Severe Outcome (severe + outcome)

Distribution by Scientific Domains

Selected Abstracts

Characterization of amplicons in neuroblastoma: High-resolution mapping using DNA microarrays, relationship with outcome, and identification of overexpressed genes

Anne Fix
Somatically acquired chromosomal imbalances are a key feature of neuroblastoma, a heterogeneous pediatric solid tumor. Among these alterations, genomic amplification targeting the MYCN oncogene and observed in about 25,30% of the cases, strongly correlates with advanced stage and poor outcome. In this work, we have used BAC and SNP arrays as well as gene expression arrays to characterize amplifications in neuroblastoma. Eighty-eight distinct BACs defining high-level amplification events were identified in 65 samples, including 43 tumors and 22 cell lines. Although the highest recurrence was observed on chromosome 2, clones on chromosomes 8, 12, 16, and 17 also revealed genomic amplification in several samples. A detailed analysis of the 2p22-2p25 MYCN containing region indicated highly complex patterns in a number of cases. Coamplifications involving MYCN and other regions were explored by FISH in three cell lines. High-resolution arrays then allowed us to further refine the mapping of 25 amplicons in 19 samples, either reducing the size of a single continuous amplicon or increasing the complexity by highlighting multiple noncontiguous regions of amplification. Combined analysis of gene expression profiling and array-CGH data indicated that 12 to 25% of the genes that are targeted by genomic amplification are actually over-expressed in tumor cells, several of them having already been implicated in cancer. Finally, our results suggest that the presence of amplicons localized outside of chromosome 2, in addition to MYCN amplification, may be linked to a particularly severe outcome in neuroblastoma patients. 2008 Wiley-Liss, Inc. [source]

Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases,

HEPATOLOGY, Issue 1 2009
Allen D. Brinker
Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.) [source]

Gorham-Stout Syndrome: A Monocyte-Mediated Cytokine Propelled Disease,

Silvia Colucci
Abstract We studied the biological features and the immunophenotype of a cell culture established from the lesion of soft tissues of a woman affected by Gorham-Stout syndrome. We found that these cells belonged to a monocytic lineage with some characteristics of immature osteoclasts and were able to release large amounts of osteoclastogenic and angiogenic molecules that may contribute to disease progression. Introduction: Gorham-Stout syndrome is a rare disease characterized by osteolysis and proliferation of vascular or lymphatic vessels, with a severe outcome. Its etiology and the identification of the cell types involved are completely unknown. Materials and Methods: A cell culture from a lesion of soft tissues was established, and its behavior in vitro and in immunodeficient mice was studied. We analyzed (1) the cell phenotype by flow cytometry; (2) the adhesive and migratory properties on different substrates; (3) the ability to differentiate into mature osteoclasts; (4) the production of osteclastogenic and angiogenic molecules; (5) the in vivo angiogenic activity of the cells subcutaneously implanted in mouse in a Matrigel plug; and (6) the ability to recapitulate the disease when transplanted in nude mice. Results and Conclusions: The established culture consisted of a morphologically homogeneous cell population belonging to a monocytic lineage having some features of an osteoclast-like cell type. Cells had an invasive phenotype, were angiogenic, and produced osteoclastogenic (IL-6, TGF-,1, IL-1,) and angiogenic (vascular endothelial growth factor-A {VEGF-A}, CXCL-8) molecules when challenged with inflammatory cytokines. Immunodeficient mice injected with these cells did not show any bone lesions or vascular alteration, but had high amounts of circulating human IL-6 and VEGF-A. Cells isolated from a cutaneous lymphangiomatosis did not show any of these findings. These data suggest that cells of monocyte-macrophage lineage play an essential role in the pathogenesis of Gorham-Stout disease, whose progression is propelled by cytokine circuits that accelerate angiogenesis and osteoclastogenesis. [source]

Methods for measuring abdominal obesity in the prediction of severe acute pancreatitis, and their correlation with abdominal fat areas assessed by computed tomography

A. Duarte-Rojo
Aliment Pharmacol Ther 2010; 32: 244,253 Summary Background, Obesity increases the risk for severe acute pancreatitis, although abdominal obesity may be a better prognostic marker. Aim, To determine if a single anthropometric parameter best predicts severe acute pancreatitis and correlates with intra-abdominal fat. Methods, Ninety-nine patients with acute pancreatitis were studied prospectively. Anthropometry included body mass index (BMI) and girths (umbilical/minimum waist, iliac/trochanter hip, thigh). Several waist-to-hip/waist-to-thigh ratios (WHR/WTR) were constructed. A CT-scan with calculation of cross-sectional abdominal fat areas was obtained in 37 cases. Results, Severe acute pancreatitis occurred in 25 patients. Waist circumference (WC), WHR and WTR , all using the umbilical reference , most accurately predicted severe acute pancreatitis. Only umbilical WC was retained in multivariate analysis: the risk for severe acute pancreatitis increased 16% with every 1 cm (OR 1.16, 95%CI: 1.1,1.3). Abdominal obesity caused a 6-fold increase in risk. Umbilical WC correlated best with subcutaneous fat area (r = 0.791, P < 0.001), whereas WHR with intra-abdominal (r = 0.594, P < 0.001). Conclusions, Abdominal obesity according to umbilical WC is a better predictor for development of severe acute pancreatitis than BMI, minimum WC, WHR and WTR. The protocol for anthropometry must be standardized as it may affect results. Both subcutaneous and intra-abdominal fat appears to affect the likelihood of a severe outcome. [source]

Management of patients with decompensated hepatitis B virus associated cirrhosis

Fabien Zoulim
Key Points 1Hepatitis B virus replication is associated with a severe outcome in patients with decompensated cirrhosis. 2Viral suppression induced by antivirals results in a clinical improvement that allows liver transplantation to be delayed or avoided. 3Early treatment intervention is mandatory in patients with decompensated cirrhosis because of the delay in the restoration of liver functions. 4Lamivudine is no longer the drug of choice because the initial enthusiasm has been tempered by the high rate of resistance development. 5Early add-on therapy with adefovir allows us to rescue lamivudine resistance, but its use may be limited by nephrotoxicity. 6Studies are ongoing with the newer generation of antivirals (telbivudine, tenofovir, entecavir, and emtricitabine) in monotherapy or in combination to determine the best strategy for achieving rapid and prolonged suppression of viral replication. These improved strategies should enhance treatment success enough to obtain clinical stabilization, to delay or prevent the need for transplantation, and to reduce the risk of hepatitis B virus recurrence on the graft. Liver Transpl 14:S1,S7, 2008. 2008 AASLD. [source]

The DERAA HLA,DR alleles in patients with early polyarthritis: Protection against severe disease and lack of association with rheumatoid arthritis autoantibodies,

Nathalie Carrier
Objective To define the association of alleles encoding the HLA,DR rheumatoid arthritis (RA) protective epitope (DERAA) with the presence of RA-associated antibodies at study inclusion and with severe outcome in patients with early polyarthritis (EPA). Methods Consecutive EPA patients (n = 210) were evaluated early (mean of 4.8 months after diagnosis) and prospectively (for 30 months). HLA class II typing was performed by polymerase chain reaction using sequence-specific primers, and HLA,DR alleles DERAA, RA-associated shared epitope (SE), and non-SE/non-DERAA (neither SE nor DERAA) were identified. RA-associated antibodies identified were anti-Sa/citrullinated vimentin, anti,cyclic citrullinated peptide 2, and IgM rheumatoid factor. Severe disease was defined according to a preset threshold of joint destruction and/or functional limitation. Results DERAA and SE alleles were present in 62 and 110 of the 210 EPA patients, respectively. At 30 months, severe disease was present in 78 patients (37%). In contrast to SE alleles, DERAA alleles were not associated with the production of RA-associated antibodies, but were strongly protective against severe disease at 30 months (odds ratio 0.30, P < 0.001). DERAA alleles emerged as a strong, independent protective marker on multivariate analysis. The protective effect of DERAA was seen only in patients who did not already have erosions at study inclusion, was independent of the presence of antibodies, but was not associated with spontaneous remission. Conclusion In our EPA cohort, the presence of a DERAA sequence was a strong independent predictor of a better prognosis, but only in the absence of erosive disease that was already present at inclusion. Identification of DERAA alleles may help in managing the large subgroup of EPA patients who do not have erosions at baseline. [source]

Prognostic factors associated with severe leptospirosis

B. Doudier
Abstract Leptospirosis is an anthropozoonosis caused by Leptospira interrogans. It occurs worldwide and is endemic in French Polynesia. Leptospirosis is associated with a large variety of clinical symptoms. Most infections caused by leptospires are either sub-clinical or of very mild severity, but 5,10% of infections result in multiple organ damage, including kidney, liver and lung lesions. Among 71 patients hospitalised in Papeete for severe leptospirosis during a period of 2 years, the main risk-factors for a severe outcome were hypotension, oliguria and an abnormal chest auscultation at the first physical examination. Survival depends on rapid diagnosis and early appropriate management. Well-defined criteria may help physicians to improve the timely treatment of high-risk patients. [source]

Litigation related to regional anaesthesia: an analysis of claims against the NHS in England 1995,2007,

ANAESTHESIA, Issue 5 2010
K. Szypula
Summary We analysed 366 claims related to regional anaesthesia and analgesia from the 841 anaesthesia-related claims handled by the National Health Service Litigation Authority between 1995 and 2007. The majority of claims (281/366, 77%) were closed at the time of analysis. The total cost of closed claims was 12 724 017 (34% of the cost of the anaesthesia dataset) with a median (IQR [range]) of 4772 (0,28 907 [0,2 070 092]). Approximately half of the claims (186/366; 51%) were related to obstetric anaesthesia and analgesia and of the non-obstetric claims, the majority (148/180; 82%) were related to neuraxial block. The total cost for obstetric closed claims was 5 433 920 (median (IQR [range]) 5678 (0,27 690 [0,1 597 565]) while that for non-obstetric closed claims was 7 290 097 (3337 (0,31 405 [0,2 070 062]). Non-obstetric claims were more likely to relate to severe outcomes than obstetric ones. The maximum values of claims were higher for claims related to neuraxial blocks and eye blocks than for peripheral nerve blocks. Despite many limitations, including lack of clinical detail for each case, the dataset provides a useful overview of the extent, patterns and cost associated with the claims. [source]