tbuckley/cabot-search huggingface dataset:
Interleukin-4 genetic variants correlate with its transcript and protein levels in patients with vitiligo
Authors: M. Imran, N.C. Laddha, M. Dwivedi, M.S. Mansuri, J. Singh, R. Rani, R.S. Gokhale, V.K. Sharma, Y.S. Marfatia, R. Begum
Journal: British Journal of Dermatology (2012)

Background Vitiligo is an acquired pigmentary disorder resulting from loss of melanocytes. Interleukin (IL)‐4 has been shown to stimulate B‐cell proliferation, to regulate immunoglobulin class switching (IgG1 and IgE) and to promote T‐cell development. Polymorphisms in the IL4 gene are known to increase its expression, thereby implicating its role in vitiligo susceptibility. Objectives To explore intron 3 VNTR (IVS3) and ‐590 C/T (rs2243250) promoter polymorphisms in the IL4 gene and to correlate them with the IL4 transcript, serum IL‐4 and IgE levels to achieve genotype–phenotype correlation in patients with vitiligo from Gujarat. A replication study was done in a North Indian population. Methods The case–control study was performed to investigate these polymorphisms in 505 patients and 744 controls in Gujarat, and 596 patients and 397 controls in North India by polymerase chain reaction (PCR) and PCR‐restriction fragment length polymorphism analysis. IL4 transcript levels were monitored by real‐time PCR. Serum IL‐4 and IgE levels were measured by enzyme‐linked immunosorbent assay and electrochemiluminescence immunoassay, respectively. Results The genotype frequencies differed significantly between patients with generalized vitiligo and controls for both the polymorphisms in both populations. Allele frequencies significantly differed between patients with generalized vitiligo and controls for both the polymorphisms in the population from Gujarat. Interestingly, genotype and allele frequencies for ‐590 C/T single nucleotide polymorphism were significantly different between patients with localized vitiligo and controls in both the populations. The study revealed significantly increased IL4 mRNA, serum IL‐4 and IgE levels in patients from Gujarat. Age of onset analysis of disease in patients suggested that the TTR2R2, TTR1R2 and CTR2R2 haplotypes had a profound effect in the early onset of the disease. Conclusions Our results suggest that these polymorphisms of the IL4 gene may be genetic risk factors for susceptibility towards vitiligo and the upregulation of the IL4 transcript, protein and IgE levels in individuals with susceptible haplotypes reveal the crucial role of IL‐4 in the pathogenesis of vitiligo.
Cognitive Substrates of Thought Disorder, II: Specifying a Candidate Cognitive Mechanism
Authors: Mark S. Aloia, Monica L. Gourovitch, David Missar, David Pickar, Daniel R. Weinberger, Terry E. Goldberg
Journal: American Journal of Psychiatry (1998)

Objective:In part I of this series, the authors found that semantic knowledge and organization accounted for most of the variance in thought disorder in a group of chronic schizophrenic patients. In the present study, they examined a possible cognitive mechanism within the semantic system that might produce thought disorder.Method:Twenty patients with chronic schizophrenia and 21 normal comparison subjects were assessed on priming (the ability to respond to a stimulus word more quickly when it is preceded by a semantically related word than when it is preceded by an unrelated word). The patients were divided into subgroups with high (N=9) and low (N=11) levels of thought disorder. The word pairs in the priming paradigm differed in their degree of association but shared a categorical membership. The paradigm involved short stimulus onset asynchronies to maximize automatic processing and required pronunciation of words to minimize decision making. All subjects were also administered neuropsychological tests to assess language, executive function, real-world knowledge, and mental status. Results:Comparison subjects showed appropriate priming in stepwise fashion at the three different levels of word association, as did the patients with mild thought disorder. The patients with high thought disorder showed inhibited responses to high and medium associates compared with their baseline reaction times. Correlations between priming and cognitive variables were significant only with measures of semantic processing. Priming abnormalities were uniformly related to ratings of global thought disorder.Conclusions:These results suggest that aberrations in the automatic spread of activation or facilitation in semantic networks may be a candidate cognitive mechanism in semantic accounts of thought disorder. Am J Psychiatry 1998; 155: 1677-1684
Localized secondary telangiectasia in patients with thyroid disease
Authors: JOHN A. THOMSON, RONA M. MACKIE
Journal: British Journal of Dermatology (1973)

The presence of telangiectatic lesions on the arms of patients who suffer from thyroid diseases is described and the histology of the lesion illustrated. The incidence of this abnormality was found to be 23% in patients attending a thyroid clinic as compared with 1% in patients attending a dermatological clinic.
Which drug or drug delivery system can change clinical practice for brain tumor therapy?
Authors: T. Siegal
Journal: Neuro-Oncology (2013)

The prognosis and treatment outcome for primary brain tumors have remained unchanged despite advances in anticancer drug discovery and development. In clinical trials, the majority of promising experimental agents for brain tumors have had limited impact on survival or time to recurrence. These disappointing results are partially explained by the inadequacy of effective drug delivery to the CNS. The impediments posed by the various specialized physiological barriers and active efflux mechanisms lead to drug failure because of inability to reach the desired target at a sufficient concentration. This perspective reviews the leading strategies that aim to improve drug delivery to brain tumors and their likelihood to change clinical practice. The English literature was searched for defined search items. Strategies that use systemic delivery and those that use local delivery are critically reviewed. In addition, challenges posed for drug delivery by combined treatment with anti-angiogenic therapy are outlined. To impact clinical practice and to achieve more than just a limited local control, new drugs and delivery systems must adhere to basic clinical expectations. These include, in addition to an antitumor effect, a verified favorable adverse effects profile, easy introduction into clinical practice, feasibility of repeated or continuous administration, and compatibility of the drug or delivery system with any tumor size and brain location.
Platelets, oxidant stress and erectile dysfunction: an hypothesis
Authors: J Jeremy
Journal: Cardiovascular Research (2000)

Time for primary review 30 days. 

The successful use of sildenafil (Viagra™) to treat vasculogenic erectile dysfunction (VED) has heightened awareness of the widespread prevalence of this disorder [1–3]. Sildenafil acts through the augmentation of nitric oxide (NO) actions on vascular/corpus cavernosal smooth muscle cell relaxation [1–4] (Fig. 1). Thus, the therapeutic use of sildenafil has also highlighted the central role played by NO in mediating normal erection and in the pathogenesis of VED. Nevertheless, we still know little about the basic pathophysiology of VED. Since prevention is preferable to cure, it is imperative to improve our understanding of the pathophysiology of VED. In this brief review, we suggest that another major consequence of diminished NO formation is the increased adhesion of platelets and leukocytes, in particular neutrophils, which may counter erection through release of vasconstrictors, superoxide and other oxygen free radicals. We also suggest that erection itself may trigger events that contribute to exacerbation of the disorder in the long-term, again through the adhesion of platelets and leukocytes.



Fig. 1 
Key events in normal penile erection — the central role of NO. Upon sexual arousal, sympathetic drive initiates erection through both sympathetic and non-adrenergic, non-cholinergic (NANC) innervation of the corpus cavernosum and pudendal arteries. NANC fibres release NO and acetylcholine stimulates the release of NO from local endothelium by activation of NO synthase (NOS). NO promotes relaxation of arterial and cavernosal smooth muscle through activation of guanylate cyclase and suppression of activator Ca2+ which in turn results in erection. It is now well established that impairment of the above systems is central to the aetiology of vasculopathic erectile dysfunction. Sildenafil promotes erection through inhibition of type V phosphodiesterase which blocks the metabolism of cGMP to inactive GMP. Thus, cGMP accumulates thereby promoting relaxation of the relevant VSMCs.



Patients with … 

* Corresponding author. Tel.: +44-117-928-3154; fax: +44-117-929-9737 j.y.jeremy{at}bristol.ac.uk
Incidence of type 2 diabetes after bariatric surgery: population-based matched cohort study
Authors: Helen Booth, Omar Khan, Toby Prevost, Marcus Reddy, Alex Dregan, Judith Charlton, Mark Ashworth, Caroline Rudisill, Peter Littlejohns, Martin C Gulliford
Journal: The Lancet Diabetes & Endocrinology (2014)

The effect of currently used bariatric surgical procedures on the development of diabetes in obese people is not well defined. We aimed to assess the effect of bariatric surgery on development of type 2 diabetes in a large population of obese individuals.We did a matched cohort study of adults (age 20–100 years) identified from a UK-wide database of family practices, who were obese (BMI ≥30 kg/m2) and did not have diabetes. We enrolled 2167 patients who had undergone bariatric surgery between Jan 1, 2002, and April 30, 2014, and matched them--according to BMI, age, sex, index year, and HbA1c--with 2167 controls who had not had surgery. Procedures included laparoscopic gastric banding (n=1053), gastric bypass (795), and sleeve gastrectomy (317), with two procedures undefined. The primary outcome was development of clinical diabetes, which we extracted from electronic health records. Analyses were adjusted for matching variables, comorbidity, cardiovascular risk factors, and use of antihypertensive and lipid-lowering drugs.During a maximum of 7 years of follow-up (median 2·8 years [IQR 1·3–4·5]), 38 new diagnoses of diabetes were made in bariatric surgery patients and 177 were made in controls. By the end of 7 years of follow-up, 4·3% (95% CI 2·9–6·5) of bariatric surgery patients and 16·2% (13·3–19·6) of matched controls had developed diabetes. The incidence of diabetes diagnosis was 28·2 (95% CI 24·4–32·7) per 1000 person-years in controls and 5·7 (4·2–7·8) per 1000 person-years in bariatric surgery patients; the adjusted hazard ratio was 0·20 (95% CI 0·13–0·30, p<0·0001). This estimate was robust after varying the comparison group in sensitivity analyses, excluding gestational diabetes, or allowing for competing mortality risk.Bariatric surgery is associated with reduced incidence of clinical diabetes in obese participants without diabetes at baseline for up to 7 years after the procedure.UK National Institute for Health Research.
Glutathione and glutamate levels in the diaphragm of patients with chronic obstructive pulmonary disease
Authors: M.P.K.J. Engelen, M. Orozco-Levi, N.E.P. Deutz, E. Barreiro, N. Hernandez, E.F.M. Wouters, J. Gea, A.M.W.J. Schols
Journal: European Respiratory Journal (2004)

Recently, decreased glutamate (Glu) and reduced glutathione (GSH) levels were reported in the quadriceps femoris of patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate whether Glu and GSH levels are also modified in the diaphragm of these patients. Nine male COPD patients (forced expiratory volume in one second (FEV<sub>1</sub>) range 28–68% of the predicted value) and seven male patients with normal pulmonary function (mean±sd FEV<sub>1</sub> 86±3% pred) submitted to thoracotomy were included. Biopsy specimens were taken from the diaphragm (both groups) and the quadriceps femoris (COPD group alone) in order to assess fibre size, myosin heavy chain expression, GSH levels and amino acid profile. The COPD group was characterised by preserved fibre size, a higher proportion of type I fibres (mean±sem 70±3 <i>versus</i> 26±4%), and higher Glu and GSH content in the diaphragm compared to the quadriceps muscle. However, Glu and GSH levels were similar in diaphragm from the COPD and control groups. Glu level correlated with GSH level in both muscles. No significant correlation was found between Glu or GSH level and fibre size or proportions. This study shows that glutamate and reduced glutathione levels are preserved in the diaphragm of chronic obstructive pulmonary disease patients. Alterations in glutamate and reduced glutathione metabolism are muscle-specific in chronic obstructive pulmonary disease, affecting the quadriceps femoris but not the diaphragm. Glutamate and reduced glutathione levels are strongly interrelated in both muscles, independent of fibre type distribution and fibre size.
IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking
Authors: Jeffrey C. Nolz, John T. Harty
Journal: Journal of Clinical Investigation (2014)

Memory and naive CD8+ T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8+ T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8+ T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8+ T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8+ T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8+ T cells. After unrelated infection or inflammatory challenge, memory CD8+ T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8+ T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8+ T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15-dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8+ T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8+ memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy.
Utility of Hemoglobin A1c for Diagnosing Prediabetes and Diabetes in Obese Children and Adolescents
Authors: Paulina Nowicka, Nicola Santoro, Haibei Liu, Derek Lartaud, Melissa M. Shaw, Rachel Goldberg, Cindy Guandalini, Mary Savoye, Paulina Rose, Sonia Caprio
Journal: Diabetes Care (2011)

Hemoglobin A(1c) (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking.We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of ∼2 years in 218 subjects.At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C <5.7%), 21% at risk for diabetes (A1C 5.7-6.4%), and 1% with diabetes (A1C >6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95% CI 0.70-0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time.The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents.
Homozygous scid/scid;beige/beige mice have low levels of spontaneous or neonatal T cell-induced B cell generation.
Authors: D E Mosier, K L Stell, R J Gulizia, B E Torbett, G L Gilmore
Journal: The Journal of Experimental Medicine (1993)

The autosomal recessive scid mutation results in defective immunoglobulin and T cell receptor gene rearrangement. The scid mutation occurred in the allotype congenic C.B-17 line, and up to 25% of C.B-17 scid mice spontaneously produce both T cells and immunoglobulin, a phenotype known as "leaky." Moreover, introduction of neonatal T cells into C.B-17 scid mice leads to immunoglobulin production by 100% of animals. We have produced mice homozygous for both the scid and beige mutations. By contrast with C.B-17 scid mice, BALB/c scid.beige mice have a &amp;lt; 2% incidence of "leakiness." This percentage does not increase with age, and introduction of neonatal T cells fails to rescue immunoglobulin production. This suggests that a gene (or genes) closely linked to the beige locus regulates B and/or T cell development.
QUANTITATIVE STUDIES ON THE MIXED LYMPHOCYTE INTERACTION IN RATS
Authors: Darcy B. Wilson, Dianne H. Fox
Journal: The Journal of Experimental Medicine (1971)

The proliferative reactivity of lymphocytes from rat donors maintained under germfree or conventional conditions was examined in mixed lymphocyte cultures stimulated with allogeneic and xenogeneic cell surface antigens. The results show (a) that lymphocytes from conventionally maintained rats are less reactive to human, hamster, guinea pig, and mouse cell surface antigens than to the major H alloantigens, and (b) that lymphocytes from germfree rats display no demonstrable reactivity to xenogeneic cells, but are quantitatively normal in their response to allogenic cells. The conclusion drawn from these observations is that the circulating lymphocyte pool of an individual consists of a greater proportion of cells reactive to H alloantigens of other members of the same species than to the xenogeneic cellular antigens of members of other species and that this large number of cells is not generated by a mechanism involving immunization to cross-reactive environmental antigens.
High Viral Load and Hepatitis B Virus Subgenotype Ce Are Associated With Increased Risk of Hepatocellular Carcinoma
Authors: Henry Lik-Yuen Chan, Chi-Hang Tse, Frankie Mo, Jane Koh, Vincent Wai-Sun Wong, Grace Lai-Hung Wong, Stephen Lam Chan, Winnie Yeo, Joseph Jao-Yiu Sung, Tony Shu-Kam Mok
Journal: Journal of Clinical Oncology (2008)

We aimed to investigate the impact of hepatitis B virus (HBV) DNA and HBV genotypes/subgenotypes on the risk of hepatocellular carcinoma (HCC).A prospective cohort of patients infected with chronic HBV in a surveillance program for HCC since 1997 was studied. Ultrasound and alpha-fetoprotein evaluation were regularly performed to detect HCC. Risk factors for HCC and the relationship between HBV DNA and HBV genotypes were determined.Among 1,006 patients with a median follow-up of 7.7 years, 86 patients (8.5%) developed HCC. With reference to the low HBV DNA stratum (log HBV DNA </= 4.5 copies/mL), the hazard ratio for HCC of the intermediate HBV DNA stratum (log HBV DNA > 4.5 to 6.5 copies/mL) was 1.62 (95% CI, 1.05 to 2.48; P = .027) and that of the high HBV DNA stratum (log HBV DNA > 6.5 copies/mL) was 2.73 (95% CI, 1.76 to 4.25; P < .001). Among patients with genotyping results, 330 patients had HBV genotype B and 439 patients had HBV genotype C (94 subgenotype Ce and 345 subgenotype Cs). With reference to HBV genotype B, HBV subgenotype Ce has the highest risk of HCC (hazard ratio = 2.75; 95% CI, 1.66 to 4.56; P < .0001) and HBV subgenotype Cs has intermediate risk (hazard ratio = 1.70; 95% CI, 1.09 to 2.64; P = .020). On multivariate analysis, HBV DNA, HBV genotypes, liver cirrhosis, male sex, older age, and lower serum albumin were independent risk factors of HCC.High HBV DNA level and HBV genotype C, particularly subgenotype Ce, increased the risk of HCC in chronic hepatitis B.
Pancreatic Inflammation Captured by Imaging Technology at the Onset of Fulminant Type 1 Diabetes
Authors: Atsushi Obata, Hideaki Kaneto, Shinji Kamei, Masashi Shimoda, Satoru Kishi, Akihiro Isogawa, Teruo Shiba
Journal: Diabetes Care (2015)

Type 1 diabetes mellitus is classified as autoimmune (type 1A) or idiopathic (type 1B) (1). Fulminant type 1 diabetes is classified as type 1B, characterized by acute onset of diabetic ketoacidosis soon after the development of typical diabetes symptoms, near-normal HbA1c level at onset, negative serum GAD antibody, and markedly acute progression of insulin deficiency (2). Infiltration of macrophage and T cells into the islets of Langerhans and complete destruction of pancreatic β-cells are characteristic. In this report, we detected pancreatic inflammation in a patient with fulminant type 1 diabetes by both dynamic computed tomography (CT) and MRI, which have been focused on as noninvasive imaging technologies for the pancreas (3).

A 36-year-old Japanese male was referred to our hospital because of diabetic ketoacidosis. He suffered from left abdominal pain, sore throat, and high fever …
A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis
Authors: Peng Jin, Anand Kumar Andiappan, Jia Min Quek, Bernett Lee, Bijin Au, Yang Yie Sio, Astrid Irwanto, Claudia Schurmann, Hans Jörgen Grabe, Bani Kaur Suri, Sri Anusha Matta, Harm-Jan Westra, Lude Franke, Tonu Esko, Liangdan Sun, Xuejun Zhang, Hong Liu, Furen Zhang, Anis Larbi, Xin Xu, Michael Poidinger, Jianjun Liu, Fook Tim Chew, Olaf Rotzschke, Li Shi, De Yun Wang
Journal: Journal of Allergy and Clinical Immunology (2015)
Wasting as predictor of survival in CF
Authors: P Aurora, A Wade
Journal: Thorax (2002)

Sharma and colleagues report the survival of 584 patients with cystic fibrosis (CF) attending the Royal Brompton Hospital between 1985 and 1996.1 They report that body wasting, as represented by % ideal weight, was a significant predictor of survival before and after correction for age, sex, % predicted FEV1, Pao2, and Paco2.

In 1997 Hayllar and colleagues reported the survival of 503 patients with CF attending the Royal Brompton Hospital between 1969 and 1993.2 They found that low blood haemoglobin concentration (Hb), low plasma albumin concentration, and short stature were significant predictors of survival although, of these, only height was included in their final predictive model. Other recent reports have shown both weight and height to be significant predictors of survival in CF.3,4

We recently reported the survival of 181 children with CF referred to the paediatric lung transplantation programme at Great Ormond Street Hospital for Children (GOSH).5 Following Hayllar's report, we opted to study a wide range of variables including Hb, albumin, and % ideal weight as markers of nutritional status. All three variables were …