tbuckley/cabot-search huggingface dataset:
Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3
Authors: Alexander J Thompson, Keyur Patel, Wan-Long Chuang, Eric J Lawitz, Maribel Rodriguez-Torres, Vinod K Rustgi, Robert Flisiak, Stephen Pianko, Moises Diago, Sanjeev Arora, Graham R Foster, Michael Torbenson, Yves Benhamou, David R Nelson, Mark S Sulkowski, Stefan Zeuzem, Erik Pulkstenis, G Mani Subramanian, John G McHutchison
Journal: Gut (2011)

<h3>Objectives</h3> Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. <h3>Methods</h3> 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. <h3>Results</h3> Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR &gt;3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p&lt;0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. <h3>Conclusions</h3> SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.
Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells
Authors: Sonya G. Fonseca, Shinsuke Ishigaki, Christine M. Oslowski, Simin Lu, Kathryn L. Lipson, Rajarshi Ghosh, Emiko Hayashi, Hisamitsu Ishihara, Yoshitomo Oka, M. Alan Permutt, Fumihiko Urano
Journal: Journal of Clinical Investigation (2010)

Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.
T cell receptor V beta repertoire in an acute infection of rhesus monkeys with simian immunodeficiency viruses and a chimeric simian-human immunodeficiency virus.
Authors: Z W Chen, Z C Kou, C Lekutis, L Shen, D Zhou, M Halloran, J Li, J Sodroski, D Lee-Parritz, N L Letvin
Journal: The Journal of Experimental Medicine (1995)

Changes in T cell receptor (TCR) V beta repertoire and their correlation with virologic events were investigated in rhesus monkeys after acute infection with the simian immunodeficiency virus (SIV). 11 genetically defined rhesus monkeys were experimentally infected with SIVmac or a chimeric simian-human immunodeficiency virus (SHIV), and their peripheral blood lymphocytes (PBL) and lymph nodes were prospectively assessed for TCR V beta gene expression. PBL and lymph nodes of the acutely infected monkeys demonstrated an expansion of selected V beta-expressing T lymphocyte subpopulations as early as 3 d after infection. These expanded V beta-expressing lymphocyte subpopulations were comprised predominantly of CD8+ cells. Six of seven infected monkeys sharing a single electrophoretically defined major histocompatibility complex class I allele exhibited a similar expansion of V beta 14-expressing PBL. Sequence analyses of V-D-J segments of TCR-beta cDNA indicated that the V beta-expressing T cell subpopulation expansion can be oligoclonal. SIVmac-specific CD8+ cytotoxic T lymphocytes were demonstrated in both PBL and lymph nodes of the infected monkeys at the time expansion of the selected V beta-expressing cell subpopulations was seen. Finally, the expansion of the selected V beta-expressing lymphocytes in PBL coincided with the emergence and clearance of SIV p27 from the plasma of the infected monkeys. These results demonstrate that acute infection of rhesus monkeys with SIVmac or SHIV results in an expansion of CD8+ lymphocyte subpopulations expressing selected V beta gene families. The selectively expanded T lymphocytes may contribute to early viral clearance after acute SIVmac or SHIV infection.
Assessing Change with Longitudinal and Clustered Binary Data
Authors: John M Neuhaus
Journal: Annual Review of Public Health (2001)

▪ Abstract Investigators often gather repeated measures on study subjects to directly measure how a subject's response changes with changes in explanatory variables. This paper focuses on several statistical issues related to assessing change with longitudinal and clustered binary data. Many popular approaches for analyzing repeated binary outcomes measure cross-sectional or between-subject, rather than within-subject, effects of covariates. The class of models known as cluster specific measures within-subject effects of covariates on responses but are subject to additional statistical complications. It is useful to decompose covariates into between- and within-cluster components. This paper describes several approaches that yield consistent estimates of the within-subject covariate effects of interest. Example data from three studies illustrate the results.
Measurement of ventilatory cycle in central apneas at high altitude
Authors: Edmundo Rosales-Mayor, Jorge Rey de Castro, Oswaldo Ortiz, Alicia Liendo, Jenny Ferreyra, César Liendo
Journal: European Respiratory Journal (2013)

Background: Central apneas can be characterized by measuring the apnea duration, ventilatory phase and respiratory cycle duration. Cardiogenic and idiopathic central apneas have distinct characteristics. Aim: We present on this report the polygraphic features of High altitude central apneas (HACA). Methods: 63 drivers, working the morning shift in a Peruvian Mine and sleeping at 6625 feet above sea level, were tested on their usual nocturnal sleep periods, and in their own sleeping quarters using the Apnea Link plus. Recording was performed on the 2nd day of working cycle. Results: 59 were analyzed. 46 were normal, 6 had Obstructive Sleep Apnea (OSA) and 7 central apnea. Patients with central apnea: Age 37.3±19.4 years, BMI 28.7±3.2 kg/m2, Epworth score 3.4±2.7, Lake-Louis score 0.4±0.8, AHI 35.7±19.3, AHI central 13.4±14.2. 85% patients with central apneas they have intermittent exposure to high altitude. Characterization of HACA:

![Figure][1] 



Cheyne-Stokes Respiration (CSR). Conclusions: High altitude driver mine workers have an incidence of sleep disordered of breathing of 22% and 7% of Central apneas. Characterization of HACA suggests that these apneas are more similar to idiopathic central apneas than CSR. Intermittent exposure to high altitude was seen in 85% of the subjects with central apneas. That may affect with the ability to acclimatizer to high altitude, which is a necessary step to improve the central apnea index at high altitude.

 [1]: pending:yes
Expression of shRNA From a Tissue-specific pol II Promoter Is an Effective and Safe RNAi Therapeutic
Authors: Jeffery C Giering, Dirk Grimm, Theresa A Storm, Mark A Kay
Journal: Molecular Therapy (2008)

It has been observed that overexpression of some short-hairpin RNAs (shRNAs) can induce acute cytotoxicity. This has raised concerns about the safety of using RNA interference (RNAi) technology as a potential therapeutic tool. We have sought to address this challenge of expression control by developing a mono-cistronic vector for the tissue-specific expression of an shRNA from a liver-derived polymerase (pol) II promoter. This new construct efficiently induces target silencing in hepatoma cells in vitro and in mouse livers in vivo. In order to demonstrate the therapeutic potential and improved safety of this approach, we selected an shRNA targeting the envelope surface antigen (sAg) of hepatitis B virus (HBV), which is among the most toxic when expressed from the commonly used U6 promoter. Packaging it as a double-stranded DNA into an adeno-associated virus (AAV) pseudotype 8 and delivering it at a high particle dose (1 × 1012) to HBV transgenic mice resulted in the stable reduction of serum sAg to 85% of starting levels, without any concomitant sign of liver damage. With this improved tolerability, the liver-specific pol II shRNA expression persisted for more than one year after the injection. We conclude that this pol II shRNA expression system combined with a potent delivery vector represents an effective alternative to either U6-based strategies or systems that achieve tissue specificity through the use of additional elements. It has been observed that overexpression of some short-hairpin RNAs (shRNAs) can induce acute cytotoxicity. This has raised concerns about the safety of using RNA interference (RNAi) technology as a potential therapeutic tool. We have sought to address this challenge of expression control by developing a mono-cistronic vector for the tissue-specific expression of an shRNA from a liver-derived polymerase (pol) II promoter. This new construct efficiently induces target silencing in hepatoma cells in vitro and in mouse livers in vivo. In order to demonstrate the therapeutic potential and improved safety of this approach, we selected an shRNA targeting the envelope surface antigen (sAg) of hepatitis B virus (HBV), which is among the most toxic when expressed from the commonly used U6 promoter. Packaging it as a double-stranded DNA into an adeno-associated virus (AAV) pseudotype 8 and delivering it at a high particle dose (1 × 1012) to HBV transgenic mice resulted in the stable reduction of serum sAg to 85% of starting levels, without any concomitant sign of liver damage. With this improved tolerability, the liver-specific pol II shRNA expression persisted for more than one year after the injection. We conclude that this pol II shRNA expression system combined with a potent delivery vector represents an effective alternative to either U6-based strategies or systems that achieve tissue specificity through the use of additional elements.
N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.
Authors: J P Cobb, C Natanson, W D Hoffman, R F Lodato, S Banks, C A Koev, M A Solomon, R J Elin, J M Hosseini, R L Danner
Journal: The Journal of Experimental Medicine (1992)

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.
Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.
Authors: J K Willson, J R Haaga, J E Trey, T A Stellato, N H Gordon, S L Gerson
Journal: Journal of Clinical Oncology (1995)

PURPOSE Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.
Tumour-infiltrating gamma/delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma
Authors: M.R. Raspollini, F. Castiglione, D. Rossi Degl'Innocenti, G. Amunni, A. Villanucci, F. Garbini, G. Baroni, G.L. Taddei
Journal: Annals of Oncology (2005)
A quarter of reported waiting times for elective care are probably wrong, MPs say
Authors: A. O'Dowd
Journal: BMJ (2014)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following A quarter of reported waiting times for elective care are probably wrong, MPs say Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Magnetic resonance imaging of chronic myocardial infarcts in formalin-fixed human autopsy hearts.
Authors: J C Hsu, G A Johnson, W M Smith, K A Reimer, R E Ideker
Journal: Circulation (1994)

BACKGROUND In post-myocardial infarction patients, three-dimensional structure of the infarct as well as infarct size are likely to be important factors affecting mortality, cardiac function, and arrhythmias. Current morphological methods for determining three-dimensional infarct structure in autopsied hearts are inexact and time consuming. The cardiac magnetic resonance imaging techniques used in living patients have shown potential in determining infarct size and structure but have limited resolution for morphometric postmortem studies. The recent development of magnetic resonance microscopy raises the possibility that three-dimensional infarct structure can be quantified at microscopic levels in autopsied hearts. The purpose of this study was to determine the ability of magnetic resonance imaging at different spatial resolutions to differentiate infarcted from noninfarcted myocardium. METHODS AND RESULTS Magnetic resonance imaging was performed at 2.0 T on cross sections taken from 10 autopsied hearts containing old myocardial infarcts. T1 was derived from six images with repetition times (TRs) for each image ranging from 100 to 3200 milliseconds. T2 was derived from multi-echo images with echo times (TEs) ranging from 10 to 60 milliseconds. Resolution was approximately 400 x 400 microns in 2-mm-thick slices. Sites of infarcted and noninfarcted tissue were identified from histological sections taken from each slice, and the T1 and T2 values of these sites were obtained. Microscopic images were acquired with voxels of 100 x 100 x 625 microns, representing tissue volumes more than 1000-fold smaller than conventional clinical images. In all cases, T1 of infarcted tissue (459 +/- 266 milliseconds, mean +/- SD) was greater than that of noninfarcted tissue (272 +/- 163 milliseconds). Also, in all cases, T2 of infarcted tissue (49 +/- 14 milliseconds) was greater than that of noninfarcted tissue (35 +/- 8 milliseconds). CONCLUSIONS T1 and T2 values for infarcted tissue are significantly different from those of noninfarcted tissue (P &lt; .001). Based on these findings, it should be possible to develop techniques to perform three-dimensional imaging and quantitation of infarcts with a resolution of 400 microns or less. When volumetric three-dimensional imaging was performed using a T1-weighted sequence, the resulting 256(3) arrays supported isotropic resolution at 400 microns (voxel volume, 0.064 mm3). Subsequent volume rendering using a compositing algorithm clearly shows the infarcted areas in three dimensions. The techniques demonstrate the potential for quantitative three-dimensional cardiac morphometry using magnetic resonance imaging.
Acceptance of the Kober Medal
Authors: Joseph L. Goldstein
Journal: Journal of Clinical Investigation (2002)

Let me begin by thanking Dan Foster and Jean Wilson for their wonderful and lively presentations.I assume that you all know that Dan and Jean are both native-born Texans, which means that they are terrific tellers of tall tales.So don't believe a word you've heard!It is truly a great honor to join the distinguished company of previous Kober medalists.And it's also a great honor to share this award with my long-term partner in crime, Michael Brown, about whom I'll have more to say in a moment.Growing up in a small town in the Old South, I was relatively insulated from the world of ideas and intellectuals.Kingstree High School was a far cry from the Bronx High School of Science.But nonetheless, I aspired to an individuality, yearned for achievement, and longed to succeed in some realm of otherness that I could not define at the time.I did not discover that mysterious otherness until I became a medical student at UT Southwestern in 1962 and experienced the thrill of medical research.As you have just heard, at Southwestern I fell under the spell of Donald Seldin, a man of towering intellect, immense erudition, keen zest for life, irrepressible curiosity, and deep respect for clinical scholarship.As a teacher, Dr. Seldin was a true maestro in the way he taught clinical medicine to third-year medical students.His discussions of pathophysiology were enriched and enlivened with stories of the virtuoso performances of famous clinical investigators.Seldin was the Toscanini of the student CPC.If a patient with pernicious anemia were presented to Dr. Seldin, he would tell the remarkable story of how William Castle discovered intrinsic factor.If the patient was a young woman with amenorrhea and hirsutism, we learned about the adrenogenital syndrome and how Fuller Albright, in a tour de force of clinical reasoning, figured out its pathophysiology and predicted its treatment with suppressive cortisone.
P08.20 * EGFR MUTATIONS STATUS AND EML4 ALK FUSION IN PATIENTS WITH BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC) AND SURVIVAL ANALYSIS: A RETROSPECTIVE STUDY
Authors: A. D. Muggeri, B. Calabrese, S. Cerrato, B. D. Diez
Journal: Neuro-Oncology (2014)

Patients with EGFR mutation may have prolonged OS after diagnosis of brain metastases independent of treatment strategy. Tumor harbouring EGFR mutation with brain metastases from NSCLC is around 10-53%, seems to be more frequent in women, never-smokers, East Asians patients and in adenocarcinomas. To explore the EGFR mutations status and EML4-ALK fusions in patients with NSCLC and brain metastases and the overall survival. To evaluate whether age ≥60 years, gender, KPS ≥70, EGFR mutation, smoking status, impacted in overall survival. Between January 2008 and January 2014 we retrospectively identified 42 patients with NSCLC brain metastases who had done EGFR test. Overall survival was analyzed by Kaplan-Meier method, with the use of two-sided log-rank test statistics. Median age: 58 years (35-81). Nineteen were female. Median follow up: 9 months (1-74). Thirty six of 42 patients (86%) were current or former smokers. All never smokers patients and only 3 of 36 (8%) current or former smokers had EGFR mutation. Of the 42 patients 9 (21,5%) harboured mutation in the EGFR gene and only one was male. Only 2 patients of 31 evaluated (6,4%) had EML4-ALK fusion. The median overall survival in patients with EGFR mutation and EGFR wild type was 17 (5-100) and 11 months (1-96) respectively (p:0.46). After brain metastases the median overall survival in patients with EGFR mutation and EGFR wild type was 13 (5-74) and 9 months (1-61) respectively (p:0.95). Patients with metachronous brain metastases had better survival (p:0,004). Only KPS did show statistically significant impact benefit on survival (p:0.026) and survival after brain metastases (p:0.03). Twenty one percent of the patients with brain metastases harboured EGFR mutation, the median overall survival was better that we expected (13 months) although the difference was not significant.