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Showing papers by "Icahn School of Medicine at Mount Sinai published in 2003"


Journal ArticleDOI
13 Feb 2003-Nature
TL;DR: It is shown that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL- 12, is the critical factor in this response.
Abstract: Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.

2,915 citations


Journal ArticleDOI
TL;DR: The term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future and a quantitative method for cumulative risk assessment of vulnerable patients needs to be developed.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

2,719 citations


Journal ArticleDOI
TL;DR: This is the first of two articles describing a symposium on insulin action, insulin resistance, inflammation, and Atherosclerosis in Niagara Falls, New York, 20–21 September 2002, which will cover topics related to atherosclerosis pathobiology and the cell biology of insulin resistance.
Abstract: This Is the second of two articles describing a symposium on the relationship between inflammation and insulin resistance that was held in Niagra Falls, NY, 20–21 September 2002. Antonio Ceriello (Udine, Italy) discussed the role of glucose intake and postprandial hyperglycemia in the development of diabetes complications, as well as the relationship of hyperglycemia to oxidative stress. The DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) study showed high 2-h postload glucose to be associated with increased mortality independent of fasting glucose (1), and the Pacific and Indian Ocean Study showed isolated 2-h hyperglycemia to double the risk of mortality (2). The Funagata Diabetes Study showed that impaired glucose tolerance (IGT) but not impaired fasting glucose was a risk factor for cardiovascular disease (CVD) (3). There is evidence that lowering postprandial glucose improves outcome. Post hoc analysis of the STOP-type 2 diabetes study showed that myocardial infarction and hypertension decrease with use of the prandial glucose-lowering agent acarbose (4). In the Kumamoto study, postprandial hyperglycemia strongly predicted retinopathy and nephropathy (5). Endothelial dysfunction (ED) is a potential mediator of the effect of prandial glycemia, with altered vasodilation and procoagulant abnormalities. ED can be induced by hyperglycemia following a 75-g oral glucose load in persons with normal or IGT or with diabetes, with reduction of flow-mediated brachial artery dilation proportional to the degree of hyperglycemia (6). In a study of 225 persons with hypertension followed for 32 months, forearm ED was a marker of future CVD events (7), with a 4.5-year follow-up of 281 persons showing both ED and measures of oxidative stress to predict CVD events (8). Acute hyperglycemia may suppress vasodilation, which may involve oxidant stress, as it is reversed with antioxidant or l-arginine treatment (9). Glucose increases endothelial cell free radical production leading …

1,773 citations


Journal ArticleDOI
TL;DR: Current knowledge about the nature and prognosis of fibrosis in different forms of chronic liver disease with recent advances in elucidating its pathophysiology form the basis for rational treatment of hepatic fibrosis, which are summarized.

1,635 citations


Journal ArticleDOI
TL;DR: In this paper, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices.
Abstract: IntroductionOver the past 20 years or so, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices. In the same period, recognition of the phenomenon of white-coat hype

1,462 citations


Journal ArticleDOI
TL;DR: Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on results, and Stratification based on disease severity showed a treatment effect in milder patients.
Abstract: Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication ("off"-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.

1,417 citations


Journal ArticleDOI
29 May 2003-Nature
TL;DR: It is concluded that FOXO1 and PGC-1α interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis, which is necessary for survival during prolonged fasting or starvation and in diabetes mellitus.
Abstract: Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis. Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-gamma co-activator 1 (PGC-1alpha; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1alpha binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1alpha. Insulin suppresses gluconeogenesis stimulated by PGC-1alpha but co-expression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1alpha interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis.

1,346 citations


Journal ArticleDOI
04 Jun 2003-JAMA
TL;DR: The majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure, and several features of the clinical presentation will be useful in raising the suspicion of SARS.
Abstract: ContextSevere acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002 and has subsequently spread worldwide.ObjectivesTo describe the clinical characteristics and short-term outcomes of SARS in the first large group of patients in North America; to describe how these patients were treated and the variables associated with poor outcome.Design, Setting, and PatientsRetrospective case series involving 144 adult patients admitted to 10 academic and community hospitals in the greater Toronto, Ontario, area between March 7 and April 10, 2003, with a diagnosis of suspected or probable SARS. Patients were included if they had fever, a known exposure to SARS, and respiratory symptoms or infiltrates observed on chest radiograph. Patients were excluded if an alternative diagnosis was determined.Main Outcome MeasuresLocation of exposure to SARS; features of the history, physical examination, and laboratory tests at admission to the hospital; and 21-day outcomes such as death or intensive care unit (ICU) admission with or without mechanical ventilation.ResultsOf the 144 patients, 111 (77%) were exposed to SARS in the hospital setting. Features of the clinical examination most commonly found in these patients at admission were self-reported fever (99%), documented elevated temperature (85%), nonproductive cough (69%), myalgia (49%), and dyspnea (42%). Common laboratory features included elevated lactate dehydrogenase (87%), hypocalcemia (60%), and lymphopenia (54%). Only 2% of patients had rhinorrhea. A total of 126 patients (88%) were treated with ribavirin, although its use was associated with significant toxicity, including hemolysis (in 76%) and decrease in hemoglobin of 2 g/dL (in 49%). Twenty-nine patients (20%) were admitted to the ICU with or without mechanical ventilation, and 8 patients died (21-day mortality, 6.5%; 95% confidence interval [CI], 1.9%-11.8%). Multivariable analysis showed that the presence of diabetes (relative risk [RR], 3.1; 95% CI, 1.4-7.2; P = .01) or other comorbid conditions (RR, 2.5; 95% CI, 1.1-5.8; P = .03) were independently associated with poor outcome (death, ICU admission, or mechanical ventilation).ConclusionsThe majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure. In the event that contact history becomes unreliable, several features of the clinical presentation will be useful in raising the suspicion of SARS. Although SARS is associated with significant morbidity and mortality, especially in patients with diabetes or other comorbid conditions, the vast majority (93.5%) of patients in our cohort survived.Published online May 6, 2003 (doi:10.1001/jama.289.21.JOC30885).

1,269 citations


Journal ArticleDOI
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

1,176 citations


Journal ArticleDOI
TL;DR: The frequency of TBI is determined, special groups at risk for TBI, and mortality from TBI are determined.
Abstract: Summary: Purpose: Traumatic brain injury (TBI) not only has considerable morbidity and mortality, but it is a major cause of epilepsy. We wish to determine the frequency of TBI, special groups at risk for TBI, and mortality from TBI. Methods: We reviewed studies of TBI that are either population based or derived from definable catchment areas that allow determination of incidence, identification of risk groups, and mortality. We review methodology used in epidemiologic studies of TBI and try to distinguish this data from that of head injury not necessarily affecting the brain. We report epidemiologic characteristics of TBI, including incidence, differences by age, gender, race and ethnic group, and geographic variation, and mortality. Results: Population-based studies in the United States suggest that the incidence of TBI is between 180 and 250 per 100,000 population per year. Incidence may be higher in Europe and South Africa. There are groups at high risk for TBI. This includes males and individuals living in regions characterized by socioeconomic deprivation. There are selective age groups at risk for TBI. This includes the very young, adolescents and young adults, and the elderly. Mortality varies by severity but is high in those with severe injury and in the elderly. Conclusions: TBI is a major public health problem as well as a major cause of epilepsy. If primary prevention is to be undertaken, we must understand the epidemiology of the condition. The primary causes of TBI vary by age, socioeconomic factors, and geographic region, so any planned interventions must be tailored accordingly.

1,171 citations


Journal ArticleDOI
TL;DR: Results supported the hypothesized relations between autonomy and well-being across cultures and gender and suggested greater internalization of horizontal relative to vertical practices.
Abstract: On the basis of self-determination theory (R. M. Ryan & E. L. Deci, 2000) and cultural descriptions drawn from H. C. Triandis (1995), the authors hypothesized that (a) individuals from different cultures internalize different cultural practices; (b) despite these differences, the relative autonomy of individuals' motivation for those practices predicts well-being in all 4 cultures examined; and (c) horizontal practices are more readily internalized than vertical practices across all samples. Five hundred fifty-nine persons from South Korea, Russia, Turkey and the United States participated. Results supported the hypothesized relations between autonomy and well-being across cultures and gender. Results also suggested greater internalization of horizontal relative to vertical practices. Discussion focuses on the distinction between autonomy and individualism and the relative fit of cultural forms with basic psychological needs.

Journal ArticleDOI
TL;DR: The Human Protein Reference Database (HPRD) as mentioned in this paper is an object database that integrates a wealth of information relevant to the function of human proteins in health and disease, including protein-protein interactions, posttranslational modifications, enzyme/substrate relationships, disease associations, tissue expression, and subcellular localization.
Abstract: Human Protein Reference Database (HPRD) is an object database that integrates a wealth of information relevant to the function of human proteins in health and disease. Data pertaining to thousands of protein-protein interactions, posttranslational modifications, enzyme/substrate relationships, disease associations, tissue expression, and subcellular localization were extracted from the literature for a nonredundant set of 2750 human proteins. Almost all the information was obtained manually by biologists who read and interpreted >300,000 published articles during the annotation process. This database, which has an intuitive query interface allowing easy access to all the features of proteins, was built by using open source technologies and will be freely available at http://www.hprd.org to the academic community. This unified bioinformatics platform will be useful in cataloging and mining the large number of proteomic interactions and alterations that will be discovered in the postgenomic era.

Journal ArticleDOI
TL;DR: It is reported herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF, and it is identified as a natural ligand forCD74, which has been implicated previously in signaling and accessory functions for immune cell activation.
Abstract: Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.

Journal ArticleDOI
TL;DR: It is reported that individuals with Noonan syndrome and juvenile myelomonocytic leukemia have germline mutations in PTPN11 and that somatic mutations in MDS and AML account for 34% of non-syndromic JMML.
Abstract: We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

Journal ArticleDOI
TL;DR: New stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD, and demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.
Abstract: Objective: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Background: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Methods: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. Results: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. Conclusions: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

Journal ArticleDOI
04 Jun 2003-JAMA
TL;DR: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.
Abstract: ContextLaboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease.ObjectiveTo determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD.DesignMulticenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications.SettingForty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium.ParticipantsParticipants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled.InterventionsOnce-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo.Main Outcome MeasuresThe primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death).ResultsThe 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group.ConclusionThe results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Journal ArticleDOI
TL;DR: It is proposed that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.
Abstract: Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterolloaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop −/− macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterolinduced apoptosis in macrophages.

Journal ArticleDOI
TL;DR: Laroscopic sleeve gastrectomy with second-stage Roux-en-Y gastric bypass are feasible and effective procedures based on short-term results.
Abstract: Background: Surgical management of the supersuper obese patient (BMI >60 kg/m2) has been a challenging problem associated with higher morbidity, mortality, and long-term weight loss failure. Current limited experience exists with a two-stage biliopancreatic diversion and duodenal switch in the supersuper obese patient, and we now present our early experience with a two-stage gastric bypass for these patients. Methods: We completed a retrospective bariatric database and chart review of super-super obese patients who underwent laparoscopic sleeve gastrectomy as a first-stage procedure followed by laparoscopic Roux-en-Y gastric bypass as a second-stage for more definitive treatment of obesity. Results: During a two-year period, 7 patients with BMI 58-71 kg/m2 underwent a two-stage laparoscopic Roux-en-Y gastric bypass by two surgeons at the Mount Sinai Medical Center. 3 patients were female, 4 patients were male, and the average age was 43. Prior to the sleeve gastrectomy, the mean weight was 181 kg with a BMI of 63. Average time between procedures was 11 months. Prior to the second-stage procedure, the mean weight was 145 kg with a BMI of 50 and average excess weight loss of 37 kg (33% EWL). Six patients have had follow-up after the second-stage procedure with an average of 2.5 months. At follow-up the mean weight was 126 kg with a BMI of 44 and average excess weight loss of 51 kg (46% EWL). The mean operative times for the two procedures were 124 and 158 minutes respectively. The average length of stay for all procedures was 2.7 days. 4 patients had 5 complications, which included splenic injury, proximal anastomotic stricture, left arm nerve praxia, trocar site hernia, and urinary tract infection.There were no mortalities in the series. Conclusions: Laparoscopic sleeve gastrectomy with second-stage Roux-en-Y gastric bypass are feasible and effective procedures based on short-term results. This two-stage approach is a reasonable alternative for surgical treatment of the high-risk supersuper obese patient.

Journal ArticleDOI
TL;DR: YAP overexpression increases, while YAP depletion decreases, p73-mediated apoptosis following DNA damage, in an Akt inhibitable manner, and Akt phosphorylation of YAP may thus suppress the induction of the proapoptotic gene expression response following cellular damage.

Journal ArticleDOI
TL;DR: Support for the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome is supported.
Abstract: Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

Journal ArticleDOI
TL;DR: The prevalence of medical errors related to the discontinuity of care from the inpatient to the outpatient setting is high and may be associated with an increased risk of rehospitalization.
Abstract: OBJECTIVE: To determine the prevalence of medical errors related to the discontinuity of care from an inpatient to an outpatient setting, and to determine if there is an association between these medical errors and adverse outcomes.

Journal ArticleDOI
TL;DR: For example, this paper found that the prevalence of self-reported peanut and tree-nut allergy increased from 0.4% in 1997 to 0.8% in 2002 by a factor of 1.04% (95% CI, 0.9-1.24%).
Abstract: Background Allergy to peanuts and tree nuts (TNs) is the leading cause of fatal and near-fatal food allergic reactions. Peanut allergy appears to be increasing in prevalence. Objectives We sought to determine the prevalence of self-reported peanut and TN allergy among the general population of the United States in 2002 by sex and age and to compare the results with prevalence estimates obtained 5 years earlier. Methods We performed a nationwide, cross-sectional, random telephone survey by using a standardized questionnaire. Results A total of 4855 households participated (53% participation rate), representing a census of 13,493 individuals. Peanut allergy, TN allergy, or both was self-reported in 166 (1.2%; 95% CI, 1.0%-1.4%) individuals in 155 (3.2%; 95% CI, 2.7%-3.7%) households, overall prevalence rates similar to those reported in 1997. Also similar to the 1997 survey, the severity level was high, with 79% reporting respiratory or multiple organ system reactions and 66% experiencing more than 5 lifetime reactions. Despite the severity and reaction frequency, only 74% of the children and 44% of the adults sought evaluation for the allergy, and fewer than half who did were prescribed self-injectable epinephrine. Applying conservative rules to adjust for persons with unconvincing reactions and a false-positive rate of the survey instrument (7%), a final prevalence estimate of 1.04% (95% CI, 0.9%-1.24%) was obtained. A male predominance of peanut-TN allergy was reported in children younger than 18 years (1.7% vs 0.7%, P = .02), and a female predominance was reported among adults (1.7% vs 0.9%, P = .0008). Although the rate of peanut allergy, TN allergy, or both was not significantly different from 1997 to 2002 among adults, the rate increased from 0.6% to 1.2% among children, primarily as a result of an increase in reported allergy to peanut (0.4% in 1997 to 0.8% in 2002, P = .05). Conclusions Self-reported peanut allergy has doubled among children from 1997 to 2002, and peanut allergies, TN allergies, or both continue to be reported by more than 3 million Americans. Considering that reactions are severe and the allergy is persistent, these allergies represent an increasing health concern.

Journal ArticleDOI
TL;DR: Recently, enzyme replacement with human -Gal A has been shown to safely reverse the pathogenesis of the major clinical manifestations, to decrease pain, and to stabilize renal function in patients with Fabry disease, and the European Agency for the Evaluation of Medicinal Products has approved the treatment and the U.S. Food and Drug Administration is currently reviewing it.
Abstract: Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder. Although the disease presents in childhood and culminates in cardiac, cerebrovascular, and end-stage renal disease, diagnosis is often delayed or missed. This paper reviews the key signs and symptoms of Fabry disease and provides expert recommendations for diagnosis, follow-up, medical management, and the use of enzyme replacement therapy. Recommendations are based on reviews of the literature on Fabry disease, results of recent clinical trials, and expertise of the authors, all of whom have extensive clinical experience with Fabry disease and lysosomal storage disorders and represent subspecialties involved in treatment. All males and female carriers affected with Fabry disease should be followed closely, regardless of symptoms or treatment status. Clinical trials have shown that recombinant human alpha-galactosidase A replacement therapy--the only disease-specific therapy currently available for Fabry disease--is safe and can reverse substrate storage in the lysosome, the pathophysiologic basis of the disease. Enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations should be initiated as early as possible. Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children, and patients with compromised renal function.

Journal ArticleDOI
TL;DR: Using admission data, clinicians can identify patients at high risk for delirium following hip fracture and undertreated pain and inadequate analgesia appear to be risk factors forDelirium in frail older adults.
Abstract: Background. Delirium and pain are common following hip fracture. Untreated pain has been shown to increase the risk of delirium in older adults undergoing elective surgery. This study was performed to examine the relationship among pain, analgesics, and other factors on delirium in hip fracture patients. Methods. We conducted a prospective cohort study at four New York hospitals that enrolled 541 patients with hip fracture and without delirium. Delirium was identified prospectively by patient interview supplemented by medical record review. Multiple logistic regression was used to identify risk factors. Results. Eighty-seven of 541 patients (16%) became delirious. Among all subjects, risk factors for delirium were cognitive impairment (relative risk, or RR, 3.6; 95% confidence interval, or CI, 1.8‐7.2), abnormal blood pressure (RR 2.3, 95% CI 1.2‐4.7), and heart failure (RR 2.9, 95% CI 1.6‐5.3). Patients who received less than 10 mg of parenteral morphine sulfate equivalents per day were more likely to develop delirium than patients who received more analgesia (RR 5.4, 95% CI 2.4‐12.3). Patients who received meperidine were at increased risk of developing delirium as compared with patients who received other opioid analgesics (RR 2.4, 95% CI 1.3‐4.5). In cognitively intact patients, severe pain significantly increased the risk of delirium (RR 9.0, 95% CI 1.8‐45.2). Conclusions. Using admission data, clinicians can identify patients at high risk for delirium following hip fracture. Avoiding opioids or using very low doses of opioids increased the risk of delirium. Cognitively intact patients with undertreated pain were nine times more likely to develop delirium than patients whose pain was adequately treated. Undertreated pain and inadequate analgesia appear to be risk factors for delirium in frail older adults.

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TL;DR: Two studies subjected rats to acute or chronic restraint stress and assessed the proliferation, survival and differentiation of newly born cells in the dentate gyrus may help understand the basis for hippocampal shrinkage and raise questions about the ultimate reversibility of the effects of chronic stress.
Abstract: Chronic restraint stress has been shown to induce structural remodelling throughout the interconnected dentate gyrus-CA3 fields. To find out how this stressor affects the rate of adult hippocampal neurogenesis, we subjected rats to acute or chronic restraint stress and assessed the proliferation, survival and differentiation of newly born cells in the dentate gyrus. We also examined polysialylated neural cell adhesion molecule expression, a molecule normally expressed in immature neurons and important for morphological plasticity. The results show that acute restraint stress did not change either the proliferation of dentate gyrus precursor cells or the expression of polysialylated neural cell adhesion molecule, whereas 3 weeks of chronic restraint stress suppressed proliferation by 24% and increased polysialylated neural cell adhesion molecule expression by 40%. The study was extended for an additional 3 weeks to trace the survival and development of the cells born after the initial 3 weeks of restraint. Rats subjected to 6 weeks of daily restraint stress exhibited suppressed cell proliferation and attenuated survival of the recently born cells after the extended time course, resulting in a 47% reduction of granule cell neurogenesis. Furthermore, 6 weeks of chronic stress significantly reduced the total number of granule cells by 13% and the granule cell layer volume by 5%. Expression of polysialylated neural cell adhesion molecule followed a biphasic time course, displaying a significant up-regulation after 3 weeks of daily restraint stress that was lost after 6 weeks of stress. These studies may help us understand the basis for hippocampal shrinkage and raise questions about the ultimate reversibility of the effects of chronic stress.

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TL;DR: The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.
Abstract: WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection1. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis2. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.

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TL;DR: A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut to one equal to almost nine peanuts, an effect that should translate into protection against most unintended ingestions of peanuts.
Abstract: background Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc e receptor on mast cells and basophils. methods We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a history of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to four weeks after the fourth dose. results From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated. conclusions A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanuts.

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TL;DR: Patients with autism spectrum disorders showed a significant reduction in repetitive behaviors following oxytocin infusion in comparison to placebo infusion, and may be partially ameliorated by synthetic oxytocIn infusion.

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TL;DR: A surveillance guideline is proposed using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.
Abstract: Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

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TL;DR: Stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34+ progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice, suggesting the potential of hematoplastic CD34-/CXCR4+cells to respond to stress signals from nonhematopoiety injured organs as an important mechanism for tissue targeting and repair
Abstract: Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34+ hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1-expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1-mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1-mediated directional migration by human CD34+ progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34+ progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34+/CXCR4+cells to respond to stress signals from nonhematopoietic injured organs as an important mechanism for tissue targeting and repair.