tbuckley/cabot-search huggingface dataset:
I148M PNPLA3 variant and progressive liver disease: A new paradigm in hepatology
Authors: Luca Valenti, Anna Alisi, Valerio Nobili
Journal: Hepatology (2012)

We read with great interest the article recently published in this journal.1 In that study, Sookoian and Pirola presented the results of a meta-analysis including 2,651 patients undergoing liver biopsy, in which the strength of I148M patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant on nonalcoholic fatty liver disease (NAFLD) severity across different populations was evaluated, together with its potential influence on intermediate associated phenotypes. The power of this study has shown that the I148M polymorphism impacts not only hepatic triglyceride content, but also the susceptibility toward a more aggressive disease (i.e., liver fibrosis). The I148M variant also influences alanine aminotransferase activity, without affecting body mass, insulin resistance, or serum lipid levels. The large dataset investigated allowed measurement of the strength of PNPLA3 genotypes on NAFLD and disease severity, which was consistent with an additive genetic model, with the only exception of a likely dominant effect of the G allele onto fibrosis. Notably, the GG genotype was associated with a 73% increase in hepatic fat content and a 3.2-fold higher risk of steatohepatitis and fibrosis, and explained 9%-33% of NAFLD variability, depending on the ethnic group.1 The same approach could be particularly useful in children affected by NAFLD, mostly because of the potential benefits of disease prediction before its clinical manifestation.2 These findings support data demonstrating a similar effect of the I148M polymorphism on the risk of alcoholic liver disease, which shares many features with NASH, and alcoholic cirrhosis in heavy drinkers in multiple ethnic groups,3 and with steatosis and fibrosis progression in chronic hepatitis C.4 Preliminary observations from cross-sectional studies also argue for an extension toward hepatocellular carcinoma development of the risk conferred by the 148M allele.4 In conclusion, it is likely that the I148M PNPLA3 variant is a common inducer of liver damage progression associated with histological features of steatohepatitis in the presence of metabolic, toxic, or viral risk factors (Fig. 1). A simplified working model showing the influence of the I148M PNPLA3 variant on the progression of chronic liver diseases. Two major challenges lay now ahead: a better understanding of PNPLA3 biology to unravel novel therapeutic targets, and evaluation of the impact of PNPLA3 and other novel genetic risk factors on clinical practice in order to improve the diagnostic protocols and personalize therapeutic strategies. Luca Valenti M.D.*, Anna Alisi Ph.D. , Valerio Nobili M.D. , * Department of Internal Medicine, Università degli Studi di Milano, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy, Unit of Hepato-metabolic Diseases and Liver Research Unit, "Bambino Gesù" Children's Hospital and Research Institute, Rome, Italy.
Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia
Authors: Katja Fiedler, Anca Sindrilaru, Grzegorz Terszowski, Enikö Kokai, Thorsten B. Feyerabend, Lars Bullinger, Hans-Reimer Rodewald, Cornelia Brunner
Journal: Blood (2010)
'Brain Death' and Organ Retrieval-Reply
Authors: Stuart J. Younger
Journal: JAMA (1989)

In Reply. —  The letter by Drs Kesterson and Benzel supports our finding that neurosurgeons oppose required request laws, and the authors offer an additional explanation, namely, their concern about potential conflict of interest when required request laws make it mandatory for physicians to urge families to donate their loved ones' organs when those families would be unduly upset by such requests. We agree that this concern is real and contributes not only to the opposition to required request laws but also to fewer families being given the donation option. Whether more families could be asked in a sensitive way that would both respect their feelings and increase organ procurement is an important question, but one we did not address in our study.  Dr Tomlinson raises three concerns about our methods. First, he argues that the vagueness of the term brain death invalidates the responses to ourquestion about the correct
A National Health Program
Authors: David U. Himmelstein
Journal: JAMA (1990)

<h3>To the Editor.—</h3> The need for a more efficient, accessible, and friendly health care system has been recognized since the time of Bismarck. Drs Woolhandler and Himmelstein's<sup>1,2</sup>sincere and persuasive commentaries concerning a proposed national health program are of interest to me as one who had the opportunity to endorse this plan but declined. The proposal has much to recommend it, particularly its relative simplicity. However, it is unlikely that our society will choose such a cataclysmic change, given the current political and economic climate. Thomas Jefferson argued that government should do for people only what they cannot do for themselves. Our national culture still seems to espouse duplication and lack of central control whether we are talking about air travel, fast food, telephone service, or health care. This is not to say we should legitimize the status quo. Rather, the more likely scenario still seems to be a
ETIOLOGY OF POLIOMYELITIS
Authors: ALBERT B. SABIN
Journal: JAMA (1941)

Poliomyelitis is an acute infectious disease that is caused by a filtrable virus with sufficiently distinct properties to permit its identification with as much certainty as is possible for any of the well known bacteria. A virus can be identified by its size, by its host range (i. e. the species of animals which it can or cannot infect), by its tissue affinities and therefore the type of disease it engenders, by the changes it produces in infected cells and by its immunologic properties. With regard to the etiologic agent of poliomyelitis it is known that it is one of the smallest filtrable viruses, its size having been estimated at approximately ten millionths of a millimeter (10 millimicrons). Thus it can pass through the finest filters and membranes, which retain not only the bacteria but most other viruses as well. It can be sedimented only by prolonged centrifugation on powerful
Return to Work after Treatment for Breast Cancer: Single Center Experience in a Cohort of 273 Patients.
Authors: C. Peugniez, C. Peugniez, S. Fantoni, A. Leroyer, A. Leroyer, J. Skrypczak, M. Duprey, J. Bonneterre, J. Bonneterre
Journal: Cancer Research (2009)

Abstract Background: An increasing number of patients (pts) are treated for breast cancer during professional life. The aim of this study was to assess medical as well as socio-professional factors impacting on the likelihood of patients to return to work after treatment.Patients and methods: 1067 pts who were less than 60 years of age, and surgically treated in our institution between January 1, 2004 and December 31, 2005 received a questionnaire with medical, sociodemographic and professional items. An answer was obtained in 586 cases. After excluding in situ carcinoma, local relapses, bilateral tumors and pts without professional activity before treatment, 273 were evaluable. All the clinical files of these patients were reviewed. We studied return to work qualitatively (by univariate, then multivariate logistic regression) and quantitatively, by measuring time until return to work (by log-rank and then multivariate Cox model).Results: Overall, 79.8% of the patients returned to work after a median delay of 11.5 months. In the multivariate analysis, the factors affecting the return to work were: age (p&amp;lt;.0001), particularly pts &amp;gt;55 years returning to work in 58% of cases vs more than 80% in younger ones, education level (p&amp;lt;.001), colleagues support (p&amp;lt;.001), chemotherapy (p&amp;lt;.05), lymphedema (p&amp;lt;.01), and the physical (p=.01) and psychological constraints of the job (p&amp;lt;.01). Surprisingly, local pain with ankylosis of the shoulder was significant only in the univariate analysis (p&amp;lt;.0001). In the multivariate analysis, the factors affecting the delay between treatment and return to work were very similar: age (p&amp;lt;.01), education level (p&amp;lt;.0001), colleagues support (p&amp;lt;.0001), chemotherapy (p&amp;lt;0001), lymphedema (p&amp;lt;.01), and the professional constraints of the job (p&amp;lt;.0001). No significant difference was observed according to type of surgery, tumorectomy vs mastectomy, sentinel lymph node vs axillary clearance, radiation therapy or not, hormonotherapy or not.Conclusion: in our study, 80% of the pts with a professional activity before treatment returned to work; the factors affecting the return to work as well as its delay were: medical (chemotherapy and lymphedema), demographic (age) and socioprofessional (education level, which induces differences in the socio-professional groups, constraints of the job, colleagues support). We could not find any influence of the other treatments such as radiotherapy or hormonotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1060.
Extrinsic Causes of Vesical Filling Defects on Scintigraphy
Authors: GERALD A. MANDELL, H THEODORE HARCKE
Journal: Clinical Nuclear Medicine (1987)

Three children are reported with vesical filling defects on scintigraphy secondary to extrinsic causes. In two chronically constipated individuals undergoing bone scintigraphy, the extrinsic pressure on the bladder by rectosigmoid feces resulted in simulation of intrinsic space-occupying lesions. Focal attenuation of bladder activity on nuclear cystography by the metal distal hook of a Harrington rod also produced the pseudo-appearance of a vesical filling defect in a third patient.
Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia
Authors: Duane L Guernsey, Haiyan Jiang, Dean R Campagna, Susan C Evans, Meghan Ferguson, Mark D Kellogg, Mathieu Lachance, Makoto Matsuoka, Mathew Nightingale, Andrea Rideout, Louis Saint-Amant, Paul J Schmidt, Andrew Orr, Sylvia S Bottomley, Mark D Fleming, Mark Ludman, Sarah Dyack, Conrad V Fernandez, Mark E Samuels
Journal: Nature Genetics (2009)
An inherited defect affecting the tricarboxylic acid cycle in a patient with congenital lactic acidosis
Authors: J. P. Blass, J. D. Schulman, D. S. Young, E. Hom
Journal: Journal of Clinical Investigation (1972)

Cultured skin fibroblasts from a 3 yr old girl with severe, diffuse neurologic disease and persistant lactic acidosis, oxidized radioactive citrate, palmitate, and pyruvate at less than one-third the rate of control cells. Her fibroblasts oxidized isocitrate and glutamate at rates comparable with controls. In disrupted cells from this patient, the activity of aconitate hydratase appeared normal. The binding of citrate to aconitate hydratase and the activities of the NAD- and NADP-linked isocitrate dehydrogenases were also normal, while the activity of citrate synthase was slightly below control values. A significant defect was, however, apparent in the activity of the pyruvate dehydrogenase complex although not in the thiamine-dependent first enzyme of that complex. This patient appears to have a partial genetic defect affecting the tricarboxylic acid cycle.
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis*
Authors: ROBERT M. SAPOLSKY, LEWIS C. KREY, BRUCE S. McEWEN
Journal: Endocrine Reviews (1986)

AS RECENTLY as 1900, tuberculosis, influenza, and pneumonia were the leading causes of death in our country (1). For the most part, however, these infectious diseases, as well as those of poor hygiene or undernutrition, no longer plague us. Instead, we succumb most frequently to heart disease and cancer, diseases of slow degeneration (1). Most of all, unlike so many in the generations before us, we are in a position to age. Regardless of what else occurs, we age, we become more constrained by the discrepancy between what we were and what we have become, and each step becomes harder. The goal in the study of aging is not to halt the process, because we can no more be cured of aging than of birth. The goal, instead, is to slow and soften the sharpest edges of the biological unraveling that constitutes aging. Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to cumulatively damage aging tissue.
Intranasal HGF Administration Ameliorates the Physiologic and Morphologic Changes in Lung Emphysema
Authors: Ahmed E Hegab, Hiroshi Kubo, Mutsuo Yamaya, Masanori Asada, Mei He, Naoya Fujino, Shinya Mizuno, Toshikazu Nakamura
Journal: Molecular Therapy (2008)

Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1–4 weeks after the establishment of emphysema in mice. HGF inhalation significantly ameliorated the enlargement of airspaces and alveolar wall destruction. Also, elevated static lung compliance returned to control levels within 2 weeks of HGF treatment. The expressions of stem-cell markers, c-kit, stem-cell antigen 1 (Sca-1), and CD34 were also significantly influenced by HGF. Most of the c-kit(+) cells were bone marrow derived, while most Sca-1(+) were lung endogenous cells. CD34(+) cells were from both sources, and a portion of the endogenous CD34(+) cells was also Sca-1(+). Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans. Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1–4 weeks after the establishment of emphysema in mice. HGF inhalation significantly ameliorated the enlargement of airspaces and alveolar wall destruction. Also, elevated static lung compliance returned to control levels within 2 weeks of HGF treatment. The expressions of stem-cell markers, c-kit, stem-cell antigen 1 (Sca-1), and CD34 were also significantly influenced by HGF. Most of the c-kit(+) cells were bone marrow derived, while most Sca-1(+) were lung endogenous cells. CD34(+) cells were from both sources, and a portion of the endogenous CD34(+) cells was also Sca-1(+). Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans.
Government must enthuse GPs to improve early diagnosis of dementia
Authors: J. Wise
Journal: BMJ (2010)

<h3>ABSTRACT</h3> <h3>Background</h3> Excessive alcohol consumption has become a growing public health concern worldwide due to the potential development of alcohol dependence (AD). Prolonged alcohol abuse leads to dysregulation of the mesocorticolimbic pathway (MCL), effectively disrupting executive functioning and the allostatic conditioning of reward response. <h3>Methods</h3> We utilized weighted gene co-expressed network analysis (WGCNA) and network preservation using a case/control study design (<i>n</i>=35) to identify unique and shared biological processes dysregulated in AD in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We used correlation and regression analyses to identify mRNA/miRNA interactions and local expression quantitative trait loci (cis-eQTL) to identify genetic regulatory mechanisms for networks significantly associated with AD. <h3>Results</h3> Network analyses revealed 6 and 3 significant mRNA modules from the NAc and PFC, respectively. Network preservation revealed immune response upregulation in both regions, whereas cellular morphogenesis/localization and cilia-based cell projection processes were upregulated only in the NAc. We observed 4 significantly correlated module eigengenes (ME) between the significant mRNA and miRNA modules in PFC, and 6 significant miRNA/mRNA ME correlations in NAc, with the mir-449a/b cluster emerging as a potential regulator for cellular morphogenesis/localization dysregulation in this brain region. Finally, we identified cis-eQTLs (37 mRNA and 9 miRNA in NAc, and 17 mRNA and 16 miRNA in PFC) which potentially mediate alcohol’s effect in a brain region-specific manner. <h3>Conclusion</h3> In agreement with previous reports, we observed a generalized upregulation of immune response processes in subjects with AD, that highlights alcohol’s neurotoxic properties, while simultaneously demonstrating distinct molecular changes in subcortical brain regions as a result of chronic alcohol abuse. Such changes further support previous neuroimaging and physiological studies that emphasize the distinct roles PFC and NAc play in the development of addictive behaviors.
OC-054 Impact of a fermentable carbohydrate restricted diet on luminal microbiota, fermentation, symptoms and nutrient intake in patients with irritable bowel syndrome: a randomised controlled trial
Authors: H Staudacher, M C Lomer, J L Anderson, J S Barrett, J G Muir, P M Irving, K Whelan
Journal: Gut (2012)

<h3>Introduction</h3> Retrospective studies suggest that dietary restriction of fermentable carbohydrates (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols, FODMAPs) improves irritable bowel syndrome (IBS) symptoms. Prebiotic fructo-oligosaccharides and galacto-oligosaccharides stimulate colonic bifidobacteria, however the effect of a fermentable carbohydrate restricted diet on the gut microbiota has never been examined. The aim of this randomised controlled trial was to investigate the impact of a fermentable carbohydrate restricted diet on luminal microbiota, fermentation and symptoms in IBS. <h3>Methods</h3> Adult patients with IBS were recruited from gastroenterology outpatient clinics. Eligible patients were randomised to the intervention diet or their habitual diet for 4 weeks. A fresh stool sample was collected and analysed for the major bacterial groups using fluorescent in situ hybridisation, short chain fatty acid (SCFA) concentration was analysed using gas liquid chromatography and pH was recorded. The incidence and severity of GI symptoms and stool output were recorded and dietary intake was assessed using food diaries. All outcome measures were recorded at baseline and 4 weeks. Continuous data were compared using an independent samples t-test and categorical data were compared using the χ<sup>2</sup> test. <h3>Results</h3> Of 41 patients randomised, six withdrew (five protocol violations, one lost to follow-up). In the intention-to-treat analysis, more patients in the intervention group reported adequate control of symptoms (68%) compared with controls (23%) (p=0.003). However, there were strikingly lower concentrations (7.4 vs 8.2 log<sub>10</sub> cells/g, p=0.001) and proportions (1.2% vs 5.5%, p=0.002) of bifidobacteria in the intervention group compared with controls at follow-up. This was not associated with any change in luminal markers of fermentation. There were no differences in energy, protein or fat intake at 4 weeks between groups but total carbohydrate intake was lower in the intervention group. <h3>Conclusion</h3> This is the first randomised controlled trial investigating the effect of a fermentable carbohydrate restricted diet, demonstrating significant improvements in symptoms but a dramatic reduction in luminal bifidobacteria, a species that have an important role in colonic health. Significant questions remain; is the shift in bifidobacteria permanent, how might it be prevented and what is the impact of reintroduction of fermentable carbohydrates on the microbiota? <h3>Competing interests</h3> None declared.
GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7
Authors: Jacqueline A. Koehler, Laurie L. Baggio, Bernardo Yusta, Christine Longuet, Katherine J. Rowland, Xiemin Cao, Dianne Holland, Patricia L. Brubaker, Daniel J. Drucker
Journal: Cell Metabolism (2015)
Abstract 3705: Deguelin suppresses epithelial to mesenchymal transition (EMT) in pancreatic cancer cells by Snail repression and RKIP induction: Pivotal role of NF-kB
Authors: Srinivas Reddy Boreddy, Sanjay K. Srivastava
Journal: Cancer Research (2011)

Abstract Metastatic disease is a primary cause of death for most cancer patients and is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics, a process known as epithelial to mesenchymal transition (EMT). Hence, targeting EMT would be a novel therapeutic modality in cancer prevention. Previous reports have shown that deguelin, a derivative of rotenone induces apoptosis in cancer cells by inhibiting AKT but its potential as anti-metastatic agent remained elusive. In the present study we investigated the anti-metastatic (EMT) properties of deguelin in PanC-1 and MIA PaCa-2 pancreatic cancer cells. Our results show that deguelin significantly (P&amp;lt;0.0001) suppressed the migration of PanC-1 and MIA PaCa-2 cells in a wound healing assay. Further, deguelin treated PanC-1 and MIA PaCa-2 cells show reduced expression of E-cadherin and cytokeratin 18, the markers of epithelial cell phenotype. On the other hand, the expression of mesenchymal markers N-cadherin and vimentin were up regulated by degulin treatment in both the cell lines. Furthermore, deguelin significantly reduced the expression of Snail, a known EMT inducer, and increased the expression of RKIP, a tumor suppressor gene in both the cell lines. Since NF-kB hyperactivation is associated with tumor metastasis via regulation of EMT, we evaluated whether deguelin inhibit the phosphorylation of NF-kB in PanC-1 and MIA PaCa-2 cells. Our results show that deguelin significantly suppressed the constitutive phosphorylation of NF-kB at Ser-536. Inhibition of NF-kB activation by deguelin was further confirmed by DNA binding activity and EMSA. IL-1β has been shown to activate NF-κB and its transcriptional target Snail leading to increase in the expression of E-cadherin. Treatment of PanC-1 cells with IL-1β significantly attenuated deguelin induced E-cadherin repression and N-cadherin induction, indicating the involvement of NF-kB in deguelin mediated anti-metastatic activity. Ectopic expression of either Snail or NF-kB completely abolished EMT protection offered by deguelin in PanC-1 cells confirming the role of NF-kB and Snail in deguelin induced EMT inhibition. Taken together our results provide convincing evidence on the anti-metastsis properties of deguelin in pancreatic cancer. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3705. doi:10.1158/1538-7445.AM2011-3705