tbuckley/cabot-search huggingface dataset:
Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation.
Authors: P S Linsley, W Brady, L Grosmaire, A Aruffo, N K Damle, J A Ledbetter
Journal: The Journal of Experimental Medicine (1991)

A successful immune response requires intercellular contact between T and B lymphocytes. We recently showed that CD28, a T cell surface protein that regulates an activation pathway, could mediate intercellular adhesion with activated B cells by interaction with the B7 antigen. Here we show that CD28 is the primary receptor for B7 on activated peripheral blood T cells, that CD28 binds to B7 in the absence of other accessory molecules, and that interaction between CD28 and B7 is costimulatory for T cell activation. To characterize the binding of CD28 to B7, we have produced genetic fusions of the extracellular portions of B7 and CD28, and immunoglobulin (Ig) C gamma 1 chains. 125I-labeled B7 Ig bound to CD28-transfected Chinese hamster ovary (CHO) cells, and to immobilized CD28 Ig with a Kd approximately 200 nM. B7 Ig also inhibited CD28-mediated cellular adhesion. The function of CD28-B7 interactions during T cell activation was investigated with soluble fusion proteins and with B7-transfected CHO cells. Immobilized B7 Ig and B7+ CHO cells costimulated T cell proliferation. Stimulation of T cells with B7+ CHO cells also specifically increased levels of interleukin 2 transcripts. These results demonstrate that the CD28 signaling pathway could be activated by B7, resulting in increased T cell cytokine production and T cell proliferation. Cellular interactions mediated by B7 and CD28 may represent an important component of the functional interactions between T and B lymphoid cells.
The VEGF-regulated transcription factor HLX controls the expression of guidance cues and negatively regulates sprouting of endothelial cells
Authors: Julia Testori, Bernhard Schweighofer, Iris Helfrich, Caterina Sturtzel, Karoline Lipnik, Sabine Gesierich, Patrick Nasarre, Renate Hofer-Warbinek, Martin Bilban, Hellmut G. Augustin, Erhard Hofer
Journal: Blood (2011)
PTH-067 Yield of Endoscopic Ultrasound (EUS) in Patients with Dilated Common Bile Duct (CBD) and or Pancreatic Duct (PD) with normal Liver Function Test (LFTS) and Cross-Sectional Imaging
Authors: V Mitra, M Nayar, S Bonnington, J Scott, K Anderson, R Charnley, B Jaques, G Sen, S White, D Manas, J French, K Oppong
Journal: Gut (2013)

<h3>Introduction</h3> The finding of dilated CBD or PD or both (double duct sign) on abdominal cross-sectional imaging (CT or MRI) in patients with normal LFTs frequently leads to further investigation by EUS if a clear cause is not demonstrated on imaging. There is limited literature on the yield of EUS in this setting. <h3>Methods</h3> A retrospective review of our prospectively maintained EUS database was carried out to identify patients who underwent EUS for dilated duct(s), normal LFTs and non-diagnostic cross-sectional imaging between January 2007 and August 2011. Our aim was to evaluate the yield of EUS in this setting. Minimum follow up was for 12 months. <h3>Results</h3> 83 patients (3% of pancreaticobiliary EUS procedures during this period) were identified. Mean age was 66.7 years (30 – 87). There was a female preponderance (73%). 40(48%) had dilated CBD only, 5(6%) had solitary PD dilatation and 38(46%) had both CBD and PD dilatation on prior imaging. EUS was concordant with prior imaging in 60(72%) patients and discordant in 23(28%) [partial agreement in 18, non-dilated ducts in 3 and different duct dilated in 2]. 16(19%) patients had a new finding on EUS [3 cbd stones, 3 cbd polyps, 4 microlithiasis, 1 ampullary adenoma, 3 chronic pancreatitis, 1 pancreatic duct adenocarcinoma (PDAC) and 1 portal vein compressing mid CBD]. Of these 11(13%) were felt to be the cause of duct dilatation. On subsequent MDT review, the PDAC was identified on the initial scan from the referring hospital. 45% (10/22) of males compared to 9.8% of (6/61) females had a new finding on EUS (p = 0.0008). Overall, more females had symptoms compared to males (p = 0.065). There was no significant association between symptoms and new finding on EUS (p = 0.24). 7(17.5%) of the isolated CBD dilatation, 3(60%) of the isolated PD dilatation and 1(2.5%) of the dilated CBD and PD had a causative diagnosis respectively. Follow up of patients with no cause of duct dilatation on EUS revealed that 18 patients (54.5%) in the dilated CBD cohort had prior cholecystectomy [one patient had peri-ampullary diverticulum and prior cholecystectomy] while 2 and 10 patients in the dilated CBD and PD cohort (n = 37) had ampullary stenosis and prior cholecystectomy respectively. <h3>Conclusion</h3> Our study shows that EUS has a significant yield in individuals with unexplained duct dilatation and normal LFT (13% had a causative diagnosis). The yield was highest in isolated PD dilatation. A new finding was significantly more likely in men then women. EUS should ideally follow review of original cross sectional imaging by a HPB radiologist. <h3>Disclosure of Interest</h3> None Declared.
Relationship of the TIMI Myocardial Perfusion Grades, Flow Grades, Frame Count, and Percutaneous Coronary Intervention to Long-Term Outcomes After Thrombolytic Administration in Acute Myocardial Infarction
Authors: C. Michael Gibson, Christopher P. Cannon, Sabina A. Murphy, Susan J. Marble, Hal V. Barron, Eugene Braunwald
Journal: Circulation (2002)

Background — Although 90-minute TIMI flow grades (TFGs), corrected TIMI frame counts (CTFCs), and TIMI myocardial perfusion grades (TMPGs) have been associated with 30-day outcomes, we hypothesized that these indices would be related to long-term outcomes after thrombolytic administration. Methods and Results — As a substudy of the TIMI 10B trial (tissue plasminogen activator versus tenecteplase), 49 centers carried out 2-year follow-up. TIMI grade 2/3 flow (Cox hazard ratio [HR] 0.41, P =0.001), reduced CTFCs (faster flow, P =0.02), and an open microvasculature (TMPG 2/3) (HR 0.51, P =0.038) were all associated with improved 2-year survival. Rescue percutaneous coronary intervention (PCI) of closed arteries (TFG 0/1) at 90 minutes was associated with reduced mortality ( P =0.03), and mortality trended lower with adjunctive PCI of open (TFG 2/3) arteries ( P =0.11). In a multivariate model correcting for previously identified correlates of mortality (age, sex, pulse, left anterior descending coronary artery infarction, and any PCI during initial hospitalization), patency (TFG 2/3) (HR 0.32, P &lt;0.001), CTFC ( P =0.01), and TMPG 2/3 remained associated with reduced mortality (HR 0.46, P =0.02). Conclusions — Both improved epicardial flow (TFG 2/3 and low CTFCs) and tissue-level perfusion (TMPG 2/3) at 90 minutes after thrombolytic administration are independently associated with improved 2-year survival, suggesting complementary mechanisms of improved long-term survival. Although rescue PCI reduced long-term mortality, improved microvascular perfusion (TMPG 2/3) before PCI was also related to improved mortality independently of epicardial blood flow and the performance of rescue or adjunctive PCI. Further prospective trials are warranted to re-examine the benefit of early PCI with thrombolysis.
THE EFFECTS OF METHYLPHENIDATE ON SYMPTOMATOLOGy AND LEARNING IN DISTURBED CHILDREN
Authors: C. KEITH CONNERS, LEON EISENBERG
Journal: American Journal of Psychiatry (1963)

This study investigated the effects of methylphenidate administered double-blind over a 10-day period to two groups of emotionally disturbed children (total N = 81). Symptom ratings by house parents and child care workers were obtained before treatment and on the last day of treatment. Total symptom scores were improved in the drug group at a statistically significant level. Changes in individual symptoms occurred mostly with outwardly directed symptoms such as "leads into trouble," and there were hints that anxiety showed an increase. The only adverse side effect was a high report (70%) of appetite loss in the drug group. Objective measures of learning and maze performance also showed reliable improvement in the drug group, minimizing the possibility that symptom changes were due to rater biases. Questionnaire measures of initial level of anxiety and impulsivity were not related to symptomatic improvement in the drug group, and some doubt as to the validity of these instruments for the type of children studied was raised by the results. The results agree with previous clinical studies and are interpreted as reflecting an activation of inhibitory controlling systems. The wide individual variation in response to the drug indicates further research on individual difference factors is required, as well as caution in the application of the drug in clinical situations.
Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients
Authors: Sophie Liabeuf, Aurélie Lenglet, Lucie Desjardins, Nathalie Neirynck, Griet Glorieux, Horst-Dieter Lemke, Raymond Vanholder, Momar Diouf, Gabriel Choukroun, Ziad A. Massy
Journal: Kidney International (2012)
MUTANT GENES IN FAMILIAL ALZHEIMER'S DISEASE AND TRANSGENIC MODELS
Authors: Donald L. Price, Sangram S. Sisodia
Journal: Annual Review of Neuroscience (1998)

▪ Abstract The most common cause of dementia occurring in mid- to late-life is Alzheimer's disease (AD). Some cases of AD, particularly those of early onset, are familial and inherited as autosomal dominant disorders linked to the presence of mutant genes that encode the amyloid precursor protein (APP) or the presenilins (PS1 or PS2). These mutant gene products cause dysfunction/death of vulnerable populations of nerve cells important in memory, higher cognitive processes, and behavior. AD affects 7–10% of individuals &gt;65 years of age and perhaps 40% of individuals &gt;80 years of age. For the late-onset cases, the principal risk factors are age and apolipoprotein (apoE) allele type, with apoE4 allele being a susceptibility factor. In this review, we briefly discuss the clinical syndrome of AD and the neurobiology/neuropathology of the disease and then focus attention on mutant genes linked to autosomal dominant familial AD (FAD), the biology of the proteins encoded by these genes, and the recent exciting progress in investigations of genetically engineered animal models that express these mutant genes and develop some features of AD.
Familial elevation of serum angiotensin converting enzyme activity
Authors: M Luisetti, M Martinetti, M Cuccia, JM Dugoujon, V De Rose, V Peona, E Pozzi, C Grassi
Journal: European Respiratory Journal (1990)

A clustering of high levels of serum angiotensin converting enzyme (S-ACE) was found in an Italian family. The elevation affected five subjects, two of whom were completely healthy and free from known causes of S-ACE increase. The values of S-ACE in hyperACEmic subjects exceeded the values found in normal relatives severalfold. HyperACEmia seemed to be inherited as an autosomal dominant trait. Immunogenetic studies were performed, but we did not find a genetic marker for this condition. The S-ACE activity was inhibited in vitro by edetic acid (EDTA) and SQ 14,225 (captopril). The S-ACE activity was also determined after 1:8 dilution and dialysis against saline of sera. From these experiments we deduced that Lieberman's intrinsic ACE inhibitor was lacking in the hyperACEmic sera. In the presence of remarkable S-ACE increase, a congenital elevation of S-ACE should be considered and it would be useful to perform a familial investigation.
Localization in clinical neurology
Authors: A. Chaudhuri
Journal: Journal of the Royal Society of Medicine (2006)

Dr Saad Shafqat is incorrect in his assertion that localization in clinical neurology has been rendered outmoded by advances in technology.1

The advances of modern neurology are built on the assumption that the neurologist can make the correct diagnosis. We were present when one of the first computerized tomography scans of the brain was performed in the 1970s. Upon seeing these first clear images of the brain, Dr Raymond Adams declared that we were witnessing the introduction of a new tool into clinical neurology. That has certainly proved to be true, but imaging is still just a tool. The treatments for neurological disease that we now possess are also not ends in themselves. They are only part of the continuous, gradual development of knowledge about the nervous system needed to solve the really big problems in clinical neurology (e.g. epilepsy, paralysis, dementia, neoplasia, degenerative disease, and stroke).

The fundamental problem that arises in degrading the examination is that all clinical analyses risk starting from the wrong point. Mistaking weakness for ataxia, tremor for seizure, functional paralysis for genuine paralysis, root pattern sensory loss from that of nerve or spinal cord, aphasia from psychosis, dystonia from joint limitation, coma from catatonia, hip arthritis from lumbar radiculopathy, apraxia from confusion: not to mention distinguishing the various types of gait and dysarthrias, create endless and misplaced testing, the results of which are as useful as the original mistake in interpretation.

In our current practices, much of what we do is to take a careful history, examine the patient and put into proper perspective all of the imaging, genetic and other laboratory testing that may or may not bear on the patient's problem. Experienced experts can learn to apply the principles correctly yet rapidly in order to conform to the time constraints of modern neurological treatment. To abandon the principles of the neurological method is to risk transforming our learned profession into a rote trade.
THE CHOLESTEROL-RAISING FACTOR FROM COFFEE BEANS
Authors: R. Urgert, M. B. Katan
Journal: Annual Review of Nutrition (1997)

▪ Abstract Some coffee brewing techniques raise the serum concentration of total and low-density-lipoprotein cholesterol in humans, whereas others do not. The responsible factors are the diterpene lipids cafestol and kahweol, which make up about 1% (wt:wt) of coffee beans. Diterpenes are extracted by hot water but are retained by a paper filter. This explains why filtered coffee does not affect cholesterol, whereas Scandinavian “boiled,” cafetiere, and Turkish coffees do. We describe the identification of the cholesterol-raising factors, their effects on blood levels of lipids and liver function enzymes, and their impact on public health, based on papers published up to December 1996.
Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: Evidence for a role of hepatocyte growth factor
Authors: V Neaud
Journal: Hepatology (1997)

The stroma of hepatocellular carcinomas (HCC) is infiltrated with myofibroblasts (MFs). Preliminary in vivo data have suggested that liver MF express hepatocyte growth factor (HGF), a cytokine that has been implicated in several tumor models. Our aim was to investigate the role of MF and HGF in HCC. Cultured liver MF expressed HGF messenger RNA (mRNA) and secreted HGF in their medium, as shown by Western blot, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Addition of MF-conditioned medium to the HepG2 HCC cell line induced cell scattering. This was associated with a decrease in cell proliferation. MF also increased about 100-fold the ability of HepG2 to invade Matrigel. Increased invasiveness was also shown for HuH7 cells, but no scattering was observed and cell proliferation was stimulated. All the effects of MF on both tumor cell types were blocked by addition of an antibody to HGF and they all could be reproduced by adding recombinant HGF to the tumor cells. RT-PCR and Western blot analysis confirmed that both tumor cell lines expressed c-met, the receptor for HGF. The effects of MF-conditioned medium were not reproduced by acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1), or platelet-derived growth factor (PDGF-BB). Reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that HGF was expressed in human HCC. Our data show that human liver MF act on HCC cells to increase their invasiveness and suggest that MF-derived HGF could be involved in the pathogenesis of HCC.
The role of disease duration and hypertension in albumin excretion of type I diabetes mellitus.
Authors: T B Wiegmann, A M Chonko, M L MacDougall, W V Moore
Journal: Journal of the American Society of Nephrology (1992)

The objective of this study was to examine the relationship between blood pressure, albumin excretion, and renal function in patients with type I diabetes mellitus. The study design was as follows: nonselected consecutive patients with type I diabetes mellitus were divided into three groups by level of albumin excretion rate (AER): less than 20 micrograms/min, 20 to 200 micrograms/min, and greater than 200 micrograms/min. The setting for the study was an outpatient diabetic clinic in a tertiary referral center. There were 166 patients studied: 53% men, 47% women, 86% white, 17% treated for hypertension. Seventy-six percent had an AER less than 20 micrograms/min, 18% had an AER of 20 to 200 micrograms/min, and 6% had an AER of greater than 200 micrograms/min. Glycosylated hemoglobin did not differ between groups. AER was increased with age and disease duration (P less than 0.005 by analysis of variance) after 10 yr of disease. Serum creatinine (P less than 0.005) and systolic (P less than 0.005) and diastolic (P less than 0.01) blood pressures were also increased with AER. Serum creatinine and blood pressure were found to be increased in parallel after 10 yr of disease, but both remained within the normal range overall. A comparison of individual blood pressures in patients not taking antihypertensive drugs (N = 138) with age-related blood pressures of nondiabetic subjects revealed increased systolic and diastolic blood pressures at all ages. Group comparison demonstrated a significant link between increased AER and serum creatinine (declining renal function) and increased blood pressure after a latent period of 10 yr. Blood pressure appears to be increased from the earliest age in diabetes compared with healthy populations.(ABSTRACT TRUNCATED AT 250 WORDS)
Non-invasive Ventilation and Weaning: Principles and Practice
Authors: N. Ambrosino
Journal: European Respiratory Journal (2011)

M. Elliott, S. Nava, B. Schonhofer Hodder Arnold UK 621 £126.65 978-0340941522

One of the most important events you may face in your life is the possibility to participate to something historic. It was a privilege to be involved in the scientifi c development and practical dissemination of noninvasive mechanical ventilation (NIV). This treatment has been one of the most important developments in respiratory medicine over the past 15 years, changing from a niche technique to fi rst-line ventilatory treatment for acute and chronic respiratory …
Angiotensin-Converting Enzyme Gene Polymorphism Is Associated with Vulnerability to Alcoholic Cardiomyopathy
Authors: Joaquim Fernández-Solà
Journal: Annals of Internal Medicine (2002)

Background: Chronic alcohol abuse has a dose-dependent toxic effect on the myocardium, leading to alcoholic cardiomyopathy. The fact that only a minority of persons with chronic alcoholism have this condition suggests the possibility of a genetic vulnerability. In this context, polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in cardiac dysfunction. Objective: To compare the ACE genotypes of alcoholic persons who have cardiomyopathy with those of comparable alcohol abusers who have normal cardiac function. Design: Case–control study over a 2-year period. Setting: An academic tertiary referral hospital in Barcelona, Spain. Patients: 30 alcoholic men with symptomatic cardiomyopathy and 27 alcoholic men with normal cardiac function. Measurements: Ethanol intake, cardiac status, left ventricular ejection fraction (LVEF), and ACE gene polymorphism. Results: The DD ACE genotype was present in 57% of alcoholic persons with an LVEF less than 0.50 and in 7% of those with normal cardiac function. Compared with persons who had an I allele, the odds ratio for development of left ventricular dysfunction in alcoholic persons with the DD genotype was 16.4. Conclusions: Vulnerability to cardiomyopathy among chronic alcohol abusers is partially genetic and is related to presence of the ACE DD genotype. This finding demonstrates genetic susceptibility to alcohol-induced myocardial damage.
Glycyrrhetinic Acid Decreases Plasma Potassium Concentrations in Patients with Anuria
Authors: Andreas Serra, Dominik E. Uehlinger, Paolo Ferrari, Bernhard Dick, Brigitte M. Frey, Felix J. Frey, Bruno Vogt
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Licorice-associated hypertension is thought to be due to increased renal sodium retention. The active compound of licorice, glycyrrhetinic acid (GA), inhibits renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and by that mechanism increases access of cortisol to the mineralocorticoid receptor that causes renal sodium retention and potassium loss. In addition, a direct vascular effect of 11β-HSD activity has recently been incriminated to promote hypertension, a contention based on in vitro observations. This investigation was designed to establish whether this extrarenal effect of 11β-HSD is relevant for BP regulation and potassium concentrations in plasma. In a prospective, double-blind, cross-over study, seven patients with anuria on chronic hemodialysis were randomly assigned after a baseline period of 2 wk to placebo or GA (1 g/d) for 2 wk, separated by a washout phase of 3 wk. The ratio of plasma cortisol/cortisone, determined by gas chromatography–mass spectrometry, increased in all patients after GA intake (F = 9.705; P < 0.004), which indicates inhibition of 11β-HSD. Twenty-four–hour BP values did not change throughout the study. The increase of the plasma cortisol/cortisone ratio was paralleled by a decline in the plasma potassium concentration in every patient. The mean ± SD plasma potassium concentration decreased from 5.5 ± 0.6 mM/L at baseline to 4.9 ± 0.7 and 4.5 ± 0.8 mM/L after 1 and 2 wk on GA, respectively (F = 9.934, P < 0.003). Extrarenal 11β-HSD activity influences serum potassium concentrations but does not regulate BP independently of renal sodium retention.
MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens
Authors: Wei Li, Han Xu, Tengfei Xiao, Le Cong, Michael I Love, Feng Zhang, Rafael A Irizarry, Jun S Liu, Myles Brown, X Shirley Liu
Journal: Genome biology (2014)

Abstract We propose the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method for prioritizing single-guide RNAs, genes and pathways in genome-scale CRISPR/Cas9 knockout screens. MAGeCK demonstrates better performance compared with existing methods, identifies both positively and negatively selected genes simultaneously, and reports robust results across different experimental conditions. Using public datasets, MAGeCK identified novel essential genes and pathways, including EGFR in vemurafenib-treated A375 cells harboring a BRAF mutation. MAGeCK also detected cell type-specific essential genes, including BCR and ABL1 , in KBM7 cells bearing a BCR-ABL fusion, and IGF1R in HL-60 cells, which depends on the insulin signaling pathway for proliferation.