North Shore University Hospital

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

Peripheral blood lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS) were grown in vitro with added T-cell growth factor and assayed for the expression and release of human T-lymphotropic retroviruses (HTLV). Retroviruses belonging to the HTLV family and collectively designated HTLV-III were isolated from a total of 48 subjects including 18 of 21 patients wih pre-AIDS, three of four clinically normal mothers of juveniles with AIDS, 26 of 72 adult and juvenile patients with AIDS, and from one of 22 normal male homosexual subjects. No HTLV-III was detected in or isolated from 115 normal heterosexual subjects. The number of HTLV-III isolates reported here underestimates the true prevalence of the virus since many specimens were received in unsatisfactory condition. Other data show that serum samples from a high proportion of AIDS patients contain antibodies to HTLV-III. That these new isolates are members of the HTLV family but differ from the previous isolates known as HTLV-I and HTLV-II is indicated by their morphological, biological, and immunological characteristics. These results and those reported elsewhere in this issue suggest that HTLV-III may be the primary cause of AIDS.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

BACKGROUND: Treatment with pegylated interferon (peginterferon) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE: To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or standard dose of ribavirin. DESIGN: Randomized, double-blind trial. SETTING: 99 international centers. PATIENTS: 1311 patients with chronic hepatitis C. INTERVENTION: Peginterferon-alpha2a, 180 microg/wk, for 24 or 48 weeks plus a low-dose (800 mg/d) or standard weight-based dose (1000 or 1200 mg/d) of ribavirin. MEASUREMENT: Sustained virologic response: undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up. RESULTS: Overall and in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks and standard-dose ribavirin was statistically superior to low-dose ribavirin. In patients with HCV genotype 1, absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2% (95% CI, 3.6% to 18.9%) and 11.9% (CI, 4.7% to 18.9%), respectively, between standard- and low-dose ribavirin. Sustained virologic response rates for peginterferon-alpha2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different. CONCLUSION: Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V(H) and V(L) gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38(+) B-CLL cells (>/=30%) than those with mutated V genes that had lower percentages of CD38(+) cells (<30%). Patients in both the unmutated and the >/=30% CD38(+) groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38(+) groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38(+) groups, males and females were virtually equally distributed, whereas in the unmutated and the >/=30% CD38(+) groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38(+) B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

BACKGROUND: Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson's disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known. METHODS: We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinson's disease (mean duration, 14 years) to receive a transplant of nerve cells or sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who received sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of -3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement. RESULTS: The mean (+/-SD) scores on the global rating scale for improvement or deterioration at one year were 0.0+/-2.1 in the transplantation group and -0.4+/-1.7 in the sham-surgery group. Among younger patients (60 years old or younger), standardized tests of Parkinson's disease revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication (P=0.01 for scores on the Unified Parkinson's Disease Rating Scale; P=0.006 for the Schwab and England score). There was no significant improvement in older patients in the transplantation group. Fiber outgrowth from the transplanted neurons was detected in 17 of the 20 patients in the transplantation group, as indicated by an increase in 18F-fluorodopa uptake on positron-emission tomography or postmortem examination. After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa. CONCLUSIONS: Human embryonic dopamine-neuron transplants survive in patients with severe Parkinson's disease and result in some clinical benefit in younger but not in older patients.

Thyroid hormone has many effects on the heart and vascular system.1 Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormone to alter cardiovascular hemodynamics.2 The hemodynamic effects of hypothyroidism are opposite to those of hyperthyroidism, although the clinical manifestations are less obvious. This review will integrate what is known about the mechanisms of thyroid hormone action on the heart25 with recent observations from both experimental and clinical studies of hyperthyroidism and hypothyroidism. We will also address the potential role of thyroid hormone treatment in patients with acute or chronic cardiac disease.Effects of . . .

Cells with properties characteristic of mononuclear phagocytes were evaluated for infectivity with five different isolates of the AIDS virus, HTLV-III/LAV. Mononuclear phagocytes cultured from brain and lung tissues of AIDS patients harbored the virus. In vitro-infected macrophages from the peripheral blood, bone marrow, or cord blood of healthy donors produced large quantities of virus. Virus production persisted for at least 40 days and was not dependent on host cell proliferation. Giant multinucleated cells were frequently observed in the macrophage cultures and numerous virus particles, often located within vacuole-like structures, were present in infected cells. The different virus isolates were compared for their ability to infect macrophages and T cells. Isolates from lung- and brain-derived macrophages had a significantly higher ability to infect macrophages than T cells. In contrast, the prototype HTLV-III beta showed a 10,000-fold lower ability to infect macrophages than T cells and virus production was one-tenth that in macrophage cultures infected with other isolates, indicating that a particular variant of HTLV-III/LAV may have a preferential tropism for macrophages or T cells. These results suggest that mononuclear phagocytes may serve as primary targets for infection and agents for virus dissemination and that these virus-infected cells may play a role in the pathogenesis of the disease.

Our concept of the pathogenesis of chronic lymphocytic leukemia has undergone remarkable changes during the past decade. This review addresses the latest ideas concerning the origin of this common form of leukemia and discusses how molecular investigations are beginning to change the management of the disease.

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

Lipopolysaccharide (LPS) is lethal to animals because it activates cytokine release, causing septic shock and tissue injury. Early proinflammatory cytokines (e.g., tumor necrosis factor [TNF] and interleukin [IL]-1) released within the first few hours of endotoxemia stimulate mediator cascades that persist for days and can lead to death. High mobility group 1 protein (HMG-1), a ubiquitous DNA-binding protein, was recently identified as a "late" mediator of endotoxin lethality. Anti-HMG-1 antibodies neutralized the delayed increase in serum HMG-1, and protected against endotoxin lethality, even when passive immunization was delayed until after the early cytokine response. Here we examined whether HMG-1 might stimulate cytokine synthesis in human peripheral blood mononuclear cell cultures. Addition of purified recombinant HMG-1 to human monocyte cultures significantly stimulated the release of TNF, IL-1alpha, IL-1beta, IL-1RA, IL-6, IL-8, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta; but not IL-10 or IL-12. HMG-1 concentrations that activated monocytes were within the pathological range previously observed in endotoxemic animals, and in serum obtained from septic patients. HMG-1 failed to stimulate cytokine release in lymphocytes, indicating that cellular stimulation was specific. Cytokine release after HMG-1 stimulation was delayed and biphasic compared with LPS stimulation. Computer-assisted image analysis demonstrated that peak intensity of HMG-1-induced cellular TNF staining was comparable to that observed after maximal stimulation with LPS. Administration of HMG-1 to Balb/c mice significantly increased serum TNF levels in vivo. Together, these results indicate that, like other cytokine mediators of endotoxin lethality (e.g., TNF and IL-1), extracellular HMG-1 is a regulator of monocyte proinflammatory cytokine synthesis.

The cardiovascular signs and symptoms of thyroid disease are some of the most profound and clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the cellular mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure, vascular resistance, and rhythm disturbances that result from thyroid dysfunction. The importance of the recognition of the effects of thyroid disease on the heart also derives from the observation that restoration of normal thyroid function most often reverses the abnormal cardiovascular hemodynamics. In the present review, we discuss the appropriate thyroid function tests to establish a suspected diagnosis as well as the treatment modalities necessary to restore patients to a euthyroid state. We also review the alterations in thyroid hormone metabolism that accompany chronic congestive heart failure and the approach to the management of patients with amiodarone-induced alterations in thyroid function tests.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Children and adults exposed to chronic interpersonal trauma consistently demonstrate psychological disturbances that are not captured in the posttraumatic stress disorder (PTSD) diagnosis. The DSM-IV (American Psychiatric Association, 1994) Field Trial studied 400 treatment-seeking traumatized individuals and 128 community residents and found that victims of prolonged interpersonal trauma, particularly trauma early in the life cycle, had a high incidence of problems with (a) regulation of affect and impulses, (b) memory and attention, (c) self-perception, (d) interpersonal relations, (e) somatization, and (f) systems of meaning. This raises important issues about the categorical versus the dimensional nature of posttraumatic stress, as well as the issue of comorbidity in PTSD. These data invite further exploration of what constitutes effective treatment of the full spectrum of posttraumatic psychopathology.

More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal "salt wasting" crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions--transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 microg per mouse) or the DNA-binding A box (600 microg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH(2)-terminal kinase and higher nuclear factor-kappaB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.

BACKGROUND: Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS: The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS: Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS: Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

BACKGROUND: The outcome of cardiogenic shock complicating myocardial infarction has not appreciably changed in the last 30 years despite the development of various percutaneous mechanical circulatory support options. It is clear that there are varying degrees of cardiogenic shock but there is no robust classification scheme to categorize this disease state. METHODS: A multidisciplinary group of experts convened by the Society for Cardiovascular Angiography and Interventions was assembled to derive a proposed classification schema for cardiogenic shock. Representatives from cardiology (interventional, advanced heart failure, noninvasive), emergency medicine, critical care, and cardiac nursing all collaborated to develop the proposed schema. RESULTS: A system describing stages of cardiogenic shock from A to E was developed. Stage A is "at risk" for cardiogenic shock, stage B is "beginning" shock, stage C is "classic" cardiogenic shock, stage D is "deteriorating", and E is "extremis". The difference between stages B and C is the presence of hypoperfusion which is present in stages C and higher. Stage D implies that the initial set of interventions chosen have not restored stability and adequate perfusion despite at least 30 minutes of observation and stage E is the patient in extremis, highly unstable, often with cardiovascular collapse. CONCLUSION: This proposed classification system is simple, clinically applicable across the care spectrum from pre-hospital providers to intensive care staff but will require future validation studies to assess its utility and potential prognostic implications.