak rate was 17% and type 2. endoleak rate was 13%, as compared with 60% and 50%, respectively, with more than six patent lumbar arteries. CONCLUSION: Sac branch vessel patency is associated with significantly higher early total and type 2 endoleak rates after stent-graft repair of AAAs; thus, patent sac branches play an important role in the pathogenesis of endoleaks. C1 Massachusetts Gen Hosp, Div Vasc Radiol, Boston, MA 02114 USA. RP Fan, CM (reprint author), Massachusetts Gen Hosp, Div Vasc Radiol, 55 Fruit St,Gray 290, Boston, MA 02114 USA. NR 19 TC 64 Z9 68 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 JAN PY 2001 VL 218 IS 1 BP 176 EP 182 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 412TW UT WOS:000167571300030 PM 11152798 ER PT J AU Ko, JP Betke, M AF Ko, JP Betke, M TI Chest CT: Automated nodule detection and assessment of change over time - Preliminary experience SO RADIOLOGY LA English DT Article DE computed tomography (CT), computer programs; computed tomography (CT), image processing; computers, diagnostic aid; lung, nodule ID COMPUTER-AIDED DIAGNOSIS; SMALL PULMONARY NODULES; LUNG-CANCER; MR-IMAGES; REGISTRATION; PET; BRAIN; IMPROVEMENT AB The authors developed a computer system that automatically identifies nodules at chest computed tomography, quantifies their diameter, and assesses for change in size at follow up. The automated nodule detection system identified 318 (86%) of 370 nodules in 16 studies (eight initial and eight follow-up studies) obtained in eight oncology patients with known nodules. Assessment of change in nodule size by the computer matched that by the thoracic radiologist (Spearman rank correlation coefficient, 0.932). C1 Boston Univ, Dept Comp Sci, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Ko, JP (reprint author), NYU, Med Ctr, Dept Radiol, 560 1st Ave, New York, NY 10016 USA. NR 26 TC 151 Z9 159 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2001 VL 218 IS 1 BP 267 EP 273 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 412TW UT WOS:000167571300045 PM 11152813 ER PT J AU Lindel, K Willett, CG Shellito, PC Ott, MJ Clark, J Grossbard, M Ryan, D Ancukiewicz, M AF Lindel, K Willett, CG Shellito, PC Ott, MJ Clark, J Grossbard, M Ryan, D Ancukiewicz, M TI Intraoperative radiation therapy for locally advanced recurrent rectal or rectosigmoid cancer SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE recurrent rectal carcinoma; intraoperative radiation therapy; local failure; salvage ID EXTERNAL-BEAM IRRADIATION; COLORECTAL-CANCER; ADJUVANT THERAPY; CURATIVE SURGERY; CARCINOMA; ELECTRON; ADENOCARCINOMA; RADIOTHERAPY; FLUOROURACIL; LEUCOVORIN AB Background and purpose: To update and summarize the experience at the Massachusetts General Hospital of a treatment program of high-dose preoperative irradiation, surgical re-resection, and intraoperative radiation therapy (IORT) as a salvage treatment for patients with recurrent rectal or rectosigmoid carcinoma. Patients and methods: From June 1978 to February 1997, the records of 69 patients with locally recurrent rectal carcinomas or rectosigmoid carcinomas without metastases referred for consideration of IORT were reviewed. Forty-nine patients received IORT and local control and disease-free survival curves were calculated using the actuarial method of Kaplan-Meier. Results: The 5-year overall survival, local control and disease-free survival rates of 49 patients receiving IORT were 27, 35, and 20%, respectively. Thirty-four patients who underwent a macroscopic complete resection had a significantly better 5-year overall survival than the remaining 15 patients with gross residual disease (33 vs. 13%, P = 0.05, log rank). For those patients, local control and disease-free survival rates were 46 and 27%, respectively. Patients with a microscopic complete resection had a superior 5-year overall survival than partially resected patients (40 vs. 14%, P = 0.0001, log rank). Chemotherapy had no significant influence on overall or disease-free survival. Conclusion: The current analysis shows the importance of a microscopic complete resection in a multi-modality approach with IORT for survival and local control. Salvage is rare for patients undergoing subtotal resection. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. RP Willett, CG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. NR 25 TC 48 Z9 49 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD JAN PY 2001 VL 58 IS 1 BP 83 EP 87 DI 10.1016/S0167-8140(00)00309-1 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 402BL UT WOS:000166966100014 PM 11165686 ER PT J AU Avruch, J Khokhlatchev, A Kyriakis, JM Luo, ZJ Tzivion, G Vavvas, D Zhang, XF AF Avruch, J Khokhlatchev, A Kyriakis, JM Luo, ZJ Tzivion, G Vavvas, D Zhang, XF TI Ras activation of the Raf kinase: Tyrosine kinase recruitment of the MAP kinase cascade SO RECENT PROGRESS IN HORMONE RESEARCH, VOL 56 SE RECENT PROGRESS IN HORMONE RESEARCH LA English DT Review ID CYSTEINE-RICH DOMAIN; RIBOSOMAL-PROTEIN S6; SIGNAL-TRANSDUCTION PATHWAY; GTP-BINDING PROTEIN; H-4 HEPATOMA-CELLS; GROWTH-FACTOR; B-RAF; PLASMA-MEMBRANE; IN-VIVO; HA-RAS AB A continuing focus of our work has been an effort to understand the signal transduction pathways through which insulin achieves its cellular actions. In the mid-1970s, we and others observed that insulin promoted an increase in Ser/Thr phosphorylation of a subset of cellular proteins. This finding was unanticipated, inasmuch as nearly all of the actions of insulin then known appeared to result from protein dephosphorylation. In fact, nearly 15 years elapsed before any physiologic response to insulin attributable to stimulated (Ser/Thr) phosphorylation was established. Nevertheless, based on the hypothesis that insulin-stimulated Ser/Thr phosphorylation reflected the activation of protein (Ser/Thr) kinases downstream of the insulin receptor, we sought to detect and purify these putative, insulin-responsive protein (Ser/Thr) kinases. Our effort was based on the presumption that an understanding of the mechanism for their activation would provide an entry into the biochemical reactions through which the insulin receptor activated its downstream effecters. To a degree that, in retrospect, is surprising, this goal was accomplished, much in the way originally envisioned, it is now well known that receptor tyrosine kinases (RTKs) recruit a large network of protein (Ser/Thr) kinases to execute their cellular programs. The first of these insulin-activated protein kinase networks to be fully elucidated was the Ras-Raf-mitogen-activated protein kinase (MAPK) cascade. This pathway is a central effector of cellular differentiation in development; moreover, its inappropriate and continuous activation provides a potent promitogenic force and is a very common occurrence in human cancers. Conversely, this pathway contributes minimally, if at all, to insulin's program of metabolic regulation. Nevertheless, the importance of the Ras-MAPK pathway in metazoan biology and human malignancies has impelled us to an ongoing analysis of the functions and regulation of Pas and Raf. This chapter will summarize briefly the way in which work from this and other laboratories on insulin signaling led to the discovery of the mammalian MAP kinase cascade and, in turn, to the identification of unique role of the Raf kinases in RTK activation of this protein (SerTThr) kinase cascade. We will then review in more detail current understanding of the biochemical mechanism through which the Ras proto-oncogene, in collaboration with the 14-3-3 protein and other protein kinases, initiates activation of the Raf kinase. C1 Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Boston Med Ctr, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RI Tzivion, Guri/D-8954-2011; OI Vavvas, Demetrios/0000-0002-8622-6478 NR 141 TC 210 Z9 214 U1 3 U2 21 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4410 USA SN 0079-9963 J9 RECENT PROG HORM RES PY 2001 VL 56 BP 127 EP 155 DI 10.1210/rp.56.1.127 PG 29 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BR87V UT WOS:000167911000007 PM 11237210 ER PT J AU Bradley, RL Cleveland, KA Cheatham, B AF Bradley, RL Cleveland, KA Cheatham, B TI The adipocyte as a secretory organ: Mechanisms of vesicle transport and secretory pathways SO RECENT PROGRESS IN HORMONE RESEARCH, VOL 56 SE RECENT PROGRESS IN HORMONE RESEARCH LA English DT Review ID MELANIN-CONCENTRATING-HORMONE; ISOLATED RAT ADIPOCYTES; OB GENE-EXPRESSION; RECEPTOR MESSENGER-RNA; PANCREATIC BETA-CELLS; TUMOR-NECROSIS-FACTOR; WHITE ADIPOSE-TISSUE; LEPTIN SECRETION; 3T3-L1 ADIPOCYTES; OBESE GENE AB Obesity is a common problem in western society that is directly linked to several disease processes and is associated with significant morbidity and mortality. Adipocytes - the primary site for energy storage (as triglycerides) and release - were long suspected to have an active role in regulating body weight homeostasis and energy balance. As a result, many studies have focused on finding abnormalities in adipocyte physiology and metabolism An ever-increasing body of evidence indicates that, in addition to serving as a repository for energy reserves, adipocytes secrete a myriad of factors that comprise a complex network of endocrine, autocrine, and paracrine signals. Very little is known regarding the molecular mechanisms utilized by the adipocyte in regulating the biosynthesis and exocytosis of these secreted products. In order to gain a better understanding of these processes, we have examined the two classical secretory pathways: regulated and constitutive. Using leptin as a model adipocyte-secretory protein, this review focuses primarily on the latter pathway. This includes regulation of leptin synthesis and secretion by insulin and glucocorticoids and, more recently, the finding that the orexigenic neuropeptide, melanin-concentrating hormone (MCH), can stimulate leptin synthesis and secretion, This chapter also incorporates new data describing the partial purification and effect of insulin on leptin-containing vesicles in rat adipocytes. These data indicate that the majority of leptin trafficking occurs via a constitutive secretory pathway and that the primary acute insulin effect on leptin secretion is to increase leptin protein content. In addition, we describe the identification and characterization of the vesicle-associated protein, pantophysin, which may play a multifunctional role in vesicle biogenesis and transport. C1 Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Bradley, RL (reprint author), Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. FU NIDDK NIH HHS [R01 DK-51668, DK-09745] NR 76 TC 51 Z9 52 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4410 USA SN 0079-9963 J9 RECENT PROG HORM RES PY 2001 VL 56 BP 329 EP 358 DI 10.1210/rp.56.1.329 PG 30 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BR87V UT WOS:000167911000016 PM 11237220 ER PT J AU Feng, Y Press, B Chen, W Zimmerman, J Wandinger-Ness, A AF Feng, Y Press, B Chen, W Zimmerman, J Wandinger-Ness, A TI Expression and properties of Rab7 in endosome function SO REGULATORS AND EFFECTORS OF SMALL GTPASES, PT E SE METHODS IN ENZYMOLOGY LA English DT Review ID MANNOSE 6-PHOSPHATE RECEPTOR; ENDOCYTIC PATHWAY; MAMMALIAN-CELLS; FUSION INVITRO; CATHEPSIN-D; TRANSPORT; LYSOSOMES; COMPARTMENTS; FUSE; DISSOCIATION C1 Harvard Univ, Sch Med, Dept Chem & Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Ctr Genome Resources, Santa Fe, NM 87505 USA. Univ Chicago, Pritzker Sch Med, Chicago, IL 60610 USA. Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. RP Feng, Y (reprint author), Harvard Univ, Sch Med, Dept Chem & Cell Biol, Boston, MA 02115 USA. RI Wandinger-Ness, Angela/J-9104-2012 OI Wandinger-Ness, Angela/0000-0003-0613-3157 FU NIDDK NIH HHS [R01-DK50141] NR 36 TC 27 Z9 27 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2001 VL 329 BP 175 EP 187 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR65C UT WOS:000167096500019 PM 11210534 ER PT J AU Hales, CA Du, HK Volokhov, A Mourfarrej, R Quinn, DA AF Hales, CA Du, HK Volokhov, A Mourfarrej, R Quinn, DA TI Aquaporin channels may modulate ventilator-induced lung injury SO RESPIRATION PHYSIOLOGY LA English DT Article DE disease; ARDS; edema; pulmonary; over-ventilation; mammals; rat; pharmacological agents; cysteine; HgCl2 ID END-EXPIRATORY PRESSURE; EVANS BLUE-DYE; WATER CHANNEL; PULMONARY-EDEMA; PERMEABILITY; TRANSPORT; MERCURY; RATS; PROTEIN AB Adult Respiratory Distress Syndrome is a disease with functional lung heterogeneity and thus a ventilator-delivered breath may over-distend non-involved areas. In rats we examined ventilator-delivered tidal volume (TV) breaths of 7 and 20 ml/kg on lung water as evidence of lung injury. We examined the role of aquaporins on ventilator-induced lung injury (VILI) by infusing HgCl2 which inhibits aquaporins by binding cysteine. Wet to dry lung weight ratio (W/D) as evidence of lung water was 4.47 +/- 0.1 SEM in controls, 4.6 +/- 0.1 and 5.5 +/- 0.2 (P < 0.05) in rats ventilated at 7 and 20 ml/kg, respectively. Pulmonary artery pressure (PAP) rose from 23 +/- 1 to 26 +/- 1 mmHg (P < 0.05, n = 7) and cardiac output fell from 104 +/- 2 to 67 +/- 3 ml/min (P < 0.05) in rats ventilated at 30 ml/kg. Left ventricular end diastolic pressure (n = 3) was unchanged. Evans Blue dye, an albumin marker, increased from a control 37 +/- 11 to 97 +/- 41 mg/g wet lung in TV 20 rats (P < 0.05). HgCl2 infused slowly by tail vein did not significantly raise PAP, but did increase W/D to 6 +/- 0.2 (P < 0.05) in rats ventilated at 20 ml/kg but not at 7 ml,kg. Equimolar cysteine: infusions prevented the HgCl2 from increasing the W/D above that seen with TV 20 ml/kg. Thus ventilation with TV of 20 ml/kg produced a protein-rich lung edema. Aquaporin channels may have a protective effect in VILI. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Med Pulm & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Hales, CA (reprint author), Massachusetts Gen Hosp, Dept Med Pulm & Crit Care, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL31950, K08HL03920] NR 33 TC 22 Z9 28 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0034-5687 J9 RESP PHYSIOL JI Respir. Physiol. PD JAN PY 2001 VL 124 IS 2 BP 159 EP 166 DI 10.1016/S0034-5687(00)00193-6 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 393DK UT WOS:000166453800008 PM 11164207 ER PT J AU Frederick, AR AF Frederick, AR TI New instruments for intraocular lens manipulation via the pars plana SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article C1 Ophthalm Consultants Boston, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Eye & Ear Infirm, Ctr Eye Res & Teaching, Boston, MA 02114 USA. RP Frederick, AR (reprint author), Ophthalm Consultants Boston, 50 Staniford St,6th Floor, 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 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PY 2001 VL 21 IS 2 BP 193 EP 194 DI 10.1097/00006982-200104000-00026 PG 2 WC Ophthalmology SC Ophthalmology GA 422ZE UT WOS:000168148600025 PM 11321157 ER PT J AU Nguyen, QD Lashkari, K Hirose, T Pruett, RC McMeel, JW Schepens, CL AF Nguyen, QD Lashkari, K Hirose, T Pruett, RC McMeel, JW Schepens, CL TI Erosion and intrusion of silicone rubber scleral buckle - Presentation and management SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE buckle/buckling; erosion; implant; intrusion; retinal detachment; rubber; sclera; silicone ID DETACHMENT; REMOVAL AB Objective: To describe the clinical presentation and management of erosion and intrusion of silicone rubber implants that are used in scleral buckling procedures for the treatment of retinal detachment. Methods: The authors identified four patients from their practices during the last 20 years (1978 -1998) who had erosion or intrusion of silicone rubber scleral buckles that were used to manage retinal detachment. Approximately 4400 scleral buckling procedures were performed during this period. A retrospective review of the medical records of all patients was performed. Factors that influenced management decisions concerning the intruding buckle are emphasized. Results: All four patients had myopia. The interval between placement of the scleral buckle and development of intrusion ranged from 1 to 20 years. The buckles were intrascleral in three cases and episcleral in one. Recurrent detachment and vitreous hemorrhage were indications for surgical intervention in three cases, After the surgical removal of buckling elements, visual acuity stabilized in all patients and the retina remained attached in all cases. Conclusions: Erosion and intrusion of scleral buckle are rare complications of scleral buckling procedures. The intruding buckle may be left intact unless there is significant threat to the integrity of ocular structures, recurrent detachment, or hemorrhage. Manipulation of the encircling band or buckle does not necessarily alter the visual acuity or the status of the retina. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm,Dept Ophthalmol, Schepens Eye Res Inst,Schepens Retina Fdn, Boston, MA 02115 USA. RP Lashkari, K (reprint author), Schepens Retina Associates, 100 Charles River Plaza,Suite 201, Boston, MA 02114 USA. NR 21 TC 27 Z9 28 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PY 2001 VL 21 IS 3 BP 214 EP 220 PG 7 WC Ophthalmology SC Ophthalmology GA 441QT UT WOS:000169241600003 PM 11421009 ER PT J AU Lit, ES Kim, RY D'Amico, DJ AF Lit, ES Kim, RY D'Amico, DJ TI Surgical removal of subfoveal choroidal neovascularization without removal of posterior hyaloid - A consecutive series in younger patients SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE choroidal neovascularization; submacular surgery; subretinal surgery ID PRESUMED OCULAR HISTOPLASMOSIS; GUIDED LASER PHOTOCOAGULATION; MACULAR DEGENERATION; SUBMACULAR SURGERY; MEMBRANES; MYOPIA; MANAGEMENT; TRANSLOCATION; EXCISION AB Purpose: Subfoveal choroidal neovascularization (CNV) remains a common and important cause of visual loss. Previous studies have suggested that submacular surgery may improve or maintain visual acuity, particularly in younger patients. The majority of reported cases included removal of the posterior hyaloid during vitrectomy. The authors present a consecutive series of patients age 55 or younger with subfoveal CNV removal without posterior hyaloid removal. Methods: Seventeen patients without age-related macular degeneration (ARMD), with subfoveal CNV from choroiditis, presumed ocular histoplasmosis syndrome, myopia, or idiopathic causes, underwent a small retinotomy technique to extract the membranes after vitrectomy without posterior hyaloid removal. Results: Median improvement in visual acuity was from 20/320 to 20/50. Eleven patients (65%) experienced an improvement of three or more lines of Snellen acuity (average 7.5), 4 (23%) were within two lines of preoperative acuity, and 2 (12%) had decreased acuity, with an average follow-up of 12 months (range 3-31). Choroidal neovascularization recurred in six patients (35%). Postoperative retinal detachment, epiretinal proliferation, or macular hole did not occur. Conclusions: In this series of younger patients with subfoveal CNV not from ARMD, visual acuity was improved in the majority after submacular membrane removal. Omission of removal of the posterior hyaloid did not adversely affect outcome. C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP D'Amico, DJ (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. NR 40 TC 15 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PY 2001 VL 21 IS 4 BP 317 EP 323 DI 10.1097/00006982-200108000-00004 PG 7 WC Ophthalmology SC Ophthalmology GA 461YL UT WOS:000170391400004 PM 11508876 ER PT S AU Mao, JR Mayer, DJ AF Mao, JR Mayer, DJ BE Sorg, BA Bell, IR TI Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain SO ROLE OF NEURAL PLASTICITY IN CHEMICAL INTOLERANCE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Role of Neural Plasticity in Chemical Intolerance CY JUN 16-19, 2000 CL ROCKEFELLER UNIV, NEW YORK, NEW YORK SP Wallace Res Fdn, USa HO ROCKEFELLER UNIV ID PROTEIN-KINASE-C; EXPERIMENTAL PERIPHERAL MONONEUROPATHY; MULTIPLE CHEMICAL-SENSITIVITY; REDUCE NOCICEPTIVE BEHAVIORS; EXCITATORY AMINO-ACIDS; DORSAL HORN NEURONS; MORPHINE-TOLERANCE; THERMAL HYPERALGESIA; NEUROPATHIC PAIN; TRANSSYNAPTIC DEGENERATION AB Convincing evidence has accumulated that indicates neuroplastic changes within the spinal cord in response to repeated exposure to opioids. Such neuroplastic changes occur at both cellular and intracellular levels. It has been generally acknowledged that the activation of N-methyl-D-aspartate (NMDA) receptors plays a pivotal role in the development of neuroplastic changes following repeated opioid exposure. Intracellular cascades can also be activated subsequent to NMDA receptor activation. In particular, protein kinase C has been shown to be a key intracellular element that contributes to the behavioral manifestation of neuroplastic changes. Moreover, interactions between NMDA and opioid receptors can lead to potentially irreversible degenerative neuronal changes in the spinal cord in association with the development of opioid tolerance. Interestingly, similar cellular and intracellular changes occur in the spinal cord following peripheral nerve injury. These findings indicate that interactions exist in the spinal cord neural structures between two seemingly unrelated conditions-chronic opioid exposure and a pathological pain state. These observations may help understand mechanisms of chemical intolerance and multiple chemical sensitivity as well as have significant clinical implications in pain management with opioid analgesics. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,MGH Pain Ctr, Boston, MA 02114 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Anesthesiol, Richmond, VA 23298 USA. RP Mao, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,MGH Pain Ctr, 15 Parkman St,Suite WACC 324, Boston, MA 02114 USA. FU NIDA NIH HHS [DA08835] NR 44 TC 64 Z9 67 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-308-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 933 BP 175 EP 184 PG 10 WC Multidisciplinary Sciences; Physiology; Toxicology SC Science & Technology - Other Topics; Physiology; Toxicology GA BT11K UT WOS:000172010000014 PM 12000019 ER PT S AU Bizheva, K Boas, D AF Bizheva, K Boas, D BE Zimnyakov, DA TI Light scattering in turbid media: Insights to optical imaging with single scattered and multiply scattered fight. SO SARATOV FALL MEETING 2000: COHERENT OPTICS OF ORDERED AND RANDOM MEDIA SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT International Workshop and Fall School for Young Scientists and Students on Optics, Laser Physics, and Biophysics (Saratov Fall Meeting 2000) CY OCT 03-06, 2000 CL SARATOV, RUSSIA SP SPIE Russia Chapter, Russian Fdn Basic Res, CRDF, TECHNOSERV-S Ltd, Almus Ltd, Yukihiro Ozaki, Kwansei Gakuin Univ, Saratov State Univ, Russian Fed, Minist Educ C1 Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02114 USA. RP Bizheva, K (reprint author), Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3920-7 J9 P SOC PHOTO-OPT INS PY 2001 VL 4242 BP 291 EP 304 DI 10.1117/12.427725 PG 4 WC Engineering, Biomedical; Optics; Physics, Applied SC Engineering; Optics; Physics GA BS73E UT WOS:000171027700039 ER PT J AU Koutkia, P Mylonakis, E Rounds, S Erickson, A AF Koutkia, P Mylonakis, E Rounds, S Erickson, A TI Leucocytoclastic vasculitis: an update for the clinician SO SCANDINAVIAN JOURNAL OF RHEUMATOLOGY LA English DT Review DE leucocytoclastic; vasculitis; autoimmune diseases ID CUTANEOUS LEUKOCYTOCLASTIC VASCULITIS; SYSTEMIC VASCULITIS; HYPERSENSITIVITY VASCULITIS AB Leucocytoclastic vasculitis is a small vessel inflammatory disease mediated mostly by deposition of immune complexes. Infections, medications, chemicals, bacteria, viruses, and diseases associated with immune complexes have been accused in the pathogenesis. Cutaneous leucocytoelastic vasculitis presents as palpable purpura most often localized in the lower extremities, often accompanied by abdominal pain, arthralgia and renal involvement. The; clinical diagnosis of leucocytoelastic vasculitis is confirmed histopathologically by skin biopsy. In order to determine the: cause of the disease, depending on the patients history, complete blood cell count, blood cultures, cryoglobulins, serum protein electrophoresis. rheumatoid factor, antinuclear antibody, and autoantibodies to neutrophilic cytoplasmic antigens and complement should be checked. Once the diagnosis of leucocytoclastic vasculitis is made, emphasis should be on the search for an etiological factor and the identification of the involved organs. If possible, the underlying cause should be treated or removed, for example discontinuation of drugs. The prognosis depends on the disease that has the cutaneous leucocytoclastic angiitis as a component, as well as the severity of internal organ involvement. For example, a patient with cutaneous leucocytoclastic angiitis and moderate nephritis as component of Henoch-Schonlein purpura has a Much better prognosis than a patient with these same findings as a component of Wegener's granulomatosis. Only if physicians recognize and report severe reactions to regulatory authorities and manufacturers, new drugs associated with a risk of such reactions can be identified. C1 Boston Univ, Dept Endocrinol Diabet & Nutr, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. Brown Univ, Vet Affairs Hosp, Providence, RI 02912 USA. RP Koutkia, P (reprint author), Boston Med Ctr, Dept Endocrinol Diabet & Nutr, 88 E Newton St,Evans Bldg,Room 201, Boston, MA 02118 USA. NR 33 TC 34 Z9 36 U1 0 U2 3 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0300-9742 J9 SCAND J RHEUMATOL JI Scand. J. Rheumatol. PY 2001 VL 30 IS 6 BP 315 EP 322 PG 8 WC Rheumatology SC Rheumatology GA 506UF UT WOS:000172989600002 PM 11846048 ER PT J AU Allen, DN Kelley, ME Miyatake, RK Gurklis, JA van Kammen, DP AF Allen, DN Kelley, ME Miyatake, RK Gurklis, JA van Kammen, DP TI Confirmation of a two-factor model of premorbid adjustment in males with schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; premorbid; symptoms; intelligence; factor analysis ID DOPAMINE-BETA-HYDROXYLASE; 1ST-EPISODE SCHIZOPHRENIA; SOCIAL COMPETENCE; NEGATIVE SYMPTOMS; DETERIORATION; INTELLIGENCE; ASSOCIATE; DEFICITS; DISORDER; GENDER AB Because schizophrenia is considered to be a neurodevelopmental disorder, premorbid adjustment is of particular interest, Premorbid adjustment is probably not a unitary construct but rather is expressed across a number of developmental domains. The current investigation examined the validity of a two-factor model that differentiated premorbid adjustment across social and academic domains and evaluated relationships between these premorbid adjustment domains and other variables of interest, Participants with schizophrenia (n = 141) underwent evaluation of premorbid adjustment (using the Premorbid Adjustment Scale), intellectual functioning, and psychiatric symptoms, Using confirmatory factor analysis, a two-factor model of premorbid adjustment was identified that included an academic domain and a social domain, The social domain was associated with symptom variables, while the academic domain was associated with measures of intelligence. Results provide evidence for at least two domains of premorbid adjustment in schizophrenia, Distinguishing between these two premorbid domains may be theoretically important because of potential differences in incidence rates and deterioration courses; some individuals with schizophrenia may exhibit adequate academic adjustment but poor social adjustment, while others may exhibit the opposite pattern. C1 Univ Nevada, Dept Psychol, Las Vegas, NV 89514 USA. VA Pittsburgh Healthcare Syst, Highland Dr Div, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Robert Wood Johnson Pharmaceut Res Inst, Raritan, NJ USA. RP Allen, DN (reprint author), Univ Nevada, Dept Psychol, 4505 Maryland Pkwy,Box 455030, Las Vegas, NV 89514 USA. FU NIMH NIH HHS [MH-44841] NR 34 TC 31 Z9 31 U1 1 U2 1 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2001 VL 27 IS 1 BP 39 EP 46 PG 8 WC Psychiatry SC Psychiatry GA 398TH UT WOS:000166772100004 PM 11215548 ER PT S AU Roy, AK Tyagi, RK Song, CS Lavrovsky, Y Ahn, SC Oh, TS Chatterjee, B AF Roy, AK Tyagi, RK Song, CS Lavrovsky, Y Ahn, SC Oh, TS Chatterjee, B BE Anthony, M Dunn, BK Sherman, S TI Androgen receptor: Structural domains and functional dynamics after ligand-receptor interaction SO SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT NIH Workshop on Selective Estrogen Receptor Modulators (SERMs) CY APR 26-28, 2000 CL BETHESDA, MARYLAND SP NIA, NCI, Div Canc Prevent, NHLBI, NIDDKD, NIAMSK, NIDCR, NIEHS, NICHHD, NIH Off Res Womens Hlth, Dept Hlth & Human Serv, Amer Federat Aging Res DE androgen receptor; SARM; endocrine disrupters; vinclozolin; procymidone; chlozolinate; receptor recycling; green fluorescent protein ID BINDING DOMAIN; GENE; MUTATIONS; ESTROGEN; COREGULATORS; SPECIFICITY; SUPERFAMILY; ANTAGONIST; PROSTATE; ALPHA AB Androgens are C-19 steroids secreted primarily from the testes and adrenals that play a critical role in reproduction. Reproductive functions of androgens are mediated through coordination of diverse physiological processes ranging from brain functions to specific cell proliferation and apoptosis. At the molecular level, most of these regulatory influences are exerted by altered expression of appropriate genes by the androgen receptor (AR), a member of the nuclear receptor (NR) superfamily. The unliganded AR is a cytoplasmic protein and, upon ligand binding, it translocates into the nucleus. Thereafter, in conjunction with other transcription factors and coactivators, the AR influences transcription of target genes through a multistep process that includes its clustering in a subnuclear compartment. Here, we describe the genomic organization of the AR, the role of individual structural domains in specific AR function, and the influence of agonistic/antagonistic ligands in the intracellular movement of the receptor. We also show that the AR is capable of undergoing multiple rounds of nucleocytoplasmic recycling after ligand binding and dissociation. Xenobiotic ligands, considered as selective androgen receptor modulators (SARMs), can modulate AR activity by inhibiting either its nuclear translocation or its subnuclear clustering and subsequent transactivation function. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Roy, AK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIA NIH HHS [R37 AG10486]; NIDDK NIH HHS [R01 DK14744] NR 32 TC 78 Z9 79 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-358-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 949 BP 44 EP 57 PG 14 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences; Reproductive Biology SC Biochemistry & Molecular Biology; Science & Technology - Other Topics; Reproductive Biology GA BT69G UT WOS:000173775800006 PM 11795379 ER PT S AU Yaffe, K AF Yaffe, K BE Anthony, M Dunn, BK Sherman, S TI Estrogens, selective estrogen receptor modulators, and dementia: What is the evidence? SO SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT NIH Workshop on Selective Estrogen Receptor Modulators (SERMs) CY APR 26-28, 2000 CL BETHESDA, MARYLAND SP NIA, NCI, Div Canc Prevent, NHLBI, NIDDKD, NIAMSK, NIDCR, NIEHS, NICHHD, NIH Off Res Womens Hlth, Dept Hlth & Human Serv, Amer Federat Aging Res DE estrogens; selective estrogen receptor modulators; raloxifene; dementia ID CHOLINE-ACETYLTRANSFERASE ACTIVITY; HORMONE REPLACEMENT THERAPY; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; POSTMENOPAUSAL WOMEN; COGNITIVE FUNCTION; GONADAL-STEROIDS; CONTROLLED TRIAL; INCREASED RISK; BREAST-CANCER AB At least 10% of people aged 65 or older have some form of cognitive impairment, increasing to around 50% by age 85. Several studies have suggested that estrogen may improve cognitive function or prevent the development of dementia, but other studies have not shown a benefit, and results from large randomized trials are lacking. Fortunately, further trials are currently being conducted. With the recognition that selective estrogen receptor modulators (SERMs) have differential tissue-dependent effects on estrogen receptor function, there is recent interest in the effects of raloxifene, tamoxifen, and other SERMs on cognition. In this paper, the current state of knowledge of the role of estrogen for preventing dementia in postmenopausal women will be reviewed. In addition, the status of ongoing and recently completed trials of estrogen and SERMs on cognitive function or on Alzheimer's disease severity will be summarized. 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, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 111G,4150 Clement St, San Francisco, CA 94121 USA. NR 58 TC 21 Z9 22 U1 1 U2 8 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-358-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 949 BP 215 EP 222 PG 8 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences; Reproductive Biology SC Biochemistry & Molecular Biology; Science & Technology - Other Topics; Reproductive Biology GA BT69G UT WOS:000173775800029 PM 11795356 ER PT S AU Zapol, NJ AF Zapol, NJ BE Anthony, M Dunn, BK Sherman, S TI Negotiating industry-sponsored clinical trial agreements - A view from the trenches SO SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT NIH Workshop on Selective Estrogen Receptor Modulators (SERMs) CY APR 26-28, 2000 CL BETHESDA, MARYLAND SP NIA, NCI, Div Canc Prevent, NHLBI, NIDDKD, NIAMSK, NIDCR, NIEHS, NICHHD, NIH Off Res Womens Hlth, Dept Hlth & Human Serv, Amer Federat Aging Res DE industry-sponsored clinical trials AB A number of possible factors, including issues of cost, enrollment, and time, contribute to the decline in the percentage of industry-sponsored clinical trials conducted in academic institutions as opposed to those conducted at for-profit entities. This piece focuses on the agreement negotiation process. If negotiators were given easier access to the sponsor's decision makers, it is likely that the negotiations would proceed more efficiently. Also noted are reports by academic investigators of difficulty in getting access to unblinded trial data, which are needed for patient care and publication. C1 Massachusetts Gen Hosp, Off Corp Sponsored Res & Licensing, Charlestown, MA 02129 USA. RP Zapol, NJ (reprint author), Partners Healthcare Syst Inc, Off Gen Counsel, 50 Staniford St,10th Floor, Boston, MA 02114 USA. NR 1 TC 1 Z9 1 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-358-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 949 BP 349 EP 351 PG 3 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences; Reproductive Biology SC Biochemistry & Molecular Biology; Science & Technology - Other Topics; Reproductive Biology GA BT69G UT WOS:000173775800049 PM 11795375 ER PT J AU Brown, RH Robberecht, W AF Brown, RH Robberecht, W TI Amyotrophic lateral sclerosis: Pathogenesis SO SEMINARS IN NEUROLOGY LA English DT Article DE amyotrophic lateral sclerosis ID CU/ZN SUPEROXIDE-DISMUTASE; MOTOR-NEURON DISEASE; SELECTIVE MOTONEURON VULNERABILITY; GLIAL GLUTAMATE TRANSPORTER; TRANSGENIC MOUSE MODEL; FAMILIAL ALS; CELL-LINE; SPINAL-CORD; TYROSINE NITRATION; CHRONIC INHIBITION AB Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by motor neuron degeneration. A subgroup of familial cases arises from mutations in the gene encoding cytosolic superoxide dismutase (SOD1). This review considers insight now being gained into ALS pathogenesis from the study of mutant SOD1 protein and its possible mechanisms of adverse effect on nerve cells. Also discussed are the status of other genetic forms of ALS and the elusive question of why this disorder so specifically targets motor neurons. Ultimately, it is hoped that insights from these types of studies will improve the prospects for developing meaningful therapies of ALS. C1 Catholic Univ Louvain, Hosp Gasthuisberg, Sch Med, Dept Neurol, B-3000 Louvain, Belgium. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Day Neuromuscular Res Lab, Boston, MA USA. RP Robberecht, W (reprint author), Catholic Univ Louvain, Hosp Gasthuisberg, Sch Med, Dept Neurol, Herestr 49, B-3000 Louvain, Belgium. NR 99 TC 69 Z9 71 U1 6 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PY 2001 VL 21 IS 2 BP 131 EP 139 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 446HE UT WOS:000169506700003 PM 11442322 ER PT J AU Lipschik, GY Kelley, MA AF Lipschik, GY Kelley, MA TI Models of critical care delivery: Physician staffing in the ICU SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE intensive care unit; critical care; intensivist; outcome; cost-effectiveness ID UNIT MEDICAL DIRECTOR; INTENSIVE-CARE; RESOURCE UTILIZATION; FULL-TIME; IMPACT; ORGANIZATION; MORTALITY; OUTCOMES AB Although a consensus has emerged over the value of intensive care units (ICUs) in improving both the outcome and efficiency of critical care, the optimal staffing configuration of physicians who provide this care remains controversial. The value of open ICUs, where many clinicians can admit and care for patients, versus closed ICUs, where an on-site intensivist or housestaff team (or both) provides primary care of the critically ill patient is one aspect of this controversy. The roles of the intensivist, the ICU housestaff team, and the ICU director have also been debated. This article reviews the available literature on physician staffing in critical care units and its relationship to outcome and cost-effectiveness of care. C1 Philadelphia Vet Affairs Med Ctr, Pulm Crit Care Sect, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Lipschik, GY (reprint author), Philadelphia Vet Affairs Med Ctr, Pulm Crit Care Sect, 111P,Univ & Woodland Ave, Philadelphia, PA 19104 USA. NR 25 TC 3 Z9 3 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEM RESP CRIT CARE M JI Semin. Respir. Crit. Care Med. PY 2001 VL 22 IS 1 BP 95 EP 100 DI 10.1055/s-2001-13844 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 410VP UT WOS:000167462000011 PM 16088665 ER PT J AU Gerrity, MS AF Gerrity, MS TI Interventions to improve physicians' well-being and patient care: a commentary SO SOCIAL SCIENCE & MEDICINE LA English DT Article; Proceedings Paper CT Symposium on the Physicians Role in Transition CY MAY, 1997 CL OSLO, NORWAY DE physicians; psychological problems; patient care; response ID JUNIOR HOUSE OFFICERS; GENERAL-PRACTITIONERS; STRESS; SATISFACTION; DOCTORS; QUALITY AB Dr. Firth-Cozens begins her paper by reviewing a broad range of research related to physicians' stress, depression, and alcoholism (Firth-Cozens, 2001, Social Science and Medicine, 52, 215-222). She then argues that these psychological problems have a negative impact on patient care and describes the possible causes of these problems. Finally, she proposes a system of organizational and individual interventions to address these problems. Before accepting her conclusions and proposed system of interventions, an important issue should be considered. Is physicians' well-being an important goal in and of itself, or do we need strong evidence that physician stress, depression, and alcoholism lead to poor patient care and outcomes? Published by Elsevier Science Ltd. C1 Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Gerrity, MS (reprint author), Oregon Hlth Sci Univ, Dept Med, 3181 SW Sam Jackson Pk Rd L455, Portland, OR 97201 USA. NR 23 TC 6 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD JAN PY 2001 VL 52 IS 2 BP 223 EP 225 DI 10.1016/S0277-9536(00)00222-7 PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 384BA UT WOS:000165918100007 PM 11144778 ER PT J AU Berkman, B Maramaldi, P AF Berkman, B Maramaldi, P TI Use of standardized measures in agency based research and practice SO SOCIAL WORK IN HEALTH CARE LA English DT Article; Proceedings Paper CT 2nd International Conference on Social Work in Health and Mental Health CY JAN 15, 1998 CL MELBOURNE, AUSTRALIA DE standardized outcome measures; Health Related Quality of Life (HRQL); SF-36+Social Work ID STAGE RENAL-DISEASE; REQUIRE OUTCOME MEASURES; SOCIAL-WORK-PRACTICE; HEALTH-STATUS; NURSING INTERVENTION; CLINICAL-TRIALS; QUALITY; LIFE; SCALES; CARE AB This article reviews criteria for social workers' selection and use of standardized outcome measures for practice and research. Issues related to reliability and validity are discussed. The utility of standardized Health Related Quality of Life (HRQL) measures, either generic or disease specific, is presented utilizing one measure, the SF-36+ Social Work, as an exemplar. The article concludes that such measures are viable and necessary for social work to demonstrate its value-added qualities in the emerging healthcare environment. (C) 2001 by The Haworth Press, Inc. All rights reserved. C1 Columbia Univ, Sch Social Work, New York, NY 10025 USA. Massachusetts Gen Hosp, Social Serv Dept, Ruth D & Archie A Abrams Res Program, Boston, MA 02114 USA. RP Berkman, B (reprint author), Columbia Univ, Sch Social Work, 622 W 113th St, New York, NY 10025 USA. NR 41 TC 5 Z9 5 U1 1 U2 1 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0098-1389 J9 SOC WORK HEALTH CARE JI Soc. Work Health Care PY 2001 VL 34 IS 1-2 BP 115 EP 129 PG 15 WC Social Work SC Social Work GA 588ZG UT WOS:000177731900009 PM 12219762 ER PT J AU Burns, SP Kapur, V Yin, KS Buhrer, R AF Burns, SP Kapur, V Yin, KS Buhrer, R TI Factors associated with sleep apnea in men with spinal cord injury: a population-based case-control study SO SPINAL CORD LA English DT Article DE spinal cord injuries; quadriplegia; sleep apnea syndromes; case-control studies; obesity; baclofen ID TETRAPLEGIA; ADULTS; RISK AB Objective: To characterize a population of spinal cord injury (SCI) patients with sleep apnea. and to determine associated factors and comorbidities. Study Design: Population-based retrospective case-control study. Subjects: 584 male patients served by a Veterans Affairs SCI service. Measures: Medical records were reviewed for sleep apnea diagnosis, demographic information, neurologic characteristics, and treatments received. Sleep study reports were not available to determine the nature of abnormal respiratory events tie central, obstructive, hypoventilation). For each case with tetraplegia, a control tetraplegic subject without sleep apnea diagnosis was selected. Results: We identified 53 subjects with diagnosed sleep apnea: 42 tetraplegic, 11 paraplegic. This represented 14.9% of all tetraplegic and 3.7% of all paraplegic patients in the population (P<0.0001) for comparison of tetraplegic and paraplegic proportions). In tetraplegic subjects, sleep apnea was associated with obesity and more rostral motor level, but not with ASIA Impairment Scale. Medical comorbidities associated with sleep apnea in non-SCI patients, such as hypertension, were more common in case subjects. Less than half of case subjects were receiving some form of treatment. For motor-complete tetraplegics, long-term positive airway pressure treatment was less common with motor level C5 and above compared to C6 and below. Conclusion: In this population, sleep apnea has been frequently diagnosed, particularly in tetraplegic subjects. The true prevalence is likely to be considerably higher, since this study considered only previously diagnosed cases. Sleep apnea was associated with obesity and higher neurologic level, but not ASIA Impairment Scale. Medical comorbidities were more frequent in this group, and treatment acceptance was poor with higher level motor-complete injuries. Since the type of sleep apnea (central or obstructive) was not distinguished, we cannot comment on the prevalence and associations based on specific types of sleep apnea. C1 VA Puget Sound Hlth Care Syst, SCI Serv 128, Seattle, WA 98108 USA. Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. RP Burns, SP (reprint author), VA Puget Sound Hlth Care Syst, SCI Serv 128, 1660 S Columbian Way, Seattle, WA 98108 USA. RI Kapur, Vishesh/K-1054-2014 OI Kapur, Vishesh/0000-0002-5417-1097 NR 22 TC 31 Z9 32 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD JAN PY 2001 VL 39 IS 1 BP 15 EP 22 DI 10.1038/sj.sc.3101103 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 397PJ UT WOS:000166703800003 PM 11224009 ER PT J AU van Os, R Sheridan, TM Robinson, S Drukteinis, D Ferrara, JLM Mauch, PM AF van Os, R Sheridan, TM Robinson, S Drukteinis, D Ferrara, JLM Mauch, PM TI Immunogenicity of Ly5 (CD45)-antigens hampers long-term engraftment following minimal conditioning in a murine bone marrow transplantation model SO STEM CELLS LA English DT Article DE engraftment; Gpi; Ly5; immunity ID HEMATOPOIETIC STEM-CELLS; TOTAL-BODY IRRADIATION; DONOR-TYPE CHIMERISM; REPOPULATING ABILITY; LETHAL IRRADIATION; MIXED CHIMERISM; HOST DISEASE; T-CELLS; RECIPIENTS; MICE AB Various techniques are available for distinguishing donor from host cells evaluating the efficacy of conditioning regimen for experimental bone marrow transplantation (BMT). Techniques include the use of extracellular immunological markers, such as Ly5 (CD45), and intracellular biochemical markers, such as glucose-phosphate-isomerase (Gpi), Because Ly5 is an extracellular protein, the disparity between donor (Ly5.1) and host (Ly5.2) antigens may induce a weak immune response whereas with Gpi, no immune response is expected, This difference may be of particular concern in experimental transplantation approaches that use minimal conditioning such as low-dose total body irradiation (TBI), Such mild conditioning mag not induce the immunosuppression required to overcome host rejection of Ly5 disparate cells. To compare the relative engraftment of Lp5.1 and Gpi-1(a) donor marrow, B6 (Gpi-1(h)/Ly5.2) mice were irradiated with low-level TBI (0-6 Gy) and transplanted with several hone marrow (BM) doses (2 x 10(6)-5 x 10(7) cells). At 8, 26, and, 52 weeks post-BMT, the level, of donor engraftment was measured using now cytometry (Ly5) or Gpi-electrophoresis, Lower engraftment levels were found in mice transplanted with Ly5 congenic BM in groups given low-dose TBI (less than or equal to 4 Gy) and/or low doses of BM cells (BMC) (2 x 10(6)), However, when higher TBI or BR IC doses were used, similar engraftment levels were found, suggesting sufficient immune suppression to allow equal engraftment of both sources of BM. These data suggest that even a minor phenotypic disparity between donor and host, such as Ly5, may necessitate high-dose TBI to prevent rejection, The combination of low-dose TBI or other nonmyeloablative conditioning strategies with small numbers of BMC may lead to reduced engraftment when extracellular immunological markers such as Ly5 are used for transplantation studies, Therefore, small immunological differences must be considered when using the Ly5 marker for engraftment. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Michigan, Ctr Canc, Combined Bone Marrow Transplantat Program, Ann Arbor, MI 48109 USA. RP van Os, R (reprint author), Leiden Univ, Med Ctr, Dept Hematol, Bldg 1,C2-R,POB 9600, NL-2300 RC Leiden, Netherlands. RI van Os, Ronald/I-1516-2013 FU NCI NIH HHS [R01-CA 10941-28]; NHLBI NIH HHS [P50-HL54785-01] NR 40 TC 37 Z9 37 U1 0 U2 1 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2001 VL 19 IS 1 BP 80 EP 87 DI 10.1634/stemcells.19-1-80 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 392DC UT WOS:000166394500008 PM 11209093 ER PT J AU Cutler, C Antin, JH AF Cutler, C Antin, JH TI Peripheral blood stem cells for allogeneic transplantation: A review SO STEM CELLS LA English DT Review DE peripheral blood stem cell; CD34(+); allogeneic; transplantation; hematologic malignancies; apheresis ID BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; VERSUS-HOST DISEASE; ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; NORMAL GRANULOCYTE DONORS; MULTIPLE-MYELOMA; PROGENITOR-CELL; HEMATOLOGIC MALIGNANCIES; INTENSIVE CHEMOTHERAPY AB Peripheral blood stem cells (PBSCs) have become increasingly popular for use in hematopoietic stem cell transplantation. PBSCs are readily collected by continuous-flow apheresis from patients and healthy donors after the administration of s.c. recombinant colony-stimulating factors with only minimal morbidity and discomfort. Although the precise identification of PBSCs remains elusive, they can be phenotypically identified as a subset of all circulating CD34(+) cells. There are important phenotypic and biologic distinctions between PBSCs and bone marrow (BM)-derived progenitor cells. PBSCs express more lineage-specific antigens but are less metabolically active than their BM-derived counterparts. The use of PBSCs for allogeneic transplantation has been compared to BM in several randomized trials and cohort studies. The use of PBSCs in leukemia, myeloma, non-Hodgkin's lymphoma, and myelodysplasia has resulted in shorter times to neutrophil and platelet engraftment at the expense of increased rates of chronic graft-versus-host disease. The increase in graft-versus-host disease is mainly due to a log-fold increase in donor T cells transferred with the graft. Relapse rates after transplantation may be lower after PBSC transplantation but a convincing survival advantage has not been demonstrated overall. It is possible that a stronger graft-versus-tumor effect may exist with PBSCs when compared with BM although the mechanisms leading to this effect are not clear. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Antin, JH (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 84 TC 53 Z9 61 U1 0 U2 2 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2001 VL 19 IS 2 BP 108 EP 117 DI 10.1634/stemcells.19-2-108 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 412WM UT WOS:000167577400006 PM 11239165 ER PT J AU Shivdasani, RA AF Shivdasani, RA TI Molecular and transcriptional regulation of megakaryocyte differentiation SO STEM CELLS LA English DT Review DE megakaryocyte; platelet; thrombopoiesis; transcriptional; regulation ID CONGENITAL AMEGAKARYOCYTIC THROMBOCYTOPENIA; STORAGE POOL DEFICIENCY; GLOBIN GENE-EXPRESSION; HUMAN BONE-MARROW; FACTOR NF-E2; FACTOR GATA-1; PLATELET FORMATION; MICE LACKING; THROMBOXANE SYNTHASE; BETA-TUBULIN AB Megakaryocytes, among the rarest of hematopoietic cells, serve the essential function of producing numerous platelets. Genetic studies have recently provided rich insights into the molecular and transcriptional regulation of megakaryocyte differentiation and thrombopoiesis. Three transcription factors, GATA-1, FOG-1, and NF-E2, are essential regulators of distinct stages in megakaryocyte differentiation, extending from the birth of early committed progenitors to the final step of platelet release; a fourth factor, Fli-1, likely also plays an important role. The putative transcriptional targets of these regulators, including the NF-E2-dependent hematopoietic-specific beta -tubulin isoform beta1, deepen our understanding of molecular mechanisms in platelet biogenesis. The study of rare syndromes of inherited thrombocytopenia in mice and man has also refined the emerging picture of megakaryocyte maturation. Synthesis of platelet-specific organelles is mediated by a variety of regulators of intracellular vesicle membrane fusion, and platelet release is coordinated through extensive and dynamic reorganization of the actin and microtubule cytoskeletons. As in other aspects of hematopoiesis, characterization of recurrent chromosomal translocations in human leukemias provides an added dimension to the molecular underpinnings of megakaryocyte differentiation. Long regarded as a mysterious cell, the megakaryocyte is thus yielding many of its secrets, and mechanisms of thrombopoiesis are becoming clearer. Although this review focuses on transcriptional control mechanisms, it also discusses recent advances in broader consideration of the birth of platelets. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NHLBI NIH HHS [R01-HL63143] NR 101 TC 121 Z9 125 U1 0 U2 7 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2001 VL 19 IS 5 BP 397 EP 407 DI 10.1634/stemcells.19-5-397 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 474LP UT WOS:000171108800005 PM 11553848 ER PT J AU Singhal, AB Wang, XY Lo, EH AF Singhal, AB Wang, XY Lo, EH TI Effects of normobaric hyperoxia in a rat model of transient focal cerebral ischemia and reperfusion SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Charlestown, MA 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA 3 BP 316 EP 316 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300071 ER PT J AU Berzin, TM Lev, MH Goodman, D Koroshetz, WJ Hunter, GJ Hamberg, L Buonanno, F Putman, C Budzik, R Eskey, C Schwamm, LH Gonzalez, RG AF Berzin, TM Lev, MH Goodman, D Koroshetz, WJ Hunter, GJ Hamberg, L Buonanno, F Putman, C Budzik, R Eskey, C Schwamm, LH Gonzalez, RG TI CT perfusion imaging versus MR diffusion weighted imaging: Prediction of final infarct size in hyperacute stroke SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA 10 BP 317 EP 317 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300078 ER PT J AU Lutsep, HL Campbell, M Clark, WM Jansen, O Lefkowitz, MA Marks, MP Norbash, A Putman, C Schumacher, M AF Lutsep, HL Campbell, M Clark, WM Jansen, O Lefkowitz, MA Marks, MP Norbash, A Putman, C Schumacher, M TI EPAR therapy system for treatment of acute stroke: Safety study results SO STROKE LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Texas, Houston, TX USA. Univ Heidelberg, Heidelberg, Germany. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Freiburg, Freiburg, Germany. RI Jansen, Olav/D-2547-2010 NR 0 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA 19 BP 319 EP 319 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300087 ER PT J AU Bove, P Lev, MH Berdichevsky, D Harris, GJ Alpert, NM Thangaraj, V Koroshetz, WJ Putman, C Gonzalez, RG AF Bove, P Lev, MH Berdichevsky, D Harris, GJ Alpert, NM Thangaraj, V Koroshetz, WJ Putman, C Gonzalez, RG TI CT perfusion imaging improves infarct conspicuity in hyperacute stroke SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. IMIPS Inc, Boston, MA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA 51 BP 325 EP 325 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300119 ER PT J AU Ezzeddine, MA Lev, MH McDonald, CT Rordorf, GA Oliveira-Filho, J Aksoy, F Segal, AZ Gonzalez, G Koroshetz, WJ AF Ezzeddine, MA Lev, MH McDonald, CT Rordorf, GA Oliveira-Filho, J Aksoy, F Segal, AZ Gonzalez, G Koroshetz, WJ TI Impact of contrast CT angiography and whole brain contrast CT perfusion study on the accuracy of cerebrovascular diagnosis in patients presenting with a major stroke-like syndrome SO STROKE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. New York Cornell Hosp, New York, NY USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA 52 BP 325 EP 325 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300120 ER PT J AU Schwamm, LH Bellon, R Norbash, A Budzik, R Ogilvy, C Putman, C AF Schwamm, LH Bellon, R Norbash, A Budzik, R Ogilvy, C Putman, C TI Continuous monitoring of jugular bulb oxygenation during carotid temporary balloon occlusion SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P19 BP 342 EP 342 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300208 ER PT J AU Ezzeddine, MA Koroshetz, WJ Lah, S Gonzalez, G Lev, MH AF Ezzeddine, MA Koroshetz, WJ Lah, S Gonzalez, G Lev, MH TI Hemispheric infarct volume prediction by CT perfusion imaging SO STROKE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P24 BP 343 EP 343 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300213 ER PT J AU Schaefer, PW He, J Hunter, G Hamberg, L Gonzalez, RG AF Schaefer, PW He, J Hunter, G Hamberg, L Gonzalez, RG TI Diffusion and perfusion MRI in predicting final infarct volume: A study of 81 patients with acute stroke SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P25 BP 343 EP 343 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300214 ER PT J AU Wu, O Schwamm, LH Koroshetz, WJ Gonzalez, RG Pan, V Benner, T Copen, WA Ostergaard, L Sorensen, AG AF Wu, O Schwamm, LH Koroshetz, WJ Gonzalez, RG Pan, V Benner, T Copen, WA Ostergaard, L Sorensen, AG TI Heterogeneous spatial-temporal evolution of DWI/PWI in human cerebral ischemia SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. MIT, Cambridge, MA 02139 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P53 BP 348 EP 348 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300242 ER PT J AU Rosand, J Eskey, C Gonzalez, RG Knudsen, KA Greenberg, SM Koroshetz, WJ AF Rosand, J Eskey, C Gonzalez, RG Knudsen, KA Greenberg, SM Koroshetz, WJ TI Dynamic single-section contrast CT measures cerebral blood flow in acute intracerebral hemorrhage SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P102 BP 357 EP 357 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300291 ER PT J AU Kelly, PJ Rosand, J Plomaritoglou, A Chang, YC Kistler, JP Furie, KL AF Kelly, PJ Rosand, J Plomaritoglou, A Chang, YC Kistler, JP Furie, KL TI Mild-to-moderate hyperhomocyst(e)inemia and risk of stroke. Result of a meta-analysis. SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P148 BP 366 EP 366 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300336 ER PT J AU Rordorf, GA Koroshetz, WJ Buonanno, F McDonald, CT Greer, D Ougorets, I Rosand, J Schwamm, LH AF Rordorf, GA Koroshetz, WJ Buonanno, F McDonald, CT Greer, D Ougorets, I Rosand, J Schwamm, LH TI CT angiography use in acute stroke patients undergoing i.v. TPA SO STROKE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2001 VL 32 IS 1 MA P170 BP 370 EP 370 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 389JF UT WOS:000166234300358 ER PT J AU Elizondo, ME Arratibel, JAA Compton, CC Warshaw, AL AF Elizondo, ME Arratibel, JAA Compton, CC Warshaw, AL TI Tuberculosis of the pancreas SO SURGERY LA English DT Editorial Material C1 Univ Basque Country, Unidad Docente Med San Sebastian, Nuestra Senora Aranzazu Hosp, San Sebastian, Spain. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Elizondo, ME (reprint author), Wiesbaden 8-2C, San Sebastian 20009, Spain. NR 4 TC 8 Z9 9 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 JAN PY 2001 VL 129 IS 1 BP 114 EP 116 DI 10.1067/msy.2001.104364 PG 3 WC Surgery SC Surgery GA 392DZ UT WOS:000166396500016 ER PT J AU Hoh, BL Ogilvy, CS AF Hoh, BL Ogilvy, CS TI B-mode ultrasonographic investigations of morphological changes in endarterectomized carotid artery - Commentary SO SURGICAL NEUROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. RP Hoh, BL (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, 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 JAN PY 2001 VL 55 IS 1 BP 56 EP 57 DI 10.1016/S0090-3019(01)00391-3 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 411AJ UT WOS:000167475700024 ER PT J AU Marino, M Pinchera, A McCluskey, RT Chiovato, L AF Marino, M Pinchera, A McCluskey, RT Chiovato, L TI Megalin in thyroid physiology and pathology SO THYROID LA English DT Review ID ACETYLGLUCOSAMINE-SPECIFIC RECEPTOR; HEYMANN NEPHRITIS; ENDOPLASMIC-RETICULUM; FOLLICLE CELLS; THYROGLOBULIN INTERACTIONS; CIRCULATING THYROGLOBULIN; LIPOPROTEIN RECEPTORS; MURINE THYROGLOBULIN; SERUM THYROGLOBULIN; ENDOCYTIC RECEPTOR AB Megalin, a member of the low density lipoprotein endocytic receptor family, is expressed on the apical surface of thyroid epithelial cells, directly facing the follicle lumen, where colloid is stored in high concentrations. Stud ies in vivo and with cultured thyroid cells have provided evidence that megalin expression on thyroid cells is TSH-dependent. Thyroglobulin (Tg), the major protein component of the colloid and the precursor of thyroid hormones, binds to megalin with high affinity and megalin mediates in part its uptake by thyrocytes. Tg internalized by megalin avoids the lysosomal pathway and is delivered by transepithelial transport (transcytosis) to the basolateral membrane of thyrocytes, from which it is released into the bloodstream. This process com petes with pathways leading to thyroid hormone release from Tg molecules, which occurs following internalization of Tg molecules from the colloid by other means of uptake (fluid phase endocytosis or endocytosis mediated by low affinity receptors) that result in proteolytic cleavage in the lyosomes. During transcytosis of Tg, a portion of megalin (secretory component) remains complexed with Tg and enters the circulation, where its detection may serve as a tool to identify the origin of serum Tg in patients with thyroid diseases. Tg endocytosis via megalin is facilitated by the interaction of Tg with cell surface heparan sulfate proteoglycans, which occurs via a carboxyl terminal heparin binding site of Tg functionally related with a major megalin binding site. Although autoantibodies against megalin can be found in the serum of similar to 50% of patients with autoimmune thyroiditis, a role or megalin in this and other thyroid diseases remains to be established. C1 Univ Pisa, Dept Endocrinol, I-56124 Pisa, Italy. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pathol Res Lab, Charlestown, MA USA. RP Marino, M (reprint author), Univ Pisa, Dept Endocrinol, Via Paradisa 2, I-56124 Pisa, Italy. FU NIDDK NIH HHS [DK 46301] NR 82 TC 19 Z9 22 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JAN PY 2001 VL 11 IS 1 BP 47 EP 56 DI 10.1089/10507250150500667 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 400WH UT WOS:000166894300008 PM 11272097 ER PT S AU Ogawa, M Tajima, F Sato, T Deguchi, T Laver, JH AF Ogawa, M Tajima, F Sato, T Deguchi, T Laver, JH BE Ikada, Y TI CD34 expression by murine hematopoietic cells with long-term engrafting capability SO TISSUE ENGINEERING FOR THERAPEUTIC USE 5 SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Symposium on Tissue Engineering for Therapeutic Use CY NOV 16-17, 2000 CL TSUKUBA, JAPAN SP Japan Soc Promot Sci DE bone marrow; CD34; hematopoiesis; stem cells; transplantation ID STEM-CELLS; BONE-MARROW; BLOOD-CELLS; ANTIGEN; TRANSPLANTATION AB Background. We reported earlier that CD34 expression by mouse stem cells reflects the activation state of stem cells and is reversible. However, the average observation period of engraftment in that study was 5 months. In order to study truly long term engrafting stem cells, we carried out measurements of the levels of engraftment at 1 year posttransplantation. Methods. Cells from Ly-5.1 C57BL/6 mice were used as donor cells and lethally irradiated Ly-5.2 mice were the recipients. The test cells were transplanted together with radioprotective marrow cells of Ly-5.2 mice. Results. The majority of the stem cells from normal adult mice with 1 year engraftment capabilities were CD34(-). Stem cells were found in both the CD34(-) and CD34(+) cell populations of 5-fluouracil (5-FU)-treated mice. We extended the observation time in experiments testing reversion of CD34(+) stem cells to CD34 stem cells. We transplanted Ly-5.1 CD34(+) post 5-FU marrow cells into Ly-5.2 primary recipients and, after the marrow achieved steady state, Ly-5.1 marrow cells of the primary recipients into Ly-5.2 secondary recipients. The majority of the Ly-5.1 cells engrafting 8 months after retransplantation were in the CD34(-) cell fraction. Conclusion. CD34 expression of long-term engrafting stem cells reflects the activation state of hematopoietic stem cells and is reversible. C1 Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Ogawa, M (reprint author), Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50554-7 J9 INT CONGR SER PY 2001 VL 1222 BP 37 EP 43 PG 7 WC Engineering, Biomedical; Medicine, Research & Experimental SC Engineering; Research & Experimental Medicine GA BS31G UT WOS:000169429900004 ER PT S AU Tilles, AW Balis, UJ Baskaran, H Yarmush, ML Toner, M AF Tilles, AW Balis, UJ Baskaran, H Yarmush, ML Toner, M BE Ikada, Y TI Internal membrane oxygenation removes substrate oxygen limitations in a small-scale flat-plate hepatocyte bioreactor SO TISSUE ENGINEERING FOR THERAPEUTIC USE 5 SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Symposium on Tissue Engineering for Therapeutic Use CY NOV 16-17, 2000 CL TSUKUBA, JAPAN SP Japan Soc Promot Sci DE bioartificial liver; mathematical modeling; oxygen uptake rate; perfusion; porcine hepatocytes ID BIOARTIFICIAL LIVER; CULTURED-HEPATOCYTES; UPTAKE RATES; FAILURE; DEVICE; DESIGN AB Background. An extracorporeal bioartificial liver (BAL) has the potential for providing temporarysupport for patients with acute or fulminant liver failure and for patients awaiting orthotopic liver transplantation. Substrate oxygen limitations in current BAL configurations have been a major problem when scaling up these devices for clinical use. The goal of this study was to fabricate and test a hepatocyte bioreactor with two key features: an internal membrane to facilitate oxygenation of all hepatocytes and a hydrodynamic height of 100 mum to minimize plasma volume. Methods. We designed and constructed one- and two-compartment flat-plate bioreactors with a micro-spaced fluid channel height of 100 mum and investigated oxygenation as a function of media flow rate, in the absence (one-compartment) and presence (two-compartment) of a membrane-based oxygenation system. Additionally, we constructed a mathematical model utilizing the Damkohler number to predict bioreactor performance and provide additional insight into optimal bioreactor designs and operating conditions for our simple geometry. Results. In the one-compartment bioreactor with hepatocytes present, the outlet oxygen tension decreased gradually from a value of 154.13 +/- 1.88 mmHg at a media flow rate of 3.5 ml/min to 114.00 +/- 4.0 mmHg at a flow rate of 0.5 ml/min, with an approximate overall decrease of 26%. As the media flow rate was further decreased to 0.1 ml/min, outlet oxygen tension precipitously decreased to 2.13 +/- 2.46 mmHg, which corresponded to a decrease of about 99% from the concentration measured at 3.5 ml/min. In the two-compartment bioreactor, at the media flow rate of 0.1 ml/min, there was a 75-fold increase in the outlet oxygen tension over that seen in the one-compartment bioreactor. The outlet oxygen concentrations in the two-compartment bioreactor also showed a statistically significant increase for the 0.5- to 0.6-ml/min media flow range and for the 0.75- to 0.8-ml/min media flow range when compared to those in the one-compartment configuration. Conclusions. Our results demonstrate that typical one-compartment bioreactor flow rate and channel height indices can lead to substrate limiting oxygen tensions in very short reactor flow distances, making device scale-up to larger sizes unfeasible. Conversely utilization of the two-compartment bioreactor design, with internal membrane oxygenation, overcame this substrate limitation. This significant benefit facilitates reactor scale-up. This study also demonstrates the utility of mathematical modeling as a tool for effective bioreactor performance prediction and optimization. C1 Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. RP Tilles, AW (reprint author), Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, 51 Blossom St, Boston, MA 02114 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50554-7 J9 INT CONGR SER PY 2001 VL 1222 BP 59 EP 71 PG 13 WC Engineering, Biomedical; Medicine, Research & Experimental SC Engineering; Research & Experimental Medicine GA BS31G UT WOS:000169429900007 ER PT J AU Hosokawa, Y Papanikolaou, A Cardiff, RD Yoshimoto, K Bernstein, M Wang, TC Schmidt, EV Arnold, A AF Hosokawa, Y Papanikolaou, A Cardiff, RD Yoshimoto, K Bernstein, M Wang, TC Schmidt, EV Arnold, A TI In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53 SO TRANSGENIC RESEARCH LA English DT Article DE breast cancer; cell cycle; oncogenes; PRAD1; TP53; tumor suppressor genes ID HUMAN BREAST-CANCER; WILD-TYPE P53; GENE AMPLIFICATION; PROTEIN EXPRESSION; GROWTH ARREST; BCL-1 GENE; CELL; APOPTOSIS; OVEREXPRESSION; CARCINOMAS AB Overexpression of the cyclin D1 oncogene and inactivation of the p53 tumor suppressor have both been implicated in substantial proportions of sporadic human breast cancers. Transgenic mice with cyclin D1 overexpression targeted to mammary tissue by the MMTV enhancer-promoter have been shown to develop mammary cancers. To investigate the relationship between pathways driven by cyclin D1 overexpression and p53 loss during the development of breast cancers, we crossed MMTV-cyclin D1 mice with p53 heterozygous null (p53(+)/-) mice. In such crossed mice, cyclin D1-driven mammary neoplasia would need to be substantially accelerated by p53 loss in order for mammary tumors to develop prior to the expected onset of non-mammary tumors characteristic of the p53-deficient background alone. Instead, in mice heterozygous or homozygous for p53 deficiency and simultaneously carrying the MMTV-cyclin D1 transgene, only tumors typically found in p53-deficient mice developed and mammary tumors were not observed. Interestingly, MMTV-cyclin D1/p53(+/-) mice appeared to develop these non-mammary tumors more rapidly than p53(+/-) mice, and a majority of the sampled non-mammary tumors from MMTV-cyclin D1/p53(+/-) mice showed 'ectopic' expression of the MMTV-driven cyclin D1 transgene. Within the constraints of possible genetic background effects and limited sensitivity due to the early emergence of non-mammary tumors, these observations provide no evidence that inactivation of p53 confers a major additional selective advantage to mammary cells overexpressing cyclin D1 in this animal model of human breast cancer. Interestingly, the results do raise the possibility that p53 inactivation might complement or cooperate with cyclin D1 deregulation during the development of some types of non-mammary tumors. C1 Univ Connecticut, Sch Med, Ctr Mol Med, Farmington, CT 06030 USA. Univ Calif Davis, Sch Med, Dept Pathol, Davis, CA 95616 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. RP Arnold, A (reprint author), Univ Connecticut, Sch Med, Ctr Mol Med, Farmington, CT 06030 USA. FU NCI NIH HHS [CA55909] NR 44 TC 11 Z9 13 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PY 2001 VL 10 IS 5 BP 471 EP 478 DI 10.1023/A:1012064911751 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 479LJ UT WOS:000171405600010 PM 11708657 ER PT B AU Podolsky, DK AF Podolsky, DK BE Asakura, H Aoyagi, Y Nakazawa, S TI Reflecting forward: Gastroenterology in the new millennium SO TRENDS IN GASTROENTEROLOGY AND HEPATOLOGY: MILLENNIUM 2000 LA English DT Proceedings Paper CT 86th Annual Congress of the Japanese-Society-of-Gastroenterology CY APR 20-22, 2000 CL NIIGATA, JAPAN SP Japanese Soc Gastroenterol C1 Massachusetts Gen Hosp, Gastrointestinal Unit GRJ719, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit GRJ719, 32 Fruit St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG TOKYO PI TOKYO PA 37-3, HONGO 3-CHOME BONKYO-KU, TOKYO, 113, JAPAN BN 4-431-70302-0 PY 2001 BP 3 EP 12 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA BS68A UT WOS:000170815700001 ER PT J AU Zietman, A AF Zietman, A TI Radiation oncology update SO UROLOGIC ONCOLOGY LA English DT Article ID TRIAL C1 Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Box 3, Boston, MA 02114 USA. NR 5 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 1078-1439 J9 UROL ONCOL JI Urol. Oncol. PD JAN-FEB PY 2001 VL 6 IS 1 BP 29 EP 30 PG 2 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 380XM UT WOS:000165729400007 ER PT J AU Oh, MK George, DJ Hackmann, K Manola, J Kantoff, PW AF Oh, MK George, DJ Hackmann, K Manola, J Kantoff, PW TI Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer SO UROLOGY LA English DT Article ID AGENT AB Objectives. To retrospectively evaluate the response to treatment with PC-SPES, an herbal supplement, because patients with androgen-independent prostate cancer have limited treatment options. Methods. A retrospective analysis was performed of patients with prostate cancer progression despite androgen ablation therapy who were treated with PC-SPES (3 capsules twice daily). We explored potential predictors of response. Results. Twenty-three patients with androgen-independent prostate cancer were treated. The median age was 70 years. Eighteen patients had received prior secondary hormonal treatment and 10 prior chemotherapy. With a median follow-up of 8 months, 20 (87%; 95% confidence interval 66% to 97%) of 23 patients experienced a post-therapy decline in prostate-specific antigen (PSA). The median decline in PSA among these patients was 40% (range 1% to 88%). Of 23 patients, 12 (52%; 95% confidence interval 31% to 73%) had a greater than 50% decline in PSA. The median duration of the PSA response was 2.5 months (range 1 to 9+); the median time from the start of therapy to PSA progression was 6 months (range 2 to 12). Seven patients died of progressive prostate cancer. Toxicity was mild and included nipple tenderness, nausea, and diarrhea. One patient with a known history of coronary artery disease developed angina. In univariate analyses, older patients and those with a longer duration of initial androgen ablation therapy were more likely to respond to PC-SPES. Conclusions. PC-SPES is a well-tolerated and active treatment for androgen-independent prostate cancer. Additional testing is necessary to identify the active components of PC-SPES and its role in the treatment of patients with androgen-independent prostate cancer. UROLOGY 57: 122-126, 2001. (C) 2001, Elsevier Science Inc. C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Oh, MK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 17 TC 2 Z9 2 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 JAN PY 2001 VL 57 IS 1 BP 122 EP 126 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 396XJ UT WOS:000166663000024 ER PT S AU Rauch, SD AF Rauch, SD BE Goebel, J Highstein, SM TI Vestibular histopathology of the human temporal bone - What can we learn? SO VESTIBULAR LABYRINTH IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Vestibular Labyrinth in Health and Disease CY NOV 16-18, 2000 CL ST LOUIS, MISSOURI SP Natl Inst Deafness & Other Commun Disorders, NASA, Natl Sci Fdn, Deafness Res Fdn, Neurocom Int Inc, Micromed Technologies Inc, Nicolet Biomed, Alcon Labs DE vestibular; histopathology; temporal bone; human; otopathology ID MENIERES-DISEASE; SCARPAS GANGLION AB Histologic sections of the human temporal bone display snapshots of the entire lifetime integrated into the moment the bone enters fixative. The bulk of the literature on vestibular histopathology is anecdotal and descriptive in nature, rather than quantitative. This is because the means of describing and measuring patients' vestibular symptoms are poorly developed, and the complex geometry of the vestibular labyrinth complicates efforts to study it in serial histologic sections. Histopathologic findings in the common peripheral vestibulopathies, including Meniere's syndrome, benign paroxysmal positional vertigo, viral labyrinthitis, vestibular neuronitis, and ototoxicity, have all been described. A new quantitative method for assessment of vestibular otopathology using Nomarski optics has recently been reported. It has been successfully applied to create a normative database of age-related changes in the vestibular hair cell populations which, in turn, has been used to study the effects of aminoglycoside ototoxicity and Meniere's syndrome. These data provide the first meaningful opportunity to make structure-function correlations between vestibular function testing and temporal bone pathology in humans. Wider clinical application of vestibular function testing and postmortem temporal bone donation should be promoted by all investigators interested in accumulating the resources necessary to gain a deeper understanding of the human vestibular system in health and disease. C1 Massachusetts Eye & Ear Infirm, Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Rauch, SD (reprint author), Massachusetts Eye & Ear Infirm, Harvard Med Sch, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 21 TC 14 Z9 15 U1 0 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-289-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 942 BP 25 EP 33 PG 9 WC Multidisciplinary Sciences; Otorhinolaryngology SC Science & Technology - Other Topics; Otorhinolaryngology GA BT31Q UT WOS:000172619200003 PM 11710467 ER PT S AU Angelaki, DE Wei, M Merfeld, DM AF Angelaki, DE Wei, M Merfeld, DM BE Goebel, J Highstein, SM TI Vestibular discrimination of gravity and translational acceleration SO VESTIBULAR LABYRINTH IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Vestibular Labyrinth in Health and Disease CY NOV 16-18, 2000 CL ST LOUIS, MISSOURI SP Natl Inst Deafness & Other Commun Disorders, NASA, Natl Sci Fdn, Deafness Res Fdn, Neurocom Int Inc, Micromed Technologies Inc, Nicolet Biomed, Alcon Labs DE eye movements; vestibular; oculomotor; navigation; inertial; gravity; neural computation ID OTOLITH-OCULAR REFLEXES; VESTIBULOOCULAR REFLEX; SQUIRREL-MONKEY; LINEAR ACCELERATION; RHESUS-MONKEYS; 3-DIMENSIONAL ORGANIZATION; SEMICIRCULAR CANALS; ECCENTRIC ROTATION; PRIMARY AFFERENT; ROLL TILT AB According to Einstein's equivalence principle, linear accelerations experienced during translational motion are physically indistinguishable from changes in orientation relative to gravity experienced during tilting movements. Nevertheless, despite these ambiguous sensory cues provided by the primary otolith afferents, perceptual and motor responses discriminate between gravity and translational acceleration. There is growing evidence to suggest that the brain resolves this ambiguity primarily by combining signals from multiple sensors, the semicircular canals being a main extra otolith contributor. Here, we summarize the experimental evidence in support of the canal influences on the neural processing of otolith cues, provide specific experimental results in rhesus monkeys, and discuss and compare previously proposed models that combine otolith and semicircular-canal signals in order to provide neural estimates of gravity and linear acceleration. C1 Washington Univ, Sch Med, Dept Neurobiol & Biomed Engn, St Louis, MO 63110 USA. Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Angelaki, DE (reprint author), Washington Univ, Sch Med, Dept Anat & Neurobiol, Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. FU NEI NIH HHS [EY10851]; NIDCD NIH HHS [DC04158, DC04260] NR 39 TC 27 Z9 27 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-289-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 942 BP 114 EP 127 PG 14 WC Multidisciplinary Sciences; Otorhinolaryngology SC Science & Technology - Other Topics; Otorhinolaryngology GA BT31Q UT WOS:000172619200010 PM 11710454 ER PT S AU Rauch, SD Velazquez-Villasenor, L Dimitri, PS Merchant, SN AF Rauch, SD Velazquez-Villasenor, L Dimitri, PS Merchant, SN BE Goebel, J Highstein, SM TI Decreasing hair cell counts in aging humans SO VESTIBULAR LABYRINTH IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Vestibular Labyrinth in Health and Disease CY NOV 16-18, 2000 CL ST LOUIS, MISSOURI SP Natl Inst Deafness & Other Commun Disorders, NASA, Natl Sci Fdn, Deafness Res Fdn, Neurocom Int Inc, Micromed Technologies Inc, Nicolet Biomed, Alcon Labs DE hair cells; dysequilibrium; dizziness; aging; vestibular function testing; Scarpa's ganglion; temporal bone ID PERIPHERAL VESTIBULAR SYSTEM; TEMPORAL BONE; SENSORY EPITHELIA AB Deterioration of balance with advancing age is a well-known fact of life. Some investigators have reported a 50% prevalence of dizziness in the elderly. Clinically, progressive dysequilibrium of aging presents as gradually worsening balance due to age-related decline in function of the peripheral vestibular system, central nervous system, vision, and musculoskeletal system. Vestibular function testing has shown clear evidence of age-related changes in peripheral and central sites. Histopathologic changes in the vestibular sensory organs include progressive hair cell degeneration, otoconial degeneration in the otolith organs, and decreasing number of Scarpa's ganglion neurons. Recently, a new quantitative method of assessing vestibular otopathology has been described, utilizing Nomarski differential interference contrast microscopy. This technique has been applied to 67 human temporal bones of individuals from birth to age 100 to create a normative database of total, type I, and type II hair cell counts as a function of age. Results show a highly significant continuous decrease in all counts from birth to age 100, best fit by a linear regression model. Type I hair cell counts in all three semicircular canal cristae decrease at a similar rate, significantly faster than the degeneration observed in type I hair cells of the maculae. Type II hair cell counts decline at the same rate for all 5 sensory epithelia. These normative data provide the basis for comparisons to hair cell counts made in temporal bones from subjects with known vestibular disorders. They also provide a basis for drawing correlations between vestibular function testing and vestibular otopathology. C1 Massachusetts Eye & Ear Infirm, Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Rauch, SD (reprint author), Massachusetts Eye & Ear Infirm, Harvard Med Sch, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 19 TC 57 Z9 60 U1 1 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-289-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2001 VL 942 BP 220 EP 227 PG 8 WC Multidisciplinary Sciences; Otorhinolaryngology SC Science & Technology - Other Topics; Otorhinolaryngology GA BT31Q UT WOS:000172619200019 PM 11710464 ER PT J AU Van Essen, DC Lewis, JW Drury, HA Hadjikhani, N Tootell, RBH Bakircioglu, M Miller, MI AF Van Essen, DC Lewis, JW Drury, HA Hadjikhani, N Tootell, RBH Bakircioglu, M Miller, MI TI Mapping visual cortex in monkeys and humans using surface-based atlases SO VISION RESEARCH LA English DT Article DE architectonic; maps; probabilistic; visual areas; visual topography ID HUMAN CEREBRAL-CORTEX; CORTICAL SURFACE; COORDINATE SYSTEM; MACAQUE MONKEY; AREAS; STRIATE; BRAIN; RETINOTOPY; ATTENTION; IMAGES AB We have used surface-based atlases of the cerebral cortex to analyze the functional organization of visual cortex in humans and macaque monkeys. The macaque atlas contains multiple partitioning schemes for visual cortex, including a probabilistic atlas of visual areas derived from a recent architectonic study, plus summary schemes that reflect a combination of physiological and anatomical evidence. The human atlas includes a probabilistic map of eight topographically organized visual areas recently mapped using functional MRI. To facilitate comparisons between species, we used surface-based warping to bring functional and geographic landmarks on the macaque map into register with corresponding landmarks on the human map. The results suggest that extrastriate visual cortex outside the known topographically organized areas is dramatically expanded in human compared to macaque cortex, particularly in the parietal lobe. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Washington Univ, Sch Med, St Louis, MO 63110 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Johns Hopkins Univ, Whiting Sch Engn, Ctr Imaging Sci, Baltimore, MD 21218 USA. RP Van Essen, DC (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. RI Hadjikhani, Nouchine/C-2018-2008; Miller, Michael I./A-3213-2010 OI Hadjikhani, Nouchine/0000-0003-4075-3106; FU NEI NIH HHS [EY02091, EY09258]; NIMH NIH HHS [R01 MH60974-06] NR 49 TC 250 Z9 252 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PY 2001 VL 41 IS 10-11 SI SI BP 1359 EP 1378 DI 10.1016/S0042-6989(01)00045-1 PG 20 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 430GB UT WOS:000168565200013 PM 11322980 ER PT J AU Grill-Spector, K Kourtzi, Z Kanwisher, N AF Grill-Spector, K Kourtzi, Z Kanwisher, N TI The lateral occipital complex and its role in object recognition SO VISION RESEARCH LA English DT Article DE object recognition; functional magnetic resonance imaging; human extrastriate cortex ID HUMAN VISUAL-CORTEX; HUMAN EXTRASTRIATE CORTEX; POSITRON EMISSION TOMOGRAPHY; HUMAN FACE PERCEPTION; MONKEY INFEROTEMPORAL CORTEX; INFERIOR TEMPORAL CORTEX; HUMAN CEREBRAL-CORTEX; HUMAN FUSIFORM GYRUS; HUMAN BRAIN ACTIVITY; FUNCTIONAL MRI AB Here we review recent findings that reveal the functional properties of extra-striate regions in the human visual cortex that are involved in the representation and perception of objects. We characterize both the invariant and non-invariant properties of these regions and we discuss the correlation between activation of these regions and recognition. Overall, these results indicate that the lateral occipital complex plays an important role in human object recognition. (C) 2001 Published by Elsevier Science Ltd. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Grill-Spector, K (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. OI Grill-Spector, Kalanit/0000-0002-5404-9606 NR 127 TC 614 Z9 621 U1 5 U2 46 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PY 2001 VL 41 IS 10-11 SI SI BP 1409 EP 1422 DI 10.1016/S0042-6989(01)00073-6 PG 14 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 430GB UT WOS:000168565200016 PM 11322983 ER PT J AU Johnson, J Caravelli, ML Brecha, NC AF Johnson, J Caravelli, ML Brecha, NC TI Somatostatin inhibits calcium influx into rat rod bipolar cell axonal terminals SO VISUAL NEUROSCIENCE LA English DT Article DE somatostatin receptors; calcium imaging; rod bipolar cells; fura-2 AM; neuropeptides ID SINGLE SYNAPTIC TERMINALS; TIGER SALAMANDER RETINA; C-LIKE IMMUNOREACTIVITY; RABBIT RETINA; MAMMALIAN RETINA; GASTROINTESTINAL-TRACT; AMACRINE CELLS; BINDING-SITES; 2A RECEPTOR; NEURONS AB In the retina, somatostatin (SST), an inhibitory peptide that influences neuronal activity, is predominantly expressed by sparsely occurring amarcine cells. The SST subtype 2A receptor is expressed by rod bipolar cells, including their axonal terminals. We used Ca2+-imaging techniques and the ratiometric Ca2+ indicator dye fura-2 AM to investigate Ca2+ dynamics in rod bipolar cell terminals. Depolarization of rod bipolar cells by the addition of high K+ (50 or 100 mM) elicited a sustained increase in [Ca2+](i) in rod bipolar terminals that returned to basal levels following K+ removal. The Ca2+ response was dependent on extracellular Ca2+, and was inhibited by the Ca2+ channel blocker Cd2+ and by the selective L-type Ca2+ channel blocker, nimodipine. SST inhibited a K depolarization-induced [Ca2+](i) response in rod bipolar terminals. This inhibition was observed with 1 nM SST and was maximal with 1 muM SST. These findings indicate that SST may regulate transmitter release from rod bipolar. terminals by activating the SST subtype 2A receptor through modulation of intracellular Ca2+. C1 Univ Calif Los Angeles, Sch Med, Med Ctr CHS, Dept Neurobiol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, CURE, Digest Dis Res Ctr, Los Angeles, CA 90095 USA. Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Brecha, NC (reprint author), Univ Calif Los Angeles, Sch Med, Med Ctr CHS, Dept Neurobiol, 10833 Le Conte Ave,Box 951763, Los Angeles, CA 90095 USA. FU NEI NIH HHS [EY 04067, EY 07026]; NIDDK NIH HHS [DK 41301] NR 65 TC 24 Z9 24 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-4930 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD JAN-FEB PY 2001 VL 18 IS 1 BP 101 EP 108 DI 10.1017/S0952523801181095 PG 8 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 419EX UT WOS:000167937300009 PM 11347807 ER PT B AU Saidman, S Theruvath, T Pascual, M Soter, J Fitzpatrick, D AF Saidman, S Theruvath, T Pascual, M Soter, J Fitzpatrick, D BE Terasaki, PI TI Monitoring donor specific HLA antibodies during treatment for chronic rejection SO VISUALS OF THE CLINICAL HISTOCOMPATIBILITY WORKSHOP LA English DT Proceedings Paper CT Visuals of the Clinical Histocompatibility Workshop CY FEB 27-MAR 03, 2001 CL HONOLULU, HI SP One Lambda Ince C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saidman, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONE LAMBDA, INC PI CANOGA PK PA 21001 KITTRIDGE STREET, CANOGA PK, CA 91303-2801 USA BN 0-945756-13-5 PY 2001 BP 27 EP 28 PG 2 WC Immunology; Transplantation SC Immunology; Transplantation GA BV84P UT WOS:000180192100012 ER PT J AU Vogt, DS Stone, ER Salgado, DM King, LA King, DW Savarese, VW AF Vogt, DS Stone, ER Salgado, DM King, LA King, DW Savarese, VW TI Gender awareness among veterans administration health-care workers: Existing strengths and areas for improvement SO WOMEN & HEALTH LA English DT Article DE women's health; gender; attitudes of health personnel; women veterans ID FEMALE-PATIENTS; WOMEN; QUALITY AB In response to the growing number of women within the Veterans Health Administration (VHA), along with the challenge of meeting their health-care needs in a historically male-focused setting, VHA has supported a variety of research projects aimed at evaluating and improving the status of women's health and health-care experiences. While these efforts have primarily focused on aspects of care such as the availability and accessibility of services and the provision of timely care, this study focused on the contribution of interpersonal aspects of care. Specifically, staff gender awareness, conceptualized as health-care workers' gender-role ideology or attitudes, gender sensitivity, and knowledge was examined. Findings revealed both strengths and weaknesses in domains of staff gender awareness and significant relationships between staff demographics and gender awareness components. (C) 2001 by The Haworth Press, Inc. All rights reserved. C1 Natl Ctr Posttraumat Stress Disorder, VA Boston Healthcare Syst, Boston, MA 02130 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Vogt, DS (reprint author), Natl Ctr Posttraumat Stress Disorder, VA Boston Healthcare Syst, 116B-5,150 S Huntington Ave, Boston, MA 02130 USA. NR 38 TC 19 Z9 19 U1 1 U2 1 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2001 VL 34 IS 4 BP 65 EP 83 DI 10.1300/J013v34n04_05 PG 19 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 511LE UT WOS:000173264700005 PM 11785858 ER PT J AU Goldfeld, AE Leung, JY Sawyer, SA Hartl, DL AF Goldfeld, AE Leung, JY Sawyer, SA Hartl, DL TI Post-genomics and the neutral theory: variation and conservation in the tumor necrosis factor-alpha promoter SO GENE LA English DT Article; Proceedings Paper CT Anton Dohrn Workshop on Neutralism and Selectionism - the End of a Debate CY MAY 03-05, 2000 CL ISCHIA, ITALY SP Int Soc Molec Evolut DE polymorphism and divergence; Poisson random field; primate molecular evolution; single nucleotide polymorphism ID DROSOPHILA-MELANOGASTER; GENE-REGULATION; TNF-ALPHA; MOLECULAR EVOLUTION; NATURAL-SELECTION; CODON BIAS; DNA LOSS; B-CELLS; T-CELLS; POLYMORPHISM AB In the post-genomics era, molecular evolutionary geneticists have come to possess the molecular, statistical, and computational tools for estimating the relative importance of selection and random genetic drift in virtually any gene in almost any organism. We have examined single-nucleotide polymorphisms (SNPs) and nucleotide divergence across a region of approximately 1 kb in the promoter of the human tumor necrosis factor alpha (TNF-alpha) gene. TNF-alpha, which plays an important role in lymphocyte biology and in the pathogenesis of infectious and autoimmune diseases, is tightly regulated at the level of transcription through sequence-specific binding of transcription factors to cognate binding sites in a relatively small region of the 5' non-coding region of the gene. Analysis of the promoter region in 207 human chromosomes revealed nine SNPs, none of which were located in regions known to be important in transcriptional activation. Comparison with one promoter sequence in each of seven species of primates revealed 162 nucleotide sites occupied by a monomorphic nucleotide in the human sample but occupied by a different nucleotide in at least one of the primate sequences (a 'fixed human difference'). The fixed human differences were found outside the regions known to be important in transcriptional activation, and their large number suggests that they might be effectively neutral (\Ns\ <<1). With regard to the human SNPs, although the hypothesis Ns similar to 0 cannot be rejected, the sample configurations suggest that the substitutions might be mildly deleterious. We emphasize the analytical insight to be gained from interspecific comparisons: through the interspecific comparisons, 3.1% of the total sequence information yielded 94.7% of the variable nucleotides. This combined approach, using interspecific comparisons and human polymorphism together with data from functional analyses, provides valuable insights into the evolutionary history and regulation of a key gene in the human immune response. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. Washington Univ, Dept Math, St Louis, MO 63130 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Hartl, DL (reprint author), Harvard Univ, Dept Organism & Evolutionary Biol, 16 Divin Ave, Cambridge, MA 02138 USA. FU NHLBI NIH HHS [HL59838]; NIGMS NIH HHS [GM56492, GM58423] NR 64 TC 7 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD DEC 30 PY 2000 VL 261 IS 1 BP 19 EP 25 DI 10.1016/S0378-1119(00)00477-7 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 398MF UT WOS:000166759700004 PM 11164033 ER PT J AU Vaida, F Xu, RH AF Vaida, F Xu, RH TI Proportional hazards model with random effects SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the International-Society-for-Clinical-Biostatistics (ISCB) CY SEP 14-17, 1999 CL HEIDELBERG, GERMANY SP Int Soc Clin Biostat ID GAMMA-FRAILTY MODEL; FAILURE TIME DATA; EM ALGORITHM; MAXIMUM-LIKELIHOOD; REGRESSION-ANALYSIS; ASYMPTOTIC THEORY; INFERENCE; VARIANCE; TESTS AB We propose a general proportional hazards model with random effects for handling clustered survival data. This generalizes the usual frailty model by allowing a multivariate random effect with arbitrary design matrix in the log relative risk, in a way similar to the modelling of random effects in linear, generalized linear and non-linear mixed models. The distribution of the random effects is generally assumed to be multivariate normal, but other (preferably symmetrical) distributions are also possible. Maximum likelihood estimates of the regression parameters, the variance components and the baseline hazard function are obtained via the EM algorithm. The E-step of the algorithm involves computation of the conditional expectations of functions of the random effects, for which we use Markov chain Monte Carlo (MCMC) methods. Approximate variances of the estimates are computed by Louis' formula, and posterior expectations and variances of the individual random effects can be obtained as a by-product of the estimation. The inference procedure is exemplified on two data sets. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vaida, F (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [AI-28076, AI-38855]; NIGMS NIH HHS [GM-29745] NR 40 TC 104 Z9 107 U1 0 U2 11 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 DEC 30 PY 2000 VL 19 IS 24 BP 3309 EP 3324 DI 10.1002/1097-0258(20001230)19:24<3309::AID-SIM825>3.0.CO;2-9 PG 16 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 392DN UT WOS:000166395500002 PM 11122497 ER PT J AU Suzuma, K Naruse, K Suzuma, I Takahara, N Ueki, K Aiello, LP King, GL AF Suzuma, K Naruse, K Suzuma, I Takahara, N Ueki, K Aiello, LP King, GL TI Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-Akt-dependent pathways in retinal vascular cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; FACTOR GENE-EXPRESSION; ANGIOGENESIS IN-VIVO; GLUCOSE-TRANSPORT; INSULIN STIMULATION; RECOMBINANT ADENOVIRUSES; DIABETIC-RETINOPATHY; FLK-1/KDR ACTIVATION; SIGNAL-TRANSDUCTION; TYROSINE KINASE AB Fibroblastic proliferation accompanies many angiogenesis-related retinal and systemic diseases. Since connective tissue growth factor (CTGF) is a potent mitogen for fibrosis, extracellular matrix production, and angiogenesis, we have studied the effects and mechanism by which vascular endothelial growth factor (VEGF) regulates CTGF gene expression in retinal capillary cells. In our study, VEGF increased CTGF mRNA levels in a time and concentration-dependent manner in bovine retinal endothelial cells and pericytes, without the need of new protein synthesis and without altering mRNA stability. VEGF activated the tyrosine receptor phosphorylation of KDR and Flt1 and increased the binding of phosphatidylinositol 3-kinase (PIS-kinase) p85 subunit to KDR and Flt1, both of which could mediate CTGF gene induction. VEGF-induced CTGF expression was mediated primarily by PI3-kinase activation, whereas PKC and ERK pathways made only minimal contributions. Furthermore, overexpression of constitutive active Akt was sufficient to induce CTGF gene expression, and inhibition of Akt activation by overexpressing dominant negative mutant of Akt abolished the VEGF-induced CTGF expression. These data suggest that VEGF can increase CTGF gene expression in bovine retinal capillary cells via KDR or Fit receptors and the activation of PI3-kinase-Akt pathway independently of PKC or Ras-ERK pathway, possibly inducing the fibrosis observed in retinal neovascular diseases. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02215 USA. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY5110] NR 65 TC 177 Z9 190 U1 0 U2 5 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 DEC 29 PY 2000 VL 275 IS 52 BP 40725 EP 40731 DI 10.1074/jbc.M006509200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 387GJ UT WOS:000166114600011 PM 11018037 ER PT J AU Schmitt-Ney, M Habener, JF AF Schmitt-Ney, M Habener, JF TI CHOP/GADD153 gene expression response to cellular stresses inhibited by prior exposure to ultraviolet light wavelength band C (UVC) - Inhibitory sequence mediating the UVC response localized to exon 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA STABILITY; PROTEIN (C/EBP)-RELATED GENE; AMINO-ACID LIMITATION; NF-KAPPA-B; DNA-DAMAGE; BINDING PROTEIN; GROWTH ARREST; CHOP GADD153; ENDOPLASMIC-RETICULUM; SIGNAL-TRANSDUCTION AB CHOP/GADD153 is both an activating and repressing transcription factor that is markedly induced in response to a variety of cellular stresses. The CHOP/ GADD153 gene was originally cloned because of its inducibility by ultraviolet light wavelength band C UVC and has since been found to be activated in response to many different cellular stresses. Some of the recent studies have questioned the UVC responsiveness of the CHOP gene. Contradiction in our own data led us to reexamine the WC effects on CHOP expression. WC is capable of strongly activating the mouse CHOP promoter in stably transfected NIH 3T3 cells but has only a modest and transient effect on the level of the CHOP messenger RNA. In addition to its positive effect on CHOP promoter activity, we show that UVC negatively affects CHOP mRNA and protein expression. Pretreatment of NIH 3T3 cells with WC markedly attenuates the subsequent induction of CHOP mRNA by the cellular stress activators methylmethane sulfate, tunicamycin, glucose deprivation, and methionine deprivation for as long as at least 16 h. This inhibitory effect of UVC on CHOP expression in response to stress is independent of the presence or absence of p53 and does not involve mRNA degradation as opposed to the WC effect that inhibits p21 expression seen only in the absence of p53. The target of the inhibitory effect of WC on CHOP expression is located in the first exon of the gene, a 5'-untranslated region that is unusually conserved between different species. These findings suggest that an unknown function encoded by the 5'-untranslated region somehow modifies the response of CHOP gene transcription to WC. C1 Harvard Univ, Mol Endocrinol Lab, Sch Med, Massachusetts Gen Hosp,Howard Hughes Med Inst, Boston, MA 02114 USA. RP Habener, JF (reprint author), Harvard Univ, Mol Endocrinol Lab, Sch Med, Massachusetts Gen Hosp,Howard Hughes Med Inst, 55 Fruit St,WEL320, Boston, MA 02114 USA. NR 59 TC 21 Z9 21 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 DEC 29 PY 2000 VL 275 IS 52 BP 40839 EP 40845 DI 10.1074/jbc.M007440200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 387GJ UT WOS:000166114600025 PM 11010973 ER PT J AU Datta, R Yoshinaga, K Kaneki, M Pandey, P Kufe, D AF Datta, R Yoshinaga, K Kaneki, M Pandey, P Kufe, D TI Phorbol ester-induced generation of reactive oxygen species is protein kinase C beta-dependent and required for SAPK activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; HUMAN-IMMUNODEFICIENCY-VIRUS; LEUKEMIA-CELL-LINE; MONOCYTIC DIFFERENTIATION; MACROPHAGE DIFFERENTIATION; JUN KINASES; EXPRESSION; STRESS; TRANSCRIPTION; PROLIFERATION AB Treatment of human U-937 myeloid leukemia cells with 12 O-tetradecanoylphorbol-13-acetate (TPA) is associated with protein kinase C (PKC) beta II-mediated activation of the stress-activated protein kinase (SAPK) pathway. The present studies demonstrate that the TPA response of U-937 cells includes the generation of reactive oxygen species (ROS), By contrast, the TPA-resistant U-937 cell variant (TUR), which is deficient in PKC beta II expression, failed to respond to TPA with the induction of ROS. Moreover, we show that TPA-induced ROS production is restored in TUR cells stably transfected to express PKC beta II, The results also demonstrate that TPA-induced ROS production is required for activation of the MEK kinase-1 (MEKI-1)--> SAPK pathway. In concert with this observation, treatment of U-937 with H2O2 as a source of ROS is associated with activation of the MEKK-1-->SAPK cascade. These findings indicate that PKC beta II is required for TPA-induced ROS production and that the MEKK-1-->SAPK pathway is activated by a ROS-mediated mechanism. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Datta, R (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [CA42802]; NIGMS NIH HHS [GM58200] NR 31 TC 60 Z9 61 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 DEC 29 PY 2000 VL 275 IS 52 BP 41000 EP 41003 DI 10.1074/jbc.M009322200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 387GJ UT WOS:000166114600047 PM 11042219 ER PT J AU Petersen, LA Normand, ST Daley, J McNeil, BJ AF Petersen, LA Normand, ST Daley, J McNeil, BJ TI Outcome of myocardial infarction in Veterans Health Administration patients as compared with medicare patients. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COOPERATIVE CARDIOVASCULAR PROJECT; PROPENSITY SCORE; CORONARY ANGIOGRAPHY; QUALITY IMPROVEMENT; CARE SYSTEM; AFFAIRS; MORTALITY; SERVICES; POPULATION; HOSPITALS AB Background: Some have the opinion that patients cared for in Veterans Health Administration (VHA) hospitals receive care of poorer quality than those cared for in non-VHA institutions. To assess the quality of care in VHA hospitals, we compared the outcome of acute myocardial infarction among patients in VHA and non-VHA institutions while controlling for potential confounders, including coexisting conditions and severity of illness. Methods: We studied 2486 veterans discharged from 81 VHA hospitals and 29,249 Medicare patients discharged from 1530 non-VHA hospitals, restricting our samples to men at least 65 years of age who were discharged with confirmed acute myocardial infarction. We compared coexisting conditions, severity of illness, and 30-day and 1-year mortality in the two samples. Results: VHA patients were significantly more likely than Medicare patients to have a recorded history of hypertension (64.3 percent vs. 57.3 percent), chronic obstructive pulmonary disease or asthma (30.9 percent vs. 23.5 percent), diabetes (34.8 percent vs. 29.0 percent), stroke (20.4 percent vs. 14.2 percent), or dementia (7.2 percent vs. 4.8 percent) (P<0.001 for all comparisons). According to both multivariate logistic regression and an analysis using 2265 matched pairs of VHA and Medicare patients, there were no significant differences in 30-day or 1-year mortality. The matched-pairs analysis found that the difference in mortality at 30 days (the mortality rate among Medicare patients minus the mortality rate among VHA patients), averaged over the 5-year age groups, was -0.8 percent (95 percent confidence interval, -2.8 to 1.3), and the difference in mortality at 1 year was -1.3 percent (95 percent confidence interval, -3.9 to 1.3). Conclusions: VHA patients had more coexisting conditions than Medicare patients. Nevertheless, we found no significant difference in mortality between VHA and Medicare patients, a result that suggests a similar quality of care for acute myocardial infarction. (N Engl J Med 2000;343:1934-41.) (C) 2000, Massachusetts Medical Society. C1 Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Partners Hlth Care Syst, Inst Hlth Policy, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Petersen, LA (reprint author), Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, 2002 Holcombe Blvd, Houston, TX 77030 USA. FU AHRQ HHS [R01-HS08071] NR 33 TC 108 Z9 108 U1 0 U2 2 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 DEC 28 PY 2000 VL 343 IS 26 BP 1934 EP 1941 DI 10.1056/NEJM200012283432606 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 386VR UT WOS:000166082700006 PM 11136265 ER PT J AU Fihn, SD AF Fihn, SD TI Does VA health care measure up? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; OF-VETERANS-AFFAIRS; MANAGEMENT; SERVICES; QUALITY; SYSTEM; FUTURE C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Fihn, SD (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. NR 19 TC 8 Z9 8 U1 0 U2 0 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 DEC 28 PY 2000 VL 343 IS 26 BP 1963 EP 1965 DI 10.1056/NEJM200012283432611 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 386VR UT WOS:000166082700011 PM 11136270 ER PT J AU Magid, DJ Calonge, BN Rumsfeld, JS Canto, JG Frederick, PD Every, NR Barron, HV AF Magid, DJ Calonge, BN Rumsfeld, JS Canto, JG Frederick, PD Every, NR Barron, HV CA Natl Registry Myocardial Infarctio TI Relation between hospital primary angioplasty volume and mortality for patients with acute MI treated with primary angioplasty vs thrombolytic therapy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PRACTICE GUIDELINES COMMITTEE; PRIMARY CORONARY ANGIOPLASTY; ASSOCIATION TASK-FORCE; BYPASS GRAFT-SURGERY; NEW-YORK-STATE; NATIONAL REGISTRY; IMMEDIATE ANGIOPLASTY; ACC/AHA GUIDELINES; SURGICAL VOLUME AB Context institutional experience with primary angioplasty has been suggested as a factor in selecting a reperfusion strategy for patients with acute myocardial infarction (AMI). However, no large studies have directly compared outcomes of primary angioplasty vs thrombolytic therapy as a function of institutional experience. Objective To compare outcomes among patients with AMI who were treated with primary angioplasty vs thrombolytic therapy at hospitals with different volumes of primary angioplasty. Design Retrospective cohort. Setting A total of 446 acute care hospitals with 112 classified as low volume (less than or equal to 16 procedures), 223 as intermediate volume (17-48 procedures), and 111 as high volume (greater than or equal to 49 procedures) based on their annual primary angioplasty volume. Patients A total of 62 299 patients with AMI treated with primary angioplasty or thrombolytic therapy from June 1, 1994, through July 31, 1999. Main Outcome Measure In-hospital mortality, Results Mortality was lower among patients who received primary angioplasty compared with those who received thrombolysis at hospitals with intermediate volumes (4.5% vs 5.9%; P<.001) and high volumes (3.4% vs 5.4%; P<.001) of primary angioplasty. At low-volume hospitals, there was no significant difference in mortality between patients treated with primary angioplasty vs those treated with thrombolysis (6.2% vs 5.9%; P=.58). Adjusting for differences in demographic, medical history, clinical presentation, treatment, and hospital characteristics did not significantly alter these findings. Conclusions in this study, patients with AMI treated at hospitals with high or intermediate volumes of primary angioplasty had lower mortality with primary angioplasty than with thrombolysis, whereas patients with AMI treated at hospitals with low angioplasty volumes had similar mortality outcomes with primary angioplasty or thrombolysis. C1 Colorado Permanente Med Grp, Clin Res Unit, Denver, CO 80231 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Div Emergency Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Family Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Div Cardiol, Denver, CO 80262 USA. Univ Alabama, Med Ctr, Birmingham, AL 35294 USA. Denver VA Med Ctr, Denver, CO 80220 USA. Univ Washington, Cardiovasc Outcomes Res Ctr, Seattle, WA 98195 USA. VA Puget Sound Healthcare Syst, Seattle, WA 98115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Genentech Inc, S San Francisco, CA 94080 USA. RP Magid, DJ (reprint author), Colorado Permanente Med Grp, Clin Res Unit, 10350 E Dakota Ave, Denver, CO 80231 USA. NR 34 TC 196 Z9 205 U1 1 U2 7 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 DEC 27 PY 2000 VL 284 IS 24 BP 3131 EP 3138 DI 10.1001/jama.284.24.3131 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 385FZ UT WOS:000165994100030 PM 11135776 ER PT J AU Yao, JK Reddy, R van Kammen, DP AF Yao, JK Reddy, R van Kammen, DP TI Abnormal age-related changes of plasma antioxidant proteins in schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE plasma; total antioxidant status; albumin; bilirubin; age; psychosis; haloperidol ID SUPEROXIDE-DISMUTASE ACTIVITY; FREE-RADICAL PATHOLOGY; FUNCTIONAL LIFE-SPAN; ACUTE-PHASE PROTEINS; TARDIVE-DYSKINESIA; GLUTATHIONE-PEROXIDASE; VITAMIN-E; HALOPERIDOL WITHDRAWAL; CEREBROSPINAL-FLUID; OXIDATIVE DAMAGE AB Albumin and bilirubin art: metal-binding proteins, shown to possess free radical scavenging properties, and may thus be selective antioxidants. Tn the present study we examined whether individual plasma antioxidants such as albumin and bilirubin, which significantly contribute to total antioxidant status (TAS), are reduced in patients with schizophrenia. We prospectively studied plasma antioxidant proteins, i.e. albumin and bilirubin, in male veteran schizophrenic patients using a within-subject, repeated measures, on-off-on haloperidol treatment design, as well as age- and sex-matched healthy volunteers. Male patients with schizophrenia either during haloperidol treatment (n = 46) or in a drug-free condition (n = 35) had significantly lower, levels of both plasma albumin and bilirubin compared with age- and sex-matched healthy volunteers (n = 31). Such reductions of plasma antioxidant proteins in schizophrenic patients appeal to be age-related changes, in contrast to those observed in healthy volunteers. On the other hand, levels of plasma albumin and bilirubin were not significantly affected by haloperidol treatment, haloperidol withdrawal, or length of drug-free period. Moreover, plasma TAS was not influenced significantly by cigarette smoking, even though it may selectively decrease plasma bilirubin but not albumin levels. The present findings, taken together with our previous results of reduced plasma TAS and uric acid, as well as an increased Red blood cell superoxide dismutase, lend further support to the hypothesis that a defect in the antioxidant defense system exists in schizophrenia that may lead to oxidative damage. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. RW Johnson Pharmaceut Res Inst, Raritan, NJ 08869 USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Bldg 13,7180 Highland Dr, Pittsburgh, PA 15206 USA. NR 69 TC 85 Z9 89 U1 1 U2 2 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 DEC 27 PY 2000 VL 97 IS 2-3 BP 137 EP 151 DI 10.1016/S0165-1781(00)00230-4 PG 15 WC Psychiatry SC Psychiatry GA 398WN UT WOS:000166779600006 PM 11166086 ER PT J AU Kauffman, HM McBride, MA Delmonic, FL AF Kauffman, HM McBride, MA Delmonic, FL TI First report of the united network for organ sharing transplant tumor registry: Donors with a history of cancer SO TRANSPLANTATION LA English DT Article ID RENAL-ALLOGRAFT RECIPIENT; GLIOBLASTOMA-MULTIFORME; MALIGNANT-TUMOR; TRANSMISSION; METASTASES; LYMPHOMA; LIVER; MEDULLOBLASTOMA; DORMANCY; ORIGIN AB Background. Severe organ shortages have led to donor pool expansion to include older individuals, patients with hypertension, diabetes, and a past history of cancer. Transmission of cancer from cadaveric donors is a risk of transplantation and carries a high mortality rate. Methods. During a 33 month period, UNOS recorded 14,705 cadaveric donors of which 257 had a past history of cancer (PHC), A total of 650 organs (397 kidneys, 178 livers, and 75 hearts) were transplanted from these 257 donors. Type of cancer, tumor-free interval at organ procurement, and whether any PHC donor transmitted a tumor to the recipient were analyzed. Results. Three PHC donor tumor types (skin, brain, genitourinary) were associated with 549 of the transplanted organs (85%), Twenty-eight recipients of PHC donor organs developed posttransplantation tumors (18 skin, 2 PTLD, 8 solid cancers). During a mean follow-up of 45 months (range 30-61 months), no recipients of organs from PHC donors developed a donor derived cancer. The majority (71.5%) of all non-skin and non-CNS system cancer donors had a cancer-free interval of greater than five years. Conclusions. Risks of cancer transmission from do nors with a history of non-melanoma skin cancer and selected cancers of the CNS appear to be small. Risks of tumor transmission with certain other types of cancer may be acceptable, particularly if the donor has a long cancer-free interval prior to organ procurement while certain other cancers pose a high transmission risk. Selective use of PHC donors may permit expansion of the donor pool. C1 United Network Organ Sharing, Richmond, VA 23225 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kauffman, HM (reprint author), United Network Organ Sharing, 1100 Boulders Pkwy,Suite 500, Richmond, VA 23225 USA. NR 37 TC 84 Z9 86 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 DEC 27 PY 2000 VL 70 IS 12 BP 1747 EP 1751 DI 10.1097/00007890-200012270-00014 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 388WN UT WOS:000166206200014 PM 11152107 ER PT J AU Gonzalez, RG Cheng, LL Westmoreland, SV Sakaie, KE Becerra, LR Lee, PL Masliah, E Lackner, AA AF Gonzalez, RG Cheng, LL Westmoreland, SV Sakaie, KE Becerra, LR Lee, PL Masliah, E Lackner, AA TI Early brain injury in the SIV-macaque model of AIDS SO AIDS LA English DT Article DE neurological/brain; magnetic resonance spectroscopy; immunohistochemistry; primate; SIV; pathogenesis ID SIMIAN IMMUNODEFICIENCY VIRUS; PROTON MR SPECTROSCOPY; MAGNETIC-RESONANCE SPECTROSCOPY; CENTRAL-NERVOUS-SYSTEM; DEMENTIA COMPLEX; HIV-INFECTION; RHESUS MACAQUES; NEURONAL LOSS; SEROPOSITIVE INDIVIDUALS; DISEASE PROGRESSION AB Objective: To specify the type and severity of cellular damage in the central nervous system soon after infection and at later stages of disease in the SIV-macaque model of AIDS. Design and methods: Adjacent samples of frontal cortical gray matter were taken from three groups of macaques: uninfected controls (n = 4), acute (14 days post-infection; n = 4), and chronic (mean 2 years post-infection; n = 7). In vitro high resolution magnetic resonance spectroscopy of snap frozen intact tissue and quantitative neuropathology measurements of synaptophysin, calbindin, and glial fibrillary acidic protein (GFAP) in formalin-fixed tissue were performed. Results: Losses in n-acetylaspartate and calbindin (indicating neuronal injury and/or death) and decreases in synaptophysin immunoreactivity (indicating synaptodendritic injury) were detected along with increases in GFAP (indicating reactive gliosis). Cellular injury worsened progressively with increased time after infection. Conclusions: These results are the first direct evidence that neuronal injury occurs soon after infection. The exacerbation of injury with time suggests a connection between the early response of the central nervous system and dementia, which occurs fate in the course of infection. This connection may have broad implications for the study of and the development of therapies for damage of the central nervous system by (C) 2000 Lippincott Williams & Wilkins. C1 Harvard Univ, Neuroradiol Div, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Dept Pathol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Southborough, MA 01772 USA. Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. RP Gonzalez, RG (reprint author), Harvard Univ, Neuroradiol Div, Sch Med, Massachusetts Gen Hosp, GRB 285,Fruit St, Boston, MA 02114 USA. OI SAKAIE, KEN/0000-0002-5633-4494 FU NCRR NIH HHS [RR13213]; NINDS NIH HHS [NS30769, NS34626] NR 55 TC 60 Z9 61 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 22 PY 2000 VL 14 IS 18 BP 2841 EP 2849 DI 10.1097/00002030-200012220-00005 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 388VW UT WOS:000166204600005 PM 11153665 ER PT J AU Miller, V Sabin, C Hertogs, K Bloor, S Martinez-Picado, J D'Aquila, R Larder, B Lutz, T Gute, P Weidmann, E Rabenau, H Phillips, A Staszewski, S AF Miller, V Sabin, C Hertogs, K Bloor, S Martinez-Picado, J D'Aquila, R Larder, B Lutz, T Gute, P Weidmann, E Rabenau, H Phillips, A Staszewski, S TI Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure SO AIDS LA English DT Article DE treatment interruption; resistance; shift to wild type; salvage therapy ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITORS; PHENOTYPIC RESISTANCE; DRUG SUSCEPTIBILITY; MUTATIONS; REGIMEN; SAQUINAVIR; RITONAVIR AB Objective: To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus. Methods: Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (greater than or equal to 2 months). Results: Treatment interruption resulted in viral load increases (mean 0.7 log(10) copies/ml; P = 0.0001) and CD4 cell count decreases (mean 89 x 10(6) cells/l; P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 x 10(6) cells/I; P = 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation; P = 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P = 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P = 0.0003); it improved with the number of new drugs received (RH 2.12; P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006). Conclusions: Changes in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered. (C) 2000 Lippincott WiIliams & Wilkins. C1 Univ Frankfurt Klinikum, Zentrum Inneren Med, D-60590 Frankfurt, Germany. UCL Royal Free & Univ Coll Med Sch, Royal Free Ctr HIV Med, London, England. UCL Royal Free & Univ Coll Med Sch, Dept Primary Care & Populat Sci, London, England. VIRCO Labs, Mechelen, Belgium. VIRCO Labs, Cambridge, England. Massachusetts Gen Hosp, Charlestown, MA USA. RP Miller, V (reprint author), Univ Frankfurt Klinikum, Zentrum Inneren Med, Infektionsambulanz Haus 68,Theodor Stern Kai 7, D-60590 Frankfurt, Germany. RI Sabin, Caroline/C-2464-2008; Phillips, Andrew/B-4427-2008; Martinez-Picado, Javier/G-5507-2012 OI Phillips, Andrew/0000-0003-2384-4807; Martinez-Picado, Javier/0000-0002-4916-2129 FU NIAID NIH HHS [AI29193] NR 31 TC 177 Z9 179 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 22 PY 2000 VL 14 IS 18 BP 2857 EP 2867 DI 10.1097/00002030-200012220-00007 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 388VW UT WOS:000166204600007 PM 11153667 ER PT J AU Zhou, XJ Havlir, DV Richman, DD Acosta, EP Hirsch, M Collier, AC Tebas, P Sommadossi, JP AF Zhou, XJ Havlir, DV Richman, DD Acosta, EP Hirsch, M Collier, AC Tebas, P Sommadossi, JP CA AIDS Clin Trials Grp Study 343 Invest TI Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients SO AIDS LA English DT Article DE indinavir; population pharmacokinetics; cerebrospinal fluid penetration; combination antiretroviral therapy ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRIOR ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; PROTEASE INHIBITOR; CONTROLLED TRIAL; DRUG-THERAPY; IN-VIVO; INFECTION; HIV-1; NEVIRAPINE AB Objectives: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. Methods: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma Values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. Results: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 I/h per kg [coefficient of variation (CV) 54.8%]: and 1.74 I/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 mu mol/l (CV 57.5%), 9.51 mu mol/l (CV 47.3%), 29.56 mu mol/l.h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 mu mol/l (CV 49.7%) and the mean CSF plasma concentration ratio was 0.017. Conclusions: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levers of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen. (C) 2000 Lippincott Williams & Wilkins. C1 Univ Alabama, Dept Clin Pharmacol, Sch Med, Birmingham Vet Affairs Med Ctr,Ctr AIDS Res, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Sch Med, Birmingham Vet Affairs Med Ctr,Ctr AIDS Res, Birmingham, AL 35294 USA. Univ Calif San Diego, San Diego, CA 92103 USA. San Diego Vet Affairs Med Ctr, San Diego, CA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, AIDS Res Ctr, Boston, MA 02115 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Washington Univ, St Louis, MO 63130 USA. RP Sommadossi, JP (reprint author), Univ Alabama, Dept Clin Pharmacol, Sch Med, Birmingham Vet Affairs Med Ctr,Ctr AIDS Res, 1670 Univ Blvd,VH G019, Birmingham, AL 35294 USA. RI Tebas, Pablo/A-7061-2008 NR 29 TC 41 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 22 PY 2000 VL 14 IS 18 BP 2869 EP 2876 DI 10.1097/00002030-200012220-00008 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 388VW UT WOS:000166204600008 PM 11153668 ER PT J AU Havas, K Flaus, A Phelan, M Kingston, R Wade, PA Lilley, DMJ Owen-Hughes, T AF Havas, K Flaus, A Phelan, M Kingston, R Wade, PA Lilley, DMJ Owen-Hughes, T TI Generation of superhelical torsion by ATP-dependent chromatin remodeling activities SO CELL LA English DT Article ID YEAST SWI/SNF COMPLEX; T4 ENDONUCLEASE-VII; SUPERCOILED DNA; NUCLEOSOME DISRUPTION; HISTONE OCTAMER; CRUCIFORM STRUCTURES; BINDING DOMAIN; SWI-SNF; TRANSCRIPTION; ISWI AB ATP-dependent chromatin remodeling activities participate in the alteration of chromatin structure during gene regulation. Ail have DNA- or chromatin-stimulated ATPase activity and many can alter the structure of chromatin; however, the means by which they do this have remained unclear. Here we describe a novel activity for ATP-dependent chromatin remodeling activities, the ability to generate unconstrained negative superhelical torsion in DNA and chromatin. We find that the ability to distort DNA is shared by the yeast SWI/SNF complex, Xenopus Mi-2 complex, recombinant ISWI, and recombinant BRG1, suggesting that the generation of superhelical torsion represents a primary biomechanical activity shared by all Snf2-prelated ATPase motors. The generation of superhelical torque provides a potent means by which ATP-dependent chromatin remodeling activities can manipulate chromatin structure. C1 Univ Dundee, Wellcome Trust Bioctr, Div Gene Regulat, Dundee DD1 5EH, Scotland. Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. RP Owen-Hughes, T (reprint author), Univ Dundee, Wellcome Trust Bioctr, Div Gene Regulat, Dundee DD1 5EH, Scotland. RI Flaus, Andrew/D-5076-2011; OI Flaus, Andrew/0000-0002-5720-7139; Owen-Hughes, Tom/0000-0002-0618-8185 FU Cancer Research UK [11722] NR 78 TC 190 Z9 192 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 22 PY 2000 VL 103 IS 7 BP 1133 EP 1142 DI 10.1016/S0092-8674(00)00215-4 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 386BQ UT WOS:000166040600015 PM 11163188 ER PT J AU Zhang, ZQ Apse, K Pang, JD Stanton, RC AF Zhang, ZQ Apse, K Pang, JD Stanton, RC TI High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVE STRESS; GROWTH-FACTOR; COMPLICATIONS; ACTIVATION; EXPRESSION; RELEASE; ENZYME AB Recent studies have shown that hyperglycemia is a principal cause of cellular damage in patients with diabetes mellitus, A major consequence of hyperglycemia is increased oxidative stress. Glucose-8-phosphate dehydrogenase (G6PD) plays an essential role in the regulation of oxidative stress by primarily regulating NADPH, the main intracellular reductant. In this paper we show that increased glucose (10-25 mM) caused inhibition of G6PD resulting in decreased NADPH levels in bovine aortic endothelial cells (BAEC), Inhibition was seen within 15 min. High glucose-induced inhibition of G6PD predisposed cells to cell death. High glucose via increased activity of adenylate cyclase also stimulated an increase in cAMP levels in BAEC. Agents that increased cAMP caused a decrease in G6PD activity. Inhibition of cAMP-dependent protein kinase A ameliorated the high glucose-induced inhibition of G6PD, Finally, high glucose stimulated phosphorylation of G6PD. These results suggest that, in BAEC, high glucose stimulated increased cAMP, which led to increased protein kinase A activity, phosphorylation of G6PD, and inhibition of G6PD activity. We conclude that these changes in G6PD activity play an important role in high glucose-induced cell damage/death. C1 Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Div Renal, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. So Connecticut State Univ, Dept Chem, New Haven, CT 06515 USA. RP Stanton, RC (reprint author), Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Div Renal, 1 Joslin Pl, Boston, MA 02215 USA. NR 32 TC 122 Z9 130 U1 0 U2 5 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 DEC 22 PY 2000 VL 275 IS 51 BP 40042 EP 40047 DI 10.1074/jbc.M007505200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 386BD UT WOS:000166039500035 PM 11007790 ER PT J AU Bjorbaek, C Lavery, HJ Bates, SH Olson, RK Davis, SM Flier, JS Myers, MG AF Bjorbaek, C Lavery, HJ Bates, SH Olson, RK Davis, SM Flier, JS Myers, MG TI SOCS3 mediates feedback inhibition of the leptin receptor via Tyr(985) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID JANUS TYROSINE KINASE; SIGNAL-TRANSDUCTION; OB-R; CYTOKINE RECEPTORS; SH2 DOMAIN; ACTIVATION LOOP; BODY-WEIGHT; BOX MOTIF; PROTEINS; RESISTANCE AB During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr985 does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) Of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr985, suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr985 Of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3. C1 Joslin Diabet Ctr, Div Res, Sect Obes, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. RP Myers, MG (reprint author), Joslin Diabet Ctr, Div Res, Sect Obes, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DKR0156731, DKR3728082] NR 65 TC 319 Z9 332 U1 1 U2 5 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 DEC 22 PY 2000 VL 275 IS 51 BP 40649 EP 40657 DI 10.1074/jbc.M007577200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 386BD UT WOS:000166039500114 PM 11018044 ER PT J AU Nakagawa, T Sheng, M AF Nakagawa, T Sheng, M TI Neurobiology - A stargazer foretells the way to the synapse SO SCIENCE LA English DT Editorial Material ID MUTANT MOUSE STARGAZER; IMPAIRMENT 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. RP Nakagawa, T (reprint author), Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. NR 9 TC 6 Z9 6 U1 0 U2 0 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 DEC 22 PY 2000 VL 290 IS 5500 BP 2270 EP + PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GQ UT WOS:000165995800029 PM 11188726 ER PT J AU Bertram, L Blacker, D Mullin, K Keeney, D Jones, J Basu, S Yhu, S McInnis, MG Go, RCP Vekrellis, K Selkoe, DJ Saunders, AJ Tanzi, RE AF Bertram, L Blacker, D Mullin, K Keeney, D Jones, J Basu, S Yhu, S McInnis, MG Go, RCP Vekrellis, K Selkoe, DJ Saunders, AJ Tanzi, RE TI Evidence for genetic linkage of Alzheimer's disease to chromosome 10q SO SCIENCE LA English DT Article ID ONSET AB Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades A beta, the principal component of beta -amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Genet & Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Gerontol Res Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Johns Hopkins Univ, Inst Med, Dept Psychiat, Baltimore, MD 21287 USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Tanzi, RE (reprint author), Massachusetts Gen Hosp E, Genet & Aging Unit, 149 13th St, Charlestown, MA 02129 USA. RI McInnis, Melvin/F-6963-2012; Bertram, Lars/K-3889-2015 OI McInnis, Melvin/0000-0002-0375-6247; Bertram, Lars/0000-0002-0108-124X NR 13 TC 385 Z9 397 U1 2 U2 12 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 DEC 22 PY 2000 VL 290 IS 5500 BP 2302 EP + DI 10.1126/science.290.5500.2302 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GQ UT WOS:000165995800042 PM 11125142 ER PT J AU Platz, EA Rimm, EB Willett, WC Kantoff, PW Giovannucci, E AF Platz, EA Rimm, EB Willett, WC Kantoff, PW Giovannucci, E TI Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANDROGEN RECEPTOR GENE; VITAMIN-D METABOLITES; I-125 LABELED TRACER; UNITED-STATES; 1,25-DIHYDROXYVITAMIN D-3; SUBSEQUENT DEVELOPMENT; PHYSICAL-ACTIVITY; SERUM ANDROGENS; CAG REPEAT; RISK AB Background: Racial variation in prostate canter incidence in the United States is pronounced, with African-American men having the highest rates. Whether differences in the distribution of known or suspected risk factors among racial groups explain this variation is unknown. Methods: We evaluated prospectively the relation between prostate cancer and race among 45410 U.S. male health professionals aged 40-75 years in 1986. We used multivariable, pooled logistic regression to adjust the rate ratio (RR) for potential dietary and lifestyle risk factors. We also measured circulating levels of steroid hormones, sex hormone-binding globulin, and vitamin D metabolites and length of the androgen receptor gene CAG repeat in a sample of African-American (n = 43), Asian (n = 52), and white (n = 55) participants and assessed variation by race in these possible prostate epithelial cell growth mediators by use of analysis of variance. Statistical tests were two-sided. Results: The age-adjusted RR for prostate cancer was 1.73 (95% confidence interval [CI] = 1.23-2.45) for African-American men compared with white men. After multivariate adjustment, the RR increased to 1.81 (95% CI = 1.27-2.58). The rate of prostate cancer did not differ between Asians and whites. Steroid hormone and 1,25-dihydroxyvitamin D levels did not vary appreciably by race. However, the mean number of androgen receptor gene CAG repeats was lower among African-Americans (mean +/- standard deviation = 20.1 +/- 3.5) than among whites (22.1 +/- 3.1; P = .007) and Asians (22.1 +/- 3.9; P = .009). Conclusions: Our results confirm the elevated incidence of prostate cancer among African Americans and show that it is not explained by differences in the distribution of possible dietary and lifestyle risk factors in this cohort. Racial variation in length of the androgen receptor gene CAG repeat may explain a small part of the excess risk of prostate cancer among African-American men in this cohort. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Channing Lab, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol,Dept Adult Oncol, Boston, MA 02115 USA. RP Platz, EA (reprint author), Johns Hopkins Sch Hyg & Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NCI NIH HHS [CA55075, CA72036]; NHLBI NIH HHS [HL35464] NR 63 TC 178 Z9 182 U1 2 U2 4 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 20 PY 2000 VL 92 IS 24 BP 2009 EP 2017 DI 10.1093/jnci/92.24.2009 PG 9 WC Oncology SC Oncology GA 384HM UT WOS:000165936800012 PM 11121463 ER PT J AU Kleinerman, RA Tarone, RE Abramson, DH Seddon, JM Li, FP Tucker, MA AF Kleinerman, RA Tarone, RE Abramson, DH Seddon, JM Li, FP Tucker, MA TI Hereditary retinoblastoma and risk of lung cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID 2ND NONOCULAR TUMORS; BILATERAL RETINOBLASTOMA; RELATIVES; SURVIVORS; MORTALITY; EXPRESSION; CARCINOMA; NEOPLASMS; EXCESS; DEATHS C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. New York Presbyterian Hosp, Cornell Med Ctr, New York, NY USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Dana Farber Canc Inst, Div Canc Epidemiol & Control, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Kleinerman, RA (reprint author), NIH, Execut Plaza S,Rm 7044, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 FU NCI NIH HHS [N01CP81121] NR 30 TC 39 Z9 39 U1 0 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 20 PY 2000 VL 92 IS 24 BP 2037 EP 2039 DI 10.1093/jnci/92.24.2037 PG 3 WC Oncology SC Oncology GA 384HM UT WOS:000165936800016 PM 11121467 ER PT J AU Luo, Y Leszyk, J Li, B Gergely, J Tao, T AF Luo, Y Leszyk, J Li, B Gergely, J Tao, T TI Proximity relationships between residue 6 of troponin I and residues in troponin C: Further evidence for extended conformation of troponin c in the troponin complex SO BIOCHEMISTRY LA English DT Article ID SKELETAL-MUSCLE; REGULATORY DOMAIN; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; PEPTIDE COMPLEX; ENERGY-TRANSFER; THIN-FILAMENTS; REGION; FLUORESCENCE; CONTRACTION AB Skeletal muscle troponin C (TnC) adopts an extended conformation when crystallized alone and a compact one when crystallized with an N-terminal troponin I (TnI) peptide, TnI(1-47) [Vassylyev et al. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 4847-4852]. The N-terminal region of TnI (residues 1-40) was suggested to play a functional role of facilitating the movement of TnI's inhibitory region between TnC and actin [Tripet et al. (1997) J. Mel. Biol. 271, 728-750]. To test this hypothesis and to investigate the conformation of TnC in the intact troponin complex and in solution, we attached fluorescence and photo-cross-linking probes to a mutant TnI with a single cysteine at residue 6. Distances from this residue to residues of TnC were measured by the fluorescence resonance energy transfer technique, and the sites of photo-cross-linking in TnC were determined by microsequencing and mass spectrometry following enzymatic digestions. Our results show that in the troponin complex neither the distance between TnI residue 6 and TnC residue 89 nor the photo-cross-linking site in TnC, Ser133, changes with Ca2+, in support of the notion that this region plays mainly a structural rather than a regulatory role. The distances to residues 12 and 41 in TnC's N-domain are both considerably longer than those predicted by the crystal structure of TnC.TnI(1-47), supporting an extended rather than a compact conformation of TnC. In the binary TnC TnI complex and the presence of Ca2+, Met43 in TnC's N-domain was identified as the photo-cross-linking site, and multiple distances between TnI residue 6 and TnC residue 41 were detected. This was taken to indicate increased flexibility in TnC's central helix and that TnC dynamically changes between a compact and an extended conformation when troponin T (TnT) is absent. Our results further emphasize the difference between the binary TnC TnI and the ternary troponin complexes and the importance of using intact proteins in the study of structure-function relationships of troponin. C1 Boston Biomed Res Inst, Muscle Res Grp, Watertown, MA 02472 USA. Massachusetts Gen Hosp, Serv Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. Univ Massachusetts, Sch Med, Dept Biochem, Shrewsbury, MA 01545 USA. RP Tao, T (reprint author), Boston Biomed Res Inst, Muscle Res Grp, 64 Grove St, Watertown, MA 02472 USA. FU NIAMS NIH HHS [AR21673] NR 43 TC 11 Z9 12 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 19 PY 2000 VL 39 IS 50 BP 15306 EP 15315 DI 10.1021/bi001259x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 383GV UT WOS:000165875500003 PM 11112516 ER PT J AU Chang, YS di Tomaso, E McDonald, DM Jones, R Jain, RK Munn, LL AF Chang, YS di Tomaso, E McDonald, DM Jones, R Jain, RK Munn, LL TI Mosaic blood vessels in tumors: Frequency of cancer cells in contact with flowing blood SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; VASCULOGENIC MIMICRY; KILLER-CELLS; SCID MICE; IN-VIVO; ANGIOGENESIS; ADENOCARCINOMA AB The presence of "mosaic" vessels in which both endothelial cells and tumor cells form the luminal surface has profound implications for metastasis, drug delivery, and antivascular therapy. Yet little is known of the frequency, and thus importance, of mosaic vessels in tumors. Using CD31 and CD105 to identify endothelial cells and endogenous green fluorescent protein labeling of tumor cells, we show that approximate to 15% of pelf used vessels of a colon carcinoma xenografted at two different sites in mice were mosaic vessels having focal regions where no CD31/CD105 immunoreactivity was detected and tumor cells appeared to contact the Vessel lumen. These regions occupied approximate to 25% of the perimeter of the mosaic vessels, or approximate to4% of the total vascular surface area in these colon carcinomas. In addition, we found similar numbers of mosaic vessels in human colon carcinoma biopsies. Our results are consistent with the observation that approximate to 10(6) cells are shed daily per g of tumor. More importantly, our data offer a possible explanation for the antivascular effects of cytotoxic agents and suggest potential strategies for targeting the tumor vasculature. C1 Harvard Univ, Sch Med, Dept Radiat Oncol, Steele Lab Tumor Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif San Francisco, Dept Anat, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Munn, LL (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Steele Lab Tumor Biol, 100 Blossom St,Cox 7, Boston, MA 02114 USA. RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU NCI NIH HHS [R35 CA 56591, P01 CA080124, P01 CA80124, T32 CA-73479, T32 CA073479]; NHLBI NIH HHS [P01 HL024136] NR 35 TC 369 Z9 398 U1 2 U2 23 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 DEC 19 PY 2000 VL 97 IS 26 BP 14608 EP 14613 DI 10.1073/pnas.97.26.14608 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385FV UT WOS:000165993700111 PM 11121063 ER PT J AU Moore, CI Stern, CE Dunbar, C Kostyk, SK Gehi, A Corkin, S AF Moore, CI Stern, CE Dunbar, C Kostyk, SK Gehi, A Corkin, S TI Referred phantom sensations and cortical reorganization after spinal cord injury in humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN SOMATOSENSORY CORTEX; BRAIN-STEM CONTRIBUTIONS; MACAQUE MONKEYS; CUNEATE NUCLEUS; ADULT MONKEYS; SOMATOTOPIC ORGANIZATION; SENSORY REORGANIZATION; PERIPHERAL INJURY; SQUIRREL-MONKEYS; LATERAL SULCUS AB To test the hypothesis that cortical remapping supports phantom sensations, we examined referred phantom sensations and cortical activation in humans after spinal-cord injury (SCI) at the thoracic level (T3-T12). Of 12 SCI subjects, 9 reported phantom sensations, and 2 reported referred phantom sensations. in both of these subjects, referred phantom sensations were evoked by contact in reference zones (RZ) that were not adjacent in the periphery and were not predicted to be adjacent in the postcentral gyrus (PoCG), suggesting that representations separated by centimeters of cortical space were simultaneously engaged. This finding was supported by functional MRI (fMRI). In a subject with a T6-level complete SCI, contact in RZ on the left or right forearm projected referred phantom sensations to the ipsilateral chest. During fMRI, contact in either forearm RZ evoked activity in the central PoCG (the position of the forearm representation) and the medial PoCG (the position of the chest representation) with greater than or equal to1.6 cm of nonresponsive cortex intervening. In contrast, stimulation in non-RZ forearm and palm regions in this subject and in lesion-matched SCI subjects evoked central but not medial PoCG activation. Our findings support a relation between PoCG activation and the percept of referred phantom sensations. These results, however, present an alternative to somatotopic cortical reorganization, namely, cortical plasticity expressed in coactivation of nonadjacent representations. The observed pattern suggests that somatotopic: subcortical remapping, projected to the cortex, can support perceptual and cortical reorganization after deafferentation in humans. C1 Massachusetts Gen Hosp, Nucl Magnet Resonance Imaging Ctr, Charlestown, MA 02129 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. MIT, Clin Res Ctr, Cambridge, MA 02139 USA. Boston Univ, Dept Psychol, Boston, MA 02215 USA. Ohio State Univ, Sch Med, Dept Neurol & Neurosci, Columbus, OH 43210 USA. RP Moore, CI (reprint author), Massachusetts Gen Hosp, Nucl Magnet Resonance Imaging Ctr, Charlestown, MA 02129 USA. RI Moore, Christopher/C-5588-2009 FU NCRR NIH HHS [M01 RR000088, RR00088] NR 61 TC 85 Z9 87 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 DEC 19 PY 2000 VL 97 IS 26 BP 14703 EP 14708 DI 10.1073/pnas.250348997 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385FV UT WOS:000165993700127 PM 11114177 ER PT J AU Gartner, F Alt, FW Monroe, RJ Seidl, KJ AF Gartner, F Alt, FW Monroe, RJ Seidl, KJ TI Antigen-independent appearance of recombination activating gene (RAG)-positive bone marrow B cells in the spleens of immunized mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE alum; germinal center; receptor editing; immunoglobulin re-rearrangement ID HEAT-STABLE ANTIGEN(HI); GERMINAL-CENTERS; LYMPHOCYTES-B; V(D)J RECOMBINATION; SOMATIC MUTATION; IN-VITRO; T-CELL; RECEPTOR; EXPRESSION; MOUSE AB Splenic B lineage cells expressing recombination activation genes (RAG(+)) in mice immunized with 4-hydroxy-3-nitrophenyl-acetyl coupled to chicken gamma -globulin (NP-CGG) and the adjuvant aluminum-hydroxide (alum) have been proposed to be mature B cells that reexpress RAG after an antigen encounter in the germinal center (GC), a notion supported by findings of RAG expression in peripheral B lymphocyte populations activated in vitro. However, recent studies indicate that these cells might be immature B cells that have not yet extinguished RAG expression. Here, we employ RAG2-green fluorescent protein (GFP) fusion gene knock-in mice to show that RAG(+) B lineage cells do appear in the spleen after the administration of alum alone, and that their appearance is independent of T cell interactions via the CD40 path-way. Moreover, splenic RAG(+) B lineage cells were detectable in immunized RAG2-deficient mice adoptively transferred with bone marrow (BM) cells, but not with spleen cells from RAG(+) mice. Although splenic RAG(+) B cells express surface markers associated with GC B cells, we also find the same basic markers on progenitor/precursor BM B cells. Finally, we did not detect RAG gene expression after the in vitro stimulation of splenic RAG(-) mature B cells with mitogens (lipopolysaccharide and anti-CD40) and cytokines (interleukin [IL]-4 and IL-7). Together, our studies indicate that RAG(+) B lineage cells from BM accumulate in the spleen after immunization, and that this accumulation is not the result of an antigen-specific response. C1 Childrens Hosp, Howard Hughes Med Inst, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Ctr Blood Res, Enders 861,300 Longwood Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [AI20047, R37 AI020047, R01 AI020047] NR 51 TC 46 Z9 48 U1 0 U2 3 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 DEC 18 PY 2000 VL 192 IS 12 BP 1745 EP 1754 DI 10.1084/jem.192.12.1745 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 385PP UT WOS:000166013100007 PM 11120771 ER PT J AU Goulder, PJR Tang, YH Brander, C Betts, MR Altfeld, M Annamalai, K Trocha, A He, SQ Rosenberg, ES Ogg, G O'Callaghan, CA Kalams, SA McKinney, RE Mayer, K Koup, RA Pelton, SI Burchett, SK McIntosh, K Walker, BD AF Goulder, PJR Tang, YH Brander, C Betts, MR Altfeld, M Annamalai, K Trocha, A He, SQ Rosenberg, ES Ogg, G O'Callaghan, CA Kalams, SA McKinney, RE Mayer, K Koup, RA Pelton, SI Burchett, SK McIntosh, K Walker, BD TI Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE peptide-major histocompatibility complex tetrameric complexes; intracellular cytokine staining; limiting dilution assays; enzyme-linked immunospot; CD8(+) T cells ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMARY IMMUNE-RESPONSE; DISEASE PROGRESSION; EFFECTOR FUNCTION; TYPE-1 INFECTION; PLASMA VIREMIA; CELL RESPONSES; VIRAL LOAD; IN-VIVO; ESCAPE AB The highly sensitive quantitation of virus-specific CD8(+) T cells using major histocompatibility complex-peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-gamma, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from < 50 to > 100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immuno-spot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-gamma was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-gamma cytokine staining. Furthermore, modifications to the LDA, using a low input cell. number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Div Infect Dis, Dallas, TX 75390 USA. Univ Natal, Dept Pediat, ZA-4015 Durban, South Africa. John Radcliffe Hosp, MRC, Human Immunol Unit, Oxford OX3 9DU, England. Duke Univ, Med Ctr, Sect Pediat Infect Dis, Durham, NC 27710 USA. Fenway Community Hlth Ctr, Boston, MA 02115 USA. Boston Med Ctr, Sect Pediat Infect Dis, Boston, MA 02118 USA. RP Goulder, PJR (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, 13th St,Bldg 149,Rm 5218, Charlestown, MA 02129 USA. FU NIAID NIH HHS [R01 AI046995, R01 AI028568, R01 AI039966, R01 AI035522, AI39966, AI35522, R37 AI028568, R01 AI047603, R01 AI030914, AI46995, R37 AI035522] NR 53 TC 115 Z9 117 U1 0 U2 4 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 DEC 18 PY 2000 VL 192 IS 12 BP 1819 EP 1831 DI 10.1084/jem.192.12.1819 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 385PP UT WOS:000166013100014 PM 11120778 ER PT J AU Kilmer, ME Miller, EL Boas, D Brooks, D AF Kilmer, ME Miller, EL Boas, D Brooks, D TI A shape-based reconstruction technique for DPDW data SO OPTICS EXPRESS LA English DT Article AB We give an approach or directly localizing and characterizing the properties of a compactly supported absorption coefficient perturbation as well as coarse scale structure of the background medium from a sparsely sampled, di use photon density wavefield. Our technique handles the problems of localization and characterization simultaneously by working directly with the data, unlike traditional techniques that require two stages. We model the unknowns as a superposition of a slowly varying perturbation on a background of unknown structure. Our model assumes that the anomaly is delineated rom the background by a smooth perimeter which is modeled as a spline curve comprised of unknown control points. The algorithm proceeds by making small perturbations to the curve which are locally optimal. The result is a global, greedy-type optimization approach designed to enforce consistency with the data while requiring the solution to adhere to prior information we have concerning the likely structure of the anomaly. At each step, the algorithm adaptively determines the optimal weighting coefficients describing the characteristics of both the anomaly and the background. The success of our approach is illustrated in two simulation examples provided for a di use photon density wave problem arising in a bio-imaging application. (C) 2001 Optical Society of America. C1 Tufts Univ, Dept Math, Medford, MA 02155 USA. Northeastern Univ, ECE Dept, Boston, MA 02115 USA. Northeastern Univ, Ctr Subsurface Sensing & Imaging Syst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Kilmer, ME (reprint author), Tufts Univ, Dept Math, Medford, MA 02155 USA. EM mkilme01@tufts.edu; elmiller@ece.neu.edu; dboas@nmr.mgh.harvard.edu; brooks@ece.neu.edu RI Miller, Eric/B-2546-2008 OI Miller, Eric/0000-0002-3156-6002 NR 10 TC 16 Z9 16 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 18 PY 2000 VL 7 IS 13 BP 481 EP 491 PG 11 WC Optics SC Optics GA 383WY UT WOS:000165908700004 PM 19407900 ER PT J AU Lehmann, LS Weeks, JC Klar, N Biener, L Garber, JE AF Lehmann, LS Weeks, JC Klar, N Biener, L Garber, JE TI Disclosure of familial genetic information: Perceptions of the duty to inform SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID OVARIAN-CANCER SUSCEPTIBILITY; BREAST-CANCER; BRCA1; WOMEN; ATTITUDES; CONFIDENTIALITY; MUTATIONS; 185DELAG; OPINIONS; HISTORY AB BACKGROUND: The familial implications of genetic information can lead to a conflict between a physician's duties to maintain patient confidentiality and to inform at-risk relatives about susceptibility to genetic diseases. As genes are discovered that can identify patients at risk of adverse outcomes, this conflict has become the subject of discussion and debate. METHODS: We performed a one-time telephone survey of a population-based sample of 200 Jewish women to assess knowledge and attitudes about genetic testing. Attitudes toward sharing genetic test results with family members were evaluated using three hypothetical scenarios that described an easily preventable disease, a disease (breast cancer) in which the only option for prevention was prophylactic mastectomies, and a nonpreventable disease. RESULTS: Nearly all respondents believed that a patient should inform at-risk family members when the disease was preventable (100% and 97% in the relevant scenarios), compared with only 85% who felt a duty to inform at-risk family members about a nonpreventable disease (P <0.001). The proportions of respondents who believed that physicians should seek out and inform at-risk family members against a patient's wishes was much lower: only 18% of respondents to the easily preventable disease scenario, 22% of respondents to the breast cancer scenario, and 16% of respondents to the nonpreventable disease scenario. CONCLUSIONS: Most women surveyed believed that genetic information should be shared within families, unless it violated a patient's wishes. These sorts of opinions should be considered in the debate over the confidentiality of genetic information. Am J Med. 2000;109:705-711. (C) 2000 by Excerpta Medica, Inc. C1 Brigham & Womens Hosp, Dept Med, Div Gen Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Adult Oncol, Div Med Eth, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA USA. Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. RP Lehmann, LS (reprint author), Brigham & Womens Hosp, Dept Med, Div Gen Med, PBB-A361,75 Francis St, Boston, MA 02115 USA. OI Biener, Lois/0000-0002-4130-8138 NR 37 TC 48 Z9 48 U1 0 U2 4 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 DEC 15 PY 2000 VL 109 IS 9 BP 705 EP 711 DI 10.1016/S0002-9343(00)00594-5 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 387LY UT WOS:000166125100002 PM 11137485 ER PT J AU Lin, SH Faller, LD AF Lin, SH Faller, LD TI Preparation of Na,K-ATPase specifically modified on the anti-fluorescein antibody-inaccessible site by fluorescein 5 '-isothiocyanate SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Na,K-ATPase; FITC; conformational change; energy transfer ID SARCOPLASMIC-RETICULUM CAATPASE; AMINO-ACID-SEQUENCE; ATP BINDING-SITE; ACTIVE-SITE; CONFORMATIONAL-CHANGES; ADENOSINE-TRIPHOSPHATASE; ENERGY-TRANSFER; SODIUM-PUMP; NA+,K+-ATPASE; ISOTHIOCYANATE AB Specific labeling is required for energy transfer measurements and to avoid artifacts in the use of fluorophores as reporter groups. Therefore, a method for specific modification by one of the most popular reagents for P-type ATPases (fluorescein 5'-isothiocyanate) has been developed. Sulfhydryl reagents protected against modification of cysteine residues, and treatment with dithiothreitol eliminated a slow doubling of the fluorescence of conventionally modified Na,K-ATPase upon dilution that is attributed to disappearance of self-energy transfer. Removal of nonspecifically bound fluorescein was also confirmed by titration of the modified Na,K-ATPase with anti-fluorescein antibody and by time resolution of the fluorescence change when the modified enzyme was mixed with Na+ in a stopped-how instrument. The only fluorescence change when specifically modified Na,K-ATPase was mixed with Na+ was the signal from fluorescein at the antibody-inaccessible, substrate-protectable site that reports the conformational change in unphosphorylated enzyme. The magnitude of the fluorescence change reporting the conformational change increased from between 8 and 12% to between 25 and 30% without affecting the kinetic constants estimated from titrations with Na+ and K+. The method should be generally applicable to the preparation of specifically labeled P-type pumps for use in kinetic and equilibrium titrations or energy transfer measurements. (C) 2000 Academic Press. C1 Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. Univ Calif Los Angeles, Sch Med, Dept Med, CURE,Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Lin, SH (reprint author), Univ Texas, Med Branch, Dept Human Biol Chem & Genet, 5-138 Med Res Bldg,Route 1055, Galveston, TX 77555 USA. NR 42 TC 7 Z9 9 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 15 PY 2000 VL 287 IS 2 BP 303 EP 312 DI 10.1006/abio.2000.4828 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 387YY UT WOS:000166151700016 PM 11112278 ER PT J AU Davies, SM Kollman, C Anasetti, C Antin, JH Gajewski, J Casper, JT Nademanee, A Noreen, H King, R Confer, D Kernan, NA AF Davies, SM Kollman, C Anasetti, C Antin, JH Gajewski, J Casper, JT Nademanee, A Noreen, H King, R Confer, D Kernan, NA TI Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program SO BLOOD LA English DT Article ID HLA-IDENTICAL SIBLINGS; LEUKEMIA AB We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 x 10(8)/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non-African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell-depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 x 10(9)/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P < .0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation. (C) 2000 by The American Society of Hematology. C1 Univ Minnesota, Minneapolis, MN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Natl Marrow Donor Program, Minneapolis, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Midwest Childrens Canc Ctr, Milwaukee, WI USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. RP Davies, SM (reprint author), MMC 422,420 Delaware St SE, Minneapolis, MN 55455 USA. NR 17 TC 123 Z9 126 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 DEC 15 PY 2000 VL 96 IS 13 BP 4096 EP 4102 PG 7 WC Hematology SC Hematology GA 380PD UT WOS:000165709500012 PM 11110679 ER PT J AU Aguiar, RCT Yakushijin, Y Kharbanda, S Salgia, R Fletcher, JA Shipp, MA AF Aguiar, RCT Yakushijin, Y Kharbanda, S Salgia, R Fletcher, JA Shipp, MA TI BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; CHROMOSOMAL-ABNORMALITIES; HISTONE; LOCALIZATION; POLYMERASE; MACROH2A AB Clinical risk factor models such as the International prognostic Index are used to identify diffuse large B-cell lymphoma (DLB-CL) patients with different risks of death from their diseases. To elucidate the molecular bases for these observed clinical differences in outcome, differential display was used to identify a novel gene, termed BAL (B-aggressive lymphoma), which is expressed at significantly higher levels in fatal high-risk DLB-CLs than in cured low risk tumors. The major BAL complementary DNA encodes a previously uncharacterized 88-kd nuclear protein with a duplicated N-terminal domain homologous to the non- histone portion of histone-macroH2A and a C-terminal alpha-helical region with 2 short coiled-coil domains. Of note, the BAL N-terminus and secondary structure resemble those of a recently identified human protein, KIAA1268. In addition, both BAL and KIAA1268 map to chromosome 3q21, further suggesting that these genes belong to a newly identified family. BAL is expressed at increased levels in DLB-CL cell lines with an activated peripheral B cell, rather than a germinal center cell, phenotype. This observation and the characteristic dissemination of high risk DLB-CLs prompted studies regarding the role of BAL in B-cell migration. In classical transwell assays, stable BAL-overexpressing B-cell lymphoma transfectants had significantly higher rates of migration than vector-only transfectants, indicating that the risk-related BAL gene promotes malignant B-cell migration. (Blood. 2000;96:4328-4334) (C) 2000 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Shipp, MA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA66996] NR 33 TC 82 Z9 83 U1 0 U2 3 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 DEC 15 PY 2000 VL 96 IS 13 BP 4328 EP 4334 PG 7 WC Hematology SC Hematology GA 380PD UT WOS:000165709500042 PM 11110709 ER PT J AU Carew, JA Pollak, ES Lapaciuk, S Bauer, KA AF Carew, JA Pollak, ES Lapaciuk, S Bauer, KA TI Anew mutation in the HNF4 binding region of the factor VII promoter in a patient with severe factor VII deficiency SO BLOOD LA English DT Article ID COAGULATION-FACTOR-VII; HEPATOCYTE NUCLEAR FACTOR-4; GENE; TRANSCRIPTION; SITE; DNA AB Investigation of the molecular basis of a severe factor VII (fVII) deficiency revealed compound heterozygosity in the fVII gene. On the paternal allele the patient had 3 structural gene abnormalities frequently associated with fVII deficiency. A new mutation, a C to T transition at position -55 relative to the translational start site, was found on the maternal allele. The study demonstrates that this mutation partially impeded binding of the transcriptional activator, hepatic nuclear factor 4, to the fVII promoter while greatly reducing reporter gene expression in hepatic cells. (Blood.2000;96:4370-4372) (C) 2000 by The American Society of Hematology. C1 VA Boston Healthcare Syst, Hematol Oncol Sect, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Inst Hematol & Blood Transfus, Lab Blood Coagulat, Warsaw, Poland. RP Bauer, KA (reprint author), VA Boston Healthcare Syst, Hematol Oncol Sect, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 17 TC 18 Z9 20 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 DEC 15 PY 2000 VL 96 IS 13 BP 4370 EP 4372 PG 3 WC Hematology SC Hematology GA 380PD UT WOS:000165709500050 PM 11110717 ER PT J AU Seth, P Lunetta, KL Bell, DW Gray, H Nasser, SM Rhei, E Kaelin, CM Iglehart, DJ Marks, JR Garber, JE Haber, DA Polyak, K AF Seth, P Lunetta, KL Bell, DW Gray, H Nasser, SM Rhei, E Kaelin, CM Iglehart, DJ Marks, JR Garber, JE Haber, DA Polyak, K TI Phenol sulfotransferases: Hormonal regulation, polymorphism, and age of onset of breast cancer SO CANCER RESEARCH LA English DT Article ID SURGICAL-ADJUVANT-BREAST; GENETIC POLYMORPHISMS; SULT1A1; BIOACTIVATION; EXPRESSION; SULFATION; TAMOXIFEN AB In recent years, significant effort has been made to identify genes that influence breast cancer risk. Because the high-penetrance breast cancer susceptibility genes BRCA1 acid 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast cancers will require the identification and analysis of several lower penetrance genes. The estrogen-signaling pathway plays a crucial role in the pathophysiology of breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and il-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen, On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited variability in SULT1A enzymatic activity, we hypothesized that polymorphism in sulfotransferase genes might influence the risk of breast cancer, Using an RFLP that distinguishes an arginine to histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast cancer risk. An analysis of 444 breast cancer patients and 227 controls revealed no effect of SULT1A1 genotype on the risk of breast cancer (P = 0.69); however, it did appear to influence tbe age of onset among early-onset affected patients (P = 0.04), Moreover, individuals with the higher activity SULT1A1*1 allele were more likely to have other tumors in addition to breast cancer (P = 0.004; odds ratio, 3.02; 95% confidence interval, 1.32, 8.09). The large number of environmental mutagens and carcinogens activated by sulfotransferases and the high frequency of the SULT1A1*1 allele in human populations warrants additional studies to address the role of SULT genes in human cancer. 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, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc Risk Anal, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Surg, 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 19 TC 74 Z9 74 U1 0 U2 0 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 DEC 15 PY 2000 VL 60 IS 24 BP 6859 EP 6863 PG 5 WC Oncology SC Oncology GA 388UM UT WOS:000166201500019 PM 11156380 ER PT J AU Brooks, LA Tidy, JA Gusterson, B Hiller, L O'Nions, J Gasco, M Marin, MC Farrell, PJ Kaelin, WG Crook, T AF Brooks, LA Tidy, JA Gusterson, B Hiller, L O'Nions, J Gasco, M Marin, MC Farrell, PJ Kaelin, WG Crook, T TI Preferential retention of codon 72 arginine p53 in squamous cell carcinomas of the vulva occurs in cancers positive and negative for human papillomavirus SO CANCER RESEARCH LA English DT Article ID CERVICAL-CANCER; P73 GENE; POLYMORPHISM; MUTATION; NEUROBLASTOMA; EXPRESSION; TUMORS; RISK; HPV AB We have sought to determine the basis for preferential loss of the codon 72 proline (72P) rather than the arginine (72R) allele in squamous cell carcinoma of the vulva with loss of heterozygosity (LOH) in p53, The proportion of eases containing human papillomavirus (HPV) 16 was not statistically different among. individuals with either 72RR or 72RP in the germ line (P > 0.99), but p53 LOH was significantly more common in individuals heterozygous 72RP than in 72RR individuals (P = 0.04). LOH more commonly involved the 72P allele in both HPV-positive and HPV-negative cancers. Our results imply that preferential loss of the 72P allele in vulval squamous fell carcinoma occurs by HPV-dependent and -independent mechanisms. C1 St Marys Hosp, Imperial Coll Sch Med, Ludwig Inst Canc Res, London W2 1PG, England. Univ Sheffield, No Gen Hosp, Dept Gynaecol Oncol, Sheffield S5 7AU, S Yorkshire, England. Univ Glasgow, Western Infirm, Dept Pathol, Glasgow G11 6NT, Lanark, Scotland. Univ Birmingham, Birmingham Clin Trials Unit, Birmingham B15 2TT, W Midlands, England. Azienda Osped S Croce & Carle, UO Oncol Med, I-12100 Cineo, Italy. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Crook, T (reprint author), St Marys Hosp, Imperial Coll Sch Med, Ludwig Inst Canc Res, Norfolk Pl, London W2 1PG, England. RI gusterson, barry/D-3752-2009; Marin Vieira, Maria del Carmen/B-8108-2015 OI Marin Vieira, Maria del Carmen/0000-0002-7149-287X NR 20 TC 62 Z9 63 U1 0 U2 3 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 DEC 15 PY 2000 VL 60 IS 24 BP 6875 EP 6877 PG 3 WC Oncology SC Oncology GA 388UM UT WOS:000166201500022 PM 11156383 ER PT J AU Salloum, RM Jaskowiak, NT Mauceri, HJ Seetharam, S Beckett, MA Koons, AM Hari, DM Gupta, VK Reimer, C Kalluri, R Posner, MC Hellman, S Kufe, DW Weichselbaum, RR AF Salloum, RM Jaskowiak, NT Mauceri, HJ Seetharam, S Beckett, MA Koons, AM Hari, DM Gupta, VK Reimer, C Kalluri, R Posner, MC Hellman, S Kufe, DW Weichselbaum, RR TI NM-3, an isocoumarin, increases the antitumor effects of radiotherapy without toxicity SO CANCER RESEARCH LA English DT Article ID CYTOTOXIC CANCER THERAPIES; TUMOR-GROWTH; IONIZING-RADIATION; CERVICAL-CANCER; IN-VIVO; ANGIOGENESIS; CARCINOMA; CHEMOTHERAPY; ANGIOSTATIN; INHIBITION AB We examined the effects of a new antiangiogenic isocoumarin, NM-3, as a radiation modifier in vitro and in vivo. The present studies demonstrate that NM-3 is cytotoxic to human umbilical vein endothelial cells (HUVECs) but not to Lewis lung carcinoma (LLC) cells nor Seg-1, esophageal adenocarcinoma cells, in clonogenic survival assays. When HUVEC cultures are treated with NM-3 combined with ionizing radiation (IR), additive cytotoxicity is observed. In addition, the combination of NM-3 and IR inhibits HUVEC migration to a greater extent than either treatment alone The effects of treatment with NM-3 and LR were also evaluated in tumor model systems. C57BL/6 female mice bearing LLC tumors were given injections for 4 consecutive days with NM-3 (25 mg/kg/day) and treated,vith IR (20 Gy) for 2 consecutive days. Combined treatment with NM-3 and IR significantly reduced mean tumor volume compared with either treatment alone. An increase in local tumor control was also observed in LLC tumors in mice receiving NM-3/IR therapy. When athymic nude mice bearing Seg-1 tumor xenografts were treated with NM-3 (100 mg/kg/day for 4 days) and 20 Gy (four 5 Gy fractions), significant tumor regression was observed after combined treatment (NM-3 and IR) compared with IR alone. Importantly, no increase in systemic or local tissue toxicity was observed after combined treatment (NM-3 and IR) when compared with IR alone. The bioavailability and nontoxic profile of NM-3 suggests that the efficacy of this agent should be tested in clinical radiotherapy. C1 Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. Univ Chicago, Dept Surg, Chicago, IL 60637 USA. ILEX Oncol Inc, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. RI Kalluri, Raghu/E-2677-2015 OI Kalluri, Raghu/0000-0002-2190-547X FU NIDCR NIH HHS [DE/CA11921] NR 30 TC 35 Z9 36 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 DEC 15 PY 2000 VL 60 IS 24 BP 6958 EP 6963 PG 6 WC Oncology SC Oncology GA 388UM UT WOS:000166201500035 PM 11156396 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 Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis SO CANCER RESEARCH LA English DT Article ID ENDOMETRIAL CARCINOMA; NUDE-MICE; CELLS; EXPRESSION; PROLIFERATION; PROGESTERONE; MECHANISMS; ESTRADIOL; SURVIVAL; BINDING AB A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of certain female cancers. ER-alpha expression in the ER-negative breast cancer cell lines inhibits their proliferation and invasive, metastatic potential in vitro. We stably overexpressed the ER-alpha in the human endometrial cancer cell line Ishikawa and showed that, unlike estradiol, high levels of ER-alpha significantly inhibit the growth of tumors xenografted from the Ishikawa cells. Subsequent to ER-alpha overexpression, in vivo down-regulation of vascular endothelial growth factor was observed in tumor xenografts. In addition, these tumors showed an inhibition of vascularization and of the angiogenic agent, integrin alpha (v)beta (3). Involvement of a switch in the angiogenic pathways during tumorigenesis has been a recent focus of interest. Our results indicate that a high level of ER-alpha may be beneficial in the control of female cancers because of its inhibitory effect on such angiogenic pathways. C1 SUNY Buffalo, Buffalo, NY 14260 USA. Roswell Pk Canc Inst, Dept Biochem, Buffalo, NY 14263 USA. Vet Adm Med Ctr, Dept Med, Buffalo, NY 14215 USA. Vet Adm Med Ctr, Dept Endocrinol, Buffalo, NY 14215 USA. Dupont Merck Pharmaceut Co, Gen Pharmacol, Wilmington, DE 19880 USA. Kaleida Hlth, Div Endocrine, Buffalo, NY USA. RP Ali, SH (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 18 TC 50 Z9 54 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 DEC 15 PY 2000 VL 60 IS 24 BP 7094 EP 7098 PG 5 WC Oncology SC Oncology GA 388UM UT WOS:000166201500055 PM 11156416 ER PT J AU Liu, XH Elia, AEH Law, SF Golemis, EA Farley, J Wang, TW AF Liu, XH Elia, AEH Law, SF Golemis, EA Farley, J Wang, TW TI A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1 SO EMBO JOURNAL LA English DT Article DE HEF1; proteasome; signal transduction; Smad3; TGF-beta ID SUBSTRATE-RELATED PROTEIN; FOCAL ADHESION KINASE; TGF-BETA; TYROSINE PHOSPHORYLATION; DOCKING PROTEIN; RECEPTOR; GROWTH; LIGATION; INTEGRIN; ASSOCIATION AB Smad3 is a key signal transducer of transforming growth factor-beta (TGF-beta) and activin, and is known to be a DNA-binding transcriptional regulator. Here we report a novel property of Smad3 in regulating the proteasomal degradation of the human enhancer of filamentation 1 (HEF1), which is a member of the Cas family of cytoplasmic docking proteins. Our studies revealed that Smad3 interacts with HEF1 and triggers the proteasomal degradation of HEF1 in overexpression systems, In addition, TGF-beta stimulation induces rapid proteasomal degradation of endogenous HEF1 in different TGF-beta -responsive cell lines. Interestingly, the degradation of HEF1 protein in epithelial cells is followed closely by an increase in HEF1 mRNA, resulting in a time-dependent increase in HEF1 protein level in TGF-beta -treated cells. Furthermore, we observed that an elevated HEF1 protein level inhibits TGF-beta -induced Smad3-mediated gene responses. These data provide the first evidence for a novel cytoplasmic activity of Smad3 in regulating proteasomal degradation of HEF1 and also suggest a role for HEF1 in a negative feedback mechanism of the TGF-beta signaling pathway. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA. RP Wang, TW (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM53710] NR 23 TC 53 Z9 55 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 15 PY 2000 VL 19 IS 24 BP 6759 EP 6769 DI 10.1093/emboj/19.24.6759 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 386GP UT WOS:000166052800014 PM 11118211 ER PT J AU Lee, JY Bielawska, AE Obeid, LM AF Lee, JY Bielawska, AE Obeid, LM TI Regulation of cyclin-dependent kinase 2 activity by ceramide SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; RETINOBLASTOMA GENE-PRODUCT; CELL-CYCLE; PROTEIN-KINASE; SPHINGOMYELIN TURNOVER; SIGNAL-TRANSDUCTION; GROWTH-INHIBITION; FACTOR-ALPHA; PHOSPHORYLATION; PHOSPHATASE AB Cyclin-dependent kinases have been implicated in the inactivation of retinoblastoma (Rb) protein and cell cycle progression. Recent studies have demonstrated that the lipid molecule ceramide is able to induce Rb hypophosphorylation leading to growth arrest and cellular senescence. In this study, we examined the underlying mechanisms of Rb hypophosphorylation and cell cycle progression utilizing the antiproliferative molecule ceramide. C-6-Ceramide induced a G0/G1 arrest of the cell cycle in WI38 human diploid fibroblasts, Employing immunoprecipitation kinase assays, we found that ceramide specifically inhibited cyclin-dependent kinase CDK2, with a mild effect on CDC2 and significantly less effect on CDK4. The effect of ceramide was specific such that C-6-dihy-droceramide was not effective. Ceramide did not directly inhibit CDK2 in vitro but caused activation of p21, a major class of CDK-inhibitory proteins, and led to a greater association of p21 to CDK2. Using purified protein phosphatases, we showed that ceramide activated both protein phosphatase 1 and protein phosphatase 2A activities specific for CDK2 in vitro. Further, calyculin A and okadaic acid, both potent protein phosphatase inhibitors, together almost completely reversed the effects of ceramide on CDK2 inhibition. Taken together, these results demonstrate a dual mechanism by which ceramide inhibits the cell cycle. Ceramide causes an increase in p21 association with CDK2 and through activation of protein phosphatases selectively regulates CDK2. These events may lead to activation of Rb protein and subsequent cell cycle arrest. (C) 2000 Academic Press. C1 Ralph H Johnson Vet Adm, Charleston, SC 29425 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, POB 250779,Room 604 Strom Thurmond Bldg, 114 Doug, Charleston, SC 29425 USA. OI obeid, lina/0000-0002-0734-0847 NR 47 TC 37 Z9 41 U1 0 U2 0 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 DEC 15 PY 2000 VL 261 IS 2 BP 303 EP 311 DI 10.1006/excr.2000.5028 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 387ZU UT WOS:000166153600001 PM 11112337 ER PT J AU Previs, SF Withers, DJ Ren, JM White, MF Shulman, GI AF Previs, SF Withers, DJ Ren, JM White, MF Shulman, GI TI Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR SUBSTRATE FAMILY; INSULIN-RESISTANCE; PHOSPHOTYROSINE PROTEIN; SIGNALING SYSTEM; MICE; MEMBER; GROWTH AB To examine the impact of homozygous genetic disruption of insulin receptor substrate (IRS)-1 (IRS-1(-/-)) or IRS-S (IRS-2(-/-)) on basal and insulin-stimulated carbohydrate and lipid metabolism in vivo, we infused 18-h fasted mice (wild-type (WT), IRS-1(-/-), and IRS-2(-/-)) with [3-H-3]glucose and [H-2(5)]glycerol and assessed rates of glucose and glycerol turnover under basal (0-90 min) and hyperinsulinemic-euglycemic clamp (90-210 min; 5 mM glucose, and 5 milliunits of insulin kg(-1).min(-1)) conditions. Both IRS-1(-/-) and IRS-2(-/-) mice were insulin-resistant as reflected by markedly impaired insulin-stimulated whole-body glucose utilization compared with WT mice. Insulin resistance in the IRS-1(-/-) mice could be ascribed mainly to decreased insulin-stimulated peripheral glucose metabolism. In contrast, IRS-2(-/-) mice displayed multiple defects in insulin-mediated carbohydrate metabolism as reflected by (i) decreased peripheral glucose utilization, (ii) decreased suppression of endogenous glucose production, and (iii) decreased hepatic glycogen synthesis. Additionally, IRS-2(-/-) mice also showed marked insulin resistance in adipose tissue as reflected by reduced suppression of plasma free fatty acid concentrations and glycerol turnover during the hyperinsulinemic-euglycemic clamp. These data suggest important tissue-specific roles for IRS-1 and IRS-2 in mediating the effect of insulin on carbohydrate and Lipid metabolism in vivo in mice. IRS-1 appears to have its major role in muscle, whereas IRS-2 appears to impact on liver, muscle, and adipose tissue. C1 Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06536 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06536 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Joslin Diabet Ctr,Dept Biochem, Boston, MA 02215 USA. RP Shulman, GI (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, 295 C Ave,POB 9812, New Haven, CT 06536 USA. RI Withers, Dominic/D-7671-2014 OI Withers, Dominic/0000-0002-8009-7521 FU NIDDK NIH HHS [P30 DK-45735, R01 DK-40936, R01 DK040936] NR 24 TC 180 Z9 189 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 DEC 15 PY 2000 VL 275 IS 50 BP 38990 EP 38994 DI 10.1074/jbc.M006490200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384PB UT WOS:000165953100008 PM 10995761 ER PT J AU Gesbert, F Sellers, WR Signoretti, S Loda, M Griffin, JD AF Gesbert, F Sellers, WR Signoretti, S Loda, M Griffin, JD TI BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27(Kip1) through the phosphatidylinositol 3-kinase/AKT pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL ONCOGENE; HEMATOPOIETIC-CELLS; TYROSINE KINASE; C-ABL; SIGNAL TRANSDUCERS; PROGENITOR CELLS; POSITIVE CELLS; CDK INHIBITORS AB Deregulation of cell cycle checkpoints is an almost universal abnormality in human cancers and is most often due to loss-of-function mutations of tumor suppressor genes such as Rb, p53, or p16(INK4a). In this study, we demonstrate that BCR/ABL inhibits the expression of a key cell cycle inhibitor, p27(Kip1), by signaling through a pathway involving phosphatidylinositol 3-kinase (PI3K). p27(Kip1) is a widely expressed inhibitor of cdk2, an essential cell cycle kinase regulating entry into S phase. We demonstrate that the decrease of p27(Kip1) is directly due to BCR/ABL in hematopoietic cells by two different approaches. First, induction of BCR/ABL by a tetracycline-regulated promoter is associated with a reversible down-regulation of p27(Kip1). Second, inhibition of BCR/ABL kinase activity with the Abl tyrosine kinase inhibitor STI571 rapidly increases p27(Kip1) levels. The PI3K inhibitor LY-294002 blocks the ability of BCR/ABL to induce p27(Kip1) down-regulation and inhibits BCR/ ABL-induced entry into S phase. The serine/threonine kinase AKT/protein kinase B is a known downstream target of PI3K. Transient expression of an activated mutant of AKT was found to decrease expression of p27(Kip1), even when PI3K was inhibited by LY-294002. The mechanism of p27(Kip1) regulation is primarily related to protein stability, since inhibition of proteasome activity increased p27(Kip1) levels in BCR/ABL-transformed cells, whereas very little change in p27 transcription was found. Overall, these data are consistent with a model in which BCR/ABL suppresses p27(Kip1) protein levels through PI3K/AKT, leading to accelerated entry into S phase. This activity is likely to explain in part previous studies showing that activation of PI3K was required for optimum transformation of hematopoietic cells by BCR/ABL in vitro and in vivo. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 65 TC 167 Z9 172 U1 0 U2 6 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 DEC 15 PY 2000 VL 275 IS 50 BP 39223 EP 39230 DI 10.1074/jbc.M007291200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384PB UT WOS:000165953100039 PM 11010972 ER PT J AU Harris, D Engelman, A AF Harris, D Engelman, A TI Both the structure and DNA binding function of the barrier-to-autointegration factor contribute to reconstitution of HIV type 1 integration in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VIRUS PREINTEGRATION COMPLEXES; RETROVIRAL DNA; CELLULAR FACTOR; IN-VITRO; PROTEIN; DOMAIN; PURIFICATION AB Retroviral integration is mediated by viral preintegration complexes (PICs), and human immunodeficiency virus type 1 (HIV-1) PICs treated with high salt lose their in vitro integration activity. Barrier-to-autointegration factor (EAF) is a host protein that efficiently restores PIC activity, but the mechanism(s) by which BAF participates in HIV-1 integration remains largely unknown. Here we developed a gel shift assay to study BAF DNA binding, and analyzed 14 mutant proteins containing substitutions of conserved residues for binding and PIC reconstitution activities, Although wild-type BAF efficiently bound double-stranded DNA, binding to single-stranded DNA, RNA, or an RNA/DNA hybrid was not detected, suggesting that BAF associates with retroviral cDNA relatively late during reverse transcription. Although some of the BAF mutant proteins efficiently bound DNA, others were defective for binding. Mutants that bound DNA efficiently reconstituted HIV-1 integration, even though in one case binding was just 0.2% of wild-type BAF, Although misfolded mutants did not reconstitute integration, a structurally intact DNA binding-defective mutant displayed partial activity at high BAF concentration. We therefore conclude that both BAF protein structure and its DNA binding activity play roles in reconstituting HIV-1 integration in vitro. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Engelman, A (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI39394] NR 19 TC 48 Z9 49 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 DEC 15 PY 2000 VL 275 IS 50 BP 39671 EP 39677 DI 10.1074/jbc.M002626200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384PB UT WOS:000165953100095 PM 11005805 ER PT J AU Sawai, H Okamoto, Y Luberto, C Mao, CG Bielawska, A Domae, N Hannun, YA AF Sawai, H Okamoto, Y Luberto, C Mao, CG Bielawska, A Domae, N Hannun, YA TI Identification of ISC1 (YER019w) as inositol phosphosphingolipid phospholipase C in Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPHINGOMYELINASE ACTIVITY; NEUTRAL SPHINGOMYELINASE; ACID SPHINGOMYELINASE; YEAST SPHINGOLIPIDS; CERAMIDE; GENE; STRESS; PHOSPHORYLCERAMIDE; PURIFICATION; RESPONSES AB Sphingolipids have emerged as novel bioactive mediators in eukaryotic cells including yeast. It has been proposed that sphingomyelin (SM) hydrolysis and the concomitant generation of ceramide are involved in various stress responses in mammalian cells, The yeast Saccharomyces cerevisiae has inositol phosphosphingolipids (IPS) instead of SM and glycolipids, and synthesis of IFS is indispensable to its growth. Although the genes responsible for the synthesis of IFS have been identified, the gene(s) for the degradation of IFS has not been reported, Here we show that ISC1 (YER019w), which has homology to bacterial neutral sphingomyelinase (SMase), encodes IFS phospholipase C (IPS-PLC). First, we observed that overexpression of ISC1 greatly increased neutral SMase activity, and this activity was dependent on the presence of phosphatidylserine. Cells deleted in ISC1 demonstrated negligible neutral SMase activity. Because yeast cells have IFS instead of SM, we investigated whether IFS are the physiologic substrates of this enzyme. Lysates of ISC1-overexpressing cells demonstrated very high PLC activities on IFS. Deletion of ISC1 eliminated endogenous IPS-PLC activities, Labeling yeast cells with [H-3]dihydrosphingosine showed that IFS were increased in the deletion mutant cells, This study identifies the first enzyme involved in catabolism of complex sphingolipids in S. cerevisiae. C1 Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Adm Hosp, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Osaka Dent Univ, Dept Med, Hirakata, Osaka 573, Japan. RP Hannun, YA (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 173 Ashley Ave, Charleston, SC 29425 USA. RI OKAMOTO, Yasuo/J-8438-2015 FU NIGMS NIH HHS [GM43825] NR 29 TC 103 Z9 105 U1 0 U2 5 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 DEC 15 PY 2000 VL 275 IS 50 BP 39793 EP 39798 DI 10.1074/jbc.M007721200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384PB UT WOS:000165953100112 PM 11006294 ER PT J AU Gommerman, JL Oh, DY Zhou, XN Tedder, TF Maurer, M Galli, SJ Carroll, MC AF Gommerman, JL Oh, DY Zhou, XN Tedder, TF Maurer, M Galli, SJ Carroll, MC TI A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: A potential mechanism for mast cell activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B-LYMPHOCYTE DEVELOPMENT; T-DEPENDENT ANTIGEN; FC-RECEPTORS; COMPLEMENT RECEPTORS; TNF-ALPHA; MICE; EXPRESSION; IMMUNITY; INFECTION; MODULATION AB Although it is now appreciated that mast cell-mediated release of TNF-alpha is critical for resolution of acute septic peritonitis, questions remain as to how mast cells are activated upon peritoneal bacterial infection, Clues to how this may occur have been derived from earlier studies by Prodeus et al, in which complement proteins C3 and C4 were shown to be required for survival following cecal ligation and puncture (CLP), a model for acute septic peritonitis, To evaluate the mechanism for mast cell activation in the CLP model, complement receptor CD21/CD35-deficient mice (Cr2(null)) were examined in the present study, Along with CD19-deficient (CD19(null)) mice, these animals exhibit decreased survival Following CLP compared with wild-type littermates. Injection of IgM before CEP does not change survival rates for Cr2(null) mice and only partially improves survival of CD19(null) mice, implicating CD21/CD35 and CD19 in mast cell activation. Interestingly,early TNF-alpha release is also impaired in Cr2(null) and CD19(null) animals, suggesting that these molecules directly affect mast cell activation. Cr2(null) and CD19(null) mice demonstrate an impairment in neutrophil recruitment and a corresponding increase in bacterial load, Examination of peritoneal mast cells by flow cytometry and confocal microscopy reveals the expression and colocalization of CD21/CD35 and CD19, Taken together, these findings suggest that the engagement of complement receptors CD21/CD35 along with CD19 on the mast cell surface by C3 fragments may be necessary for the full expression of mast cell activation in the CLP model. C1 Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. MIT, Cambridge, MA 02139 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP Carroll, MC (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol, Boston, MA 02115 USA. NR 34 TC 72 Z9 73 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 DEC 15 PY 2000 VL 165 IS 12 BP 6915 EP 6921 PG 7 WC Immunology SC Immunology GA 381XZ UT WOS:000165790500035 PM 11120817 ER PT J AU Guenette, SY Bertram, L Crystal, A Bakondi, B Hyman, BT Rebeck, GW Tanzi, RE Blacker, D AF Guenette, SY Bertram, L Crystal, A Bakondi, B Hyman, BT Rebeck, GW Tanzi, RE Blacker, D TI Evidence against association of the FE65 gene (APBB1) intron 13 polymorphism in Alzheimer's patients SO NEUROSCIENCE LETTERS LA English DT Article DE Alzheimer's disease; FE65; APBB1; polymorphism; family-based association; case control sample ID AMYLOID PRECURSOR PROTEIN; BETA-PROTEIN; SIBSHIP TEST; DISEASE; LINKAGE; DOMAIN; ONSET AB A genetic polymorphism in intron 13 of the FE65 gene (APBB1) was reported to be associated with Alzheimer's disease (AD). Our analyses of this polymorphism, both in a family-based or a case-control sample, fail to support the association between the FE65 intron 13 polymorphism and AD. We performed the sibship disequilibrium test (SDT, P = 0.77)and the sib transmission/disequilibrium test (Sib-TDT, P = 0.56) in a family-based study which included 526 subjects from 158 sibships. In addition, we compared the genotype and allele frequencies of this biallelic polymorph ism in 311 AD patients to those of a control group consisting of 260 subjects and found no significant difference (chi (2), P = 0.847 and P = 0.586, respectively). Furthermore, our two-point linkage analysis in a family-based sample was in agreement with a genome wide scan for linkage to AD and showed no evidence for linkage to the short arm of chromosome 11 where the FE65 gene is located. We conclude that the association of the FE65 intron 13 polymorphism with AD, if any, is smaller than previously reported. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Psychiat, Gerontol Res Unit, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Guenette, SY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, 149 13th St, Charlestown, MA 02129 USA. RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X NR 20 TC 14 Z9 15 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 15 PY 2000 VL 296 IS 1 BP 17 EP 20 DI 10.1016/S0304-3940(00)01607-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 383AN UT WOS:000165859700005 PM 11099823 ER PT J AU Ubeda, M Habener, JF AF Ubeda, M Habener, JF TI CHOP gene expression in response to endoplasmic-reticular stress requires NFY interaction with different domains of a conserved DNA-binding element SO NUCLEIC ACIDS RESEARCH LA English DT Article ID UNFOLDED PROTEIN RESPONSE; GLUCOSE-REGULATED PROTEINS; FACTOR CBF/NF-Y; TRANSMEMBRANE PROTEIN; GRP78/BIP PROMOTER; GROWTH ARREST; TRANSCRIPTIONAL INDUCTION; SACCHAROMYCES-CEREVISIAE; (C/EBP)-RELATED GENE; GADD153 AB The transcription factor CHOP/GADD153 gene is induced by cellular stress and is involved in mediating apoptosis. We report the identification of a conserved region in the promoter of the CHOP gene responsible for its inducibility by endoplasmic reticulum (ER) stress, Deletion mutants of the human CHOP promoter Identify a region comprising nucleotides -75 to -104 required for both constitutive and ER-stress-inducible expression. This region of the promoter, the ER-stress element (ERSE) is sufficient to confer both increased basal activity and PH-stress inducibility to an otherwise inactive heterologous promoter. The CHOP ERSE is a novel Variant of the ERSE as it contains two different functional domains, and a GA- instead of CC-rich intervening sequence, The CCAAT-box domain occupied by the constitutive transcriptional activator nuclear factor Y (NFY) is required for constitutive activation whereas the variant GCACG 'inducible' domain uniquely mediates ER-stress inducibility. By UV-crosslinking analysis NFY makes contact not only with the constitutive activator CCAAT box but also with the inducible GCACG domain. Deletions and nucleotide substitutions in the CCAAT box as well as its replacement by an SP1 site failed to support ER inducibility, These findings support the notion that NFY is not only required for constitutive activation of CHOP gene transcription, but is also an active and essential element for the assembly of an ER-stress-inducible enhanceosome that activates CHOP gene expression in response to cellular stress. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Mol Endocrinol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Habener, JF (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Mol Endocrinol Lab, 55 fruit St,WEL320, Boston, MA 02114 USA. NR 39 TC 56 Z9 58 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC 15 PY 2000 VL 28 IS 24 BP 4987 EP 4997 DI 10.1093/nar/28.24.4987 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384QJ UT WOS:000165956100020 PM 11121490 ER PT J AU Dunn, A Boas, D AF Dunn, A Boas, D TI Transport-based image reconstruction in turbid media with small source-detector separations SO OPTICS LETTERS LA English DT Article ID TOMOGRAPHY; CONTRAST AB We demonstrate a new method for imaging through several millimeters of a turbid sample with a resolution of approximately 100 mum by combining aspects of confocal reflectance microscopy and diffuse optical tomography. By laterally displacing the pinhole aperture of a confocal microscope we can achieve small source-detector separations and detect minimally scattered light. A reconstruction algorithm based on the first Born approximation to the radiative transport equation is then used to reconstruct an image of a 100-mum absorbing object located 2 mm beneath the surface. (C) 2000 Optical Society of America. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Dunn, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. NR 10 TC 54 Z9 55 U1 0 U2 5 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD DEC 15 PY 2000 VL 25 IS 24 BP 1777 EP 1779 DI 10.1364/OL.25.001777 PG 3 WC Optics SC Optics GA 382GL UT WOS:000165814600011 PM 18066341 ER PT J AU Traver, D Akashi, K Manz, M Merad, M Miyamoto, T Engleman, EG Weissman, IL AF Traver, D Akashi, K Manz, M Merad, M Miyamoto, T Engleman, EG Weissman, IL TI Development of CD8 alpha-positive dendritic cells from a common myeloid progenitor SO SCIENCE LA English DT Article ID MOUSE BONE-MARROW; T-CELLS; IN-VIVO; LYMPHOID ORGANS; B-CELLS; EXPRESSION; MARKERS; SPLEEN AB Dendritic cells (DCs) are critical in both initiating adaptive immune responses and maintaining tolerance to self antigens. These apparently contradictory roles have been suggested to depend on different subsets of DCs that arise from either myeloid or Lymphoid hematopoietic origins, respectively, Although DC expression of CD8 alpha is attributed to a lymphoid origin, here we show that both CD8 alpha (+) and CD8 alpha (-) DCs can arise from clonogenic common myeloid progenitors in both thymus and spleen. Thus, expression of CD8 alpha is not indicative of a lymphoid origin, and phenotypic and functional differences among DC subsets are likely to reflect maturation status rather than ontogeny. C1 Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Manz, M (reprint author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. RI Manz, Markus/C-7588-2011 FU NCI NIH HHS [CA42551]; NIAID NIH HHS [5T32 AI-07290] NR 24 TC 284 Z9 289 U1 1 U2 3 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 DEC 15 PY 2000 VL 290 IS 5499 BP 2152 EP 2154 DI 10.1126/science.290.5499.2152 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 383ER UT WOS:000165870600058 PM 11118150 ER PT J AU Kwong, PD Wyatt, R Majeed, S Robinson, J Sweet, RW Sodroski, J Hendrickson, WA AF Kwong, PD Wyatt, R Majeed, S Robinson, J Sweet, RW Sodroski, J Hendrickson, WA TI Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates SO STRUCTURE LA English DT Article DE 17b; antibody; CD4; complex; X-ray ID HUMAN-IMMUNODEFICIENCY-VIRUS; SOLUBLE CD4; MONOCLONAL-ANTIBODIES; CHEMOKINE RECEPTORS; V3 LOOP; NEUTRALIZATION SENSITIVITY; MOLECULAR CHARACTERIZATION; 3-DIMENSIONAL STRUCTURE; CELLULAR RECEPTOR; PROTEIN CRYSTALS AB Background: The gp120 exterior envelope glycoprotein of HIV-1 binds sequentially to CD4 and chemokine receptors on cells to initiate virus entry. During natural infection, gp120 is a primary target of the humoral immune response, and it has evolved to resist antibody-mediated neutralization. We previously reported the structure at 2.5 Angstrom of a gp120 core from the HXBc2 laboratory-adapted isolate in complex with a 2 domain fragment of CD4 and the antigen binding fragment of a human antibody. This revealed atomic details of gp120-receptor interactions and suggested multiple mechanisms of immune evasion. Results: We have now extended the HXBc2 structure in P222(1) crystals to 2.2 Angstrom. The enhanced resolution enabled a more accurate modeling of less-well-ordered regions and provided conclusive identification of the density in the central cavity at the crux of the gp120-CD4 interaction as isopropanol from the crystallization medium. We have also determined the structure of a gp120 core from the primary clinical HIV-1 isolate, YU2, in the same ternary complex but in a C2 crystal lattice. Comparisons of HXBc2 and YU2 showed that while CD4 binding was rigid, portions of the gp120 core were conformationally flexible; overall differences were minor, with sequence changes concentrated on a surface expected to be exposed on the envelope oligomer. Conclusions: Despite dramatic antigenic differences between primary and laboratory-adapted HIV-1, the gp120 cores from these isolates are remarkably similar. Taken together with chimeric substitution and sequence analysis, this indicates that neutralization resistance is specified by quaternary interactions involving the major variable loops and thus affords a mechanism for viral adaptation. Conservation of the central cavity suggests the possibility of therapeutic inhibitors. The structures reported here extend in detail and generality our understanding of the biology of the gp120 envelope glycoprotein. C1 Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70112 USA. SmithKline Beecham Pharmaceut, Dept Immunol, King Of Prussia, PA 19406 USA. RP Kwong, PD (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. FU NIAID NIH HHS [AI 240320, AI 31783, AI 39420] NR 74 TC 306 Z9 312 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 15 PY 2000 VL 8 IS 12 BP 1329 EP 1339 DI 10.1016/S0969-2126(00)00547-5 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 420TY UT WOS:000168022400014 PM 11188697 ER PT J AU Rosen, F AF Rosen, F TI The war within us: Everyman's guide to infection and immunity SO NATURE LA English DT Book Review C1 Ctr Blood Res, Boston, MA 02115 USA. RP Rosen, F (reprint author), Ctr Blood Res, Warren Alpert Bldg,200 Longwood Ave, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 14 PY 2000 VL 408 IS 6814 BP 769 EP 769 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 382PK UT WOS:000165831300018 ER PT J AU Hughes, SL Weaver, FM Giobbie-Hurder, A Manheim, L Henderson, W Kubal, JD Ulasevich, A Cummings, J AF Hughes, SL Weaver, FM Giobbie-Hurder, A Manheim, L Henderson, W Kubal, JD Ulasevich, A Cummings, J TI Effectiveness of team-managed home-based primary care - A randomized multicenter trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID COST-EFFECTIVENESS; CLINICAL-TRIAL; HEALTH; INTERVENTION; VETERANS; LESSONS AB Context Although home-based health care has grown over the past decade, its effectiveness remains controversial. A prior trial of Veterans Affairs (VA) Team-Managed Home-Based Primary Care (TM/HBPC) found favorable outcomes, but the replicability of the model and generalizability of the findings are unknown. Objectives To assess the impact of TM/HBPC on functional status, health-related quality of life (HR-QoL), satisfaction with care, and cost of care. Design and Setting Multisite randomized controlled trial conducted from October 1994 to September 1998 in 16 VA medical centers with HBPC programs. Participants A total of 1966 patients with a mean age of 70 years who had 2 or more activities of daily living impairments or a terminal illness, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). Intervention Home-based primary care (n=981), including a primary care manager, 24-hour contact for patients, prior approval of hospital readmissions, and HBPC team participation in discharge planning, vs customary VA and private sector care (n=985). Main Outcome Measures Patient functional status, patient and caregiver HR-QoL and satisfaction, caregiver burden, hospital readmissions, and costs over 12 months. Results Functional status as assessed by the Barthel Index did not differ for terminal (P=.40) or nonterminal (those with severe disability or who had CHF or COPD) (P=.17) patients by treatment group. Significant improvements were seen in terminal TM/HBPC patients in HR-QoL scales of emotional role function, social function, bodily pain, mental health, vitality, and general health. Team-Managed HBPC nonterminal patients had significant increases of 5 to 10 points in 5 of 6 satisfaction with care scales. The caregivers of terminal patients in the TM/HBPC group improved significantly in HR-QoL measures except for vitality and general health. Caregivers of nonterminal patients improved significantly in QoL measures and reported reduced caregiver burden (P=.008). Team-Managed HBPC patients with severe disability experienced a 22% relative decrease (0.7 readmissions/patient for TM/HBPC group vs 0.9 readmissions/patient for control group) in hospital readmissions (P=.03) at 6 months that was not sustained at 12 months. Total mean per person costs were 6.8% higher in the TM/HBPC group at 6 months ($19 190 vs $17 971) and 12.1% higher at 12 months ($31 401 vs $28 008). Conclusions The TM/HBPC intervention improved most HR-QoL measures among terminally ill patients and satisfaction among non-terminally ill patients. It improved caregiver HR-QoL, satisfaction with care, and caregiver burden and reduced hospital readmissions at 6 months, but it did not substitute for other forms of care. The higher costs of TM/HBPC should be weighed against these benefits. C1 US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Cooperat Studies Program Coordinating Ctr, Hines, IL 60141 USA. Univ Illinois, Sch Publ Hlth, Ctr Hlth & Aging, Chicago, IL 60607 USA. US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Midwest Ctr Hlth Serv & Policy Res, Hines, IL 60141 USA. Northwestern Univ, Inst Hlth Serv Res & Policy Studies, Evanston, IL USA. Vet Integrated Serv Network 12, Hines, IL USA. RP Hughes, SL (reprint author), Univ Illinois, Sch Publ Hlth, Hlth Res Ctr, MC 275,850 W Jackson Blvd,Suite 400, Chicago, IL 60607 USA. NR 28 TC 164 Z9 164 U1 2 U2 15 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 DEC 13 PY 2000 VL 284 IS 22 BP 2877 EP 2885 DI 10.1001/jama.284.22.2877 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 380RJ UT WOS:000165717000027 PM 11147984 ER PT J AU Johnston, SC Gress, DR Browner, WS Sidney, S AF Johnston, SC Gress, DR Browner, WS Sidney, S TI Short-term prognosis after emergency department diagnosis of TIA SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TRANSIENT-ISCHEMIC-ATTACKS; AMERICAN-HEART-ASSOCIATION; HEALTH MAINTENANCE ORGANIZATION; AD-HOC-COMMITTEE; STROKE-COUNCIL; FIRST-EVER; INTEROBSERVER AGREEMENT; CARE PROFESSIONALS; MANAGEMENT; GUIDELINES AB Context Management of patients with acute transient ischemic attack (TIA) varies widely, with some institutions admitting all patients and others proceeding with outpatient evaluations. Defining the short-term prognosis and risk factors for stroke after TIA may provide guidance in determining which patients need rapid evaluation. Objective To determine the short-term risk of stroke and other adverse events after emergency department (ED) diagnosis of TIA. Design and Setting Cohort study conducted from March 1997 through February 1998 in 16 hospitals in a health maintenance organization in northern California. Patients A total of 1707 patients (mean age, 72 years) identified by ED physicians as having presented with TIA. Main Outcome Measures Risk of stroke during the 90 days after index TIA; other events, including death, recurrent TIA, and hospitalization for cardiovascular events. Results During the 90 days after index TIA, 180 patients (10.5%) returned to the ED with a stroke, 91 of which occurred in the first 2 days. Five factors were independently associated with stroke: age greater than 60 years (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-2.7; P=.01), diabetes mellitus (OR, 2.0; 95% CI, 1.4-2.9; P<.001), symptom duration longer than 10 minutes (OR, 2.3; 95% CI, 1.3-4.2; P=.005), weakness (OR, 1.9, 95% CI, 1.4-2.6; P<.001), and speech impairment (OR, 1.5, 95% CI, 1.1-2.1; P=.01). Stroke or other adverse events occurred in 428 patients (25.1%) in the 90 days after the TIA and included 44 hospitalizations for cardiovascular events (2.6%), 45 deaths (2.6%), and 216 recurrent TIAs (12.7%). Conclusions Our results indicate that the short-term risk of stroke and other adverse events among patients who present to an ED with a TIA is substantial. Characteristics of the patient and the TIA may be useful for identifying patients who may benefit from expeditious evaluation and treatment. C1 Univ Calif San Francisco, Dept Neurol, Neurovasc Serv, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Johnston, SC (reprint author), Univ Calif San Francisco, Dept Neurol, Neurovasc Serv, 505 Parnassus Ave,M-798, San Francisco, CA 94143 USA. FU NINDS NIH HHS [NS 02042, NS 36016] NR 37 TC 702 Z9 751 U1 1 U2 19 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 DEC 13 PY 2000 VL 284 IS 22 BP 2901 EP 2906 DI 10.1001/jama.284.22.2901 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 380RJ UT WOS:000165717000030 PM 11147987 ER PT J AU Rubenstein, MH Harrell, LC Sheynberg, BV Schunkert, H Bazari, H Palacios, IF AF Rubenstein, MH Harrell, LC Sheynberg, BV Schunkert, H Bazari, H Palacios, IF TI Are patients with renal failure good candidates for percutaneous coronary revascularization in the new device era? SO CIRCULATION LA English DT Article; Proceedings Paper CT 71st Scientific Session of the American-Heart-Association Meeting CY NOV 08-12, 1998 CL DALLAS, TEXAS SP Amer Heart Assoc DE renal failure; angioplasty; stents; coronary devices ID CHRONIC DIALYSIS PATIENTS; BALLOON ANGIOPLASTY; ROTATIONAL ATHERECTOMY; CHRONIC-HEMODIALYSIS; RISK-FACTORS; RESTENOSIS; DISEASE; TRIAL; COMPLICATIONS; EFFICACY AB Background-Patients with end-stage renal disease undergoing conventional balloon angioplasty have reduced procedural success and increased complication rates. This study was designed to determine the immediate and long-term outcomes of patients with varying degrees of renal failure undergoing percutaneous coronary intervention in the current device era. Methods and Results-We compared the immediate and long-term outcomes of 362 renal failure patients (creatinine >1.5 mg/dL) with those of 2972 patients with normal renal function who underwent percutaneous coronary intervention between 1994 and 1997. Patients with renal failure were older and had more associated comorbidities. They had reduced procedural success (89.5% versus 92.9%, P=0.007) and greater in-hospital combined major event (death, Q-wave myocardial infarction, emergent CABG; 10.8% versus 1.8%; P<0.0001) rates. Renal failure was an independent predictor of major adverse cardiac events (MACEs) (OR, 3.41; 95% CI, 1.84 to 6.22; P<0.00001). Logistic regression analysis identified shock, peripheral vascular disease, balloon angioplasty strategy, and unstable angina as independent predictors of in-hospital MACEs in the renal group. Compared with 362 age- and sex-matched patients selected from the control group, patients with renal failure had a lower survival rate (27.7% versus 6.1%, P<0.0001) and a greater MACE rate (51% versus 33%, P<0.001) at long-term follow-up. Cox regression analysis identified age and PTCA strategy as independent predictors of long-term MACEs in the renal group. Finally, within the renal failure population, the dialysis and nondialysis patients experienced remarkably similar immediate and long-term outcomes. Conclusions-Although patients with renal failure can be treated with a high procedural success rate in the new device era, they have an increased rate of major events both in hospital and at long-term follow-up. Nevertheless, utilization of stenting and debulking techniques improves immediate and long-term outcomes. C1 Massachusetts Gen Hosp, Cardiac Catheterizat Labs, Cardiac Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Palacios, IF (reprint author), Massachusetts Gen Hosp, Cardiac Catheterizat Labs, Cardiac Unit, 55 Fruit St, Boston, MA 02114 USA. NR 25 TC 162 Z9 170 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 DEC 12 PY 2000 VL 102 IS 24 BP 2966 EP 2972 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 382GA UT WOS:000165813600017 PM 11113047 ER PT J AU Soukos, NS Crowley, K Bamberg, MP Gillies, R Doukas, AG Evans, R Kollias, N AF Soukos, NS Crowley, K Bamberg, MP Gillies, R Doukas, AG Evans, R Kollias, N TI A rapid method to detect dried saliva stains swabbed from human skin using fluorescence spectroscopy SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE fluorescence; spectroscopy; trace evidence; forensic science ID AMYLASE AB Saliva on skin is important in forensic trace evidence. if areas where saliva is present can be outlined, this may lead to DNA analysis and identification. This study describes a rapid and non-destructive method to detect dried saliva on the surface of the skin by fluorescence spectroscopy. Eighty-two volunteers deposited samples of their own saliva on the skin of their Ventral forearm. a control sample of water was deposited at three different sites on the contralateral arm. Saliva and water control were then allowed to air-dry. Swab samples were taken from dried saliva and control sites and were dissolved in 0.1 M KCl solution. Emission spectra were obtained from the solution and were characterized by a principal maximum at 345-355 nm with excitation at 282 nm. The fluorescence emission intensity was greater than background readings obtained from the control swab site in 80 of 82 volunteers (similar to 97.6%). The fluorescence profile of saliva samples were similar to those obtained from aqueous samples of pure amylase and tryptophan, an endogenous fluorophore in alpha-amylase. The presence of an emission peak at 345-355 nm with excitation at 282 nm could provide a strong presumptive indication of saliva deposition. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, Boston, MA 02114 USA. State Massachusetts, Off Chief Med Examiner, Boston, MA 02118 USA. RP Soukos, NS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, Boston, MA 02114 USA. NR 17 TC 14 Z9 16 U1 1 U2 11 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD DEC 11 PY 2000 VL 114 IS 3 BP 133 EP 138 DI 10.1016/S0379-0738(00)00292-9 PG 6 WC Medicine, Legal SC Legal Medicine GA 369HZ UT WOS:000165061000002 PM 11027866 ER PT J AU Scully, R Puget, N Vlasakova, K AF Scully, R Puget, N Vlasakova, K TI DNA polymerase stalling, sister chromatid recombination and the BRCA genes SO ONCOGENE LA English DT Article DE BRCA1; BRCA2; DNA polymerase; genomic integrity; homologous recombination; sister chromatid ID DOUBLE-STRAND BREAKS; WERNERS-SYNDROME GENES; CELL-CYCLE REGULATION; BLOOMS-SYNDROME; MEIOTIC CELLS; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; TARGETED DISRUPTION AB Heritable predisposition to breast and/or ovarian cancer is determined, in part, by germline mutation affecting one of two tumor suppressor genes, BRCA1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995). These genes are required for the maintenance of genomic integrity and for control of homologous recombination in somatic and meiotic cells. Here, we explore the hypothesis that a major role of the BRCA gene products in the somatic DNA damage response centers upon the control of recombination between sister chromatids during S phase. By analogy with model organisms, we suggest that stalling of a mammalian DNA polymerase complex by its encounter with abnormal DNA structure calls forth a series of responses that collaborate to enforce appropriate recombinational outcomes, and to suppress inappropriate or 'illegitimate' recombination. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Scully, R (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Scully, Ralph/F-5008-2013 FU NCI NIH HHS [K01 CA079576] NR 80 TC 53 Z9 56 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 11 PY 2000 VL 19 IS 53 BP 6176 EP 6183 DI 10.1038/sj.onc.1203971 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 387KH UT WOS:000166121400011 PM 11156531 ER PT J AU Cui, Y Wong, WH AF Cui, Y Wong, WH TI Multiple-sequence information provides protection against mis-specified potential energy functions in the lattice model of proteins SO PHYSICAL REVIEW LETTERS LA English DT Article ID LANDSCAPE PERSPECTIVE; STATISTICAL-MECHANICS; GLOBULAR PROTEIN; TRANSITION; KINETICS; HETEROPOLYMERS; SIMULATIONS; COPOLYMERS; STABILITY; DYNAMICS AB The neutral nets in the lattice models of proteins are composed of a group of similar sequences that encode for the same native structure. The maximal neutral nets in an HP and an AB lattice model are investigated by exhaustive enumeration in the conformation space. The result demonstrates that the performance of mis-specified potential functions can be improved significantly by averaging over sequences in the neutral nets. C1 Harvard Univ, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. RP Wong, WH (reprint author), Harvard Univ, Dept Biostat, Boston, MA 02115 USA. NR 35 TC 5 Z9 5 U1 0 U2 3 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD DEC 11 PY 2000 VL 85 IS 24 BP 5242 EP 5245 DI 10.1103/PhysRevLett.85.5242 PG 4 WC Physics, Multidisciplinary SC Physics GA 382CC UT WOS:000165800000057 ER PT J AU Sweadner, KJ Wetzel, RK Arystarkhova, E AF Sweadner, KJ Wetzel, RK Arystarkhova, E TI Genomic organization of the human FXYD2 gene encoding the gamma subunit of the Na,K-ATPase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE sodium potassium ATPase; FXYD gene family; genomic DNA; exon; intron; promoter; alternative splicing; ESTs; human ID SODIUM-PUMP; RENAL NA,K-ATPASE; EXPRESSION; CLONING; CELLS AB Although the gamma subunit of the Na,K-ATPase has only 66 or 68 amino acids, its human gene (FXYD2) was found to span 9.2 kb and have seven exons, including two alternatively spliced exons encoding different N-termini. Two candidate promoters with consensus sites for transcription factors Sp1, AP-1, and AP-2 are present, consistent with independent transcription of the splice variants. Multiple ESTs support the transcriptional competence of the identified gene elements. In the FXYD2 gene, there are two closely spaced polyadenylation signals, and both are used. A proposed third splice variant encoding a 31-residue N-terminal extension was not found in the gene, nor was the predicted larger protein found in human kidney Na,K-ATPase. Instead, evidence was found for the origin of the larger cDNA clone in homologous recombination with unrelated DNA from chromosome 2. FXYD2 is on chromosome 11q23 close to a site of tumorigenic chromosomal translocations, and has a number of repeat elements. 2000 Academic Press. C1 Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA 02129 USA. RP Sweadner, KJ (reprint author), Massachusetts Gen Hosp, Ctr Neurosci, 149 13th St, Charlestown, MA 02129 USA. EM sweadner@helix.mgh.harvard.edu FU NHLBI NIH HHS [R01 HL36271] NR 19 TC 33 Z9 34 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 DEC 9 PY 2000 VL 279 IS 1 BP 196 EP 201 DI 10.1006/bbrc.2000.3907 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 383GB UT WOS:000165873800031 PM 11112438 ER PT J AU Shang, YF Hu, X DiRenzo, J Lazar, MA Brown, M AF Shang, YF Hu, X DiRenzo, J Lazar, MA Brown, M TI Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription SO CELL LA English DT Article ID RNA-POLYMERASE-II; NUCLEAR-RECEPTOR; ALPHA-AMANITIN; VITAMIN-D-3 RECEPTOR; COACTIVATOR COMPLEX; CHROMATIN STRUCTURE; N-COR; ACTIVATION; INHIBITOR; BINDING AB Many cofactors bind the hormone-activated estrogen receptor (ER), yet the specific regulators of endogenous ER-mediated gene transcription are unknown. Using chromatin immunoprecipitation (ChIP), we find that ER and a number of coactivators rapidly associate with estrogen responsive promoters following estrogen treatment in a cyclic fashion that is not predicted by current models of hormone activation. Cycles of ER complex assembly are followed by transcription. In contrast, the anti-estrogen tamoxifen (TAM) recruits corepressors but not coactivators. Using a genetic approach, we show that recruitment of the p160 class of coactivators is sufficient for gene activation and for the growth stimulatory actions of estrogen in breast cancer supporting a model in which ER cofactors play unique roles in estrogen signaling. C1 Brigham & Womens Hosp, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, 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, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Penn Diabet Ctr, Philadelphia, PA 19104 USA. RP Brown, M (reprint author), Brigham & Womens Hosp, Dept Adult Oncol, 75 Francis St, Boston, MA 02115 USA. RI Myles, Brown/B-6906-2008; OI Brown, Myles/0000-0002-8213-1658 FU NCI NIH HHS [CA57374]; NIDDK NIH HHS [DK43806] NR 50 TC 1240 Z9 1266 U1 4 U2 47 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 8 PY 2000 VL 103 IS 6 BP 843 EP 852 DI 10.1016/S0092-8674(00)00188-4 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382CR UT WOS:000165801300004 PM 11136970 ER PT J AU Chi, NW Lodish, HF AF Chi, NW Lodish, HF TI Tankyrase is a Golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STIMULATED GLUCOSE-TRANSPORT; 3T3-L1 ADIPOCYTES; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; INSULIN; DOMAIN; RAT; TRANSLOCATION; LOCALIZATION; ANKYRIN AB The poly(ADP-ribose) polymerase tankyrase was originally described as a telomeric protein whose catalytic activity was proposed to regulate telomere function. Subsequent studies revealed that most tankyrase is actually extranuclear, but a discordant pattern of cytoplasmic targeting was reported, Here we used fractionation and immunofluorescence to show in 3T3-L1 fibroblasts that tankyrase is a peripheral membrane protein associated with the Golgi. We further colocalized tankyrase with GLUT4 storage vesicles in the juxtanuclear region of adipocytes. Consistent with this colocalization, we found that tankyrase binds specifically to a resident protein of GLUT4 vesicles, IRAP (insulin-responsive amino peptidase). The binding of tankyrase to IRAP involves the ankyrin repeats of tankyrase and a defined sequence ((96)RQSPDG(101)) in the IRAP cytosolic domain (IRAP(1-109)). Tankyrase is a novel signaling target of mitogen-activated protein kinase (MAPK); it is stoichiometrically phosphorylated upon insulin stimulation. Phosphorylation enhances the poly(ADP-ribose) polymerase activity of tankyrase but apparently does not mediate the acute effect of insulin on GLUT4 targeting. Taken together, tankyrase is a novel target of MAPK. signaling in the Golgis, where it is tethered to GLUT4 vesicles by binding to IRAP. We speculate that tankyrase may be involved in the long term effect of the MAPK cascade on the metabolism of GLUT4 vesicles. C1 Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lodish, HF (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. FU NIDDK NIH HHS [R37DK47618, DK02540] NR 41 TC 184 Z9 197 U1 1 U2 6 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 DEC 8 PY 2000 VL 275 IS 49 BP 38437 EP 38444 DI 10.1074/jbc.M007635200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 381AH UT WOS:000165739800041 PM 10988299 ER PT J AU Chen, DX Stetler, RA Cao, GD Pei, W O'Horo, C Yin, XM Chen, J AF Chen, DX Stetler, RA Cao, GD Pei, W O'Horo, C Yin, XM Chen, J TI Characterization of the rat DNA fragmentation factor 35/inhibitor of caspase-activated DNase (short form) - The endogenous inhibitor of caspase-dependent DNA fragmentation in neuronal apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-DEATH; CHROMATIN CONDENSATION; NEURODEGENERATIVE DISEASES; PROTEASES; NUCLEASE; FAMILY; INDUCTION; ISCHEMIA; EXTRACTS; PROTEIN AB Nuclear changes, including internucleosomal DNA fragmentation, are classical manifestations of apoptosis for which the biochemical mechanisms have not been fully elucidated, particularly in neuronal cells. We have cloned the rat DNA fragmentation factor 35/inhibitor of caspase-activated DNase (short form) (DFF35/ICAD(S)) and found it to be the predominant form of ICAD present in rodent brain cells as well as in many other types of cells. DFF35/ICAD(S) forms a functional complex with DFF40/caspase-activated DNase (CAD) in the nucleus, and when its caspase-resistant mutant is over-expressed, it inhibits the nuclease activity, internucleosomal DNA fragmentation and nuclear fragmentation but not the shrinkage and condensation of the nucleus, in neuron-differentiated PC12 cells in response to apoptosis inducers. DFF40/CAD is found to be localized mainly in the nucleus, and during neuronal apoptosis, there is no evidence of further nuclear translocation of this molecule. It is further suggested that inactivation of DFF40/CAD-bound DFF35 and subsequent activation of DFF40/CAD during apoptosis of neuronal cells may not occur in the cytosol but rather in the nucleus through a novel mechanism that requires nuclear translocation of caspases. These results establish that DFF35/ICAD(S) is the endogenous inhibitor of DFF40/CAD and caspase-dependent apoptotic DNA fragmentation in neurons. C1 Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Pittsburgh Inst Neurodegenerat Disorders, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S-506 Biomed Sci Tower, Pittsburgh, PA 15213 USA. FU NINDS NIH HHS [NS36736, NS35965, NS38560] NR 33 TC 35 Z9 36 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 DEC 8 PY 2000 VL 275 IS 49 BP 38508 EP 38517 DI 10.1074/jbc.M003906200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 381AH UT WOS:000165739800051 PM 10984476 ER PT J AU Xiong, JP Li, R Essafi, M Stehle, T Arnaout, MA AF Xiong, JP Li, R Essafi, M Stehle, T Arnaout, MA TI An isoleucine-based allosteric switch controls affinity and shape shifting in integrin CD11b A-domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; FUNCTION-ASSOCIATED ANTIGEN-1; NEUTROPHIL INHIBITORY FACTOR; LIGAND-BINDING SITE; I-DOMAIN; CRYSTAL-STRUCTURE; DIVALENT-CATION; ALPHA-SUBUNIT; ACTIVATION; ALPHA(M)BETA(2) AB In response to cell activation signals, integrins switch from a low to a high affinity state. Physiologic ligands bind to integrins through a von Willebrand Factor A-type domain. Crystallographic studies revealed two conformations of this domain, "closed" and "open." The latter crystallizes in complex with a pseudoligand or ligand, suggesting that it represents the high affinity state; data linking structure and activity are lacking however. In this communication, we expressed stable low and high affinity forms of integrin CD11b A-domain and determined their binding isotherms and crystal structures. The low affinity form, generated by deleting an N-terminal extension extrinsic to the domain, did not bind to physiologic ligands, and crystallized in the closed conformation. The high affinity form was generated by either deleting or substituting an invariable C-terminal Ile(316), wedged into a hydrophobic socket in the closed form, but displaced from it in the open structure. Both mutants crystallized in the open conformation, and the Ile316 --> Gly-modified integrin displayed high affinity. Structural differences between the low and high affinity forms were detected in solution. These data establish the structure-function correlates for the CD11b A-domain, and define a ligand-independent isoleucine-based allosteric switch intrinsic to this domain that controls its conformation and affinity. C1 Massachusetts Gen Hosp, Renal Unit, Leukocyte Biol & Inflammat Program, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Arnaout, MA (reprint author), Massachusetts Gen Hosp, Renal Unit, Leukocyte Biol & Inflammat Program, 149 13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [HL54227]; NIDDK NIH HHS [DK48549] NR 37 TC 101 Z9 102 U1 1 U2 10 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 DEC 8 PY 2000 VL 275 IS 49 BP 38762 EP 38767 DI 10.1074/jbc.C000563200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 381AH UT WOS:000165739800085 PM 11034990 ER PT J AU Ding, HF Lin, YL McGill, G Juo, P Zhu, H Blenis, J Yuan, JY Fisher, DE AF Ding, HF Lin, YL McGill, G Juo, P Zhu, H Blenis, J Yuan, JY Fisher, DE TI Essential role for caspase-8 in transcription-independent apoptosis triggered by p53 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WILD-TYPE P53; HUMAN CANCER-CELLS; CYTOCHROME-C; P53-DEPENDENT APOPTOSIS; CD95 FAS/APO-1; DEATH DOMAIN; P53-MEDIATED APOPTOSIS; RECEPTOR/LIGAND SYSTEM; P53-INDUCED APOPTOSIS; MEDIATED APOPTOSIS AB p53's dual regulation of arrest versus apoptosis may underlie tumor-selective effects of anti-cancer therapy. p53's apoptotic effect has been suggested to involve both transcription-dependent and -independent mechanisms. It is shown here that caspase-8 is activated early in cells undergoing p53-mediated apoptosis and in S100 cell-free extracts that recapitulate transcription-independent apoptosis, Depletion or inactivation of caspase-8 either in cells or cell-free extracts completely prevents this transcription-independent apoptosis and significantly attenuates overall death induced by wildtype p53. Importantly, caspase-8 activation appears to be independent of FADD, and caspase-8 is found in a novel 600-kDa complex following p53 activation. These findings highlight the roles of both transcription-dependent and -independent apoptosis by p53 and identify an essential role for caspase-8 in the transcription-independent pathway. C1 Dana Farber Canc Inst, Div Pediat Hematol Oncol, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Dana Farber Canc Inst, Div Pediat Hematol Oncol, Dept Pediat Hematol Oncol, D630,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA69531] NR 76 TC 103 Z9 108 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 DEC 8 PY 2000 VL 275 IS 49 BP 38905 EP 38911 DI 10.1074/jbc.M004714200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 381AH UT WOS:000165739800104 PM 10988287 ER PT J AU Kimura, T Takahashi, MP Okuda, Y Kaido, M Fujimura, H Yanagihara, T Sakoda, S AF Kimura, T Takahashi, MP Okuda, Y Kaido, M Fujimura, H Yanagihara, T Sakoda, S TI The expression of ion channel mRNAs in skeletal muscles from patients with myotonic muscular dystrophy SO NEUROSCIENCE LETTERS LA English DT Article DE myotonic muscular dystrophy; voltage-gated ion channel; SK3; H1; amyotrophic lateral sclerosis; polymyositis; semiquantitative reverse transcriptase-polymerase chain reaction ID ACTIVATED POTASSIUM CHANNELS; SMALL-CONDUCTANCE; RECEPTOR; GENE AB We investigated gene expression patterns of ion channels including the apamin-sensitive small-conductance Ca2+-activated K+ (SK3) channel, the adult isoform of the skeletal muscle Na+ channel (SkM1), the fetal isoform of skeletal muscle Na+ channel (H1), and the Cl- channel (CIC-1) by using the semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for muscle samples from patients with adult onset myotonic dystrophy (DM), amyotrophic lateral sclerosis, and polymyositis. Patients with DM showed a significant increase in SK3 mRNA but not in mRNAs for other ion channels. The increased expression of SK3 gene in DM did not correlate with HI, the marker of muscle denervation, or the percentage of type 2C fiber, the marker of muscle regeneration. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Osaka Univ, Grad Sch Med, Dept Neurol D4, Suita, Osaka 5650871, Japan. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Sakoda, S (reprint author), Osaka Univ, Grad Sch Med, Dept Neurol D4, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. NR 18 TC 27 Z9 27 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 8 PY 2000 VL 295 IS 3 BP 93 EP 96 DI 10.1016/S0304-3940(00)01598-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 379TL UT WOS:000165658500006 PM 11090982 ER PT J AU Kansal, AR Torquato, S Chiocca, EA Deisboeck, TS AF Kansal, AR Torquato, S Chiocca, EA Deisboeck, TS TI Emergence of a subpopulation in a computational model of tumor growth SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article ID MATHEMATICAL-MODEL; GLIOBLASTOMA-MULTIFORME; HETEROGENEOUS TUMORS; CANCER-CHEMOTHERAPY; DRUG-RESISTANCE; GLIOMAS; POPULATIONS; PHENOTYPE AB Malignant brain tumors consist of a number of distinct subclonal populations. Each of these subpopulations may be characterized by its own behaviors and properties. These subpopulations arise from the constant genetic and epigenetic alteration of existing cells in the rapidly growing tumor. However, since each single-cell mutation only leads to a small number of offspring initially, very few newly arisen subpopulations survive more than a short time. The present work quantifies "emergence", i.e, the likelihood of an isolated subpopulation surviving for an extended period of time. Only competition between clones is considered; there are no cooperative effects included. The probability that a subpopulation emerges under these conditions is found to be a sigmoidal function of the degree of change in cell division rates. This function has a non-zero value for mutations which confer no advantage in growth rate, which represents the emergence of a distinct subpopulation with an advantage that has yet to be selected for, such as hypoxia tolerance or treatment resistance. A logarithmic dependence on the size of the mutated population is also observed. A significant probability of emergence is observed for subpopulations with any growth advantage that comprise even 0.1% of the proliferative cells in a tumor. The impact of even two clonal populations within a tumor is shown to be sufficient such that a prognosis based on the assumption of a monoclonal tumor can be markedly inaccurate. (C) 2000 Academic Press. C1 Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. Princeton Univ, Princeton Mat Inst, Princeton, NJ 08544 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brain Tumor Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp E, Mol Neurooncol Lab, Charlestown, MA 02129 USA. RP Torquato, S (reprint author), Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. FU NCI NIH HHS [CA84509, CA69246] NR 20 TC 56 Z9 57 U1 1 U2 6 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD DEC 7 PY 2000 VL 207 IS 3 BP 431 EP 441 DI 10.1006/jtbi.2000.2186 PG 13 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 379LY UT WOS:000165644600012 PM 11082311 ER PT J AU Kamisago, M Sharma, SD DePalma, SR Solomon, S Sharma, P McDonough, B Smoot, L Mullen, MP Woolf, PK Wigle, ED Seidman, JG Seidman, CE AF Kamisago, M Sharma, SD DePalma, SR Solomon, S Sharma, P McDonough, B Smoot, L Mullen, MP Woolf, PK Wigle, ED Seidman, JG Seidman, CE TI Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID X-LINKED GENE; HYPERTROPHIC CARDIOMYOPATHY; HEART-FAILURE; TROPONIN-C; MYOSIN; LOCUS; FREQUENCY; LINKAGE; DOMAIN; SYSTEM AB Background: The molecular basis of idiopathic dilated cardiomyopathy, a primary myocardial disorder that results in reduced contractile function, is largely unknown. Some cases of familial dilated cardiomyopathy are caused by mutations in cardiac cytoskeletal proteins; this finding implicates defects in contractile-force transmission as one mechanism underlying this disorder. To elucidate this important cause of heart failure, we investigated other genetic causes of dilated cardiomyopathy. Methods: Clinical evaluations were performed in 21 kindreds with familial dilated cardiomyopathy. A genome-wide linkage study prompted a search of the genes encoding beta -myosin heavy chain, troponin T, troponin I, and alpha -tropomyosin for disease-causing mutations. Results: A genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-13 (maximal lod score, 5.11; theta =0), where the gene for cardiac beta -myosin heavy chain is encoded. Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds. Cardiac beta -myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponin T (Delta Lys210) caused early-onset ventricular dilatation (average age at diagnosis, 24 years) and diminished contractile function and frequently resulted in heart failure. Affected persons had neither antecedent cardiac hypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor histopathological findings characteristic of hypertrophy. Conclusions: Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction. Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins on muscle mechanics must trigger two different series of events that remodel the heart. (N Engl J Med 2000;343:1688-96.) (C) 2000, Massachusetts Medical Society. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. New York Med Coll, Westchester Cty Med Ctr, Dept Pediat, Valhalla, NY 10595 USA. Univ Toronto, Toronto Gen Hosp, Dept Med, Toronto, ON M5G 1L7, Canada. RP Seidman, CE (reprint author), Harvard Univ, Sch Med, Dept Genet, Alpert Bldg,Rm 533,200 Longwood Ave, Boston, MA 02115 USA. NR 37 TC 397 Z9 414 U1 2 U2 10 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 DEC 7 PY 2000 VL 343 IS 23 BP 1688 EP 1696 DI 10.1056/NEJM200012073432304 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 380PX UT WOS:000165711900004 PM 11106718 ER PT J AU Zhang, M Shi, Y Magit, D Furth, PA Sager, R AF Zhang, M Shi, Y Magit, D Furth, PA Sager, R TI Reduced mammary tumor progression in WAP-TAg/WAP-maspin bitransgenic mice SO ONCOGENE LA English DT Article DE maspin; WAP-TAg transgenic mice; mammary tumor progression ID BREAST-CANCER; T-ANTIGEN; SERPIN; CELLS; EXPRESSION; SUPPRESSOR; SV40; GENE; TRANSACTIVATION; INVASION AB Maspin is a unique serpin involved in the suppression of tumor growth and metastasis. To investigate whether increased levels of maspin protect against tumor progression in vivo, we established a transgenic model in which maspin is targeted to mammary epithelial cells by the Whey Acidic Protein (WAP) promoter for overexpression. We crossed these WAP-maspin transgenic mice with the WAP-TAg mouse model of tumor progression. Maspin overexpression increased the rate of apoptosis of both preneoplastic and carcinomatous mammary epithelial cells. Maspin reduced tumor growth through a combination of reduced angiogenesis and increased apoptosis, The number of pulmonary metastases was reduced in the presence of maspin overexpression, These data demonstrate that targeted overexpression of maspin can inhibit tumor progression in vivo, likely through a combination of increased apoptosis, decreased angiogenesis, and inhibition of tumor cell migration. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zhang, M (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. FU NCI NIH HHS [CA79736] NR 27 TC 60 Z9 65 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 7 PY 2000 VL 19 IS 52 BP 6053 EP 6058 DI 10.1038/sj.onc.1204006 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 382MY UT WOS:000165827900012 PM 11146557 ER PT J AU Phillips, KA Shlipak, MG Coxson, P Heidenreich, PA Hunink, MGM Goldman, PA Williams, LW Weinstein, MC Goldman, L AF Phillips, KA Shlipak, MG Coxson, P Heidenreich, PA Hunink, MGM Goldman, PA Williams, LW Weinstein, MC Goldman, L TI Health and economic benefits of increased beta-blocker use following myocardial infarction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; QUALITY-OF-LIFE; COOPERATIVE CARDIOVASCULAR PROJECT; RANDOMIZED CLINICAL-TRIALS; COST-EFFECTIVENESS; UNITED-STATES; PRACTICE GUIDELINES; ELDERLY PATIENTS; DRUG-TREATMENT; POLICY MODEL AB Context beta -Blockers are underused in patients who have myocardial infarction (MI), despite the proven efficacy of these agents. New evidence indicates that beta -blockers can have benefit in patients with conditions that have been considered relative contraindications, Understanding the consequences of underuse of beta -blockers is important because of the implications for current policy debates over quality-of-care measures and Medicare prescription drug coverage, Objective To examine the potential health and economic impact of increased use of beta -blockers in patients who have had MI. Design and Setting We used the Coronary Heart Disease (CHD) Policy Model, a computer-simulation Markov model of CHD in the US population, to estimate the epidemiological impact and cost-effectiveness of increased beta -blocker use from current to target levels among survivors of MI aged 35 to 84 years. Simulations included 1 cohort of MI survivors in 2000 followed up for 20 years and 20 successive annual cohorts of all first-MI survivors in 2000-2020. Mortality and morbidity from CHD were derived from published meta-analyses and recent studies. This analysis used a societal perspective. Main Outcome Measures Prevented Mis, CHD mortality, life-years gained, and cost per quality-adjusted life-year (QALY) gained in 2000-2020, Results Initiating beta -blocker use for all MI survivors except those with absolute contraindications in 2000 and continuing treatment for 20 years would result in 4300 fewer CHD deaths, 3500 Mis prevented, and 45000 life-years gained compared with current use. The incremental cost per QALY gained would be $4500, If this increase in beta -blocker use were implemented in all first-MI survivors annually over 20 years, beta -blockers would save $18 million and result in 72000 fewer CHD deaths, 62000 Mis prevented, and 447000 life-years gained. Sensitivity analyses demonstrated that the cost-effectiveness of beta -blocker therapy would always be less than $11000 per QALY gained, even under unfavorable assumptions, and may even be cost saving, Restricting beta -blockers only to ideal patients (those without absolute or relative contraindications) would reduce the epidemiological impact of beta -blocker therapy by about 60%, Conclusions Our simulation indicates that increased use of beta -blockers after MI would lead to impressive gains in health and would be potentially cost saving. C1 Univ Calif San Francisco, Sch Pharm, Inst Hlth Policy Studies, Dept Clin Pharm, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Excellence Hlth Care Markets & Managed Care, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Stanford Univ, Palo Alto VA Hlth Care Syst, Palo Alto, CA 94304 USA. Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. RP Phillips, KA (reprint author), Univ Calif San Francisco, Sch Pharm, Inst Hlth Policy Studies, Dept Clin Pharm, 3333 Calif St,Room 420,Box 0613, San Francisco, CA 94143 USA. NR 51 TC 73 Z9 73 U1 1 U2 5 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 DEC 6 PY 2000 VL 284 IS 21 BP 2748 EP 2754 DI 10.1001/jama.284.21.2748 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 377JB UT WOS:000165509500029 PM 11105180 ER PT J AU Shen, JN Wenger, N Glaspy, J Hays, RD Albert, PS Choi, C Shekelle, PG AF Shen, JN Wenger, N Glaspy, J Hays, RD Albert, PS Choi, C Shekelle, PG TI Electroacupuncture for control of myeloablative chemotherapy-induced emesis - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CANCER-CHEMOTHERAPY; SUBSTANCE-P; ACUPUNCTURE; CISPLATIN; ANTIEMETICS; CYCLOPHOSPHAMIDE; ONDANSETRON; ENKEPHALIN; THERAPY; NAUSEA AB Context High-dose chemotherapy poses considerable challenges to emesis management. Although prior studies suggest that acupuncture may reduce nausea and emesis, it is unclear whether such benefit comes from the nonspecific effects of attention and clinician-patient interaction. Objective To compare the effectiveness of electroacupuncture vs minimal needling and mock electrical stimulation or antiemetic medications alone in controlling emesis among patients undergoing a highly emetogenic chemotherapy regimen. Design Three-arm, parallel-group, randomized controlled trial conducted from March 1996 to December 1997, with a 5-day study period and a 9-day follow-up. Setting Oncology center at a university medical center. Patients One hundred four women (mean age, 46 years) with high-risk breast cancer. Interventions Patients were randomly assigned to receive low-frequency electroacupuncture at classic antiemetic acupuncture points once daily for 5 days (n=37), minimal needling at control points with mock electrostimulation on the same schedule (n=33); or no adjunct needling (n=34). All patients received concurrent triple antiemetic pharmacotherapy and high-dose chemotherapy (cyclophosphamide, cisplatin, and carmustine). Main Outcome Measures Total number of emesis episodes occurring during the 5-day study period and the proportion of emesis-free days, compared among the 3 groups. Results The number of emesis episodes occurring during the 5 days was lower for patients receiving electroacupuncture compared with those receiving minimal needling or pharmacotherapy alone (median number of episodes, 5, 10, and 15, respectively; P<.001). The electroacupuncture group had fewer episodes of emesis than the minimal needling group (P<.001), whereas the minimal needling group had fewer episodes of emesis than the antiemetic pharmacotherapy alone group (P=.01), The differences among groups were not significant during the 9-day follow-up period (P=.18), Conclusions in this study of patients with breast cancer receiving high-dose chemotherapy, adjunct electroacupuncture was more effective in controlling emesis than minimal needling or antiemetic pharmacotherapy alone, although the observed effect had limited duration. C1 NIAAA, Clin Studies Lab, Brain Electrophysiol & Imaging Sect, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. W Los Angeles Vet Affairs Med Ctr, Dept Med, Vet Affairs Hlth Serv REs & Dev Serv, Los Angeles, CA 90073 USA. RP Shen, JN (reprint author), NIAAA, Clin Studies Lab, Brain Electrophysiol & Imaging Sect, NIH, Room 6 S-240,Mail Stop 1610,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. RI Hays, Ronald/D-5629-2013 FU BHP HRSA HHS [PE19001-09] NR 31 TC 149 Z9 158 U1 3 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 6 PY 2000 VL 284 IS 21 BP 2755 EP 2761 DI 10.1001/jama.284.21.2755 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 377JB UT WOS:000165509500030 PM 11105182 ER PT J AU Signoretti, S Montironi, R Manola, J Altimari, A Tam, C Bubley, G Balk, S Thomas, G Kaplan, I Hlatky, L Hahnfeldt, P Kantoff, P Loda, M AF Signoretti, S Montironi, R Manola, J Altimari, A Tam, C Bubley, G Balk, S Thomas, G Kaplan, I Hlatky, L Hahnfeldt, P Kantoff, P Loda, M TI Her-2-neu expression and progression toward androgen independence in human prostate cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID EPIDERMAL GROWTH-FACTOR; IN-SITU HYBRIDIZATION; HER-2/NEU ONCOGENE AMPLIFICATION; RECEPTOR GENE-MUTATIONS; HUMAN-BREAST; PROGNOSTIC VALUE; CARCINOMA-CELLS; OVARIAN-CANCER; NEU ONCOGENE; KINASE AB Background: Human prostate cancers are initially androgen dependent but ultimately become androgen independent. Overexpression of the Her-2-neu receptor tyrosine kinase has been associated with the progression to androgen independence in prostate cancer cells. Ne examined the expression of Her-2-neu in normal and cancerous prostate tissues to assess its role in the progression to androgen independence. Methods: Prostate cancer tissue sections were obtained from 67 patients treated by surgery alone (UNT tumors), 34 patients treated with total androgen ablation therapy before surgery (TAA tumors), and 18 patients in whom total androgen ablation therapy failed and who developed bone metastases (androgen-independent [A1] disease). The sections were immunostained for Her-2-neu, androgen receptor (AR), prostate-specific antigen (PSA), and Ki-67 (a marker of cell proliferation) protein expression. Messenger RNA (mRNA) levels and gene amplification of Her-2-neu were examined by RNA in situ hybridization and fluorescent ill situ hybridization(FISH), respectively, in a subset of 27 tumors (nine UNT, 11 TAA, and seven AI), All statistical tests were two-sided. Results: Her-2-neu protein expression was statistically significantly higher in TAA. tumors than in UNT tumors with the use of two different scoring methods (P = .008 and P = .002), The proportion of Her-2-neu-positive tumors increased from the UNT group (17 of 67) to the TAA group (20 of 34) to the AI group (14 of 18) (P<.001). When compared with UNT tumors, tumor cell proliferation was higher in Al tumors (P = .014) and lower in TAA tumors (P<.001). All tumors expressed AR and PSA proteins. Although Her-2-neu mRNA expression was high in TAA and AI tumors, no Her-2-neu gene amplification was detected by FISH in any of the tumor types. Conclusions: Her-2-neu expression appears to increase with progression to androgen independence. Thus, therapeutic targeting of this tyrosine kinase in prostate cancer may be warranted. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Ancona, Ancona, Italy. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Radiat Therapy, Boston, MA USA. Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA USA. RP Loda, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 740B,44 Binney St, Boston, MA 02215 USA. FU NCI NIH HHS [5R01CA81755-03] NR 63 TC 264 Z9 273 U1 1 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 6 PY 2000 VL 92 IS 23 BP 1918 EP 1925 DI 10.1093/jnci/92.23.1918 PG 8 WC Oncology SC Oncology GA 379LP UT WOS:000165643800013 PM 11106683 ER PT J AU Zhou, QL Zhou, Q Forman, SA AF Zhou, QL Zhou, Q Forman, SA TI The n-alcohol site in the nicotinic receptor pore is a hydrophobic patch SO BIOCHEMISTRY LA English DT Article ID ACETYLCHOLINE-RECEPTOR; GENERAL-ANESTHETICS; ION-CHANNEL; OPEN STATE; M2 DOMAIN; MUTATIONS; RESIDUES; ALKANOLS; ETHANOL; TORPEDO AB Alcohols and volatile anesthetics inhibit peripheral nicotinic acetylcholine receptors noncompetitively, primarily via an open-channel block mechanism. Analysis of hydrophobic mutations near the middle of the pore-forming M2 domains suggested that alcohols interact with the pore in this vicinity. To establish the extent of this inhibitory site, we created a series of hydrophobicity-altering mutations scanning most of the alpha subunit M2 domain. Using both single-channel and rapid patch perfusion electrophysiology, we measured how these mutations affect nAChR sensitivity to ethanol and hexanol. We find a near-contiguous series of amino acids in alpha -M2, extending from alpha L250 (8') to alpha V255 (13'), where mutagenesis strongly influences inhibition by alcohols. These results support the existence of a large inhibitory patch in the nAChR pore lining where interactions with alcohols an primarily due to hydrophobic forces. Ethanol appears to interact with deeper regions of this site than does hexanol. Because alcohols apparently act as open-channel blockers, we infer from our results that most of the residues between alpha L250 and alpha V255 are exposed to the aqueous environment of the pore when the channel is open. The location and extent of this site can explain why small alcohols occupy the nAChR pore at the same time as larger alcohols or charged blockers, while two large alcohols bind in a mutually exclusive manner. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02114 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, CLN-3, Boston, MA 02114 USA. FU NIAAA NIH HHS [K21AA00206]; NIGMS NIH HHS [P01GM58448] NR 31 TC 31 Z9 31 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 5 PY 2000 VL 39 IS 48 BP 14920 EP 14926 DI 10.1021/bi001281q PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 378XF UT WOS:000165610100024 PM 11101308 ER PT J AU Cooper, JA Miller, GJ Bauer, KA Morrissey, JH Meade, TW Howarth, DJ Barzegar, S Mitchell, JP Rosenberg, RD AF Cooper, JA Miller, GJ Bauer, KA Morrissey, JH Meade, TW Howarth, DJ Barzegar, S Mitchell, JP Rosenberg, RD TI Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease SO CIRCULATION LA English DT Article DE coronary disease; coagulation; risk factors; epidemiology ID MIDDLE-AGED MEN; ACTIVATED FACTOR-VII; CARDIOVASCULAR-DISEASE; NEUTROPHIL ELASTASE; FACTOR-XII; FACTOR-IX; COAGULATION; PLASMA; ATHEROSCLEROSIS; THROMBOSIS AB Backgroud-This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment. Methods and Results-Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk. Conclusions-Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors. C1 Wolfson Inst Prevent Med, MRC, Epidemiol & Med Care Unit, London EC1M 6BQ, England. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA 02215 USA. Oklahoma Med Res Fdn, Cardiovasc Biol Res Program, Oklahoma City, OK 73104 USA. MIT, Dept Biol, Cambridge, MA USA. RP Miller, GJ (reprint author), Wolfson Inst Prevent Med, MRC, Epidemiol & Med Care Unit, Charterhouse Sq, London EC1M 6BQ, England. FU NHLBI NIH HHS [HL-33014, HL-54502] NR 31 TC 126 Z9 130 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 5 PY 2000 VL 102 IS 23 BP 2816 EP 2822 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 378VZ UT WOS:000165607000005 PM 11104738 ER PT J AU Strom, BL Abrutyn, E Berlin, JA Kinman, JL Feldman, RS Stolley, PD Levison, ME Korzeniowski, OM Kaye, D AF Strom, BL Abrutyn, E Berlin, JA Kinman, JL Feldman, RS Stolley, PD Levison, ME Korzeniowski, OM Kaye, D TI Risk factors for infective endocarditis - Oral hygiene and nondental exposures SO CIRCULATION LA English DT Article DE endocarditis; heart diseases; infection ID AMERICAN-HEART-ASSOCIATION; BACTERIAL-ENDOCARDITIS; CRITERIA; RECOMMENDATIONS; PREVENTION; PROGNOSIS AB Background-The risks of infective endocarditis (IE) associated with various conditions and procedures are poorly defined. Methods and Results-This was a population-based case-control study conducted in 54 Philadelphia, Pa-area hospitals from 1988 to 1990. Community-acquired IE cases unassociated with intravenous drug use were: compared with matched community residents. Subjects were interviewed for risk factors. Diagnoses were confirmed by expert review of medical record abstracts with risk factor data removed. Cases were more likely than controls to suffer from prior severe kidney disease (adjusted OR [95% CI]=16.9 [1.5 to 193], P=0.02) and diabetes mellitus (adjusted OR [95% CI]=2.7 [1.4 to 5.2], P=0.004). Cases infected with skin flora had received intravenous fluids more often (adjusted OR [95% CI]=6.7 [1.1 to 41], P=0.04) and had more often had a previous skin infection (adjusted OR [95% CI]=3.5 [0.7 to 17], P=0.11). No association was seen with pulmonary, gastrointestinal, cardiac, or genitourinary procedures or with surgery. Edentulous patients had a lower risk of IE from dental flora than patients who had teeth but did not floss. Daily flossing was associated with a borderline decreased IE risk. Conclusions-Within the limits of the available sample size, the data showed that IE patients differ from people without IE with regard to certain important risk factors but not regarding recent procedures. C1 Univ Penn, Sch Med, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Dent Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Dent Med, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Dent Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. MCP Hahnemann Sch Med, Dept Med, Philadelphia, PA USA. Vet Affairs Med Ctr, Philadelphia, PA USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Strom, BL (reprint author), Univ Penn, Sch Med, Dept Epidemiol & Biostat, Room 824 Blockley Hall, Philadelphia, PA 19104 USA. FU NHLBI NIH HHS [R01 HL39000] NR 22 TC 86 Z9 93 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 5 PY 2000 VL 102 IS 23 BP 2842 EP 2848 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 378VZ UT WOS:000165607000009 PM 11104742 ER PT J AU Budts, W Pokreisz, P Nong, ZX Van Pelt, N Gillijns, H Gerard, R Lyons, R Collen, D Bloch, KD Janssens, S AF Budts, W Pokreisz, P Nong, ZX Van Pelt, N Gillijns, H Gerard, R Lyons, R Collen, D Bloch, KD Janssens, S TI Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats SO CIRCULATION LA English DT Article DE nitric oxide synthase; hypertension, pulmonary; genes; vasculature; remodeling ID RIGHT-VENTRICULAR HYPERTROPHY; STRUCTURAL-CHANGES; INHALED NO; LUNGS; CIRCULATION; RELAXATION; EXPRESSION; ARTERIES; GROWTH; VASOCONSTRICTION AB Background-Nitric oxide (NO) is a potent vasodilator with an important role in the regulation of pulmonary vascular tone. The effects of NO synthase (NOS) gene transfer on pulmonary vascular remodeling associated with hypoxic pulmonary hypertension are unknown. Methods and Results-We aerosolized 3X10(9) pfu of an adenoviral vector containing inducible NOS gene (AdNOS2), constitutive NOS3 gene (AdNOS3), or no transgene (AdRR5) into rat lungs. Exhaled NO levels, monitored with chemiluminescence, were higher in AdNOS2-infected rats than in AdNOS3- and AdRR5-infected rats (at 3 days, 33+/-6 ppb, n=9, versus 17+/-4, n=9, and 6+/-2 ppb, n=3, P<0.05 for both). Exposure to FIO2 0.10 for 7 days increased pulmonary artery pressure from 19+/-4 mm Hg (baseline) to 27+/-1 and 26+/-2 mm Hg in AdNOS3- and AdRR5-infected rats, respectively, but only to 21+/-1 mm Hg in AdNOS2-infected animals (P<0.05). After 7 days of hypoxia, total pulmonary resistance in AdRR5- and AdNOS3-infected rats was significantly higher than in AdNOS2-infected animals (0.41+/-0.05 and 0.39+/-0.07 versus 0.35+/-0.03 mmHg . mL(-1) . min(-1), respectively; P<0.05). Right ventricular hypertrophy was reduced in AdNOS2-infected rats [right ventricular/(left ventricular+septal) weight, 0.19+/-0.10 versus 0.28+/-0.10 and 0.32+/-0.10 in AdRR5- and AdNOS3-infected rats, respectively, P<0.05]. The percentage of muscularized precapillary pulmonary resistance vessels was also significantly decreased (18+/-4% versus 25+/-8% and 30+/-5% in AdRR5- and AdNOS3-infected rats, P<0.05). Conclusions-Aerosol NOS2 gene transfer increases pulmonary NO production and significantly reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Aerosol NOS2 gene transfer may be a promising strategy to target pulmonary vascular disorders. C1 Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, B-3000 Leuven, Belgium. Katholieke Univ Leuven VIB, Dept Cardiol, B-3000 Leuven, Belgium. Univ New Mexico, Hlth & Sci Ctr, Albuquerque, NM 87131 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Janssens, S (reprint author), Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, 49 Herestr, B-3000 Leuven, Belgium. EM stefan.janssens@med.kuleuven.ac.be FU PHS HHS [55377] NR 45 TC 48 Z9 51 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 DEC 5 PY 2000 VL 102 IS 23 BP 2880 EP 2885 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 378VZ UT WOS:000165607000015 PM 11104748 ER PT J AU Caplan, D AF Caplan, D TI Language-related cortex in deaf individuals: Functional specialization for language or perceptual plasticity? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ORGANIZATION C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, Vincent Burnham 827,Fruit St, Boston, MA 02114 USA. FU NIDCD NIH HHS [R01 DC002146] NR 7 TC 4 Z9 5 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 DEC 5 PY 2000 VL 97 IS 25 BP 13476 EP 13477 DI 10.1073/pnas.97.25.13476 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800006 PM 11106391 ER PT J AU Colas, P Cohen, B Ferrigno, PK Silver, PA Brent, R AF Colas, P Cohen, B Ferrigno, PK Silver, PA Brent, R TI Targeted modification and transportation of cellular proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE peptide aptamers; combinatorial peptide libraries; protein interactions; cellular nanotechnology; protein design ID PEPTIDE APTAMERS; GENETIC SELECTION; ESCHERICHIA-COLI; DNA-BINDING; UBIQUITIN; MUTAGENESIS; SPECIFICITY; CONNECTIONS; THIOREDOXIN; ACTIVATION AB Peptide aptamers are proteins selected from combinatorial libraries that display conformationally constrained variable regions. Peptide aptamers can disrupt specific protein interactions and thus represent a useful method for manipulating protein function in vivo. Here, we describe aptamer derivatives that extend the range of functional manipulations. We isolated an aptamer with increased affinity for its Cdk2 target by mutagenizing an existing aptamer and identifying tighter binding mutants with calibrated two-hybrid reporter genes. We used this and other anti-Cdk2 aptamers as recognition domains in chimeric proteins that contained other functional moieties. Aptamers fused to the catalytic domain of a ubiquitin ligase specifically decorated LexA-Cdk2 with ubiquitin moieties in vivo. Aptamers against Cdk2 and another protein, Ste5, that carried a nuclear localization sequence transported their targets into the nucleus. These experiments indicate that fusion proteins containing aptameric recognition moieties will be useful for specific modification of protein function in vivo. C1 Inst Mol Sci, Berkeley, CA 94704 USA. Ecole Normale Super Lyon, Lab Biol Mol & Cellulaire, F-69364 Lyon 07, France. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brent, R (reprint author), Inst Mol Sci, Berkeley, CA 94704 USA. NR 40 TC 35 Z9 36 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 DEC 5 PY 2000 VL 97 IS 25 BP 13720 EP 13725 DI 10.1073/pnas.97.25.13720 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800049 PM 11106396 ER PT J AU Lauderdale, J Wilensky, JS Oliver, ER Walton, DS Glaser, T AF Lauderdale, J Wilensky, JS Oliver, ER Walton, DS Glaser, T TI 3 ' deletions cause aniridia by preventing PAX6 gene expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HOMEOBOX-CONTAINING GENE; FAMILIAL ANIRIDIA; SONIC HEDGEHOG; WILMS-TUMOR; MUTATIONS; EYE; REGION; LOCUS; MICE; MALFORMATIONS AB Aniridia is a panocular human eye malformation caused by heterozygous null mutations within PAX6, a paired-box transcription factor, or cytogenetic deletions of chromosome 11p13 that encompass PAX6. Chromosomal rearrangements also have been described that disrupt 11p13 but spare the PAX6 transcription unit in two families with aniridia. These presumably cause a loss of gene expression, by removing positive cis regulatory elements or juxtaposing negative DNA sequences. We report two submicroscopic de novo deletions of 11p13 that cause aniridia but are located >11 kb from the 3' end of PAX6. The clinical manifestations are indistinguishable from cases with chain-terminating mutations in the coding region. Using human x mouse retinoblastoma somatic cell hybrids, we show that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Our findings suggest that remote 3' regulatory elements are required for initiation of PAX6 expression. C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Glaser, T (reprint author), Univ Michigan, Dept Internal Med, 4510 MSRB 1,Box 0650,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 46 TC 94 Z9 98 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 DEC 5 PY 2000 VL 97 IS 25 BP 13755 EP 13759 DI 10.1073/pnas.240398797 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800055 PM 11087823 ER PT J AU Roberts, CWM Galusha, SA McMenamin, ME Fletcher, CDM Orkin, SH AF Roberts, CWM Galusha, SA McMenamin, ME Fletcher, CDM Orkin, SH TI Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SWI/SNF COMPLEX; MULTISUBUNIT COMPLEX; GENE-PRODUCTS; YEAST; HSNF5/INI1; MUTATIONS; TRANSCRIPTION; STIMULATION; COMPONENTS; BINDING AB Malignant rhabdoid tumor (MRT) is an aggressive, highly lethal cancer of young children. Tumors occur in various locations, including kidney, brain, and soft tissues. Despite intensive therapy, 80% of affected children die, often within 1 year of diagnosis. The majority of MRT samples and cell lines have sustained biallelic inactivating mutations of the hSNF5 (integrase interactor 1) gene, suggesting that hSNF5 may act as a tumor suppressor. We sought to examine the role of Snf5 in development and cancer in a murine model. Here we report that Snf5 is widely expressed during embryogenesis with focal areas of high-level expression in the mandibular portion of the first branchial arch and central nervous system. Homozygous knockout of Snf5 results in embryonic lethality by embryonic day 7, whereas heterozygous mice are born at the expected frequency and appear normal. However, beginning as early as 5 weeks of age, heterozygous mice develop tumors consistent with MRT, The majority of tumors arise in soft tissues derived from the first branchial arch. Our findings constitute persuasive genetic evidence that Snf5, a core member of the Swi/Snf chromatin-remodeling complex, functions as a tumor suppressor gene, and, moreover, Snf5 heterozygotes provide a murine model of this lethal pediatric cancer. C1 Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Dana Farber Canc Inst, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol, 300 Longwood Ave,Enders Bldg,Room 761, Boston, MA 02115 USA. NR 27 TC 245 Z9 250 U1 1 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 DEC 5 PY 2000 VL 97 IS 25 BP 13796 EP 13800 DI 10.1073/pnas.250492697 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800062 PM 11095756 ER PT J AU Andre, P Hartwell, D Hrachovinova, I Saffaripour, S Wagner, DD AF Andre, P Hartwell, D Hrachovinova, I Saffaripour, S Wagner, DD TI Pro-coagulant state resulting from high levels of soluble P-selecain in blood SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CIRCULATING ADHESION MOLECULES; SELECTIN-DEFICIENT MICE; VON-WILLEBRAND-FACTOR; TISSUE FACTOR; ADHERENT PLATELETS; PROCOAGULANT ACTIVITY; NEUTROPHIL ADHESION; THROMBUS FORMATION; PLASMA-PROTEIN; WHOLE-BLOOD AB The plasma concentration of soluble adhesion receptors is increased under pathological circumstances, but their function remains enigmatic. Soluble P-selectin (sP-sel) is shed from activated platelets and endothelial cells, Mice genetically engineered to express P-selectin without the cytoplasmic tail (Delta CT) constitutively show a 3- to 4-fold increase of sP-sel in plasma. We observed that the Delta CT mice formed fibrin Very readily. In an ex vivo perfusion chamber, there was more fibrin deposited at the site of platelet thrombus formation than in wild type (WT), whereas no fibrin deposits were detected using P-selectin-deficient blood during the same interval. Similarly, in vivo, the hemorrhage produced by local Shwartzman reaction was smaller in the Delta CT mice than in WT. In contrast, we previously showed hemorrhage to be more prominent in P-selectin knock-out mice. Infusion of mouse P-sel-1g chimera produced the same protective effect in WT mice as seen in the Delta CT mice, indicating that the effect was due to increased levels of sP-sel, Mice infused with P-sel-1g showed significantly more fibrin deposited on the luminal face of the injured vessels than control mice. Plasma from Delta CT mice or mice infused with P-sel-1g contained higher concentration of pro-coagulant microparticles and clotted one minute faster than WT. This pro-coagulant phenotype of Delta CT mice could be reversed by a 4-day treatment with PSGL-1g, a P-selectin inhibitor. We propose that sP-sel should no longer be considered only as a marker of inflammation or platelet activation, but also as a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [P01 HL056949, P01 HL56949, R01 HL053756, R01 HL53756] NR 49 TC 213 Z9 226 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 DEC 5 PY 2000 VL 97 IS 25 BP 13835 EP 13840 DI 10.1073/pnas.250475997 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800069 PM 11095738 ER PT J AU Dimitroff, CJ Lee, JY Fuhlbrigge, RC Sackstein, R AF Dimitroff, CJ Lee, JY Fuhlbrigge, RC Sackstein, R TI A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADHESION MOLECULES; P-SELECTIN; PROGENITOR CELLS; T-CELLS; GLYCOPROTEIN LIGAND-1; PLATELET RECOVERY; HYALURONIC-ACID; MARROW CULTURES; CD34(+) CELLS; EXPRESSION AB We previously have obtained operational evidence of a hematopoietic cell L-selectin ligand expressed on normal human hematopoietic cells and on leukemic blasts. Using a technique developed in our laboratory for analyzing and identifying adhesion molecules, we show here that hematopoietic cell L-selectin ligand is a specialized glycoform of CD44. This L-selectin ligand activity of CD44 requires sialofucosylated N-linked glycans and is sulfation-independent. These data provide important insights on the structural biology of CD44 and reveal a role for this protein as an L-selectin ligand on human hematopoietic cells. C1 Harvard Univ, Inst Med, Sch Med, Skin Dis Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. RP Sackstein, R (reprint author), Harvard Univ, Inst Med, Sch Med, Skin Dis Res Ctr, 77 Ave Louis Pasteur,Room 671, Boston, MA 02115 USA. FU NHLBI NIH HHS [R01 HL60528, R01 HL060528] NR 42 TC 80 Z9 82 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 DEC 5 PY 2000 VL 97 IS 25 BP 13841 EP 13846 DI 10.1073/pnas.250484797 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800070 PM 11095749 ER PT J AU Calvert, PD Krasnoperova, NV Lyubarsky, AL Isayama, T Nicolo, M Kosaras, B Wong, G Gannon, KS Margolskee, RF Sidman, RL Pugh, EN Makino, CL Lem, J AF Calvert, PD Krasnoperova, NV Lyubarsky, AL Isayama, T Nicolo, M Kosaras, B Wong, G Gannon, KS Margolskee, RF Sidman, RL Pugh, EN Makino, CL Lem, J TI Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha-subunit SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-BETA-SUBUNIT; RECESSIVE RETINITIS-PIGMENTOSA; STATIONARY NIGHT BLINDNESS; CONE PHOTORECEPTORS; GAMMA-SUBUNIT; RHODOPSIN GENE; GATED CHANNEL; OUTER SEGMENT; RETINAL RODS; 3RD FORM AB Retinal photoreceptors use the heterotrimeric: G protein transducin to couple rhodopsin to a biochemical cascade that underlies the electrical photoresponse. Several isoforms of each transducin subunit are present in the retina. Although rods and cones seem to contain distinct transducin subunits, it is not known whether phototransduction in a given cell type depends strictly on a single form of each subunit. To approach this question, we have deleted the gene for the rod transducin cu-subunit in mice. In hemizygous knockout mice, there was a small reduction in retinal transducin cr-subunit content but retinal morphology and the physiology of single rods were largely normal. In homozygous knockout mice, a mild retinal degeneration occurred with age. Rod-driven components were absent from the electroretinogram, whereas cone-driven components were retained. Every photoreceptor examined by single-cell recording failed to respond to flashes, with one exception. The solitary responsive cell was insensitive, as expected for a cone, but had a rod-like spectral sensitivity and flash response kinetics that were slow, even for rods. These results indicate that most if not ail rods use a single transducin type in phototransduction. C1 Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. New England Med Ctr, Dept Ophthalmol, Boston, MA 02111 USA. New England Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. Univ Penn, Inst Neurol Sci, Philadelphia, PA 19104 USA. CUNY Mt Sinai Sch Med, Dept Physiol & Biophys, Howard Hughes Med Inst, New York, NY 10029 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 01772 USA. Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Genet Program, Boston, MA 02111 USA. RP Makino, CL (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY06857, EY02660, EY11358, F32 EY006857, P30 EY012196, R01 EY002660, R01 EY011358, R29 EY011358]; NIDCD NIH HHS [R01 DC003055] NR 50 TC 198 Z9 200 U1 2 U2 13 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 DEC 5 PY 2000 VL 97 IS 25 BP 13913 EP 13918 DI 10.1073/pnas.250478897 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 380XH UT WOS:000165728800082 PM 11095744 ER PT J AU Smoller, JW Lunetta, KL Robins, J AF Smoller, JW Lunetta, KL Robins, J TI Implications of comorbidity and ascertainment bias for identifying disease genes SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetic; comorbidity; transmission/disequilibrium test; ascertainment bias; psychiatric ID SOCIAL PHOBIA; DEPRESSION; LIFETIME; PREVALENCE; DISORDERS; MORBIDITY; ANXIETY; SAMPLE AB Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples, An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagnostic evaluation We refer to the component of the comorbidity between illnesses due to such ascertainment bias as "spurious comorbidity." When spurious comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an association between the locus and a comorbid phenotype, This phenomenon, which we call "spurious comorbidity bias," could thus produce misleading association findings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association studies. Because of the extremely high rates of comorbidity among psychiatric disorders in clinical samples, this problem may be particularly salient for genetic studies of neuropsychiatric disorders, We conclude that ascertainment bias may contribute to the frequent difficulty in replicating candidate gene study findings in psychiatry. (C) 2000 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Psychiat Genet Program Mood & Anxiety Disorders, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Smoller, JW (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WACC-815, Boston, MA 02114 USA. FU NIMH NIH HHS [MH59532-02, MH60485-01, T32MH17119] NR 17 TC 20 Z9 20 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 4 PY 2000 VL 96 IS 6 BP 817 EP 822 DI 10.1002/1096-8628(20001204)96:6<817::AID-AJMG25>3.0.CO;2-A PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 380RM UT WOS:000165717300025 PM 11121189 ER PT J AU Collins, JS Perry, RT Watson, B Harrell, LE Acton, RT Blacker, D Albert, MS Tanzi, RE Bassett, SS McInnis, MG Campbell, RD Go, RCP AF Collins, JS Perry, RT Watson, B Harrell, LE Acton, RT Blacker, D Albert, MS Tanzi, RE Bassett, SS McInnis, MG Campbell, RD Go, RCP TI Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE chromosome 6; HLA; TNF; cytokine; dementia ID AMYLOID BETA-PROTEIN; DEPENDENT DIABETES-MELLITUS; FACTOR-ALPHA; APOLIPOPROTEIN-E; TNF-ALPHA; TRANSMISSION/DISEQUILIBRIUM TEST; ALPHA-2-MACROGLOBULIN GENE; RHEUMATOID-ARTHRITIS; IN-VITRO; CYCLOOXYGENASE-2 EXPRESSION AB Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines, Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene, Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings, These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test, Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families, This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD, (C) 2000 Wiley-Liss, Inc. C1 Univ Alabama, Dept Epidemiol & Int Hlth, Birmingham, AL 35294 USA. Univ Alabama, Dept Human Genet, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Immunogenet Program, Birmingham, AL 35294 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Genet & Aging Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Johns Hopkins Univ, Inst Med, Dept Psychiat, Baltimore, MD USA. MRC, UK HGMP Resource Ctr, Cambridge, England. RP Go, RCP (reprint author), Univ Alabama, Dept Epidemiol & Int Hlth, 220A Ryals Bldg,1665 Univ Blvd, Birmingham, AL 35294 USA. RI McInnis, Melvin/F-6963-2012 OI McInnis, Melvin/0000-0002-0375-6247 FU NIA NIH HHS [U24 AG021886]; NIMH NIH HHS [R01 MH60001, U01 MH46373, U01 MH51024] NR 90 TC 91 Z9 101 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 4 PY 2000 VL 96 IS 6 BP 823 EP 830 DI 10.1002/1096-8628(20001204)96:6<823::AID-AJMG26>3.0.CO;2-I PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 380RM UT WOS:000165717300026 PM 11121190 ER PT J AU Bester, H Beggs, S Woolf, CJ AF Bester, H Beggs, S Woolf, CJ TI Changes in tactile stimuli-induced behavior and c-Fos expression in the superficial dorsal horn and in parabrachial nuclei after sciatic nerve crush SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Review DE parabrachial area; dorsal horn; allodynia; nerve injury; pain, plasticity ID RAT SPINAL-CORD; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; SUBSTANCE-P RECEPTOR; PRIMARY AFFERENT TERMINALS; ROOT GANGLION-CELLS; LAMINA-I NEURONS; PERIPHERAL-NERVE; ELECTROPHYSIOLOGICAL EVIDENCE; EFFERENT PROJECTIONS; PHA-L AB Neurons in the superficial laminae of the dorsal horn are dominated by input from peripheral nociceptors. Following peripheral nerve injury, low threshold mechanoreceptive A beta- fibers sprout from their normal termination site in laminae III/IV into laminae I-II and this structural reorganization may contribute to neuropathic tactile pain hypersensitivity. We have now investigated whether a sciatic nerve crush injury alters the behavioral response in rats to tactile stimuli and whether this is associated with a change in the pattern of c-Fos expression in the dorsal horn and the parabrachial area of the brainstem. Sciatic nerve crush resulted in a patchy but marked tactile allodynia manifesting first at 3 weeks and persisting for up to 52 weeks. C-Fos expression in the dorsal horn and parabrachial region was never observed on brushing the skin of the sciatic nerve territory in animals with intact nerves, but was found after sciatic nerve crush with peripheral regeneration. We conclude that after nerve injury, low threshold mechanoreceptor fibers may play a major role in producing pain-related behavior by activating normally nociceptive-specific regions of the central nervous system such as the superficial laminae of the dorsal horn and the parabrachial area. (C) 2000 Wiley-Liss, Inc. C1 UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Neuronal Plast Res Grp, Charlestown, MA 02129 USA. RP Bester, H (reprint author), UCL, Dept Anat & Dev Biol, Gower St, London WC1E 6BT, England. EM h.bester@ucl.ac.uk FU NINDS NIH HHS [NS38253-01] NR 105 TC 82 Z9 83 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 4 PY 2000 VL 428 IS 1 BP 45 EP 61 DI 10.1002/1096-9861(20001204)428:1<45::AID-CNE5>3.0.CO;2-A PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 370NN UT WOS:000165129300005 PM 11058224 ER PT J AU Haas, NB Manola, J Hudes, G Citrin, DL Kies, MS Davis, TE AF Haas, NB Manola, J Hudes, G Citrin, DL Kies, MS Davis, TE TI Phase II pilot study of combined chemohormonal therapy with doxorubicin and estramustine in metastatic prostate cancer - Eastern Cooperative Oncology Group study PH882 SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE chemohormonal therapy; doxorubicin; estramustine; prostate cancer; metastases ID ORAL ESTRAMUSTINE; CARCINOMA; ADENOCARCINOMA; ADRIAMYCIN; PHOSPHATE; TRIAL AB Twenty-nine patients with progressive hormone-refractory metastatic adenocarcinoma of the prostate were treated with daily estramustine phosphate at 10 mg/kg, and I.V. doxorubicin 50 mg/m(2) every 3 weeks. Twenty-six patients were evaluable. Four of seven patients with nonosseous measurable disease had partial responses lasting 3 to 10 months. Eleven of 19 patients with osseous metastases had stable disease or improvement on bone scan, 6 of these for 7 months or longer. Median time to progression was 20 weeks, and the median survival was 43 weeks. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. RP Haas, NB (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. FU NCI NIH HHS [CA27525, CA23118, CA17145] NR 14 TC 10 Z9 10 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD DEC PY 2000 VL 23 IS 6 BP 589 EP 592 DI 10.1097/00000421-200012000-00012 PG 4 WC Oncology SC Oncology GA 383XT UT WOS:000165910500012 PM 11202803 ER PT J AU Brogi, E Cibas, ES AF Brogi, E Cibas, ES TI Cytologic detection of Toxoplasma gondii tachyzoites in cerebrospinal fluid SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Toxoplasma gondii; toxoplasmosis; cytology; cerebrospinal fluid; AIDS; immunosuppression; opportunistic infection ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CENTRAL-NERVOUS-SYSTEM; CEREBRAL TOXOPLASMOSIS; AIDS; ENCEPHALITIS; INFECTION; NEUROPATHOLOGY; PATIENT AB We reviewed our case records to see how often Toxoplasma gondii organisms were identified by cytologic evaluation of cerebrospinal fluid (CSF). During a 12-year period, 6,090 CSF specimens were examined, and 2 cases (0.03%) showed tachyzoites. Both patients were immunocompromised. One patient underwent lumbar and ventricular taps, and the other underwent only ventricular tap. Organisms were identified in the ventricular specimens but not in the lumbar sample. Both patients were treated, and subsequent ventricular CSF samples were negative. Toxoplasma gondii can be identified by cytologic examination of CSF. Our results confirm prior observations that in patients with obstructive hydrocephalus, tachyzoites are more likely to be found in ventricular rather than lumbar specimens. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cibas, ES (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. NR 18 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC CLIN PATHOLOGISTS PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2000 VL 114 IS 6 BP 951 EP 955 PG 5 WC Pathology SC Pathology GA 378DG UT WOS:000165569300015 PM 11338485 ER PT J AU Gralnek, IM Hays, RD Kilbourne, A Rosen, HR Keeffe, EB Artinian, L Kim, S Lazarovici, D Jensen, DM Busuttil, RW Martin, P AF Gralnek, IM Hays, RD Kilbourne, A Rosen, HR Keeffe, EB Artinian, L Kim, S Lazarovici, D Jensen, DM Busuttil, RW Martin, P TI Development and evaluation of the liver disease quality of life instrument in persons with advanced, chronic liver disease - The LDQOL 1.0 SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID CHRONIC HEPATITIS-C; HEALTH SURVEY SF-36; OF-LIFE; MONTE-CARLO; TRANSPLANTATION; RELIABILITY; QUESTIONNAIRE; OUTCOMES; VALIDITY; IMPACT AB OBJECTIVES: Assessment of health-related quality of life (HRQOL) outcomes in studies of liver disease and liver transplantation is necessary. Reliable and valid disease-targeted HRQOL measures are thus needed. The objective of this study was to develop a reliable and valid self-report HRQOL instrument for ambulatory adults with chronic liver disease. METHODS: The Liver Disease Quality of Life instrument, LDQOL 1.0 (an HRQOL measure that uses the SF-36 as a generic core and 12 disease-targeted multi-item scales) was administered in a multicenter, cross-sectional field test to 221 ambulatory adults with advanced, chronic liver disease referred for primary liver transplantation evaluation. Disease-targeted scales included liver disease-related symptoms, liver disease-related effects on activities of daily living, concentration, memory, sexual functioning, sexual problems, sleep, loneliness, hopelessness, quality of social interaction, health distress, and self-perceived stigma of liver disease. We estimated the internal consistency reliability (Cronbach's alpha) for multi-item scales and construct validity. RESULTS: Internal consistency reliability coefficients were excellent, ranging from 0.62 to 0.95, with 19 of 20 scales >0.70. Multitrait scaling analysis provided strong support for item discrimination across scales, and exploratory factor analysis demonstrated distinguishable physical, mental, and social health dimensions. Significant associations were found between worse HRQOL and worse Child-Pugh class, worse self-rated liver disease severity, and increased number of disability days. CONCLUSIONS: The results of this multicenter field test provide support for the reliability and validity of the LDQOL 1.0 as an HRQOL outcome measure for individuals with chronic liver disease. (C) 2000 by Am. Cell. of Gastroenterology. C1 Vet Affairs Greater Los Angeles Hlth Care Syst, Div Gastroenterol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Div Digest Dis,Ctr Study Digest Hlth Care Qual &, Dept Med,Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dumont Transplant Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Vet Affairs Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. Portland Vet Affairs Med Ctr, Portland, OR USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. RP Gralnek, IM (reprint author), Vet Affairs Greater Los Angeles Hlth Care Syst, Div Gastroenterol, 11301 Wilshire Blvd,CURE Bldg 115 Room 318, Los Angeles, CA 90073 USA. RI Hays, Ronald/D-5629-2013 NR 64 TC 89 Z9 93 U1 2 U2 5 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 DEC PY 2000 VL 95 IS 12 BP 3552 EP 3565 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 383GC UT WOS:000165873900034 PM 11151892 ER PT J AU El-Serag, HB Everhart, JE AF El-Serag, HB Everhart, JE TI Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PORTAL-HYPERTENSION; RECORDS; LIVER; FILES AB OBJECTIVES: Over the past two decades, several modalities have become widely used in the management of esophageal variceal hemorrhage. The effectiveness of these measures on the outcome of patients with this type of hemorrhage remains unknown. METHODS: Using the Department of Veterans Affairs (VA) Patient Treatment File, we identified two cohorts of patients diagnosed with an initial variceal hemorrhage: an early cohort during 1981-1982 (1339 patients), and a late cohort during 1988-1991 (3636 patients). Each cohort was followed for 6 yr for rebleeding and death. Analyses were performed with proportional hazards survival analysis controlling for confounding factors. RESULTS: On presentation, patients in the late cohort were older (57 yr vs 55 yr, p < 0.0001) and had more ascites (25% vs 13%, p < 0.0001), more peritonitis (4% vs 2%, p < 0.0001), and more encephalopathy (14% vs 9%, p = 0.0003). The late cohort experienced a significant decline in mortality at 30 days (20.8% vs 29.6%, p = 0.0001) and at 6 yr (69.7% vs 74.5%, p = 0.0001). This improvement was accentuated in multivariate survival analysis when controlling for the more severe illness in the late cohort. For patients who survived the first 30 days, no significant difference in 6-yr mortality was found on univariate analysis between the early cohort (63.7%) and late cohort (61.8%) (p = 0.25), but survival was slightly better in the late cohort on multivariate analysis (p = 0.01). In the late cohort, patients with sclerotherapy during the initial hospitalization had better 30-day (17%) and 6-yr mortality (68%) than did the rest of the late cohort. CONCLUSIONS: Between the years 1981-1982 and 1988-1991, improvements in long-term survival after an initial episode of esophageal variceal hemorrhage resulted primarily from better short-term mortality. Sclerotherapy offers a partial explanation for improved survival. (C) 2000 by Am. Cell. of Gastroenterology. C1 Houston Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. NIDDK, Bethesda, MD USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr, Gastroenterol Sect, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. NR 30 TC 112 Z9 117 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 DEC PY 2000 VL 95 IS 12 BP 3566 EP 3573 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 383GC UT WOS:000165873900035 PM 11151893 ER PT J AU Lake, SL Blacker, D Laird, NM AF Lake, SL Blacker, D Laird, NM TI Family-based tests of association in the presence of linkage SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HAPLOTYPE RELATIVE RISK; ONSET ALZHEIMER-DISEASE; TRANSMISSION/DISEQUILIBRIUM TEST; GENOMIC SCREEN; CHROMOSOME-12; ALPHA-2-MACROGLOBULIN; DISEQUILIBRIUM; TRANSMISSION; LOCUS; GENE AB Linkage analysis may not provide the necessary resolution for identification of the genes underlying phenotypic variation. This is especially true for gene-mapping studies that focus on complex diseases that do not exhibit Mendelian inheritance patterns. One positional genomic strategy involves application of association methodology to areas of identified linkage. Detection of association in the presence of linkage localizes the gene(s) of interest to more-refined regions in the genome than is possible through linkage analysis alone. This strategy introduces a statistical complexity when family-based association tests are used: the marker genotypes among siblings are correlated in linked regions. Ignoring this correlation will compromise the size of the statistical hypothesis test, thus clouding the interpretation of test results. We present a method for computing the expectation of a wide range of association test statistics under the null hypothesis that there is linkage but no association. To standardize the test statistic, an empirical variance-covariance estimator that is robust to the sibling marker-genotype correlation is used. This method is widely applicable: any type of phenotypic measure or family configuration can be used. For example, we analyze a deletion in the A2M gene at the 5' splice site of "exon II" of the bait region in Alzheimer disease (AD) discordant sibships. Since the A2M gene lies in a chromosomal region (chromosome 12p) that consistently has been linked to AD, association tests should be conducted under the null hypothesis that there is linkage but no association. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lake, SL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. FU NIMH NIH HHS [U01 MH046373, MH 59532, R01 MH059532, R01 MH060009, R01 MH60009, U01 MH046281, U01 MH046290] NR 46 TC 206 Z9 214 U1 0 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC PY 2000 VL 67 IS 6 BP 1515 EP 1525 DI 10.1086/316895 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 378WE UT WOS:000165607600016 PM 11058432 ER PT J AU Lin, AE Pierpont, MEM AF Lin, AE Pierpont, MEM TI Heart development and the genetic aspects of cardiovascular malformations SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Editorial Material ID DISEASE; MORPHOGENESIS C1 Brigham & Womens Hosp, Teratol Program, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Minnesota, Minneapolis, MN USA. Childrens Hosp, St Paul, MN USA. RP Lin, AE (reprint author), Brigham & Womens Hosp, Teratol Program, Old PBBH-B501,75 Francis St, Boston, MA 02115 USA. NR 24 TC 1 Z9 1 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD WIN PY 2000 VL 97 IS 4 BP 235 EP 237 DI 10.1002/1096-8628(200024)97:4<235::AID-AJMG1273>3.0.CO;2-S PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 427CW UT WOS:000168388100001 PM 11376434 ER PT J AU Pierpont, MEM Markwald, RR Lin, AE AF Pierpont, MEM Markwald, RR Lin, AE TI Genetic aspects of atrioventricular septal defects SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE atrioventricular septal defect; endocardial cushions; atrioventricular septal defect susceptibility gene; atrioventricular canal defect; endocardial cushion defect; Down syndrome; heterotaxy ID CONGENITAL HEART-DISEASE; HOLT-ORAM-SYNDROME; ENDOCARDIAL CUSHION DEFECT; FACIAL-SKELETAL SYNDROMES; DOWN-SYNDROME; CANAL DEFECT; NOONAN-SYNDROME; CARDIOVASCULAR MALFORMATIONS; CARDIAC-MALFORMATIONS; ASPLENIA SYNDROME AB Formation of the atrioventricular canal (AVC) results from complex interactions of components of the extracellular matrix. In response to signaling molecules, endothelial/mesenchymal transformations are crucial to normal development of the AVC. Atrioventricular septal defects (AVSDs) can result from arrest or interruption of normal endocardial cushion development. The presence of AVSDs has been associated with chromosome abnormalities, laterality or left-right axis abnormalities, and a variety of syndromes. An AVSD susceptibility gene has been identified in a large kindred with many affected members. Studies of transcription factors and signaling molecules in heart development over the past decade are paving the way for our understanding of the heterogeneous mechanisms of causation of AVSDs. Am. J. Med. Genet. (Semin. Med. Genet.) 97:289-296, 2000. (C) 2001 Wiley-Liss, Inc. C1 Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Childrens Hosp, St Paul, MN USA. Med Univ S Carolina, Dept Cell Biol & Anat, Charleston, SC 29425 USA. Med Univ S Carolina, Cardiovasc Dev Biol Ctr, Charleston, SC 29425 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Pierpont, MEM (reprint author), Univ Minnesota, Dept Pediat, MMC94,420 Delaware St SE, Minneapolis, MN 55455 USA. NR 75 TC 44 Z9 44 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD WIN PY 2000 VL 97 IS 4 BP 289 EP 296 DI 10.1002/1096-8628(200024)97:4<289::AID-AJMG1279>3.3.CO;2-L PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 427CW UT WOS:000168388100007 PM 11376440 ER PT J AU Iglesias, JI Hamburger, RJ Feldman, L Kaufman, JS AF Iglesias, JI Hamburger, RJ Feldman, L Kaufman, JS TI The natural history of incidental renal artery stenosis in patients with aortoiliac vascular disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID ATHEROSCLEROTIC RENOVASCULAR DISEASE; ISCHEMIC NEPHROPATHY; CARDIAC-CATHETERIZATION; AORTIC DISEASE; REVASCULARIZATION; PREVALENCE; HYPERTENSION; POPULATION; FAILURE; RECONSTRUCTION AB PURPOSE: To examine the association between incidentally discovered renal artery stenosis and deterioration of renal function as determined by the change in serum creatinine concentration over time. SUBJECTS AND METHODS: We performed a retrospective review of consecutive patients who underwent aortography for aortoiliac vascular disease. Angiograms were reviewed for renal artery stenosis, defined as a narrowing of at least 20% compared with adjacent normal renal artery. For patients with at least 180 days of subsequent follow-up, the change in serum creatinine concentration per year was compared in patients who had or did not have renal artery stenosis. RESULTS: Of the 201 patients, 96 (48%) had some degree of renal artery stenosis in one or both renal arteries, including 53 (26%) who had at least one stenosis greater than or equal to 50% and 40 (20%) who had bilateral stenoses. The only clinical predictor of renal artery stenosis was a history of coronary artery disease (odds ratio = 2.0, 95% confidence interval: 1.2 to 3.8, P = 0.001). Among the 174 patients with greater than or equal to 180 days of follow-up, there was no statistically significant difference (P = 0.88) in the mean change in serum creatinine concentration per year in the 78 patients with renal artery stenosis (0.06 +/- 0.33 mg/dL per year) as compared with the 96 patients without renal artery stenosis (0.06 +/- 0.22 mg/dL per year). Grouping the patients by the maximal percentage of stenosis did not reveal any difference in the mean changes in serum creatinine concentration per year. CONCLUSIONS: Although renal artery stenosis is a common incidental finding in patients with atherosclerotic vascular disease, it is an uncommon cause of progressive renal disease. (C) 2000 by Excerpta Medica, Inc. C1 VA Boston Healthcare Syst, Renal Sect 111RE, Boston, MA 02130 USA. VA Boston Healthcare Syst, Radiol Sect, Boston, MA 02130 USA. Boston Univ, Sch Med, Dept Med, Renal Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. RP Kaufman, JS (reprint author), VA Boston Healthcare Syst, Renal Sect 111RE, 150 S Huntington Ave, Boston, MA 02130 USA. NR 50 TC 46 Z9 47 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 DEC 1 PY 2000 VL 109 IS 8 BP 642 EP 647 DI 10.1016/S0002-9343(00)00605-7 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 378UX UT WOS:000165604000006 PM 11099684 ER PT J AU To, K Adamian, M Dryja, TP Berson, EL AF To, K Adamian, M Dryja, TP Berson, EL TI Retinal histopathology of an autopsy eye with advanced retinitis pigmentosa in a family with rhodopsin Glu181Lys SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID MUTATION AB PURPOSE: To compare histologic findings in an autopsy eye of an 84-year-old man with advanced retinitis pigmentosa and rhodopsin, Glu181Lys, with two cases of autosomal dominant retinitis pigmentosa (one with rhodopsin, Pro23His, and one with rhodopsin, Cys110Arg) and with a normal control, all of comparable age. METHODS: All eyes were prepared for light and electron microscopy within 6 hours after death. RESULTS: Extensive photoreceptor degeneration was revealed in the eyes with retinitis pigmentosa. Some macular cones showed membranous swirls only in the eye with rhodopsin, Glu181Lys. CONCLUSION: The retinal degeneration caused by rhodopsin, Glu181Lys, can feature membranous swirls in the inner segments of cones in the macula. These swirls have not been reported in other cases of dominant retinitis pigmentosa studied so far, and their pathogenesis remains to be defined. (C) 2000 by Elsevier Science Inc. All rights reserved. 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 Berson, EL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, 243 Charles St, Boston, MA 02114 USA. NR 7 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2000 VL 130 IS 6 BP 790 EP 792 DI 10.1016/S0002-9394(00)00559-6 PG 3 WC Ophthalmology SC Ophthalmology GA 384FQ UT WOS:000165932500015 PM 11124299 ER PT J AU Signoretti, S Waltregny, D Dilks, J Isaac, B Lin, D Garraway, L Yang, A Montironi, R McKeon, F Loda, M AF Signoretti, S Waltregny, D Dilks, J Isaac, B Lin, D Garraway, L Yang, A Montironi, R McKeon, F Loda, M TI p63 is a prostate basal cell marker and is required for prostate development SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EPITHELIAL-CELLS; P53 HOMOLOG; EXPRESSION; PROLIFERATION; PROTEIN; CANCER; REGENERATION; ASSOCIATION; CULTURES; BENIGN AB The p53 homologue p63 encodes for different isotypes able to either transactivate p53 reporter genes (TAP63) or act as p53-dominant-nebatives (Delta Np63). p63 is expressed in the basal cells of many epithelial organs and its germline inactivation in the mouse results in agenesis of organs such as skin appendages and the breast. Here, we show that prostate basal cells, but not secretory or neuroendocrine cells, express p63, In addition, prostate basal cells in culture predominantly express the Delta Np63 alpha isotype, In contrast, p63 protein is not detected in human prostate adenocarcinomas. Finally, and most importantly, p63(-/-) mice do not develop the prostate. These results indicate that p63 is required for prostate development and support the hypothesis that basal cells represent and/or include prostate stem cells. Furthermore, our results show that p63 immunohistochemistry may be a valuable tool in the differential diagnosis of benign versus malignant prostatic lesions. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. Univ Ancona, Dept Pathol, Ancona, Italy. RP Loda, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 740B,44 Binney St, Boston, MA 02215 USA. FU NCI NIH HHS [CA 81755-03] NR 27 TC 364 Z9 384 U1 0 U2 10 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 DEC PY 2000 VL 157 IS 6 BP 1769 EP 1775 DI 10.1016/S0002-9440(10)64814-6 PG 7 WC Pathology SC Pathology GA 379XK UT WOS:000165668300003 PM 11106548 ER PT J AU LaMontagne, KR Moses, MA Wiederschain, D Mahajan, S Holden, J Ghazizadeh, H Frank, DA Arbiser, JL AF LaMontagne, KR Moses, MA Wiederschain, D Mahajan, S Holden, J Ghazizadeh, H Frank, DA Arbiser, JL TI Inhibition of MAP kinase kinase causes morphological reversion and dissociation between soft agar growth and in vivo tumorigenesis in angiosarcoma cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RIE-1 EPITHELIAL-CELLS; NIH 3T3 CELLS; RAS TRANSFORMATION; TUMOR ANGIOGENESIS; CYCLE ARREST; ACTIVATION; EXPRESSION; DIFFERENTIATION; SUFFICIENT; ONCOGENES AB Activated ras causes increased activity of several signal transduction systems, including the mitogen-activated protein kinase kinase (MAPKK) pathway and the phosphoinositol-3-kinase (PI-3-K) pathway. We have previously shown that the PI-3-K pathway plays a major role in regulation of ras-mediated tumor angiogenesis in angiosarcoma cells. However, the contribution of the MAPKK pathway to tumorigenesis and angiogenesis is not fully understood. Overexpression of constitutively active forms of MAPKK has previously been shown to transform nonmalignant MH3T3 fibroblasts, but the effect of down-regulation of MAPKK on tumorigenesis and angiogenesis in a well established tumor has not been fully explored. We introduced a dominant negative MAPKK gene into SVR murine angiosarcoma cells. Introduction of a dominant negative MAPKK causes a significant decrease in proliferation rate in vitro and morphological reversion, Cells expressing the dominant negative MAPKK have a greatly decreased ability to form colonies in soft agar compared with wild-type cells. Despite the decreased cell growth in vitro and inability to grow in soft agar, the cells were equally tumorigenic in nude mice. Our results suggest that the MAPKK pathway is required for soft agar growth of angiosarcoma cells, and separates the phenotypes of soft agar growth versus in vivo tumorigenicity. These findings have implications in the development of signal transduction modulators as potential antineoplastic agents. C1 Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Skin Dis Res Core Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Harvard Univ, Sch Med, Dept Surg, Surg Res Lab, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Arbiser, JL (reprint author), Emory Univ, Sch Med, Dept Dermatol, WMB 5309, Atlanta, GA 30322 USA. FU NIAMS NIH HHS [R03AR44947, P30 AR 42687, P30 AR042687, K08 AR02030] NR 32 TC 38 Z9 38 U1 0 U2 0 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 DEC PY 2000 VL 157 IS 6 BP 1937 EP 1945 DI 10.1016/S0002-9440(10)64832-8 PG 9 WC Pathology SC Pathology GA 379XK UT WOS:000165668300021 PM 11106566 ER PT J AU Blinman, TA Gukovsky, I Mouria, M Zaninovic, V Livingston, E Pandol, SJ Gukovskaya, AS AF Blinman, TA Gukovsky, I Mouria, M Zaninovic, V Livingston, E Pandol, SJ Gukovskaya, AS TI Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE nuclear factor-kappa B; chemokines; interleukin-6; monocyte chemotactic protein-1; pancreatitis ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE; TRANSCRIPTION FACTOR; CELLULAR STRESSES; GENE-EXPRESSION; CULTURE; INTERLEUKIN-6; NEUTROPHILS; INHIBITORS AB Cytokines produced by pancreatic acinar cells may mediate cell death and recruitment of inflammatory cells into pancreas in pancreatitis and other disorders. Here, we demonstrate mRNA expression for a number of cytokines in acini isolated from rat pancreas. Using RNA from microscopically selected individual cells, we confirmed the acinar cell as a source for cytokine expression. Competitive RT-PCR, Western blot analysis, and immunocytochemistry showed large amounts of monocyte chemotactic protein-1 and interleukin-6 compared with other cytokines. Cytokine expression was inhibited by either inhibitors of p38 mitogen-activated protein kinase (MAPK), SB-202190 and SB-203580, or (less strongly) by the transcription factor nuclear factor (NF)-kappaB inhibitor MG-132. A combination of SB-203580 and MG-132 inhibited mRNA expression of all cytokines by > 90%. The results suggest a major role for p38 MAPK and involvement of NF-kappaB in cytokine expression in pancreatic acinar cells. In contrast to isolated acini, we detected no or very low cytokine expression in normal rat pancreas. Our results indicate that activation of p38 MAPK, transcription factors, and cytokines occurs during removal of the pancreas from the animal and isolation of acini. C1 VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90073 USA. RP Gukovskaya, AS (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, Bldg 258,Rm 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 43 TC 82 Z9 84 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2000 VL 279 IS 6 BP C1993 EP C2003 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 373HJ UT WOS:000165283000037 PM 11078716 ER PT J AU Ellis, DZ Nathanson, JA Sweadner, KJ AF Ellis, DZ Nathanson, JA Sweadner, KJ TI Carbachol inhibits Na+-K+-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE nitric oxide; guanosine 3 ',5 '-cyclic monophosphate ID DEPENDENT PROTEIN-KINASE; BETA-SUBUNIT ISOFORMS; CAMP-REGULATED PHOSPHOPROTEIN; NITRIC-OXIDE SYNTHASE; NA+,K+-ATPASE ACTIVITY; BRAIN-BARRIER; ALPHA-SUBUNIT; CYCLIC-GMP; NA,K-ATPASE; PHOSPHORYLATION AB Secretion of cerebrospinal fluid by the choroid plexus can be inhibited by its cholinergic innervation. We demonstrated that carbachol inhibits the Na+ -K+-ATPase in bovine choroid tissue slices and investigated the mechanism. Many of the actions of cholinergic agents are mediated by nitric oxide (NO), which plays important roles in fluid homeostasis. The inhibition of Na+-K+-ATPase was blocked by the NO synthase inhibitor [N-omega-nitro-L-arginine methyl ester] and was quantitatively mimicked by the NO agonists sodium nitroprusside (SNP) and diethylenetriamine NO. Inhibition by SNP correlated with an increase in tissue cGMP and was abolished by H-1-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 muM) and KT-5823 (2.0 mM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na+-K+-ATPase. The data suggest that cholinergic regulation of the Na+-K+-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP. C1 Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA 02129 USA. RP Sweadner, KJ (reprint author), 149 6118 Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. FU NEI NIH HHS [EY-05077]; NINDS NIH HHS [NS-27653] NR 47 TC 37 Z9 38 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2000 VL 279 IS 6 BP C1685 EP C1693 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 373HJ UT WOS:000165283000003 PM 11078682 ER PT J AU Griffin, JL O'Donnell, JM White, LT Hajjar, RJ Lewandowski, ED AF Griffin, JL O'Donnell, JM White, LT Hajjar, RJ Lewandowski, ED TI Postnatal expression and activity of the mitochondrial 2-oxoglutarate-malate carrier in intact hearts SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE functional expression; tricarboxylic acid cycle; nuclear magnetic resonance spectroscopy; mitochondria; metabolism ID CITRIC-ACID CYCLE; C-13 NMR-SPECTROSCOPY; RAT-HEART; OXOGLUTARATE CARRIER; METABOLITE TRANSPORT; CARBON FLUX; PIG-HEART; MALATE; MYOCARDIUM; GLYCOLYSIS AB This study examines the functional implications of postnatal changes in the expression of the mitochondrial transporter protein, 2-oxoglutarate-malate carrier (OMC). Online C-13 nuclear magnetic resonance (C-13 NMR) measurements of isotope kinetics in hearts from neonate (3-4 days) and adult rabbits provided tricarboxylic acid cycle flux rates and flux rates through OMC. Neonate and adult hearts oxidizing 2.5 mM [2,4-C-13(2)]butyrate were subjected to either normal or high cytosolic redox state (2.5 mM lactate) conditions to evaluate the recruitment of malate-aspartate activity and the resulting OMC flux. During development from neonate (3-4 days) to adult, mitochondrial protein density in the heart increased from 19 +/- 3% to 31 +/- 2%, whereas OMC expression decreased by 65% per mitochondrial protein content (P < 0.05). Correspondingly, OMC flux was lower in adults hearts than in neonates by 73% (neonate = 7.4 +/- 0.4, adult = 2.0 +/- 0.1 mol/min per 100 mg mitochondrial protein; P < 0.05). Despite clear changes in OMC content and flux, the responsiveness of the malate-aspartate shuttle to increased cytosolic NADH was similar in both adults and neonates with an approximate threefold increase in OMC flux (in densitometric units/100 mg mitochondrial protein: neonate = 25.8 +/- 2.5, adult = 6.0 +/- 0.2; P < 0.05). The C-13 NMR data demonstrate that OMC activity is a principal component of the rate of labeling of glutamate. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Metab Res Lab, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Metab Res Lab, Boston, MA USA. RP Lewandowski, ED (reprint author), Univ Illinois, Coll Med, Dept Physiol & Biophys, MC 901,835 S Wolcott Ave,Rm 240, Chicago, IL 60612 USA. FU NHLBI NIH HHS [R01-HL-49244, R01-HL-62702, R01-HL-56178] NR 32 TC 18 Z9 18 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2000 VL 279 IS 6 BP C1704 EP C1709 PG 6 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 373HJ UT WOS:000165283000005 PM 11078684 ER PT J AU Hirose, M Kaneki, M Sugita, H Yasuhara, S Martyn, JAJ AF Hirose, M Kaneki, M Sugita, H Yasuhara, S Martyn, JAJ TI Immobilization depresses insulin signaling in skeletal muscle SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE insulin receptor; insulin resistance; insulin receptor substrate-1; muscle wasting; phosphatidylinositol 3-kinase ID RECEPTOR SUBSTRATE FAMILY; NITRIC-OXIDE SYNTHASE; GROWTH-FACTOR-I; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-TRANSPORT; PROTEIN-TURNOVER; PHOSPHOTYROSINE PROTEIN; DIABETES-MELLITUS; THERMAL-INJURY; RESISTANCE AB Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor beta -subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. RP Martyn, JAJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Serv, 32 Fruit St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM-31569-18, GM-55082-4, GM-61411-01] NR 46 TC 31 Z9 33 U1 0 U2 1 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 DEC PY 2000 VL 279 IS 6 BP E1235 EP E1241 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 377BM UT WOS:000165492100004 PM 11093909 ER PT J AU Easson, AM Pawlik, TM Fischer, CP Conroy, JL Sgroi, D Souba, WW Bode, BP AF Easson, AM Pawlik, TM Fischer, CP Conroy, JL Sgroi, D Souba, WW Bode, BP TI Tumor-influenced amino acid transport activities in zonal-enriched hepatocyte populations SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE digitonin-collagenase; cancer; liver; glutamine; arginine ID DIGITONIN COLLAGENASE PERFUSION; RAT-LIVER CELLS; HEPATIC GLUTAMINE-METABOLISM; BEARING RAT; PERIVENOUS HEPATOCYTES; PROTEIN-SYNTHESIS; NECROSIS-FACTOR; MESSENGER-RNA; EXPRESSION; ARGININE AB Cancer influences hepatic amino acid metabolism in the host. To further investigate this relationship, the effects of an implanted fibrosarcoma on specific amino acid transport activities were measured in periportal (PP)- and perivenous (PV)-enriched rat hepatocyte populations. Na+-dependent glutamate transport rates were eightfold higher in PV than in PP preparations but were relatively unaffected during tumor growth. System N-mediated glutamine uptake was 75% higher in PV than in PP preparations and was stimulated up to twofold in both regions by tumor burdens of 9 +/- 4% of carcass weight compared with hepatocytes from pair-fed control animals. Excessive tumor burdens (26 +/- 7%) resulted in hypophagia, loss of PV-enriched system N activities, and reduced transporter stimulation. Conversely, saturable arginine uptake was enhanced fourfold in PP preparations and was induced twofold only after excessive tumor burden. These data suggest that hepatic amino acid transporters are differentially influenced by cancer in a spatial and temporal manner, and they represent the first report of reciprocal zonal enrichment of system N and saturable arginine uptake in the mammalian liver. C1 Massachusetts Gen Hosp, Dept Surg, Surg Oncol Res Labs, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bode, BP (reprint author), St Louis Univ, Dept Biol, 3507 Laclede Ave, St Louis, MO 63103 USA. FU NCI NIH HHS [CA-47690]; NIDDK NIH HHS [1-P30-DK-40561] NR 56 TC 4 Z9 4 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD DEC PY 2000 VL 279 IS 6 BP G1209 EP G1218 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 377HH UT WOS:000165507700011 PM 11093943 ER PT J AU Berg, JT Deem, S Kerr, ME Swenson, ER AF Berg, JT Deem, S Kerr, ME Swenson, ER TI Hemoglobin and red blood cells alter the response of expired nitric oxide to mechanical forces SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE shear stress; pulmonary circulation; positive end-expiratory pressure; pulmonary blood flow; pulmonary venous pressure ID ENDOTHELIAL FUNCTION; VASCULAR-RESISTANCE; EXHALED GAS; RAT LUNGS; RELEASE; RABBITS; VASOCONSTRICTION; STIMULATION; INCREASES; STRETCH AB Expired nitric oxide (NOe) varies with hemodynamic or ventilatory perturbations, possibly due to shear stress- or stretch-stimulated NO production. Since hemoglobin (Hb) binds NO, NOe changes may reflect changes in blood volume and flow. To determine the role of blood and mechanical forces, we measured NOe in anesthetized rabbits, as well as rabbit lungs perfused with buffer, red blood cells (RBCs) or Hb following changes in flow, venous pressure (P-v), and positive end-expiratory pressure (PEEP). In buffer-perfused lungs decreases in flow and P-v reduced NOe, but NOe rose when RBCs and Hb were present. These findings are consistent with changes in vascular NO production, whose detection is obscured in blood-perfused lungs by the more dominant effect of Hb NO scavenging. PEEP decreased NOe in all perfused lungs but increased NOe in live rabbits. The NOe fall with PEEP in isolated lungs is consistent with flow redistribution from alveolar septal capillaries to extra-alveolar vessels and decreased surface area or a direct, stretch-mediated depression of lung epithelial NO production. In live rabbits, increased NOe may reflect blood flow reduction and decreased Hb NO scavenging and/or autonomic responses that increase NO production. We conclude that blood and systemic responses render it difficult to use NOe changes as an accurate measure of lung tissue NO production. C1 Univ Washington, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Dept Anesthesiol, Seattle, WA 98108 USA. RP Berg, JT (reprint author), Vet Affairs Med Ctr, Pulm Res Labs, 151-L,1660 S Columbian Way, Seattle, WA 98108 USA. FU NHLBI NIH HHS [HL-45571] NR 25 TC 16 Z9 18 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2000 VL 279 IS 6 BP H2947 EP H2953 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 375NZ UT WOS:000165409300046 PM 11087251 ER PT J AU Douillet, CD Velarde, V Christopher, JT Mayfield, RK Trojanowska, ME Jaffa, AA AF Douillet, CD Velarde, V Christopher, JT Mayfield, RK Trojanowska, ME Jaffa, AA TI Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE collagen; tissue inhibitor of metalloproteinase 1; transforming growth factor-beta; mitogen-activated protein kinase ID ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR-BETA; GENE-EXPRESSION; TRANSFORMING GROWTH-FACTOR-BETA-1; TISSUE INHIBITOR; MESANGIAL CELLS; COLLAGEN GENE; NITRIC-OXIDE; II RECEPTOR; PROLIFERATION AB Accumulation of extracellular matrix (ECM) is a hallmark feature of vascular disease. We have previously shown that hyperglycemia induces the expression of B-2-kinin receptors in vascular smooth muscle cells (VSMC) and that bradykinin (BK) and hyperglycemia synergize to stimulate ECM production. The present study examined the cellular mechanisms through which BK contributes to VSMC fibrosis. VSMC treated with BK (10(-8) M) for 24 h significantly increased alpha (2) (I) collagen mRNA levels. In addition, BK produced a two- to threefold increase in alpha (2) (I) collagen promoter activity in VSMC transfected with a plasmid containing the alpha (2)(I) collagen promoter. Furthermore, treatment of VSMC with BK for 24 h produced a two- to threefold increase in the secretion rate of tissue inhibitor of metalloproteinase 1 (TIMP-1). The increase in alpha (2)(I) collagen mRNA levels and alpha (2)(I) collagen promoter activity, as well as TIMP-1 secretion, in response to BK were blocked by anti-transforming growth factor-beta (anti-TGF-beta) neutralizing antibodies. BK (10(-8) M) increased the endogenous production of TGF-beta1 mRNA and protein levels. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 inhibited the increase of alpha (2)(I) collagen promoter activity, TIMP-1 production, and TGF-beta1 protein levels observed in response to BK. These findings provide the first evidence that BK induces collagen type I and TIMP-1 production via autocrine activation of TGF-beta1 and implicate MAPK pathway as a key player in VSMC fibrosis in response of BK. C1 Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Cell & Mol Pharmacol & Exptl Therapeut, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Jaffa, AA (reprint author), Med Univ S Carolina, Dept Med Endocrinol Diabet Med Genet, 114 Doughty St,POB 250776, Charleston, SC 29425 USA. FU NHLBI NIH HHS [HL-07260, HL-55782]; NIDDK NIH HHS [DK-46543] NR 46 TC 43 Z9 43 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2000 VL 279 IS 6 BP H2829 EP H2837 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 375NZ UT WOS:000165409300033 PM 11087238 ER PT J AU Schutzer, WE Xue, H Reed, JF Roullet, JB Anderson, S Mader, SL AF Schutzer, WE Xue, H Reed, JF Roullet, JB Anderson, S Mader, SL TI Angiotensin II enhances beta-adrenergic receptor-mediated vasorelaxation in aortas from young but not old rats SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article; Proceedings Paper CT Experimental Biology 2000 Meeting CY APR 14-18, 2000 CL SAN DIEGO, CALIFORNIA DE cAMP; Fischer 344; forskolin; hypertension; isoproterenol ID VASCULAR SMOOTH-MUSCLE; AGE-RELATED-CHANGES; PROTEIN-KINASE-C; AGONIST-INDUCED DESENSITIZATION; CELLS; CONTRACTION; RELAXATION; PHOSPHORYLATION; VASODILATION; ACCUMULATION AB beta -Adrenergic receptor (beta -AR)-mediated (cAMP-dependent) vasorelaxation declines with advancing age. It has been shown that angiotensin II (ANG II), a potent vasoconstrictor, enhances cAMP-mediated vasorelaxation. Therefore, we questioned whether ANG II could reverse age-related, impaired beta -AR-mediated vasorelaxation and cAMP production. Pretreatment of aortic rings from 6-wk-old or 6-mo-old male Fischer 344 rats with ANG II significantly enhanced vasorelaxation induced by isoproterenol (Iso), a beta -AR agonist, and forskolin, a direct activator of adenylyl cyclase, but not dibutyryl-cAMP or isobutylmethylxanthine. The ANG II effect was blocked by losartan but not PD-123319 and was not observed in the aortas from 12- and 24-mo-old animals. Iso-stimulated cAMP production in the aorta was enhanced in the presence of ANG II in the 6-wk-old and 6-mo-old age groups only. Results suggest ANG II cannot reverse the age-related impairment in beta -AR-dependent vasorelaxation. We conclude aging may affect a factor common to both ANG II-receptors and beta -AR signaling pathways or aging may impair cross-talk between these two receptor pathways. C1 Portland Vet Affairs Med Ctr, Res Serv, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Sch Med, Portland, OR 97201 USA. RP Mader, SL (reprint author), Portland Vet Affairs Med Ctr, Res Serv, R&D 26,3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. FU NIA NIH HHS [AG-14699] NR 43 TC 6 Z9 6 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2000 VL 279 IS 6 BP H2807 EP H2814 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 375NZ UT WOS:000165409300030 PM 11087235 ER PT J AU Jedrzkiewicz, S Nakamura, H Silverman, ES Luster, AD Mansharamani, N In, KH Tamura, G Lilly, CM AF Jedrzkiewicz, S Nakamura, H Silverman, ES Luster, AD Mansharamani, N In, KH Tamura, G Lilly, CM TI IL-1 beta induces eotaxin gene transcription in A549 airway epithelial cells through NF-kappa B SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE cytokine; chemokine; eosinophil; asthma ID ASTHMATIC BRONCHIAL EPITHELIUM; RECEPTOR ANTAGONIST IL-1RA; BRONCHOALVEOLAR LAVAGE; MESSENGER-RNA; EXPRESSION; ACTIVATION; INFLAMMATION; MECHANISM; CYTOKINES; CCR3 AB Eotaxin is an asthma-related C-C chemokine that is produced in response to interleukin-1 beta (IL-1 beta). We detected an increase in newly transcribed eotaxin mRNA in IL-1 beta -stimulated airway epithelial cells. Transient transfection assays using promoter-reporter constructs identified a region as essential for IL-1 beta -induced increases in eotaxin transcription. Using site-directed mutagenesis, we found that a nuclear factor-kappaB (NF-kappaB) site located 46 bp upstream from the transcriptional start site was both necessary and sufficient for IL-1 beta induction of reporter construct activity. Electrophoretic mobility shift assay demonstrated that IL-1 beta -stimulated airway epithelial cells produced p50 and p65 protein that bound this site in a sequence-specific manner. The functional importance of the NF-kappaB site was demonstrated by coexpression experiments in which increasing doses of p65 expression vector were directly associated with reporter activity exclusively in constructs with an intact NF-kappaB site (r(2) = 0.97, P = 0.002). Moreover, IL-1 beta -induced increases in eotaxin mRNA expression are inhibited by inhibitors of NF-kappaB. Our findings implicate NF-kappaB and its binding sequence in IL-1 beta -induced transcriptional activation of the eotaxin gene. C1 Brigham & Womens Hosp, Dept Med, Combined Program Pulm & Crit Care Med, Div Resp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Lilly, CM (reprint author), Brigham & Womens Hosp, Dept Med, Combined Program Pulm & Crit Care Med, Div Resp, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-64104, HL-03283]; NIAID NIH HHS [AI-40618] NR 35 TC 36 Z9 37 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD DEC PY 2000 VL 279 IS 6 BP L1058 EP L1065 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 375GY UT WOS:000165392200006 PM 11076795 ER PT J AU Gong, H Szymusiak, R King, J Steininger, T McGinty, D AF Gong, H Szymusiak, R King, J Steininger, T McGinty, D TI Sleep-related c-Fos protein expression in the preoptic hypothalamus: effects of ambient warming SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE thermosensitive neurons; median preoptic nucleus; ventrolateral preoptic area ID EYE-MOVEMENT SLEEP; BASAL FOREBRAIN; THERMOSENSITIVE NEURONS; POSTERIOR HYPOTHALAMUS; NERVOUS-SYSTEM; RAT; TEMPERATURE; WAKEFULNESS; BRAIN; DEPRIVATION AB Preoptic area (POA) neuronal activity promotes sleep, but the localization of critical sleep-active neurons is not completely known. Thermal stimulation of the POA also facilitates sleep. This study used the c-Fos protein immunostaining method to localize POA sleep-active neurons at control (22 degrees C) and mildly elevated (31.5 degrees C) ambient temperatures. At 22 degrees C, after sleep, but not after waking, we found increased numbers of c-Fos immunoreactive neurons (IRNs) in both rostral and caudal parts of the median preoptic nucleus (MnPN) and in the ventrolateral preoptic area (VLPO). In animals sleeping at 31.5 degrees C, significantly more Fos IRNs were found in the rostral MnPN compared with animals sleeping at 22 degrees C. In VLPO, Fos IRN counts were no longer increased over waking levels after sleep at the elevated ambient temperature. Sleep-associated Fos IRNs were also found diffusely in the POA, but counts were lower than those made after waking. This study supports a hypothesis that the MnPN, as well as the VLPO, is part of the POA sleep-facilitating system and that the rostral MnPN may facilitate sleep, particularly at elevated ambient temperatures. C1 Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. RP McGinty, D (reprint author), VAGLAHS, 16111 Plummer St, Sepulveda, CA 90037 USA. FU NHLBI NIH HHS [HL-60296]; NIMH NIH HHS [MH-47480] NR 50 TC 88 Z9 89 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 2000 VL 279 IS 6 BP R2079 EP R2088 PG 10 WC Physiology SC Physiology GA 374LV UT WOS:000165347400016 PM 11080072 ER PT J AU Butters, MA Becker, JL Nebes, RD Zmuda, MD Mulsant, BH Pollock, BG Reynolds, CF AF Butters, MA Becker, JL Nebes, RD Zmuda, MD Mulsant, BH Pollock, BG Reynolds, CF TI Changes in cognitive functioning following treatment of late-life depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 106th Annual Convention of the American-Psychological-Association CY AUG 14-18, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Psychol Assoc ID MINI-MENTAL-STATE; GERIATRIC DEPRESSION; NEUROPSYCHOLOGICAL DEFICITS; ELDERLY DEPRESSIVES; MAJOR DEPRESSION; DEMENTIA; HYPERINTENSITIES; SEVERITY; SCALE AB Objective: Knowledge of the relationship between various clinical characteristics and cognitive functioning is advancing, but little is known about the cognitive response to treatment for geriatric depression. The purpose of this study was to examine the cognitive response to treatment for patients with late-life depression. Method: Subjects included 45 nondemented, elderly depressed patients who achieved remission after 12 weeks of antidepressant treatment and 20 elderly comparison subjects. All subjects were administered a battery of clinical measures, including cognitive screening instruments, before and after treatment. Results: As a group, the elderly depressed patients showed a small improvement in overall cognitive functioning after treatment. Among depressed patients with concomitant cognitive impairment at baseline, performance on the Mattis Dementia Rating Scale domains of conceptualization and initiation/perseveration improved significantly relative to those of depressed patients with normal cognition. Despite the improvement following treatment, the overall level of cognitive functioning in the elderly depressed patients with cognitive impairment at baseline remained mildly impaired, especially in the memory and initiation/perseveration domains. Conclusions: Elderly depressed patients with cognitive impairment may experience improvement in specific domains following antidepressant treatment but may not necessarily reach normal levels of performance, particularly in memory and executive functions. This subgroup of late-life depression patients is likely at high risk of developing progressive dementia. C1 Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Med Ctr, Dept Neurosci, Pittsburgh, PA 15260 USA. VA Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Butters, MA (reprint author), Western Psychiat Inst & Clin, Dept Psychiat, 3811 OHara St,E831, Pittsburgh, PA 15213 USA. FU NIA NIH HHS [AG-05133]; NIMH NIH HHS [MH-01684, MH-52247] NR 29 TC 201 Z9 212 U1 2 U2 11 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 DEC PY 2000 VL 157 IS 12 BP 1949 EP 1954 DI 10.1176/appi.ajp.157.12.1949 PG 6 WC Psychiatry SC Psychiatry GA 378NA UT WOS:000165589400009 PM 11097959 ER PT J AU Rosenbaum, JF Biederman, J Hirshfeld-Becker, DR Kagan, J Snidman, N Friedman, D Nineberg, A Gallery, DJ Faraone, SV AF Rosenbaum, JF Biederman, J Hirshfeld-Becker, DR Kagan, J Snidman, N Friedman, D Nineberg, A Gallery, DJ Faraone, SV TI A controlled study of behavioral inhibition in children of parents with panic disorder and depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ANXIETY DISORDERS; NORADRENERGIC FUNCTION; SEPARATION ANXIETY; SCHOOL PHOBIA; CHILDHOOD; COMORBIDITY; AGORAPHOBIA; RISK; SYMPTOMS; HISTORY AB Objective: "Behavioral inhibition to the unfamiliar" has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. Method: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research ("dichotomous behavioral inhibition") was compared with two other definitions. Results: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. Conclusions: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children. C1 Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Rosenbaum, JF (reprint author), Massachusetts Gen Hosp, Clin Psychopharmacol Unit, WACC 812,15 Parkman St, Boston, MA 02114 USA. EM jrosenbaum@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [MH-01538, MH-47077] NR 46 TC 123 Z9 125 U1 2 U2 12 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2000 VL 157 IS 12 BP 2002 EP 2010 DI 10.1176/appi.ajp.157.12.2002 PG 9 WC Psychiatry SC Psychiatry GA 378NA UT WOS:000165589400017 PM 11097967 ER PT J AU Gottlieb, DJ Luisetti, M Stone, PJ Allegra, L Cantey-Kiser, JM Grassi, C Snider, GL AF Gottlieb, DJ Luisetti, M Stone, PJ Allegra, L Cantey-Kiser, JM Grassi, C Snider, GL CA Amer-Italian AATD Study Grp TI Short-term supplementation therapy does not affect elastin degradation in severe alpha(1)-antitrypsin deficiency SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID ALPHA-1-ANTITRYPSIN DEFICIENCY; URINARY DESMOSINE; EXCRETION; EMPHYSEMA; INHIBITOR; SMOKERS AB We evaluated the ability of intravenous supplementation therapy with alpha (1)-antitrypsin (AAT) to reduce the rate of urinary excretion of desmosine (DES), a specific marker of elastin degradation, in eight men and four women with emphysema due to severe, congenital deficiency of AAT (range 17-69 mg/dl). Nine were former cigarette smokers, two were current smokers, and one reported never smoking; their mean age was 54 (SD 12) yr and their mean FEV, was 41 (18%) of predicted. Urinary DES was measured by isotope dilution and HPLC. Prior to the start of AAT supplementation, mean DES excretion was 13.0 (5.0) mug/g creatinine, 73% higher than in healthy nonsmokers. During 8 wk of supplementation therapy, mean urinary DES excretion was 13.0 (1.9) mug/g creatinine, unchanged from the baseline period (p = 0.85 by repeated measures ANOVA). We conclude that baseline levels of elastin degradation in emphysematous patients with severe AAT deficiency were abnormally high and that 8 wk of AAT supplementation therapy did not appreciably reduce the rate of elastin degradation. These findings raise the possibilities that protective levels of AAT in the lungs are insufficient or that elastin degradation in the lungs of these subjects is not dependent upon neutrophil elastase at this time. C1 Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. VA Boston Healthcare Syst, Dept Med, Boston, MA USA. Univ Pavia, IRCCS Policlin San Matteo, Clin Malattie Apparato Resp, Pavia, Italy. Univ Milan, IRCCS Osped Policlin, Ist Tisiol & Malattie Resp, Milan, Italy. RP Gottlieb, DJ (reprint author), Boston Univ, Sch Med, Ctr Pulm, 715 Albany St,R-304, Boston, MA 02118 USA. NR 19 TC 43 Z9 47 U1 0 U2 3 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 DEC PY 2000 VL 162 IS 6 BP 2069 EP 2072 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 381ZV UT WOS:000165794700018 PM 11112116 ER PT J AU Morrell, MJ Finn, L Kim, H Peppard, PE Badr, MS Young, T AF Morrell, MJ Finn, L Kim, H Peppard, PE Badr, MS Young, T TI Sleep fragmentation, awake blood pressure, and sleep-disordered breathing in a population-based study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID OBSTRUCTIVE APNEAS; EEG AROUSALS; HYPERTENSION; HYPOXIA; HUMANS; RESPONSES; MODEL AB Arousal from sleep produces transient increases in systemic blood pressure, leading to the suggestion that repeated arousals are associated with a sustained increase in daytime blood pressure. Using data from the Wisconsin Sleep Cohort Study, a population-based study, we tested the hypothesis that sleep fragmentation is associated with elevated awake blood pressure. Sleep, breathing, and seated blood pressure measurements from 1,021 participants (age 42 +/- 8 yr; 590 males) were analyzed. Sleep fragmentation was defined as the total number of awakenings and shifts to Stage 1 sleep divided by the total sleep time (sleep fragmentation index: SFI). To reduce the confounding influence of sleep-disordered breathing, which is related to both increased daytime blood pressure and sleep fragmentation, all participants with an apnea-hypopnea index (AHI) greater than or equal to 1 were analyzed separately. Accounting for the influences of sex, age, body mass index, and antihypertensive medication use, the SFI was significantly associated with higher levels of awake systolic blood pressure in people with an AHI < 1; a 2 standard deviation increase in the SFI was associated with a 3.1 mm Hg rise in awake systolic: blood pressure. in participants with an AHI 1, there was no independent association between the SFI and awake blood pressure after controlling for the influence of the AHI. C1 Univ Wisconsin, Sch Med, Dept Prevent Med, Madison, WI USA. Univ Wisconsin, Sch Med, Dept Med, Madison, WI USA. William S Middleton Mem Vet Adm Hosp, Madison, WI USA. RP Morrell, MJ (reprint author), Royal Brompton Hosp, Sleep & Ventilat Unit, S Block,Sydney St, London SW3 6NP, England. FU NCRR NIH HHS [MO1 RR3186]; NHLBI NIH HHS [P01 HL 42242] NR 33 TC 64 Z9 65 U1 0 U2 3 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 DEC PY 2000 VL 162 IS 6 BP 2091 EP 2096 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 381ZV UT WOS:000165794700022 PM 11112120 ER PT J AU Silverman, EK Weiss, ST Drazen, JM Chapman, HA Carey, V Campbell, EJ Denish, P Silverman, RA Celedon, JC Reilly, JJ Ginns, LC Speizer, FE AF Silverman, EK Weiss, ST Drazen, JM Chapman, HA Carey, V Campbell, EJ Denish, P Silverman, RA Celedon, JC Reilly, JJ Ginns, LC Speizer, FE TI Gender-related differences in severe, early-onset chronic obstructive pulmonary disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID LONGITUDINAL DATA-ANALYSIS; GENERAL-POPULATION; LUNG-FUNCTION; SMOKING; PROGNOSIS; COPD; BRONCHODILATOR; EPIDEMIOLOGY; SMOKERS; RESPONSIVENESS AB Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily Increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha(1)-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV1/ FVC (81.4 +/- 17.2% in females versus 87.0 +/- 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV1) (7.7 +/- 9.4% pred in females versus 4.1 +/- 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV1 (< 40% pred) than male smoking first-degree relatives (p = 0.03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV1 < 80% pred (OR 1.91, 95% CI 1.03-3.54), FEV1 < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV1 (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD. C1 Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. RP Silverman, EK (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. RI Drazen, Jeffrey/E-5841-2012 FU NCRR NIH HHS [MO1 RR02635]; NHLBI NIH HHS [HL 61575, HL07427] NR 36 TC 141 Z9 144 U1 0 U2 0 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 DEC PY 2000 VL 162 IS 6 BP 2152 EP 2158 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 381ZV UT WOS:000165794700032 PM 11112130 ER PT J AU Arellano, RS Boland, GWL Mueller, PR AF Arellano, RS Boland, GWL Mueller, PR TI Adrenal biopsy in a patient with lung cancer: Imaging algorithm and biopsy indications, technique, and complications SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID CT-GUIDED BIOPSY; CONTRAST-ENHANCED CT; PERCUTANEOUS BIOPSY; NEEDLE ASPIRATION; PREDICTIVE VALUE; MASSES; ADENOMAS; NONADENOMAS; GLAND; DIFFERENTIATION C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Boland, GWL (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Ellison 234,55 Fruit St, Boston, MA 02114 USA. NR 36 TC 7 Z9 7 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 DEC PY 2000 VL 175 IS 6 BP 1613 EP 1617 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 376JN UT WOS:000165454600026 PM 11090388 ER PT J AU Rubin, BP Pins, MR Nielsen, GP Rosen, S Hsi, BL Fletcher, JA Renshaw, AA AF Rubin, BP Pins, MR Nielsen, GP Rosen, S Hsi, BL Fletcher, JA Renshaw, AA TI Isochromosome 7q in adult Wilms' tumors: Diagnostic and pathogenetic implications SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article; Proceedings Paper CT XXIInd International Congress of the International-Academy-of-Pathology CY OCT 18-23, 1998 CL NICE, FRANCE SP Int Acad Pathol DE Wilms' tumor; genetics; adults; prognosis ID CLEAR-CELL-SARCOMA; PRIMITIVE NEUROECTODERMAL TUMOR; METANEPHRIC ADENOMA; KIDNEY; GENE; NEPHROBLASTOMA; CHROMOSOME-11; TRANSLOCATION; CARCINOMA; NEOPLASIA AB Wilms' tumors affecting adults are rare and are thought to have a worse prognosis than similar stage tumors in the pediatric population. To understand these turners better, the authors reviewed their multi-institutional experience in a series of nine lesions diagnosed as Wilms' tumors in adults. In addition to histologic and immunohistochemical examination, they performed cytogenetic analysis and fluorescence in situ hybridization. On review, four cases were reclassified: two "blastema only" as Ewing's sarcoma/primitive neuroectodermal tumor and the other two as clear cell sarcoma of soft parts and sarcoma not otherwise specified (NOS). Of the remaining five cases, three exhibited biphasic histology and two were triphasic. In this group, there were three women and two men, and patient age ranged from 17 to 37 years (median age, 26 years). Tumor size was large and ranged from 10 to 31 cm (median tumor size, 12.5 cm). Histologically, the tumors showed the typical features of Wilms' tumors with varying amounts of blastema (n = 5), epithelium (n = 5), and stroma(n = 2). No tumors contained anaplasia, and persistent renal blastema was not identified in the non-neoplastic kidney in any specimen. All tumors were positive fur cytokeratins (CK7, n = 3; pankeratin, n = 5), and one tumor was weakly positive for CD99 (O-13). Molecular analysis including dual color fluorescence in situ hybridization (all tumors), and cytogenetic analysis (n = 2) disclosed the presence of isochromosome 7q in three of five tumors whereas all tumors were diploid with respect to chromosome 12, Follow-up data ranged from 6 to 133 months (median follow-up, 82 months) with progression in only one patient who had stage TV disease with lymph node and lung metastases at presentation. The authors conclude that adult Wilms' tumor has been overdiagnosed. Most "blastema-only" tumors in adults are not Wilms' tumors, and in an adult, biphasic morphology should be the minimum criteria for their diagnosis. Using strict diagnostic criteria, adult Wilms' tumors have a relatively favorable prognosis. The characteristic Endings of isochromosome 7q, lack of trisomy or tetrasomy for chromosome 12, and absence of persistent renal blastema suggest that the pathogenesis of Wilms' tumors in adults may be different than in the pediatric population. These genetic features may be helpful in distinguishing adult Wilms' tumors from other primary renal tumors. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. NW Mem Hosp, Dept Pathol, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Rubin, BP (reprint author), Univ Washington, Med Ctr, Dept Pathol, 1959 NE Pacific St,Room BB210E,Box 356100, Seattle, WA 98195 USA. NR 43 TC 18 Z9 18 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 DEC PY 2000 VL 24 IS 12 BP 1663 EP 1669 DI 10.1097/00000478-200012000-00011 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 378NL UT WOS:000165590400011 PM 11117788 ER PT J AU Kavanagh, KD Morgan, BA AF Kavanagh, KD Morgan, BA TI Regulating differentiation in vertebrates: functional homology and evolutionary co-option in Ikaros family genes. SO AMERICAN ZOOLOGIST LA English DT Meeting Abstract C1 Museum Comparat Zool, Cambridge, MA 02138 USA. Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC ZOOLOGISTS PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0003-1569 J9 AM ZOOL JI Am. Zool. PD DEC PY 2000 VL 40 IS 6 BP 1083 EP 1083 PG 1 WC Zoology SC Zoology GA 422RA UT WOS:000168132000414 ER PT J AU Sun, RL Conway, S Zawaideh, S Niederman, R AF Sun, RL Conway, S Zawaideh, S Niederman, R TI Benchmarking the clinical orthodontic evidence on Medline SO ANGLE ORTHODONTIST LA English DT Article DE bibliometrics; orthodontics; etiology; diagnosis; therapeutics; prognosis ID RANDOMIZED CONTROLLED TRIALS; MEDICINE; HEALTH; SEARCHES; PAPER; CARE; READ AB The purpose of this study was to identify and quantify the availability of orthodontic literature for evidence-based clinical decision-making (ie, sound clinical studies of etiology, diagnosis, treatment, or prognosis meeting basic methodologic criteria for direct clinical use). This is a first step toward developing online decision analysis systems. A search strategy based on Medical Subject Headings (MeSH) for orthodontics was developed to examine MEDLINE using the Ovid Web Gateway search engine. Sensitive and specific methodologic search filters were then employed to identify the 4 categories of information. The results were then subdivided by year to identify trends and sorted to identify source of publications, In the period 1990 to 1998, the MEDLINE searches identified 6938 English-language articles about orthodontics. The mean number of articles (+/-SD) per year ranged from 42 +/- 25 for specific searches to 314 +/- 214 for sensitive searches. The number of articles identified by the specific or sensitive searches increased 14% to 21% annually. When subdivided by clinical category, the mean numbers of articles per year for specific and sensitive searches were respectively: etiology 19 +/- 15 and 91 +/- 37, diagnosis 11 +/- 5 and 80 +/- 35, therapy 3 +/- 1 and 50 +/- 23, and prognosis 10 +/- 7 and 93 +/- 33. Five dental journals accounted for nearly half of these publications. These results provide several key findings: (1) there is a substantial literature of clinically relevant information in orthodontics upon which to base clinical decisions; (2) the information appears to be balanced between etiology, diagnosis, treatment, and prognosis; (3) approximately 45% of the articles reside in 5 journals, whereas the remainder reside in approximately 66 other journals, making it difficult to stay current; (4) the number of articles is increasing significantly each year; (5) to stay current, one would need to read between 1 and 6 articles per week, 52 weeks per year; (6) these trends suggest the need fur computer-based clinical knowledge systems; and (7) the methods used here can be immediately employed to identify the best and most current clinical orthodontic evidence. (Angle Orthod 2000;70:000-000.). C1 Harvard Univ, Sch Dent Med, Off Evidence Based Dent, Boston, MA 02115 USA. Forsyth Inst, Boston, MA USA. Countway Lib Med, Reference & Educ Serv, Boston, MA USA. Harvard Univ, Sch Dent Med, Dept Growth & Dev, Boston, MA 02115 USA. RP Niederman, R (reprint author), Harvard Univ, Sch Dent Med, Off Evidence Based Dent, 188 Longwood Ave, Boston, MA 02115 USA. NR 18 TC 7 Z9 9 U1 0 U2 1 PU ANGLE ORTHODONTISTS RES EDUC FOUNDATION INC PI APPLETON PA 100 W LAWRENCE ST, SUITE 406,, APPLETON, WI 54911 USA SN 0003-3219 J9 ANGLE ORTHOD JI Angle Orthod. PD DEC PY 2000 VL 70 IS 6 BP 464 EP 470 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 385LY UT WOS:000166007000013 PM 11138650 ER PT J AU Nitsch, RM Deng, MH Tennis, M Schoenfeld, D Growdon, JH AF Nitsch, RM Deng, MH Tennis, M Schoenfeld, D Growdon, JH TI The selective muscarinic M1 agonist AF102B decreases levels of total A beta in cerebrospinal fluid of patients with Alzheimer's disease SO ANNALS OF NEUROLOGY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E; CONTROLLED TRIAL; SECRETION; ACTIVATION; RELEASE; PHYSOSTIGMINE; DERIVATIVES; RECEPTORS; KINASE AB beta -Amyloid (A beta) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing A beta deposition is a goal of drug therapy for AD, because excessive amounts of A beta may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited A beta secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective MI agonist AF102B to 13 AD patients and measured total A beta (A beta (total)) levels in cerebrospinal fluid (CSF) before and during treatment. A beta (total) levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in A beta (total) levels in CSF during treatments in. separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF A beta (total) levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces A beta levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Ctr Biostat, Boston, MA 02114 USA. Univ Zurich, Div Psychiat Res, Zurich, Switzerland. RP Growdon, JH (reprint author), Massachusetts Gen Hosp, Dept Neurol, WACC 830,Fruit St, Boston, MA 02114 USA. FU NIA NIH HHS [P50 AG 05134]; PHS HHS [5-MO1-01066-23] NR 32 TC 109 Z9 114 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2000 VL 48 IS 6 BP 913 EP 918 DI 10.1002/1531-8249(200012)48:6<913::AID-ANA12>3.0.CO;2-S PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 378WD UT WOS:000165607500012 PM 11117548 ER PT J AU Bueno, R Richards, WG Swanson, SJ Jaklitsch, MT Lukanich, JM Mentzer, SJ Sugarbaker, DJ AF Bueno, R Richards, WG Swanson, SJ Jaklitsch, MT Lukanich, JM Mentzer, SJ Sugarbaker, DJ TI Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 31-FEB 02, 2000 CL FT LAUDERDALE, FLORIDA SP Soc Thorac Surg ID GROUP-B PROTOCOL-8935; RANDOMIZED TRIAL; CELL; CHEMOTHERAPY; N2; CARCINOMA; RESECTION; RADIATION; SURGERY; DISEASE AB Background. This study was undertaken to determine the predictive value of nodal status at resection in regards to long-term outcome of patients undergoing neoadjuvant therapy and resection for stage IIIA N2-positive non-small cell lung cancer (NSCLC). Methods. We reviewed the medical records of all patients found on surgical staging to have N2-positive NSCLC and who underwent induction therapy followed by resection between 1988 and 1996 at our hospital. Complete follow-up information was examined utilizing Kaplan-Meier survival analysis and Cox proportional hazards multivariate analysis. Results. One hundred three patients (59 men) with stage IIIA N2-positive NSCLC received neoadjuvant therapy before surgical resection. Preoperative therapy consisted of platinum-based chemotherapy (76), radiotherapy (18), or chemoradiation (9). Operations included pneumonectomy (38), bilobectomy (6), and lobectomy (59). There were four deaths and seven major complications. Eighty-five patients were followed until death. Median survival among 18 living patients is 60.9 months (range 29 to 121 months). Twenty-nine patients were downstaged to NO and had 5-year survival of 35.8% (median survival 21.3 months). Seventy-four patients with persistent tumor in their lymph nodes (25 N1 and 49 N2) had significantly worse, 9%, 5-year survival, p = 0.023 (median survival 15.9 months). Other negative prognostic factors were adenocarcinoma and pneumonectomy. Conclusions. Patients with N2-positive NSCLC whose nodal disease is eradicated after neoadjuvant therapy and surgery enjoy significantly improved cancer-free survival. These data support surgical resection for patients downstaged by induction therapy; however, patients who are not downstaged do not benefit from surgical resection. Direct effort should be made to improve the accuracy of restaging before resection. (Ann Thorac Surg 2000;70:1826-31) (C) 2000 by The Society of Thoracic Surgeons. C1 Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Thorac Surg, Boston, MA 02115 USA. RP Bueno, R (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. NR 16 TC 156 Z9 164 U1 1 U2 1 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 DEC PY 2000 VL 70 IS 6 BP 1826 EP 1831 DI 10.1016/S0003-4975(00)01585-X PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 385UT UT WOS:000166022900011 PM 11156079 ER PT J AU Ince, D Hooper, DC AF Ince, D Hooper, DC TI Mechanisms and frequency of resistance to premafloxacin in Staphylococcus aureus: Novel mutations suggest novel drug-target interactions SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID YEAST TOPOISOMERASE-II; DNA GYRASE; STREPTOCOCCUS-PNEUMONIAE; QUINOLONE RESISTANCE; FLUOROQUINOLONE RESISTANCE; COUMARIN ACTIVITY; IV; LOCUS; GENE; GRLA AB Premafloxacin is a novel 8-methoxy fluoroquinolone with enhanced activity against Staphylococcus aureus. We found premafloxacin to be 32-fold more active than ciprofloxacin against wild-type S. aureus. Single mutations in either subunit of topoisomerase IV caused a four- to eightfold increase in the MICs of both quinolones, A double mutation (gyrA and either grlA or grlB) caused a 32-fold increase in the MIC of premafloxacin, while the MIC of ciprofloxacin increased 128-fold, Premafloxacin appeared to be a poor substrate for NorA, with NorA overexpression causing an increase of twofold or less in the MIC of premafloxacin in comparison to a fourfold increase in the MIC of ciprofloxacin, The frequency of selection of resistant mutants was 6.4 x 10(-10) to 4.0 x 10(-7) at twofold the MIC of premafloxacin, 2 to 4 log(10) less than that with ciprofloxacin. Single step mutants could not be selected at higher concentrations of premafloxacin. In five single-step mutants, only one previously described uncommon mutation (Ala116Glu), and four novel mutations (Arg43Cys, Asp69Tyr, Ala176Thr, and Pro157Leu), three of which were outside the quinolone resistance determining region (QRDR) were found. Genetic linkage studies, in which incross of grlA(+) and outcross of mutations were performed, showed a high correlation between the mutations and the resistance phenotypes, and allelic exchange experiments confirmed the role of the novel mutations in grlA in resistance. Our results suggest that although topoisomerase IV is the primary target of premafloxacin, premafloxacin appears to interact with topoisomerase TV in a manner different from that of other quinolones and that the range of the QRDR of grl4 should be expanded. C1 Massachusetts Gen Hosp, Div Infect Dis, Harvard Med Sch, Boston, MA 02114 USA. Massachusetts Gen Hosp, Med Serv, Harvard Med Sch, Boston, MA 02114 USA. RP Hooper, DC (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [R01 AI023988, R01AI23988] NR 34 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2000 VL 44 IS 12 BP 3344 EP 3350 DI 10.1128/AAC.44.12.3344-3350.2000 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 405JP UT WOS:000167156500016 PM 11083638 ER PT J AU Duvic, M Friedman-Kien, AE Looney, DJ Miles, SA Myskowski, PL Scadden, DT Von Roenn, J Galpin, JE Groopman, J Loewen, G Stevens, V Truglia, JA Yocum, RC AF Duvic, M Friedman-Kien, AE Looney, DJ Miles, SA Myskowski, PL Scadden, DT Von Roenn, J Galpin, JE Groopman, J Loewen, G Stevens, V Truglia, JA Yocum, RC TI Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel - Results of phase 1 and 2 trials SO ARCHIVES OF DERMATOLOGY LA English DT Article ID IMMUNE-DEFICIENCY-SYNDROME; RETINOIC ACID RECEPTORS; II TRIAL; INTRALESIONAL VINBLASTINE; X-RECEPTORS; AIDS; THERAPY; CELLS; ACTIVATION; MANAGEMENT AB Objective: To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD 1057], Panretin gel, Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS). Design: Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated. Setting: Nine academic clinical centers. Patients: One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS. Main Outcome Measures: AIDS Clinical Trials Group response criteria. Results: Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/muL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P=.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity. Conclusions: Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated. C1 Univ Texas, Sch Med, MD Anderson Canc Ctr, Dermatol Sect, Houston, TX 77030 USA. Univ Texas, Sch Med, Dept Dermatol, Houston, TX 77030 USA. NYU Med Ctr, Dept Dermatol, New York, NY 10016 USA. Mem Sloan Kettering Canc Ctr, Dept Med, Dermatol Serv, New York, NY 10021 USA. Univ Calif San Diego, Dept Med, Div Hematol & Oncol, San Diego, CA 92103 USA. Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. Deaconess Hosp, Dept Med, Div Hematol & Oncol, Boston, MA USA. Northwestern Univ, Dept Med, Div Hematol & Oncol, Chicago, IL 60611 USA. Shared Med Res, Tarzana, CA USA. Ligand Pharmaceut Inc, San Diego, CA USA. RP Duvic, M (reprint author), Univ Texas, Sch Med, MD Anderson Canc Ctr, Dermatol Sect, Box 28,1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [CA-16672-22]; NIAMS NIH HHS [AR39915] NR 35 TC 37 Z9 37 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 DEC PY 2000 VL 136 IS 12 BP 1461 EP 1469 DI 10.1001/archderm.136.12.1461 PG 9 WC Dermatology SC Dermatology GA 383EA UT WOS:000165869100004 PM 11115156 ER PT J AU Unsold, AS Rizzo, JF Lessell, S AF Unsold, AS Rizzo, JF Lessell, S TI Optic neuropathy after burns SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article C1 Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Lessell, S (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. NR 30 TC 3 Z9 3 U1 0 U2 0 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 DEC PY 2000 VL 118 IS 12 BP 1696 EP 1698 PG 3 WC Ophthalmology SC Ophthalmology GA 380ZX UT WOS:000165738800016 PM 11115269 ER PT J AU Arevalo-Silva, CA Eavey, RD Cao, YL Vacanti, M Weng, YL Vacanti, CA AF Arevalo-Silva, CA Eavey, RD Cao, YL Vacanti, M Weng, YL Vacanti, CA TI Internal support of tissue-engineered cartilage SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID CHONDROCYTES AB Background: Auricles previously created by tissue engineering in nude mice used a biodegradable internal scaffold to maintain the desired shape of an ear. However, the biodegradable scaffold incited a compromising inflammatory response in subsequent experiments in immunocompetent animals. Objective: To test the hypothesis that tissue-engineered autologous cartilage can be bioincorporated with a nonreactive, permanent endoskeletal scaffold. Materials and Methods: Auricular elastic cartilage was harvested from Yorkshire swine. The chondrocytes were isolated and suspended into a hydrogel (Pluronic F-127) at a cell concentration of 5 x 10(7) cells/mL. Nonbiodegradable endoskeletal scaffolds were formed with 1 of 5 polymers: (1) high-density polyethylene, (2) soft acrylic, (3) polymethylmethaclylate, (4) extrapurified Silastic, and (5) conventional Silastic. Three groups were studied: (1) a control group using only the 5 polymers, (2) the 5 polymers enveloped by Pluronic F-127 only, and (3) the implants coated with Pluronic F-127 seeded with chondrocytes. All constructs were implanted subdermally; implants containing cells were implanted into the same animal from which the cells had been islolated. The implants were harvested after 8 weeks of in vivo culture and histologically analyzed. Results: Only implants coated by hydrogel plus cells generated healthy new cartilage. With 3 polymers (high-density polyethylene, acrylic, and extrapurified Silastic), the coverage was nearly complete by elastic cartilage, with minimal fibrocartilage and minimal to no inflammatory reaction. The Food and Drug Administration-approved conventional Silastic implants resulted in fragments of fibrous tissue mixed with elastic cartilage plus evidence of chronic inflammation. The polymethylmethacrylate implant was intermediate in the amount of cartilage formed and degree of inflammation. Conclusions: This pilot technique combining tissue-engineered autologous elastic cartilage with a permanent biocompatible endoskeleton demonstrated success in limiting the inflammatory response to the scaffold, especially to high-density polyethylene, acrylic, and extrapurified Silastic. This model facilitates the potential to generate tissue of intricate shape, such as the human ear, by internal support. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Univ Massachusetts, Med Ctr, Lab Tissue Engn, Dept Anesthesia, Worcester, MA USA. Univ Massachusetts, Med Ctr, Dept Pathol, Worcester, MA USA. RP Eavey, RD (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 13 TC 37 Z9 42 U1 1 U2 6 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 DEC PY 2000 VL 126 IS 12 BP 1448 EP 1452 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 380ZR UT WOS:000165738300005 PM 11115280 ER PT J AU Wolfson, AM Doctor, JN Burns, SP AF Wolfson, AM Doctor, JN Burns, SP TI Clinician judgments of functional outcomes: How bias and perceived accuracy affect rating SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE activities of daily living; judgment; observer bias; rehabilitation ID INDEPENDENCE MEASURE FIM; DECISION-MAKING; HEALTH-CARE; REHABILITATION; INFORMATION; RELIABILITY; HEURISTICS; VALIDITY; AGE AB Objective: To evaluate the accuracy of clinician judgments of patient function, the susceptibility of judges to bias, and the relation between a judge's degree of belief in his/her accuracy of classification to observed accuracy when using the FIM(TM) instrument. Participants: Fifty rehabilitation professionals. Setting: 3 urban medical centers. Design: Four randomized experiments among subjects to examine the effect of potentially biasing information on FIM ratings of patient vignettes. Participants answered 60 true/false questions regarding patient function and FIM score and indicated confidence in the accuracy of their answers. Interventions: Manipulation of patient information. Main Outcome Measures: The standard FIM 7-point scale, observed proportion of correct responses to the 60 true/false questions, and a 6-category confidence scale for each of the 60 questions were used as dependent measures. Results: FIM ratings assigned to others biased participants' FIM ratings of patient vignettes. Functional ability was over estimated when ratings in other domains were high and underestimated when they were low. Participants were overconfident in their ability to answer FIM questions accurately across all professional disciplines. Conclusion: Bias and poor judgment of level accuracy play a significant role in clinician ratings of patient functioning. Blind ratings and training in debiasing are potential solutions to the problem. C1 Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Wolfson, AM (reprint author), Univ Washington, Sch Med, Dept Rehabil Med, Box 356490, Seattle, WA 98195 USA. NR 48 TC 19 Z9 19 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2000 VL 81 IS 12 BP 1567 EP 1574 DI 10.1053/apmr.2000.16345 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 380JU UT WOS:000165698800005 PM 11128891 ER PT J AU Huang, Y Fleming, AJ Wu, S Virella, G Lopes-Virella, MF AF Huang, Y Fleming, AJ Wu, S Virella, G Lopes-Virella, MF TI Fc-gamma receptor cross-linking by immune complexes induces matrix metalloproteinase-1 in U937 cells via mitogen-activated protein kinase SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article; Proceedings Paper CT 72nd Annual Scientific Session of the American-Heart-Association CY NOV 07-10, 1999 CL ATLANTA, GEORGIA SP Amer Heart Assoc DE LDL; metalloproteinase; immune complex; collagen ID LOW-DENSITY-LIPOPROTEIN; MONOCYTE-DERIVED MACROPHAGES; OXIDIZED LDL; ATHEROSCLEROTIC PLAQUE; CAROTID ATHEROSCLEROSIS; CIRCUMFERENTIAL STRESS; TYROSINE KINASES; TISSUE INHIBITOR; THP-1 CELLS; TNF-ALPHA AB Matrix metalloproteinase-1 (MMP-1) secreted by macrophages potentially contributes to plaque rupture. Because large quantities of immunoglobulin G and ICs (ICs), including low density lipoprotein-containing ICs (LDL-ICs), are present in atherosclerotic lesions, we examined the effect of LDL-ICs on macrophage MMP-1 expression. With the use of ICs prepared with human LDL and rabbit anti-LDL antiserum, our enzyme-linked immunosorbent assays and Northern blots showed that MMP-1 secretion and expression by U937 histiocytes were induced by LDL-ICs, Furthermore, our results showed that blocking of Fc-gamma receptor I and II (Fc gamma RI and Fc gamma RII) inhibited 70% and 55%, respectively, of the LDL-IC-induced secretion of MMP-1. Finally, our data showed that both PD98059, an inhibitor of the mitogen-activated protein kinase pathway, and Ro-31-2880, an inhibitor of protein kinase C, inhibited LDL-IC-stimulated MMP-1 secretion in a dose-dependent manner, with 96% and 95% inhibition, respectively, at the respective doses of 50 mu mol/L and 80 nmol/L. In conclusion, this study demonstrated for the first time that LDL-ICs induce macrophage MMP-1 secretion by cocross-linking Fc gamma RI and Fc gamma RII and triggering a protein kinase C-dependent mitogen-activated protein kinase pathway. These results suggest that LDL-ICs and other ICs localized in atherosclerotic plaques may be potent stimulators for macrophage MMP-1 expression and may contribute to plaque rupture and acute coronary events. C1 Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Immunol & Microbiol, Charleston, SC 29403 USA. Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Huang, Y (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, 114 Doughty St, Charleston, SC 29403 USA. FU NHLBI NIH HHS [HL-55782] NR 47 TC 39 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2000 VL 20 IS 12 BP 2533 EP 2538 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 383EJ UT WOS:000165869900011 PM 11116049 ER PT J AU McFarlane, AC Yehuda, R AF McFarlane, AC Yehuda, R TI Clinical treatment of posttraumatic stress disorder: conceptual challenges raised by recent research SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Article DE aetiology; cognitive and behaviour therapy; pharmacotherapy; phenomenology; posttraumatic stress disorder; psychotherapy; treatment ID EYE-MOVEMENT DESENSITIZATION; AVOIDANCE SYMPTOMS; INJURED SURVIVORS; FLOODING THERAPY; TERRORIST ATTACK; PREDICTIVE VALUE; EARLY INTRUSION; RAPE VICTIMS; TRAUMA; PSYCHOTHERAPY AB Objective: This paper highlights some of the recent findings in the field of posttraumatic stress disorder (PTSD) and examines their impact on conceptions of trauma-focused clinical treatment. Method: A series of research findings in the area of epidemiology, phenomenology, neurobiology and treatment are summarised. Results: The findings from these studies present critical challenges for clinicians who wish to treat trauma survivors using specialised trauma treatments, The major challenge is one of avoiding a simplistic view of PTSD as a singular response to trauma, as this perception may result in an underestimation of the complexity and disabling quality of the disorder, and lead to the formulation of treatment plans that are simplistic or incomplete. Conclusions: A more precise characterisation of the nature and range of the stress responses of trauma victims will significantly improve treatments of trauma survivors. C1 Mt Sinai Sch Med, New York, NY USA. Bronx Vet Affairs Med Ctr, New York, NY USA. Univ Adelaide, Queen Elizabeth Hosp, Adelaide, SA 5005, Australia. RP Yehuda, R (reprint author), Bronx Vet Affairs, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. NR 82 TC 28 Z9 29 U1 0 U2 4 PU BLACKWELL SCIENCE ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0004-8674 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD DEC PY 2000 VL 34 IS 6 BP 940 EP 953 DI 10.1080/000486700268 PG 14 WC Psychiatry SC Psychiatry GA 385UB UT WOS:000166021100006 PM 11127624 ER PT J AU Biederman, J Faraone, SV Wozniak, J Monuteaux, MC AF Biederman, J Faraone, SV Wozniak, J Monuteaux, MC TI Parsing the association between bipolar, conduct, and substance use disorders: A familial risk analysis SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar disorder; conduct disorder; substance use; familial risk ID DEFICIT HYPERACTIVITY DISORDER; MANIC-DEPRESSIVE ILLNESS; COCAINE ABUSERS; PSYCHIATRIC-DISORDERS; ONSET MANIA; COMORBIDITY; ADOLESCENTS; ALCOHOL; ADHD; MOOD AB Background: Bipolar disorder has emerged as a risk factor for substance use disorders (alcohol or drug abuse or dependence) in youth; however, the association between bipolar disorder and substance use disorders is complicated by comorbidity with conduct disorder. We used familial risk analysis to disentangle the association between the three disorders, Methods: We compared relatives of four proband groups. 1) conduct disorder + bipolar disorder, 2) bipolar disorder without conduct disorder, 3) conduct disorder without bipolar disorder, and 4) control subjects without bipolar disorder or conduct disorder. All subjects were evaluated with structured diagnostic interviews. For the analysis of substance use disorders, Cox proportional hazard survival models were utilized to compare age-at-onset distributions. Results: Bipolar disorder in probands was a risk factor for both drug and alcohol addiction in relatives, independent of conduct disorder in probands, which was a risk factor for alcohol dependence in relatives independent of bipolar disorder in probands, but not for drug dependence. The effects of bipolar disorder and conduct disor- der in probands combined additively to predict the risk for substance use disorders in relatives. Conclusions: The combination of conduct disorder + bipolar disorder in youth predicts especially high rates of substance use disorders in relatives. These findings support previous results documenting that when bipolar disorder and conduct disorder occur comorbidly, both are validly diagnosed disorders. (C) 2000 Society of Biological Psychiatry. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Child Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Inst Psychiat Epidemiol & Genet, Dept Psychiatl,Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. Commonwealth Res Ctr, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Child Psychiat Serv, ACC 725,15 Parkman St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R0I MH41314-07, R0IMH57934-01] NR 53 TC 43 Z9 44 U1 4 U2 8 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 DEC 1 PY 2000 VL 48 IS 11 BP 1037 EP 1044 DI 10.1016/S0006-3223(00)00906-9 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 377EH UT WOS:000165498600001 PM 11094136 ER PT J AU Teale, P Reite, M Rojas, DC Sheeder, J Arciniegas, D AF Teale, P Reite, M Rojas, DC Sheeder, J Arciniegas, D TI Fine structure of the auditory M100 in schizophrenia and schizoaffective disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; schizoaffective disorder; magnetoencephalography; M100; auditory-evoked fields; laterality ID SENSORY MEMORY; NEUROMAGNETIC EVIDENCE; LEFT-HEMISPHERE; ABNORMALITIES; COMPONENT; ASYMMETRY AB Background: Several studies have demonstrated anomalous asymmetry of the 100-msec latency auditory-evoked field (M100) in schizophrenia Recent evidence suggests this may be a compound component however Our study examines the localization of two M100 subcomponents in patients with schizophrenia and schizoaffective disorder. Methods: Magnetoencephalographic recordings of auditory-evoked fields were obtained for 14 subjects with schizophrenia, 12 with schizoaffective disorder and 23 control subjects. Two M100 subcomponents were identified and localized in each hemisphere. Results: Both patient groups exhibited different lateralization compared with control subjects, with the second subcomponent tending to be less lateralized Conclusions: The second subcomponent may be the major contributor to previously reported laterality differences. Future studies might benefit by separating M100 subcomponents so that specific functions could be addressed. (C) 2000 Society of Biological Psychiatry. C1 Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Biomagnet Imaging Lab, Denver, CO 80262 USA. Denver VA Med Ctr, Denver, CO USA. RP Reite, M (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Biomagnet Imaging Lab, 4200 E 9th Ave,Box C268-68, Denver, CO 80262 USA. RI Arciniegas, David/A-3792-2009; Rojas, Don/F-4296-2012; OI Rojas, Don/0000-0001-6560-9616; Sheeder, Jeanelle/0000-0002-4463-3569 FU NIMH NIH HHS [MH47476] NR 17 TC 18 Z9 18 U1 0 U2 0 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 DEC 1 PY 2000 VL 48 IS 11 BP 1109 EP 1112 DI 10.1016/S0006-3223(00)00941-0 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 377EH UT WOS:000165498600010 PM 11094145 ER PT J AU Goetghebeur, E Ryan, L AF Goetghebeur, E Ryan, L TI Semiparametric regression analysis of interval-censored data SO BIOMETRICS LA English DT Article DE Breslow estimator; EM algorithm; proportional hazards ID PROPORTIONAL HAZARDS MODEL; EM ALGORITHM; LIKELIHOOD; INFERENCE AB We propose a semiparametric approach to the proportional hazards regression analysis of interval-censored data. An EM algorithm based on an approximate likelihood leads to an hi-step that involves maximizing a standard Cox partial likelihood to estimate regression coefficients and then using the Breslow estimator for the unknown baseline hazards. The E-step takes a particularly simple form because all incomplete data appear as linear terms in the complete-data log likelihood. The algorithm of Turnbull (1976, Journal of the Royal Statistical Society, Series B 38, 290-295) is used to determine times at which the hazard can take positive mass. We found multiple imputation to yield an easily computed variance estimate that appears to be more reliable than asymptotic methods with small to moderately sized data sets. In the right-censored survival setting, the approach reduces to the standard Cox proportional hazards analysis, while the algorithm reduces to the one suggested by Clayton and Cuzick (1985, Applied Statistics 34, 148-156). The method is illustrated on data from the breast cancer cosmetics trial, previously analyzed by Finkelstein (1986, Biometrics 42, 845-854) and several subsequent authors. C1 State Univ Ghent, TWI, B-9000 Ghent, Belgium. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Goetghebeur, E (reprint author), State Univ Ghent, TWI, Krijgslaan 281-S9, B-9000 Ghent, Belgium. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 FU NCI NIH HHS [CA48061] NR 25 TC 47 Z9 47 U1 1 U2 11 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2000 VL 56 IS 4 BP 1139 EP 1144 DI 10.1111/j.0006-341X.2000.01139.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 383FN UT WOS:000165872600023 PM 11129472 ER PT J AU Contreras, M Ryan, LM AF Contreras, M Ryan, LM TI Fitting nonlinear and constrained generalized estimating equations with optimization software SO BIOMETRICS LA English DT Article DE BCa method; developmental toxicity study; nonlinear programming ID RISK ASSESSMENT; REGRESSION AB In this article, we present an estimation approach for solving nonlinear constrained generalized estimating equations that can be implemented using object-oriented software for nonlinear programming, such as nlminb in Splus or fmincon and Isqnonlin in Matlab. We show how standard estimating equation theory includes this method as a special case so that our estimates, when unconstrained, will remain consistent: and asymptotically normal. To illustrate this method, we fit a nonlinear dose-response model with nonnegative mixed bound constraints to clustered binary data from a developmental toxicity study. Satisfactory confidence intervals are found using a nonparametric bootstrap method when a common correlation coefficient is assumed for all the dose groups and for some of the dose-specific groups. C1 Cornell Univ, Dept Biometry, Ithaca, NY 14853 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Contreras, M (reprint author), Cornell Univ, Dept Biometry, 435 Warren Hall, Ithaca, NY 14853 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 FU NCI NIH HHS [CA48061] NR 14 TC 6 Z9 6 U1 1 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2000 VL 56 IS 4 BP 1268 EP 1271 DI 10.1111/j.0006-341X.2000.01268.x PG 4 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 383FN UT WOS:000165872600043 PM 11129490 ER PT J AU Li, Y Lin, XH AF Li, Y Lin, XH TI Covariate measurement errors in frailty models for clustered survival data SO BIOMETRIKA LA English DT Article DE asymptotic bias; EM algorithm; frailty measurement error model; identifiability; nonparametric maximum likelihood estimation; variance components ID PROPORTIONAL HAZARDS MODEL; LONGITUDINAL DATA; ASYMPTOTIC THEORY; TIME AB We propose a new class of frailty measurement error models for clustered survival data when covariates are measured with error. We show that the induced hazard function conditional on the observed covariates also follows a frailty model but of a more complicated form. We study the asymptotic bias in regression coefficients and variance components when measurement error is ignored, and the impact of censoring on this asymptotic bias. We show that the naive estimator of the regression coefficient is attenuated and the naive estimator of the variance component is inflated when measurement error is ignored. As the censoring proportion increases, the asymptotic bias in the former becomes larger, but the asymptotic bias in the latter interestingly becomes smaller. We develop a structural approach for parameter estimation using the nonparametric maximum likelihood method, where the baseline hazard is estimated nonparametrically. We prove model identifiability and the existence of the nonparametric maximum likelihood estimators. An EM algorithm is developed for calculating the nonparametric maximum likelihood estimates. The method is applied to the western Kenya parasitaemia data and its performance is evaluated through simulations. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Li, Y (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NR 17 TC 24 Z9 25 U1 0 U2 3 PU BIOMETRIKA TRUST PI LONDON PA UNIV COLLEGE LONDON GOWER ST-BIOMETRIKA OFFICE, LONDON, ENGLAND WC1E 6BT SN 0006-3444 J9 BIOMETRIKA JI Biometrika PD DEC PY 2000 VL 87 IS 4 BP 849 EP 866 DI 10.1093/biomet/87.4.849 PG 18 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 387QG UT WOS:000166132800008 ER PT J AU Cai, T Wei, LJ Wilcox, M AF Cai, T Wei, LJ Wilcox, M TI Semiparametric regression analysis for clustered failure time data SO BIOMETRIKA LA English DT Article DE censoring; Gaussian process; Kaplan-Meier estimate; linear transformation model; prediction; proportional hazards model; proportional odds model ID TRANSFORMATION MODELS; CENSORED-DATA; LIKELIHOOD; HAZARDS AB Inference procedures based on the partial likelihood function for the Cox proportional hazards model have been generalised to the case in which the data consist of a large number of independent small groups of correlated failure time observations (Lee, Wei & Amato, 1992; Liang, Self & Chang, 1993; Cai & Prentice, 1997). However, the Cox model may not fit the data well. A class of linear transformation models, which includes the proportional hazards and odds models as special cases, has been studied extensively for univariate event times. In this paper, statistical methods to analyse such correlated observations are proposed for these models. We use the data from a recent study of the genetic aetiology of alcoholism to illustrate the new procedures for estimation, prediction and model selection. C1 Harvard Univ, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cai, T (reprint author), Harvard Univ, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM cai@hsph.harvard.edu; wei@hsph.harvard.edu; mwilcox@hsph.harvard.edu NR 22 TC 55 Z9 56 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD DEC PY 2000 VL 87 IS 4 BP 867 EP 878 DI 10.1093/biomet/87.4.867 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 387QG UT WOS:000166132800009 ER PT J AU Bauer, MS Vojta, C Kinosian, B Altshuler, L Glick, H AF Bauer, MS Vojta, C Kinosian, B Altshuler, L Glick, H TI The Internal State Scale: replication of its discriminating abilities in a multisite, public sector sample SO BIPOLAR DISORDERS LA English DT Article DE assessment instruments; bipolar disorder; receiver operating characteristic (ROC) curves ID DYSPHORIC MANIA; HYPOMANIA AB Objective: The internal State Scale (ISS) is a self-report instrument that has been validated for discriminating mood states in patients with bipolar disorder. This study a) extends investigation to a multisite public sector sample and b) tests a revised scoring algorithm that formally identifies patients in mixed states. Methods: Eighty-Six patients with bipolar disorder from four Veterans Affairs medical centers were assessed in a doss-sectional design. Physician-conducted semi-structured interviews used DSM-IV criteria to identify subjects as meeting criteria for euthymia, mania or hypomania, depression, or mixed state (mania or hypomania plus depression). A revised ISS scoring algorithm independently assigned mood state. Mean subscale scores were analyzed across groups. Receiver-operating characteristic (ROC) curve analysis was conducted to determine optimal algorithm structure. Results: Analysis of mean scores for the ISS subscales replicated original results for Activation. Well-Being, and Perceived Conflict. but indicated differences from the original results for the Depression Index. The ROC curve analysis identified optimal cut-off scores for the revised algorithm. The overall kappa score indicated moderate agreement between ISS and physician ratings of mood state, including mixed states. Limitations: The study used a sample consisting primarily of male veterans. Mood state was assigned by experts using expert clinician diagnosis. not structured interviews. Conclusion: The performance of the ISS in this multisite. public sector sample was similar to the performance in the initial research clinic sample. This finding confirms the validity of the ISS as a discriminator of mood states in bipolar disorder. The development of a revised scoring algorithm makes feasible formal identification of mired episodes with the ISS. C1 Brown Univ, Sch Med, Providence, RI 02912 USA. Providence VA Med Ctr, Providence, RI USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Bauer, MS (reprint author), VAMC-116R,830 Chalkstone Ave, Providence, RI 02908 USA. NR 16 TC 68 Z9 68 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD DEC PY 2000 VL 2 IS 4 BP 340 EP 346 DI 10.1034/j.1399-5618.2000.020409.x PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 428PQ UT WOS:000168470400009 PM 11252648 ER PT J AU Cheson, BD Bennett, JM Kantarjian, H Pinto, A Schiffer, CA Nimer, SD Lowenberg, B Beran, M de Witte, TM Stone, RM Mittelman, M Sanz, GF Wijermans, PW Gore, S Greenberg, PL AF Cheson, BD Bennett, JM Kantarjian, H Pinto, A Schiffer, CA Nimer, SD Lowenberg, B Beran, M de Witte, TM Stone, RM Mittelman, M Sanz, GF Wijermans, PW Gore, S Greenberg, PL TI Report of an international working group to standardize response criteria for myelodysplastic syndromes SO BLOOD LA English DT Editorial Material ID CHRONIC MYELOGENOUS LEUKEMIA; INTERFERON-ALPHA THERAPY; MARROW TRANSPLANTATION; CLASSIFICATION; EVOLUTION; SURVIVAL; DISEASE AB Standardized criteria for assessing response are essential to ensure comparability among clinical trials for patients with myelodysplastic syndromes (MDS). An international working group of experienced clinicians involved in the management of patients with MDS reviewed currently used response definitions and developed a uniform set of guidelines for future clinical trials in MDS. The MDS differ from many other hematologic malignancies in their chronicity and the morbidity and mortality caused by chronic cytopenias, often without disease progression to acute myeloid leukemia. Whereas response rates may be an important endpoint for phase 2 studies of new agents and may assist regulatory agencies in their evaluation and approval processes, an important goal of clinical trials in MDS should be to prolong patient survival. Therefore, these response criteria reflected 2 sets of goals in MDS: altering the natural history of the disease and alleviating disease-related complications with improved quality of life. It is anticipated that the recommendations presented will require modification as more is learned about the molecular biology and genetics of these disorders. Until then, it is hoped these guidelines will serve to improve communication among investigators and to ensure comparability among clinical trials. (C) 2000 by The American Society of Hematology. C1 NCI, Bethesda, MD 20892 USA. Univ Rochester, Ctr Canc, Rochester, NY 14627 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Ctr Riferimento Oncol, I-33081 Aviano, Italy. Wayne State Univ, Karmanos Canc Ctr, Detroit, MI USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Rotterdam Hosp, Rotterdam, Netherlands. Univ Nijmegen Hosp, Rijmegen, Netherlands. Dana Farber Canc Inst, Boston, MA 02115 USA. Hasharon Hosp, Rabin Med Ctr, IL-49372 Petah Tiqwa, Israel. Tel Aviv Univ, IL-69978 Tel Aviv, Israel. Univ Valencia, Hosp La Fe, Valencia, Spain. Ziekenhuis The Hague, The Hague, Netherlands. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. Vet Adm Hosp, Palo Alto, CA USA. RP Cheson, BD (reprint author), NCI, Execut Plaza N,Room 741, Bethesda, MD 20892 USA. RI Witte, T.J.M./L-4762-2015; OI SANZ, GUILLERMO/0000-0002-2767-8191 NR 22 TC 457 Z9 490 U1 1 U2 5 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 DEC 1 PY 2000 VL 96 IS 12 BP 3671 EP 3674 PG 4 WC Hematology SC Hematology GA 377LA UT WOS:000165514000002 PM 11090046 ER PT J AU Ney, PA D'Andrea, AD AF Ney, PA D'Andrea, AD TI Friend erythroleukemia revisited SO BLOOD LA English DT Review ID FOCUS-FORMING VIRUS; RECEPTOR TYROSINE KINASE; MURINE ERYTHROPOIETIN RECEPTOR; LONG TERMINAL REPEAT; CELLULAR P53 GENE; LEUKEMIA-VIRUS; GP55 GLYCOPROTEIN; ENVELOPE PROTEIN; CROSS-LINKING; EPO RECEPTOR C1 Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. St Jude Childrens Hosp, Dept Biochem, Memphis, TN 38105 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM alan_dandrea@dici.harvard.edu FU NCI NIH HHS [P30 CA21765, R01 CA084214, R01 CA084214-01, R01 CA084214-02, R01 CA084214-03, R01 CA084214-04, R01 CA084214-05, R01 CA84214] NR 101 TC 47 Z9 48 U1 1 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 DEC 1 PY 2000 VL 96 IS 12 BP 3675 EP 3680 PG 6 WC Hematology SC Hematology GA 377LA UT WOS:000165514000003 PM 11090047 ER PT J AU Schwartz, DL Schechter, GP Seltzer, S Chauncey, TR AF Schwartz, DL Schechter, GP Seltzer, S Chauncey, TR TI Radiation myelitis following allogeneic stem cell transplantation and consolidation radiotherapy for non-Hodgkin's lymphoma SO BONE MARROW TRANSPLANTATION LA English DT Article DE radiation myelitis; spinal cord toxicity; transplantation; total body irradiation; consolidation radiotherapy; lymphoma ID CENTRAL-NERVOUS-SYSTEM; BONE-MARROW TRANSPLANTATION; TOTAL-BODY IRRADIATION; CERVICAL SPINAL-CORD; MYELOPATHY; TOLERANCE; DISEASE; TOXICITY; THERAPY; TRIAL AB Myelitis is a rare but well documented complication of therapeutic radiation exposure to the spinal cord and is characterized by delayed development of paresthesias, sensory changes and, in severe cases, progressive paresis and paralysis. Although accepted radiation tolerance limits for the spinal cord have successfully limited the incidence of this problem (45-50 Gy, in daily 1.8-2 Gy fractions), aggressive systemic therapy may render patients more susceptible to radiation-related neurotoxicity. We describe the case of a 38-year-old man with refractory non-Hodgkin's lymphoma who underwent matched sibling peripheral blood stem cell transplant following a conditioning regimen of cyclophosphamide (60 mg/kg x 2) and total body irradiation (120 cGy x 11), This was followed by delivery of 30.6 Gy involved-field radiation at 1.8 Gy/day to the mediastinum and left supraclavicular fossa for bulky residual tumor. Although maximum cumulative radiation dose to the spinal cord was less than 45 Gy, the patient subsequently developed progressive lower extremity weakness and MRI abnormalities of the spinal cord limited to the radiation field. This represents the second report in the literature of this unexpected complication, prompting a need to reexamine current guidelines for radiotherapy in the context of high-dose systemic treatment. C1 VA Puget Sound Hlth Care Syst, Marrow Transplant Unit, Dept Radiat Oncol, Seattle, WA 98108 USA. Univ Washington, Div Oncol, Dept Radiat Oncol, Seattle, WA 98195 USA. VA Med Ctr, Hematol Sect, Washington, DC USA. VA Med Ctr, Serv Radiol, Washington, DC USA. George Washington Univ, Washington, DC USA. RP Chauncey, TR (reprint author), VA Puget Sound Hlth Care Syst, Marrow Transplant Unit, Dept Radiat Oncol, S-111-MTU,1660 S Columbian Way, Seattle, WA 98108 USA. NR 27 TC 13 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD DEC PY 2000 VL 26 IS 12 BP 1355 EP 1359 DI 10.1038/sj.bmt.1702705 PG 5 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 394YW UT WOS:000166552800015 PM 11223979 ER PT J AU Harris, T Wexler, K Holcomb, P AF Harris, T Wexler, K Holcomb, P TI An ERP investigation of binding and coreference SO BRAIN AND LANGUAGE LA English DT Article DE event-related potentials; ERP; binding; syntax; pragmatics; P600; reflexive; coreference; argument ID BRAIN POTENTIALS; ANOMALIES; FREQUENCY; LANGUAGE; WORDS AB This study examines the nature of violations in processing one class of binding construction, namely those involving reflexives and their antecedents. When arguments of verbs appear at the point where a syntactic violation is detected, a centro-parietal positivity occurs, peaking at 600 ms after the presentation of the stimulus (P600), as is consistent with other types of syntactic anomalies. However, nonarguments in similar sentences fail to elicit the same response. For example, the reflexive in John's brothers like himself is in an argument position and elicits the P600 when compared to its grammatical counterpart. The nonargument, participating in the same type of mismatch, John's brothers like Bill and himself; does not elicit the same positivity. This provides evidence that there are two processes involved in parsing this binding construction, one syntactic and another as yet unidentified, per haps involving meaning or pragmatics, (C) 2000 Academic Press. C1 Univ Calif San Diego, La Jolla, CA 92093 USA. MIT, Cambridge, MA 02139 USA. Tufts Univ, Medford, MA 02155 USA. RP Harris, T (reprint author), Massachusetts Gen Hosp, NMR Ctr, 149 13th St, Boston, MA 02129 USA. NR 33 TC 26 Z9 27 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD DEC PY 2000 VL 75 IS 3 BP 313 EP 346 DI 10.1006/brln.2000.2318 PG 34 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 383HN UT WOS:000165877200001 PM 11112289 ER PT J AU Hamblin, MR Del Governatore, M Rizvi, I Hasan, T AF Hamblin, MR Del Governatore, M Rizvi, I Hasan, T TI Biodistribution of charged 17.1A photoimmunoconjugates in a murine model of hepatic metastasis of colorectal cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE photodynamic therapy; photoimmunotherapy; monoclonal antibody; photosensitizer; polylysine; intraperitoneal PDT ID PHOTODYNAMIC THERAPY; MONOCLONAL-ANTIBODY; OVARIAN-CANCER; TISSUE DISTRIBUTION; LIVER METASTASES; CARCINOMA CELLS; TUMOR-THERAPY; NUDE-MOUSE; RAT-LIVER; PHOTOIMMUNOTHERAPY AB Optimizing photodynamic therapy involves attempting to increase both the absolute tumour content of photosensitizer and the selectivity between tumour and surrounding normal tissue. One reason why photodynamic therapy has not been considered suitable for treatment of metastatic tumours in the liver, is the poor selectivity of conventional photosensitizers for tumour compared to normal liver. This report details an alternative approach to increasing this selectivity by the use of antibody-targeted photosensitizers (or photoimmunoconjugates) to target intrahepatic tumours caused by human colorectal cancer cells in the nude mouse, and explores the role of molecular charge on the tumour-targeting efficiency of macromolecules. The murine monoclonal antibody 17.1A (which recognizes an antigen expressed on HT 29 cells) was used to prepare site-specific photoimmunoconjugates with the photosensitizer chlorine6. The conjugates had either a predominant cationic or anionic charge and were injected i.v. into tumour-bearing mice. Biodistribution 3 or 24 h later was measured by extraction of tissue samples and quantitation of chlorine6 content by fluorescence spectroscopy. The photoimmunoconjugates were compared to the polylysine conjugates in an attempt to define the effect of molecular charge as well as antibody targeting. The anionic 17.1A conjugate delivered more than twice as much photosensitizer to the tumour at 3 h than other species (5 times more than the cationic 17.1A conjugate) and had a tumour:normal liver ratio of 2.5. Tumour-to-liver ratios were greater than one for most compounds at 3 h but declined at 24 h. Tumour-to-skin ratios were high (> 38) for all conjugates but not for free chlorines. Cationic species had a high uptake in the lungs compared to anionic species. The photoimmunoconjugates show an advantage over literature reports of other photosensitizers, which can result in tumour:normal liver ratios of less than 1. (C) 2000 cancer Research Campaign http://www.bjcancer.com. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. Osped Policlin S Orsola, Dept Chirurg 3, I-40100 Bologna, Italy. RP Hasan, T (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. OI Rizvi, Imran/0000-0001-9673-4700; Hamblin, Michael/0000-0001-6431-4605 FU NIAMS NIH HHS [R01 AR40352] NR 38 TC 45 Z9 48 U1 1 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD DEC PY 2000 VL 83 IS 11 BP 1544 EP 1551 DI 10.1054/bjoc.2000.1486 PG 8 WC Oncology SC Oncology GA 378UL UT WOS:000165603000023 PM 11076666 ER PT J AU Li, JZ Xia, YP Kuter, DJ AF Li, JZ Xia, YP Kuter, DJ TI The platelet thrombopoietin receptor number and function are markedly decreased in patients with essential thrombocythaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE thrombopoietin; c-mpl; platelets; essential thrombocythaemia; myeloproliferative disorders ID C-MPL LIGAND; FAMILIAL ESSENTIAL THROMBOCYTHEMIA; VERA STUDY-GROUP; MYELOPROLIFERATIVE DISORDERS; POLYCYTHEMIA-VERA; CLONAL DISORDER; REACTIVE THROMBOCYTOSIS; MEGAKARYOCYTE GROWTH; DIAGNOSTIC-VALUE; STEM-CELL AB Essential thrombocythaemia (ET) is a relatively common myeloproliferative disorder characterized by an elevated platelet count. As thrombopoietin (TPO) and the TPO receptor (c-mpl) regulate platelet production in normal physiology, their role in ET was investigated. A well-characterized cohort of 23 ET patients was evaluated and followed for 3 years. The TPO levels in these ET patients (189 +/- 131 pg/ml) were the same as in normal subjects (179 +/- 112 pg/ml) and TPO was not produced by ET platelets. There were 5.6 +/- 5.5 TPO binding sites/ET platelet vs. 56 +/- 17 TPO binding sites/normal platelet and this was associated in ET patients with normal-sized platelet c-mpl protein and mRNA, but a 10-fold reduction in platelet c-mpl mRNA. The K-d for the TPO receptor on ET platelets was 66 +/- 30 pmol/l vs. 163 +/- 31 pmol/l on normal platelets, but the c-mpl cDNA had a normal nucleic acid sequence. The decreased number of ET platelet TPO receptors resulted in a fourfold decrease in the platelet-dependent TPO clearance (0.30 +/- 0.14 ml/h/10(9) ET platelets vs. 1.24 +/- 0.38 ml/h/10(9) normal platelets) at a time when the platelet count in ET patients was 2.7-fold above normal. The fourfold decrease in the TPO clearance, elevated platelet mass and resulting normal total TPO clearance explain the normal TPO levels. These results also suggest that the thrombocytosis in ET may be attributed to an alteration of the normal feedback interaction between TPO and its receptor and not as a result of any defect in the structure of TPO or c-mpl. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Hematol Oncol Unit, Boston, MA 02114 USA. RP Kuter, DJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Hematol Oncol Unit, COX 640,100 Blossom St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL54838, HL61222] NR 54 TC 33 Z9 33 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2000 VL 111 IS 3 BP 943 EP 953 PG 11 WC Hematology SC Hematology GA 384JK UT WOS:000165938900032 PM 11122159 ER PT J AU Lee, SJ AF Lee, SJ TI Chronic myelogenous leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE chronic myelogenous leukaemia ID CHRONIC MYELOID-LEUKEMIA; BONE-MARROW TRANSPLANTATION; INTERFERON-ALPHA THERAPY; POLYMERASE-CHAIN-REACTION; VERSUS-HOST DISEASE; CHRONIC GRANULOCYTIC-LEUKEMIA; TOTAL-BODY IRRADIATION; CYTOGENETIC CLONAL EVOLUTION; DONOR LYMPHOCYTE INFUSION; BLOOD PROGENITOR-CELL C1 Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Lee, SJ (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 75267-01] NR 149 TC 38 Z9 40 U1 1 U2 5 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2000 VL 111 IS 4 BP 993 EP 1009 DI 10.1046/j.1365-2141.2000.02216.x PG 17 WC Hematology SC Hematology GA 399DL UT WOS:000166795900003 PM 11167734 ER PT J AU Braslow, JT AF Braslow, JT TI Therapeutics and thc history of psychiatry SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Editorial Material ID FACTS C1 Univ Calif Los Angeles, NPI, Hlth Serv Res Ctr, Dept Psychiat & Hist, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. RP Braslow, JT (reprint author), Univ Calif Los Angeles, NPI, Hlth Serv Res Ctr, Dept Psychiat & Hist, 10920 Wilshire Blvd,Suite 300, Los Angeles, CA 90024 USA. NR 47 TC 2 Z9 2 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD WIN PY 2000 VL 74 IS 4 BP 794 EP 802 DI 10.1353/bhm.2000.0161 PG 9 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 392RW UT WOS:000166427100007 PM 11201268 ER PT J AU Beck, JC Schouten, R AF Beck, JC Schouten, R TI Workplace violence and psychiatric practice SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article; Proceedings Paper CT 21st Annual Menninger Winter Psychiatry Conference CY MAR, 1999 CL PARK CITY, UTAH SP Menninger Clin AB The authors provide an overview of what is known about workplace violence and discuss how to deal with issues of workplace violence that arise in clinical practice. They review, myths and facts about workplace violence, including research on prevention. Legal issues relating to the psychiatrist as employer and the Americans with Disability Act are presented. General principles of violence assessment are reviewed and the authors then discuss the psychiatrist as consultant to the workplace and as clinician treating a victim or perpetrator of workplace violence. Three cases illustrate the general principles provided. C1 Cambridge Hosp, Dept Psychiat, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Law & Psychiat Serv Program, Boston, MA 02114 USA. RP Beck, JC (reprint author), Cambridge Hosp, Dept Psychiat, 1493 Cambridge St, Cambridge, MA 02139 USA. NR 15 TC 3 Z9 3 U1 0 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0025-9284 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD WIN PY 2000 VL 64 IS 1 BP 36 EP 48 PG 13 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA 282HJ UT WOS:000085212000004 PM 10695158 ER PT J AU Mullins, ME Sabloff, B Aquino, SL McLoud, TC AF Mullins, ME Sabloff, B Aquino, SL McLoud, TC TI Case of the month #80 SO CANADIAN ASSOCIATION OF RADIOLOGISTS JOURNAL-JOURNAL DE L ASSOCIATION CANADIENNE DES RADIOLOGISTES LA English DT Article C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Dept Diagnost Imaging, Houston, TX 77030 USA. Lahey Clin, Dept Radiol, Burlington, MA USA. RP Mullins, ME (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders House, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0846-5371 J9 CAN ASSOC RADIOL J JI Can. Assoc. Radiol. J.-J. Assoc. Can. Radiol. PD DEC PY 2000 VL 51 IS 6 BP 361 EP 361 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 386BM UT WOS:000166040300009 ER PT J AU Strauss, GM AF Strauss, GM TI Randomized population trials and screening for lung cancer - Breaking fire cure barrier SO CANCER LA English DT Article; Proceedings Paper CT International Conferece on Prevention and Early Diagnosis of Lung Cancer CY DEC 09-10, 1998 CL VARESE, ITALY SP Amer Canc Soc DE early detection; screening; lung carcinoma; randomized population trials; randomized clinical trials; mortality; cure; paradigm ID LOCALIZED PROSTATE-CANCER; INTERNATIONAL STAGING SYSTEM; FECAL OCCULT BLOOD; BREAST-CANCER; FOLLOW-UP; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; RADICAL PROSTATECTOMY; MALIGNANT NEOPLASMS; COLORECTAL-CANCER AB BACKGROUND. At the current time, there is nearly universal agreement that screening for the early detection of lung carcinoma is not justified. This is based on the fact that, to the author's knowledge, no randomized population trial (RPT) to date has demonstrated a significant reduction in lung carcinoma mortality as a result of any screening intervention. METHODS. To date, four RPTs, which have included a total of 37,724 male cigarette smokers, have been conducted. Studies at Memorial Sloan-Kettering Cancer Center and Johns Hopkins demonstrate no incremental effect by the addition of sputum cytology to annual chest X-ray (CXR) screening alone. However, CXR screening in all participants likely was responsible for stage and long term survival rates that were two-to three-fold higher than predicted based on contemporary statistics. Studies at the Mayo Clinic and in Czechoslovakia demonstrated significantly superior stage distribution and survival, but slightly inferior mortality in experimental populations that underwent periodic CXR screening. Such contradictory findings were made possible by a higher cumulative incidence rate of lung carcinoma in experimental populations. The constellation of improved survival, higher rate of incidence, and similar mortality led to the hypothesis that CXR screening leads to the overdiagnosis of lung carcinoma. RESULTS. Abundant evidence based on epidemiologic, pathologic, and clinical considerations conclusively demonstrate that CXR screening does not lead to the significant overdiagnosis of lung carcinoma. Moreover, overdiagnosis is the only way to reconcile the results of existing RPTs with the conclusion that CXR screening is ineffective. The alternative conclusion is that significant stage, resectability, and long term survival advantages reflected the ability of CXR screening to improve cure rates. Population heterogeneity accounts for the failure of mortality to reflect screening efficacy accurately in these trials. There is direct evidence that population heterogeneity tvas responsible for the trend toward increased lung carcinoma mortality in the Czech study. Moreover, review of all RPTs demonstrates a consistent pattern in which population heterogeneity confounds the ability of mortality to represent an accurate measure of screening effectiveness. CONCLUSIONS. Systematic analysis of RPTs supports two major conclusions: 1) an improvement in the cure rate rather than a reduction is cause specific mortality is the proper measure of screening effectiveness in the RPT setting and 2) CXR screening is associated with a two- to three-fold improvement in lung carcinoma cure rates. A paradigm shift is mandatory for the proper evaluation of conventional and newer screening modalities. Indeed, hundreds of thousands of lives would be saved annually on a global basis if CXR screening were offered to individuals at high risk for lung carcinoma. Cancer 2000;89:2399-421. (C) 2000 American Cancer Society. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Univ Massachusetts Mem Hlth Care, Div Hematol Oncol, Worcester, MA USA. RP Strauss, GM (reprint author), Roger Williams Canc Ctr, 825 Chalkstone Ave, Providence, RI 02908 USA. NR 115 TC 20 Z9 20 U1 3 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2000 VL 89 IS 11 SU S BP 2399 EP 2421 DI 10.1002/1097-0142(20001201)89:11+<2399::AID-CNCR15>3.0.CO;2-T PG 23 WC Oncology SC Oncology GA 380QE UT WOS:000165712900015 PM 11147619 ER PT J AU Strauss, GM Dominioni, L AF Strauss, GM Dominioni, L TI Perception, paradox, paradigm - Alice in the Wonderland of lung cancer prevention and early detection SO CANCER LA English DT Article; Proceedings Paper CT International Conferece on Prevention and Early Diagnosis of Lung Cancer CY DEC 09-10, 1998 CL VARESE, ITALY SP Amer Canc Soc DE lung cancer; cigarette smoking; prevention; early detection; screening; randomized population trials; randomized clinical trials ID RANDOMIZED CONTROLLED TRIAL; WOMEN; INTERVENTION; STATISTICS; SMOKERS; HEALTH; AGE AB BACKGROUND. In less than a century, lung cancer has progressed from a medical curiosity to the most deadly of all malignant diseases on our planet. Because cigarette smoking is responsible for the existing global lung cancer epidemic, policy initiatives have focused almost exclusively on primary prevention. There is no question that smoking prevention is the most effective method of reducing future lung cancer mortality rates among children, adolescents, and young adults. However, smoking cessation has limited effectiveness as a lung cancer prevention strategy among long term smokers, particularly in the short term. PERCEPTION. Conventional wisdom maintains that screening for lung cancer is ineffective. This is because no randomized trial has demonstrated a significant reduction in lung cancer mortality Indeed, mortality was higher in two of four randomized trials focusing on chest X-ray (CXR) screening for lung cancer. Accordingly, the recommendation against CXR screening is believed to be based upon powerful and direct evidence hom randomized trials that CXR screening is ineffective. PARADOX. Because lung cancer is almost uniformly fatal, a plausible explanation for the ineffectiveness of lung cancer screening, at least with CXR, is readily apparent Coventional widsom maintains that in lung cancer, the asymptomatic preclinical interval is so short that apparently localized cancers are already metastatic when they are detected at an apparently localized stage. Accordingly, "early" lesions are not truly amenable to cure through surgical resection. The problem with this interpretation, however, is that it pays no heed to what the data actually show. While mortality reductions have not been observed, significant stage and long term survival advantages have consistently been demonstrated in populations randomized to screening. Interpretation of existing trials within the strict constraints of our accepted paradigm lends support to the hypothesis that CXR screening detects and labels as cancer a substantial number of early stage lesions that are clinically unimportant in that they would never have become clinically evident during the life of the patient. The paradox is that this hypothesis, known as overdiagnosis, is biologically implausible and is not supported by any epidemiologic or clinical evidence. PARADIGM. Based upon our accepted paradigm, a reduction in cause specific mortality in a population-based randomized trial is accepted without question as an unbiased and definitive measure of screening effectiveness. The mortality paradigm is dependent upon true assumptions, which relate first, to the randomization process, and second, to the confounding influence of screening biases on other endpoints. The fundamental problem, however, is that these assumptions, which should always have been the focus of investigation rather than supposition, are invalid. Reconsideration of our assumptions is imperative to a proper understanding of the effect of interventions in population-based research. Indeed, reexamination of our paradigm is key to reducing the global burden of lung cancer mortality. Cancer 2000;89:2422-31. (C) 2000 American Cancer Society. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Univ Massachusetts Mem Hlth Care, Div Hematol Oncol, Worcester, MA USA. Univ Varese, Ctr Thorac Surg, Varese, Italy. RP Strauss, GM (reprint author), Roger Williams Canc Ctr, 825 Chalkstone Ave, Providence, RI 02908 USA. NR 63 TC 11 Z9 13 U1 1 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2000 VL 89 IS 11 SU S BP 2422 EP 2431 DI 10.1002/1097-0142(20001201)89:11+<2422::AID-CNCR16>3.0.CO;2-E PG 10 WC Oncology SC Oncology GA 380QE UT WOS:000165712900016 PM 11147620 ER PT J AU Sugarbaker, DJ Strauss, GM AF Sugarbaker, DJ Strauss, GM TI Extent of surgery and survival in early lung carcinoma - Implications for overdiagnosis in stage IA nonsmall cell lung carcinoma SO CANCER LA English DT Article; Proceedings Paper CT International Conferece on Prevention and Early Diagnosis of Lung Cancer CY DEC 09-10, 1998 CL VARESE, ITALY SP Amer Canc Soc DE nonsmall cell lung carcinoma; survival rate; mortality rate; overdiagnosis ID WEDGE RESECTION; CANCER AB BACKGROUND. With the advent of minimally invasive surgical techniques, a determination of the efficacy of limited resection in Stage IA nonsmall cell lung carcinoma (NSCLC) must be determined. The critical question is whether the probability of cure is equivalent with limited resection and with standard lobectomy. DATA ANALYSIS. The results of three independent reports are analyzed. The only randomized trial is that of the Lung Cancer Study Group, in which 247 patients with peripheral Stage IA lesions were randomized to lobectomy or limited resection. The results indicate that recurrence rate and lung carcinoma mortality rates are higher among those undergoing limited resection. In another nonrandomized series, which involved 218 consecutive Stage IA patients, there was a significantly inferior survival rates among those undergoing limited resection compared with lobectomy. The third study is a retrospective analysis involving 244 Stage I patients treated at the Brigham and Women's Hospital (BWH). This trial shows that limited resection is inferior to anatomic resection in both Stage IA and Stage IB NSCLC. Indeed, the importance of complete resection is underscored by the finding that Stage IA patients undergoing limited resection were significantly less likely to be cured that Stage IB patients undergoing lobectomy. Accordingly the BWH trial supports the conclusion that the extent of surgical resection is more powerful determinant of survival than natural history of disease in Stage I NSCLC. Cumulatively, the results of these three trials show that among patients with Stage I NSCLC, limited resection is inferior to lobectomy with regard to the probability of producing cure. CONCLUSIONS. The finding that limited resection is inferior to lobectomy has relevance to the hypothesis that chest X-ray screening may lead to the identification of clinically unimportant lung carcinomas, which have been termed pseudotumors. This hypothesis, known as overdiagnosis, is the only alternative to the conclusion from four existing randomized trials that chest X-ray screening leads to an improvement in lung cancer cure rates. However, if extent of surgical resection is the major determinant of survival in Stage IA NSCLC, then these lesions must be clinically important. These findings support the conclusion that chest X-ray screening does not lead to the detection of Stage IA pseudotumors of the lung. Accordingly, current public policy calling for no routine screening for the early detection of lung cancer must be reconsidered. Cancer 2000;89:2432-7. (C) 2000 American Cancer Society. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Thorac Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Surg Serv, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Sugarbaker, DJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. NR 25 TC 19 Z9 19 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 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2000 VL 89 IS 11 SU S BP 2432 EP 2437 DI 10.1002/1097-0142(20001201)89:11+<2432::AID-CNCR17>3.0.CO;2-A PG 6 WC Oncology SC Oncology GA 380QE UT WOS:000165712900017 PM 11147621 ER PT J AU Caro, JJ Klittich, WS Strauss, G AF Caro, JJ Klittich, WS Strauss, G TI Could chest X-ray screening for lung cancer be cost-effective? SO CANCER LA English DT Article; Proceedings Paper CT International Conferece on Prevention and Early Diagnosis of Lung Cancer CY DEC 09-10, 1998 CL VARESE, ITALY SP Amer Canc Soc DE lung cancer; screening; chest X-ray; cost-effectiveness ID PROGRAM AB BACKGROUND. Currently, no screening program for lung cancer is advocated, yet recent review of the clinical trials has raised questions about the conclusion that it would not be effective. If a screening program is to be considered, its potential economic impact needs to be assessed. METHODS. An economic model was created comparing lung cancer mortality in male smokers ages 45-80 years, screened versus unscreened. Estimates of the potential reduction in mortality and cost of screening are applied. The outcomes of the model include deaths avoided, life years gained, net casts, and cost-effectiveness. RESULTS. The base analysis (mortality reduction of 18%) estimates that nearly 3000 deaths would be avoided in a population of 100,000 male smokers age 40-80 years, at a cost-effectiveness of $9000 per undiscounted life year gained. A program resulting in only 6% mortality reduction would increase the ratio to $25,000 per undiscounted life years gained. CONCLUSIONS. If further examination of lung cancer screening supports its effectiveness, the results of this model suggest that implementation would be economically efficient. Cancer 2000;89:2502-5. (C) 2000 American Cancer Society. C1 Caro Res, Concord, MA USA. McGill Univ, Royal Victoria Hosp, Div Gen Internal Med, Montreal, PQ H3A 1A1, Canada. Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. RP Caro, JJ (reprint author), 336 Baker Ave, Concord, MA 01742 USA. NR 14 TC 8 Z9 8 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 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2000 VL 89 IS 11 SU S BP 2502 EP 2505 DI 10.1002/1097-0142(20001201)89:11+<2502::AID-CNCR32>3.0.CO;2-N PG 4 WC Oncology SC Oncology GA 380QE UT WOS:000165712900032 PM 11147636 ER PT J AU Haigh, PI Glass, EC Essner, R AF Haigh, PI Glass, EC Essner, R TI Accuracy of gamma probes in localizing radioactivity: In-vitro assessment and clinical implications SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article ID EARLY-STAGE MELANOMA; SENTINEL NODE BIOPSY; MALIGNANT-MELANOMA; BREAST-CANCER; LYMPH-NODE; RADIOIMMUNOGUIDED SURGERY; RADIOGUIDED SURGERY; COLORECTAL-CANCER; LOCALIZATION; PATIENT AB Background: Radioguided surgery (RGS) uses gamma probes to localize radioactive targets. We examined the in-vitro localizing properties of commercially available gamma probes for three common RGS radioisotopes: technetium-99m (Tc-99m), indium-111 (In-111), and iodine-125 (I-125). Methods: The linear and angular localizing properties of five gamma probes were assessed. Radioactive counts in air were obtained at multiple energy threshold settings for each radioisotope. The full width half maximum (FWHM) and angular half maximum (AHM) were calculated to determine localizing acccuracy. Results: The FWHM of the five probes ranged from 1.2 to 3.4 cm for (TC)-T-99m, 1.8 to 2.7 cm for In-111 and 1.6 to 2.8 cm for I-125. AHM of the probes ranged from 20 to 49 degrees for Tc-99m, 14 to 35 degrees for In-111, and 18 to 47 degrees for I-125. The ranking of probe accuracy depended on the radioisotope studied. Absolute count rates varied with energy threshold settings for each probe and radioisotope. Probes required individualized energy threshold settings for optimal performance. Conclusions: The five probes varied in their characteristics for localizing the three radioisotopes. Each probe has particular detection characteristics that may change with different radioisotopes. Differences in radioisotope detection may explain intraoperative variation in localization during lymphatic mapping and sentinel lymph node dissection (LM/SL). Surgeons should be aware of probe performance characteristics before intraoperative use. C1 Univ Toronto, Dept Surg Oncol, Princess Margaret Hosp, Toronto, ON M5R 3C3, Canada. W Los Angeles Vet Adm Med Ctr, Dept Nucl Med, Los Angeles, CA USA. St Johns Hlth Ctr, John Wayne Canc Inst, Div Surg Oncol, Santa Monica, CA USA. RP Haigh, PI (reprint author), Univ Toronto, Dept Surg Oncol, Princess Margaret Hosp, 610 Univ Ave,Suite 3-130, Toronto, ON M5R 3C3, Canada. FU NCI NIH HHS [CA12582, CA29605] NR 23 TC 10 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD DEC PY 2000 VL 15 IS 6 BP 561 EP 569 DI 10.1089/cbr.2000.15.561 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 426WK UT WOS:000168371300005 PM 11190488 ER PT J AU Simonova, M Wall, A Weissleder, R Bogdanov, A AF Simonova, M Wall, A Weissleder, R Bogdanov, A TI Tyrosinase mutants are capable of prodrug activation in transfected nonmelanotic cells SO CANCER RESEARCH LA English DT Article ID MALIGNANT-MELANOMA-CELLS; IN-VIVO; GENE-THERAPY; ENDOPLASMIC-RETICULUM; CYTOSINE DEAMINASE; MEDIATED TRANSFER; HUMAN MELANOCYTES; CYTOPLASMIC TAIL; THYMIDINE KINASE; SUICIDE GENE AB Tyrosinase has been suggested as a prodrug-converting enzyme for the treatment of melanoma, We hypothesized that tyrosinase expression in transfected nonmelanotic cells can be used in a gene therapy paradigm of prodrug activation. To verify our hypothesis, we used the following tyrosinase variants: (a) a full-length human tyrosinase clone (T); (b) a mutant lacking the COOH-terminal cytoplasmic domain (T DeltaC); (c) a mutant lacking the COOH-terminal transmembrane and cytoplasmic domains (T Delta TC); and (d) a fusion with the eight COOH-terminal amino acids of lysosome-associated membrane protein-1 (TL), Expression of mutant and wild-type tyrosinases was induced by transfection in nontumorigenic human cells of epithelial origin (293HEK, MCF-10A adenoma, and NHDF-Ad human dermal fibroblasts) as well as in tumor cells (9L gliosarcoma, MCF7 adenocarcinoma, and HT-1080 fibrosarcoma), When compared with the wild-type tyrosinase transfectants, truncated mutant expression resulted in higher mRNA levels that paralleled higher enzyme activity of the truncated mutants. Two model tyrosinase prodrugs, hydroxyphenyl-propanol (HPP) and N-acetyl-4S-cysteaminylphenol (NAcSCAP) inhibited proliferation and caused cell death of transfected cells in a dose-dependent manner. Effects of prodrug treatment were compared for tumorigenic cells and their nontumorigenic counterparts. Two truncated mutants (T DeltaC and T Delta TC) showed low endogenous cytotoxicity and efficiently suppressed proliferation and induced cytotoxicity in transfected tumor cells in the presence of NAcSCAP, Overall, these results indicate that the developed tyrosinase mutants hold promise as prodrug activation systems for tumoral gene therapy. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Bogdanov, A (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [5RO1 CA74421-01]; NINDS NIH HHS [5RO1 NS35258-03] NR 48 TC 21 Z9 21 U1 1 U2 2 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 DEC 1 PY 2000 VL 60 IS 23 BP 6656 EP 6662 PG 7 WC Oncology SC Oncology GA 379JJ UT WOS:000165638700019 PM 11118049 ER PT J AU Tu, YP Gardner, A Lichtenstein, A AF Tu, YP Gardner, A Lichtenstein, A TI The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; DEXAMETHASONE-INDUCED APOPTOSIS; P70 S6 KINASE; PROTEIN-KINASE; INHIBITS APOPTOSIS; GENE-EXPRESSION; ACTIVATION; INTERLEUKIN-6; INSULIN; RECEPTOR AB Interleukin 6 (IL-6) and insulin-like growth factor I (IGF-I) induce proliferative and antiapoptotic responses in multiple myeloma (MM) plasma cells. Because these cytokines may activate the phosphatidylinositol 3-kinase (PI 3-K)/AKT kinase pathway in other cell types, we investigated the role of PI 3-K/AKT in MM cell responses. IGF-I effectively activated PI3-K in 8226 and OCI-My5 MM cells, but IL-6 was ineffective, However, IL-6 successfully activated PI 3-K in AF-10 MM cells and IL-6-dependent MH.60 plasmacytoma/hybridoma cells. IGF-I also successfully activated PI 3-K in four of four MM patient specimens, and IL-6 activated PI 3-K in three of four specimens. Inhibition of PI 3-K activity with wortmannin or Ly294002 blocked the antiapoptotic effect of IGF-I and the proliferative effect of IL-6 in the myeloma cell lines. Furthermore, a dominant negative PI 3-K construct, expressed in AF-10 cells by adenoviral infection, also significantly inhibited the IL-6 proliferative response in MM cells. In correlation with activation of PI 3-K, IGF-I also effectively activated the AKT kinase in 8226 and OCI-My5 cells, and IL-6 activated AKT in AF-10 and MH.60 cells. However, although incapable of activating PI 3-K in 8226 and OCI-My5 cells, IL-6 successfully activated AKT in these MM lines, suggesting PI 3-K-independent mechanisms of AKT activation. The prevention of a myeloma cell proliferative response resulting from inhibition of PI 3-K activity was not associated with an inhibition of IL-6-dependent extracellular signal-regulated kinase (ERK) activation. These results support a role for the PI 3-K/AKT pathway in cytokine-dependent responses in myeloma cells, which is independent of any activation of the ERK pathway. C1 W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. Jonsson Comprehens Canc Ctr, Los Angeles, CA 90073 USA. RP Lichtenstein, A (reprint author), W Los Angeles Vet Adm Hosp, W111H,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 49 TC 173 Z9 179 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 DEC 1 PY 2000 VL 60 IS 23 BP 6763 EP 6770 PG 8 WC Oncology SC Oncology GA 379JJ UT WOS:000165638700034 PM 11118064 ER PT J AU Dawson, SL Cotin, S Meglan, D Shaffer, DW Ferrell, MA AF Dawson, SL Cotin, S Meglan, D Shaffer, DW Ferrell, MA TI Designing a computer-based simulator for interventional cardiology training SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE simulation; training; interventions; computer-based education; haptics ID SURGERY SIMULATION; VOLUME AB Interventional cardiology training traditionally involves one-on-one experience following a master-apprentice model, much as other procedural disciplines. Development of a realistic computer-based training system that includes hand-eye coordination, catheter and guide wire choices, three-dimensional anatomic representations, and an integrated learning system is desirable, in order to permit learning to occur safely, without putting patients at risk, Here we present the first report of a PC-based simulator that incorporates synthetic fluoroscopy, real-time three-dimensional interactive anatomic display, and selective right- and left-sided coronary catheterization and angiography using actual catheters, Significant learning components also are integrated into the simulator, Cathet Cardiovasc. Intervent 51:522-527, 2000. (C) 2000 Wiley-Liss, Inc. C1 Ctr Innovat Minimally Invas Therapy, Boston, MA USA. Mitsubishi Elect, Informat Technol Ctr Amer, Med Applicat Grp, Cambridge, MA USA. Virtual Presence Inc, Boston, MA USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Dawson, SL (reprint author), Massachusetts Gen Hosp, CIMIT, HGX2, 55 Fruit St, Boston, MA 02114 USA. EM dawson.steven@mgh.harvard.edu NR 14 TC 75 Z9 78 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD DEC PY 2000 VL 51 IS 4 BP 522 EP 527 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 378YZ UT WOS:000165614900029 PM 11108693 ER PT J AU Korsmeyer, SJ Wei, MC Saito, M Weller, S Oh, KJ Schlesinger, PH AF Korsmeyer, SJ Wei, MC Saito, M Weller, S Oh, KJ Schlesinger, PH TI Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE BAK; BAX; tBID oligomerization; mitochondria ID PROGRAMMED CELL-DEATH; MITOCHONDRIAL OUTER-MEMBRANE; BCL-2 FAMILY PROTEINS; ION-CHANNEL; BH3 DOMAIN; IN-VIVO; X-L; BCL-X(L); PHOSPHORYLATION; SURVIVAL AB We review data supporting a model in which activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux, The BH3 domain of tBID is not required for targeting but remains on the mitochondrial surface where it is required to trigger BAK to release cytochrome c. tBID functions not as a pore-forming protein but as a membrane targeted and concentrated death ligand, tBID induces oligomerization of BAK, and both Bid and Bak knockout mice indicate the importance of this event in the release of cytochrome c. In parallel, the full pro-apoptotic member BAX, which is highly homologous to BAK, rapidly forms pores in liposomes that release intravesicular FITC-cytochrome c similar to 20 Angstrom. A definable pore progressed from similar to 11 Angstrom consisting of two BAX molecules to a similar to 22 Angstrom pore comprised of four BAX molecules, which transported cytochrome c. Thus, an activation cascade of pro-apoptotic proteins from BID to BAK or BAX integrates the pathway from surface death receptors to the irreversible efflux of cytochrome c. C1 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. Washington Univ, Sch Med, Div Biol & Biomed Sci, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Physiol & Cell Biol, St Louis, MO 63110 USA. RP Korsmeyer, SJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Pathol, Boston, MA 02115 USA. RI Schlesinger, Paul/C-6049-2012 NR 56 TC 661 Z9 689 U1 8 U2 34 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 DEC PY 2000 VL 7 IS 12 BP 1166 EP 1173 DI 10.1038/sj.cdd.4400783 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 385NF UT WOS:000166010000004 PM 11175253 ER PT J AU Wagner, AD Koutstaal, W Maril, A Schacter, DL Buckner, RL AF Wagner, AD Koutstaal, W Maril, A Schacter, DL Buckner, RL TI Task-specific repetition priming in left inferior prefrontal cortex SO CEREBRAL CORTEX LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; FUNCTIONAL-ANATOMY; MEMORY RETRIEVAL; IMPLICIT MEMORY; WORKING-MEMORY; BRAIN; FMRI; DISSOCIATION; INFORMATION; GENERATION AB Previous neuroimaging studies have shown that activation in left inferior prefrontal cortices (LIPC) is reduced during repeated (primed) relative to initial (unprimed) stimulus processing. These reductions in anterior (similar to PA 45/47) and posterior (similar to BA 44/6) LIPC activation have been interpreted as reflecting implicit memory for initial semantic or phonological processing. However, prior studies do not unambiguously indicate that LIPC priming effects are specific to the recapitulation of higher-level (semantic and/or phonological), rather than lower-level (perceptual), processes. Moreover, no prior study has shown that the patterns of priming in anterior and posterior LIPC regions are dissociable. To address these issues, the present fMRI study examined the nature of priming in LIPC by examining the task-specificity of these effects. Participants initially processed words in either a semantic or a nonsemantic manner. Subsequently, participants were scanned while they made semantic decisions about words that had been previously processed in a semantic manner (within-task repetition), words that had been previously processed in a nonsemantic manner (across-task repetition), and words that had not been previously processed (novel words). Behaviorally, task-specific priming was observed: reaction times to make the semantic decision declined following prior semantic processing but not following prior nonsemantic processing of a word, Priming in anterior LIPC paralleled these results with signal reductions being observed following within-task, but not following across-task, repetition. Importantly, neural priming in posterior LIPC demonstrated a different pattern: priming was observed following both within-task and across-task repetition, with the magnitude of priming tending to be greater in the within-task condition. Direct comparison between anterior and posterior LIPC regions revealed a significant interaction. These findings indicate that anterior and posterior LIPC demonstrate distinct patterns of priming, with priming in the anterior region being task-specific, suggesting that this facilitation derives from repeated semantic processing of a stimulus. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02114 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Washington Univ, Dept Psychol, St Louis, MO 63130 USA. RP Wagner, AD (reprint author), MIT, Dept Brain & Cognit Sci, NE20-463, Cambridge, MA 02139 USA. OI Schacter, Daniel/0000-0002-2460-6061 FU NIA NIH HHS [AG05778]; NIDCD NIH HHS [DC30245]; NIMH NIH HHS [MH57506] NR 44 TC 197 Z9 201 U1 4 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD DEC PY 2000 VL 10 IS 12 BP 1176 EP 1184 DI 10.1093/cercor/10.12.1176 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 377RG UT WOS:000165526700003 PM 11073867 ER PT J AU Canver, CC Nichols, RD AF Canver, CC Nichols, RD TI Use of intraoperative hetastarch priming during coronary bypass SO CHEST LA English DT Article DE cardiopulmonary bypass; coronary bypass; hetastarch; transfusions ID CARDIOPULMONARY BYPASS; FLUID RESUSCITATION; ALBUMIN; SHOCK; CRYSTALLOIDS; OPERATIONS; PULMONARY; COLLOIDS; SURGERY AB Background: The use of hetastarch during coronary bypass surgery has been limited due to its unresolved potential risk for hemorrhage. Therefore, the purpose of this study was to investigate the effects of using 6% hetastarch in priming cardiopulmonary bypass (CPB) circuitry on the need for blood product transfusions and outcome after coronary bypass. Materials and methods: This nonrandomized retrospective study involved 887 patients who underwent isolated primary coronary artery bypass grafting. Based on the type of solution used in priming the CPB circuitry, patients were stratified into the following four different groups: group 1, crystalloid (500 mL; n = 211); group 2, 25% human albumin (50 mL; n = 217); group 3, 6% hetastarch (500 mL; n = 298); and group 4, 25% human albumin (50 mL) and 6% hetastarch (500 mL; n = 161). Patient characteristics and clinical variables were compared among the groups using the Kruskal-Wallis test. Patient survival estimates were compared using log-rank test. Results: Demographic patient characteristics for all groups were similar (p > 0.05). Intraoperative and perioperative variables among groups were comparable (p > 0.05). The use of hetastarch as a part of prime solution in CPB circuitry did not alter the need for banked blood, platelets, or fresh frozen plasma transfusions (p > 0.05). The length of stay in the ICU or in the hospital was unaffected in all groups. The early (ie, 30-day) mortality rate was 1.4% in group 1, 1.8% in group 2, 1.0% in group 3, and 3.1% in group 4. Long-term survival among the groups was unaffected by the type of priming solution. Conclusions: The use of hetastarch in priming CPB circuitry is devoid of any added hemorrhagic risk after coronary bypass, and the type of prime solution for CPB has no influence on the early or late survival rates of patients undergoing primary coronary bypass. C1 William S Middleton Mem Vet Adm Hosp, Madison, WI USA. Albany Med Coll, Div Cardiothorac Surg, Albany, NY 12208 USA. RP Canver, CC (reprint author), Albany Med Coll, Div Cardiothorac Surg, 47 New Scotland Ave,Mail Code S5, Albany, NY 12208 USA. NR 14 TC 14 Z9 15 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2000 VL 118 IS 6 BP 1616 EP 1620 DI 10.1378/chest.118.6.1616 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 384PF UT WOS:000165953500018 PM 11115448 ER PT J AU Ryan, PD Chabner, BA AF Ryan, PD Chabner, BA TI On receptor inhibitors and chemotherapy SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID GROWTH-FACTOR-RECEPTOR; TAXOL-INDUCED APOPTOSIS; RENAL-CELL CARCINOMA; PROTEIN-KINASE-A; ANTIBODY C225; MONOCLONAL-ANTIBODIES; ANTITUMOR-ACTIVITY; NUDE-MICE; XENOGRAFTS; CANCER C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Chabner, BA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Cox Bldg,Room 640,100 Blossom St, Boston, MA 02114 USA. NR 29 TC 38 Z9 40 U1 1 U2 2 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 DEC PY 2000 VL 6 IS 12 BP 4607 EP 4609 PG 3 WC Oncology SC Oncology GA 388CQ UT WOS:000166160200003 PM 11156209 ER PT J AU Tatlidil, R New, P Mayberg, H AF Tatlidil, R New, P Mayberg, H TI FDG positron emission tomography in diffuse Lewy body disease - A case report SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE dementia; fluorodeoxyglucose; Lewy body disease; parkinsonism; positron emission tomography ID CEREBRAL GLUCOSE-METABOLISM; ALZHEIMERS-DISEASE; DEMENTIA; DIAGNOSIS; BODIES AB Lewy body disease is a clinicopathologic condition that includes Parkinson's disease at one end and diffuse Lewy body disease at the other hand. The latter is often associated with progressive cognitive deterioration, levodopa-responsive parkinsonism, fluctuations of cognitive and motor functions, and visual and auditory hallucinations. In addition, it can be a familial disease. Clinical and positron emission tomographic findings are described in a patient with atypical dementia and movement disorder and a pathologically proved diagnosis of diffuse Lewy body disease. C1 Univ Texas, Res Imaging Ctr, San Antonio, TX 78285 USA. Univ Texas, Dept Neurol, San Antonio, TX 78285 USA. Univ Texas, Vet Affairs Med Ctr, San Antonio, TX 78285 USA. RP Tatlidil, R (reprint author), 1362 Sokak,14A Cankaya, TR-35230 Izmir, Turkey. NR 16 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD DEC PY 2000 VL 25 IS 12 BP 1004 EP 1006 DI 10.1097/00003072-200012000-00009 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 378QX UT WOS:000165596000009 PM 11129133 ER PT J AU Penson, RT Joel, SP Bakhshi, K Clark, SJ Langford, RM Slevin, ML AF Penson, RT Joel, SP Bakhshi, K Clark, SJ Langford, RM Slevin, ML TI Randomized placebo-controlled trial of the activity of the morphine glucuronides SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID HEALTHY-VOLUNTEERS; ANALGESIC ACTIVITY; INTRATHECAL MORPHINE-6-GLUCURONIDE; OPIOID RECEPTOR; MORPHINE-3-GLUCURONIDE; PHARMACOKINETICS; 6-GLUCURONIDE; METABOLITES; RAT AB Background: Morphine-6-glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity Morphine-3-glucuronide (M3G), the most prevalent metabolite, has minimal affinity for opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G. Methods: We performed a double-blind placebo-controlled trial with 10 healthy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphine, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg/70 kg of M6G; all were give by slow intravenous bolus. Analgesia was assessed with the use of the submaximal ischemic pain model. The effects were quantified on numerical and visual analogue scales. Respiratory parameters and response to steady state 5% carbon dioxide challenge were assessed with spirometry, mass spectroscopy, and earlobe blood gas analysis. Results: Morphine and M6G produced significant pain relief compared with placebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26). Pain relief with morphine and M6G were not significantly altered by M3G (P = .59 and P = .28, respectively). Significant and similar dysphoria and sedation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo (morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively). Conclusions: M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine. C1 St Bartholomews Hosp, Dept Med Oncol, London, England. St Bartholomews Hosp, Dept Anaesthet, London, England. RP Penson, RT (reprint author), Massachusetts Gen Hosp, Dept Hematol Oncol, Cox 809, 100 Blossom St, Boston, MA 02114 USA. NR 37 TC 85 Z9 89 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 2000 VL 68 IS 6 BP 667 EP 676 DI 10.1067/mcp.2000.111934 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 390NM UT WOS:000166302800012 PM 11180027 ER PT J AU Einhorn, D Rendell, M Rosenzweig, J Egan, JW Mathisen, AL Schneider, RL AF Einhorn, D Rendell, M Rosenzweig, J Egan, JW Mathisen, AL Schneider, RL CA Pioglitazone 027 Study Grp TI Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes melitus: A randomized, placebo-controlled study SO CLINICAL THERAPEUTICS LA English DT Article; Proceedings Paper CT 59th Scientific Session of the American-Diabetes-Association CY JUN 18-22, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Diabet Assoc DE pioglitazone; metformin; glycemic control; lipids ID HOMEOSTASIS MODEL ASSESSMENT; INSULIN-RESISTANCE; LIPID-METABOLISM; GLUCOSE; MELLITUS; PLASMA; THERAPY; OBESE AB Background: Their complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes. Objective: This study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus. Methods: This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA(1c)] greater than or equal to8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for greater than or equal to 30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin. Results: Three hundred twenty-eight patients were randomized to treatment (168 pioglitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years. most (84%) were white and slightly more than half (57%) were male. Patients receiving pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA(1c) (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P less than or equal to 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin (P less than or equal to 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA(1c) and -63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value greater than or equal to3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed. Conclusions: In this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA(1c) and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension. C1 Diabet & Endocrine Associates, San Diego, CA USA. Sharp HealthCare, San Diego, CA USA. Creighton Diabet Ctr, Omaha, NE USA. Rose Salter Med Res Fdn, Baltimore, MD USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Takeda Amer Res & Dev Ctr Inc, Princeton, NJ USA. RP Egan, JW (reprint author), Takeda Amer Res & Dev Ctr, 475 Half Day Rd,Suite 500, Lincolnshire, IL 60069 USA. NR 27 TC 236 Z9 242 U1 2 U2 13 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD DEC PY 2000 VL 22 IS 12 BP 1395 EP 1409 DI 10.1016/S0149-2918(00)83039-8 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 391NT UT WOS:000166362600003 PM 11192132 ER PT J AU King, R Googe, PB Mihm, MC AF King, R Googe, PB Mihm, MC TI Thin melanomas SO CLINICS IN LABORATORY MEDICINE LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; STAGE-I MELANOMA; PROGNOSTIC FACTORS; MULTIVARIATE-ANALYSIS; TUMOR PROGRESSION; MULTIFACTORIAL ANALYSIS; INTEGRIN EXPRESSION; REGRESSION-ANALYSIS; LOCALIZED MELANOMA; LESS-THAN-1.5 MM AB Thin melanoma refers to that grouping of melanomas that statistically have a good prognosis and survival rate. Molecular studies suggest that thin melanomas may have different properties to thicker and metastatic melanomas. The factors governing the ability of thin melanomas to metastasize and cause mortality are not known. Certain histologic and molecular parameters may provide clues to understanding parameters governing the aggressive nature of some of lesions. Further research is required to enhance our understanding of thin melanomas. C1 Univ Tennessee, Dept Pathol, Knoxville, TN USA. Vanderbilt Univ, Dept Pathol, Nashville, TN USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatopathol, Boston, MA USA. RP King, R (reprint author), Knoxville Dermatopathol Lab, 6311 Kingston Pike, Knoxville, TN 37919 USA. NR 85 TC 7 Z9 7 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD DEC PY 2000 VL 20 IS 4 BP 713 EP + PG 18 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 401VD UT WOS:000166948200005 PM 11221511 ER PT J AU Kimble, MO AF Kimble, MO TI The case of Howard SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article ID POSTTRAUMATIC STRESS DISORDER AB This paper presents the case of Howard, a 51-year-old self-referred Vietnam veteran who was seeking a posttraumatic stress disorder (PTSD) compensation evaluation and treatment recommendations at his local VA hospital. At the time of the assessment, Howard was divorced, had not worked regularly for 7 years, and was living in the suburbs with his 9-year-old son. The evaluation revealed the presence of multiple Axis I disorders, including PTSD, major depression, obsessive-compulsive disorder, and somatization disorder. His primary concerns at initial presentation were intrusive memories of Vietnam, an inability to work, and ongoing health complaints. Further evaluation revealed additional concerns with paranoia, difficulties concentrating, and significant social isolation. This case study emphasizes Howard's psychosocial history, symptom presentation, and psychometric test results. Case summary and treatment recommendations are deferred until the final case conceptualization (Kimble 2000). C1 VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Kimble, MO (reprint author), Boston VA Med Ctr, Natl Ctr PTSD, Behav Sci Div, Psychol 116B-2,150 S Huntington Ave, Boston, MA 02130 USA. NR 10 TC 5 Z9 5 U1 1 U2 1 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD WIN PY 2000 VL 7 IS 1 BP 118 EP 122 DI 10.1016/S1077-7229(00)80012-7 PG 5 WC Psychology, Clinical SC Psychology GA 360TA UT WOS:000089682300011 ER PT J AU Otto, MW AF Otto, MW TI Constructing a model of change: Clinical commentary on a complex case SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material ID WELL-BEING THERAPY AB In this clinical case commentary, attention was Placed on the selection of the optimal targets and order of interventions for a 51-year-old male who meets criteria for four Axis I disorders: posttraumatic stress disorder (PTSD), major depression, somatization disorder; and obsessive-compulsive disorder (OCD). A theoretical model of what was learned in the context of trauma was developed to aid conceptualization of the interrelationship among the patient's symptoms. A model of change was Presented, emphasizing cognitive-behavior therapy delivered in the context of a well-being therapy approach. C1 Massachusetts Gen Hosp, Cognit Behav Therapy Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Otto, MW (reprint author), Massachusetts Gen Hosp, Cognit Behav Therapy Program, WACC-815, Boston, MA 02114 USA. NR 8 TC 4 Z9 4 U1 0 U2 1 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD WIN PY 2000 VL 7 IS 1 BP 123 EP 126 DI 10.1016/S1077-7229(00)80013-9 PG 4 WC Psychology, Clinical SC Psychology GA 360TA UT WOS:000089682300012 ER PT J AU Riggs, DS AF Riggs, DS TI Treatment of concurrent PTSD and OCD: A commentary on the case of Howard SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material AB The complexity inherent in treating patients diagnosed with multiple disorders often leaves clinicians feeling unsure of how best to encourage change, or even where to begin. The present commentary discusses the interplay between the symptoms of posttraumatic stress disorder and obsessive-compulsive disorder (Kimble, 2000). Focusing on fire need to assess the interplay of the two symptom clusters, the paper presents a model for understanding the etiological and functional relations that could link the symptoms of posttraumatic stress disorder and obsessive-compulsive disorder Further, the paper discusses ways in which a clinician might approach such complex cases in order to address all of the client's needs in an effective and efficient manner. C1 VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Riggs, DS (reprint author), Boston VA Med Ctr, Psychol 116B-2,S Huntington Ave, Boston, MA 02130 USA. NR 6 TC 5 Z9 5 U1 0 U2 1 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD WIN PY 2000 VL 7 IS 1 BP 130 EP 132 DI 10.1016/S1077-7229(00)80015-2 PG 3 WC Psychology, Clinical SC Psychology GA 360TA UT WOS:000089682300014 ER PT J AU Kimble, MO AF Kimble, MO TI Treating PTSD in the presence of multiple comorbid disorders: The case of Howard SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER AB This paper integrates the comments of Otto (2000), Bufka (2000), and Rig(gs (2000) on the case of Howard (Kimble, 2000), a 51-year-old Vietnam veteran who presented with multiple comorbid psychiatric concerns. This summary conceptualization outlines themes that were common among all three case commentaries and emphasizes issues related to comorbidity. Common themes include the importance of patient preparation for treatment, the necessity for initial and ongoing functional assessments, the value of utilizing patient strengths, the significance of acknowledging the interplay among symptoms, and the advantages of multidisciplinary treatment. All three case commentaries were cautiously optimistic that change could be implemented even in this complicated and chronic case. C1 VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Kimble, MO (reprint author), Boston VA Med Ctr, Behav Sci Div, Natl Ctr PTSD, Psychol 116B-2,150 S Huntington Ave, Boston, MA 02130 USA. NR 18 TC 3 Z9 3 U1 2 U2 3 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD WIN PY 2000 VL 7 IS 1 BP 133 EP 137 DI 10.1016/S1077-7229(00)80016-4 PG 5 WC Psychology, Clinical SC Psychology GA 360TA UT WOS:000089682300015 ER PT J AU Legedza, ATR Ibrahim, JG AF Legedza, ATR Ibrahim, JG TI Longitudinal design for phase I clinical trials using the continual reassessment method SO CONTROLLED CLINICAL TRIALS LA English DT Article DE phase I clinical trial; longitudinal design; Continual Reassessment Method; maximum tolerated dose; cumulative toxicity; clearance; titration AB The goal of phase I clinical trials is to estimate the maximum tolerated dose (MTD), the highest dose at which a specified probability of toxic response is not exceeded. However, this is not the only piece of information that is useful for the design of phase II and phase III clinical trials. Information on cumulative toxicity is important as well. To study the effect of cumulative toxicity in patients, it is necessary to examine how patients respond to multiple-dose administrations. To this end, we propose a longitudinal dose-response model that accommodates this concern, which is motivated from clearance-rate considerations and from a model proposed by Simon et al. To appropriately titrate an individual's dosage at each time period, we also propose an updating mechanism based on the Bayesian paradigm. We select individual and group MTDs using Legedza and Ibrahim's extension of O'Quigley et al.'s Continual Reassessment Method. Simulations are described to demonstrate the usefulness of our proposal. (C) Elsevier Science Inc. 2000. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Legedza, ATR (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA 70101-01, CA 74015-01] NR 6 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2000 VL 21 IS 6 BP 574 EP 588 DI 10.1016/S0197-2456(00)00091-X PG 15 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 384KF UT WOS:000165940800005 PM 11146151 ER PT J AU Jones, SP Girod, WG Huang, PL Lefer, DJ AF Jones, SP Girod, WG Huang, PL Lefer, DJ TI Myocardial reperfusion injury in neuronal nitric oxide synthase deficient mice SO CORONARY ARTERY DISEASE LA English DT Article DE neuronal nitric oxide synthase; reperfusion injury; heart; ischemia; murine ID CARDIAC-MUSCLE; ISCHEMIA; HEART; GENE AB Background A substantial amount of data suggesting that endothelial cell nitric oxide synthase (eNOS) plays a cardioprotective role in animal models of ischemia-reperfusion injury has amassed. We have previously demonstrated that eNOS-deficient (-/-) mice exhibit significantly larger myocardial infarcts than do wild-type mice. Few investigations have examined the neuronal form of nitric oxide synthase in the heart. The two constitutive isoforms have been demonstrated to play differing roles in studies of cerebral ischemia-reperfusion, Objective To characterize the role of neuronal nitric oxide synthase (nNOS) in myocardial ischemia-reperfusion injury, Methods Wild-type and nNOS -/- mice were subjected to 20 min of coronary artery occlusion and 120 min of reflow. Results We found no significant difference between the two groups in terms of infarct size, Microscopic cross-sections from both groups were examined for infiltration of polymorphonuclear leukocyte, Hearts of nNOS -/-mice exhibited significantly (P< 0.05) more polymorphonuclear leukocytes than did hearts of wild-type mice. Conclusion Despite the fact that eNOS plays a cardioprotective role in the ischemic-reperfused myocardium, we observed no change in size of myocardial infarcts when nNOS was genetically disrupted, Coron Artery Dis 11:593-597 (C) 2000 Lippincott Williams & Wilkins. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RP Lefer, DJ (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Cellular & Mol Physiol, 1501 Kings Highway, Shreveport, LA 71130 USA. RI Lefer, David/A-6372-2012; Jones, Steven/D-5092-2009 OI Jones, Steven/0000-0001-5376-8089 FU NHLBI NIH HHS [R01 HL 60849]; NIDDK NIH HHS [P01 DK 43785] NR 24 TC 21 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD DEC PY 2000 VL 11 IS 8 BP 593 EP 597 DI 10.1097/00019501-200012000-00004 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 376PC UT WOS:000165465100004 PM 11107506 ER PT J AU Greene, R AF Greene, R TI Computed tomography: High technology imaging comes to the bedside SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE CT scan; portable CT; mobile CT C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Greene, R (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 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 DEC PY 2000 VL 28 IS 12 BP 3936 EP 3938 DI 10.1097/00003246-200012000-00038 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 388NB UT WOS:000166186200028 PM 11153641 ER PT J AU Bayir, H Kagan, VE Tyurina, YY Tyurin, V Ruppel, RA Adelson, PD Graham, SH Janesko, KL Clark, RSB Kochanek, PM AF Bayir, H Kagan, VE Tyurina, YY Tyurin, V Ruppel, RA Adelson, PD Graham, SH Janesko, KL Clark, RSB Kochanek, PM TI Assessment of antioxidant reserve and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 Safar Ctr Resuscitat Res, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Childrens Hosp, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. RI Kochanek, Patrick/D-2371-2015 OI Kochanek, Patrick/0000-0002-2627-913X NR 3 TC 1 Z9 1 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 DEC PY 2000 VL 28 IS 12 SU S MA 80 BP A52 EP A52 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 388ZD UT WOS:000166212200081 ER PT J AU Ezzeddine, MA Oliveira, J Sheik, S Flibotte, J Greer, D Ougorets, I Rosand, J Ogilvy, C Carter, B Rordorf, G Koroshetz, WJ McDonald, CT AF Ezzeddine, MA Oliveira, J Sheik, S Flibotte, J Greer, D Ougorets, I Rosand, J Ogilvy, C Carter, B Rordorf, G Koroshetz, WJ McDonald, CT TI Serum amylase correlates with the clinical severity of subarachnoid hemorrhage SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2000 VL 28 IS 12 SU S MA 647 BP A207 EP A207 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 388ZD UT WOS:000166212200647 ER PT J AU Ezzeddine, MA Oleiveira, J Flibotte, J Greer, D Ougoretz, I Rosand, J Rordorf, G Schwamm, L Buonnano, F Koroshetz, WJ Mcdonald, CT AF Ezzeddine, MA Oleiveira, J Flibotte, J Greer, D Ougoretz, I Rosand, J Rordorf, G Schwamm, L Buonnano, F Koroshetz, WJ Mcdonald, CT TI Predictors of extubation failure of mechanically ventilated patients in the neuroscience intensive care unit SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2000 VL 28 IS 12 SU S MA 251 BP A99 EP A99 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 388ZD UT WOS:000166212200252 ER PT J AU Lundberg, AS Hahn, WG Gupta, P Weinberg, RA AF Lundberg, AS Hahn, WG Gupta, P Weinberg, RA TI Genes involved in senescence and immortalization SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID HUMAN-DIPLOID FIBROBLASTS; REPLICATIVE LIFE-SPAN; NORMAL HUMAN-CELLS; TUMOR-SUPPRESSOR; TELOMERASE ACTIVITY; EPITHELIAL-CELLS; ONCOGENIC RAS; P53; EXPRESSION; CANCER AB Senescence is now understood to be the final phenotypic state adopted by a cell in response to several distinct cell physiological processes, including proliferation, oncogene activation and oxygen free radical toxicity. The role of telomere maintenance in immortalization and the roles of p16(INK4A) p19(ARF), p53 and other genes in senescence are being further elucidated. Significant progress continues to be made in our understanding of cellular senescence and immortalization. C1 Whitehead Inst, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Lundberg, AS (reprint author), Whitehead Inst, 9 Cambridge Ctr, Cambridge, MA 02142 USA. NR 57 TC 195 Z9 205 U1 0 U2 14 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2000 VL 12 IS 6 BP 705 EP 709 DI 10.1016/S0955-0674(00)00155-1 PG 5 WC Cell Biology SC Cell Biology GA 375AC UT WOS:000165376500008 PM 11063935 ER PT J AU Rosenthal, N Birchmeier, C AF Rosenthal, N Birchmeier, C TI Cell differentiation SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Max Delbrueck Ctr, Abt Med Genet, D-13125 Berlin, Germany. RP Rosenthal, N (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2000 VL 12 IS 6 BP 717 EP 718 DI 10.1016/S0955-0674(00)00157-5 PG 2 WC Cell Biology SC Cell Biology GA 375AC UT WOS:000165376500010 ER PT J AU Rosenthal, N Xavier-Neto, J AF Rosenthal, N Xavier-Neto, J TI From the bottom of the heart: anteroposterior decisions in cardiac muscle differentiation SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID RETINOIC ACID SYNTHESIS; VENTRAL MORPHOGENESIS; TRANSCRIPTION FACTOR; TUBE FORMATION; EXPRESSION; GATA-4; GENE; RALDH-2; NKX2-5 AB Recently, studies on specification of axes in the developing embryo have focused on the heart, which is the first functional organ to form and probably responds to common cues controlling positional information in surrounding tissues. The early differentiation of heart cells affords an opportunity to link the acquisition of regional identity with the signals underlying terminal differentiation. In the past year, a wealth of information on these signals has emerged, elucidating the general pathways controlling body axes in the context of the developing heart. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. FMUSP, HC, Lab Genet & Cardiol Mol, BR-05403000 Sao Paulo, Brazil. Univ Sao Paulo, ICB, Dept Histol & Embriol, BR-05508900 Sao Paulo, Brazil. RP Rosenthal, N (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. NR 29 TC 34 Z9 34 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2000 VL 12 IS 6 BP 742 EP 746 DI 10.1016/S0955-0674(00)00162-9 PG 5 WC Cell Biology SC Cell Biology GA 375AC UT WOS:000165376500015 PM 11063942 ER PT J AU Avni, O Rao, A AF Avni, O Rao, A TI T cell differentiation: a mechanistic view SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CYTOKINE GENE-EXPRESSION; TRANSCRIPTIONAL INDUCTION; HYPERSENSITIVE SITES; NUCLEAR FACTOR; DNA-BINDING; CHROMATIN; LYMPHOCYTES; INTERLEUKIN-4; ACTIVATION; ENHANCER AB It has recently become clear that cytokine expression by T cells involves epigenetic changes in chromatin structure, locus accessibility and DNA methylation that occur during differentiation of naive T cells into mature effector T cells. These changes require the coordinate actions of antigen- and cytokine-induced transcription factors, chromatin remodeling complexes, histone-modifying enzymes and subset-specific transcription factors. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. RP Avni, O (reprint author), Harvard Univ, Sch Med, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI44432] NR 58 TC 60 Z9 61 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2000 VL 12 IS 6 BP 654 EP 659 DI 10.1016/S0952-7915(00)00158-8 PG 6 WC Immunology SC Immunology GA 372DA UT WOS:000165218000007 PM 11102768 ER PT J AU Benoist, C Howard, M AF Benoist, C Howard, M TI Autoimmunity - Editorial overview SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 Joslin Diabet Ctr, Immunol Sect, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. Corixa, Div Autoimmune Dis, Redwood City, CA 94063 USA. RP Benoist, C (reprint author), Joslin Diabet Ctr, Immunol Sect, 1 Joslin Pl, Boston, MA 02215 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2000 VL 12 IS 6 BP 661 EP 663 DI 10.1016/S0952-7915(00)00159-X PG 3 WC Immunology SC Immunology GA 372DA UT WOS:000165218000008 ER PT J AU Henson, JW AF Henson, JW TI Early genetic events in the formation of astrocytomas SO CURRENT OPINION IN NEUROLOGY LA English DT Editorial Material ID COMPARATIVE GENOMIC HYBRIDIZATION; SECONDARY GLIOBLASTOMAS; P53 MUTATIONS; BRAIN-TUMORS; DE-NOVO; GLIOMA; PROGRESSION; EXPRESSION; SURVIVAL; PROTEIN C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurooncol Labs,Brain Tumor Ctr, Boston, MA 02114 USA. RP Henson, JW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurooncol Labs,Brain Tumor Ctr, 100 Blossom St,Cox 315, Boston, MA 02114 USA. NR 32 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD DEC PY 2000 VL 13 IS 6 BP 613 EP 617 DI 10.1097/00019052-200012000-00001 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 425HG UT WOS:000168284700001 PM 11148659 ER PT J AU Kieran, MW AF Kieran, MW TI Advances in pediatric neuro-oncology SO CURRENT OPINION IN NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PRIMARY BRAIN-TUMORS; PRIMITIVE NEUROECTODERMAL TUMORS; CRANIOSPINAL RADIATION-THERAPY; NEUTRON-CAPTURE THERAPY; LOW-GRADE GLIOMAS; GROUP PHASE-II; MALIGNANT GLIOMAS; STEM GLIOMAS; GENE-THERAPY AB A number of exciting advances have been reported over the past few years in the understanding and treatment of children with brain tumors. The present review highlights many of the publications from this period. focusing on their relevance within the major diagnostic and treatment domains of pediatric oncology (surgery, radiation therapy, chemotherapy, neuropathology, and neuroradiology), Although many of the publications cited provide confirmation of previously reported work, when taken together they form a good framework of the state of the field from the past few years. Curr Opin Neurol 13:617-634. (C) 2000 Lippincott Williams & Wilkins. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kieran, MW (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. OI Kieran, Mark/0000-0003-2184-7692 NR 100 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD DEC PY 2000 VL 13 IS 6 BP 627 EP 634 DI 10.1097/00019052-200012000-00003 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 425HG UT WOS:000168284700003 PM 11148661 ER PT J AU Wang, JH Reinherz, EL AF Wang, JH Reinherz, EL TI Structural basis of cell-cell interactions in the immune system SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID MHC CLASS-I; ADHESION MOLECULE CD2; NATURAL-KILLER-CELLS; CRYSTAL-STRUCTURE; INHIBITORY RECEPTOR; SOLUBLE FORM; COMPLEX; PEPTIDE; RECOGNITION; RESOLUTION AB During the past year, advances in our understanding of receptor-ligand interactions between opposing cell surfaces have occurred at a structural level. These include adhesion involving CD2-CD58, antigen-specific T-cell receptor interactions with peptides bound to major histocompatibility complex molecules (both pMHCI and pMHCII), the CD8 alpha alpha co-receptor-pMHCI interaction and the binding of two distinct classes of natural kilter receptors to self-MHC ligands. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Wang, JH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI19807, AI21226]; NIGMS NIH HHS [GM56088] NR 33 TC 29 Z9 29 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2000 VL 10 IS 6 BP 656 EP 661 DI 10.1016/S0959-440X(00)00150-0 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 394DQ UT WOS:000166509100006 PM 11114502 ER PT J AU Nguyen, NQ Moy, RL AF Nguyen, NQ Moy, RL TI The impact of dermatologic surgery SO DERMATOLOGIC SURGERY LA English DT Article C1 Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Div Dermatol, Los Angeles, CA USA. RP Moy, RL (reprint author), 100 UCLA Med Plaza,Suite 590, Los Angeles, CA 90024 USA. NR 2 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD DEC PY 2000 VL 26 IS 12 BP 1089 EP 1091 PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA 386AD UT WOS:000166036600011 PM 11134982 ER PT J AU Nguyen, NQ Moy, RL AF Nguyen, NQ Moy, RL TI Authors in dermatologic surgery SO DERMATOLOGIC SURGERY LA English DT Article ID JOURNALS AB Authors of scientific papers have been evaluated in the past by how frequently the medical literature cites them. In this analysis, we specifically identify those individuals who have contributed to the field of cutaneous surgery through publications in Dermatologic Surgery. We further analyze those publications frequently cited in Dermatologic Surgery, allowing us to determine topics of utmost value and interest. Using a citation database provided by the Institute for Scientific Information, we first identify all publications and citations from 1981 to 1999 for Dermatologic Surgery and the Journal of Dermatologic Surgery and Oncology (the previous name for this journal). Of the original articles published during this time frame, 3099 authors published 2167 papers. We quantify the publications from each author, and identify 57 authors with at least 10 original articles. When expanding the database parameters to include original articles, reviews, notes, and proceedings (as defined by the Science Citation Index), we find that the eight authors with the greatest number of publications are the same individuals with the greatest number of original articles. This reflects significant contributions to the field of cutaneous surgery by these authors. This analysis further identifies source papers for authors in Dermatologic Surgery. Publications frequently cited include those papers discussing laser surgery, with Dermatologic Surgery serving as the most frequently cited journal. C1 Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Div Dermatol, Los Angeles, CA 90024 USA. RP Moy, RL (reprint author), Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Div Dermatol, 100 UCLA Med Plaza,Suite 530, Los Angeles, CA 90024 USA. NR 3 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD DEC PY 2000 VL 26 IS 12 BP 1092 EP 1095 DI 10.1046/j.1524-4725.2000.00252.x PG 4 WC Dermatology; Surgery SC Dermatology; Surgery GA 386AD UT WOS:000166036600012 PM 11134983 ER PT J AU Ruvinsky, I Gibson-Brown, JJ AF Ruvinsky, I Gibson-Brown, JJ TI Genetic and developmental bases of serial homology in vertebrate limb evolution SO DEVELOPMENT LA English DT Review DE vertebrate; limb; evolution; development; T-box gene; Hox gene; Pitx1; selector gene; serial homology ID T-BOX GENES; ULNAR-MAMMARY SYNDROME; HOLT-ORAM SYNDROME; HOX GENES; DIFFERENTIAL EXPRESSION; TRANSCRIPTION FACTOR; GROWTH-FACTORS; IDENTITY; SPECIFICATION; FAMILY AB Two sets of paired appendages are a characteristic feature of the body plan of jawed vertebrates, While the fossil record provides a good morphological description of limb evolution, the molecular mechanisms involved in this process are only now beginning to be understood. It is likely that the genes essential for limb development in modern vertebrates were also important players during limb evolution. In recent years, genes from a number of gene families have been described that play important roles both in limb induction and in later patterning processes. These advances facilitate inquiries into several important aspects of limb evolution such as their origin, position along the body axis, number and identity. Integrating paleontological, developmental and genetic data, we propose models to explain the evolution of paired appendages in vertebrates. Whereas previous syntheses have tended to focus on the roles of genes from a single gene family, most notably Hox genes, we emphasize the importance of considering the interactions among multiple genes from different gene families for understanding the evolution of complex developmental systems. Our models, which underscore the roles of gene duplication and regulatory 'tinkering', provide a conceptual framework for elucidating the evolution of serially homologous structures in general, and thus contribute to the burgeoning field seeking to uncover the genetic and developmental bases of evolution. C1 Princeton Univ, Dept Biol Mol, Princeton, NJ 08544 USA. Washington Univ, Dept Biol, St Louis, MO 63130 USA. RP Gibson-Brown, JJ (reprint author), Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA. FU NICHD NIH HHS [HD-20275] NR 104 TC 70 Z9 72 U1 1 U2 16 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC PY 2000 VL 127 IS 24 BP 5233 EP 5244 PG 12 WC Developmental Biology SC Developmental Biology GA 388VY UT WOS:000166204800002 PM 11076746 ER PT J AU Pold, M Pold, A Ma, HJ Sjak-Shie, NN Vescio, RA Berenson, JR AF Pold, M Pold, A Ma, HJ Sjak-Shie, NN Vescio, RA Berenson, JR TI Cloning of the first invertebrate MAGE paralogue: an epitope that activates T-cells in humans is highly conserved in evolution SO DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY LA English DT Article DE homology search; MAGE gene family; DMAGE; D. melanogaster; shared tumor antigens; developmentally regulated expression; MHC; protostome-deuterostome divergence ID PRADER-WILLI-SYNDROME; SYNTHETIC PEPTIDE; SEX REVERSAL; NECDIN GENE; IDENTIFICATION; FAMILY; LYMPHOCYTES; EXPRESSION; REGION; VERTEBRATES AB The MAGE (Melanoma Associated Antigen) family tumor-specific antigens are shared by a number of histologically different rumors. Till date, only human and mouse MAGE genes have been characterized. Our study describes the first non-mammalian member of MAGE super-family, DMAGE from D. melanogaster. A conceptual translation of the cDNA of DMAGE identifies a putative protein that contains a motif that shares eight out of nine amino acids with the previously identified promiscuous, HLA-A2 restricted antigenic epitope in the C-terminus of human MAGE-B1 and -B2. Similarly, this motif of DMAGE shares seven out of nine amino acids with the same antigenic epitope of human MAGE-A3 and -A12. Thus, the phylogeny of proteins that activate tumor specific T-cells in mammals as unmutated self-proteins began at least 100 million years earlier in evolution than the emergence of the adaptive immune system of higher vertebrates. Northern analysis revealed that DMAGE is a developmentally regulated gene highly expressed in adult fruit Ay and in the embryo of D. melanogaster. In contrast, the expression level of the mRNA of DMAGE in fruit fly larva is substantially lower than in embryo and adult fly. We propose that studies of DMAGE on D. melanogaster may help define the function(s) of MAGE super-family genes. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 W Los Angeles Vet Affairs Med Ctr, Brentwood Biomed Res Inst, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Div Hematol & Oncol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. RP Pold, M (reprint author), W Los Angeles Vet Affairs Med Ctr, Brentwood Biomed Res Inst, 11301 Wilshire Blvd,Bldg 304,E1-110, Los Angeles, CA 90073 USA. NR 32 TC 10 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-305X J9 DEV COMP IMMUNOL JI Dev. Comp. Immunol. PD DEC PY 2000 VL 24 IS 8 BP 719 EP 731 DI 10.1016/S0145-305X(00)00027-6 PG 13 WC Immunology; Zoology SC Immunology; Zoology GA 338HM UT WOS:000088413300001 PM 10906385 ER PT J AU Faraone, SV Biederman, J AF Faraone, SV Biederman, J TI Nature, nurture, and attention deficit hyperactivity disorder SO DEVELOPMENTAL REVIEW LA English DT Article ID DOPAMINE TRANSPORTER GENE; CATECHOL-O-METHYLTRANSFERASE; RECEPTOR POLYMORPHISM; TOURETTE-SYNDROME; MATERNAL SMOKING; NOVELTY SEEKING; DRD4 GENE; ASSOCIATION; CHILDREN; RISK AB This commentary shows that Joseph's (this issue) review of the genetics of attention deficit hyperactivity disorder (ADHD) contains errors of scientific logic and ignores much relevant research. Thus, we reject his conclusions. We also reject Joseph's approach of pitting nature against nurture as if these two facets of human life are at odds with one another. Instead, most scientists who study the genetics of psychiatric disorders embrace the idea that these disorders are influenced by both genes and environmental factors. In fact, the twin studies criticized by Joseph provide the strongest evidence that environmental risk factors play a substantial role in the etiology of ADHD. They do so by showing that when one identical twin has ADHD the risk to the co-twin is much less than 100%. a fact which can only be explained by environmental risk factors. We also reject the idea that genetic studies have hindered psychosocial research, stigmatized patients, or promoted psychopharmacologic treatments. Genetic studies have aimed at solving one part of the puzzle of ADHD. By testing a parsimonious theory, they have set the stage for gene discovery and the delineation of how genes and environment combine to cause this impairing disorder. (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Child Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Inst Psychiat Epidemiol & Genet, Cambridge, MA 02138 USA. Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. RP Faraone, SV (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol ACC 725, 15 Parkman St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 NR 70 TC 28 Z9 28 U1 2 U2 14 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2297 J9 DEV REV JI Dev. Rev. PD DEC PY 2000 VL 20 IS 4 BP 568 EP 581 DI 10.1006/drev.2000.0515 PG 14 WC Psychology, Developmental SC Psychology GA 379LZ UT WOS:000165644700004 ER PT J AU Thomas, MK Rastalsky, N Lee, JH Habener, JF AF Thomas, MK Rastalsky, N Lee, JH Habener, JF TI Hedgehog signaling regulation of insulin production by pancreatic beta-cells SO DIABETES LA English DT Article ID LEFT-RIGHT ASYMMETRY; SONIC HEDGEHOG; INDIAN HEDGEHOG; POLARITY GENE; TRANSDUCING HEDGEHOG; CUBITUS INTERRUPTUS; DROSOPHILA SEGMENT; TOUT-VELU; PROTEIN; EXPRESSION AB Hedgehogs (Hhs) are intercellular signaling molecules that regulate tissue patterning in mammalian development. Mammalian Hhs include Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). The absence of Shh expression is required for the early development of the endocrine and exocrine pancreas, but whether Hh signaling functions in the fully developed adult endocrine pancreas is unknown. Here we report that Hhs Ihh and Dhh and their receptors patched (Ptc) and smoothened are expressed in the endocrine islets of Langerhans of the fully developed rat pancreas and in the clonal beta -cell line INS-1. We demonstrate the coexpression of Ptc with insulin in p-cells of mouse pancreatic islets, indicating that beta -cells are targets of active Hh signaling. The administration of cyclopamine, a Hh signaling inhibitor, decreases both insulin secretion from and insulin content of INS-1 cells. The effects of Hh signaling on insulin production occur at the transcriptional level because activation of Hh signal transduction by ectopic expression of Shh increases rat insulin I promoter activation in a dose-dependent manner in transient transfections of INS-1 and MIN6 beta -cell lines. In contrast, inhibition of Hh signaling with increasing concentrations of cyclopamine progressively reduces insulin promoter activity. Furthermore, the treatment of INS-1 cells with cyclopamine diminishes endogenous insulin mRNA expression. We propose that Hh signaling is not restricted to patterning in early pancreas development but also continues to signal in differentiated beta -cells of the endocrine pancreas in regulating insulin production. Thus, defective Hh signaling in the pancreas should be considered as a potential factor in the pathogenesis of type 2 diabetes. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Howard Hughes Med Inst,Lab Mol Endocrinol, Boston, MA 02114 USA. RP Habener, JF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Howard Hughes Med Inst,Lab Mol Endocrinol, 55 Fruit St,WEL320, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK30457, DK55365, DK30834] NR 62 TC 95 Z9 97 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2039 EP 2047 DI 10.2337/diabetes.49.12.2039 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500010 PM 11118005 ER PT J AU Andrikopoulos, S Verchere, CB Terauchi, Y Kadowaki, T Kahn, SE AF Andrikopoulos, S Verchere, CB Terauchi, Y Kadowaki, T Kahn, SE TI beta-Cell glucokinase deficiency and hyperglycemia are associated with reduced islet amyloid deposition in a mouse model of type 2 diabetes SO DIABETES LA English DT Article ID INDUCED INSULIN-SECRETION; FIBRIL FORMATION; TRANSGENIC MICE; IN-VITRO; TARGETED DISRUPTION; POLYPEPTIDE; GLUCOSE; MELLITUS; PEPTIDES; GENE AB Type 2 diabetes is characterized by impaired P-cen function, hyperglycemia, and islet amyloid deposition. he primary constituent of islet amyloid is the 37-amino acid beta -cell product called islet amyloid polypeptide (IAPP) or amylin. To study mechanisms of islet amyloid formation, we developed a transgenic mouse model that produces and secretes the amyloidogenic human IAPP (hIAPP) molecule and have shown that 81% of male transgenic mice develop islet amyloid after 14 months on a high-fat diet. To test whether impaired beta -cell function and hyperglycemia could enhance islet amyloid formation, me cross-bred our hIAPP transgenic mice with beta -cell glucokinase-knockout mice (GKKO) that have impaired glucose-mediated insulin secretion and fasting hyperglycemia. The resulting nem (hIAPP x GKKO) Line of mice had higher basal plasma glucose concentrations than the hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.05), as did GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.05). Basal plasma immunoreactive insulin (IRI) levels mere lower in hIAPP x GKKO mice than in hIAPP transgenic mice at 6 months of age (P < 0.05). The area under the glucose curve in response to an intraperitoneal glucose challenge (1 g/kg body weight) was larger in hIAPP x GKKO mice than in hIAPP transgenic mice at 3, 6, and 12 months of age (P < 0.005) and in GKKO mice compared with hIAPP transgenic mice at 6 and 12 months of age (P < 0.005). The area under the IRI curve was lower in hIAPPxGKKO mice at 6 and 12 months of age (P < 0.05) than in hIAPP transgenic mice and in GKKO mice compared with hIAPP transgenic mice at 12 months of age (P < 0.05). Despite the presence of hyperglycemia, hIAPPxGKKO mice had a lower incidence (4 of 17 vs. 12 of 19, P < 0.05) and amount (0.40 +/- 0.24 vs. 1.2 +/- 0.3 arbitrary units, P < 0.05) of islet amyloid than hIAPP transgenic mice had. As expected, no islet amyloid mas observed in GKKO mice lacking the hIAPP transgene (0 of 13). There was no difference in pancreatic content of IRI and hIAPP among the three groups of mice. Thus, despite the presence of impaired islet function and hyperglycemia, hIAPPxGKKO mice had a decreased incidence and quantity of islet amyloid. Therefore, our data suggest that impaired -cell glucose metabolism or hyperglycemia are not Likely to contribute to islet amyloid formation in diabetes. Furthermore, this finding may explain the lack of progression of glycemia in patients with maturity-onset diabetes of the young. C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Univ Tokyo, Dept Internal Med, Tokyo, Japan. RP Kahn, SE (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 151,1660 S Columbian Way, Seattle, WA 98108 USA. FU NIDDK NIH HHS [DK-35816, DK-17047, DK-50703] NR 33 TC 32 Z9 32 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2056 EP 2062 DI 10.2337/diabetes.49.12.2056 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500012 PM 11118007 ER PT J AU Mauvais-Jarvis, F Virkamaki, A Michael, MD Winnay, JN Zisman, A Kulkarni, RN Kahn, CR AF Mauvais-Jarvis, F Virkamaki, A Michael, MD Winnay, JN Zisman, A Kulkarni, RN Kahn, CR TI A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes SO DIABETES LA English DT Article ID GLUCOSE-TRANSPORT; ADIPOSE-TISSUE; IN-VIVO; PIMA-INDIANS; MICE; NIDDM; RECEPTOR; LEPTIN; RAT; PATHOGENESIS AB Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout ((MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta -cell-specific insulin receptor knockout (beta IRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, me created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, beta IRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to beta IRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta -cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK09825-02, DK31036, DK36836] NR 46 TC 53 Z9 56 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2126 EP 2134 DI 10.2337/diabetes.49.12.2126 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500021 PM 11118016 ER PT J AU Jenkins, AJ Velarde, V Klein, RL Joyce, KC Phillips, KD Mayfield, RK Lyons, TJ Jaffa, AA AF Jenkins, AJ Velarde, V Klein, RL Joyce, KC Phillips, KD Mayfield, RK Lyons, TJ Jaffa, AA TI Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells SO DIABETES LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; PROTEIN-KINASE; DIABETIC COMPLICATIONS; ENDOTHELIAL-CELLS; KIDNEY-DISEASES; END-PRODUCTS; OXIDIZED LDL; C ACTIVATION; OXIDATION; GLYCATION AB Glycation and/or oddation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects of LDL on ERR phosphorylation in cultured rat mesangial cells. In cells exposed to 100 mug/ml native LDL or LDL modified by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure to 10-100 mug/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity. Also, 10 mug/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERR activation than that induced by copper-oxidized LDL +/- glycation (P < 0.05). Pretreatment of cells with Src kinase and MAPK kinase inhibitors blocked ERK activation by 50-80% (P < 0.05). Native and mildly modified LDL, which are recognized by the native LDL receptor, induced a transient spike of intracellular calcium. Copper-oxidized (+/- glycation) LDL, recognized by the scavenger receptor, induced a sustained rise in intracellular calcium. The intracellular calcium chelator (EGTA/AM) further increased ERK activation by native and mildly modified LDL (P < 0.05). These findings demonstrate that native and modified LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cells and provide evidence for a potential link between modified LDL and the development of glomerular injury in diabetes. C1 Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Pharmacol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. RP Jaffa, AA (reprint author), Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Med, 114 Doughty St,POB 250776, Charleston, SC 29425 USA. FU NHLBI NIH HHS [HL-55782]; NIDDK NIH HHS [DK-46543]; PHS HHS [R2910697] NR 59 TC 49 Z9 51 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2160 EP 2169 DI 10.2337/diabetes.49.12.2160 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500026 PM 11118021 ER PT J AU Araki, S Moczulski, DK Hanna, L Scott, LJ Warram, JH Krolewski, AS AF Araki, S Moczulski, DK Hanna, L Scott, LJ Warram, JH Krolewski, AS TI APOE polymorphisms and the development of diabetic nephropathy in type 1 diabetes - Results of case-control and family-based studies SO DIABETES LA English DT Article ID APOLIPOPROTEIN EPSILON-2 ALLELE; LIPOPROTEIN GLOMERULOPATHY; ALZHEIMERS-DISEASE; LINKAGE DISEQUILIBRIUM; CHOLESTEROL TRANSPORT; GENE REGION; MELLITUS; NIDDM; RISK; RECEPTORS AB The goal. of this study was to examine the association between known polymorphisms in the apolipoprotein E gene (APOE) and diabetic nephropathy (DN) in type 1 diabetes. We used both a case-control comparison and a family-based study design known as the transmission/disequilibrium test (TDT). For the case-control comparison, me collected DNA from 223 subjects with clinically diagnosed DN and 196 control subjects with normoalbuminuria and long-duration type I diabetes (greater than or equal to 15 years). For the family-based study, we obtained DNA hom both parents of 154 DN subjects and 81 control subjects. The frequency of the epsilon2 allele of exon 4 of APOE was significantly higher in DN subjects than in control subjects. The risk of DN was 3.1 times higher (95% CI 1.6-5.9) in carriers of this allele than in noncarriers. In the family study, heterozygous parents for the epsilon2 allele preferentially transmitted epsilon2 to DN offspring (64 vs. 36%,P < 0.03). Four additional polymorphisms (i.e., -491 A/T-219 G/T, IE1 G/C, and APOCI insertion/deletion [I/D]) that flank the APOE locus mere not associated with DN in either the case-control comparison or in the family-based study. In conclusion, the results of the case-control as web as the family-based study provide evidence that the 2 allele of APOE increases the risk of DN in type 1 diabetes. The molecular mechanisms underlying this risk are unclear at present. C1 Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK41526, DK53534] NR 40 TC 65 Z9 70 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2190 EP 2195 DI 10.2337/diabetes.49.12.2190 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500029 PM 11118024 ER PT J AU Meigs, JB Cupples, LA Wilson, PWF AF Meigs, JB Cupples, LA Wilson, PWF TI Parental transmission of type 2 diabetes - The Framingham Offspring Study SO DIABETES LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; MATERNAL HISTORY; UNITED-STATES; NIDDM; MELLITUS; PREVALENCE; DISEASE; EXCESS; FAMILIES; OBESITY AB Study of parental transmission of diabetes provides insight into the relative contributions of underlying maternal and paternal influences. We estimated risk for type 2 diabetes and milder degrees of glucose intolerance associated with parental diabetes among subjects of the population-based Framingham Offspring Study, in which participants are primarily Caucasian and at relatively low risk for diabetes and for which both parental and offspring phenotypes were ascertained by direct examination. Parental diabetes, assessed over 40 years of biennial follow-up, was defined by use of hypoglycemic drug therapy or a casual plasma glucose level greater than or equal to 11.1 mmol/l at any examination. Offspring glucose tolerance, assessed over 20 years of quadrennial follow-up, was defined by fasting plasma glucose levels greater than or equal to7.8 mmol/l at any two examinations, use of hypoglycemic drug therapy at any examination, or with a 75-g oral glucose tolerance test (1980 World Health Organization criteria) at the most recent examination. We calculated odds ratios (ORs) and 95% CIs for offspring glucose tolerance status using generalized estimating equations to account fdr differential correlations within and between families. The 2,527 offspring came from 1,303 nuclear families, of which 77.6% had two or more siblings per family and in which the prevalence of parental diabetes was 24.6%. The mean offspring age was 54 years (range 26-82), 53% were women, 8.6% had diabetes, 11.4% had impaired glucose tolerance, 76.3% had no parental diabetes, 10.5% had maternal diabetes, 11.5% had paternal diabetes, and 1.7% had bilineal diabetes. Relative to individuals without parental diabetes, the age-adjusted ORs (95% CI) for offspring type 2 diabetes or abnormal glucose tolerance (fasting plasma glucose greater than or equal to6.1 mmol/l or. 2-h postchallenge glucose tolerance greater than or equal to7,8 mmol/l) among individuals with maternal diabetes were 3.4 (2.3-4.9) and 2.7 (2.0-3.7), respectively; among individuals with paternal diabetes were 3.5 (2.3-5.2) and 1.7 (1.2-2.4), respectively; and among individuals with bilineal diabetes were 6.1 (2.9-13.0) and 5.2 (2.6-10.5), respectively. Although maternal and paternal diabetes conferred equivalent risk for offspring type 2 diabetes, offspring with maternal diabetes were slightly more likely to have abnormal glucose tolerance compared with those with paternal diabetes (OR 1.6, 95% CI 1.1-2.4). Offspring with maternal diabetes and an age Of onset of <50 years had marked increased risk for both type 2 diabetes (9.7, 4.3-22.0) and abnormal glucose tolerance (9.0, 4.2-19.7). We conclude that risk ratios for offspring type 2 diabetes are consistent with a simple additive risk model, where risk when both parents are affected equals the sum of risk when either parent is affected. For maternal diabetes to confer excess risk for mild but not overt glucose intolerance, offspring of diabetic fathers may transit abnormal to impaired glucose tolerance relatively quickly, or diabetic mothers may transmit risk for a mild slowly progressive form of abnormal glucose tolerance in addition to overt diabetes. Very high risk for abnormal glucose homeostasis among offspring with young age-of-onset maternal diabetes is consistent with hypotheses that perinatal exposures increase diabetes risk. Given equivalent risk ratios for type 2 diabetes, fathers may transmit unique paternal genetic factors of similar strength to maternal environmental factors. C1 Massachusetts Gen Hosp, Gen Internal Med Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Meigs, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Gen Internal Med Unit S50 9, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NHLBI NIH HHS [N01-HC-38083] NR 43 TC 250 Z9 258 U1 2 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2201 EP 2207 DI 10.2337/diabetes.49.12.2201 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500031 PM 11118026 ER PT J AU Klupa, T Malecki, MT Pezzolesi, M Ji, LO Curtis, S Langefeld, CD Rich, SS Warram, JH Krolewski, AS AF Klupa, T Malecki, MT Pezzolesi, M Ji, LO Curtis, S Langefeld, CD Rich, SS Warram, JH Krolewski, AS TI Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2 SO DIABETES LA English DT Article ID SIB PAIRS; MELLITUS; LINKAGE; ONSET; GENE; NIDDM; SCAN; 20Q AB We previonsly reported suggestive linkage between type 2 diabetes and markers in a region on chromosome 20q using data from a collection of 29 Caucasian families in which type 2 diabetes with middle-age-onset was segregated as an autosomal-dominant disorder. To map more precisely the susceptibility locus (or loci) within this broad region, we increased the family collection and genotyped all families for additional markers, both within the critical region and spaced over the rest of chromosome 20. Altogether 526 individuals (including 241 with diabetes) from the total collection of 43 families were included in the study. All individuals mere genotyped for 23 highly polymorphic markers. Positive evidence for Linkage was found for a 10-cM region on the long arm of chromosome 20q13.1-q13.2 between markers D20S119 and D20S428. The strongest evidence in two-point as well as multipoint linkage analysis (P = 1.8 x 10(-5)) occurred at the position corresponding to marker D20S196. The individuals with diabetes in the seven most strongly linked families had high serum insulin levels during fasting and 2-h post-glucose load periods. me did not find any evidence for linkage between type 2 diabetes and any other region on chromosome 20. In conclusion, our larger and more comprehensive study showed very strong evidence for a susceptibility gene for insulin-resistant type 2 diabetes located on the long arm of chromosome 20 around marker D20S196. C1 Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Jagiellonian Univ, Sch Med, Dept Metab Dis, Krakow, Poland. Beijing Med Univ, Peoples Hosp, Dept Endocrinol & Metab, Beijing 100083, Peoples R China. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK-36836, DK-47475] NR 22 TC 73 Z9 82 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2000 VL 49 IS 12 BP 2212 EP 2216 DI 10.2337/diabetes.49.12.2212 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 378FC UT WOS:000165573500033 PM 11118028 ER PT J AU Mauvais-Jarvis, F Kahn, CR AF Mauvais-Jarvis, F Kahn, CR TI Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: What can we learn from transgenic and knockout mice? SO DIABETES & METABOLISM LA English DT Review DE type 2 diabetes; transgenic mice; knockout mice; insulin resistance ID ISLET AMYLOID POLYPEPTIDE; BETA-CELL GLUCOKINASE; ADIPOSE-TISSUE; RECEPTOR GENE; GLUCOSE-HOMEOSTASIS; TARGETED DISRUPTION; SKELETAL-MUSCLE; PHOSPHOINOSITIDE 3-KINASE; HETEROZYGOUS KNOCKOUT; OVEREXPRESSING GLUT4 AB The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta -cells to compensate by adequate insulin secretion. Here, we review studies obtained from genetically engineered mice that have helped dissect the pathophysiology of this disease. Transgenic/knockout models with monogenic impairment in insulin action and insulin secretion have highlighted potential molecular mechanisms for insulin resistance and suggested a mechanism for the development of MODY in humans. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, pointing out the importance of interactions of different genetic loci in the production of diabetes. Tissue specific knockouts of the insulin receptor have challenged current concepts on the regulation of glucose homeostasis and have highlighted the importance of insulin action in pancreatic beta -cells and brain. The impact of the genetic background on insulin action, insulin secretion and the incidence of diabetes is also evident in these models. These findings highlight potential new therapeutic targets in the treatment of type 2 diabetes. C1 Hop Lariboisiere, Dept Endocrinol & Metab Dis, F-75010 Paris, France. Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr,Res Div, Boston, MA USA. RP Mauvais-Jarvis, F (reprint author), Hop Lariboisiere, Dept Endocrinol & Metab Dis, 2 Rue Ambroise Pare, F-75010 Paris, France. NR 120 TC 32 Z9 34 U1 0 U2 1 PU MASSON EDITEUR PI PARIS 06 PA 120 BLVD SAINT-GERMAIN, 75280 PARIS 06, FRANCE SN 0338-1684 J9 DIABETES METAB JI Diabetes Metab. PD DEC PY 2000 VL 26 IS 6 BP 433 EP 448 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 397BD UT WOS:000166672700001 PM 11173714 ER PT J AU Araki, S Makita, Y Canani, I Ng, D Warram, JH Krolewski, AS AF Araki, S Makita, Y Canani, I Ng, D Warram, JH Krolewski, AS TI Polymorphisms of human paraoxonase 1 gene (PON1) and susceptibility to diabetic nephropathy in Type I diabetes mellitus SO DIABETOLOGIA LA English DT Article DE diabetic nephropathy; PON1; polymorphism; case-control study; Type I diabetes ID CORONARY HEART-DISEASE; COMPLICATIONS AB Aims/hypothesis. Oxidative stress is a putative mechanism in the development of diabetic nephropathy. Paraoxonase gene 1 is an HDL-bound enzyme that protects tissues against oxidative damage. Three common polymorphisms of paraoxonase gene 1, T-107C in the promoter, Leu54Met and Gln192Arg, that modify paraoxonase activity have been associated with cardiovascular disease. This study aimed to find whether these polymorphisms also contribute to the development of diabetic nephropathy. Methods. The association between diabetic nephropathy and these three polymorphisms was examined in a case-control study. For this purpose, genomic DNA was collected from 188 patients with Type I (insulin-dependent) diabetes mellitus and diabetic nephropathy and from 179 unrelated patients with Type I diabetes but without diabetic nephropathy despite the duration of diabetes of 15 or more years. Results. The genotype and allele frequencies for each of the three polymorphisms (T-107C, Leu54Met and Gln192Arg) were similar in cases and control subjects. Conclusion/interpretation. The three polymorphisms in paraoxonase gene 1 that have been associated with serum levels of paraoxonase are not associated with diabetic nephropathy. We show that this genetically determined component of the antioxidant capacity of HDL does not play a critical part in the development of diabetic nephropathy. C1 Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK 47475, DK 41526] NR 10 TC 22 Z9 25 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 DEC PY 2000 VL 43 IS 12 BP 1540 EP 1543 DI 10.1007/s001250051566 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 381GT UT WOS:000165754500012 PM 11151764 ER PT J AU Zhang, SL Tang, SS Chen, X Filep, JG Ingelfinger, JR Chan, JSD AF Zhang, SL Tang, SS Chen, X Filep, JG Ingelfinger, JR Chan, JSD TI High levels of glucose stimulate angiotensinogen gene expression via the p38 mitogen-activated protein kinase pathway in rat kidney proximal tubular cells SO ENDOCRINOLOGY LA English DT Article ID ELEMENT-BINDING PROTEIN; CELLULAR HYPERTROPHY; DIABETIC NEPHROPATHY; MESANGIAL CELLS; MESSENGER-RNA; TGF-BETA; TRANSCRIPTION; RECEPTOR; RENIN; ISOPROTERENOL AB The present studies investigated whether the effect of high levels of glucose on angiotensinogen (ANG) secretion and gene expression in kidney proximal tubular cells is mediated at least in part via the activation of p38 mitogen-activated protein kinase (p38 MAPK). Rat immortalized renal proximal tubular cells (IRPTCs) were cultured in monolayer. The levels of immunoreactive rat ANG (IR-rANG) secreted into the medium and the levels of cellular ANG messenger RNA were determined by a specific RIA for rat ANG and a RT-PCR assay, respectively. Phosphorylation of cellular p38 MAPK was determined by Western blot analysis using the Phospho Plus p38 MAPK antibody kit. High levels of glucose (i.e. 25 mM) and phorbol 12-myristate 13-acetate (PMA; 10(-7) M) increased the secretion of IR-rANG and cellular ANG messenger RNA as well as phosphorylation of p38 MAPK in IRPTCs. This stimulatory effect of high levels of glucose and PMA was blocked by SE 203580 (a specific inhibitor of p38 MAPK), but not by SE 202474 (a negative control of SE 203580). High levels of D-sorbitol or 2-deoxy-D-glucose (i.e. greater than or equal to 35 mM) also stimulated the phosphorylation of p38 MAPK, but did not stimulate ANG secretion or gene expression. GF 109203X (an inhibitor of protein kinase C) blocked the stimulatory effect of high levels of glucose and PMA on ANG gene expression, whereas it did not block the effect of high levels of glucose, sorbitol, or 2-deoxy-D-glucose on p38 MAPK phosphorylation in IRPTCs. These studies demonstrate that the stimulatory effect of a high level of glucose (25 mM) on ANG gene expression in IRPTCS may be mediated at least in part via activation of p38 MAPK signal transduction pathway and is protein kinase C independent. C1 Univ Montreal, Maisonneuve Rosemont Hosp, Res Ctr, Montreal, PQ H1T 2M4, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Chan, JSD (reprint author), Univ Montreal, CHU Montreal, Hop Hotel Dieu, Pavillon Masson,3850 St Urbain St, Montreal, PQ H2W 1T8, Canada. NR 46 TC 39 Z9 43 U1 0 U2 10 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 DEC PY 2000 VL 141 IS 12 BP 4637 EP 4646 DI 10.1210/en.141.12.4637 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 374TR UT WOS:000165360900040 PM 11108278 ER PT J AU Delaney, ME Zisman, A Kettyle, WM AF Delaney, ME Zisman, A Kettyle, WM TI Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article ID LOW-DOSE INSULIN; CEREBRAL EDEMA; SODIUM-BICARBONATE; PHOSPHATE THERAPY; RENAL-FUNCTION; GLUCOSE-UPTAKE; COMA; MELLITUS; INFUSION; MANAGEMENT AB Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS) are life-threatening acute metabolic complications of diabetes mellitus. Although there are some important differences, the pathophysiology, the presenting clinical challenge, and the treatment of these metabolic derangements are similar. Each of these complications can be seen in type 1 or type 2 diabetes, although DKA is usually seen in patients with type 1 diabetes and HHNS in patients with type 2 disease. The clinical management of these syndromes involves careful evaluation and correction of the metabolic and volume status of the patient, identification and treatment of precipitating and comorbid conditions, a smooth transition to a long-term treatment regimen, and a plan to prevent recurrence. C1 Brigham & Womens Hosp, Div Endocrine Hypertens, Boston, MA 02115 USA. Joslin Diabet Ctr, Sect Mol & Cellular Physiol, Boston, MA 02215 USA. MIT, Dept Med, Cambridge, MA 02139 USA. RP Delaney, ME (reprint author), Brigham & Womens Hosp, Div Endocrine Hypertens, 221 Longwood Ave, Boston, MA 02115 USA. NR 100 TC 63 Z9 71 U1 1 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2000 VL 29 IS 4 BP 683 EP + DI 10.1016/S0889-8529(05)70159-6 PG 24 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 385LA UT WOS:000166004700003 PM 11149157 ER PT J AU Laffel, L AF Laffel, L TI Sick-day management in type 1 diabetes SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article ID SUBCUTANEOUS INSULIN INFUSION; BETA-HYDROXYBUTYRATE; KETOACIDOSIS; KETONE; PLASMA; INTERRUPTION; CHILDREN; MELLITUS; HUMANS; MESNA AB This article reviews the importance of sick-day management in persons with type 1 diabetes. Topics include current sick-day protocols and new technologies that may improve home management of uncontrolled diabetes in an attempt to avoid full-blown metabolic decompensation and the development of diabetic ketoacidosis (DKA). Prevention of DKA with adequate sick-day management will reduce the human and economic toll of this complication. Increased awareness of this therapy, which involves frequent monitoring to detect hyperglycemia and ketosis and supplemental insulin administration, is the key to its successful use at home. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr,Pediat & Adolescent Unit, Joslin Clin,Genet & Epidemiol Unit, Boston, MA 02215 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat, Boston, MA 02215 USA. RP Laffel, L (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr,Pediat & Adolescent Unit, Joslin Clin,Genet & Epidemiol Unit, 1 Joslin Pl, Boston, MA 02215 USA. NR 71 TC 36 Z9 38 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 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2000 VL 29 IS 4 BP 707 EP + DI 10.1016/S0889-8529(05)70160-2 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 385LA UT WOS:000166004700004 PM 11149158 ER PT J AU Li, XD Boppart, SA Van Dam, J Mashimo, H Mutinga, M Drexler, W Klein, M Pitris, C Krinsky, ML Brezinski, ME Fujimoto, JG AF Li, XD Boppart, SA Van Dam, J Mashimo, H Mutinga, M Drexler, W Klein, M Pitris, C Krinsky, ML Brezinski, ME Fujimoto, JG TI Optical coherence tomography: Advanced technology for the endoscopic imaging of Barrett's esophagus SO ENDOSCOPY LA English DT Article ID BIOPSY; TISSUE; INTERFEROMETER; SURVEILLANCE; MICROSCOPY; THERAPY; CANCER; TIME AB Background and Study Aims: Endoscopic optical coherence tomography (OCT) is an emerging medical technology capable of generating high-resolution cross-sectional imaging of tissue microstructure in situ and in real time, We assess the use and feasibility of OCT for real-time screening and diagnosis of Barrett's esophagus, and also review state-of-the-art OCT technology for endoscopic imaging. Materials and Methods: OCT imaging was performed as an adjunct to endoscopic imaging of the human esophagus, Real-time OCT (13-mum resolution) was used to perform image-guided evaluation of normal esophagus and Barrett's esophagus, Beam delivery was accomplished with a l-mm diameter OCT catheter-probe that can be introduced into the accessory channel of a standard endoscope, Different catheter-probe imaging designs which performed linear and radial scanning were assessed, Novel ultrahigh-resolution (1.1 mum resolution) and spectroscopic OCT techniques were used to image in vitro specimens of Barrett's esophagus. Results: Endoscopic OCT images revealed distinct layers of normal human esophagus extending from the epithelium to the muscularis propria, In contrast, the presence of gland- and crypt-like morphologies and the absence of layered structures were observed in Barrett's esophagus, All OCT images showed strong correlations with architectural morphology in histological findings, Ultrahigh-resolution OCT techniques achieved 1.1 mum image resolution in in vitro specimens and showed enhanced resolution of architectural features. Spectroscopic OCT identified localized regions of wavelength-dependent optical scattering, enhancing the differentiation of Barrett's esophagus. Conclusions: OCT technology with compact fiberoptic imaging probes can be used as an adjunct to endoscopy for real-time image-guided evaluation of Barrett's esophagus. Linear and radial scan patterns have different advantages and limitations depending upon the application, Ultrahigh-resolution and spectroscopic OCT techniques improve structural tissue recognition and suggest future potential for resolution and contrast enhancements in clinical studies, A new balloon catheter-probe delivery device is proposed for systematic imaging and screening of the esophagus. C1 MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, Cambridge, MA 02139 USA. Harvard Univ, MIT Div Hlth Sci & Technol, Cambridge, MA 02138 USA. Stanford Univ, Med Ctr, Div Gastroenterol, Stanford, CA 94305 USA. W Roxbury VA Med Ctr, Div Gastroenterol, W Roxbury, MA USA. Harvard Univ, Dept Med, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Brigham & Womens Hosp, Div Gastroenterol, Sch Med, Cambridge, MA 02138 USA. W Roxbury VA Med Ctr, Dept Pathol, W Roxbury, MA USA. RP Van Dam, J (reprint author), Stanford Univ, Med Ctr, Div Gastroenterol & Hepatol, 300 Pasteur Dr,Room H1121, Stanford, CA 94305 USA. RI Boppart, Stephen/C-7338-2009; Li, Xingde/F-7663-2012; OI Pitris, Costas/0000-0002-5559-1050 FU NCI NIH HHS [9-RO1-CA75289-03]; NEI NIH HHS [9-RO1-EY11289-14]; NIAMS NIH HHS [R01-AR44812-02] NR 34 TC 149 Z9 154 U1 2 U2 16 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0013-726X J9 ENDOSCOPY JI Endoscopy PD DEC PY 2000 VL 32 IS 12 BP 921 EP 930 DI 10.1055/s-2000-9626 PG 10 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 382KZ UT WOS:000165822600001 PM 11147939 ER PT J AU Fukai, I Hussey, RE Sunder-Plassmann, R Reinherz, EL AF Fukai, I Hussey, RE Sunder-Plassmann, R Reinherz, EL TI A critical role for p59(fyn) in CD2-based signal transduction SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE kinase; motility; T cell; immune receptor; docking protein ID T-CELL ACTIVATION; PROLINE-RICH SEQUENCES; KINASE C-THETA; TYROSINE PHOSPHORYLATION; LYMPHOCYTE ACTIVATION; CD2 STIMULATION; IL-2 PROMOTER; MICE LACKING; RAS PATHWAY; PROTEIN AB TCR- but not CD2-triggered IL-2 production is p56(lck) dependent. To test the hypothesis that p59(fyn), a second src-family protein tyrosine kinase (PTK) expressed in T lymphocytes, might be an essential upstream component of the CD2 signaling pathway, we generated human (h) CD2 transgenic (tg) fyn(+/+) and fyn(-/-) mice. Clustering of hCD2 molecules on resting peripheral T lymphocytes results in Ca2+ mobilization, activation of MARK and cellular proliferation. In contrast, in the absence of p59(fyn), these CD2-initiated activities are markedly reduced, while TCR-triggered proliferation is unaffected. Several CD2 pathway components regulated by p59(fyn) have been identified including phospholipase C-gamma1 (PLC-gamma1), Vav, protein kinase C-theta isoform (PKC-theta), docking protein (Dok), focal adhesion kinase (FAK) and Pyk2. Decreased inducible PKC-theta catalytic activity and Vav phosphorylation likely account for diminished p38 and JNK activation in hCD2tg fyn(-/-) mice. Moreover, deficiency in fyn-dependent PLC-gamma1 catalytic activity may contribute to reduced PKC-alpha -dependent ERK activation. Of note, CD2-dependent Dok but not linker from activated T cells (LAT) tyrosine phosphorylation requires p59(fyn). Furthermore, that FAK and Pyk2 are target substrates implies that p59(fyn) may be an important regulator of T cell adhesion as well. Collectively, these data identify p59(fyn) as a key PTK in CD2-mediated activation of mature T lymphocytes. C1 Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. NR 52 TC 27 Z9 28 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2000 VL 30 IS 12 BP 3507 EP 3515 DI 10.1002/1521-4141(2000012)30:12<3507::AID-IMMU3507>3.0.CO;2-O PG 9 WC Immunology SC Immunology GA 384YU UT WOS:000165975500020 PM 11093170 ER PT J AU Wang, T Aoki, T Iwata, K Takata, T Uchida, T Knauper, V Llano, E Okada, Y Bartlett, JD AF Wang, T Aoki, T Iwata, K Takata, T Uchida, T Knauper, V Llano, E Okada, Y Bartlett, JD TI One-step sandwich enzyme immunoassay using monoclonal antibodies for detection of human enamelysin (MMP-20) SO EUROPEAN JOURNAL OF ORAL SCIENCES LA English DT Article DE sandwich enzyme immunoassay; enamelysin; MMP-20; monoclonal antibody ID MATRIX METALLOPROTEINASE-7 MATRILYSIN; TISSUE INHIBITOR; IV COLLAGENASE; PURIFICATION; TOOTH; CELLS; LOCALIZATION; EXPRESSION; ACTIVATION; FRAGMENTS AB A one-step sandwich enzyme immunoassay (EIA) system for human matrix metalloproteinase 20 (MMP-20, enamelysin) was established by use of a solid-phase monoclonal antibody and a separate peroxidase-labeled monoclonal antibody. The EIA system was shown to be sensitive and quantitative for the detection of MMP-20. As little as 1.0 ng/ml (50 pg/assay) of MMP-20 protein could be reliably detected. The EIA system was linear over a range of 2.5-160 ng/ml (125-8,000 pg/assay), and the EIA system was versatile in that it was capable of detecting with equal sensitivity proMMP-20, active MMP-20, and MMP-20 with COOH-terminal deletions. The EIA system was validated by the successful detection of MMP-20 in the culture medium of Chinese hamster ovary cells (CHO-K1) that were transfected with an MMP-20 expression vector. No MMP-20 was detected in normal human serum, normal saliva, or in selected tumors. However, when recombinant human MMP-20 was added to human saliva, the EIA system did detect quantifiable amounts of the MMP-20, indicating that the system will work within the framework of complex in biological fluids. C1 Fuji Chem Ind Ltd, Dept Biopharmaceut, Toyama 9338511, Japan. Hiroshima Univ, Sch Dent, Dept Oral Pathol, Hiroshima, Japan. Hiroshima Univ, Sch Dent, Dept Oral Anat, Hiroshima, Japan. Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. Univ Oviedo, Fac Med, Dept Bioquim Biol Mol, Oviedo, Spain. Keio Univ, Sch Med, Dept Pathol, Tokyo 160, Japan. Forsyth Inst, Dept Biomineralizat, Boston, MA USA. Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA USA. RP Iwata, K (reprint author), Fuji Chem Ind Ltd, Dept Biopharmaceut, 530 Chokeiji, Toyama 9338511, Japan. RI Okada, Yasunori/B-5550-2014; OI Okada, Yasunori/0000-0001-9208-4755; Knauper, Vera/0000-0002-3965-9924 FU NIDCR NIH HHS [R29 DE012098] NR 31 TC 5 Z9 5 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0909-8836 J9 EUR J ORAL SCI JI Eur. J. Oral Sci. PD DEC PY 2000 VL 108 IS 6 BP 530 EP 537 DI 10.1034/j.1600-0722.2000.00922.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 384HU UT WOS:000165937400008 PM 11153928 ER PT J AU Bertram, L Blacker, D Crystal, A Mullin, K Keeney, D Jones, J Basu, S Yhu, S Guenette, S McInnis, M Go, R Tanzi, R AF Bertram, L Blacker, D Crystal, A Mullin, K Keeney, D Jones, J Basu, S Yhu, S Guenette, S McInnis, M Go, R Tanzi, R TI Candidate genes showing no evidence for association or linkage with Alzheimer's disease using family-based methodologies SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT 5th International Symposium on the Neurobiology and Neuroendocrinology of Aging CY JUL 23-28, 2000 CL BREGENZ, AUSTRIA DE Alzheimer genetics; linkage studies; family-based association tests; candidate genes ID RECEPTOR-RELATED PROTEIN; BUTYRYLCHOLINESTERASE-K-VARIANT; APOLIPOPROTEIN-E RECEPTOR; CATHEPSIN-D; LRP GENE; ONSET; POLYMORPHISM; SITES; FE65; AGE AB Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date, a large number of candidate genes have been associated with the disease, however none of these findings has been consistently replicated in independent datasets. In this study we report the results of family-based analyses for polymorphisms of five such candidates on chromosomes 2 (interleukin-1 beta, IL-1B), 3 (butyrylcholinesterase, BCHE), 11 (cathepsin D, CTSD; Fe65, APBB1) and 12 (lipoprotein receptor-related protein-1, LRP1) that were all suggested to be associated with AD in recent case-control studies. To minimize the possibility of spurious findings due to population admixture, we used a family-based design applying the sibship disequilibrium test (SDT) as well as two-point parametric linkage analyses on families from the National Institute of Mental Health (NIMH) Genetics initiative. Contrary to the initial reports, none of the polymorphisms that were analyzed showed evidence for association or linkage with AD in our families. Our results suggest that the previously reported associations from case-control studies are either (a) false positive results, e.g. due to type I error or population admixture, (b) smaller than initially proposed, or (c) due to linkage disequilibrium with an as yet unidentified polymorphism nearby. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Charlestown, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA USA. Johns Hopkins Univ, Inst Med, Dept Psychiat, Baltimore, MD USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. RP Tanzi, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, Charlestown, MA 02129 USA. RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X NR 37 TC 46 Z9 48 U1 0 U2 0 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 DEC PY 2000 VL 35 IS 9-10 SI SI BP 1353 EP 1361 DI 10.1016/S0531-5565(00)00193-5 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 384XQ UT WOS:000165972900019 PM 11113613 ER PT J AU Robinson, SN Freedman, AS Neuberg, DS Nadler, M Mauch, PM AF Robinson, SN Freedman, AS Neuberg, DS Nadler, M Mauch, PM TI Loss of marrow reserve from dose-intensified chemotherapy results in impaired hematopoietic reconstitution after autologous transplantation: CD34(+), CD34(+)38(-), and week-6 CAFC assays predict poor engraftment SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE hematopoiesis; marrow reserve capacity; impaired hematopoiesis; autologous bone marrow transplantation; hematopoietic stem cells ID STEM-CELL TRANSPLANTATION; LONG-TERM CULTURE; BONE-MARROW; LIMITING-DILUTION; PROLIFERATIVE CAPACITY; PROGENITOR CELLS; CYTOTOXIC AGENTS; IN-VIVO; THERAPY; BLOOD AB Objective. Autologous hematopoietic stem cell transplantation (HSCT) is an increasingly successful modality for treating a variety of malignant disorders in the clinic. Experimental and clinical data suggest that prior exposure to cytotoxic agents that damage primitive stem cells results in impaired hematopoiesis after autologous HSCT. To further investigate the ability to predict for impaired hematopoiesis, we measured different stent/progenitor cell populations transplanted and time to engraftment. Methods. Patients with previously untreated, advanced-stage follicular lymphoma were treated in sequential prospective protocols with 6-8 cycles of standard-dose (SD) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or four cycles of a higher-dose (HD) CHOP and granulocyte colony-stimulating factor, to induce remission prior to high-dose cyclophosphamide, total body irradiation, and autologous bone marrow transplantation (ABMT). Cryopreserved marrow samples obtained prior to ABMT were assayed for CD34(+), CD34(+)38(-), and cobblestone area-forming cell (CAFC) frequencies. Results. Despite receiving similar numbers of nucleated cells at ABMT, HD-CHOP patients took significantly longer to attain platelet engraftment than the SD-CHOP patients. Marrow from the HD-CHOP patients contained significantly lower CD34(+), CD34(+)38(-), and week 6-8 CAFC frequencies than marrow from SD-CHOP-treated patients. Time to platelet engraftment was plotted against progenitor/stem cell numbers transplanted for each patient and threshold values were developed for all three stem/progenitor cell populations. These values were 0.5 X 10(6) CD34(+) cells/kg, 0.14 x 10(6) CD34(+)38(-) cells/kg, and 9500 week-6 CAFC/kg transplanted. Approximately 50% of patients received marrow progenitor/stem cell numbers above the threshold values and all engrafted without delay. However, transplantation of stem/progenitor cell numbers below threshold values did not uniformly predict for delayed platelet engraftment. Conclusions. These data provide further evidence for the association of low marrow reserve at ABMT, low numbers of stem/progenitor cells transplanted, and delayed hematopoietic recovery. However, there remains a group of patients who have rapid platelet engraftment after ABMT despite low numbers of progenitor/stem cells transplanted. These data suggest the presence of a crucial stem cell population not represented by the stem/progenitor cell populations studied in these experiments. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 Harvard Univ, Sch Med, Dept Radiat Oncol, Joint Ctr Radiat Therapy, Boston, MA USA. Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Biostat, Boston, MA 02115 USA. RP Mauch, PM (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1 K2, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA 10941-26]; NHLBI NIH HHS [P50 HL 54785-01] NR 49 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD DEC PY 2000 VL 28 IS 12 BP 1325 EP 1333 DI 10.1016/S0301-472X(00)00547-6 PG 9 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 385XB UT WOS:000166029500006 PM 11146154 ER PT J AU Gazda, H Lipton, JM Willig, TN Ball, S Niemeyer, CM Tchernia, G Mohandas, N Daly, MJ Ploszynska, A Vlachos, A Glader, BE Orfali, KA Rokicka-Milewska, R Ohara, A Pospisilova, D Baker, B Webber, A Viskochil, DH Nathan, DG Beggs, AH Sieff, CA AF Gazda, H Lipton, JM Willig, TN Ball, S Niemeyer, CM Tchernia, G Mohandas, N Daly, MJ Ploszynska, A Vlachos, A Glader, BE Orfali, KA Rokicka-Milewska, R Ohara, A Pospisilova, D Baker, B Webber, A Viskochil, DH Nathan, DG Beggs, AH Sieff, CA TI Evidence for a second Diamond-Blackfan anemia gene on human chromosome 8p23-22, and for at least one other DBA gene SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Div Pediat Hematol & Oncol, Boston, MA 02115 USA. Childrens Hosp, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 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 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD DEC PY 2000 VL 28 IS 12 MA 906 BP 1493 EP 1493 DI 10.1016/S0301-472X(00)00565-8 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 385XB UT WOS:000166029500031 ER PT J AU Abreu, MT Palladino, AA Arnold, ET Kwon, RS McRoberts, JA AF Abreu, MT Palladino, AA Arnold, ET Kwon, RS McRoberts, JA TI Modulation of barrier function during fas-mediated apoptosis in human intestinal epithelial cells SO GASTROENTEROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; CD95 (APO-1/FAS)-MEDIATED APOPTOSIS; TRANSFORMED MODEL EPITHELIUM; INFLAMMATORY BOWEL-DISEASE; VERSUS-HOST DISEASE; CROHNS-DISEASE; TNF-ALPHA; IFN-GAMMA; PERMEABILITY; DEATH AB Background & Aims: Intestinal epithelial cell apoptosis occurs continually without apparent permeability defects and is increased in response to intestinal inflammation. We hypothesized that increased, immune-mediated apoptosis during inflammation might result in barrier dysfunction of the epithelium. Methods: T84 cells were cultured as a polarized monolayer and exposed to agonist antibody to Fas. Barrier function was assessed by transepithelial resistance and permeability measurements. Immunofluorescent staining was used to examine junctional protein expression. Results: Fas expression is predominantly basolateral in polarized T84 monolayers. Basolateral cross-linking of the Fas receptor resulted in T84 cell apoptosis and a loss of 50% of the cells within 24 hours. Apoptosis was coincident with a decrease in transepithelial electrical resistance and increased flux of small but not large molecules. Preservation of barrier function was associated with dramatic rearrangement of tight junctions and desmosomal junctions in apoptotic monolayers. E-cadherin-mediated cell contact was maintained between intact cells in the monolayer, thus sealing gaps created by apoptotic cells. Apoptosis and barrier dysfunction could be prevented by caspase inhibition. Conclusions: Immune-mediated apoptosis of intestinal epithelial cells may contribute to the permeability defects associated with inflammatory conditions of the bower, but the intestinal epithelium is remarkably resilient in the face of apoptosis. C1 Cedars Sinai Med Ctr, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Burns & Allen Res Inst, Los Angeles, CA 90048 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Abreu, MT (reprint author), Cedars Sinai Med Ctr, Ctr Inflammatory Bowel Dis, 8631 West 3rd St,Suite 245E, Los Angeles, CA 90048 USA. FU NIDDK NIH HHS [DK41301, K08 DK02635-02] NR 52 TC 106 Z9 110 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2000 VL 119 IS 6 BP 1524 EP 1536 DI 10.1053/gast.2000.20232 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 382QM UT WOS:000165833800016 PM 11113074 ER PT J AU Maillot, C Million, M Wei, JY Gauthier, A Tache, Y AF Maillot, C Million, M Wei, JY Gauthier, A Tache, Y TI Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats SO GASTROENTEROLOGY LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; CENTRAL-NERVOUS-SYSTEM; FACTOR CRF ANTAGONIST; SMOOTH-MUSCLE CELLS; GUINEA-PIG; PARAVENTRICULAR NUCLEUS; SMALL-INTESTINE; FASTED RATS; HORMONE; UROCORTIN AB Background & Aims: Corticotropin-releasing factor (CRF) exerts its action through CRF receptors 1 and 2 (CRF-R1 and CRF-R2). CRF has preferential affinity for CRF-R1, whereas urocortin displays high affinity for both. We investigated changes in colonic motor function after intraperitoneal (IP) injection of CRF-related peptides. Methods: Colonic motility was recorded in vivo in conscious vats equipped with electrodes chronically implanted in the cecum and proximal colon or in vitro in distal colon; fecal output was monitored in naive rats. Results: Rat CRF, rat urocortin, and amphibian sauvagine (10 mug/kg, IP) induced a new pattern of cecocolonic myoelectric activity characterized by clustered spike bursts of long duration; the percentage of occurrence was highest after CRF. The rank order of potency tb increase fecal pellet output after IP peptide injection (0.3-10 mug/kg, IF) was CRF > urocortin = sauvagine. The CRF-R1/R2 antagonist astressin (33 mug/kg, IF) and the CRF-R1 antagonist CP-154,526 (20 mg/kg, subcutaneously) inhibited IP CRF-induced changes in cecocolonic myoelectric activity and IP CRF and water avoidance stress-induced fecal output. In vitro, CRF injected into the inferior mesenteric artery increased distal colonic myoelectric activity compared with saline injection. Conclusions: These results demonstrate that CRF acts peripherally to stimulate colonic motility and that CRF-RI is primarily involved in mediating IP CRF/urocortin- and water avoidance stress-induced colonic motor response. C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr,Dept Med,Sch Med, Los Angeles, CA 90073 USA. RP Maillot, C (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr,Dept Med,Sch Med, Bldg 115,Room 124,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-41301, DK-57238, DK-33061] NR 46 TC 140 Z9 141 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2000 VL 119 IS 6 BP 1569 EP 1579 DI 10.1053/gast.2000.20251 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 382QM UT WOS:000165833800020 PM 11113078 ER PT J AU Sang, Q Goyal, RK AF Sang, Q Goyal, RK TI Lower esophageal sphincter relaxation and activation of medullary neurons by subdiaphragmatic vagal stimulation in the mouse SO GASTROENTEROLOGY LA English DT Article ID UPPER ALIMENTARY-TRACT; DORSAL MOTOR NUCLEUS; SOLITARY TRACT; VISCEROTOPIC REPRESENTATION; VAGUS NERVE; RAT; PROJECTIONS; AMBIGUUS; MOTILITY; BRANCHES AB Background & Aims: isolated lower esophageal sphincter (LES) relaxation associated with belching and vomiting and the transient IES relaxation associated with gastroesophageal reflux are gastric afferent-mediated vagovagal reflexes. We aimed to identify the brain stem vagal subnuclei involved in these reflexes. Methods: In anesthetized mice, LES pressures were recorded using a manometric technique and response to electrical stimulation of the ventral trunk of subdiaphragmatic vagus was investigated. Anatomy of the vagal subnuclei was defined, and activated subnuclei with ventral subdiaphragmatic vagus stimulation were detected by c-fos immunohistochemical staining Results: Ventral subdiaphragmatic vagal stimulation elicited frequency-dependent LES relaxation without evoking esophageal contractions and induced c-fos expression in interneurons in medial, dorsomedial, and commissural subnuclei along with outer shell of area postrema and motoneurons in the caudal dorsal motor nucleus of vagus. Brain stem subnuclei including interstitial, intermediate, and central subnuclei, and nucleus ambiguus, which have been reported to be involved in the response to swallowing, were not activated. Conclusions: Stimulation of the ventral subdiaphragmatic vagus causes isolated LES relaxation and activates neurons in select vagal subnuclei that may represent the brain stem circuit involved in the abdominal vagal-afferent-evoked isolated LES relaxation. These observations suggest that different brain stem circuits are involved in swallow-induced and gastric afferent-mediated isolated LES relaxations. C1 Dept Vet Affairs Med Ctr, Ctr Swallowing & Motil Disorders, W Roxbury, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sang, Q (reprint author), VA Boston Healthcare Syst, Res & Dev 151, 1400 VFW Pkwy, Boston, MA 02132 USA. FU NIDDK NIH HHS [DK 31092] NR 35 TC 20 Z9 20 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2000 VL 119 IS 6 BP 1600 EP 1609 DI 10.1053/gast.2000.20234 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 382QM UT WOS:000165833800023 PM 11113081 ER PT J AU Brugge, WR AF Brugge, WR TI The role of EUS in the diagnosis of cystic lesions of the pancreas SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID MUCIN-PRODUCING TUMOR; DIFFERENTIAL-DIAGNOSIS; NEEDLE ASPIRATION; FLUID ANALYSIS; ACCURACY; ULTRASOUND; NEOPLASMS; ANTIGEN; BIOPSY; CT C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Brugge, WR (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Blake 452C, Boston, MA 02114 USA. NR 20 TC 42 Z9 46 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD DEC PY 2000 VL 52 IS 6 SU S BP S18 EP S22 DI 10.1067/mge.2000.110720 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 384MY UT WOS:000165950100005 PM 11115943 ER PT J AU Tibbetts, RS Cortez, D Brumbaugh, KM Scully, R Livingston, D Elledge, SJ Abraham, RT AF Tibbetts, RS Cortez, D Brumbaugh, KM Scully, R Livingston, D Elledge, SJ Abraham, RT TI Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress SO GENES & DEVELOPMENT LA English DT Article DE BRCA1; ATR; checkpoint; DNA damage; phosphorylation; replication ID CELL-CYCLE CHECKPOINT; DNA-DAMAGE RESPONSE; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; TRANSCRIPTIONAL ACTIVATION; DEPENDENT PHOSPHORYLATION; OVARIAN-CANCER; PROTEIN-KINASE; MEIOTIC CELLS; FHA DOMAIN AB The BRCA1 gene encodes a tumor suppressor that is mutated in 50% of familial breast cancers. The BRCA1 protein has been implicated in the DNA damage response, as DNA damage induces the phosphorylation of BRCA1 and causes its recruitment into nuclear foci that contain DNA repair proteins. The ataxia-telangiectasia-mutated (ATM) gene product controls overall BRCA1 phosphorylation in response to gamma -irradiation (IR). In this study, we show that BRCA1 phosphorylation is only partially ATM dependent in response to IR and ATM independent in response to treatment with UV light, or the DNA replication inhibitors hydroxyurea (HU) and aphidicolin (APH). We provide evidence that the kinase responsible for this phosphorylation is the ATM-related kinase, ATR. ATR phosphorylates BRCA1 on six Ser/Thr residues, including Ser 1423, in vitro. Increased expression of ATR enhanced the phosphorylation of BRCA1 on Ser 1423 following cellular exposure to HU dr UV light, whereas doxycycline-induced expression of a kinase-inactive ATR mutant protein inhibited HU- or UV light-induced Ser 1423 phosphorylation in GM847 fibroblasts, and partially suppressed the phosphorylation of this site in response to IR. Thus, ATR, like ATM, controls BRCA1 phosphorylation in vivo. Although ATR isolated from DNA-damaged cells does not show enhanced kinase activity in vitro, we found that ATR responds to DNA damage and replication blocks by forming distinct nuclear foci at the sites of stalled replication forks. Furthermore, ATR nuclear foci overlap with the nuclear foci formed by BRCA1. The dramatic relocalization of ATR in response to DNA damage points to a possible mechanism for its ability to enhance the phosphorylation of substrates in response to DNA damage. Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic. stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. C1 Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Abraham, RT (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. RI Scully, Ralph/F-5008-2013 FU NCI NIH HHS [CA52995, CA76193, F32 CA083319, K01 CA079576, R01 CA076193, U01 CA052995, U19 CA052995]; NIGMS NIH HHS [R37 GM044664, GM44664, R01 GM044664] NR 66 TC 349 Z9 357 U1 4 U2 16 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 DEC 1 PY 2000 VL 14 IS 23 BP 2989 EP 3002 DI 10.1101/gad.851000 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 381XD UT WOS:000165788600007 PM 11114888 ER PT J AU Scott, L Rogus, JJ AF Scott, L Rogus, JJ TI Using unaffected child trios to test for transmission distortion SO GENETIC EPIDEMIOLOGY LA English DT Article DE TDT; association testing; prevalent diseases; gene-environment interaction ID DEPENDENT DIABETES-MELLITUS; CASE-PARENTS DESIGN; TRANSMISSION/DISEQUILIBRIUM TEST; RELATIVE-RISKS; PIMA-INDIANS; DISEQUILIBRIUM; ASSOCIATION; NEPHROPATHY; DISEASE; TRAITS AB The transmission disequilibrium test (TDT), an alternative to case-control analysis that is not influenced by population stratification, focuses on affected child trios (ACTs) comprising affected cases and their parents. Unaffected child trios (UCTs) have also been proposed but mainly to rule out segregation distortion. To explore situations when UCTs are preferable to detect transmission distortion, we compared the number of UCTs and ACTs needed to achieve 80% power for a wide variety of scenarios. For a given genetic model, UCT sample size declined rapidly with increasing disease prevalence, whereas ACT sample size remained constant. Furthermore, at some prevalence value (40-60% depending on model parameters), detection of transmission distortion could be accomplished with fewer UCTs than ACTs. Such high prevalence may be found in special populations (diabetes among Pima Indians), secondary conditions (renal/retinal complications in diabetes), and pharmacogenetics (responders to treatment). Also, because exposure to an additional risk factor can increase the disease prevalence in an exposed sub-group, we explored how sample size requirements vary by exposure status. Whereas power differences between exposed and unexposed ACTs could be explained solely by genetic risk ratios, sub-group-specific disease prevalence also played an important role in UCTs. Finally, we considered the impact of including 5, 10, 20, or 30% misclassified ACTs in the UCT sample and found that a 24, 58, 180, or 550% larger sample would be required. In conclusion, UCTs can detect transmission distortion more effectively than ACTs when disease prevalence reaches 40-60%, although some efficiency may be lost owing to misclassification. Moreover, focusing on particular sub-groups defined by exposure status can potentially increase power, but such gains depend heavily on the nature of the gene-exposure interaction. (C) 2000 Wiley-Liss. Inc. C1 Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Rogus, JJ (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. FU FDA HHS [T32BK-72-21/22]; NIDDK NIH HHS [DK-53534] NR 27 TC 6 Z9 6 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2000 VL 19 IS 4 BP 381 EP 394 DI 10.1002/1098-2272(200012)19:4<381::AID-GEPI9>3.0.CO;2-B PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 376HP UT WOS:000165452400009 PM 11108647 ER PT J AU Ton, C Hwang, DM Dempsey, AA Tang, HC Yoon, J Lim, M Mably, JD Fishman, MC Liew, CC AF Ton, C Hwang, DM Dempsey, AA Tang, HC Yoon, J Lim, M Mably, JD Fishman, MC Liew, CC TI Identification, characterization, and mapping of expressed sequence tags from an embryonic zebrafish heart cDNA library SO GENOME RESEARCH LA English DT Article ID GENETIC-LINKAGE MAP; RADIATION HYBRID MAP; CARDIOVASCULAR-SYSTEM; DANIO-RERIO; GENOME; EVOLUTION; SEARCH; RODENT; MOUSE AB The generation of expressed sequence tags (ESTs) has proven to be a rapid and economical approach by which to identify and characterize expressed genes. We generated 5102 ESTs from a 3-d-old embryonic zebrafish heart cDNA library. Of these, 57.6% matched to known genes, 14.2% matched only to other ESTs, and 27.8% showed no match to any ESTs or known genes. Clustering of all ESTs identified 359 unique clusters comprising 1771 ESTs, whereas the remaining 3331 ESTs did not cluster. This estimates the number of unique genes identified in the data set to be approximately 3690. A total of 1242 unique known genes were used to analyze the gene expression patterns in the zebrafish embryonic heart. These were categorized into seven categories on the basis of gene function. The largest class of genes represented those involved in gene/protein expression (25.9% of known transcripts). This class was followed by genes involved in metabolism (18.7%), cell structure/motility (16.4%), cell signaling and communication (9.6%), cell/organism defense (7.1%) and cell division (4.4%). Unclassified genes constituted the remaining 17.91%. Radiation hybrid mapping was performed for 102 ESTs and comparison of map positions between zebrafish and human identified new synteny groups. Continued comparative analysis will be useful in defining the boundaries of conserved chromosome segments between zebrafish and humans, which will facilitate the transfer of genetic information between the two organisms and improve our understanding of vertebrate evolution. C1 Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1L5, Canada. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Gen Unit, Boston, MA 02115 USA. RP Liew, CC (reprint author), Univ Toronto, Dept Lab Med & Pathobiol, 100 Coll St, Toronto, ON M5G 1L5, Canada. NR 42 TC 27 Z9 28 U1 2 U2 6 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 2000 VL 10 IS 12 BP 1915 EP 1927 DI 10.1101/gr.10.12.1915 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 382QN UT WOS:000165833900009 PM 11116087 ER PT J AU Champliaud, MF Baden, HP Koch, M Jin, W Burgeson, RE Viel, A AF Champliaud, MF Baden, HP Koch, M Jin, W Burgeson, RE Viel, A TI Gene characterization of sciellin (SCEL) and protein localization in vertebrate epithelia displaying barrier properties SO GENOMICS LA English DT Article ID CORNIFIED ENVELOPE; EXPRESSION; EVOLUTION AB Sciellin is a precursor of the cornified envelope of mammalian stratified epithelia characterized by a central core of nonidentical repeats. We characterized the genomic structure of human sciellin and showed that each homologous repeat was encoded by one exon. We also characterized mouse sciellin and showed that mouse sciellin and human sciellin (HGMW-approved symbol SCEL) share a similar gene organization and protein expression pattern. This one exon/one repeat organization is unique among other cornified envelope precursors characterized by homologous repeats. me identified an alternatively spliced isoform of human sciellin, absent in mouse, characterized by an additional repeat at the beginning of the core domain. During embryonic development, the accumulation of sciellin transcript and the accumulation of sciellin protein in the epidermis correlated with the activation of markers of terminal differentiation in epidermis. Mouse sciellin was also identified in simple epithelia with barrier properties, lending further support to its importance in epithelial function, (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Dermatol, Charlestown, MA 02129 USA. RP Viel, A (reprint author), Massachusetts Gen Hosp E, CBRC, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 11 TC 15 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD DEC 1 PY 2000 VL 70 IS 2 BP 264 EP 268 DI 10.1006/geno.2000.6390 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 383RM UT WOS:000165896600013 PM 11112355 ER PT J AU Goyal, RK AF Goyal, RK TI Targets of enteric motor neurones: smooth muscle cells SO GUT LA English DT Article ID NITRIC-OXIDE SYNTHASE; RELEASE; MICE C1 VA Med Ctr, VA Boston Hlth Care Syst, ACOS Res & Dev, W Roxbury, MA 02132 USA. RP Goyal, RK (reprint author), VA Med Ctr, VA Boston Hlth Care Syst, ACOS Res & Dev, 1400 VFW Pkwy,, W Roxbury, MA 02132 USA. NR 13 TC 6 Z9 6 U1 2 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD DEC PY 2000 VL 47 SU 4 BP 38 EP 39 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 380EX UT WOS:000165687600019 ER PT J AU del Carmen, MG McIntyre, JF Fuller, AF Nikrui, N Goodman, A AF del Carmen, MG McIntyre, JF Fuller, AF Nikrui, N Goodman, A TI Intraoperative radiation therapy in the treatment of pelvic gynecologic malignancies: A review of fifteen cases SO GYNECOLOGIC ONCOLOGY LA English DT Article DE intraoperative radiation therapy; advanced primary gynecologic malignancies; recurrent gynecologic malignancies; gross residual disease; gross total resection; pelvic recurrence; distant metastasis ID ADVANCED CERVICAL-CANCER; RADIOTHERAPY; EXENTERATION; EXPERIENCE; CISPLATIN AB Objective. The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic pelvic malignancies at the Massachusetts General Hospital. Methods. From July 3, 1996, through July 28, 1999, 15 patients were treated with IORT for gynecologic malignancies in a dedicated IORT operating room suite at the Massachusetts General Hospital. Hospital medical records, radiation oncology records, and office charts were reviewed on all patients treated with IORT. IORT was given in the presence of positive surgical margins and where the doses needed for adjuvant postoperative external beam radiotherapy (EBRT) would exceed those tolerated by normal structures. One patient presented with primary disease and 14 with local or regional recurrence. Follow-up time ranged from 3 to 36 months. Results. Treatment in conjunction with IORT included surgery only (7 patients); preoperative EBRT, preoperative brachytherapy, and surgery (1 patient); preoperative chemotherapy and surgery (2 patients); and surgery and postoperative chemotherapy (5 patients). IORT doses ranged from 10 to 22.5 Gy. At the completion of this review, 4 patients (26.6%) have died, 6 (40%) are alive and free of disease, and 5 (33%) are alive with disease persistence or relapse. Of the 10 patients with gross total resection, 5 are alive and free of disease. Of the 5 women with gross residual disease at the time of IORT, only 1 is alive and free of disease. Conclusions. The volume of residual disease prior to IORT may be an important prognostic indicator for disease relapse. Both local recurrence and distant metastasis were more common among patients with gross residual disease at the time of IORT. Our institutional experience with IORT further supports the importance of optimal surgical resection. (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Vincent Gynecol Oncol Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Vincent Gynecol Oncol Serv, Boston, MA 02114 USA. NR 13 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2000 VL 79 IS 3 BP 457 EP 462 DI 10.1006/gyno.2000.6002 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 383ZC UT WOS:000165913700018 PM 11104619 ER PT J AU Rettew, DC AF Rettew, DC TI Avoidant personality disorder, generalized social phobia, and shyness: Putting the personality back into personality disorders SO HARVARD REVIEW OF PSYCHIATRY LA English DT Review ID NATIONAL-COMORBIDITY-SURVEY; BEHAVIORAL-INHIBITION; PANIC DISORDER; CHILDHOOD SHYNESS; ANXIETY DISORDER; AXIS-II; SUBTYPES; CHILDREN; PSYCHOPATHOLOGY; CLASSIFICATION AB With increasing recognition of social phobia as a common and often debilitating disorder, interest is developing in its boundaries with other disorders such as avoidant personality disorder and temperamental constructs such as shyness. Such interest reflects the more general debate concerning Axis I disorders, personality disorders, and what is considered normal personality variance. This review summarizes the available literature comparing avoidant personality disorder (APD), generalized social phobia (GSP), and shyness. In studies comparing APD and GSP, comorbidity rates have varied from approximately 25% to numbers high enough that the ability to diagnose one disorder without the other was questioned. Comparisons of the characteristics of APD and GSP have yielded few qualitative differences, although some studies have shown evidence that APD may represent a more severe form of GSP with respect to levels of symptoms, fear of negative evaluation, anxiety, avoidance, and depression. Personality dimensions including, but not limited to, shyness have been found to be strongly associated with GSP and APD, and there is some evidence that persons who suffer from social anxiety also suffer from fears and avoidance across nonsocial domains. In conclusion, although there is evidence that shyness, GSP, and APD exist along a continuum, the factors that constitute this continuum may need to be revised. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. McLean Hosp, Belmont, MA 02178 USA. RP Rettew, DC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, WACC 725,15 Parkman St, Boston, MA 02114 USA. NR 86 TC 42 Z9 44 U1 7 U2 24 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1067-3229 J9 HARVARD REV PSYCHIAT JI Harv. Rev. Psychiatr. PD DEC PY 2000 VL 8 IS 6 BP 283 EP 297 DI 10.1093/hrp/8.6.283 PG 15 WC Psychiatry SC Psychiatry GA 388XN UT WOS:000166208500002 PM 11133823 ER PT J AU Voss, SE Rosowski, JJ Merchant, SN Peake, WT AF Voss, SE Rosowski, JJ Merchant, SN Peake, WT TI Acoustic responses of the human middle ear SO HEARING RESEARCH LA English DT Article DE middle-ear mechanics; middle-ear model; temporal-bone measurements ID HUMAN TEMPORAL BONES; INPUT IMPEDANCE; RECONSTRUCTED EARS; MEASURING SYSTEM; UMBO VIBRATION; MECHANICS; CAT; STAPES AB Measurements on human cadaver ears are reported that describe sound transmission through the middle ear. Four response variables were measured with acoustic stimulation at the tympanic membrane: stapes velocity, middle-ear cavity sound pressure, acoustic impedance at the tympanic membrane and acoustic impedance of the middle-ear cavity. Measurements of stapes velocity at different locations on the stapes suggest that stapes motion is predominantly 'piston-like', for frequencies up to at least 2000 Hz. The measurements are generally consistent with constraints of existing models. The measurements are used (1) to show how the cavity pressure and the impedance at the tympanic membrane are related, (2) to develop a measurement-based middle-ear cavity model, which shows that the middle-ear cavity has only small effects on the motion of the tympanic membrane and stapes in the normal earl although it may play a more prominent role in pathological ears, and (3) to show that inter-ear variations in the impedance at the tympanic membrane and the stapes velocity are not well correlated. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA 02139 USA. MIT, Elect Res Lab, Cambridge, MA 02139 USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Cambridge, MA 02139 USA. MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Voss, SE (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. NR 50 TC 124 Z9 127 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD DEC PY 2000 VL 150 IS 1-2 BP 43 EP 69 DI 10.1016/S0378-5955(00)00177-5 PG 27 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 374WM UT WOS:000165367400004 PM 11077192 ER PT J AU Thiers, FA Burgess, BJ Nadol, JB AF Thiers, FA Burgess, BJ Nadol, JB TI Prevalence and ultrastructural morphology of axosomatic synapses on spiral ganglion cells in humans of different ages SO HEARING RESEARCH LA English DT Article DE spiral ganglion; synapse; efferent; maturation; degeneration ID OUTER HAIR-CELLS; ELECTRON-MICROSCOPIC OBSERVATIONS; ANTEROVENTRAL COCHLEAR NUCLEUS; MEDIAL OLIVOCOCHLEAR SYSTEM; CAT; NERVE; INNERVATION; MATURATION; NEURONS; DEGENERATION AB Axosomatic synapses were found on human spiral ganglion cells (HSGCs). Ultrastructural characterization and calculation of the prevalence of these synapses were performed by electron microscopic semi-serial sections of both type I and type II HSGCs, in specimens from subjects of ages 1 day, 14 days, 21 years and 51 years. Synapses on type I HSGCs were extremely rare. In contrast, axosomatic synapses were present on approximately 50% of type II HSGCs of a young adult. This prevalence seemed to vary by age. Thus, no synapses were found in a I-day old neonate, few in a 14-day old, and on approximately 15% of the type II SGCs from a 51-year old specimen. The origin of the nerve fibers synapsing on the type II HSGCs could not be determined. In view of the fact that some of the fibers projected from the intraganglionic spiral bundle, which is known to contain olivocochlear efferents, these fibers may represent an efferent pathway to the spiral ganglion. However, since there was morphological evidence of more than one type of nerve fiber synapsing on type II HSGCs, other neural origins must be considered. Although the physiological function of these synapses is unknown, they may mediate pre-synaptic neural modulation of the type II HSGCs at the level of the spiral ganglion. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [R01DC00152-20] NR 40 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD DEC PY 2000 VL 150 IS 1-2 BP 119 EP 131 DI 10.1016/S0378-5955(00)00193-3 PG 13 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 374WM UT WOS:000165367400009 PM 11077197 ER PT J AU Ravicz, ME Merchant, SN Rosowski, JJ AF Ravicz, ME Merchant, SN Rosowski, JJ TI Effect of freezing and thawing on stapes-cochlear input impedance in human temporal bones SO HEARING RESEARCH LA English DT Article DE cochlear impedance; stapes impedance; middle-ear mechanics; freezing and thawing; temporal bone; human ID HUMAN MIDDLE-EAR AB The use of thawed frozen temporal bones offers advantages over fresh bones in the study of middle-ear and inner-ear mechanical function. We show, however, that freezing and thawing can cause a reduction in the magnitude of the input impedance of the stapes and cochlea Z(SC) in unfixed temporal bones from human cadavers of as much as a factor of 3-10 over the frequency range 25 Hz-7 kHz. Z(SC) is considered to be the sum of the impedances of the annular ligament Z(S) and the cochlea Z(C) and has been shown to be controlled by Z(S) below 1 kHz and by Z(C) at higher frequencies [Merchant et al., 1996. Hear. Res. 97; 30-45]. Experiments in which the inner ear was opened, drained, and refilled identified two mechanisms by which freezing and thawing can cause a reduction in the magnitude of Z(SC) (\Z(SC)\) Freezing can allow air to enter the inner ear, with the result that \Z(C)\ is reduced above about 1 kHz; and freezing can reduce \Z(S)\, which causes a reduction in \Z(SC)\ below 1 kHz. Changes in the phase angle of Z(SC) induced by freezing were small and were consistent with changes in \Z(SC)\. Removing air from the inner ear returned Z(C) to near its value in fresh bones, but \Z(SC)\ remained lower in some thawed bones by a factor of 2-3. Investigations of middle-ear function for which Z(SC) is critical should use fresh temporal bones only or should allow for the possible reduction in \Z(SC)\ in thawed frozen bones. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. MIT, Elect Res Lab, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA 02139 USA. RP Ravicz, ME (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [P01DC00119, P01 DC000119, R29DC003657] NR 14 TC 15 Z9 15 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD DEC PY 2000 VL 150 IS 1-2 BP 215 EP 224 DI 10.1016/S0378-5955(00)00200-8 PG 10 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 374WM UT WOS:000165367400017 PM 11077205 ER PT J AU Talavage, TM Ledden, PJ Benson, RR Rosen, BR Melcher, JR AF Talavage, TM Ledden, PJ Benson, RR Rosen, BR Melcher, JR TI Frequency-dependent responses exhibited by multiple regions in human auditory cortex SO HEARING RESEARCH LA English DT Article DE auditory cortex; functional magnetic resonance imaging; tonotopy; human ID TONOTOPIC ORGANIZATION; HUMAN-BRAIN; MAGNETIC-FIELDS; ARCHITECTONIC FIELDS; CORTICAL ACTIVATION; SENSORY STIMULATION; STIMULUS FREQUENCY; NEURONAL-ACTIVITY; MACAQUE MONKEYS; FUNCTIONAL MRI AB Recordings in experimental animals have detailed the tonotopic organization of auditory cortex, including the presence of multiple tonotopic maps. In contrast, relatively little is known about tonotopy within human auditory cortex, for which even the number and location of tonotopic maps remains unclear. The present study begins to develop a more complete picture of cortical tonotopic organization in humans using functional magnetic resonance imaging, a technique that enables the non-invasive localization of neural activity in the brain. Subjects were imaged while listening to lower- (below 660 Hz) and higher- (above 2490 Hz) frequency stimuli presented alternately and at moderate intensity. Multiple regions on the superior temporal lobe exhibited responses that depended upon stimulus spectral content. Eight of these 'frequency-dependent response regions' (FDRRs) were identified repeatedly across subjects. Four of the FDRRs exhibited a greater response to higher frequencies, and four exhibited a greater response to lower frequencies. Based upon the location of the eight FDRRs, a correspondence is proposed between FDRRs and anatomically defined cortical areas on the human superior temporal lobe. Our findings suggest that a larger number of tonotopically organized areas exist (i.e., four or more) in the human auditory cortex than was previously recognized. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA USA. Massachusetts Gen Hosp, Dept Radiol, MGH NMR Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Dept Otolaryngol, Boston, MA 02114 USA. RP Talavage, TM (reprint author), Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. FU NIDCD NIH HHS [T32DC00038-04, P01 DC000119-260023, P01DC00119] NR 89 TC 116 Z9 116 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD DEC PY 2000 VL 150 IS 1-2 BP 225 EP 244 DI 10.1016/S0378-5955(00)00203-3 PG 20 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 374WM UT WOS:000165367400018 PM 11077206 ER PT J AU Dong, ZZ Zuber, C Spiro, MJ Spiro, RG Roth, J AF Dong, ZZ Zuber, C Spiro, MJ Spiro, RG Roth, J TI Immunohistochemical evaluation of endomannosidase distribution in rat tissues: evidence for cell type-specific expression SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE endomannosidase; immunohistochemistry; endothelia; rat ID N-LINKED OLIGOSACCHARIDES; GOLGI APPARATUS LOCALIZATION; ENZYME GLUCOSIDASE-II; ALPHA-D-GALACTOSAMINE; ENDOPLASMIC-RETICULUM; GLYCOPROTEIN GLUCOSYLTRANSFERASE; SACCHAROMYCES-CEREVISIAE; SECRETORY PATHWAY; PROCESSING ENZYME; QUALITY-CONTROL AB Asparagine-linked oligosaccharides of glycoproteins are subject to a series of trimming reactions by glucosidases and mannosidases in the endoplasmic reticulum which result in the removal of all three glucose residues and several of the nine mannose residues. At present, endomannosidase represents the only processing enzyme which cleaves internally and provides an alternate deglucosylation pathway. However, in contrast to the endoplasmic reticulum residential proteins glucosidase I and II, endomannosidase is primarily situated in the Golgi apparatus of rat liver hepatocytes and hepatocyte cell lines. We have performed a confocal immunohistochemical study to investigate endomannosidase in various rat tissues and used a monoclonal antibody against Golgi mannosidase II as a marker for the Golgi apparatus. Although immunofluorescence for both endomannosidase and Golgi mannosidase II was detectable in the epithelia of many tissues, renal proximal tubular cells, cortex and medulla of adrenal gland, gastric mucosa, and Leydig cells of testis were unreactive for endomannosidase. Furthermore, the endothelia in all studied tissues were unreactive for endomannosidase but positive for Golgi mannosidase II. It is concluded that by immunohistochemistry endomannosidase exhibits a cell type-specific expression in rat tissues. C1 Univ Zurich, Dept Pathol, Div Cell & Mol Pathol, CH-8091 Zurich, Switzerland. Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. RP Roth, J (reprint author), Univ Zurich, Dept Pathol, Div Cell & Mol Pathol, CH-8091 Zurich, Switzerland. NR 55 TC 11 Z9 11 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD DEC PY 2000 VL 114 IS 6 BP 461 EP 467 PG 7 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 392NJ UT WOS:000166417300004 PM 11201607 ER PT J AU Brown, KG Kuo, TL Guo, HR Ryan, LM Abernathy, CO AF Brown, KG Kuo, TL Guo, HR Ryan, LM Abernathy, CO TI Sensitivity analysis of US EPA's estimates of skin cancer risk from inorganic arsenic in drinking water SO HUMAN AND ECOLOGICAL RISK ASSESSMENT LA English DT Article DE arsenic; skin cancer; drinking water; Taiwan ID DISTRICTS AB The current U.S. Environmental Protection Agency's (USEPA's) risk analysis on the Integrated Risk Information System (IRIS) for arsenic in drinking water is based on an epidemiological study of skill cancer in Taiwan. Assumptions used in the USEPA application of the multistage-Weibull model for risk estimation were varied to assess the effect on predicted risk of skin cancer to die U.S. population at arsenic concentrations of 1 to 50 mug/L in drinking water. Among the assumptions tested, die only notable change in risk estimates was a reduction when the arsenic concentration used as representative for Taiwan villages in the low range (<300 g/L) was increased to the 75th percentile (245 mug/L) in place of the mean used in the USEPA analysis (170 mug/L), but the representative value for Taiwan villages in the high range (greater than or equal to 600 mug/L) was not increased simultaneously to the 75th percentile. Additionally, a simulation study was conducted using records of arsenic measurements in wells from the same period and region of Taiwan as the original study. The exposure-response curve estimated from 60 villages (60 data points) differed only marginally from the outcome when data were summarized into four data points (as in the USEPA skin cancer analysis). Briefly discussed are differences between the study area of Taiwan and the U.S, in nutritional status and consumption of inorganic arsenic in food that might bias predicted U.S. skin cancer risks. C1 Kenneth G Brown Inc, Chapel Hill, NC 27516 USA. Natl Taiwan Univ, Coll Med, Taipei, Taiwan. Natl Cheng Kung Univ, Coll Med, Tainan 70101, Taiwan. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. US EPA, Washington, DC 20460 USA. RP Brown, KG (reprint author), POB 16608, Chapel Hill, NC 27516 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 NR 16 TC 4 Z9 4 U1 1 U2 3 PU CRC PRESS LLC PI BOCA RATON PA 2000 CORPORATE BLVD NW, JOURNALS CUSTOMER SERVICE, BOCA RATON, FL 33431 USA SN 1080-7039 J9 HUM ECOL RISK ASSESS JI Hum. Ecol. Risk Assess. PD DEC PY 2000 VL 6 IS 6 BP 1055 EP 1074 DI 10.1080/10807030091124284 PG 20 WC Biodiversity Conservation; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 392FF UT WOS:000166399800011 ER PT J AU Burock, MA Dale, AM AF Burock, MA Dale, AM TI Estimation and detection of event-related fMRI signals with temporally correlated noise: A statistically efficient and unbiased approach SO HUMAN BRAIN MAPPING LA English DT Article DE EEG; hemodynamic response; statistics; system identification; noise estimation; temporal autocorrelation ID FUNCTIONAL MRI; EXPERIMENTAL-DESIGN; HUMAN BRAIN; TRIALS; RATES AB Recent developments in analysis methods for event-related functional magnetic resonance imaging (fMRI) has enabled a wide range of novel experimental designs. As with selective averaging methods used in event-related potential (ERP) research, these methods allow for the estimation of the average time-locked response to particular event-types, even when these events occur in rapid succession and in an arbitrary sequence. Here we present a flexible framework for obtaining efficient and unbiased estimates of event-related hemodynamic responses, in the presence of realistic temporally correlated (nonwhite) noise. We further present statistical inference methods based upon the estimated responses, using restriction matrices to formulate temporal hypothesis tests about the shape of the evoked responses. The accuracy of the methods is assessed using synthetic noise, actual fMRI noise, and synthetic activation in actual noise; Actual false-positive rates were compared to nominal false-positive rates assuming white noise, as well as local and global noise estimates in the estimation procedure (assuming white noise resulted in inappropriate inference, while both global and local estimates corrected false-positive rates). Furthermore, both local and global noise estimates were found to increase the statistical power of the hypothesis tests, as measured by the receiver operating characteristics (ROC). This approach thus enables appropriate univariate statistical inference with improved statistical power, without requiring a priori assumptions about the shape or timing of the event-related hemodynamic response. Hum. Brain Mapping 11:249-260, 2000. (C) 2000 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Dale, AM (reprint author), Massachusetts Gen Hosp, NMR Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Dale, Anders/A-5180-2010 FU NCRR NIH HHS [P41-RR14075, R01-RR13609] NR 31 TC 182 Z9 184 U1 1 U2 3 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 DEC PY 2000 VL 11 IS 4 BP 249 EP 260 DI 10.1002/1097-0193(200012)11:4<249::AID-HBM20>3.0.CO;2-5 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 380DY UT WOS:000165684500002 PM 11144754 ER PT J AU Klopp, J Marinkovic, K Chauvel, P Nenov, V Halgren, E AF Klopp, J Marinkovic, K Chauvel, P Nenov, V Halgren, E TI Early widespread cortical distribution of coherent fusiform face selective activity SO HUMAN BRAIN MAPPING LA English DT Article DE intracranial EEG; humans; prefrontal cortex; temporal lobe; supramarginal gyrus; gamma rhythm; alpha rhythm; binding ID DEPTH-RECORDED POTENTIALS; HUMAN EXTRASTRIATE CORTEX; INTRACEREBRAL POTENTIALS; VISUAL-STIMULI; RARE TARGET; SPATIOTEMPORAL STAGES; SYNCHRONIZATION; PERCEPTION; MEMORY; LOBE AB Intracranial EEG was analyzed from 16 pharmaco-resistant epilepsy patients. Subjects participated in memory tasks for faces and/or words. Face-selective coherence increases were found between the fusiform gyrus and temporal, parietal, and frontal cortices at 160-230 ms poststimulus onset. Word stimuli elicited weak or negligible response at the same latency. Phase lag increased monotonically with distance from the fusiform region. The slope was consistent with conduction velocities of myelinated cortico-cortical pathways. These results suggest that the contribution of the fusiform gyrus to face processing at around 200 ms poststimulus onset is rapidly projected to widespread cortical regions. Hum. Brain Mapping 11:286-293, 2000. (C) 2000 Wiley-Liss, Inc. C1 Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH NMR Ctr, Cambridge, MA 02138 USA. INSERM, F-13258 Marseille, France. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Div Neurosurg, Brain Monitoring & Modeling Lab, Los Angeles, CA USA. RP Halgren, E (reprint author), Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Room 2301,Bldg 149,13th St, Charlestown, MA 02129 USA. FU NINDS NIH HHS [NS18741, R01 NS018741] NR 30 TC 45 Z9 46 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 DEC PY 2000 VL 11 IS 4 BP 286 EP 293 DI 10.1002/1097-0193(200012)11:4<286::AID-HBM80>3.3.CO;2-I PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 380DY UT WOS:000165684500005 PM 11144757 ER PT J AU Rogowska, J Brezinski, ME AF Rogowska, J Brezinski, ME TI Evaluation of the adaptive speckle suppression filter for coronary optical coherence tomography imaging SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE coronary plaque; image speckle; optical coherence tomography; rotating kernel transformation technique ID MEDICAL ULTRASOUND; ENHANCEMENT; IMAGES AB During the last few years, optical coherence tomography (OCT) has demonstrated considerable promise as a method of high-resolution intravascular Imaging. The goal of this study was to apply and to test the applicability of the rotating kernel transformation (RKT) technique to the speckle reduction and enhancement of OCT images. The technique is locally adaptive, It is based on sequential application of directional masks and selection of the maximum of all outputs. This method enhances the image features by emphasizing thin edges while suppressing a noisy background. Qualitatively, the RKT algorithm provides noticeable improvement over the original image. All processed images are smoother and have better-defined borders of media, intima, and plaque, The quantitative evaluation of RKT performance showed that in terms of average contrast-to-noise ratio, there Is a significant improvement in image quality between original and enhanced images. The RKT image enhancement technique shows great promise in improving OCT images for superior boundary Identification. C1 McLean Hosp, BIC, Belmont, MA 02178 USA. Harvard Univ, Sch Med, Belmont, MA 02178 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02478 USA. RP Rogowska, J (reprint author), McLean Hosp, BIC, 115 Mill St, Belmont, MA 02178 USA. FU NHLBI NIH HHS [1 R01 HL63953-01, NIH-1-R29-HL55686-01A1]; NIAMS NIH HHS [NIH-RO1-AR44812-01] NR 10 TC 75 Z9 76 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2000 VL 19 IS 12 BP 1261 EP 1266 DI 10.1109/42.897820 PG 6 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 400CC UT WOS:000166850200014 PM 11212376 ER PT J AU Malherbe, L Filippi, C Julia, V Foucras, G Moro, M Appel, H Wucherpfennig, K Guery, JC Glaichenhaus, N AF Malherbe, L Filippi, C Julia, V Foucras, G Moro, M Appel, H Wucherpfennig, K Guery, JC Glaichenhaus, N TI Selective activation and expansion of high-affinity CD4(+) T cells in resistant mice upon infection with Leishmania major SO IMMUNITY LA English DT Article ID MURINE CUTANEOUS LEISHMANIASIS; IN-VIVO; SUSCEPTIBLE MICE; LYMPH-NODE; ANTIGEN; IMMUNITY; REPERTOIRE; RESPONSES; GAMMA; DIFFERENTIATION AB Using multimers of MHC class II molecules linked to a peptide derived from the Leishmania LACK antigen, we have compared the fate of parasite-specific CD4(+) T cells in resistant and susceptible mice transgenic far the beta chain of a LACK-specific TCR. Activated T cells were readily detected in the draining lymph nodes of infected animals. Although the kinetics of activation and expansion were similar in both strains, T cells from susceptible and resistant mice expressed low- and high-affinity TCR, respectively. As T cells from resistant mice produced more IFN-gamma and less IL-4 than those from susceptible animals, our results suggest that differences in TCR usage between MHC-matched animals may influence the development of the antiparasite immune response. C1 Univ Nice, CNRS, F-06560 Valbonne, France. Hop Purpan, INSERM, Unite U28, F-31059 Toulouse, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Glaichenhaus, N (reprint author), Univ Nice, CNRS, 660 Route Lucioles, F-06560 Valbonne, France. RI GUERY, Jean-Charles/G-1452-2013 OI GUERY, Jean-Charles/0000-0003-4499-3270 FU NIAID NIH HHS [P01 AI45757] NR 40 TC 85 Z9 87 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC PY 2000 VL 13 IS 6 BP 771 EP 782 DI 10.1016/S1074-7613(00)00075-3 PG 12 WC Immunology SC Immunology GA 387VJ UT WOS:000166142300003 PM 11163193 ER PT J AU Rosen, FS AF Rosen, FS TI A brief history of immunodeficiency disease SO IMMUNOLOGICAL REVIEWS LA English DT Review ID ADENOSINE-DEAMINASE DEFICIENCY; LUPUS-ERYTHEMATOSUS; T-CELLS; COMPLEMENT; INFECTIONS; LOCALIZATION; COMPONENT; ADHESION; IMMUNITY; DEFECT C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Rosen, FS (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntingdon Ave, Boston, MA 02115 USA. NR 48 TC 6 Z9 6 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD DEC PY 2000 VL 178 BP 8 EP 12 DI 10.1034/j.1600-065X.2000.17881.x PG 5 WC Immunology SC Immunology GA 394NK UT WOS:000166530000002 PM 11213810 ER PT J AU Tzianabos, AO Chandraker, A Kalka-Moll, W Stingele, F Dong, VM Finberg, RW Peach, R Sayegh, MH AF Tzianabos, AO Chandraker, A Kalka-Moll, W Stingele, F Dong, VM Finberg, RW Peach, R Sayegh, MH TI Bacterial pathogens induce abscess formation by CD4(+) T-cell activation via the CD28-B7-2 costimulatory pathway SO INFECTION AND IMMUNITY LA English DT Article ID BACTEROIDES-FRAGILIS; CAPSULAR POLYSACCHARIDE; B7 MOLECULES; EXPRESSION; SEPSIS; SHOCK; PROTECTION; REJECTION; BLOCKADE; RECEPTOR AB Abscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naive rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, including Staphylococcus aureus, Bacteroides fragilis, and a combination of Enterococcus faecium and Bacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28-B7-2 pathway. C1 Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Brigham & Womens Hosp, Div Renal, Lab Immunogenet & Transplantat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Infect Dis, Boston, MA 02115 USA. Bristol Myers Squibb Co, Princeton, NJ 08543 USA. RP Tzianabos, AO (reprint author), Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. RI Finberg, Robert/E-3323-2010 FU NIAID NIH HHS [AI 34073, AI 34965, AI 39576, R01 AI034965, R01 AI039576] NR 43 TC 34 Z9 34 U1 0 U2 2 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 DEC PY 2000 VL 68 IS 12 BP 6650 EP 6655 DI 10.1128/IAI.68.12.6650-6655.2000 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 403AH UT WOS:000167020000019 PM 11083777 ER PT J AU Cario, E Podolsky, DK AF Cario, E Podolsky, DK TI Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease SO INFECTION AND IMMUNITY LA English DT Article ID DROSOPHILA TOLL; CUTTING EDGE; LPS GENE; KAPPA-B; LIPOPOLYSACCHARIDE; PATHOGENESIS; RECOGNITION; COLITIS; MICE; ACTIVATION AB Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLRL4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders. C1 Massachusetts Gen Hosp, Gastrointestinal Unit GRJ719, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit GRJ719, 32 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK41557, DK43351, P30 DK043351, R01 DK041557, R37 DK041557] NR 43 TC 802 Z9 841 U1 3 U2 42 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 DEC PY 2000 VL 68 IS 12 BP 7010 EP 7017 DI 10.1128/IAI.68.12.7010-7017.2000 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 403AH UT WOS:000167020000068 PM 11083826 ER PT J AU Kartsonis, NA D'Aquila, RT AF Kartsonis, NA D'Aquila, RT TI Clinical monitoring of HIV-1 infection in the era of antiretroviral resistance testing SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEASE INHIBITOR THERAPY; REVERSE-TRANSCRIPTASE GENE; SOCIETY-USA PANEL; DRUG-RESISTANCE; COMBINATION THERAPY; ZIDOVUDINE RESISTANCE; VERTICAL TRANSMISSION; CONFERS RESISTANCE; CROSS-RESISTANCE AB The advent of ultrasensitive viral load assays and combination antiretroviral therapy has led to the precise monitoring and effective treatment of HIV-1 infected patients. Despite these successes, patients fail antiretroviral therapy for several reasons, including the development of antiretroviral resistance. Although the mechanisms surrounding antiretroviral resistance are complex, several different genotypic and phenotypic assays have been developed within the last decade to rapidly assess for resistance. This article focuses on these various resistance assays, with emphasis on potential roles and scientific data supporting their use in the clinical arena. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP D'Aquila, RT (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 149 13th St, Charlestown, MA 02129 USA. NR 84 TC 5 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0891-5520 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD DEC PY 2000 VL 14 IS 4 BP 879 EP + DI 10.1016/S0891-5520(05)70138-0 PG 23 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 382YQ UT WOS:000165855300006 PM 11144643 ER PT J AU O'Connor, PG Scadden, DT AF O'Connor, PG Scadden, DT TI AIDS oncology SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMA; CENTRAL-NERVOUS-SYSTEM; EPSTEIN-BARR-VIRUS; COLONY-STIMULATING FACTOR; SARCOMA-ASSOCIATED HERPESVIRUS; PEGYLATED-LIPOSOMAL DOXORUBICIN; PRIMARY EFFUSION LYMPHOMA; LOW-DOSE CHEMOTHERAPY; KAPOSIS-SARCOMA AB Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and squamous cell carcinoma are among the malignancies seen with increased frequency in patients infected with HIV. The outlook for patients with these malignancies has improved significantly with the utilization of highly active antiretroviral therapy (HAART) and more aggressive cytotoxic therapies. Novel biologic therapies with lesser side effects are currently being evaluated. This article reviews the current knowledge about HIV malignancies, their epidemiology, pathogenesis, clinical manifestations, and treatment. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Canc Ctr, Boston, MA 02129 USA. RP Scadden, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, 149 13th St,Room 5212, Boston, MA 02129 USA. NR 109 TC 6 Z9 6 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 0891-5520 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD DEC PY 2000 VL 14 IS 4 BP 945 EP + DI 10.1016/S0891-5520(05)70141-0 PG 22 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 382YQ UT WOS:000165855300009 PM 11144646 ER PT J AU Hurford, WE AF Hurford, WE TI Preface SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Hurford, WE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP XV EP XV PG 1 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900001 ER PT J AU Dunn, PF AF Dunn, PF TI Physiology of the lateral decubitus position and one-lung ventilation SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID PULMONARY BLOOD-FLOW; END-EXPIRATORY PRESSURE; DOUBLE-LUMEN TUBE; ANESTHETIZED-PARALYZED MAN; ARTERIAL OXYGENATION; ENDOBRONCHIAL ANESTHESIA; MECHANICAL VENTILATION; ISOFLURANE ANESTHESIA; SPATIAL-DISTRIBUTION; VASCULAR PRESSURES C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Dunn, PF (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. NR 78 TC 13 Z9 23 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP 25 EP 53 DI 10.1097/00004311-200001000-00004 PG 29 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900003 PM 10723668 ER PT J AU Sandberg, W AF Sandberg, W TI Anesthesia and airway management for tracheal resection and reconstruction SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID FREQUENCY JET VENTILATION; LARYNGEAL MASK AIRWAY; CARDIOPULMONARY BYPASS; STENOSIS; DELIVERY; PATIENT C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Sandberg, W (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. OI Sandberg, Warren/0000-0002-9246-777X NR 42 TC 11 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP 55 EP 75 DI 10.1097/00004311-200001000-00005 PG 21 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900004 PM 10723669 ER PT J AU Hurford, WE AF Hurford, WE TI The bronchospastic patient SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID MECHANICALLY VENTILATED PATIENTS; INDUCED AIRWAY CONSTRICTION; METERED-DOSE INHALER; STATUS-ASTHMATICUS; BRONCHIAL HYPERREACTIVITY; PERMISSIVE HYPERCAPNIA; HALOTHANE ANESTHESIA; DRUG-THERAPY; ISOFLURANE; ENFLURANE C1 Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Hurford, WE (reprint author), Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 61 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP 77 EP 90 DI 10.1097/00004311-200001000-00006 PG 14 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900005 PM 10723670 ER PT J AU Shank, ES Muth, CM AF Shank, ES Muth, CM TI Decompression illness, latrogenic gas embolism, and carbon monoxide poisoning: The role of hyperbaric oxygen therapy SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Review ID VENOUS AIR-EMBOLISM; CEREBRAL BLOOD-FLOW; PULMONARY BAROTRAUMA; DELAYED TREATMENT; ISCHEMIA; BUBBLES; LIDOCAINE; SICKNESS; PROTEINS; EDEMA C1 Harvard Univ, Massachusetts Eye & Ear Inst, Div Hyperbar Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Univ Hosp Homborg, Druckkammerzentrum Homburg, Homburg, Germany. Univ Saarland, Saarbrucken, Germany. RP Shank, ES (reprint author), Harvard Univ, Massachusetts Eye & Ear Inst, Div Hyperbar Med, Boston, MA 02114 USA. NR 127 TC 17 Z9 17 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP 111 EP 138 DI 10.1097/00004311-200001000-00008 PG 28 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900007 PM 10723672 ER PT J AU Barach, P AF Barach, P TI Management of the critically ill patient in the hyperbaric chamber SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article C1 Massachusetts Gen Hosp, Massachusetts Eye & Ear Inst, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Barach, P (reprint author), Massachusetts Gen Hosp, Massachusetts Eye & Ear Inst, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RI Barach, paul/B-9915-2016 OI Barach, paul/0000-0002-7906-698X NR 24 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD WIN PY 2000 VL 38 IS 1 BP 153 EP 166 DI 10.1097/00004311-200001000-00010 PG 14 WC Anesthesiology SC Anesthesiology GA 287RC UT WOS:000085518900009 PM 10723674 ER PT J AU Messenger, JC Chen, SYJ Carroll, JD Burchenal, JEB Kioussopoulos, K Groves, BM AF Messenger, JC Chen, SYJ Carroll, JD Burchenal, JEB Kioussopoulos, K Groves, BM TI 3D coronary reconstruction from routine single-plane coronary angiograms: Clinical validation and quantitative analysis of the right coronary artery in 100 patients SO INTERNATIONAL JOURNAL OF CARDIAC IMAGING LA English DT Article DE coronary angiography; coronary arteries; image processing (computer-assisted); three-dimensional reconstruction ID 3-DIMENSIONAL RECONSTRUCTION; BIPLANE ANGIOGRAMS; 3-D RECONSTRUCTION; IMAGING GEOMETRY; VASCULAR TREE; VIEWS; DISEASE; STENTS AB Background: Current coronary angiographic techniques display complex three-dimensional (3D) coronary structures in two dimensions (2D). We have developed a 3D reconstruction (3DR) algorithm using standard single-plane angiographic images that allows for 3D display of coronary structures. The purpose of this study was to validate our 3DR algorithm and quantify anatomic characteristics of the right coronary artery (RCA) in vivo. Methods: Accuracy and reproducibility studies were performed using 3DRs of a coronary phantom and in vivo following 3DRs in 40 patients. The anatomic features of the RCA were then quantified in 100 patients. Results: Comparison of length and bifurcation angles (BA) from the phantom to the 3DRs revealed good accuracy and correlation for both (r = 0.95 and 0.93 respectively), with diameter error of <7%. In vivo, the average root mean square (RMS) error in the spatial coordinates of the vessel centerlines was 3.12 +/- 0.77 and 3.16 +/- 0.75 mm in 20 left coronary arteries (LCA) and 20 RCAs respectively. Interobserver average RMS error was 3.47 +/- 1.96 mm and intraobserver average RMS error was 3.02 +/- 1.07 and 3.44 +/- 1.57 mm for two different operators (p = NS). The average RCA length was 10.2 +/- 1.7 cm, average radius of curvature (ROC) was 52 +/- 9 degrees, and the average 3D bifurcation angle of the posterior descending artery (PDA) from the RCA was 55 +/- 22 degrees. Foreshortening (FS) of the segments of the RCA in three 'standard' projections ranged from 0-60, 0-75, and 0-82% respectively. Conclusions: Using our 3DR algorithm patient-specific anatomic characteristics can be accurately displayed and quantified, expanding the information that can be derived from routine coronary angiography. C1 Denver VA Med Ctr, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Div Cardiol,Adult Cardiac Catheterizat Lab, Denver, CO 80262 USA. RP Carroll, JD (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Med, Div Cardiol,Adult Cardiac Catheterizat Lab, 4200 E 9th Ave,Box B-132, Denver, CO 80262 USA. EM john.carroll@uhcolorado.edu NR 31 TC 53 Z9 61 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-9899 J9 INT J CARDIAC IMAG JI Int. J. Card. Imaging PD DEC PY 2000 VL 16 IS 6 BP 413 EP 427 DI 10.1023/A:1010643426720 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 443GR UT WOS:000169333800001 PM 11482706 ER PT J AU Soncin, F Asea, A Zhang, XF Stevenson, MA Calderwood, SK AF Soncin, F Asea, A Zhang, XF Stevenson, MA Calderwood, SK TI Role of calcium activated kinases and phosphatases in heat shock factor-1 activation SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE calcium; CMK II; heat shock; HSF-1; transcriptional regulation ID TRANSCRIPTIONAL ACTIVATION; DNA-BINDING; NUCLEAR-LOCALIZATION; FACTOR-I; STRESS; PROTEIN; CELLS; GENE; DOMAIN; PHOSPHORYLATION AB HSF-1 is regulated at multiple molecular levels through intra- and intermolecular protein-protein interactions as well as by post-translational modification through phosphorylation. We have found that elevating intracellular calcium ion levels by exposure to the ionophore A23187 or thapsigargin inhibits the conversion of HSF-1 from a latent cytoplasmic form to its nuclear/DNA binding form. To examine a role for calcium/calmodulin regulated enzymes in this process, we examined the ability of specific inhibitors to abrogate the effects of calcium elevation. While the inhibitor of calmodulin dependent kinase II, KCN62 enhanced activation of HSF-1 during heat shock, it failed to block the inhibitory effects of calcium increase. By contrast, the immunosuppresant drugs cyclosporin A and FK506 abolished the effects of calcium elevation on HSF-1 activation. As the biological effects of the drugs are effected through inhibition of the calcium/calmodulin regulated phosphatase calcineurin, this suggests a role for calcineurin in antagonizing HSF-1 activity. The experiments suggest the existence of phosphorylated residue(s) in HSF-1 important in one or more of the processes that lead to activation (trimerization, nuclear localization, DNA binding) and which becomes dephosphorylated due to the activation of a calcium/calmodulin/calcineurin complex. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol,Div Radiat Oncol, Boston, MA 02115 USA. RP Calderwood, SK (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol,Div Radiat Oncol, 44 Binney St,D810, Boston, MA 02115 USA. RI SONCIN, Fabrice/A-1475-2009; Asea, Alexzander/I-4112-2013 OI Asea, Alexzander/0000-0003-3592-3481 NR 31 TC 11 Z9 11 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD DEC PY 2000 VL 6 IS 6 BP 705 EP 710 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 376TK UT WOS:000165472700016 PM 11078832 ER PT J AU Steinhauer, SR Condray, R Kasparek, A AF Steinhauer, SR Condray, R Kasparek, A TI Cognitive modulation of midbrain function: task-induced reduction of the pupillary light reflex SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article; Proceedings Paper CT 10th World Congress of Psychophysiology CY FEB 08-13, 2000 CL SYDNEY, AUSTRALIA SP Int org Psychophysiol DE pupil light reaction; cognitive activation; resource allocation; inhibition; task difficulty; autonomic nervous system AB The activation of processing resources has widespread effects in the nervous system. A model of pupillary control systems (Steinhauer S.R., Hakerem G., 1992. The pupillary response in cognitive psychophysiology and schizophrenia. Arm. N.Y. Acad. Sci. 658, 182-204) had predicted that ongoing cognitive activation should result in inhibition of the light reaction at the level of the oculomotor nucleus, n. III, in the midbrain. In this study, modification of parameters of the pupillary reaction to light were examined during varying task demands. The averaged light reaction was recorded from 33 male and female healthy volunteers during the performance of a serial 7 subtraction task and compared to a 'no task' condition. For 13 subjects, an additional verbalization task with little processing demand (add 1) also was presented. Two types of effects were observed. Firstly, the tonic pupil diameter increased from the no task to the easy (add 1) task, and increased further in the more demanding condition (subtract 7). Secondly, the extent of the phasic light reaction was significantly reduced and the latency at the end of the contraction was significantly decreased in the 'subtract 7' condition compared to both the no task and easy conditions (which did not differ from each other). The locus of interference with the light reaction was the Edinger-Westphal complex of the oculomotor nucleus, which is the motor center for the pupillary sphincter muscles. Descending cortical influences inhibited the activity of the Edinger-Westphal complex. Thus, increasing activation had a tonic inhibitory effect on this center, while higher levels of processing complexity produced a separate component of inhibition that interacted with dynamic activation at this midbrain site. It was suggested that the variation in the light reaction is quantitatively responsive to varying processing loads, and may be utilized as a sensitive metric for a wide variety of cognitive operations. (C) 2000 Elsevier Science B.V. All rights reserved. C1 VA Pittsburgh Healthcare Syst, Biomet Res Program, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15206 USA. RP Steinhauer, SR (reprint author), VA Pittsburgh Healthcare Syst, Biomet Res Program, 151R,7180 Highland Dr, Pittsburgh, PA 15206 USA. FU NIMH NIH HHS [MH55762] NR 22 TC 28 Z9 29 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD DEC PY 2000 VL 39 IS 1 BP 21 EP 30 DI 10.1016/S0167-8760(00)00119-7 PG 10 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 392QA UT WOS:000166421500005 PM 11120344 ER PT J AU Sachs, RK Levy, D Chen, AM Simpson, PJ Cornforth, MN Ingerman, EA Hahnfeld, P Hlatky, LR AF Sachs, RK Levy, D Chen, AM Simpson, PJ Cornforth, MN Ingerman, EA Hahnfeld, P Hlatky, LR TI Random breakage and reunion chromosome aberration formation model; an interaction-distance version based on chromatin geometry SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; MONTE-CARLO SIMULATIONS; X-RAYS; MOLECULAR MECHANISMS; EXCHANGE ABERRATIONS; IONIZING-RADIATION; COMPLEX EXCHANGES; HUMAN-FIBROBLASTS; FISH; REPAIR AB Purpose: Using published FISH data for chromosome aberration production in human fibroblasts by hard X-rays to test a breakage-and-reunion model. Methods: The model assumed pairwise misrejoining, random apart from proximity effects, of DNA double-strand break (DSB) free ends. CAS (chromosome aberration simulator) Monte Carlo computer software implementing the model was modified to use a distance algorithm for misrejoining instead of using DSB interaction sites. The modification (called CAS2) allowed a somewhat more realistic approach to large-scale chromatin geometry, chromosome territories and proximity effects. It required adding a third adjustable parameter, the chromosome territory intersection factor, quantifying the amount of intertwining among different chromosomes. Results: CAS2 gave somewhat better results than GAS. A reasonable fit with a few discrepancies was obtained for the frequencies at three different radiation doses of many different aberration types and of aberrations involving Various specific chromosomes in a large data set using one-paint FISH scoring. The optimal average chromosome territory intersection factor was similar to1.1, indicating that, for an arbitrarily chosen location in the nucleus, on average slightly more than two chromosomes have very nearby loci. Without changing the three parameter values, a fit was also obtained for a corresponding, smaller, two-paint data set. Conclusions: A random breakage-and-reunion model incorporating proximity effects by using a distance algorithm gave acceptable approximations for many details of hard X-ray aberration patterns. However, enough discrepancies were found that the possibility of an additional or alternate formation mechanism remains. C1 Dairy Prod Res Ctr, Fermoy, Cork, Ireland. Univ Texas, Med Branch, Galveston, TX 77550 USA. Harvard Univ, Sch Med, DFCI, Boston, MA USA. RP Sachs, RK (reprint author), Univ Calif Berkeley, Dept Math, Berkeley, CA 94720 USA. FU NCI NIH HHS [CA78496, CA86823]; NIGMS NIH HHS [GM57245] NR 41 TC 26 Z9 27 U1 0 U2 0 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 DEC PY 2000 VL 76 IS 12 BP 1579 EP 1588 PG 10 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 383WF UT WOS:000165906800001 PM 11133039 ER PT J AU Wenkel, E Thornton, AF Finkelstein, D Adams, J Lyons, S De La Monte, S Ojeman, RG Munzenrider, JE AF Wenkel, E Thornton, AF Finkelstein, D Adams, J Lyons, S De La Monte, S Ojeman, RG Munzenrider, JE TI Benign meningioma: Partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE benign meningioma; radiation therapy; protons; 3D conformal planning ID RADIATION-THERAPY; STEREOTAXIC RADIOSURGERY; MANAGEMENT; BASE AB Purpose/Objective: To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma. Methods and Materials: Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207). Results: Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol. Conclusion: Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy. (C) 2000 Elsevier Science Inc. C1 Univ Erlangen Nurnberg, Dept Diagnost Radiol, D-91054 Erlangen, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. MGH Canc Ctr, Biostat Grp, Boston, MA USA. Univ Erlangen Nurnberg, Dept Diagnost Radiol, Erlangen, Germany. RP Wenkel, E (reprint author), Univ Erlangen Nurnberg, Dept Diagnost Radiol, Maximilianspl 1, D-91054 Erlangen, Germany. RI Wenkel, Evelyn/B-3731-2011 NR 28 TC 75 Z9 76 U1 0 U2 1 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 DEC 1 PY 2000 VL 48 IS 5 BP 1363 EP 1370 DI 10.1016/S0360-3016(00)01411-5 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 378VC UT WOS:000165604600013 PM 11121635 ER PT J AU Tayani, R Rubin, PAD AF Tayani, R Rubin, PAD TI Laser applications in oculoplastic surgery and their postoperative complications SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID CARBON-DIOXIDE LASER; PULSED-DYE-LASER; SWITCHED RUBY-LASER; CO2-LASER BLEPHAROPLASTY; COLD-STEEL; ABLATION; REMOVAL; TATTOOS; SCARS; WARTS C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Tayani, R (reprint author), Retina Specialists Boston, 100 Charles River Pl, Boston, MA 02114 USA. NR 47 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 13 EP 26 PG 14 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400003 PM 10713911 ER PT J AU Jakobiec, FA Shiuey, Y AF Jakobiec, FA Shiuey, Y TI Postoperative complications in ophthalmic surgery - Preface SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Editorial Material C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02115 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 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP XIX EP XX PG 2 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400001 ER PT J AU Stechschulte, SU Azar, DT AF Stechschulte, SU Azar, DT TI Complications after penetrating keratoplasty SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR; HERPES-SIMPLEX KERATITIS; COLLABORATIVE CORNEAL TRANSPLANTATION; EXPULSIVE CHOROIDAL HEMORRHAGE; OCULAR SURFACE DISORDERS; EPITHELIAL DOWNGROWTH; INTRAOCULAR-PRESSURE; POSTKERATOPLASTY ASTIGMATISM; GRAFT FAILURE; AUTOGRAFT TRANSPLANTATION C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA 02114 USA. RP Stechschulte, SU (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. NR 116 TC 24 Z9 27 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 27 EP 43 DI 10.1097/00004397-200040010-00005 PG 17 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400004 PM 10713912 ER PT J AU Melki, SA Proano, CE Azar, DT AF Melki, SA Proano, CE Azar, DT TI Optical disturbances and their management after myopic laser in situ keratomileusis SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID CORNEAL LIGHT-SCATTERING; PHOTOREFRACTIVE KERATECTOMY; REFRACTIVE SURGERY; GELATINASE-B; IATROGENIC KERATECTASIA; CENTRAL ISLANDS; LASIK; INTERFACE; COMPLICATIONS; DISPLACEMENT C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA 02114 USA. RP Melki, SA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. NR 46 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 45 EP 56 DI 10.1097/00004397-200040010-00006 PG 12 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400005 PM 10713913 ER PT J AU Samson, CM Foster, CS AF Samson, CM Foster, CS TI Chronic postoperative endophthalmitis SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID PROPIONIBACTERIUM-ACNES ENDOPHTHALMITIS; EXTRACAPSULAR CATARACT-EXTRACTION; ENDOGENOUS FUNGAL ENDOPHTHALMITIS; INTRAOCULAR-LENS IMPLANTATION; SYSTEMIC FLUCONAZOLE; MANAGEMENT; DIAGNOSIS; SURGERY; CONTAMINATION; VITRECTOMY C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Immunol & Uveitis Serv, Boston, MA 02114 USA. RP Samson, CM (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. NR 60 TC 11 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 57 EP 67 PG 11 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400006 PM 10713914 ER PT J AU Gasch, AT Foster, CS Grosskreutz, CL Pasquale, LR AF Gasch, AT Foster, CS Grosskreutz, CL Pasquale, LR TI Postoperative sympathetic ophthalmia SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID KOYANAGI-HARADA DISEASE; DALEN-FUCHS NODULES; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; RETINAL-PIGMENT EPITHELIUM; ANTERIOR UVEITIS EAAU; YAG CYCLOTHERAPY; S-ANTIGEN; ELECTRON-MICROSCOPY; INDUCTION; PROTEIN C1 Massachusetts Eye & Ear Infirm, Glaucoma Consultat Serv, Boston, MA 02114 USA. RP Gasch, AT (reprint author), 4100 Cathedral Ave 510, Washington, DC 20016 USA. NR 131 TC 18 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 69 EP 84 DI 10.1097/00004397-200040010-00008 PG 16 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400007 PM 10713915 ER PT J AU Cyriac, IC Pineda, R AF Cyriac, IC Pineda, R TI Postoperative complications of periocular anesthesia SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID RETROBULBAR ANESTHESIA; PERIBULBAR ANESTHESIA; GLOBE C1 Brigham & Womens Hosp, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Cyriac, IC (reprint author), Brigham & Womens Hosp, Massachusetts Eye & Ear Infirm, 221 Longwood Ave, Boston, MA 02115 USA. NR 13 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 85 EP 91 DI 10.1097/00004397-200040010-00009 PG 7 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400008 PM 10713916 ER PT J AU Egan, R Rizzo, JF AF Egan, R Rizzo, JF TI Neuroophthalmological complications of ocular surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID NERVE SHEATH DECOMPRESSION; VISUAL-FIELD LOSS; RECTUS MUSCLE OVERACTION; PARS-PLANA VITRECTOMY; MACULAR HOLE SURGERY; OPTIC-NERVE; RETROBULBAR ANESTHESIA; CATARACT-EXTRACTION; PSEUDOTUMOR CEREBRI; COSMETIC BLEPHAROPLASTY C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Egan, R (reprint author), Casey Eye Inst, 3375 SW Terwillinger Blvd, Portland, OR 97201 USA. NR 53 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 93 EP 105 DI 10.1097/00004397-200040010-00010 PG 13 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400009 PM 10713917 ER PT J AU Harper, SL Foster, CS AF Harper, SL Foster, CS TI Intraocular lens explantation in uveitis SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID JUVENILE RHEUMATOID-ARTHRITIS; CATARACT-EXTRACTION; POSTERIOR CHAMBER; PARS PLANITIS; HUMAN-SERUM; IMPLANTATION; SURGERY C1 Massachusetts Eye & Ear Infirm, Ocular Immunol & Uveitis Serv, Boston, MA 02114 USA. RP Harper, SL (reprint author), Massachusetts Eye & Ear Infirm, Ocular Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. NR 23 TC 6 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 107 EP 116 DI 10.1097/00004397-200040010-00011 PG 10 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400010 PM 10713918 ER PT J AU Ching-Costa, A Chen, TC AF Ching-Costa, A Chen, TC TI Malignant glaucoma SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID CATARACT-EXTRACTION; LENS IMPLANTATION; INTRAOCULAR-LENS; VITRECTOMY; MANAGEMENT; CAPSULOTOMY C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Ching-Costa, A (reprint author), 500 11-B Santol St,Sta Mesa, Manila 1016, Philippines. NR 21 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 117 EP 125 PG 9 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400011 PM 10713919 ER PT J AU Rahman, A Mendonca, M Simmons, RB Simmons, RJ AF Rahman, A Mendonca, M Simmons, RB Simmons, RJ TI Hypotony after glaucoma filtration surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID MITOMYCIN-C; ARGON-LASER; TRABECULECTOMY; MACULOPATHY; BLEBS C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Rahman, A (reprint author), Vanderbilt Univ, Dept Ophthalmol, Med Ctr 8000, 221 Kirkland Hall, Nashville, TN 37232 USA. NR 30 TC 10 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 127 EP 136 DI 10.1097/00004397-200040010-00013 PG 10 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400012 PM 10713920 ER PT J AU Ang, RET Grosskreutz, CL AF Ang, RET Grosskreutz, CL TI Bleb complications after filtration surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID FAILED FILTERING BLEBS; NEODYMIUM-YAG LASER; MITOMYCIN-C; ADJUNCTIVE 5-FLUOROURACIL; SURGICAL-MANAGEMENT; NEEDLE REVISION; LEAKING BLEBS; TRABECULECTOMY; ENDOPHTHALMITIS; GLAUCOMA C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Ang, RET (reprint author), 340 Rizal Ave Extens,Grace Pk, Caloocan City, Philippines. NR 40 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 137 EP 148 PG 12 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400013 PM 10713921 ER PT J AU Guerrero, AH Latina, MA AF Guerrero, AH Latina, MA TI Complications of glaucoma drainage implant surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID CLINICAL-EXPERIENCE; VALVE IMPLANT; NEOVASCULAR GLAUCOMA; BAERVELDT IMPLANT; MOLTENO IMPLANT; LIGATURE; DEVICES; EYES; TUBE C1 Massachusetts Eye & Ear Infirm, Glaucoma Serv, Boston, MA 02114 USA. RP Guerrero, AH (reprint author), Massachusetts Eye & Ear Infirm, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. NR 31 TC 10 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 149 EP 163 DI 10.1097/00004397-200040010-00015 PG 15 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400014 PM 10713922 ER PT J AU Kim, RY D'Amico, DJ AF Kim, RY D'Amico, DJ TI Postoperative complications of pneumatic retinopexy SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID TEMPORARY BALLOON BUCKLE; RETINAL-DETACHMENT C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Kim, RY (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. NR 21 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 165 EP 173 DI 10.1097/00004397-200040010-00016 PG 9 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400015 PM 10713923 ER PT J AU Ambati, J Arroyo, JG AF Ambati, J Arroyo, JG TI Postoperative complications of scleral buckling surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID RETINAL-DETACHMENT SURGERY; EXTRAOCULAR-MUSCLE IMBALANCE; CYSTOID MACULAR EDEMA; REMOVAL; REATTACHMENT; OPERATIONS; INFECTION C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. RP Ambati, J (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. NR 86 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 175 EP 185 DI 10.1097/00004397-200040010-00017 PG 11 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400016 ER PT J AU Krzystolik, MG D'Amico, DJ AF Krzystolik, MG D'Amico, DJ TI Complications of intraocular tamponade: Silicone oil versus intraocular gas SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID ADVANCED PROLIFERATIVE VITREORETINOPATHY; PARS-PLANA VITRECTOMY; SULFUR-HEXAFLUORIDE; RETINAL-DETACHMENT; PERFLUOROCARBON GASES; LIQUID SILICONE; INTRAVITREAL SILICONE; FLUOROSILICONE OILS; VITREOUS SURGERY; ANTERIOR-CHAMBER C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. RP Krzystolik, MG (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. NR 73 TC 13 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 187 EP 200 DI 10.1097/00004397-200040010-00018 PG 14 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400017 PM 10713925 ER PT J AU Fleckner, MR Hochman, MA Buzney, SM Weiter, JJ Tolentino, FI Khadem, JJ AF Fleckner, MR Hochman, MA Buzney, SM Weiter, JJ Tolentino, FI Khadem, JJ TI Complications of surgery for subfoveal choroidal neovascularization SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID PRESUMED OCULAR HISTOPLASMOSIS; MACULAR DEGENERATION; SUBMACULAR SURGERY; SURGICAL REMOVAL; VITREOUS SURGERY; MEMBRANES; HOLES; CHORIOCAPILLARIS; DEBRIDEMENT; INSTRUMENTS C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Fleckner, MR (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. NR 47 TC 0 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 201 EP 214 DI 10.1097/00004397-200040010-00019 PG 14 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400018 PM 10713926 ER PT J AU Graham, K D'Amico, DJ AF Graham, K D'Amico, DJ TI Postoperative complications of epiretinal membrane surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID PARS-PLANA VITRECTOMY; INTRAOCULAR-LENS IMPLANTATION; EXTRACAPSULAR CATARACT-EXTRACTION; NUCLEAR SCLEROTIC CATARACT; MACULAR PUCKER; COMBINED PHACOEMULSIFICATION; ENDOPHTHALMITIS SURVEY; DIABETIC-RETINOPATHY; SURGICAL-MANAGEMENT; INSERTION C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. RP Graham, K (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. NR 49 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 215 EP 223 DI 10.1097/00004397-200040010-00020 PG 9 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400019 PM 10713927 ER PT J AU Javid, CG Lou, PL AF Javid, CG Lou, PL TI Complications of macular hole surgery SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Javid, CG (reprint author), Retina Associates SW, 6561 E Carondelet Dr, Tucson, AZ 85710 USA. NR 15 TC 0 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD WIN PY 2000 VL 40 IS 1 BP 225 EP 232 DI 10.1097/00004397-200040010-00021 PG 8 WC Ophthalmology SC Ophthalmology GA 278VV UT WOS:000085010400020 PM 10713928 ER PT J AU Graham, MA Rawe, I Dartt, DA Joyce, NC AF Graham, MA Rawe, I Dartt, DA Joyce, NC TI Protein kinase C regulation of corneal endothelial cell proliferation and cell cycle SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID INHIBITOR P27(KIP1); ALPHA EXPRESSION; PHORBOL ESTERS; LACRIMAL GLAND; DELTA; PROGRESSION; ACTIVATION AB PURPOSE. The purpose of this study was to determine the role of protein kinase C (PKC) in corneal endothelial cell proliferation. METHODS. Immunochemistry and Western blotting were used to define the PKC isoforms expressed in primary cultures of rat corneal endothelial cells. For proliferation studies, primary cultures of rat corneal endothelial cells were serum-starved for 48 hours and incubated for 2 hours with the PKC inhibitors staurosporine (10(-9) to 10(-7) M), chelerythrine (10(-9) to 5 x 10(-8) M), or calphostin C (10(-9) to 10(-7) M). Individual PKC isoforms were inhibited using PKC alpha antisense oligonucleotide transfection or exposure for 1 hour to myristoylated, pseudosubstrate-derived peptide inhibitors against PKC alpha, -alpha beta gamma, -epsilon, and -delta (10(-8) to 10(-6) M). Cells were then stimulated with 2.5% serum for 24 hours. Cell proliferation was measured with bromodeoxyuridine (BrDU) and Ki67 immunocytochemistry. Protein level of cyclin E was determined by Western blotting. RESULTS. PKC alpha, -beta II, -delta, -epsilon, -iota, -eta, -gamma, and -theta were detected in corneal endothelial cells. Maximum inhibition of PKC with staurosporine, calphostin C, and chelerythrine reduced cell proliferation to 7%, 31%, and 48% of control, respectively. Myristoylated peptide inhibition of PKC alpha and -epsilon reduced cell proliferation to 57% and 59% of control, respectively. PKC alpha antisense oligonucleotide reduced cell proliferation to 35% of control. Cyclin E protein level was decreased to 70%, 38%, 57%, and 43% of control in cells treated with calphostin C, staurosporine, chelerythrine, and PKC alpha antisense, respectively. CONCLUSIONS. PKC activity, in particular PKC alpha and -epsilon activity, is important in promoting corneal endothelial cell proliferation. Inhibition of PKC activity prohibits G1/S-phase progression and reduces cyclin E protein levels. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Joyce, NC (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. FU NEI NIH HHS [R01 EY009057, R01 EY05767, R01 EY09057] NR 38 TC 19 Z9 24 U1 0 U2 1 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 DEC PY 2000 VL 41 IS 13 BP 4124 EP 4132 PG 9 WC Ophthalmology SC Ophthalmology GA 378HL UT WOS:000165578900012 PM 11095605 ER PT J AU Baldessarini, RJ Tondo, L Floris, G Hennen, J AF Baldessarini, RJ Tondo, L Floris, G Hennen, J TI Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE bipolar I and II disorders; illness course; lithium; rapid cycling ID ANTI-DEPRESSANTS; MOOD DISORDERS; CARBONATE; VALIDITY; MANIA AB Introduction: Rapid cycling (RC) in bipolar disorders is widely believed to predict future morbidity and poor treatment response, although empirical testing of its predictive utility remains limited. Methods: In 360 DSM-IV bipolar I (N = 218) and II (N = 142) disorder subjects (64% women) followed over an average of 13.3 years, we evaluated factors associated with RC status with bivariate and multivariate techniques, and response to lithium maintenance treatment (recurrence rates, time ill, survival analysis of time to recurrence on lithium). Results: RC risk (15.6% of cases) was 5.1-times greater in bipolar II vs. I subjects (30.3%/6.0%), ill minor excess in women vs. men (17.9%/11.5%), and associated with premorbid cyclothymia, depressive first episodes, older onset age, and being employed or married. Before lithium: RC vs. non-RC cases had more mean total (3.9/1.2), manic, and depressive episodes/year, and greater percent time ill (60%/38%). During treatment, prior RC status was unrelated to time to first recurrence and other measures of morbidity and improvement including percent time ill, although depressive episodes were 2.7-times more frequent, and there was 13.7% less chance of full protection from all recurrences in RC cases. Limitations: The study is naturalistic, without random assignment or blind assessment. Conclusions: The RC bipolar subtype was strongly associated with type II diagnosis, higher average prelithium episode frequency and percent time ill, and weakly with female sex, but not with greater overall morbidity during treatment. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Int Consortium Bipolar Disorder Res, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Bipolar & Psychot Disorders Program, Consolidated Dept Psychiat,McLean Div, Boston, MA USA. Ctr Lucio Bini, Cagliari, Sardinia, Italy. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr 312, 115 Mill St, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-47370] NR 24 TC 75 Z9 76 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD DEC PY 2000 VL 61 IS 1-2 BP 13 EP 22 DI 10.1016/S0165-0327(99)00196-2 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 384PW UT WOS:000165954900002 PM 11099736 ER PT J AU Moye, J AF Moye, J TI Mr. Franks refuses surgery - Cognition and values in competency determination in complex cases SO JOURNAL OF AGING STUDIES LA English DT Article ID LIFE-SUSTAINING TREATMENT; ALZHEIMERS-DISEASE; DECISIONS; STANDARDS; CONSENT; PREFERENCES; CAPACITY; QUALITY; ADULTS AB The evaluation of medical decision-making competency is challenging and subject to low reliability for many reasons including potentially difference life perspectives and cognitive processes between evaluators and patients, but especially because of the difficulties in defining and determining "competency" in complex cases. In this article, the case of an elderly man who is refusing surgery is presented to illustrate such difficulties. In these situations, the evaluator can assess both specific decisional tasks and personal values relevant to health care. Instruments designed to assess such specific decision-making abilities and values have benefits and limitations. C1 VA Boston Hlth Care Syst, Brockton, MA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Moye, J (reprint author), Brockton VA Med Ctr, 940 Belmont St, Brockton, MA 02301 USA. RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 45 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 0890-4065 J9 J AGING STUD JI J. Aging Stud. PD DEC PY 2000 VL 14 IS 4 BP 385 EP 401 DI 10.1016/S0890-4065(00)80004-3 PG 17 WC Gerontology SC Geriatrics & Gerontology GA 378QD UT WOS:000165594300004 ER PT J AU Karel, MJ AF Karel, MJ TI The assessment of values in medical decision making SO JOURNAL OF AGING STUDIES LA English DT Article ID LIFE-SUSTAINING TREATMENT; ADVANCE DIRECTIVES; HEALTH-CARE; TREATMENT PREFERENCES; PATIENT PREFERENCES; ELDERLY OUTPATIENTS; HOSPITALIZED-PATIENTS; SUBSTITUTED JUDGMENT; TREATMENT CHOICES; OLDER POPULATION AB Individuals, families, and health care providers consider medical treatment decisions ill light of their respective values about life in varying states of health. The clarification of health rare values is important not only in the context of everyday clinical decision making, but also for advance care planning and the resolution of ethical dilemmas. This article argues that objective assesment tools may facilitate the process of clarifying and communicating health care values in these contexts. The article reviews arguments for the importance of values assessment in health care planning methods used to date for health care values assessment, conceptual and methodological challenges for the measurement of health care values, and lessons learned through the process of developing and piloting a Health Care Values Survey. Objective values assessment tools appear useful for eliciting health care values, although multiple challenges for reliable, valid and clinically useful measurement of values are identified. C1 VA Boston Hlth Care Syst, Brockton, MA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Karel, MJ (reprint author), Brockton VA Med Ctr, 940 Belmont St, Brockton, MA 02301 USA. NR 78 TC 20 Z9 21 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0890-4065 J9 J AGING STUD JI J. Aging Stud. PD DEC PY 2000 VL 14 IS 4 BP 403 EP 422 DI 10.1016/S0890-4065(00)80005-5 PG 20 WC Gerontology SC Geriatrics & Gerontology GA 378QD UT WOS:000165594300005 ER PT J AU Coull, BA Catalano, PJ Godleski, JJ AF Coull, BA Catalano, PJ Godleski, JJ TI Semiparametric analyses of cross-over data with repeated measures SO JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS LA English DT Article DE autoregressive errors; local regression; longitudinal data; nonparametric regression; partial linear model; smoothing ID SMOOTHING SPLINE MODELS; LONGITUDINAL DATA; CURVES; REGRESSION; SAMPLES AB A model is proposed to analyze data arising from a cross-over experiment in which measurements on a control and an exposed subject are recorded over time within each crossover period. The model uses locally weighted quadratic regression to control for nuisance temporal trends common to both control and exposed subjects within each period and specifies a first-order autoregressive process to account for dependence among measurements within each longitudinal sequence. We apply the model to a motivating data set in which laboratory animals are exposed to concentrated air particles. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Coull, BA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntingtonave, Boston, MA 02115 USA. NR 22 TC 2 Z9 2 U1 0 U2 1 PU AMER STATISTICAL ASSOC & INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1444 I ST NW, STE 700, WASHINGTON, DC 20005 USA SN 1085-7117 J9 J AGRIC BIOL ENVIR S JI J. Agric. Biol. Environ. Stat. PD DEC PY 2000 VL 5 IS 4 BP 417 EP 429 DI 10.2307/1400658 PG 13 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 382GX UT WOS:000165815500003 ER PT J AU Esch, TR Jonsson, MV Levanos, VA Poveromo, JD Sorkin, BC AF Esch, TR Jonsson, MV Levanos, VA Poveromo, JD Sorkin, BC TI Leukocytes infiltrating the submandibular glands of NOD mice express E-cadherin SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE adhesion molecules; autoimmunity; in vivo animal models; rodent ID LYMPHOCYTE INTEGRIN ALPHA(E)BETA(7); NONOBESE DIABETIC MICE; MOLECULE E-CADHERIN; T-CELL DEVELOPMENT; LIGAND E-CADHERIN; SJOGRENS-SYNDROME; EPITHELIAL-CELLS; MURINE THYMOCYTES; EXOCRINE TISSUES; ADHESION AB Sjogren's syndrome [SS] is typified by infiltration of mononuclear cells [MNC] into the salivary and lacrimal glands, although the biological role of these infiltrating cells remains unclear. We report here that E-cadherin, which mediates cell-cell adhesion and regulates differentiation, proliferation, and apoptosis of epithelial cells, is expressed ectopically by MNC in the salivary glands in the NOD mouse model of SS. Flow cytometric analysis of CD45(+) cells from NOD submandibular glands revealed that over 90% express E-cadherin. More detailed phenotypic analyses demonstrated that E-cadherin expression is high (>90%) among mature T cells (CD3(+)), B cells (CD19(+)), NK cells (DX5(+)), and monocyte/macrophages (CD11b(+)) within the infiltrates. Expression of other surface antigens, such as CD90 and CD117, above expected values suggests the presence of immature leukocytes, possibly of the T cell lineage, within the foci. We also present evidence that E-cadherin-expressing T cells in the glands do not exhibit normal proliferative responses to immobilized anti-CD3 antibody. While infiltrating MNC are not likely to be the direct cause of salivary hypofunction, the expression of E-cadherin by these cells may have implications for the progression of disease. (C) 2000 Academic Press. C1 Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USA. Forsyth Inst, Dept Immunol, Boston, MA USA. Univ Bergen, Fac Odontol, Bergen, Norway. Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. RP Esch, TR (reprint author), Forsyth Inst, Harvard Forsyth Dept Oral Biol, 140 Fenway, Boston, MA 02115 USA. OI Sorkin, Barbara/0000-0001-8198-6921 FU NIAID NIH HHS [AI43297] NR 27 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2000 VL 15 IS 4 BP 387 EP 393 DI 10.1006/jaut.2000.0451 PG 7 WC Immunology SC Immunology GA 380VZ UT WOS:000165725300001 PM 11090237 ER PT J AU Tang, Y Tang, J Chen, ZG Trost, C Flockerzi, V Lin, M Ramesh, V Zhu, MX AF Tang, Y Tang, J Chen, ZG Trost, C Flockerzi, V Lin, M Ramesh, V Zhu, MX TI Association of mammalian Trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; EXCHANGER REGULATORY FACTOR; CA2+-PERMEABLE CATION CHANNEL; ACTIVATED CA2+ INFLUX; NA+/H+-EXCHANGER; STORE DEPLETION; DROSOPHILA TRP; BETA(2)-ADRENERGIC RECEPTOR; FUNCTIONAL-CHARACTERIZATION; SIGNALING COMPLEXES AB Mammalian homologues of Drosophila Trp have been implicated to form channels that are activated following the depletion of Ca2+ from internal stores. Recent studies indicate that actin redistribution is required for the activation of these channels. Here we show that murine Trp4 and Trp5, as well as phospholipase C beta1 and beta2 interact with the first PDZ domain of NHERF, regulatory factor of the Na+/H+ exchanger. We demonstrated the association of Trp4 and phospholipase C-beta1 with NHERF in vivo in an HEK293 cell line expressing Trp4 and in adult mouse brain by immuno-coprecipitation. NIIERF is a two PDZ domain-containing protein that associates with the actin cytoskeleton via interactions with members of ezrin/radixin/moesin family. Thus, store-operated channels involving Trp4 and Trp5 can form signaling complexes with phospholipase C isozymes via interactions with NHERF and thereby linking the lipase and the channels to the actin cytoskeleton. The interaction with the PDZ protein may constitute an important mechanism for distribution and regulation of store-operated channels. C1 Ohio State Univ, Neurobiotechnol Ctr, Columbus, OH 43210 USA. Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. Univ Saarlandes, Inst Pharmakil & Toxikol, D-66421 Homburg, Germany. Johns Hopkins Univ, Sch Med, Dept Physiol & Neurosci, Baltimore, MD 21205 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. RP Zhu, MX (reprint author), Ohio State Univ, Neurobiotechnol Ctr, 168 Rightmire Hall,1060 Carmack Rd, Columbus, OH 43210 USA. FU NIGMS NIH HHS [GM54235] NR 59 TC 183 Z9 195 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 DEC 1 PY 2000 VL 275 IS 48 BP 37559 EP 37564 DI 10.1074/jbc.M006635200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 379AL UT WOS:000165618700036 PM 10980202 ER PT J AU Yang, L Chansky, HA Hickstein, DD AF Yang, L Chansky, HA Hickstein, DD TI EWS center dot Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRE-MESSENGER-RNA; EWINGS-SARCOMA TRANSLOCATION; ROUND-CELL TUMOR; BINDING PROTEIN; DNA-BINDING; CHROMOSOME-TRANSLOCATION; TRANSCRIPTION FACTOR; EWS GENE; MYXOID LIPOSARCOMA; MALIGNANT-MELANOMA AB Ewing's sarcoma displays a characteristic chromosomal translocation that results in fusion of the N-terminal domain of the Ewing's sarcoma protein (EWS) to the C-terminal DNA-binding domain of the ETS family transcription factor Fli-1 (Friend leukemia integration-1). EWS possesses structural motifs suggesting a role in transactivation as well as RNA binding. We demonstrate that wild-type EWS protein functions as an adapter molecule coupling transcription to RNA splicing by binding to hyperphosphorylated RNA polymerase II through the N-terminal domain of EWS and recruiting serine-arginine (SR) splicing factors through the C-terminal domain of EWS. The oncogenic EWS Fli-1 fusion protein retains the ability to bind to hyperphosphorylated RNA polymerase II but lacks the ability to recruit SR proteins because of replacement of the C-terminal domain of EWS by Fli-1. In an in vivo splicing assay, the EWS.Fli-1 fusion protein inhibits SR protein-mediated E1A pre-mRNA splicing in a dominant-negative manner. These results indicate that EWS Fli-1 interferes with the normal function of EWS and implicate uncoupling of gene transcription from RNA splicing in the pathogenesis of Ewing's sarcoma. C1 Univ Washington, Sch Med, Dept Med Oncol, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Orthoped, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. RP Hickstein, DD (reprint author), Univ Washington, Sch Med, Dept Med Oncol, Box 358280,1660 S Columbian Way,GMR 151, Seattle, WA 98108 USA. NR 43 TC 97 Z9 102 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 DEC 1 PY 2000 VL 275 IS 48 BP 37612 EP 37618 DI 10.1074/jbc.M005739200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 379AL UT WOS:000165618700043 PM 10982800 ER PT J AU Liu, L Sazonova, IY Turner, RB Chowdhry, SA Tsai, J Houng, AK Reed, GL AF Liu, L Sazonova, IY Turner, RB Chowdhry, SA Tsai, J Houng, AK Reed, GL TI Leucine 42 in the fibronectin motif of streptokinase plays a critical role in fibrin-independent plasminogen activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THROMBOLYTIC THERAPY; MONOCLONAL-ANTIBODY; SYNTHETIC PEPTIDES; BINDING REGION; COMPLEX; MECHANISM; CONVERSION; FRAGMENTS; SEQUENCE; DOMAINS AB The NH2 terminus (residues 1-59) of streptokinase (SK) is a molecular switch that permits fibrin-independent plasminogen activation. Targeted mutations were made in recombinant (r) SK1-59 to identify structural interactions required for this process. Mutagenesis established the functional roles of Phe-37and Glu-39, which were projected to interact with microplasmin in the activator complex. Mutation of Leu-42 (rSK1-59(L42A)), a conserved residue in the SK fibronectin motif that lacks interactions with microplasmin, strongly reduced plasminogen activation (k(cat) decreased 50-fold) but not amidolysis (k(cat) decreased 1.5-fold). Otherwise rSK1-59(L42A) and native rSK1-59 were indistinguishable in several parameters. Both displayed saturable and specific binding to Glu-plasminogen or the remaining SK fragment (rSK Delta 59), Similarly rSK1-59 and rSK1-59(L42A) bound simultaneously to two different plasminogen molecules, indicating that both plasminogen binding sites were intact. However, when bound to SK1-59, rSK1-59(L42A) was less effective than rSK1-59 in restructuring the native conformation of the SK A domain, as detected by conformation-dependent monoclonal antibodies. In the light of previous studies, these data provide evidence that SK1-59 contributes to fibrin-independent plasminogen activation through 1) intermolecular interactions with the plasmin in the activator complex, 2) binding interactions with the plasminogen substrate, and 3) intramolecular interactions that structure the A domain of SK for Pg substrate processing. C1 Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Reed, GL (reprint author), Cardiovasc Biol Lab, HSHP 2-127,677 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL57314] NR 35 TC 11 Z9 11 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 DEC 1 PY 2000 VL 275 IS 48 BP 37686 EP 37691 DI 10.1074/jbc.M003963200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 379AL UT WOS:000165618700053 PM 10961989 ER PT J AU Whyte, MP Mills, BG Reinus, WR Podgornik, MN Roodman, GD Gannon, FH Eddy, MC McAlister, WH AF Whyte, MP Mills, BG Reinus, WR Podgornik, MN Roodman, GD Gannon, FH Eddy, MC McAlister, WH TI Expansile skeletal hyperphosphatasia: A new familial metabolic bone disease SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article; Proceedings Paper CT 21st Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 29-OCT 04, 1999 CL ST LOUIS, MISSOURI SP Amer Soc Bone & Mineral Res DE alkaline phosphatase; hypercalcemia; deafness; Paget's bone disease ID PAGET-DISEASE; DIAPHYSEAL DYSPLASIA; HEARING-LOSS; OSTEOLYSIS; TRANSCRIPTS AB We describe a new familial metabolic bone disease characterized by expanding hyperostotic long bones, early onset deafness, premature tooth loss, and episodic hypercalcemia, The condition affects a mother and daughter studied at the age of 36 years and 11 years, respectively. Both individuals lost all hearing in early childhood and suffered premature shedding of teeth. Skeletal pains began just before puberty. Swelling and aching of most middle phalanges in the hands is an especially troublesome manifestation. The mother also had episodes of symptomatic hypercalcemia first documented in late childhood and subsequently during intercurrent illness and postpartum lactation. Radiographs show hyperostosis and/or osteosclerosis predominantly in the skull and appendicular skeleton, Long bones also are expanded considerably, especially the middle phalanges in the fingers. The mother's skeletal abnormalities are more severe. Biochemical parameters of bone turnover, including serum alkaline phosphatase (ALP) activity, are elevated substantially. In the proposita, dynamic histomorphometry of nondecalcified sections of iliac crest revealed rapid skeletal remodeling, In the mother, who had been treated with bisphosphonates, electron microscopy (EM) showed disorganized collagen bundles as well as necrotic and apoptotic bone cells but no osteocytic osteolysis. Measles virus gene transcripts were not detected in peripheral blood monocytes, Karyotyping was normal, 46,XX. Hyperphosphatasia with bone disease previously has been reported as either a sporadic or autosomal recessive condition. Expansile skeletal hyperphosphatasia (ESH) is probably inherited as an autosomal dominant trait with a high degree of penetrance. C1 Shriners Hosp Children, Metab Res Unit, St Louis, MO 63131 USA. Washington Univ, Sch Med, Barnes Jewish Hosp, Div Bone & Mineral Dis, St Louis, MO USA. JV Luck Res Ctr Orthoped Hosp, Los Angeles, CA USA. Washington Univ, Sch Med, Barnes Jewish Hosp, Mallinckrodt Inst Radiol, St Louis, MO USA. Audie Murphy Vet Adm Hosp, San Antonio, TX USA. Armed Forces Inst Pathol, Dept Orthoped Pathol, Washington, DC 20306 USA. Washington Univ, Sch Med, St Louis Childrens Hosp, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Whyte, MP (reprint author), Shriners Hosp Children, Metab Res Unit, 2001 S Lindbergh Blvd, St Louis, MO 63131 USA. NR 40 TC 43 Z9 46 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2000 VL 15 IS 12 BP 2330 EP 2344 DI 10.1359/jbmr.2000.15.12.2330 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 376NH UT WOS:000165463300006 PM 11127198 ER PT J AU Reppe, S Rian, E Jemtland, R Olstad, OK Gautvik, VT Gautvik, KM AF Reppe, S Rian, E Jemtland, R Olstad, OK Gautvik, VT Gautvik, KM TI Sox-4 messenger RNA is expressed in the embryonic growth plate and regulated via the parathyroid hormone/parathyroid hormone-related protein receptor in osteoblast-like cells SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article; Proceedings Paper CT 21st Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 29-OCT 04, 1999 CL ST LOUIS, MISSOURI SP Amer Soc Bone & Mineral Res DE Sox-4; osteoblasts; chondrocytes; growth plate; parathyroid hormone ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; CHONDROCYTE-SPECIFIC ENHANCER; AUTOSOMAL SEX REVERSAL; TAG PCR SUBTRACTION; SRY-RELATED GENE; HMG-BOX PROTEIN; SACCHAROMYCES-CEREVISIAE; CAMPOMELIC DYSPLASIA; PTH/PTHRP RECEPTOR; DETERMINING REGION AB Parathyroid hormone (PTH) and PTH-related protein (PTHrP) exert potent and diverse effects in cells of the osteoblastic and chondrocytic lineages. However, downstream mediators of these effects are characterized inadequately. We identified a complementary DNA (cDNA) clone encoding the 5' end of the transcription Factor Sox-4, using a subtracted cDNA library enriched in PTH-stimulated genes from the human osteoblast-like cell line OHS. The SOX-4 gene is a member of a gene family (SOX and SRY) comprising transcription factors that bind to DNA through their high mobility group (HMG)-type binding domain, and previous reports have implicated Sox proteins in various developmental processes. In situ hybridization of fetal and neonatal mouse hindlimbs showed that Sox-4 messenger RNA (mRNA) was expressed most intensely in the zone of mineralizing cartilage where chondrocytes undergo hypertrophy, and by embryonic day 17 (ED17), after the primary ossification center was formed, its expression was detected only in the region of hypertrophic chondrocytes. Sox-4 mRNA was detected in osteoblastlike cells of both human and rodent origin. In OHS cells, physiological concentrations (10(-10)-10(-9) M) of human PTH 1-84 [hPTH(1-84)] and hPTH(1-34), but not hPTH(3-84), stimulated Sox-4 mRNA expression in a time-dependent manner, indicating involvement of the PTH/PTHrP receptor. Sox-4 transcripts also were detected in various nonosteoblastic human cell lines and tissues, in a pattern similar to that previously reported in mice. The presence of Sox-4 mRNA in hypertrophic chondrocytes within the mouse epiphyseal growth plate at sites that overlap or are adjacent to target cells for PTH and PTHrP, and its strong up-regulation via activated PTH/PTHrP receptors in OHS cells, makes it a promising candidate for mediating downstream effects of PTH and PTHrP in bone. C1 Univ Oslo, Dept Biochem Med, N-0317 Oslo, Norway. Norwegian Radium Hosp, Oslo, Norway. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Reppe, S (reprint author), Univ Oslo, Dept Biochem Med, POB 1112 Blindern, N-0317 Oslo, Norway. NR 52 TC 29 Z9 31 U1 3 U2 3 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2000 VL 15 IS 12 BP 2402 EP 2412 DI 10.1359/jbmr.2000.15.12.2402 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 376NH UT WOS:000165463300013 PM 11127205 ER PT J AU London, MJ Grunwald, GK Shroyer, ALW Grover, FL AF London, MJ Grunwald, GK Shroyer, ALW Grover, FL TI Association of fast-track cardiac management and low-dose to moderate-dose glucocorticoid administration with perioperative hyperglycemia SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Cardiovascular-Anesthesiologists CY MAY 10-14, 1997 CL BALTIMORE, MARYLAND SP Soc Cardiovasc Anesthesiologists DE adult-onset diabetes mellitus; corticosteroids; hyperglycemia; methylprednisolone; clinical protocols; postoperative complications ID CARDIOPULMONARY BYPASS; METABOLIC RESPONSE; EARLY EXTUBATION; HEART-SURGERY; RISK-FACTORS; GLUCOSE; METHYLPREDNISOLONE; ANESTHESIA; FENTANYL; PATIENT AB Objective: To delineate associations between preoperative risk factors and clinical processes of care and perioperative glucose tolerance in patients managed on a fast-track cardiac surgery clinical pathway with prebypass methylprednisolone administration. Design: Retrospective sequential cohort study, Setting: University-affiliate Department of Veterans Affairs medical center. Participants: Fast-track patients (n = 293; n = 72 low-dose methylprednisolone [100-125 mg]; n = 221 moderate-dose methylprednisolone [500 mg]) plus pre-fast-track patients (n = 258; no methylprednisolone) undergoing cardiac surgery with cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Multivariate linear regression was used to model the association of 17 preoperative risk and intraoperative process-of-care variables with serum glucose concentration on arrival in the intensive care unit. Preoperative serum glucose concentrations were not significantly different among the pre-fast-track, fast-track with low-dose methylprednisolone, and fast-track with moderate-dose methylprednisolone cohorts (129 +/- 54, 137 +/- 55, 127 +/- 46 mg/dL [mean +/- SD]). Postoperative serum glucose concentrations were significantly different (171 +/- 58, 223 +/- 56, 250 +/- 75 mg/dL; p < 0.03, for all pairwise comparisons). Using backward elimination from the full 17-variable multivariate model (R-square = 0.63), 4 variables remained significant (all p < 0.0001; R-square = 0.60): (1) Preoperative diabetes status (adjusted mean postoperative glucose level, mg/dL; (95% confidence interval (CI)1): no treatment, 193 (188-199); oral agent, 276 (262-291); insulin requiring, 301 (283-320); (2) steroid group: pre-fast-track, 201 (195-209), fast-track with low-dose methylprednisolone, 271 (256-287); fast-track with moderate-dose methylprednisolone, 295 (284-306); (3) volume of glucose-containing cardioplegia (beta coefficient, 95% CI): 2.22% (1.37-3.10) increase per 100 mt; and (4) intraoperative epinephrine infusion: none, 231 (224-239); yes, 276 (264-288). No significant interactions were identified. No significant effect of opioid dose was observed. Conclusion:At this institution, implementation of the fast-track pathway was associated with a deterioration of glucose tolerance. Preoperative diabetes, pre-cardiopulmonary bypass administration of steroids, volume of glucose-containing cardioplegia solution administered, and use of epinephrine infusions were significantly associated multivariate factors. Copyright (C) 2000 by W.B. Saunders Company. C1 Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Anesthesia & Perioperat Med, San Francisco, CA 94121 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver Vet Affairs Med Ctr, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver Vet Affairs Med Ctr, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Surg, Denver Vet Affairs Med Ctr, Denver, CO 80262 USA. RP London, MJ (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Anesthesia & Perioperat Med, 4150 Clement St, San Francisco, CA 94121 USA. NR 38 TC 9 Z9 10 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 1053-0770 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD DEC PY 2000 VL 14 IS 6 BP 631 EP 638 DI 10.1053/jcan.2000.18298 PG 8 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA 381NT UT WOS:000165770000002 PM 11139100 ER PT J AU Gramling-Babb, PM Zile, MR Reeves, ST AF Gramling-Babb, PM Zile, MR Reeves, ST TI Preliminary report on high thoracic epidural analgesia: Relationship between its therapeutic effects and myocardial blood flow as assessed by stress thallium distribution SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE high thoracic epidural analgesia; angina; treatment ID UNSTABLE ANGINA-PECTORIS; CORONARY-ARTERY DISEASE; ANESTHESIA AB Objectives: To extend the duration of high thoracic epidural analgesia (HTEA) treatment compared with the authors' previous studies, to test the hypothesis that the mechanism by which HTEA reduces angina during longterm treatment includes an improvement in myocardial blood flow distribution and a reduction in stress-induced ischemia, and to show that new myocardial infarctions are not masked or missed in patients receiving HTEA. Design: Prospective consecutive study. Setting: Department of Veteran's Affairs medical center and university-affiliate hospital, Participants: Six consenting adult patients. Interventions: Patients were evaluated before HTEA catheter insertion and >2 months after HTEA catheter insertion with stress thallium tests. Measurements and Main Results: Two of 6 patients had improvement but not resolution of stress-induced ischemia at 8 and 12 months. The remaining 4 patients had no change in stress-induced ischemia. None of the 6 patients had any new areas of ischemia or infarction as determined by stress thallium tests. Conclusions: The authors previously showed that HTEA is safe and effective in relieving refractory angina pectoris. The current study shows that this therapeutic effect persists and does not appear to be related to a change in myocardial blood flow; rather the improvement in symptoms probably results, in part, from an anesthetic effect. HTEA does not mask the development of new myocardial infarctions. Copyright (C) 2000 by W.B, Saunders Company. C1 Med Univ S Carolina, Dept Anesthesia & Perioperat Med, Charleston, SC 29425 USA. Med Univ S Carolina, Div Cardiol, Dept Med, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. RP Reeves, ST (reprint author), Med Univ S Carolina, Dept Anesthesia & Perioperat Med, 165 Ashley Ave,Suite 525,POB 250912, Charleston, SC 29425 USA. NR 13 TC 6 Z9 8 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 1053-0770 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD DEC PY 2000 VL 14 IS 6 BP 657 EP 661 DI 10.1053/jcan.2000.18312 PG 5 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA 381NT UT WOS:000165770000006 PM 11139104 ER PT J AU Kelly, SJ Myles, PS Bain, D Rosow, C Ramsay, J AF Kelly, SJ Myles, PS Bain, D Rosow, C Ramsay, J TI CASE 8-2000 - Intraoperative bispectral index monitoring and early extubation after cardiac surgery in patients with a history of awareness under anesthesia SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE awareness; bispectral index; cardiac surgery; monitoring; early extubation; depth of anesthesia ID GENERAL-ANESTHESIA; CARDIOPULMONARY BYPASS; NITROUS-OXIDE; IV ANESTHESIA; PROPOFOL; RECALL; RECOVERY; SEDATION; MEMORY; CONSCIOUSNESS C1 Alfred Hosp, Dept Anaesthesia & Pain Management, Prahran, Vic 3181, Australia. Monash Univ, Clayton, Vic 3168, Australia. Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Sch Med, Dept Anesthesiol, Div Crit Care Med Anesthesiol, Atlanta, GA 30322 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. RP Myles, PS (reprint author), Alfred Hosp, Dept Anaesthesia & Pain Management, Commercial Rd, Prahran, Vic 3181, Australia. OI Myles, Paul/0000-0002-3324-5456 NR 30 TC 2 Z9 2 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 1053-0770 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD DEC PY 2000 VL 14 IS 6 BP 726 EP 730 DI 10.1053/jcan.2000.18581 PG 5 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA 381NT UT WOS:000165770000021 PM 11232545 ER PT J AU Farah, SG Olafsson, E Gwynn, DG Azar, DT Brightbill, FS AF Farah, SG Olafsson, E Gwynn, DG Azar, DT Brightbill, FS TI Outcome of corneal and laser astigmatic axis alignment in photoastigmatic refractive keratectomy SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article; Proceedings Paper CT Symposium on Cataract, IOL and Refractive Surgery CY APR, 1999 CL SEATTLE, WASHINGTON SP IOL ID PHOTOREFRACTIVE KERATECTOMY; MYOPIC ASTIGMATISM; ABLATIONS AB Purpose: To compare the refractive results of laser astigmatic treatment in eyes in which the astigmatic axes of the eye and laser are aligned by limbal marking at the 6 o'clock position and in eyes that are not marked. Setting: University Hospital and Clinics, Madison, Wisconsin, USA. Methods: This retrospective study comprised 143 eyes that had photoastigmatic refractive keratectomy with the VISX Star excimer laser. The eyes were divided into marked (G1) and unmarked (G2) groups. Based on the preoperative astigmatism each group was subdivided into low astigmatism (less than or equal to1.00 diopter [D]) and high astigmatism (greater than or equal to1.25 D). Early postoperative manifest refractions (1.0 to 2.5 months) were analyzed. The Alpine vector analysis method was used to calculate the target induced astigmatism, surgically induced astigmatism, difference vector (DV), magnitude of error (ME), angle of error (AE), and index of success (IS). Results: There was no significant difference between the groups in DV, ME, and IS. When the subgroups were analyzed, the DV and ME were comparable; the IS in the G1 high astigmatism subgroup was significantly better than that in the G2 high astigmatism subgroup (0.22 +/- 0.08 and 0.29 +/- 0.04, respectively; P < .0001). There was comparable scatter of AE values; 30% and 36% in G1 and G2, respectively, had an AE of 0. Similar scatter was observed in the subgroups. Of the eyes that had an AE of 0, 90% and 43% in the high astigmatism subgroups of G1 and G2, respectively (P < .05), had full correction of astigmatism. Conclusion: Limbal marking and subsequent eye and laser astigmatic axis alignment improved the refractive outcome of laser astigmatic treatment of greater than or equal to1.25 D. A preliminary report of an ongoing prospective randomized study of eyes that had laser in situ keratomileusis is included. Ur Cataract Refract Surg 2000; 26:1722-1728 (C) 2000 ASCRS and ESCRS. C1 Univ Wisconsin, Dept Ophthalmol & Visual Sci, Cornea Serv, Madison, WI USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv, Boston, MA USA. RP Brightbill, FS (reprint author), 2870 Univ Ave,Suite 102, Madison, WI 53705 USA. NR 15 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD DEC PY 2000 VL 26 IS 12 BP 1722 EP 1728 DI 10.1016/S0886-3350(00)00695-7 PG 7 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 385QQ UT WOS:000166015500012 PM 11134870 ER PT J AU Varnum-Finney, B Wu, LZ Yu, M Brashem-Stein, C Staats, S Flowers, D Griffin, JD Bernstein, ID AF Varnum-Finney, B Wu, LZ Yu, M Brashem-Stein, C Staats, S Flowers, D Griffin, JD Bernstein, ID TI Immobilization of Notch ligand, Delta-1, is required for induction of Notch signaling SO JOURNAL OF CELL SCIENCE LA English DT Article DE Notch; Delta; myoblast development; ligand immobilization ID INTRACELLULAR DOMAIN; CELL FATE; IN-VIVO; DROSOPHILA; RECEPTOR; SERRATE; DIFFERENTIATION; ACTIVATION AB Cell-cell interactions mediated by Notch and its ligands are known to effect many cell fate decisions in both invertebrates and vertebrates, However, the mechanisms involved in ligand induced Notch activation are unknown, Recently it was shown that, in at least some cases, endocytosis of the extracellular domain of Notch and ligand by the signaling cell is required for signal induction in the receptive cell. These results imply that soluble ligands (ligand extracellular domains) although capable of binding Notch would be unlikely to activate it. To test the potential activity of soluble Notch ligands, we generated monomeric and dimeric forms of the Notch ligand Delta-1 by fusing the extracellular domain to either a series of myc epitopes (Delta-1(ext-myc)) or to the Fc portion of human IgG-1 Delta-1(ext-IgG)), respectively. Notch activation, assayed by inhibition of differentiation in C2 myoblasts and by HES1 transactivation in U20S cells, occurred when either Delta-1(ext-myc) or Delta-1(ext-IgG) were first immobilized on the plastic surface. However, Notch was not activated by either monomeric or dimeric ligand in solution (non-immobilized). Furthermore, both non-immobilized Delta-1(ext-myc) and Delta-1(ext-IgG) blocked the effect of immobilized Delta. These results indicate that Delta-1 extracellular domain must be immobilized to induce Notch activation in C2 or U20S cells and that non-immobilized Delta-1 extracellular domain is inhibitory to Notch function. These results imply that ligand stabilization may be essential for Notch activation. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Varnum-Finney, B (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. FU NCI NIH HHS [CA36167]; NHLBI NIH HHS [P50HL54881] NR 26 TC 176 Z9 179 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC PY 2000 VL 113 IS 23 BP 4313 EP 4318 PG 6 WC Cell Biology SC Cell Biology GA 384YR UT WOS:000165975300018 PM 11069775 ER PT J AU Asahi, M Asahi, K Jung, JC del Zoppo, GJ Fini, ME Lo, EH AF Asahi, M Asahi, K Jung, JC del Zoppo, GJ Fini, ME Lo, EH TI Role for matrix metalloproteinase 9 after focal cerebral ischemia, effects of gene knockout and enzyme inhibition with BB-94 SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE stroke; proteolysis; extracellular matrix; neuroprotection; gene knockout; mouse ID CENTRAL-NERVOUS-SYSTEM; EXPRESSION; BRAIN; RAT; ASTROCYTES; PROTEIN; DAMAGE; FAMILY; GROWTH AB It has been shown recently that matrix metalloproteinases (MMPs) are elevated after cerebral ischemia. In the current study, we investigated the pathophysiologic role for MMP-9 (gelatinase B, EC.3.4.24.35) in a mouse model of permanent focal cerebral ischemia, using a combination of genetic and pharmacologic approaches. Zymography and Western blot analysis demonstrated that MMP-9 protein levels were rapidly up-regulated in brain after ischemic onset. Reverse transcription polymerase chain reaction showed increased transcription of MMP-9. There were no differences in systemic hemodynamic parameters and gross cerebrovascular anatomy between wild type mice and mutant mice with a targeted knockout of the MMP-9 gene. After induction of focal ischemia, similar reductions in cerebral blood flow were obtained. In the MMP-9 knockout mice, ischemic lesion volumes were significantly reduced compared with wild type littermates in male and female mice. In normal wild type mice, the broad spectrum MMP inhibitor BB-94 (batimastat) also significantly reduced ischemic lesion size. However, BB-94 had no detectable protective effect when administered to MMP-9 knockout mice subjected to focal cerebral ischemia. These data demonstrate that MMP-9 plays a deleterious role in the development of brain injury after focal ischemia. C1 Harvard Univ, Sch Med, Dept Neurol, Neuroprotect Res Lab,Program Neurosci, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA USA. Tufts Univ, Sch Med, New England Eye Ctr, Vis Res Labs, Boston, MA 02111 USA. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA USA. RP Lo, EH (reprint author), Harvard Univ, Sch Med, Dept Neurol, Neuroprotect Res Lab,Program Neurosci, MGH E 149-2322, Charlestown, MA 02129 USA. FU NINDS NIH HHS [R01-NS37074, R01-NS38731, R01-NS40529] NR 39 TC 424 Z9 447 U1 0 U2 5 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 DEC PY 2000 VL 20 IS 12 BP 1681 EP 1689 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 380HX UT WOS:000165696700007 PM 11129784 ER PT J AU Freedman, R Adams, CE Leonard, S AF Freedman, R Adams, CE Leonard, S TI The alpha 7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Article DE post mortem; nicotinic receptor; cholecystokinin; somatostatin; GABA; nitric oxide; human chromosome 15; hippocampus; cerebral cortex; thalamus ID ALPHA-BUNGAROTOXIN BINDING; SOMATOSTATIN-LIKE IMMUNOREACTIVITY; NITRIC-OXIDE SYNTHASE; CHRNA7 GENE REGION; NICOTINIC RECEPTORS; RAT HIPPOCAMPUS; ALZHEIMERS-DISEASE; CEREBRAL-CORTEX; MESSENGER-RNA; SYNAPTIC TRANSMISSION AB This paper is a review of a recent findings on the pathology of hippocampal interneurons in schizophrenia, with specific emphasis on a protein expressed by these cells, the alpha7-nicotinic acetylcholine receptor subunit. Convergent information indicates that interneurons in the hippocampus and other forebrain structures are decreased in number and function in subjects with schizophrenia. Among the neurochemical markers that are decreased in the hippocampus are synapsin I, cholecystokinin, somatostatin, glutamic acid decarboxylase, and nitric oxide synthase. GABA uptake sites and the GABA synthetic enzyme glutamic acid decarboxylase are also diminished. Included among these findings is decreased binding of alpha -bungarotoxin, which binds to low-affinity nicotinic acetylcholine receptors, such as the alpha -nicotinic receptor. Co-labeling experiments in rodents indicate that these markers are expressed on overlapping populations of hippocampal interneurons. Thus. the finding of decreased neurochemical function of hippocampal interneurons is a widely replicated finding, with different groups reporting markedly similar findings using independent post mortem samples and different neurochemical strategies. Decreased alpha -bungarotoxin binding or decreased alpha7-nicotinic receptor immunoreactivity has also been found in the frontal cortex and in the nucleus reticularis thalami of schizophrenic subjects. The alpha7-nicotinic receptor subunit gene on chromosome 15q14 is a site of heritability for schizophrenia and bipolar affective disorder, and in, particular, for a deficit in inhibitory neuronal function associated with these illnesses. Thus, the post mortem data are further supported by psychophysiologic and genetic investigations that indicate a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor. The alpha7-receptor is a ligand-gated ion channel that admits calcium ions into cells, and it has been proposed to have various developmental roles. Its malfunction may be part of the developmental pathogenesis of schizophrenia. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmacol & Psychiat, Denver, CO 80262 USA. Denver VA Med Ctr, Denver, CO 80262 USA. RP Freedman, R (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmacol & Psychiat, Campus Box C-268-71,Room 3F10,4200 E 9th Ave, Denver, CO 80262 USA. NR 79 TC 147 Z9 151 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD DEC PY 2000 VL 20 IS 3-4 BP 299 EP 306 DI 10.1016/S0891-0618(00)00109-5 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 404TP UT WOS:000167117200010 PM 11207427 ER PT J AU Cullen, DJ Bates, DW Leape, LL AF Cullen, DJ Bates, DW Leape, LL CA Adverse Drug Event Prevention Stu TI Prevention of adverse drug events: A decade of progress in patient safety SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE human error; system analysis; medication errors; incident reports; intensive care units; computerized physician order entry; clinical pharmacists ID INTENSIVE-CARE UNIT; PHYSICIAN ORDER ENTRY; 2000 INCIDENT REPORTS; HOSPITALIZED-PATIENTS; PULSE OXIMETRY; CLOSED CLAIMS; ANESTHETIC COMPLICATIONS; MEDICATION ERRORS; PHARMACIST; MEDICINE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Cullen, DJ (reprint author), St Elizabeths Med Ctr, Dept Anesthesiol, 736 Cambridge St, Boston, MA 02135 USA. FU AHRQ HHS [R01-HS07107-01] NR 80 TC 29 Z9 30 U1 5 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD DEC PY 2000 VL 12 IS 8 BP 600 EP 614 DI 10.1016/S0952-8180(00)00226-9 PG 15 WC Anesthesiology SC Anesthesiology GA 402TP UT WOS:000167004500006 PM 11173000 ER PT J AU Urbanek, M Wu, XQ Vickery, KR Kao, LC Christenson, LK Schneyer, A Legro, RS Driscoll, DA Strauss, JF Dunaif, A Spielman, RS AF Urbanek, M Wu, XQ Vickery, KR Kao, LC Christenson, LK Schneyer, A Legro, RS Driscoll, DA Strauss, JF Dunaif, A Spielman, RS TI Allelic variants of the follistatin gene in polycystic ovary syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACTIVIN; DISEQUILIBRIUM; LINKAGE; TRAIT; WOMEN AB In an earlier study of 37 candidate genes for polycystic ovary syndrome (PCOS), the strongest evidence for genetic linkage was found with the region of the follistatin gene. We have now carried out studies to detect variation in the follistatin gene and assess its relevance to PCOS. By sequencing the gene in 85 members of 19 families of PCOS patients, we found sequence variants at 17 sites. Of these, 16 sites have variants that are too rare to make a major contribution to susceptibility; the only common variant is a single base pair change in the last exon at a site that is not translated, In our sample of 249 families, the evidence for linkage between PCOS and this variant is weak. We also examined the expression of the follistatin gene; messenger RNA levels in cultured fibroblasts from PCOS and control women did not differ appreciably. We conclude that contributions to the etiology of PCOS from the follistatin gene, if any, are likely to be small. C1 Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Brigham & Womens Hosp, Div Womens Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. Penn State Univ, Coll Med, Dept Obstet & Gynecol, Hershey, PA 17033 USA. RP Urbanek, M (reprint author), Univ Penn, Sch Med, Dept Genet, 415 Curie Blvd, Philadelphia, PA 19104 USA. EM murbanek@mail.upenn.edu RI Christenson, Lane/G-6435-2013 FU NICHD NIH HHS [U54HD34449, K08HD0118]; NIDDK NIH HHS [R01DK40605] NR 23 TC 60 Z9 60 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 DEC PY 2000 VL 85 IS 12 BP 4455 EP 4461 DI 10.1210/jc.85.12.4455 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 390CM UT WOS:000166277800007 PM 11134093 ER PT J AU Swerdloff, RS Wang, C Cunningham, G Dobs, A Iranmanesh, A Matsumoto, AM Snyder, PJ Weber, T Longstreth, J Berman, N AF Swerdloff, RS Wang, C Cunningham, G Dobs, A Iranmanesh, A Matsumoto, AM Snyder, PJ Weber, T Longstreth, J Berman, N CA Testosterone Gel Study Grp TI Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CLINICAL RESEARCH-CENTER; SYSTEM; DELIVERY; REPLACEMENT; THERAPY; AGE AB Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in an study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate. C1 Univ Calif Los Angeles, Harbor Med Ctr, Dept Med, Div Endocrinol, Torrance, CA 90509 USA. Univ Calif Los Angeles, Harbor Med Ctr, Dept Pediat, Div Endocrinol, Torrance, CA 90509 USA. Res & Educ Inst, Torrance, CA 90509 USA. Baylor Coll Med, Vet Affairs Med Ctr, Houston, TX 77030 USA. Vet Affairs Med Ctr, Salem, VA 24153 USA. Johns Hopkins Univ, Baltimore, MD 21287 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. Duke Univ, Med Ctr, Durham, NC 27705 USA. Unimed Pharmaceut Inc, Deerfield, IL 60015 USA. RP Wang, C (reprint author), Univ Calif Los Angeles, Harbor Med Ctr, Gen Clin Res Ctr, 1000 W Carson St, Torrance, CA 90509 USA. EM wang@gcrc.humc.edu FU NCRR NIH HHS [M01RR0030, M01RR00425] NR 26 TC 210 Z9 216 U1 0 U2 7 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 DEC PY 2000 VL 85 IS 12 BP 4500 EP 4510 DI 10.1210/jc.85.12.4500 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 390CM UT WOS:000166277800013 PM 11134099 ER PT J AU Kahn, CR Chen, LH Cohen, SE AF Kahn, CR Chen, LH Cohen, SE TI Unraveling the mechanism of action of thiazolidinediones SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID ADIPOSE-TISSUE; ANTIDIABETIC AGENT; INSULIN-RECEPTOR; GENE-EXPRESSION; TROGLITAZONE; KNOCKOUT; INVITRO; CS-045; LIGAND; CELLS C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. NR 26 TC 105 Z9 107 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2000 VL 106 IS 11 BP 1305 EP 1307 DI 10.1172/JCI11705 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 379MZ UT WOS:000165647800001 PM 11104782 ER PT J AU Colleoni, M O'Neill, A Goldhirsch, A Gelber, RD Bonetti, M Thurlimann, B Price, KN Castiglione-Gertsch, M Coates, AS Lindtner, J Collins, J Senn, HJ Cavalli, F Forbes, J Gudgeon, A Simoncini, E Cortes-Funes, H Veronesi, A Fey, M Rudenstam, CM AF Colleoni, M O'Neill, A Goldhirsch, A Gelber, RD Bonetti, M Thurlimann, B Price, KN Castiglione-Gertsch, M Coates, AS Lindtner, J Collins, J Senn, HJ Cavalli, F Forbes, J Gudgeon, A Simoncini, E Cortes-Funes, H Veronesi, A Fey, M Rudenstam, CM CA Intl Ludwig Breast Canc Study Grp TI Identifying breast cancer patients at high risk for bone metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ISOLATED LOCOREGIONAL RECURRENCE; BISPHOSPHONATES INHIBIT; PROPHYLACTIC TREATMENT; FAILURE PROBABILITIES; ADJUVANT TREATMENT; COMPETING RISK; PAST DECADE; FOLLOW-UP; TUMOR; MASTECTOMY AB Purpose: To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates. Patients and Methods: We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10.7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence. Results: For the entire population with operable disease, the cumulative incidence of bone metastases at any time wets 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years). Conclusion: Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue. (C) 2000 by American Society of Clinical Oncology. C1 European Inst Oncol, Div Med Oncol, Int Breast Canc Study Grp, I-20141 Milan, Italy. Osped Civile, Brescia, Italy. Ctr Riferimento Oncol Aviano, Aviano, Italy. Dana Farber Canc Inst, Dept Biostat Sci, Int Breast Canc Study Grp, Ctr Stat, Boston, MA 02115 USA. Kantonsspital, St Gallen, Switzerland. Zentrum Tumordiagnost & Prevent, St Gallen, Switzerland. Int Breast Canc Study Grp, Coordinating Ctr, Bern, Switzerland. Univ Bern, Inselspital, Inst Med Oncol, CH-3010 Bern, Switzerland. Osped Civico, Lugano, Switzerland. Univ Sydney, Australian Canc Soc, Sydney, NSW 2006, Australia. Royal Melbourne Hosp, Melbourne, Vic, Australia. New Zealand Trials Grp, Waratah, Australia. Inst Oncol, Ljubljana, Slovenia. Wynberg Hosp, Cape Town, South Africa. Hosp Seguridad Social, Madrid, Spain. Sahlgrens Univ Hosp, Molndal, Sweden. RP Colleoni, M (reprint author), European Inst Oncol, Div Med Oncol, Int Breast Canc Study Grp, Via Ripamonti 435, I-20141 Milan, Italy. OI Bonetti, Marco/0000-0003-2304-4180 NR 43 TC 74 Z9 77 U1 3 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 DEC 1 PY 2000 VL 18 IS 23 BP 3925 EP 3935 PG 11 WC Oncology SC Oncology GA 380UJ UT WOS:000165721600007 PM 11099322 ER PT J AU Ackerman, DL Greenland, S Bystritsky, A Small, GW AF Ackerman, DL Greenland, S Bystritsky, A Small, GW TI Side effects and time course of response in a placebo-controlled trial of fluoxetine for the treatment of geriatric depression SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; PATTERN-ANALYSIS; DRUG RESPONSE; MAJOR DEPRESSION; RATING-SCALE; TRUE DRUG; ANTIDEPRESSANTS; IMPACT; HETEROGENEITY; BLINDABILITY AB A high rate of improvement among patients who receive placebo in controlled trials of antidepressants can complicate the evaluation of true drug effect, Placebo response may be a reaction to the psychosocial factors of study participation or a function of changes in the natural course of depression. Drug side effects may also influence patients' expectations, and they should be distinguished fi om the somatic symptoms associated with major depression. The authors reanalyzed data from a large, multicenter, placebo-controlled clinical trial of fluoxetine treatment of geriatric depression to evaluate similarities and differences between responders and nonresponders in both treatment groups. Specifically, the authors examined weekly somatic complaints as possible predictors of response and of dropout, as well as the time course and onset of response. Fluoxetine was superior to placebo on all outcome measures. Among somatic complaints associated with fluoxetine response, headache before and after randomization was associated with a good response and anxiety after randomization was associated with a poor response. Somnolence before and after randomization was associated with a good placebo response. Early and persistent improvement occurred among similar proportions of responders in both groups. The difference between fluoxetine and placebo seemed to be a persistent response beginning during the 4th week, Pretreatment somnolence was associated with early, persistent improvement in both groups and may serve as a marker for placebo response. C1 Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Ctr Aging, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Ackerman, DL (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Box 951772, Los Angeles, CA 90095 USA. FU NIMH NIH HHS [MH-53935] NR 46 TC 8 Z9 8 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD DEC PY 2000 VL 20 IS 6 BP 658 EP 665 DI 10.1097/00004714-200012000-00012 PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 377AU UT WOS:000165490400010 PM 11106138 ER PT J AU Faraone, SV Biederman, J Spencer, TJ Wilens, TE AF Faraone, SV Biederman, J Spencer, TJ Wilens, TE TI The drug-placebo response curve: A new method for assessing drug effects in clinical trials SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID DSM-III-R; AUTISTIC DISORDER; HYPERACTIVITY; CRITERIA AB Unlike many other areas of medicine, psychiatric clinical trials have no gold standard laboratory tests with which to measure drug effects. Although reliable and valid psychometric measures are available, the standard analysis of such measures obscures the clinical relevance of drug effects. In this study, the authors sought to address this problem by developing a graphical display called the drug-placebo response curve. The features of the drug-placebo response curve are described by applying it to a previously published, controlled clinical trial of desipramine in the treatment of adults with attention-deficit/hyperactivity disorder. Unlike the standard analysis, the drug-placebo response curve showed that desipramine was effective over the full range of response and that it prevented worsening, in addition to increasing the likelihood of improvement. The drug-placebo response curve provides clinically relevant information about the effect of drugs on continuous outcomes in controlled clinical trials. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Child Psychiat Serv,Pediat Psychopharmacol Unit A, Boston, MA 02114 USA. Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA USA. RP Faraone, SV (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Child Psychiat Serv,Pediat Psychopharmacol Unit A, 15 Parkman St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NICHD NIH HHS [R01HD37694]; NIMH NIH HHS [R01 MH57934, R13 MH59126] NR 30 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD DEC PY 2000 VL 20 IS 6 BP 673 EP 679 DI 10.1097/00004714-200012000-00014 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 377AU UT WOS:000165490400012 PM 11106140 ER PT J AU Detmar, M AF Detmar, M TI The role of VEGF and thrombospondins in skin angiogenesis SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Article; Proceedings Paper CT Shiseido Science Symposium on Skin Care in the New Millennium CY APR 15, 2000 CL TOKYO, JAPAN SP Shiseido Co Ltd DE VEGF; TSP-1; TSP-2; skin ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; TRANSGENIC MICE; TUMOR-CELLS; OVEREXPRESSION; EXPRESSION; RECEPTORS; VPF/VEGF; DENSITY AB The vasculature in adult skin remains normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, skin retains the capacity for brisk initiation of angiogenesis, the growth of new blood vessels from preexisting vessels, during tissue repair and in numerous diseases, including inflammatory skin diseases such as psoriasis and skin cancers such as cutaneous squamous cell carcinomas. Moreover, cyclic vascular expansion occurs during the growth phase of the hair follicle. Recent evidence suggests vascular endothelial growth factor as the major skin angiogenesis factor. During skin angiogenesis, expression of vascular endothelial growth factor is induced in epidermal keratinocytes by several stimuli including transforming growth factor-cc and hypoxia, leading to increased vascularization of the dermis. In contrast, vascular endothelial growth factor-C induces skin lymphangiogenesis. Thrombospondin-l and thrombospondin-2 are endogenous inhibitors of angiogenesis that are expressed in normal skin, maintaining the quiescence of cutaneous vessels. Both inhibitors potently inhibit skin cancer growth via inhibition of tumor angiogenesis. Targeting cutaneous blood vessels represents a promising new therapeutic approach for the treatment of a variety of skin diseases. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. NR 30 TC 75 Z9 83 U1 1 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD DEC PY 2000 VL 24 SU 1 BP S78 EP S84 DI 10.1016/S0923-1811(00)00145-6 PG 7 WC Dermatology SC Dermatology GA 392PW UT WOS:000166421100012 PM 11137400 ER PT J AU Nishiyama, T Amano, S Tsunenaga, M Kadoya, K Takeda, A Adachi, E Burgeson, RE AF Nishiyama, T Amano, S Tsunenaga, M Kadoya, K Takeda, A Adachi, E Burgeson, RE TI The importance of laminin 5 in the dermal-epidermal basement membrane SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Article; Proceedings Paper CT Shiseido Science Symposium on Skin Care in the New Millennium CY APR 15, 2000 CL TOKYO, JAPAN SP Shiseido Co Ltd DE laminin 5; basement membrane; anchoring complex; dermal-epidermal junction; keratinocyte sheet; transplantation ID EPIDERMOLYSIS-BULLOSA; INTEGRIN RECEPTORS; VII COLLAGEN; GENE LAMC2; KERATINOCYTES; KALININ; CELLS; DIFFERENTIATION; ALPHA-6-BETA-4; LOCALIZATION AB The skin consists of two main layers, epidermis and dermis, separated by the basement membrane. Epidermal-dermal communication through the basement membrane is important for skin homeostasis. The basement membrane contains specialized structures, called the anchoring complex, which ensure the stability of connection and communication between these two tissue compartments. The proteins within the anchoring complex provide links to both the intracellular cytoskeletal keratins in keratinocytes and connective tissue proteins of the dermis. One of the key components of the complex is laminin 5, which is essential to epidermal cell attachment. The biological function of laminin 5 has been investigated by using a skin equivalent model in vitro and during keratinocyte sheet grafting in vivo. As a major link between the epidermal basal cells and the papillary dermis, laminin 5 initiates hemidesmosome formation and provides stable attachment of the epidermis to the dermis. Laminin 5 also accelerates the assembly of basement membranes and may enhance the recovery of damaged skin. An intact basement membrane at the epidermal-dermal junction is essential to stability of the skin. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Shiseido Life Sci Res Ctr, Yokohama, Kanagawa, Japan. Kitasato Univ, Sch Med, Dept Plast & Reconstruct Surg, Sagamihara, Kanagawa 228, Japan. Kitasato Univ, Postgrad Med Sch, Dept Mol Morphol, Sagamihara, Kanagawa 228, Japan. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Nishiyama, T (reprint author), Shiseido Life Sci Res Ctr, Yokohama, Kanagawa, Japan. EM toshio.nishiyama@to.shiseido.co.jp RI Nishiyama, Toshio/C-5434-2013 NR 28 TC 35 Z9 35 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD DEC PY 2000 VL 24 SU 1 BP S51 EP S59 DI 10.1016/S0923-1811(00)00142-0 PG 9 WC Dermatology SC Dermatology GA 392PW UT WOS:000166421100009 PM 11137397 ER PT J AU Nahas, Z DeBrux, C Chandler, V Lorberbaum, JP Speer, AM Molloy, MA Liberatos, C Risch, SC George, MS AF Nahas, Z DeBrux, C Chandler, V Lorberbaum, JP Speer, AM Molloy, MA Liberatos, C Risch, SC George, MS TI Lack of significant changes on magnetic resonance scans before and after 2 weeks of daily left prefrontal repetitive transcranial magnetic stimulation for depression SO JOURNAL OF ECT LA English DT Article DE depression; repetitive transcranial magnetic stimulation; magnetic resonance imaging ID MAJOR DEPRESSION; HEARING-LOSS; CORTEX; BRAIN; RTMS; MOOD; SAFETY AB Repetitive transcranial magnetic stimulation (rTMS) is a new technology for exploring brain function. With this method, a small electromagnet is placed on the scalp; by activating and deactivating it, nerve cells in the underlying superficial cortex are depolarized. Several studies have found that prefrontal rTMS has potential efficacy in treating depression, and this technology, in addition to being a research tool, may soon play a role in psychiatric practice. Thus, establishing the safety of this technology is important and has been studied insufficiently. The authors performed T1-weighted three-dimensional volumetric magnetic resonance (MR) imaging on 22 depressed adults (15 active, 7 control) before and after they participated in a 2-week double-blinded, placebo-controlled trial of daily left prefrontal rTMS for the treatment of depression (a total of 16,000 stimuli). Seventeen patients also had paired T2-weighted scans. In a blinded manner, MR scans were qualitatively and quantitatively assessed for structural changes. No qualitative structural differences were observed before and after treatment. In addition, volumetric analysis of the prefrontal lobe showed no changes in the 2 weeks of the study. In conclusion, 10 days of daily prefrontal rTMS at these intensities and frequencies does not cause observable structural changes on MR scans in depressed adults. C1 Med Univ S Carolina, Inst Psychiat, Dept Psychiat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Ralph H Johnson Vet Adm Med Ctr, Dept Psychiat, Charleston, SC USA. RP Nahas, Z (reprint author), Med Univ S Carolina, Inst Psychiat, Dept Psychiat, 67 President St, Charleston, SC 29425 USA. NR 41 TC 40 Z9 40 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1095-0680 J9 J ECT JI J. ECT PD DEC PY 2000 VL 16 IS 4 BP 380 EP 390 DI 10.1097/00124509-200012000-00008 PG 11 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 382HC UT WOS:000165816000008 PM 11314876 ER PT J AU Meredith, LS Jackson-Triche, M Duan, NH Rubenstein, LV Camp, P Wells, KB AF Meredith, LS Jackson-Triche, M Duan, NH Rubenstein, LV Camp, P Wells, KB TI Quality improvement for depression enhances long-term treatment knowledge for primary care clinicians SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care clinicians; depression; quality improvement; treatment knowledge; managed care ID MANAGED PRIMARY-CARE; PHYSICIAN PERFORMANCE; UNITED-STATES; INTERVENTION; GUIDELINES; DISORDERS; IMPACT; MODEL AB OBJECTIVE: We evaluated the effect of implementing quality improvement (QI) programs for depression, relative to usual care, on primary care clinicians' knowledge about treatment. DESIGN AND METHODS: Matched primary care clinics (46) from seven managed care organizations were randomized to usual care (mailed written guidelines only) versus one of two QI interventions. Self-report surveys assessed clinicians' knowledge of depression treatments prior to full implementation (June 1996 to March 1997) and 18 months later. We used an intent-to-treat analysis to examine intervention effects on change in knowledge, controlling for clinician and practice characteristics, and the nested design. PARTICIPANTS: One hundred eighty-one primary care clinicians. INTERVENTIONS: The interventions included institutional commitment to QI, training local experts, clinician education, and training nurses for patient assessment and education. One intervention had resources for nurse follow-up on medication use (QI-meds) and the other had reduced copayment for therapy from trained, local therapists (QI-therapy). RESULTS:Clinicians in the intervention group had greater increases compared with clinicians in the usual care group over 18 months in knowledge of psychotherapy (by 20% for QI-meds, P = .04 and by 33% for QI-therapy, P = .004), but there were no significant increases in medication knowledge. Significant increases in knowledge scores (P = .01) were demonstrated by QI-therapy clinicians but not clinicians in the QI-meds group. Clinicians were exposed to multiple intervention components. CONCLUSIONS: Dissemination of QI programs for depression in managed, primary care practices improved clinicians' treatment knowledge over 18 months, but breadth of learning was somewhat greater for a program that also included active collaboration with local therapists. C1 RAND Corp, Hlth Program, Santa Monica, CA 90407 USA. Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Med, Neuropsychiat Inst & Hosp, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. RP Meredith, LS (reprint author), RAND Corp, Hlth Program, 1700 Main St, Santa Monica, CA 90407 USA. FU AHRQ HHS [R01 HS008349, R01-HS08349]; NIMH NIH HHS [R29-MH55223-01] NR 33 TC 35 Z9 35 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 DEC PY 2000 VL 15 IS 12 BP 868 EP 877 DI 10.1046/j.1525-1497.2000.91149.x PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 385GG UT WOS:000165994800005 PM 11119183 ER PT J AU Jain, S Chou, CL AF Jain, S Chou, CL TI Use of an orientation clinic to reduce failed new patient appointments in primary care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-of-General-Internal-Medicine CY APR 29-MAY 01, 1999 CL SAN FRANCISCO, CALIFORNIA SP Soc Gen Internal Med ID ATTENDANCE RATES AB Patients who fail to attend initial appointments reduce clinic efficiency. To maximize attendance by newly referred outpatients, we introduced a mandatory group orientation clinic for all new patients and determined its effects on no-show rates. Orientation clinic also provided health care screening and opportunities for patient feedback. The new patient no-show rate for initial provider visits decreased significantly from 45% before institution of orientation clinic to 18% afterwards (P < .0001). The total no-show (patients who failed to attend orientation clinic or an Initial provider visit) rate of the postintervention group was 51% (P = .28, compared with before the intervention). This intervention improved the efficiency and minimized the wasted time of our clinicians. C1 Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, Gen Internal Med Sect,Med Serv 111, San Francisco, CA 94121 USA. RP Jain, S (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, Gen Internal Med Sect,Med Serv 111, 4150 Clermont St, San Francisco, CA 94121 USA. NR 6 TC 4 Z9 5 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 DEC PY 2000 VL 15 IS 12 BP 878 EP 880 DI 10.1046/j.1525-1497.2000.00201.x PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 385GG UT WOS:000165994800006 PM 11119184 ER PT J AU Saint, S Christakis, DA Saha, S Elmore, JG Welsh, DE Baker, P Koepsell, TD AF Saint, S Christakis, DA Saha, S Elmore, JG Welsh, DE Baker, P Koepsell, TD TI Journal reading habits of internists SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID EVIDENCE-BASED MEDICINE; USERS GUIDES; RESEARCH ARTICLES; HELP ME; ABSTRACTS; QUALITY; INFORMATION; ACCURACY; WILL; NEED AB We assessed the reading habits of internists with and without epidemiological training because such information may help guide medical journals as they make changes in how articles are edited and formatted. In a 1998 national self-administered mailed survey of 143 internists with fellowship training in epidemiology and study design and a random sample of 121 internists from the American Medical Association physician master file. we asked about the number of hours spent reading medical journals per week and the percentage of articles for which only the abstract is read. Respondents also were asked which of nine medical journals they subscribe to and read regularly. Of the 399 eligible participants, 264 returned surveys (response rate 66%). Respondents reported spending 4.4 hours per week reading medical journal articles and reported reading only the abstract for 63% of the articles: these findings were similar for internists with and without epidemiology training. Respondents admitted to a reliance on journal editors to provide rigorous and useful information, given the limited time available for critical reading. We conclude that internists, regardless of training in epidemiology, rely heavily on abstracts and prescreening of articles by editors. C1 Univ Michigan, Div Gen Med, Ann Arbor, MI USA. Univ Washington, Div Gen Pediat, Seattle, WA USA. Univ Washington, Div Gen Internal Med, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA USA. Univ Washington, Dept Hlth Serv, Seattle, WA USA. Oregon Hlth Sci Univ, Portland VA Med Ctr, Div Gen Internal Med, Portland, OR USA. Ann Arbor Va Hlth Serv Res & Dev, Ann Arbor, MI USA. Seattle VA Med Ctr, Seattle, WA USA. RP Saint, S (reprint author), 300 N Ingalls Bldg,Room 7E08,Campus Box 0429, Ann Arbor, MI 48109 USA. NR 21 TC 65 Z9 66 U1 0 U2 4 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 DEC PY 2000 VL 15 IS 12 BP 881 EP 884 DI 10.1046/j.1525-1497.2000.00202.x PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 385GG UT WOS:000165994800007 PM 11119185 ER PT J AU Govardovskii, VI Calvert, PD Arshavsky, VY AF Govardovskii, VI Calvert, PD Arshavsky, VY TI Commentary - Photoreceptor light adaptation: Untangling desensitization and sensitization SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Editorial Material ID PHOTOTRANSDUCTION; MECHANISMS; CALCIUM; RODS C1 IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Govardovskii, VI (reprint author), IM Sechenov Evolutionary Physiol & Biochem Inst, Thorez Pr 44, St Petersburg 194223, Russia. NR 12 TC 7 Z9 9 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD DEC PY 2000 VL 116 IS 6 BP 791 EP 794 DI 10.1085/jgp.116.6.791 PG 4 WC Physiology SC Physiology GA 381LK UT WOS:000165764200005 PM 11099348 ER PT J AU Caprioli, J Samson, CM Foster, CS Araie, M Rockwood, EJ AF Caprioli, J Samson, CM Foster, CS Araie, M Rockwood, EJ TI Uveitis and glaucoma SO JOURNAL OF GLAUCOMA LA English DT Editorial Material C1 Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Massachusetts Eye & Ear Infirm, Ocular Immunol & Uveitis Serv, Boston, MA 02114 USA. Univ Tokyo, Dept Ophthalmol, Tokyo 113, Japan. Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA. RP Caprioli, J (reprint author), Univ Calif Los Angeles, Jules Stein Eye Inst, 100 Stein Plaza, Los Angeles, CA 90024 USA. OI Caprioli, Joseph/0000-0002-2383-7263 NR 2 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1057-0829 J9 J GLAUCOMA JI J. Glaucoma PD DEC PY 2000 VL 9 IS 6 BP 463 EP 467 PG 5 WC Ophthalmology SC Ophthalmology GA 384XJ UT WOS:000165972300008 PM 11131753 ER PT J AU Cooper, DKC Keogh, AM Brink, J Corris, PA Klepetko, W Pierson, RN Schmoeckel, M Shirakura, R Stevenson, LW AF Cooper, DKC Keogh, AM Brink, J Corris, PA Klepetko, W Pierson, RN Schmoeckel, M Shirakura, R Stevenson, LW TI Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: The present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Review ID XENOREACTIVE NATURAL ANTIBODIES; PORCINE ENDOTHELIAL-CELLS; DECAY-ACCELERATING FACTOR; EXTRACORPOREAL MEMBRANE-OXYGENATION; CYCLOSPORINE-TREATED BABOONS; VENTRICULAR ASSIST DEVICE; ALPHA-GALACTOSYL EPITOPES; PIG ENDOGENOUS RETROVIRUS; EXPRESSING HUMAN CD59; HYPERACUTE REJECTION AB An urgent and steadily increasing need exists worldwide for a greater supply of donor thoracic organs. Xenotransplantation offers the possibility of an unlimited supply of hearts and lungs that could be available electively when required. However, antibody-mediated mechanisms cause the rejection of pig organs transplanted into non-human primates, and these mechanisms provide major immunologic barriers that have not yet been overcome. Having reviewed the literature on xenotransplantation, we present a number of conclusions on its present status with regard to thoracic organs, and we make a number of recommendations relating to eventual clinical trials. Although pig hearts have functioned in heterotopic sites in non-human primates for periods of several weeks, median survival of orthotopically transplanted hearts is currently <1 month. No transplanted pig lung has functioned for even 24 hours. Current experimental results indicate that a clinical trial would be premature. A potential risk exists, hitherto undetermined, of transferring infectious organisms along with the donor pig organ to the recipient, and possibly to other members of the community. A clinical trial of xenotransplantation should not be undertaken until experts in microbiology and the relevant regulatory authorities consider this risk to be minimal. A clinical trial should be considered when proximately 60% survival of life-supporting pig organs in non-human primates has been achieved for a minimum of 3 months, with at least 10 animals surviving for this minimum period. Furthermore, evidence should suggest that longer survival (>6 months) can be achieved. These results should be achieved in the absence of life-threatening complications caused by the immunosuppressive regimen used. The relationship between the presence of anti-HLA antibody and anti-pig antibody and their crossreactivity, and the outcome of pig-organ xenotransplantation in recipients previously sensitized to HLA antigens require further investigation. We recommend that the patients who initially enter into a clinical trial of cardiac xenotransplantation be unacceptable for allotransplantation, or acceptable for allotransplantation but unlikely to survive until a human cadaveric organ becomes available, and in whom mechanical assist-device bridging is not possible. National bodies that have wide-reaching government-backed control over all aspects of the trials should regulate the initial clinical trial and all subsequent clinical xenotransplantation procedures for the foreseeable future. We recommend coordination and monitoring of these trials through an international body, such as the International Society for Heart and Lung Transplantation, and setting up a registry to record and widely disperse the results of these trials. Xenotransplantation has the potential to solve the problem of donor-organ supply, and therefore rei search in this field should be actively encouraged and supported. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. Univ New S Wales, St Vincent Hosp, Cardiothorac Transplant Unit, Sydney, NSW, Australia. Univ Cape Town, Groote Schuur Hosp, Dept Cardiothorac Surg, ZA-7925 Cape Town, South Africa. Univ Newcastle Upon Tyne, Freeman Hosp, Dept Resp Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Vienna, Dept Cardiothorac Surg, Vienna, Austria. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. Osaka Univ, Grad Sch Med, Ctr Biomed Res, Div Organ Transplantat, Osaka, Japan. RP Cooper, DKC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 253 TC 80 Z9 80 U1 0 U2 6 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 DEC PY 2000 VL 19 IS 12 BP 1125 EP 1165 DI 10.1016/S1053-2498(00)00224-2 PG 41 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 384FE UT WOS:000165931500001 PM 11124485 ER PT J AU Lu, L Dai, MS Ge, Y Wang, LS Braun, SE Wait, CL Griffith, DJ Heinrich, MC Broxmeyer, HE AF Lu, L Dai, MS Ge, Y Wang, LS Braun, SE Wait, CL Griffith, DJ Heinrich, MC Broxmeyer, HE TI Co-transduction of cDNAs for c-kit and steel factor into single CD34(+) cord blood cells further enhances the growth of erythroid and multipotential progenitors SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Article ID MEDIATED GENE TRANSDUCTION; RECEPTOR TYROSINE KINASE; HUMAN-ERYTHROPOIETIN RECEPTOR; COLONY FORMATION; TRANSFORMING GROWTH-FACTOR-BETA-1; SIGNAL-TRANSDUCTION; LIGAND LACKING; STROMAL CELLS; SI-LOCUS; V-KIT AB Previous studies have demonstrated that the c-kit encoded tyrosine kinase receptor and its ligand, steel factor (SLF), are critical for normal blood cell development. We have reported that transduction of the c-kif gene into single hematopoietic progenitor cells (HPC), CD34(+++) cells, from cord blood (CB) enhances erythroid colony formation via a SLF-dependent mechanism. We therefore decided to evaluate the impact on cell proliferation of co-transducing c-kif and SLF cDNAs into these cells. CD34(+++) cells were sorted as a population or as 1 cell/well for cells expressing the highest levels of CD34 and different levels of c-kit. Cells were then prestimulated with granulocyte macrophage (GM)-colony stimulating factor (CSF), interleukin (IL)-3, IL-6, erythropoietin (Epo) in the presence and absence of various concentrations of SLF. Cells were then transduced with SLF and/or c-kit cDNAs, and then assayed for colony formation with the same cytokine combination. At a single cell level, co-transduction with c-kif and SLF genes significantly enhanced colony formation compared with individual gene transduction, especially by erythroid and multipotential progenitors that responded to stimulation by added cytokines. Little or no growth was seen with the c-kit- and/or SLF-transduced cells without addition of cytokines. The degree of enhancement effected by co-transduction inversely correlated with the degree of expression of c-kit protein before transduction. Optimal enhancing effects were noted in CD34(+++) kit(Lo/-) cells co-transduced with both c-kit and SLF cDNAs. Reverse transcriptase-polymerase chain (RT-PCR) analysis of SLF mRNA expression in CD34(+++) cells and enzyme-linked immunoadsorbent assay (ELISA) measurement of secreted SLF protein demonstrated that the transduced SLF cDNA was expressed and soluble SLF was released in medium cultured with SLP gene transduced MACS-separated CD34(+) cells in the presence, but not in the absence, of IL-3, GM-CSF, IL-6, and Epo. These results demonstrate the enhancement of the proliferation of growth factor responsive HPC that express transduced c-kit and SLF genes. C1 Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med Hematol Oncol, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN USA. Oregon Hlth Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Lu, L (reprint author), Indiana Univ, Sch Med, Walther Oncol Ctr, 1044 W Walnut St,Room 302, Indianapolis, IN 46202 USA. FU NHLBI NIH HHS [R01 HL 56416]; NIDDK NIH HHS [R01 DK 53674] NR 36 TC 3 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD DEC PY 2000 VL 9 IS 6 BP 813 EP 825 DI 10.1089/152581600750062246 PG 13 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 399DX UT WOS:000166797000004 PM 11177593 ER PT J AU zu Putlitz, J Encke, J Wands, JR AF zu Putlitz, J Encke, J Wands, JR TI Cytotoxic T cell responses against hepatitis B virus polymerase induced by genetic immunization SO JOURNAL OF HEPATOLOGY LA English DT Article DE cytotoxic T lymphocytes; ELISA; hepatitis; polymerase; vaccine; vaccinia ID DNA-BASED IMMUNIZATION; ACUTE VIRAL-HEPATITIS; LYMPHOCYTE RESPONSE; NUCLEOCAPSID ANTIGEN; IMMUNE-RESPONSE; CORE; EPITOPE; MICE; INFECTION; PROTEIN AB Background/Aims: Individuals with chronic hepatitis B may benefit from genetic (DNA-based) immunization through induction of viral clearance by enhancement of suboptimal cellular immune responses. While marked cellular immune responses to hepatitis B virus (HBV) nucleocapsid and envelope proteins occur after genetic immunization in mice, it is unknown whether genetic immunization is capable of eliciting such responses to HBV polymerase. We wished to develop assays for the determination of HBV polymerase specific immune responses in mice and investigate whether genetic immunization may elicit humoral and cellular immune responses to HBV polymerase. Methods: BALB/c (H-2(d)) mice were injected with a DNA expression construct for HBV polymerase. Humoral immune responses to HBV polymerase were analyzed with a newly established ELISA. Cellular immune responses were determined using recombinant vaccinia virus infected target cells expressing HBV polymerase at high levels. Results: Assays for the detection of HBV polymerase-specific immune responses were developed. Immunized animals exhibited substantial polymerase-specific cytotoxic T lymphocyte responses. However, no humoral immune responses to HBV polymerase were detectable. Conclusions: Our study demonstrates that DNA-based immunization will generate substantial CTL responses to HBV polymerase and may be an important component of an immunotherapeutic strategy to combat chronic HBV infection. C1 Massachusetts Gen Hosp, Ctr Canc, Mol Hepatol Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wands, JR (reprint author), Liver Res Ctr, 55 Claverick St,4th Floor, Providence, RI 02903 USA. FU NCI NIH HHS [CA-35711]; NIAAA NIH HHS [AA-02169] NR 28 TC 8 Z9 9 U1 1 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD DEC PY 2000 VL 33 IS 6 BP 986 EP 991 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 378QU UT WOS:000165595700018 PM 11131463 ER PT J AU Breininger, JF Baskin, DG AF Breininger, JF Baskin, DG TI Fluorescence in situ hybridization of scarce leptin receptor mRNA using the enzyme-labeled fluorescent substrate method and tyramide signal amplification SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE leptin; NPY; POMC; brain; arcuate nucleus; obesity ID ALKALINE-PHOSPHATASE ACTIVITY; MESSENGER-RNA EXPRESSION; LONG-FORM; RAT HYPOTHALAMUS; ARCUATE NUCLEUS; BRAIN; LOCALIZATION; NEURONS; CELLS; DNA AB To increase the sensitivity of fluorescence in situ hybridization (FISH) for detection of low-abundance mRNAs, we performed FISH on cryostat sections of rat hypothalamus with biotin-labeled riboprobes to leptin receptor (ObRb) and amplified the signal by combining tyramide signal amplification (TSA) and Enzyme-Labeled Fluorescent alkaline phosphatase substrate (ELF) methods. First, TSA amplification was done with biotinylated tyramide. Second, streptavidin-alkaline phosphatase was followed by the ELF substrate, producing a bright green fluorescent reaction product. FISH signal for ObRb was undetectable when TSA or ELF methods were used alone, but intense ELF FISH signal was visible in hypothalamic neurons when the ELF protocol was preceded by TSA. The TSA-ELF was combined with FISH for pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) mRNAs by hybridizing brain sections in a cocktail containing digoxigenin-labeled riboprobes to NPY or POMC mRNA and biotin-labeled riboprobes to ObRb mRNA. Dioxigenin-labeled NPY or POMC mRNA hybrids were subsequently detected first with IgG-Cy3. Then biotin-labeled leptin receptor hybrids were detected with the TSA-ELF method. Combining the ELF and TSA amplification techniques enabled FISH detection of scarce leptin receptor mRNAs and permitted the identification of leptin receptor mRNA in cells that also express NPY and POMC gene products. C1 VA Puget Sound Hlth Care Syst, Div Endocrinol Metab, Med Res Serv, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Biol Struct, Seattle, WA 98195 USA. RP Baskin, DG (reprint author), VA Puget Sound Hlth Care Syst, Div Endocrinol Metab, Med Res Serv, Mail Stop 151,1660 So Columbian Way, Seattle, WA 98108 USA. FU NIDDK NIH HHS [DK17047] NR 33 TC 32 Z9 33 U1 3 U2 9 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD DEC PY 2000 VL 48 IS 12 BP 1593 EP 1599 PG 7 WC Cell Biology SC Cell Biology GA 384BV UT WOS:000165919900002 PM 11101627 ER PT J AU Zusman, RM Prisant, LM Brown, MJ AF Zusman, RM Prisant, LM Brown, MJ CA Sildenafil Study Grp TI Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication SO JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; heart rate; hypertension; antihypertensive agents; erectile dysfunction; sildenafil citrate ID HYPERTENSION; POPULATION; IMPOTENCE; DISEASE AB Objectives To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Design Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies. Setting Private-practice and academic urology clinics. Patients A total of 1685 men with erectile dysfunction of greater than or equal to 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta -blocker, alpha -blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo). Interventions The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit Patients taking antihypertensive medication maintained usual dosing schedules. Main outcome measurements Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit). Results Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and -0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SEP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small. Conclusions The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication. (C) 2000 Lippincott Williams & Wilkins. C1 Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. Med Coll Georgia, Cardiol Sect, Augusta, GA 30912 USA. Addenbrookes Hosp, Dept Clin Pharmacol, Cambridge, England. RP Zusman, RM (reprint author), Massachusetts Gen Hosp, Cardiac Unit, 15 Parkman St,WACC 482, Boston, MA 02114 USA. NR 18 TC 63 Z9 64 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD DEC PY 2000 VL 18 IS 12 BP 1865 EP 1869 DI 10.1097/00004872-200018120-00022 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 381DK UT WOS:000165746900022 PM 11132612 ER PT J AU Gaglia, JL Greenfield, EA Mattoo, A Sharpe, AH Freeman, GJ Kuchroo, VK AF Gaglia, JL Greenfield, EA Mattoo, A Sharpe, AH Freeman, GJ Kuchroo, VK TI Intercellular adhesion molecule 1 is critical for activation of CD28-deficient T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VERSUS-HOST DISEASE; COSTIMULATORY REQUIREMENTS; ALLOGRAFT-REJECTION; IMMUNE-RESPONSES; GENE-EXPRESSION; CD28; ICAM-1; CD4(+); MICE; BLOCKADE AB Presentation of Ag to T lymphocytes in the absence of the requisite costimulatory signals leads to an Ag-specific unresponsiveness termed anergy, whereas Ag presentation in conjunction with costimulation leads to clonal expansion, B7/CD28 signaling has been shown to provide this critical costimulatory signal and blockade of this pathway may inhibit in vitro and in vivo immune responses. Although T cells from CD28-deficient mice are lacking in a variety of responses, they nonetheless are capable of various primary and secondary responses without the induction of anergy expected in the absence of costimulation, This suggests that there may be alternative costimulatory pathways that can replace CD28 signaling under certain circumstances. In this paper, we show that ICAM-1becomes a dominant costimulatory molecule for CD28-deficient T cells. ICAM-1 costimulates anti-CD3-mediated T cell proliferation and IL-2 secretion in CD28-deficient murine T cells. Furthermore, splenocytes from ICAM-1-deficient mice could not activate CD28-deficient T cells and splenocytes lacking both ICAM and CD28 fail to proliferate in response to anti-CD3-induced T cell signals. This confirms that not only can ICAM-1 act as a CD28-independent costimulator, but it is the dominant, requisite costimulatory molecule for the activation of T cells in the absence of B7/CD28 costimulation. C1 Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Kuchroo, VK (reprint author), Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. FU NIAID NIH HHS [P01AI39671-01A1]; NINDS NIH HHS [R01NS30843, R01NS35685] NR 42 TC 50 Z9 52 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 DEC 1 PY 2000 VL 165 IS 11 BP 6091 EP 6098 PG 8 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100011 PM 11086041 ER PT J AU Ostrowski, MA Justement, SJ Ehler, L Mizell, SB Lui, SY Mican, J Walker, BD Thomas, EK Seder, R Fauci, AS AF Ostrowski, MA Justement, SJ Ehler, L Mizell, SB Lui, SY Mican, J Walker, BD Thomas, EK Seder, R Fauci, AS TI The role of CD4(+) T cell help and CD40 ligand in the in vitro expansion of HIV-1-specific memory cytotoxic CD8(+) T cell responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACQUIRED IMMUNODEFICIENCY SYNDROME; PRIMARY IMMUNE-RESPONSE; MHC CLASS-II; DENDRITIC CELLS; LYMPHOCYTE RESPONSES; HIV-1 INFECTION; SOLUBLE-ANTIGEN; VIRUS-INFECTION; PLASMA VIREMIA; ACTIVATION AB CD4(+) T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8(+) CTL response in murine models. Recent studies have demonstrated that CD4(+) T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells, The role of CD4(+) T cell help in the expansion of virus-specific CD8(+) memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4(+) T cell help was required for optimal in vitro expansion of influenza specific CTL responses, Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4(+) T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4(+) T cell help was required for optimal expansion of HIV-l-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4(+) T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4(+) T cell help. In those HIV-l-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8(+) memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2, Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4(+) T cell-depleted conditions, where IL-2 is lacking. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Div Infect Dis, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. RP Ostrowski, MA (reprint author), Univ Toronto, Div Clin Sci, Room 6271,1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. EM m.ostrowski@utoronto.ca NR 51 TC 80 Z9 83 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 DEC 1 PY 2000 VL 165 IS 11 BP 6133 EP 6141 PG 9 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100016 PM 11086046 ER PT J AU Shi, HN Liu, HY Nagler-Anderson, C AF Shi, HN Liu, HY Nagler-Anderson, C TI Enteric infection acts as an adjuvant for the response to a model food antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; IN-VIVO; CLONAL EXPANSION; IMMUNE-RESPONSES; PERIPHERAL TOLERANCE; CHOLERA-TOXIN; INDUCTION; ACTIVATION; MUCOSAL; RECEPTOR AB Oral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness, However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs, To examine the consequences of mucosal infection for the T cell response to orally administered Ag, we adoptively transferred transgenic, OVA-specific, T cells into normal mice. We found that helminth infection enhances the expansion and survival of transgenic T cells induced by Ag feeding. Transfer of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled donor,cells showed that T cell proliferation in response to Ag feeding takes place primarily. in the mesenteric lymph nodes. Upon subsequent peripheral exposure to Ag in adjuvant, the proliferative capacity of the transferred transgenic T cells was reduced in noninfected mice that had been fed OVA, Helminth infection abrogated this reduction in proliferative capacity. Our data suggests that enteric infection can act as an adjuvant for the response to dietary Ags and has implications for allergic responses to food and the efficacy of oral vaccination. C1 Massachusetts Gen Hosp, Mucosal Immunol Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Nagler-Anderson, C (reprint author), Massachusetts Gen Hosp E, Mucosal Immunol Lab, Room 3308,Bldg 149,13th St, Charlestown, MA 02129 USA. FU NIDDK NIH HHS [DK47017, DK35506] NR 36 TC 27 Z9 29 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 DEC 1 PY 2000 VL 165 IS 11 BP 6174 EP 6182 PG 9 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100021 PM 11086051 ER PT J AU Lim, DG Bourcier, KB Freeman, GJ Hafler, DA AF Lim, DG Bourcier, KB Freeman, GJ Hafler, DA TI Examination of CD8(+) T cell function in humans using MHC class I tetramers: Similar cytotoxicity but variable proliferation and cytokine production among different clonal CD8(+) T cells specific to a single viral epitope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR REPERTOIRE; NEUROLOGICAL DISEASE; DIRECT VISUALIZATION; IMMUNE-RESPONSE; LYMPHOCYTES-T; INFLUENZA-A; ANTIGEN; INFECTION; PEPTIDE; ACTIVATION AB Following infection by human T cell lymphotrophic virus-I (HTLV-I), high frequencies of polyclonal Tax11-19-reactive CD8(+) T cells can be detected in the peripheral blood. To investigate whether there are differences in the effector functions of these cells, we generated a panel of Tax11-19 reactive T cell clones by single cell sorting of HLA-A2/Tax11-19 tetramer binding CD8(+) T cells followed by repeated stimulation with PHA and IL-2, Examination of the TCRs revealed 17 different T cell clones with unique clonal origins. Nine representative CD8(+) T cell clones showed a similar cytotoxic dose-response activity against Ag-pulsed target cells, even though they express different TCRs, This cytotoxic effector function was not influenced by the engagement of either CD28 or CD2 costimulatory molecules, In contrast to the cytotoxic activity, qualitatively different degrees of proliferative response and cytokine secretion were observed among T cell clones of different clonal origin, The induction of proliferation and cytokine secretion required the engagement of costimulatory molecules, particularly CD2-LFA-3 interaction. These results indicate that functionally diverse, polyclonal CTL populations can be activated specific to a single immunodominant viral epitope; they can manifest virtually identical cytotoxic effector function but have marked differences in proliferation and cytokine secretion. C1 Brigham & Womens Hosp, Ctr Neurol Dis, Lab Mol Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Hafler, DA (reprint author), Brigham & Womens Hosp, Ctr Neurol Dis, Lab Mol Immunol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. NR 41 TC 57 Z9 58 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 DEC 1 PY 2000 VL 165 IS 11 BP 6214 EP 6220 PG 7 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100025 PM 11086055 ER PT J AU Tai, YT Teoh, G Lin, B Davies, FE Chauhan, D Treon, SP Raje, N Hideshima, T Shima, Y Podar, K Anderson, KC AF Tai, YT Teoh, G Lin, B Davies, FE Chauhan, D Treon, SP Raje, N Hideshima, T Shima, Y Podar, K Anderson, KC TI Ku86 variant expression and function in multiple myeloma cells is associated with increased sensitivity to DNA damage SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; STRAND BREAK REPAIR; X-RAY RESISTANCE; V(D)J RECOMBINATION; CATALYTIC SUBUNIT; IN-VIVO; AUTOANTIGEN; BINDING; ANTIGEN; KU70 AB Ku is a heterodimer of Ku70 and Ku86 that binds to double-stranded DNA breaks (DSBs), activates the catalytic subunit (DNA-PKcs) when DNA is bound, and is essential in DSB repair and V(D)J recombination, Given that abnormalities in Ig gene rearrangement and DNA damage repair are hallmarks of multiple myeloma (MM) cells, we have characterized Ku expression and function in human MM cells. Tumor cells (CD38(+)CD45RA(-)) from 12 of 14 (86%) patients preferentially express a 69-kDa variant of Ku86 (Ku86v), Immunoblotting of whole cell extracts (WCE) from MM patients shows reactivity with Abs targeting Ku86 N terminus (S10B1) but no reactivity with Abs targeting Ku86 C terminus (111), suggesting that Ku86v has a truncated C terminus. EMSA confirmed a truncated C terminus in Ku86v and further demonstrated that Ku86v in MM cells had decreased Ku-DNA end binding activity. Ku86 forms complexes with DNA-PKcs and activates kinase activity, but Ku86v neither binds DNA-PKcs nor activates kinase activity. Furthermore, MM cells with Ku86v have increased sensitivity to irradiation, mitomycin C, and bleomycin compared with patient MM cells or normal bone marrow donor cells with Ku86, Therefore, this study suggests that Ku86v in MM cells may account for decreased DNA repair and increased sensitivity to radiation and chemotherapeutic agents, whereas Ku86 in MM cells confers resistance to PNA damaging agents. Coupled with a recent report that Ku86 activity correlates with resistance to radiation and chemotherapy, these results have implications for the potential role of Ku86 as a novel therapeutic target. 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, M557,44 Binney St, Boston, MA 02115 USA. NR 50 TC 37 Z9 48 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2000 VL 165 IS 11 BP 6347 EP 6355 PG 9 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100042 PM 11086072 ER PT J AU MacLean, JA De Sanctis, GT Ackerman, KG Drazen, JM Sauty, A DeHaan, E Green, FHY Charo, IF Luster, AD AF MacLean, JA De Sanctis, GT Ackerman, KG Drazen, JM Sauty, A DeHaan, E Green, FHY Charo, IF Luster, AD TI CC chemokine receptor-2 is not essential for the development of antigen-induced pulmonary eosinophilia and airway hyperresponsiveness SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCED BRONCHIAL HYPERREACTIVITY; CELL-DEFICIENT MICE; MURINE MODEL; MAST-CELLS; T-CELLS; FUNCTIONAL EXPRESSION; CYTOKINE RESPONSES; INFLAMMATION; LYMPHOCYTES; CLONING AB Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma, The only identified receptor for these two chemokines to date is the CCR2, To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2(-/-) mice with those of wild-type (WT) littermates following immunization and challenge with OVA, OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2(-/-) mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2-/- mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2(-/-) mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-gamma were also similar in WT and CCR2-/- mice. Finally, OVA/OVA CCR2(-/-) mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Brigham & Womens Hosp, Div Pulm, Boston, MA 02114 USA. Brigham & Womens Hosp, Crit Care Div, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Univ Calgary, Dept Pathol, Fac Med, Calgary, AB, Canada. Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94141 USA. RP MacLean, JA (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Bulfinch 422,50 Blossom St, Boston, MA 02114 USA. RI Drazen, Jeffrey/E-5841-2012 FU NCI NIH HHS [CA69212]; NIAID NIH HHS [AI40618, AI41129] NR 45 TC 29 Z9 31 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 DEC 1 PY 2000 VL 165 IS 11 BP 6568 EP 6575 PG 8 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100070 PM 11086100 ER PT J AU Cooke, KR Hill, GR Gerbitz, A Kobzik, L Martin, TR Crawford, JM Brewer, JP Ferrara, JLM AF Cooke, KR Hill, GR Gerbitz, A Kobzik, L Martin, TR Crawford, JM Brewer, JP Ferrara, JLM TI Hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental idiopathic pneumonia syndrome: Potential role for a gut-lung axis of inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; TUMOR-NECROSIS-FACTOR; VERSUS-HOST DISEASE; GALACTOSAMINE-TREATED MICE; TOTAL-BODY IRRADIATION; FACTOR-ALPHA; T-CELLS; FAS LIGAND; IN-VIVO; ACUTE GVHD AB Idiopathic pneumonia syndrome (LPS) is a major complication of allogeneic bone marrow transplantation (BMT), We have shown that experimental IFS is associated with increased levels of LPS and TNF-alpha in the bronchoalveolar lavage (BAL) fluid, We hypothesized that the deleterious effects of these inflammatory mediators in the lung may be linked to gut injury that develops after BMT, To test this hypothesis, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental BMT model, Lethally irradiated C3FeB6F(1) hosts received BMT from either LPS-sensitive or LPS-resistant donors. Five weeks after BMT, LPS-resistant BMT recipients had significantly less lung injury compared with recipients of LPS-sensitive BMT, This effect was associated with reductions in TNF-alpha secretion (both in vitro and in vivo), BAL fluid LPS levels, and intestinal injury. The relationship between TNF-alpha, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-alpha resulted in a significant reduction in gut histopathology, BAL fluid LPS levels, and pulmonary dysfunction compared with control-treated animals, We conclude that donor resistance to endotoxin reduces IFS in this model by decreasing the translocation of LPS across the intestinal border and systemic and pulmonary TNF-alpha production. These data demonstrate a potential etiologic link between gut and lung damage after BMT and suggest that methods that reduce inflammatory responses to LPS, and specifically, those that protect the integrity of the gut mucosa, may be effective in reducing IFS after BMT. C1 Univ Michigan, Ctr Canc, Dept Internal Med, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Div Pediat Pulmonol, Boston, MA 02115 USA. Univ Florida, Sch Med, Dept Pathol, Gainesville, FL 32610 USA. RP Cooke, KR (reprint author), Univ Michigan, Ctr Canc, Dept Internal Med, Blood & Marrow Transplantat Program, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. RI Hill, Geoffrey/O-2630-2016 OI Hill, Geoffrey/0000-0003-2994-0429 FU NHLBI NIH HHS [HL55162, HL 03565]; NIDDK NIH HHS [DK39512] NR 67 TC 39 Z9 40 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 DEC 1 PY 2000 VL 165 IS 11 BP 6612 EP 6619 PG 8 WC Immunology SC Immunology GA 376PZ UT WOS:000165467100076 PM 11086106 ER PT J AU Kaya, G Augsburger, E Stamenkovic, I Saurat, JH AF Kaya, G Augsburger, E Stamenkovic, I Saurat, JH TI Decrease in epidermal CD44 expression as a potential mechanism for abnormal hyaluronate accumulation in superficial dermis in lichen sclerosus et atrophicus SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE adhesion molecule; glycosaminoglycan; keratinocytes skin; transgenic mice ID ET-ATROPHICUS; FIBROBLASTS; SKIN; GLYCOSAMINOGLYCAN; SCLERODERMA; RECEPTOR; BEARING AB CD44 is a polymorphic integral membrane glycoprotein that serves as the principal cell surface receptor for hyaluronate, the major component of the extracellular matrix. CD44 is abundantly found in the skin and functions as a cell adhesion molecule. In a recent study we have observed a massive dermal accumulation of hyaluronate as a result of the in vivo selective suppression of CD44 in keratinocytes in mice expressing a keratin 5 promoter-driven CD44 anti-sense transgene. As the histologic features of the dorsal skin of these transgenic mice display some similarities to those of the skin lesions of lichen sclerosus et atrophicus, we explored the nature of the material accumulated in the dermis of genital and extragenital lesions of 14 patients with lichen sclerosus et atrophicus by Alcian Blue and human CD44 receptor globulin stainings, as well as the epidermal expression of CD44 protein and mRNA by immunohistochemistry and in situ hybridization. In this study we provide evidence that hyaluronate is accumulated in the superficial dermis of lichen sclerosus et atrophicus lesions, in particular by the use of human CD44 receptor globulin staining, which binds specifically to hyaluronate. In addition we show that the protein and mRNA expression of CD44 in the epidermis of the involved lichen sclerosus et atrophicus skin from genital and extragenital areas is significantly decreased, and in some cases completely lost. In contrast, keratinocyte CD44 expression was unaltered in the skin lesions of lupus erythematosus, scleroderma and reticular erythematous mucinosis, despite the presence of a mucinous material in the dermis. These results suggest that a decrease in CD44 in the keratinocytes may be correlated with an abnormal dermal accumulation of hyaluronate in the lesions of lichen sclerosus et atrophicus, and may play a pathogenetic role in this disease. C1 Univ Hosp Geneva, DHURDV, Dept Dermatol, CH-1211 Geneva 4, Switzerland. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kaya, G (reprint author), Univ Hosp Geneva, DHURDV, Dept Dermatol, 24 Rue Micheli du Crest, CH-1211 Geneva 4, Switzerland. NR 28 TC 34 Z9 34 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 DEC PY 2000 VL 115 IS 6 BP 1054 EP 1058 DI 10.1046/j.1523-1747.2000.00194.x PG 5 WC Dermatology SC Dermatology GA 390FT UT WOS:000166285600020 PM 11121141 ER PT J AU Skobe, M Detmar, M AF Skobe, M Detmar, M TI Structure, function, and molecular control of the skin lymphatic system SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Article; Proceedings Paper CT 48th Annual Montagna Symposium on the Biology of Skin CY AUG 07-11, 1999 CL SNOWMASS, COLORADO SP Orentreich Fdn, Johnson & Johnson, Galderma, Estee Lauder Inc, Fdn Basic Cutaneous Res, Nat Psoriasis Fdn, Avon, Allergan DE lymphatic vessels; lymphangiogenesis; skin; VEGF-C ID GROWTH-FACTOR RECEPTOR-3; ENDOTHELIAL-CELLS; CUTANEOUS MICROVASCULATURE; VEGF-C; VESSELS; BLOOD; CAPILLARIES; EXPRESSION; ULTRASTRUCTURE; IDENTIFICATION AB The mechanisms of angiogenesis have been studied extensively over the past years, The focus, however, has been almost exclusively on blood vessels, whereas little effort has been directed toward understanding lymphangiogenesis and the role of lymphatic vessels in physiology and pathology, The lymphatic system, acting in concert with the blood vascular system, is of fundamental importance in maintaining tissue homeostasis, and disorders of the lymphatic system are common, often resulting in chronic, disabling conditions. This overview summarizes the most important aspects of the structure and function of the lymphatic system with emphasis on the skin lymphatic vasculature and the differences between blood and lymphatic vessels. Special attention has been given to the methods employed in research of the lymphatic system, Finally, we describe molecular mechanisms involved in the regulation of lymphangiogenesis, Vascular endothelial growth factor and vascular endothelial growth factor-C, expressed by distinct skin cell populations, play an important role in the molecular control of skin angiogenesis and lymphangiogenesis. C1 Massachusetts Gen Hosp, Dept Dermatol, CBRC, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Skobe, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, CBRC, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA69184] NR 45 TC 113 Z9 119 U1 0 U2 6 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD DEC PY 2000 VL 5 IS 1 BP 14 EP 19 DI 10.1046/j.1087-0024.2000.00001.x PG 6 WC Dermatology SC Dermatology GA 384PJ UT WOS:000165953800004 PM 11147669 ER PT J AU Detmar, M AF Detmar, M TI Tumor angiogenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Article; Proceedings Paper CT 48th Annual Montagna Symposium on the Biology of Skin CY AUG 07-11, 1999 CL SNOWMASS, COLORADO SP Orentreich Fdn, Johnson & Johnson, Galderma, Estee Lauder Inc, Fdn Basic Cutaneous Res, Nat Psoriasis Fdn, Avon, Allergan DE skin; TSP-1; TSP-2; VEGF ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; IN-VIVO; PROTEIN THROMBOSPONDIN-2; TRANSGENIC MICE; TYROSINE KINASE; CELL GROWTH; 3T3 CELLS; EXPRESSION; INHIBITION AB In order to grow beyond minimal size and to metastasize, tumors need to induce the growth of new blood vessels (angiogenesis). Whereas in normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli, tumor angiogenesis is induced by increased secretion of angiogenic factors and/or by downregulation of angiogenesis inhibitors. Recent evidence suggests vascular endothelial growth factor (VEGF) as the major tumor angiogenesis factor, promoting tumor growth, invasion, and metastasis. Conversely, blocking of VEGF function inhibits angiogenesis and suppresses tumor growth in vivo. Newly identified members of the VEGF family of angiogenesis factors include placental growth factor, VEGF-B, VEGF-C, and VEGF-D, and show overlapping binding patterns to specific endothelial cell receptors. VEGF-C appears to play a major role as a lymphangiogenesis factor and as a growth factor for Kaposi's sarcoma, In contrast, endogenous inhibitors prevent blood vessel growth in normal tissues. In particular, thrombospondin-1 (TSP-1) and TSP-2 are expressed in normal skin and, when introduced into squamous cell carcinomas, potently inhibit malignant tumor growth via inhibition of tumor angiogenesis. C1 Massachusetts Gen Hosp, Dept Dermatol, CBRC, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, CBRC, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 56 TC 57 Z9 62 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD DEC PY 2000 VL 5 IS 1 BP 20 EP 23 DI 10.1046/j.1087-0024.2000.00003.x PG 4 WC Dermatology SC Dermatology GA 384PJ UT WOS:000165953800005 PM 11147670 ER PT J AU Li, ZH Kako, Y Pang, L Freeman, MW Glick, JM Wang, XZ Goldberg, IJ AF Li, ZH Kako, Y Pang, L Freeman, MW Glick, JM Wang, XZ Goldberg, IJ TI Effects of overexpression of the amino-terminal fragment of apolipoprotein B on apolipoprotein B and lipoprotein production SO JOURNAL OF LIPID RESEARCH LA English DT Article DE adenovirus; microsomal triglyceride transfer protein lipoprotein lipase; very low density lipoproteins; chylomicrons ID TRIGLYCERIDE TRANSFER PROTEIN; TRANSGENIC MICE; ENDOPLASMIC-RETICULUM; HEPG2 CELLS; SECRETION; DEGRADATION; EXPRESSION; BINDING; LIPASE; ABETALIPOPROTEINEMIA AB In vitro studies have shown that the binding site for microsomal triglyceride transfer protein (MTP) is within the first 17% of apoB (apoB-17), Expression of apoB-48 in McArdle cells decreases endogenous lipoprotein production; however, overexpression of human apoB in transgenic mice does not decrease endogenous mouse apoB expression. To assess this inconsistency, adenoviruses expressing human apoB-17 (AdB17) or apoB-17-beta (which contains apoB-17 plus a small lipid-binding beta -sheet region of apoB, AdB-17 beta) were produced. Hepatoma cells were infected with AdB17 or AdB17-beta with AdLacZ, an adenovirus expressing beta -galactosidase, as a control. Overexpression of apoB-17 and apoB-17-beta in hepatoma cells to levels 2- to 3-fold greater than that of endogenous apoB did not alter endogenous apoB production. This was also true in the presence of oleic acid and N-acetyl-leucyl-leucyl-norleucinal. High levels of apoB-17 or beta -galactosidase expression reduced apoB-100 production; however, control protein production was also reduced, To assess the effects of apoB-17 expression in vivo, mice of three different strains were injected with AdB17, Two days after injection, plasma apoB-17 was approximately 24 times the amount of endogenous apoB in the C57BL/6 mice, 2 times the apoB-100 in human apoB transgenic mice, and 4 times the apoB-48 in apoE knockout mice. Overexpression of apoB-17 did not decrease apoE-100 or apoB-48 concentrations in mouse plasma as assessed by Western blot analysis. These results demonstrate that although the apoB-17 binds to MTP in vitro, it does not alter endogenous apoB expression in mice or in hepatoma cells. C1 Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Univ Penn, Sch Med, Inst Human Gene Therapy, Philadelphia, PA 19104 USA. RP Goldberg, IJ (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, 630 W 168th St, New York, NY 10032 USA. FU NHLBI NIH HHS [HL 45098, HL 56985]; PHS HHS [R01-62301] NR 37 TC 2 Z9 2 U1 0 U2 0 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD DEC PY 2000 VL 41 IS 12 BP 1912 EP 1920 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 385UG UT WOS:000166021700002 PM 11108724 ER PT J AU Fu, YC Luo, NL Lopes-Virella, MF AF Fu, YC Luo, NL Lopes-Virella, MF TI Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages SO JOURNAL OF LIPID RESEARCH LA English DT Article DE oxidized low density lipoprotein; signaling pathways; atherosclerosis ID LOW-DENSITY-LIPOPROTEIN; FATTY-ACID-BINDING; NF-KAPPA-B; ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; GENE-EXPRESSION; TRANSCRIPTION FACTOR; SCAVENGER-RECEPTOR; IMMUNE-COMPLEXES; HUMAN MONOCYTES AB The adipocyte lipid-binding protein (ALBP/aP2) belongs to a multigene family of fatty acid and retinoid transport proteins. This protein is abundantly expressed in the cytoplasm and nuclear region of adipocytes and is postulated to serve as a lipid shuttle, solubilizing hydrophobic fatty acids and delivering them to the appropriate metabolic system for utilization. This report demonstrates that human cholesterol-loaded THP-1 macrophages express ALBP/aP2 and that its expression can be stimulated by oxidized low density lipoprotein (oxLDL). The increase in mRNA expression was paralleled by a similar increase in ALBP/aP2 protein. The increase in ALBP/aP2 mRNA and protein in oxLDL-stimulated THP-1 macrophages is concentration and time dependent and is inhibited by treatment of the cells with an antioxidant inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate (PDTC), and with protein kinase C (PKC) inhibitors bisindolylmaleimide I and Ro-31-8220. These results suggest that activation of both NF-kappaB and PKC signaling pathways is necessary for oxLDL- induced ALBP/aP2 gene expression in THP-1 macrophages and that the upregulation of the fatty acid carrier may be a necessary event in foam cell formation. C1 Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29403 USA. Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29401 USA. RP Fu, YC (reprint author), Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. NR 49 TC 85 Z9 91 U1 1 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD DEC PY 2000 VL 41 IS 12 BP 2017 EP 2023 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 385UG UT WOS:000166021700013 PM 11108735 ER PT J AU Szudek, J Birch, P Friedman, JM AF Szudek, J Birch, P Friedman, JM CA Natl Neurofibromatosis Foundation TI Growth in North American white children with neurofibromatosis 1 (NF1) SO JOURNAL OF MEDICAL GENETICS LA English DT Article DE neurofibromatosis 1; stature; occipitofrontal circumference; macrocephaly ID DEPENDENT PROTEIN-KINASE; DOUBLE DATA-ENTRY; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; OLIGODENDROCYTE DIFFERENTIATION; DROSOPHILA NF1; CYCLIC-AMP; TYPE-1 NF1; CYCLASE; CHARTS; TRIALS AB Objective-To analyse the distributions of and generate growth charts for stature and occipitofrontal circumference (OFC) in neurofibromatosis I (NF1) patients. Design-Cross sectional database survey. Setting-The National Neurofibromatosis Foundation International Database (NFDE) includes clinical information on NF1 patients fi om 14 participating centres in North America. Subjects-A total of 569 white, North American, NF1 patients, 55% female and 45% male. Main outcome measures-Stature and OFC measurements of NF1 patients were compared to age and sex matched population norms using z score standardisation and centile curves. Results-The distributions of stature and OFC are shifted and unimodal among NF1 patients; 13% of patients have short stature (greater than or equal to2 standard deviations below the population mean) and 24% have macrocephaly (OFC greater than or equal to2 standard deviations above the population mean). Conclusions-Alterations of stature and OFC are not limited to NF1 patients with frank short stature or macrocephaly. C1 Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada. Univ Washington, Seattle, WA 98195 USA. Fdn Jimenez Diaz, E-28040 Madrid, Spain. Boston Childrens Hosp, Boston, MA USA. Scottish Rite Childrens Med Ctr, Atlanta, GA USA. Jikei Univ, Tokyo, Japan. Childrens Hosp, Sydney, NSW, Australia. Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. Oulu Univ Hosp, Oulu, Finland. Mt Sinai Med Ctr, New York, NY 10029 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Alfred I Dupont Inst, Wilmington, DE 19899 USA. Univ Padua, I-35100 Padua, Italy. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Utah, Med Ctr, Salt Lake City, UT USA. IM Sechenov Med Acad, Moscow, Russia. Childrens Hosp, Cincinnati, OH 45229 USA. Inst Med Genet, Berlin, Germany. Univ Virginia, Med Ctr, Charlottesville, VA USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Lebonheur Childrens Hosp & Med Ctr, Memphis, TN USA. Newcastle Western Suburbs Hosp, Newcastle, NSW, Australia. Free Univ Berlin, D-1000 Berlin, Germany. Hop Henri Mondor, F-94010 Creteil, France. Univ Muenchen, Neurol Klin, Munich, Germany. RP Szudek, J (reprint author), Univ British Columbia, Dept Med Genet, 222-6174 Univ Blvd, Vancouver, BC V6T 1Z3, Canada. EM szudek@unixg.ubc.ca RI North, Kathryn/K-6476-2012 OI North, Kathryn/0000-0003-0841-8009 NR 39 TC 40 Z9 42 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2000 VL 37 IS 12 BP 933 EP 938 DI 10.1136/jmg.37.12.933 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 385BQ UT WOS:000165982100006 PM 11106357 ER PT J AU Williams, LJS Abou-Samra, AB AF Williams, LJS Abou-Samra, AB TI The transcription factors SP1 and MAZ regulate expression of the parathyroid hormone/parathyroid hormone-related peptide receptor gene SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID ZINC-FINGER PROTEIN; FUNCTIONAL-CHARACTERIZATION; DEVELOPMENTAL EXPRESSION; PTH/PTHRP RECEPTOR; C-MYC; PROMOTER; BINDS; MOUSE; RAT; IDENTIFICATION AB The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor regulates extracellular calcium concentrations and is therefore important for mineral homeostasis. ROS 17/2.8 cells, a rat osteoblast-like osteosarcoma cell line, express the PTH/PTHrP receptor and provide a good model for examining the transcriptional regulation of its gene. The rat PTH/PTHrP receptor gene has two promoters, U1 and U3, which were shown to be important for its expression. Using extracts from ROS 17/2.8 cells, we have demonstrated two regions (termed FP1 and FP2) of nuclear protein/DNA interaction within promoter sequences previously shown to be important for the activity of the U3 promoter. Nuclear extracts from rat 2 fibroblasts, which do not express the PTH/PTHrP receptor, produced one site of protein/DNA interaction which was found at a position on the promoter identical to the position of FP1 produced by a ROS 17/2.8 nuclear extract. Mutation of these two sites of protein/DNA interaction resulted in reduced U3 promoter activity. Furthermore, we have demonstrated that the transcription factors SP1 and MAZ regulate U3 promoter expression and have shown their functional significance using mutational analysis. These data demonstrate that SP1 and MAZ bind to the PTH/PTHrP receptor promoter and that they are involved in cell-specific expression of its gene product. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Abou-Samra, AB (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Bulfinch 327, Boston, MA 02114 USA. OI Abou-Samra, Abdul/0000-0001-8735-1142 FU NIDDK NIH HHS [DK45485] NR 28 TC 17 Z9 17 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD DEC PY 2000 VL 25 IS 3 BP 309 EP 319 DI 10.1677/jme.0.0250309 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413PM UT WOS:000167621000006 PM 11116210 ER PT J AU Rabizadeh, S Ye, X Sperandio, S Wang, JJL Ellerby, HM Ellerby, LM Giza, C Andrusiak, RL Frankowski, H Yaron, Y Moayeri, NN Rovelli, G Evans, CJ Butcher, LL Nolan, GP Assa-Munt, N Bredesen, DE AF Rabizadeh, S Ye, X Sperandio, S Wang, JJL Ellerby, HM Ellerby, LM Giza, C Andrusiak, RL Frankowski, H Yaron, Y Moayeri, NN Rovelli, G Evans, CJ Butcher, LL Nolan, GP Assa-Munt, N Bredesen, DE TI Neurotrophin dependence domain - A domain required for the mediation of apoptosis by the p75 neurotrophin receptor SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE p75(NTR); apoptosis; dependence; neurotrophin; dimerization ID NERVE GROWTH-FACTOR; CEREBELLAR GRANULE NEURONS; CELL-FREE SYSTEM; SIGNAL-TRANSDUCTION; DEATH DOMAIN; SYMPATHETIC NEURONS; NMR STRUCTURE; PC12 CELLS; INDUCTION; P75(NTR) AB The mechanisms underlying neurotrophin dependence, and cellular dependent states in general, are unknown. We show that a 29 amino acid region in the intracellular domain of the common neurotrophin receptor, p75(NTR), is required for the mediation of apoptosis by p75(NTR) Furthermore, contrary to results obtained with Fas, monomeric p75(NTR) is required for apoptosis induction, whereas multimerization inhibits the pro-apoptotic effect. Within the 29-residue domain required for apoptosis induction by p75(NTR), a 14-residue region is sufficient as a peptide inducer of apoptosis. This 14-residue peptide requires the positively charged carboxyterminal residues for its effect on cell death, and these same residues are required by the full-length p75(NTR). These studies define a novel type of domain that mediates neurotrophin dependence, and suggest that other cellular dependent states may be mediated by proteins displaying similar domains. C1 Buck Inst Age Res, Novato, CA 94945 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Burnham Inst, Program Aging, La Jolla, CA 92037 USA. Burnham Inst, Program Struct Biol, La Jolla, CA 92037 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Med Sci Training Program, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Novartis Pharmaceut AG, Basel, Switzerland. Stanford Univ, Sch Med, Dept Mol Pharmacol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. RP Bredesen, DE (reprint author), Buck Inst Age Res, 8001 Redwood Blvd, Novato, CA 94945 USA. FU NCI NIH HHS [CA69381]; NIDA NIH HHS [P50 DA005010] NR 48 TC 30 Z9 32 U1 1 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD DEC PY 2000 VL 15 IS 3 BP 215 EP 229 DI 10.1385/JMN:15:3:215 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 415XR UT WOS:000167749300008 PM 11303785 ER PT J AU McGuire, M Bakst, K Fairbanks, L McGuire, M Sachinvala, N von Scotti, H Brown, N AF McGuire, M Bakst, K Fairbanks, L McGuire, M Sachinvala, N von Scotti, H Brown, N TI Cognitive, mood, and functional evaluations using touchscreen technology SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article ID COMPUTER; RELIABILITY AB We describe the design and development of the Cognitive Evaluation Protocol(R) (CEP), a computer software program for evaluating cognitive and functional capacities and mood. The program is self-administered by subjects using touchscreen monitors for input. Stimuli in CEP subtests are randomized to reduce the effects of learning on repeated assessments. Findings demonstrate that a) minimum instruction is required for touchscreen use, even for computer-naive subjects; c) both normative subjects and psychiatric patients respond positively to self-administered evaluations; and c) CEP can be used for within-subject repeated evaluations with minimal distortion of results due to practice effects. The CEP Report Generator(R) provides immediate printed performance results and creates a database for long-term digital storage and information use. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Sheppard Pratt Hlth Syst, Baltimore, MD 21285 USA. Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. Evaluat Technol Inc, Sherman Oaks, CA 91423 USA. RP McGuire, M (reprint author), POB 1646, Cottonwood, CA 96022 USA. NR 14 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD DEC PY 2000 VL 188 IS 12 BP 813 EP 817 DI 10.1097/00005053-200012000-00004 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 387HL UT WOS:000166117100004 PM 11191581 ER PT J AU Crandall, JE Dibble, C Butler, D Pays, L Ahmad, N Kostek, C Puschel, AW Schwarting, GA AF Crandall, JE Dibble, C Butler, D Pays, L Ahmad, N Kostek, C Puschel, AW Schwarting, GA TI Patterning of olfactory sensory connections is mediated by extracellular matrix proteins in the nerve layer of the olfactory bulb SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE olfactory axon guidance; galectin; laminin; semaphorin; neuropilin ID CHEMOREPELLENT SEMAPHORIN-III; SPATIOTEMPORAL PATTERNS; RECEPTOR EXPRESSION; ENSHEATHING CELLS; SYSTEM; PROJECTION; NEURONS; AXONS; ADHESION; GROWTH AB in early rat embryos when axons from sensory neurons first contact the olfactory bulb primordium, lactosamine-containing glycans (LCG) are detected on neurons that are broadly distributed within the olfactory epithelium, but that project axons to a very restricted region of the ventromedial olfactory bulb. LCG(+) axons extend through channels defined by the coexpression of galectin-1 and beta2-laminin. These two extracellular matrix molecules are differentially expressed, along with semaphorin 3A, by subsets of ensheathing cells in the ventral nerve layer of the olfactory bulb. The overlapping expression of these molecules creates an axon-sorting domain that is capable of promoting and repelling subsets of olfactory axons. Specifically, LCG(+) axons preferentially grow into the region of the nerve layer that expresses high amounts of galectin-1, beta2-laminin, and semaphorin 3A, whereas neuropilin-1(+) axons grow in a complementary pattern, avoiding the ventral nerve layer and projecting medially and laterally. These studies suggest that initial patterning of olfactory epithelium to olfactory bulb connections is, in part, dependent on extracellular components of the embryonic nerve layer that mediate convergence and divergence of specific axon subsets. (C) 2000 John Wiley & Sons. Inc. C1 Shriver Ctr, Waltham, MA 02452 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Max Planck Inst Brain Res, Dept Neurochem, Genet Mol Lab, D-60528 Frankfurt, Germany. RP Schwarting, GA (reprint author), Shriver Ctr, 200 Trapelo Rd, Waltham, MA 02452 USA. FU NICHD NIH HHS [HD05515]; NIDCD NIH HHS [DC00953] NR 57 TC 53 Z9 53 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD DEC PY 2000 VL 45 IS 4 BP 195 EP 206 DI 10.1002/1097-4695(200012)45:4<195::AID-NEU1>3.0.CO;2-Y PG 12 WC Neurosciences SC Neurosciences & Neurology GA 378MV UT WOS:000165588900001 PM 11077424 ER PT J AU Park, CC Hartmann, C Folkerth, R Loeffler, JS Wen, PY Fine, HA Black, PM Shafman, T Louis, DN AF Park, CC Hartmann, C Folkerth, R Loeffler, JS Wen, PY Fine, HA Black, PM Shafman, T Louis, DN TI Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE genomic instability; glioblastoma; metastasis; mutation; TP53 ID MOLECULAR-GENETIC-ANALYSIS; BRAIN-TUMOR SPECIMENS; EXTRANEURAL METASTASES; P53 MUTATIONS; MULTIFORME; ASTROCYTOMAS; GLIOMAS; PROGRESSION; PROTEIN; PATHWAYS AB Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathological and molecular genetic findings in 6 patients with metastatic glioblastoma. Four patients were under the age of 32 and all but 1 patient died within 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site. We evaluated DNA from both primary and metastatic glioblastomas for genetic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR amplification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 cases had no detectable genetic alterations. In 2 cases, the primary and metastatic tumors had identical genotypes. Remarkably, however, 2 cases had different TP53 alterations in the primary and metastatic lesions, or among the metastatic tumors, which suggests that some metastatic deposits may represent emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demonstrate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutations and differential clonal selection. C1 Massachusetts Gen Hosp, Mol Neurooncol Lab, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Neurosurg Serv, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA 02129 USA. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Louis, DN (reprint author), Massachusetts Gen Hosp, Mol Neurooncol Lab, CNY6,149 13th St, Charlestown, MA 02129 USA. RI Hartmann, Christian/D-1882-2010 FU NCI NIH HHS [CA57683] NR 37 TC 26 Z9 26 U1 0 U2 0 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 DEC PY 2000 VL 59 IS 12 BP 1044 EP 1050 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 383XR UT WOS:000165910400003 PM 11138924 ER PT J AU Gilg, AG Singh, AK Singh, I AF Gilg, AG Singh, AK Singh, I TI Inducible nitric oxide synthase in the central nervous system of patients with X-Adrenoleukodystrophy SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE astrocytes; inducible nitric oxide synthase; macrophage/microglia; very long chain fatty acids; X-adrenoleukodystrophy ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; LINKED ADRENOLEUKODYSTROPHY; GLIAL-CELLS; MEMBRANE-PROTEIN; SJL MICE; GENE; PEROXYNITRITE; PEROXISOMES; INHIBITION AB X-Adrenoleukodystrophy (X-ALD) is an inherited peroxisomal disorder of deficient catabolism of very long-chain (VLC) fatty acids with resulting neuroinflammatory demyelinating disease. Our recent documentation of nitric oxide (NO)mediated increase in VLC fatty acid levels in glial cells and demonstration of greater increase of VLC fatty acids levels in the inflammatory region (plaque) of X-ALD brain as compared to the normal-looking region away from the plaque prompted us to investigate the possible involvement of NO in the pathophysiology of X-ALD. Herein we provide evidence of the expression of inducible nitric oxide synthase (iNOS) in the CNS of X-ALD patients. In situ hybridization demonstrated that iNOS mRNA was present in brain tissues from X-ALD patients but not in normal controls. Double-labeling immunofluorescence studies using cell-specific markers confirmed that iNOS-expressing cells in the CNS of X-ALD were astrocytes and microglia/macrophages. Finally, antibodies against nitrotyrosine strongly immunoreacted with tissues from the center of the plaque region of X-ALD brains suggesting the presence of the NO reaction product nitrotyrosine in the CNS of X-ALD. Taken together, these results demonstrate that iNOS is expressed in the brains of patients with X-ALD and may contribute to the pathogenesis of the disease. C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Dept Pathol & Lab Med, Charleston, SC USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. FU NINDS NIH HHS [NS-37766, NS-22576, NS-34741] NR 39 TC 46 Z9 46 U1 0 U2 0 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 DEC PY 2000 VL 59 IS 12 BP 1063 EP 1069 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 383XR UT WOS:000165910400005 PM 11138926 ER PT J AU Mendez, MF Chow, T Ringman, J Twitchell, G Hinkin, CH AF Mendez, MF Chow, T Ringman, J Twitchell, G Hinkin, CH TI Pedophilia and temporal lobe disturbances SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID COMMON PATHOLOGICAL FEATURE; HIPPOCAMPAL SCLEROSIS; CLINICAL-DIAGNOSIS; SEXUAL-BEHAVIOR; DEMENTIA; HYPERSEXUALITY; NEUROPATHOLOGY; LESIONS; DISEASE; HUMANS AB Paraphilias may occur with brain disease, but the nature of this relationship is unclear. The authors report 2 patients with late-life homosexual pedophilia. The first met criteria for frontotemporal dementia; the second had bilateral hippocampal sclerosis, Both weve professional men with recent increases in sexual behavior. In both, 18-fluorodeoxyglucose positron emission tomography revealed prominent right temporal lobe hypometabolism. These eases and the literature suggest that bilateral anterior temporal disease affecting right mure than left temporal lobe can increase sexual interest. A predisposition to pedophilia may be unmasked by hypersexuality from brain disease. These observations have potential implications for all neurologically based paraphilias. C1 VA Greater Los Angeles Healthcare Syst, Neurobehav Unit 116AF, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Mendez, MF (reprint author), VA Greater Los Angeles Healthcare Syst, Neurobehav Unit 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 37 TC 91 Z9 94 U1 1 U2 17 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2000 VL 12 IS 1 BP 71 EP 76 PG 6 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 280JY UT WOS:000085100700012 PM 10678516 ER PT J AU Struyk, AF Scoggan, KA Bulman, DE Cannon, SC AF Struyk, AF Scoggan, KA Bulman, DE Cannon, SC TI The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE depolarization; inactivation; Na channel; hypokalemic periodic paralysis; mutation; skeletal muscle ID SODIUM-CHANNELS; S4 SEGMENT; ACTIVATION; MEMBRANE; MYOTONIA; CURRENTS; MYOTUBES; AXONS; R528H; IV AB Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita, and potassium-aggravated myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca2+ channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an similar to 10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02114 USA. Dept Med, Div Neurol, Ottawa, ON K1H 7W9, Canada. Ottawa Hosp, Res Inst, Ottawa, ON K1H 7W9, Canada. RP Cannon, SC (reprint author), Massachusetts Gen Hosp, Dept Neurobiol, Edwards Res Bldg 417,Fruit St, Boston, MA 02114 USA. FU NIAMS NIH HHS [AR42703]; NINDS NIH HHS [K08-NS02137] NR 37 TC 67 Z9 73 U1 0 U2 3 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 DEC 1 PY 2000 VL 20 IS 23 BP 8610 EP 8617 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 378PD UT WOS:000165592000012 PM 11102465 ER PT J AU Krakauer, JW Pine, ZM Ghilardi, MF Ghez, C AF Krakauer, JW Pine, ZM Ghilardi, MF Ghez, C TI Learning of visuomotor transformations for vectorial planning of reaching trajectories SO JOURNAL OF NEUROSCIENCE LA English DT Article DE vectorial planning; motor learning; visuomotor transformations; reaching movements; psychophysics; generalization ID ARM MOVEMENTS; MOTOR; DIRECTION; ERRORS; ADAPTATION; VARIABILITY; ACCURACY; BIASES; SPACE AB The planning of visually guided reaches is accomplished by independent specification of extent and direction. We investigated whether this separation of extent and direction planning for well practiced movements could be explained by differences in the adaptation to extent and directional errors during motor learning. We compared the time course and generalization of adaptation with two types of screen cursor transformation that altered the relationship between hand space and screen space. The first was a gain change that induced extent errors and required subjects to learn a new scaling factor. The second was a screen cursor rotation that induced directional errors and required subjects to learn new reference axes. Subjects learned a new scaling factor at the same rate when training with one or multiple target distances, whereas learning new reference axes took longer and was less complete when training with multiple compared with one target direction. After training to a single target, subjects were able to transfer learning of a new scaling factor to previously unvisited distances and directions. In contrast, generalization of rotation adaptation was incomplete; there was transfer across distances and arm configurations but not across directions. Learning a rotated reference frame only occurred after multiple target directions were sampled during training. These results suggest the separate processing of extent and directional errors by the brain and support the idea that reaching movements are planned as a hand-centered vector whose extent and direction are established via learning a scaling factor and reference axes. C1 Columbia Univ, New York State Psychiat Inst, Ctr Neurobiol & Behav, Coll Phys & Surg, New York, NY 10032 USA. Univ Calif San Francisco, Ctr Aging, San Francisco, CA 94143 USA. San Francisco Vet Adm Med Ctr, Div Geriatr, San Francisco, CA USA. CNR, INB, I-20133 Milan, Italy. RP Ghez, C (reprint author), Columbia Univ, New York State Psychiat Inst, Ctr Neurobiol & Behav, Coll Phys & Surg, 1051 Riverside Dr, New York, NY 10032 USA. FU NINDS NIH HHS [NS 01961, NS 02138, NS 22713] NR 37 TC 405 Z9 406 U1 1 U2 16 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 DEC 1 PY 2000 VL 20 IS 23 BP 8916 EP 8924 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 378PD UT WOS:000165592000049 PM 11102502 ER PT J AU Rauch, SL Kim, H Makris, N Cosgrove, GR Cassem, EH Savage, CR Price, BH Nierenberg, AA Shera, D Baer, L Buchbinder, B Caviness, VS Jenike, MA Kennedy, DN AF Rauch, SL Kim, H Makris, N Cosgrove, GR Cassem, EH Savage, CR Price, BH Nierenberg, AA Shera, D Baer, L Buchbinder, B Caviness, VS Jenike, MA Kennedy, DN TI Volume reduction in the caudate nucleus following stereotactic placement of lesions in the anterior cingulate cortex in humans: a morphometric magnetic resonance imaging study SO JOURNAL OF NEUROSURGERY LA English DT Article DE cingulotomy; segmentation; parcellation; caudate nucleus; amygdala; thalamus ID OBSESSIVE-COMPULSIVE DISORDER; BASAL GANGLIA; RHESUS-MONKEY; HUMAN BRAIN; DEPRESSION; PROJECTIONS; SCHIZOPHRENIA; PARCELLATION; CINGULOTOMY; CONNECTIONS AB Object. The goal of this study was to test hypotheses regarding changes in volume in subcortical structures following anterior cingulotomy. Methods. Morphometric magnetic resonance (MR) imaging methods were used to assess volume reductions in subcortical regions following anterior cingulate lesioning in nine patients. Magnetic resonance imaging data obtained before and 9 +/- 6 months following anterior cingulotomy were subjected to segmentation and subcortical parcellation. Significant volume reductions were predicted and found bilaterally within the caudate nucleus, but not in the amygdala, thalamus, lenticular nuclei, or hippocampus. Subcortical parcellation revealed that the volume reduction in the caudate nucleus was principally referrable to the body, rather than the head. Furthermore, the magnitude of volume reduction in the caudate body was significantly correlated with total lesion volume. Conclusions. Taken together, these findings implicate significant connectivity between a region of anterior cingulate cortex (ACC) lesioned during cingulotomy and the caudate body. This unique data set complements published findings in nonhuman primates, and advances our knowledge regarding patterns of cortical-subcortical connectivity involving the ACC in humans. Moreover, these findings indicate changes distant from the site of anterior cingulotomy lesions that may play a role in the clinical response to this neurosurgical procedure. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. McLean Hosp, Dept Neurol, Belmont, MA 02178 USA. RP Rauch, SL (reprint author), Massachusetts Gen Hosp E, Dept Psychiat, 9th Floor,Bldg 149,13th St, Charlestown, MA 02129 USA. RI Kennedy, David/H-3627-2012 FU NIMH NIH HHS [R01MH50275, K20MH01215, K21MH01230] NR 41 TC 44 Z9 44 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2000 VL 93 IS 6 BP 1019 EP 1025 DI 10.3171/jns.2000.93.6.1019 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 379XC UT WOS:000165667600015 PM 11117844 ER PT J AU Sikes, JW Ghali, GE Troulis, MJ AF Sikes, JW Ghali, GE Troulis, MJ TI Expansile intraosseous lesion of the maxilla SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID CALCIFYING ODONTOGENIC CYST; ODONTOMA C1 Louisiana State Univ, Med Ctr, Dept Surg, Div Oral & Maxillofacial Surg, Shreveport, LA 71130 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA USA. RP Ghali, GE (reprint author), Louisiana State Univ, Med Ctr, Dept Surg, Div Oral & Maxillofacial Surg, 1501 Kings Highway, Shreveport, LA 71130 USA. NR 16 TC 2 Z9 5 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 DEC PY 2000 VL 58 IS 12 BP 1395 EP 1400 DI 10.1053/joms.2000.18274 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 378QA UT WOS:000165594000016 PM 11117688 ER EF