tbuckley/cabot-search huggingface dataset:
Localization of Bipolar Susceptibility Locus by Molecular Genetic Analysis of the Chromosome 12q23-q24 Region in Two Pedigrees With Bipolar Disorder and Darier’s Disease
Authors: Elaine Green, Gareth Elvidge, Nick Jacobsen, Beate Glaser, Ian Jones, Michael C. O’Donovan, George Kirov, Michael J. Owen, Nick Craddock
Journal: American Journal of Psychiatry (2004)

The authors previously reported two families (pedigrees 324 and 5501) in which Darier's disease-a rare, autosomal dominant skin disease-and bipolar disorder cosegregate. In each of these families there is complete cosegregation of mood disorder with a segment of chromosome 12q23-q24, consistent with the existence of a highly penetrant dominant variant. Here molecular genetic analyses aimed at localizing and identifying the susceptibility gene in this region are reported.In the two families, the authors undertook 1) linkage and haplotype studies using 45 highly polymorphic molecular genetic markers in order to delineate the region of interest and 2) direct analysis of genes within this region.Linkage and haplotype information from the most severely affected individuals defined a region of interest that spanned two neighboring regions of 19 megabases (Mb) (D12S362-D12S1646) and 7 Mb (D12S1718-D12S837). Information from all individuals refined the region of interest to 6.5 Mb (D12S127-D12S1646). Systematic study of the coding and flanking intronic regions of 25 known genes within this latter region failed to identify any highly penetrant autosomal dominant disease-conferring mutations in these pedigrees.This linkage and haplotype analysis, together with data from several other linkage studies, provides compelling evidence for the existence in the 12q23-q24 region of one or more genes involved in the pathogenesis of bipolar disorder. Further molecular genetic analysis of this region is required to identify the gene(s).
Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia
Authors: David G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, Peter A. Crawford
Journal: Journal of Clinical Investigation (2014)

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.
Bile acid malabsorption a differential diagnosis for patients presenting with diarrhoea predominant irritable bowel syndrome type symptoms?
Authors: M. Kurien, K. E. Evans, J. S. Leeds, A. D. Hopper, A. Harris, M. Hanney, D. S. Sanders
Journal: Gut (2011)

<h3>Introduction</h3> Irritable Bowel Syndrome (IBS) should be a positive diagnosis rather than a diagnosis of exclusion. However, in unselected patients presenting with IBS type symptoms it is important to recognise other differential diagnosis. Bile acid malabsorption (BAM) has been reported as a possible cause of diarrhoea predominant (D)-IBS type symptoms. For this reason we aimed to determine how commonly patients with D-IBS type symptoms had a diagnosis of BAM as demonstrated by a positive SeHCAT (<sup>75</sup>Selenium HomotauroCholic Acid Taurine) test (retention &lt;10% at 7 days). <h3>Methods</h3> (Group A) A retrospective analysis was undertaken of patient9s records for all patients who underwent a SeHCAT scan in a 9-year period between 2001 and 2010 in a tertiary Gastroenterology Department. Patient demographics, symptoms, previous medical and surgical history, as well as laboratory investigations (including full blood count, serum folate, vitamin B<sub>12</sub>, ferritin and albumin) were analysed. Statistical analysis was performed using SPSS (version 19.0 for windows) with χ<sup>2</sup> analysis used to compare the data. Concurrently a cohort of patients (Group B) with D-IBS type symptoms (fulfilling Rome II criteria) was examined to determine the potential utility of SeHCAT test. <h3>Results</h3> In Group A of the 415 patients who underwent a SeHCAT, 368 patient records were located and analysed (mean age 49.3, 114 male). 153 patients (41.6%) had a positive result. The mean time from first hospital visit to SeHCAT result was 32 weeks. Patient characteristics predictive of a positive SeHCAT were: terminal ileal Crohn9s (p&lt;0.01), terminal ileal resection (p&lt;0.01), inflammatory bowel disease (p&lt;0.01), previous small bowel surgery (p&lt;0.01) and previous cholecystectomy (p&lt;0.01). 47 of the 153 patients (30.7%) of the patients referred with D-IBS type symptoms had a positive SeHCAT scan. In Group B the D-IBS control cohort (n=316, mean age 46.1 years, 96 males) only 6/316 (1.9%) patients had been referred for a SeHCAT scan (p&lt;0.001 compared to Group A) meaning that potentially 96 patients could have been missed. <h3>Conclusion</h3> BAM is common and should be considered earlier in patients with predisposing factors (including inflammatory bowel disease, terminal ileal disease, previous small bowel surgery and post cholecystectomy). Consideration should also be given for BAM when investigating unselected patients with D-IBS type symptoms.
Hormesis: Implications for Public Policy Regarding Toxicants
Authors: Lester B Lave
Journal: Annual Review of Public Health (2001)

▪ Abstract Protecting workers and the public from toxic chemicals, particularly carcinogens, has been a principal goal of public policy. In the absence of knowing by what mechanism of action a toxicant harms people, regulatory toxicology assumes that even tiny doses can cause harm. Risk aversion has led to legislation and regulation that seek to ban toxic chemicals or lower exposure to trivial levels. Contradicting this policy, many studies show health benefits from low-level exposure to toxicants, including some carcinogens. This is known as hormesis. Thus, hormesis could lead to a fundamental change in the policy for regulating toxic substances. In particular, all toxicants that benefit health at low-level exposures should face similar change in regulations for low-dose exposure. The result would be the dissolving of the source of differences in policy for carcinogens and noncarcinogens at low doses. Two questions must be answered before hormesis can be incorporated into regulatory policy. (a) Are there sensitive individuals who would be harmed at doses that would help most people? (b) Is the hormetic effect toxicant specific or would exposure to just a few toxicants achieve the full benefit from hormesis?
Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations
Authors: Núria Planell, Juan J Lozano, Rut Mora-Buch, M Carme Masamunt, Mireya Jimeno, Ingrid Ordás, Miriam Esteller, Elena Ricart, Josep M Piqué, Julián Panés, Azucena Salas
Journal: Gut (2012)

<h3>Objective</h3> Ulcerative colitis (UC) is a chronic condition characterised by the relapsing inflammation despite previous endoscopic and histological healing. Our objective was to identify the molecular signature associated with UC remission. <h3>Design</h3> We performed whole-genome transcriptional analysis of colonic biopsies from patients with histologically active and inactive UC, and non-inflammatory bowel disease (non-IBD) controls. Real-time reverse transcriptase-PCR and immunostaining were used for validating selected genes in independent cohorts of patients. <h3>Results</h3> Microarray analysis (n=43) demonstrates that UC patients in remission present an intestinal transcriptional signature that significantly differs from that of non-IBD controls and active patients. Fifty-four selected genes were validated in an independent cohort of patients (n=30). Twenty-nine of these genes were significantly regulated in UC-in-remission subjects compared with non-IBD controls, including a large number of epithelial cell-expressed genes such as REG4, S100P, SERPINB5, SLC16A1, DEFB1, AQP3 and AQP8, which modulate epithelial cell growth, sensitivity to apoptosis and immune function. Expression of inflammation-related genes such as REG1A and IL8 returned to control levels during remission. REG4, S100P, SERPINB5 and REG1A protein expression was confirmed by immunohistochemistry (n=23). <h3>Conclusions</h3> Analysis of the gene signature associated with remission allowed us to unravel pathways permanently deregulated in UC despite histological recovery. Given the strong link between the regulation of some of these genes and the growth and dissemination of gastrointestinal cancers, we believe their aberrant expression in UC may provide a mechanism for epithelial hyper-proliferation and, in the context of malignant transformation, for tumour growth.
Chronic Hypoxia-Inducible Transcription Factor-2 Activation Stably Transforms Juxtaglomerular Renin Cells into Fibroblast-Like Cells In Vivo
Authors: Birguel Kurt, Katharina Gerl, Christian Karger, Ilona Schwarzensteiner, Armin Kurtz
Journal: Journal of the American Society of Nephrology (2014)

On the basis of previous observations that deletion of the von Hippel–Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppresses renin and induces erythropoietin expression, this study aimed to characterize the events underlying this striking change of hormone expression. We found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, from a cuboid and multiple vesicle-containing form into a flat and elongated form without vesicles. This shift of cell phenotype was accompanied by the disappearance of marker proteins for renin cells (e.g., aldo-keto reductase family 1, member 7 and connexin 40) and by the appearance of markers of fibroblast-like cells (e.g., collagen I, ecto-5′-nucleotidase, and PDGF receptor-β). Furthermore, hypoxia-inducible transcription factor-2α (HIF-2α) protein constitutively accumulated in these transformed cells. Codeletion of pVHL and HIF-2α in JG cells completely prevented the phenotypic changes. Similar to renin expression in normal JG cells, angiotensin II negatively regulated erythropoietin expression in the transformed cells. In summary, chronic activation of HIF-2 in renal JG cells leads to a reprogramming of the cells into fibroblast-like cells resembling native erythropoietin-producing cells located in the tubulointerstitium.
Serum and Bronchoalveolar Fluid KL-6 Levels in Patients with Pulmonary Alveolar Proteinosis
Authors: TORU TAKAHASHI, MITSURU MUNAKATA, ISAMU SUZUKI, YOSHIKAZU KAWAKAMI
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Pulmonary alveolar proteinosis (PAP) is a disease characterized by the filling of alveolar spaces with periodic acid-Schiff-positive proteinaceous material and by the hypertrophy of type II pneumocytes in the alveolar interstitium. To examine if KL-6, a mucinlike glycoprotein, is useful for the diagnosis of PAP and the estimation of its activity, serum KL-6 levels in patients with PAP were measured by an enzyme-linked immunosorbent assay and compared with those of patients with other lung diseases. Furthermore, to estimate the origin of KL-6 in some patients, measurements of KL-6 levels in bronchoalveolar lavage (BAL) fluid and immunohistochemical staining of the lung tissues with a monoclonal antibody to KL-6 antigen were performed. Serum KL-6 levels in patients with PAP were extremely high and were significantly higher than those in patients with interstitial lung diseases in which elevation of serum KL-6 has been recognized. BAL-fluid KL-6 levels in patients with PAP were higher than serum levels. Both serum and BAL-fluid KL-6 levels in patients with PAP correlated well with the disease activity. Immunohistochemically, positive staining was observed in proliferating type II pneumocytes. These results suggest the usefulness of KL-6 measurement in the diagnosis and estimation of disease activity of PAP.
Chronic thromboembolic pulmonary hypertension.
Authors: Nick H Kim, Marion Delcroix, David P Jenkins, Richard Channick, Philippe Dartevelle, Pavel Jansa, Irene Lang, Michael M Madani, Hitoshi Ogino, Vittorio Pengo, Eckhard Mayer
Journal: Circulation (2006)

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France.
Meningococcal disease in Wales: Clinical features, outcome and public health management
Authors: S.R. Palmer, J. Corson, R. Hall, S. Payne, J. Ludlow, B. Deere, H. Jones, S. Kaul, J. Stubbins, R. Williams, M. Walapu, A. Spence, P. Jenkins, D. Donald
Journal: Journal of Infection (1992)
Exercise-associated collapse: an evidence-based review and primer for clinicians
Authors: Chad A Asplund, Francis G O'Connor, Timothy D Noakes
Journal: British Journal of Sports Medicine (2011)

Exercise-associated collapse (EAC) commonly occurs after the completion of endurance running events. EAC is a collapse in conscious athletes who are unable to stand or walk unaided as a result of light headedness, faintness and dizziness or syncope causing a collapse that occurs after completion of an exertional event. Although EAC is perhaps the most common aetiology confronted by the medical provider attending to collapsed athletes in a finish-line tent, providers must first maintain vigilance for other potential life-threatening aetiologies that cause collapse, such as cardiac arrest, exertional heat stroke or exercise-associated hyponatraemia. Previously, it has been believed that dehydration and hyperthermia were primary causes of EAC. On review of the evidence, EAC is now believed to be principally the result of transient postural hypotension caused by lower extremity pooling of blood once the athlete stops running and the resultant impairment of cardiac baroreflexes. Once life-threatening aetiologies are ruled out, treatment of EAC is symptomatic and involves oral hydration and a Trendelenburg position – total body cooling, intravenous hydration or advanced therapies is generally not needed.
Endoscopic Papillary Balloon Dilation for the Management of Common Bile Duct Stones: Experience of 226 Cases
Authors: Y. Komatsu, T. Kawabe, N. Toda, M. Ohashi, M. Isayama, K. Tateishi, S. Sato, Y. Koike, M. Yamagata, M. Tada, Y. Shiratori, H. Yamada, M. Ihori, T. Kawase, M. Omata
Journal: Endoscopy (1998)

Endoscopic sphincterotomy is a widely accepted technique for the treatment of patients with common bile duct stones. However, it is still associated with occasional complications. The recently developed technique of endoscopic papillary balloon dilation seems to be a safe and effective procedure, and to have great potential for replacing endoscopic sphincterotomy. However, few reports have been published on the use of this technique for bile duct stones. The present study was undertaken to evaluate its safety and efficacy.Endoscopic papillary balloon dilation was used to remove common bile duct stones in 226 consecutive patients including 41 patients of ASA classification III/IV, 41 elderly patients (> 80 years) 24 with liver cirrhosis, and 86 with periampullary diverticulum. After dilation of the papilla with a balloon diameter of 8 mm, the stones were retrieved.In conjunction with the use of a mechanical or/and electrohydraulic lithotriptor in 79 patients (35%) with large stones (> 10 mm in diameter), clearance of the common bile duct was achieved in 225 of 226 patients (99%) without serious complications, such as hemorrhage or severe pancreatitis; mild (n = 13) or moderate (n = 2) pancreatitis occurred in 7% of cases.Endoscopic papillary balloon dilation is a safe and effective technique for the treatment of common bile duct stones, even in high-risk patients.
Hidradenitis suppurativa: a pilot study to determine the capability of patients to self-assess their Hurley stage
Authors: I.E. Deckers, D. Mihajlović, E.P. Prens, J. Boer
Journal: British Journal of Dermatology (2014)

Journal Article Hidradenitis suppurativa: a pilot study to determine the capability of patients to self‐assess their Hurley stage Get access I.E. Deckers, I.E. Deckers Department of Dermatology Erasmus University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar D. Mihajlović, D. Mihajlović Department of Dermatology Erasmus University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar E.P. Prens, E.P. Prens Department of Dermatology Erasmus University Medical Center Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J. Boer J. Boer Department of Dermatology Deventer Hospital Deventer the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 5, 1 May 2015, Pages 1418–1419, https://doi.org/10.1111/bjd.13502 Published: 01 May 2015
MHC Class I Loss Is a Frequent Mechanism of Immune Escape in Papillary Thyroid Cancer That Is Reversed by Interferon and Selumetinib Treatment<i>In Vitro</i>
Authors: Trevor E. Angell, Melissa G. Lechner, Julie K. Jang, Jonathan S. LoPresti, Alan L. Epstein
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines. Experimental Design: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production. Results: Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3+, CD8+, CD16+) and suppressor (FoxP3+) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25+ of CD3+) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment. Conclusions: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. Clin Cancer Res; 20(23); 6034–44. ©2014 AACR.
OBSERVATIONS ON RESISTANCE TO THE FLOW OF BLOOD TO AND FROM THE LUNGS
Authors: Richmond L. Moore, Carl A. L. Binger
Journal: The Journal of Experimental Medicine (1927)

1. Embolism of pulmonary arterioles and capillaries produced by the intravenous injection of starch grains results in a dilatation of the pulmonary artery and the right chambers of the heart. This has been demonstrated both by x-ray studies and direct inspection. 2. The dilatation of the pulmonary artery and heart occurs synchronously with the acceleration of respirations. 3. Dilatation of these structures produced by other means, such as obstruction to the flow of blood to and from the lungs, by gradually clamping either the pulmonary artery (cat and dog) or pulmonary veins (cat) does not, however, give rise to rapid and shallow breathing. 4. The effect of these maneuvers on respiration does not become apparent until respirations suddenly cease. 5. Neither does sudden restriction of the pulmonary vascular bed by clamping the left branch of the pulmonary artery give rise to rapid and shallow breathing, though this procedure may cause an increase in CO(2) tension and in hydrogen ion concentration of the blood. 6. Since rapid and shallow breathing is not the result of (1) anoxemia, (2) increased pCO(2) and hydrogen ion concentration of the serum, (3) restriction of pulmonary vascular bed by nearly half, (4) increase in resistance to the flow of blood to and from the lungs) (5) the presence of starch grains in the lungs acting as a local irritant, it must be the result of the secondary pathological changes which occur in the pulmonary parenchyma following embolism. 7. The nature of these changes, congestion and edema, has been discussed elsewhere. Whether they operate directly on nerve endings or through their influence on lung volume and tissue elasticity is not certain. 8. Various important clinical analogies have been emphasized.
<i> <b>Circulation Research</b> </i> Editors’ Yearly Report: 2001
Authors: Eduardo Marbán, Roberto Bolli, Gerda Breitwieser, Rudi Busse, Hal Dietz, Masao Endoh, Toren Finkel, David Kass, Charles Lowenstein, Marlene Rabinovitch, Gordon Tomaselli
Journal: Circulation Research (2002)