tbuckley/cabot-search huggingface dataset:
Systemic but not intraocular Epo Gene Transfer Protects the Retina from Light-and Genetic-Induced Degeneration
Authors: Tonia S. Rex, Mariacarmela Allocca, Luciano Domenici, Enrico M. Surace, Albert M. Maguire, Arkady Lyubarsky, Alessandro Cellerino, Jean Bennett, Alberto Auricchio
Journal: Molecular Therapy (2004)

Molecules with neurotrophic activity are being evaluated for treatment of retinitis pigmentosa in animal models. In particular, great interest has been focused recently on erythropoietin (Epo). Evidence of its neurotrophic activity comes mainly from data demonstrating photoreceptor protection in a rodent light-damage model through systemic administration of a recombinant form of this hormone. Our goal was to test whether Epo retinal gene transfer can rescue or delay photoreceptor cell death. We delivered adeno-associated viral vectors encoding Epo intraocularly and, for comparison, intramuscularly to one light-induced and two genetic models of retinal degeneration. Intraocular Epo gene transfer resulted in sustained hormone expression in the eye, which was undetectable systemically. In contrast, Epo intramuscular gene transfer resulted in hormone secretion in the circulation, which was not detected in ocular fluids. The protein secreted from muscle and retina is of the same molecular weight as a commercial recombinant human Epo. Interestingly, following systemic but not intraocular Epo delivery, morphological photoreceptor protection was observed in the light-damage and rds/peripherin (Prph2) models of retinal degeneration. In the light-damage model, the morphological rescue was accompanied by a significant electrophysiological improvement of photoreceptor function. In contrast, no photoreceptor rescue was observed following Epo gene transfer in the rd10 model. This suggests that different apoptotic mechanisms, with varying sensitivities to Epo, occur in different retinal degeneration models. In conclusion, our data support Epo as a neuroprotective agent in some, but not all, retinal degenerations. Further, rescue is observed in specific models after systemic but not intraocular Epo gene transfer.
An overview of how asbestos exposure affects the lung
Authors: G. P Currie, S. J Watt, N. A Maskell
Journal: BMJ (2009)

#### Summary points

People exposed to asbestos often develop lung disease in later life; manifestations include benign, malignant, or diffuse interstitial lung disease. This evidence based review covers who is considered to be at risk, different ways that exposure to asbestos affect the lung, and matters relating to compensation. Because many doctors in primary and secondary care encounter patients who have been exposed to asbestos, they need to be aware of how different people can be affected.

#### Sources and selection criteria

We comprehensively searched articles published up to February 2009 using PubMed and Medline. Key words and phrases used were “asbestos”, “malignant mesothelioma”, “pleural plaques”, “pleural thickening”, “asbestosis”, “lung cancer”, “cigarette smoking”, “pleural effusions”, “compensation”, “occupation”, “chemotherapy”, “radiotherapy”, “surgery”, “treatment”, and “survival”

All people who have worked with asbestos are at potential risk of asbestos related lung disease through inhalation of fibres. Asbestos is a mineral silicate that occurs naturally in various forms. It is resistant to heat and other means of destruction, which explains its extensive use during the 19th and 20th centuries. The fibrous nature of asbestos allows it to be woven into cloth or incorporated into cement materials, ceiling tiles, brake and clutch linings, pipe and boiler …
Israel moves to GP gatekeeper system
Authors: J. Siegel-Itzkovich
Journal: BMJ (1998)

Israeli citizens, whose universal health insurance system makes their medical care among the most accessible systems in the world, are due to lose some of their personal autonomy.

At the moment residents can go directly to any hospital specialist and don't have to be referred by a primary care doctor. But the health ministry is planning to introduce a system on 1 January 2000 whereby every resident must register with a doctor who will serve …
World Cup 2014: festival of football or alcohol?
Authors: J. Gornall
Journal: BMJ (2014)

<h3>Background</h3> Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown. <h3>Methods</h3> We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR&lt;60 ml/min per 1.73m<sup>2</sup>. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. <h3>Results</h3> At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE), compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or ESKD over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. <h3>Conclusions</h3> In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.
Response to Comment on: Jeon et al. <i>Helicobacter pylori</i> Infection Is Associated With an Increased Rate of Diabetes. Diabetes Care 2012;35:520–525
Authors: Christie Y. Jeon, Mary N. Haan, Caroline Cheng, Erin R. Clayton, Elizabeth R. Mayeda, Joshua W. Miller, Allison E. Aiello
Journal: Diabetes Care (2012)

We appreciate the commentary by Polyzos et al. (1), which brings to light current evidence on the association between Helicobacter pylori (H. pylori) infection and insulin resistance. As the authors note in their review of our article (2), six of eight studies identified significantly elevated levels of insulin resistance in those infected with H. pylori compared with uninfected control subjects, suggesting a possible mechanistic relationship between H. pylori and diabetes (3). However, all eight studies were cross-sectional in design and most had not adjusted for potential confounders, warranting …
Oxacillin in Staphylococcal Infections
Authors: Alexander M. Rutenburg, Harold L. Greenberg
Journal: JAMA (1964)

OXACILLIN is a synthetic penicillin resistant to degradation by penicillinase and reported to be effective in the treatment of staphylococcal infections.<sup>1-5</sup>Whereas previous publications<sup>1-4, 6-8</sup>have dealt largely with the use of the oral preparation and described a meager clinical experience, the present report presents a three-year experience with the parenteral, as well as the oral, forms of oxacillin in the management of staphylococcal infections in 302 patients. <h3>Oral Administration.—</h3> One hundred and seventy eight patients received sodium oxacillin orally from the beginning of therapy. The usual daily dose was 2 gm divided into four equal portions. Patients with severe infections were given 1 gm four times daily during the acute phase of their infections. Since oxacillin is probably hydrolyzed to some extent by gastric acid it was generally given to patients who had not eaten one to two hours prior to meals. The duration of therapy was determined by the clinical and bacteriological response
Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER)
Authors: Fabrice André, Thomas Bachelot, Frederic Commo, Mario Campone, Monica Arnedos, Véronique Dieras, Magali Lacroix-Triki, Ludovic Lacroix, Pascale Cohen, David Gentien, Jose Adélaide, Florence Dalenc, Anthony Goncalves, Christelle Levy, Jean-Marc Ferrero, Jacques Bonneterre, Claudia Lefeuvre, Marta Jimenez, Thomas Filleron, Hervé Bonnefoi
Journal: The Lancet Oncology (2014)
A systematic review and meta-analysis of clinical trials on physical interventions for lateral epicondylalgia
Authors: L Bisset, A Paungmali, B Vicenzino, E Beller
Journal: British Journal of Sports Medicine (2005)

A systematic review of the literature on the effectiveness of physical interventions for lateral epicondylalgia (tennis elbow) was carried out. Seventy six randomised controlled trials were identified, 28 of which satisfied the minimum criteria for meta-analysis. The evidence suggests that extracorporeal shock wave therapy is not beneficial in the treatment of tennis elbow. There is a lack of evidence for the long term benefit of physical interventions in general. However, further research with long term follow up into manipulation and exercise as treatments is indicated.
A Vesicle Superpool Spans Multiple Presynaptic Terminals in Hippocampal Neurons
Authors: Kevin Staras, Tiago Branco, Jemima J. Burden, Karine Pozo, Kevin Darcy, Vincenzo Marra, Arjuna Ratnayaka, Yukiko Goda
Journal: Neuron (2010)

Synapse-specific vesicle pools have been widely characterized at central terminals. Here, we demonstrate a vesicle pool that is not confined to a synapse but spans multiple terminals. Using fluorescence imaging, correlative electron microscopy, and modeling of vesicle dynamics, we show that some recycling pool vesicles at synapses form part of a larger vesicle "superpool." The vesicles within this superpool are highly mobile and are rapidly exchanged between terminals (turnover: ∼4% of total pool/min), significantly changing vesicular composition at synapses over time. In acute hippocampal slices we show that the mobile vesicle pool is also a feature of native brain tissue. We also demonstrate that superpool vesicles are available to synapses during stimulation, providing an extension of the classical recycling pool. Experiments using focal BDNF application suggest the involvement of a local TrkB-receptor-dependent mechanism for synapse-specific regulation of presynaptic vesicle pools through control of vesicle release and capture to or from the extrasynaptic pool.
Methods of measuring intracellular pH in the heart
Authors: O. Frohlich, M. A Wallert
Journal: Cardiovascular Research (1995)

Journal Article Methods of measuring intracellular pH in the heart Get access Otto Fröhlich, Otto Fröhlich * aDepartment of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA *Correspondence to Dr Fröhlich. Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark A Wallert Mark A Wallert bDepartment of Biology, Moorhead State University, Moorhead, MN, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 2, February 1995, Pages 194–202, https://doi.org/10.1016/S0008-6363(96)88570-1 Published: 01 February 1995 Article history Received: 04 July 1994 Accepted: 23 November 1994 Published: 01 February 1995
Occupational Lung Disorders
Authors: Mitchell Friedman
Journal: JAMA (1982)

Since the publication in 1974 of the first edition of<i>Occupational Lung Disorders</i>by W. R. Parkes, this text has become a standard reference in the area of occupational lung diseases. The second edition is organized similarly to the previous edition, with the addition of a new chapter on the important subject, "Occupational Asthma including Byssinosis" as well as a short chapter on "Lung Cancer and Occupation." The first five chapters cover the basic area of geochemistry, normal physiology of inhaled materials and their deposition within the lung, fundamental aspects of pathology, and an excellently illustrated chapter on the chest roentgenogram. The remaining chapters cover the entire field of occupational lung diseases. The new edition is larger than the previous edition and contains more illustrations, which are well done. The writing is excellent and easy to follow. The references are extensive and up to date, and the text is well
A Phase I and Pharmacokinetic Study of Pemetrexed Plus Irinotecan in Patients with Advanced Solid Malignancies
Authors: Eric K. Rowinsky, Muralidhar Beeram, Lisa A. Hammond, Garry Schwartz, Johann De Bono, Baharam Forouzesh, Quincy Chu, Jane E. Latz, Shengyan Hong, William John, Binh Nguyen
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies. Experimental Design: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation. Results: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m2; further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m2, which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses. Conclusions: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m2 every 3 weeks with vitamin supplementation.
Prodigiosin Rescues Deficient p53 Signaling and Antitumor Effects via Upregulating p73 and Disrupting Its Interaction with Mutant p53
Authors: Bo Hong, Varun V. Prabhu, Shengliang Zhang, A. Pieter J. van den Heuvel, David T. Dicker, Levy Kopelovich, Wafik S. El-Deiry
Journal: Cancer Research (2013)

Abstract p53 reactivation offers a broad-based strategy for cancer therapy. In this study, we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53-deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell-cycle arrest and apoptosis in p53-deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot TP53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting antitumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by upregulating p73 and targeting mutant p53/p73 interaction there. Cancer Res; 74(4); 1153–65. ©2013 AACR.
The Mature Stomach
Authors: Mark Feldman
Journal: JAMA (1997)

Not too long ago, conventional wisdom held that gastric acid secretion declined as part of the normal aging process. This notion prevailed even though it seemed inconsistent with the increased incidence of peptic ulcer known to accompany advancing age.<sup>1</sup>Within the past decade, the long-held concept that gastric acid secretion normally declines with aging has been challenged by 3 prospective studies.<sup>2-4</sup>Goldschmiedt et al<sup>2</sup>measured fasting, food-stimulated, and gastrin-stimulated gastric acid secretion in 21 healthy young US men and women (ages, 23 to 42 years; mean, 33 years) and in 20 healthy older men and women (ages, 44 to 71 years; mean, 57 years). Surprisingly, older men had higher acid secretion rates than their younger counterparts, whereas acid secretion rates in older, postmenopausal women did not differ significantly from those in younger, premenopausal women.<sup>2</sup> See also p 659. Subsequent prospective studies in Australia<sup>3</sup>and the United
First do no harm: the impact of recent armed conflict on maternal and child health in Sub-Saharan Africa
Authors: B. A M O'Hare, D. P Southall
Journal: Journal of the Royal Society of Medicine (2007)

ObjectivesTo compare the rates of under-5 mortality, malnutrition, maternal mortality and other factors which influence health in countries with and without recent conflict. To compare central government expenditure on defence, education and health in countries with and without recent conflict. To summarize the amount spent on SALW and the main legal suppliers to countries in Sub-Saharan African countries (SSA), and to summarize licensed production of Small Arms and Light Weapons (SALW) in these countries. DesignWe compared the under-5 mortality rate in 2004 and the adjusted maternal mortality ratio in SSA which have and have not experienced recent armed conflict (post-1990). We also compared the percentage of children who are underweight in both sets of countries, and expenditure on defence, health and education. SettingDemographic data and central government expenditure details (1994–2004) were taken from UNICEF's The State of the World's Children 2006 report. Results21 countries have and 21 countries have not experienced recent conflict in this dataset of 42 countries in SSA. Median under-5 mortality in countries with recent conflict is 197/1000 live births, versus 137/1000 live births in countries without recent conflict. In countries which have experienced recent conflict, a median of 27% of under-5s were moderately underweight, versus 22% in countries without recent conflict. The median adjusted maternal mortality in countries with recent conflict was 1000/100,000 births versus 690/100,000 births in countries without recent conflict. Median reported maternal mortality ratio is also significantly higher in countries with recent conflict. Expenditure on health and education is significantly lower and expenditure on defence significantly higher if there has been recent conflict. ConclusionsThere appears to be an association between recent conflict and higher rates of under-5 mortality, malnutrition and maternal mortality. Governments spend more on defence and less on health and education if there has been a recent conflict. SALW are the main weapon used and France and the UK appear to be the two main suppliers of SALW to SSA.
Down-regulation of connective tissue growth factor by inhibition of transforming growth factor β blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma
Authors: Antonio Mazzocca, Emilia Fransvea, Francesco Dituri, Luigi Lupo, Salvatore Antonaci, Gianluigi Giannelli
Journal: Hepatology (2009)

Tumor–stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor β (TGF-β) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-β–dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-β1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-β1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-β–dependent CTGF expression may offer clinical benefits. Conclusion: Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials. (Hepatology 2009.)
Growth hormone resistance exacerbates cholestasis‐induced murine liver fibrosis
Authors: Patricia Stiedl, Robert McMahon, Leander Blaas, Victoria Stanek, Jasmin Svinka, Beatrice Grabner, Gernot Zollner, Sonja M. Kessler, Thierry Claudel, Mathias Müller, Wolfgang Mikulits, Martin Bilban, Harald Esterbauer, Robert Eferl, Johannes Haybaeck, Michael Trauner, Emilio Casanova
Journal: Hepatology (2014)

Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the GH receptor gene (Ghr –/– , a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2 –/– ), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr –/– ;Mdr2 –/– mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation, and increased collagen deposition relative to Mdr2 –/– mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr –/– ;Mdr2 –/– mice had a pronounced down‐regulation of hepatoprotective genes Hnf6 , Egfr , and Igf‐1 , and significantly increased levels of reactive oxygen species (ROS) and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr –/– ) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis, and bile infarcts compared to their wild‐type littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr –/– ;Mdr2 –/– mice displayed a significant decrease in tumor incidence compared to Mdr2 –/– mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. Conclusion : GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. (H epatology 2015;61:613‐626)