tbuckley/cabot-search huggingface dataset:
Indomethacin, Amiloride, or Eplerenone for Treating Hypokalemia in Gitelman Syndrome
Authors: Anne Blanchard, Rosa Vargas-Poussou, Marion Vallet, Aurore Caumont-Prim, Julien Allard, Estelle Desport, Laurence Dubourg, Matthieu Monge, Damien Bergerot, Stéphanie Baron, Marie Essig, Frank Bridoux, Ivan Tack, Michel Azizi
Journal: Journal of the American Society of Nephrology (2014)

Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.
Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Infected Women Receiving Cotrimoxazole Prophylaxis: A Multicenter Randomized Placebo-Controlled Trial
Authors: Raquel González, Meghna Desai, Eusebio Macete, Peter Ouma, Mwaka A. Kakolwa, Salim Abdulla, John J. Aponte, Helder Bulo, Abdunoor M. Kabanywanyi, Abraham Katana, Sonia Maculuve, Alfredo Mayor, Arsenio Nhacolo, Kephas Otieno, Golbahar Pahlavan, María Rupérez, Esperança Sevene, Laurence Slutsker, Anifa Vala, John Williamsom, Clara Menéndez
Journal: PLoS Medicine (2014)

Clara Menéndez and colleagues conducted a randomized controlled trial among HIV-positive pregnant women in Kenya, Mozambique, and Tanzania to investigate the safety and efficacy of mefloquine as intermittent preventative therapy for malaria in women receiving cotrimoxazole prophylaxis and long-lasting insecticide treated nets. Please see later in the article for the Editors' Summary
Precursor keratin protein from human epidermis
Authors: J. BAYNES, M. LEVINE, A. McLEOD, A. WILKINSON
Journal: British Journal of Dermatology (1978)

Prekeratin has been isolated from human epidermis using the method of Matoltsy for bovine nose epidermis. Analysis by sedimentation equilibrium indicates that human prekeratin is heterogeneous in solution. The molecular weight range is from about 200 X 10(3) to at least 2 X 10(6). Polyacrylamide gel electrophoresis shows three polypeptide chains of molecular weights 65,000 60,000 and 58,000. A lower than average ratio of polar/apolar amino acid residues suggests that hydrophobic interactions are important for stability.
Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals
Authors: J. W. Tyner
Journal: Journal of Clinical Investigation (2006)

Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.
Penicillin to Prevent Recurrent Leg Cellulitis
Authors: Kim S. Thomas, Angela M. Crook, Andrew J. Nunn, Katharine A. Foster, James M. Mason, Joanne R. Chalmers, Ibrahim S. Nasr, Richard J. Brindle, John English, Sarah K. Meredith, Nicholas J. Reynolds, David de Berker, Peter S. Mortimer, Hywel C. Williams
Journal: New England Journal of Medicine (2013)

Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis.
Adverse reaction to pomegranate ingestion
Authors: J. M. IGEA, J. CUESTA, M. CUEVAS, L. M. ELIAS, C. MARCOS, M. LAZARO, J. A. COMPAIRED
Journal: Allergy (1991)

We present a non‐atopic 85‐year‐old woman, with a late‐onset recidivant tongue angioedema due to pomegranate intake, as proven by a double blind oral challenge test. This is the first case ever reported about adverse reaction to pomegranate. We have been unable to demonstrate an IgE‐mediated mechanism (prick test, histamine release test and RAST with pomegranate were all negative). We emphasize the importance of clinical history and oral challenge test in the diagnosis of food allergy.
Immunogenic Cell Death and Cross-Priming Are Reaching the Clinical Immunotherapy Arena
Authors: Ignacio Melero, Ainhoa Arina, Oihana Murillo, Juan Dubrot, Carlos Alfaro, Jose L. Pérez-Gracia, Maurizio Bendandi, Sandra Hervás-Stubbs
Journal: Clinical Cancer Research (2006)

In this issue of Clinical Cancer Research , Saji et al. ([1][1]) show the preclinical therapeutic efficacy of combining photodynamic therapy and intratumoral injection of dendritic cells (DC) in s.c. transplanted tumors. The investigators have used systemic doses of a hydrophilic photosensitizer and
Apoptosis Repressor With Caspase Recruitment Domain Is Required for Cardioprotection in Response to Biomechanical and Ischemic Stress
Authors: Stefan Donath, Peifeng Li, Christian Willenbockel, Nidal Al-Saadi, Volkmar Gross, Thomas Willnow, Michael Bader, Ulrich Martin, Johann Bauersachs, Kai C. Wollert, Rainer Dietz, Rüdiger von Harsdorf
Journal: Circulation (2006)

Ischemic heart disease and heart failure are associated with an increased loss of cardiomyocytes due to apoptosis. Whether cardiomyocyte apoptosis plays a causal role in the pathogenesis of heart failure remains enigmatic. The apoptosis repressor with caspase recruitment domain (ARC) is a recently discovered antiapoptotic factor with a highly specific expression pattern in striated muscle and neurons. ARC is a master regulator of cardiac death signaling because it is the only known factor that specifically inhibits both the intrinsic and extrinsic apoptotic death pathway. In this study we attempted to elucidate the physiological role of ARC and to understand pathophysiological consequences resulting from its deletion.We generated ARC-deficient mice, which developed normally to adulthood and had no abnormality in cardiac morphology and function under resting conditions. On biomechanical stress induced by aortic banding, ARC-deficient mice developed accelerated cardiomyopathy compared with littermate controls, which was characterized by reduced contractile function, cardiac enlargement, and myocardial fibrosis. Likewise, ischemia/reperfusion injury of ARC-deficient mice resulted in markedly increased myocardial infarct sizes. Although in both instances a significant increase in apoptotic cardiomyocytes could be observed in ARC-deficient mice, neither in vitro nor in vivo studies revealed any effect of ARC on classic hypertrophic cardiomyocyte growth responses. The pathophysiological relevance of downregulated ARC levels was underscored by specimens from failing human hearts showing markedly reduced ARC protein levels.Our study identifies a tissue-specific antiapoptotic factor that is downregulated in human failing myocardium and that is required for cardioprotection in pressure overload and ischemia.
Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease
Authors: Joel T. Dudley, Marina Sirota, Mohan Shenoy, Reetesh K. Pai, Silke Roedder, Annie P. Chiang, Alex A. Morgan, Minnie M. Sarwal, Pankaj Jay Pasricha, Atul J. Butte
Journal: Science Translational Medicine (2011)

Computationally predicted repositioning of an anticonvulsant for inflammatory bowel disease is confirmed experimentally.
Prospective Multicenter Study of the Impact of the 21-Gene Recurrence Score Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection
Authors: Shelly S. Lo, Patricia B. Mumby, John Norton, Karen Rychlik, Jeffrey Smerage, Joseph Kash, Helen K. Chew, Ellen R. Gaynor, Daniel F. Hayes, Andrew Epstein, Kathy S. Albain
Journal: Journal of Clinical Oncology (2010)

Purpose The 21-gene Recurrence Score (RS) assay has been validated to quantify the risk of distant recurrence in tamoxifen-treated patients with lymph node–negative, estrogen receptor–positive breast cancer and predict magnitude of chemotherapy benefit. This multicenter study was designed to prospectively examine whether RS affects physician and patient adjuvant treatment selection and satisfaction. Patients and Methods Before and after obtaining the 21-gene RS assay, medical oncologists stated their adjuvant treatment recommendation and confidence in it. Patients also indicated their treatment choice pre- and post-RS assay. Patients completed measures for decisional conflict, anxiety, and quality of life. Results Seventeen medical oncologists at one community and three academic practices consecutively enrolled 89 assessable patients. The medical oncologist treatment recommendation changed for 28 patients (31.%). Twenty-four patients (27%) changed their treatment decision. The largest change after the RS results was conversion from the medical oncologist's pretest recommendation for chemotherapy plus hormonal therapy (CHT) to post-test recommendation for hormone therapy (HT) in 20 cases (22.5%). Nine patients (10.1%) changed their treatment decision from CHT to HT. RS results increased medical oncologist confidence in their treatment recommendation in 68 cases (76%). Patient anxiety and decisional conflict were significantly lower after RS results. Conclusion The results of this study indicate that the RS assay impacts medical oncologist adjuvant treatment recommendations, patient treatment choice, and patient anxiety.
Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation
Authors: Christoph Reinhardt, Marie-Luise von Brühl, Davit Manukyan, Lenka Grahl, Michael Lorenz, Berid Altmann, Silke Dlugai, Sonja Hess, Ildiko Konrad, Lena Orschiedt, Nigel Mackman, Lloyd Ruddock, Steffen Massberg, Bernd Engelmann
Journal: Journal of Clinical Investigation (2008)

The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased — and, under conditions of decreased platelet adhesion, PDI inhibition reduced — fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet–secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury.
Diaphragmatic rupture resulting from gastrointestinal barotrauma in a scuba diver.
Authors: J D Hayden, J B Davies, I G Martin
Journal: British Journal of Sports Medicine (1998)

A fit young man sustained a ruptured diaphragm during a recreational scuba dive three months after undergoing an uncomplicated laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease. It is proposed that this rare occurrence was attributable to gastrointestinal barotrauma. The injury was treated by laparotomy, mobilisation of herniated abdominal viscera back into the abdomen, repair of the crura and gastropexy. He made a full postoperative recovery. It is concluded that scuba diving should be avoided in patients who have undergone fundoplication.
The immune response to resistive breathing
Authors: T. Vassilakopoulos
Journal: European Respiratory Journal (2004)

Resistive breathing is an "immune challenge" for the body, initiating an inflammatory response consisting of an elevation of plasma cytokines, and the recruitment and activation of lymphocyte subpopulations. These cytokines do not originate from monocytes, but are, instead, produced within the diaphragm, secondary to the increased muscle activation. Oxidative stress is a major stimulus for the cytokine induction, secondary to resistive breathing. The production of cytokines within the diaphragm may be mediating the diaphragm muscle fibre injury that occurs with strenuous contractions, or contributing towards the expected repair process. These cytokines may also compromise diaphragmatic contractility or contribute towards the development of muscle cachexia. They may also have systemic effects, mobilising glucose from the liver and free fatty acid from the adipose tissue to the strenuously working respiratory muscles. At the same time, they stimulate the hypothalamic-pituitary-adrenal axis, leading to production of adrenocorticotropin and β-endorphins. The adrenocorticotropin response may represent an attempt of the organism to reduce the injury occurring in the respiratory muscles <i>via</i> the production of glucocorticoids and the induction of the acute phase-response proteins. The β-endorphin response would decrease the activation of the respiratory muscles and change the pattern of breathing, which becomes more rapid and shallow, possibly in an attempt to reduce and/or prevent further injury to the respiratory muscles.
Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease
Authors: H.R. Gosker, B. Kubat, G. Schaart, G.J. van der Vusse, E.F.M. Wouters, A.M.W.J. Schols
Journal: European Respiratory Journal (2003)

Despite the fact that muscle weakness is a major problem in chronic obstructive pulmonary disease (COPD), detailed information on myopathological changes at the microscopic level in these patients is scarce, if indeed available at all. Vastus lateralis biopsies of 15 COPD weight-stable patients (body mass index (BMI) 23.9±1.0 kg·m −2 ; fat-free mass index (FFMI) 17.2±1.7 kg·m −2 ) and 16 healthy age-matched controls (BMI 26.3±0.8 kg·m −2 ; FFMI 19.6±2.2 kg·m −2 ) were evaluated. Histochemistry was used to evaluate myopathological features. Immunohistochemistry was used for the detection of macrophages and leukocytes, and active caspase 3 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL) as markers of apoptosis. Fatty cell replacement and fibrosis were observed in both groups, the latter being slightly, but significantly, more pronounced in COPD. No differences between COPD and controls were found with respect to central nuclei, necrosis, regeneration, or fibre splitting. Signs of mitochondrial abnormalities were absent and normal numbers of inflammatory cells were found. Active caspase 3 positive myocytes were not observed and no difference was found in the number of TUNEL-positive myonuclei between controls and COPD patients (1.1% versus 1.0%, respectively). The cross-sectional area of type-IIX muscle fibres was smaller in COPD than in controls (2,566 versus 4,248 µm 2 ). Except for the I to IIX shift in fibre types, the selective type-IIX atrophy and a slight accompanying increase in fibrosis and fat cell replacement in chronic obstructive pulmonary disease relative to age-matched controls, no other morphological abnormalities were observed in the muscle biopsies of chronic obstructive pulmonary disease patients. Also, in this group of clinically and weight stable chronic obstructive pulmonary disease patients, apoptosis appeared not to be involved in muscle pathology.
Outcomes Associated with Corticosteroid Dosage in Critically Ill Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Tyree H. Kiser, Richard R. Allen, Robert J. Valuck, Marc Moss, R. William Vandivier
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Studies evaluating corticosteroid (CS) dosing for patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) have largely excluded patients admitted directly to the intensive care unit (ICU), and none have evaluated the effect of CS dosing regimens on mortality.To examine the effectiveness and safety of lower- versus high-dose CS in patients admitted to the ICU with an AECOPD.This pharmacoepidemiologic cohort study evaluated ICU patients with AECOPD admitted to one of 473 hospitals and treated with CS within the first 2 days between January 1, 2003 and December 31, 2008. Patients were grouped into lower-dose (methylprednisolone, ≤240 mg/d) or high-dose (methylprednisolone, >240 mg/d) groups based on CS dosage on hospital Day 1 or 2. The primary outcome was hospital mortality.A total of 17,239 patients were included; 6,156 (36%) were in the lower-dose and 11,083 (64%) in the high-dose CS group. After propensity score matching and adjustment for unbalanced covariates, lower-dose CS was not associated with a significant reduction in mortality (odds ratio, 0.85; 95% confidence interval [CI], 0.71-1.01; P = 0.06), but it was associated with reduced hospital (-0.44 d; 95% CI, -0.67 to -0.21; P < 0.01) and ICU (-0.31 d; 95% CI, -0.46 to -0.16; P < 0.01) length-of-stay, hospital costs (-$2,559; 95% CI, -$4,508 to -$609; P = 0.01), length of invasive ventilation (-0.29 d; 95% CI, -0.52 to -0.06; P = 0.01), need for insulin therapy (22.7% vs. 25.1%; P < 0.01), and fungal infections (3.3% vs. 4.4%; P < 0.01).Two-thirds of patients admitted to the ICU with an AECOPD are treated with high doses of CS that are associated with worse outcomes and more frequent adverse effects. Lower dosage strategies should be encouraged for patients admitted to the ICU and the optimum dose should be determined through clinical trials.
Effects of Particulate Matter on Genomic DNA Methylation Content and <i>iNOS</i> Promoter Methylation
Authors: Letizia Tarantini, Matteo Bonzini, Pietro Apostoli, Valeria Pegoraro, Valentina Bollati, Barbara Marinelli, Laura Cantone, Giovanna Rizzo, Lifang Hou, Joel Schwartz, Pier Alberto Bertazzi, Andrea Baccarelli
Journal: Environmental Health Perspectives (2008)

BackgroundAltered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined.ObjectivesWe aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 μm (PM10).MethodsWe measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual PM10 exposure was between 73.4 and 1,220 μg/m3.ResultsGlobal methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. PM10 exposure levels were negatively associated with methylation in both Alu [β = −0.19 %5-methylcytosine (%5mC); p = 0.04] and LINE-1 [β = −0.34 %5mC; p = 0.04], likely reflecting long-term PM10 effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = −0.61 %5mC; p = 0.02).ConclusionsWe observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.
An evaluation of the International Diabetes Federation definition of metabolic syndrome in Chinese patients older than 30 years and diagnosed with type 2 diabetes mellitus
Authors: Bin Lu, Yehong Yang, Xiaoyan Song, Xuehong Dong, Zhaoyun Zhang, Linuo Zhou, Yiming Li, Naiqing Zhao, XiXing Zhu, Renming Hu
Journal: Metabolism (2006)
Protective Role of Raf-1 in <i>Salmonella</i>-Induced Macrophage Apoptosis
Authors: Veronika Jesenberger, Katarzyna J. Procyk, Jochen Rüth, Martin Schreiber, Hans-Christian Theussl, Erwin F. Wagner, Manuela Baccarini
Journal: The Journal of Experimental Medicine (2001)

Invasive Salmonella induces macrophage apoptosis via the activation of caspase-1 by the bacterial protein SipB. Here we show that infection of macrophages with Salmonella causes the activation and degradation of Raf-1, an important intermediate in macrophage proliferation and activation. Raf-1 degradation is SipB- and caspase-1–dependent, and is prevented by proteasome inhibitors. To study the functional significance of Raf-1 in this process, the c-raf-1 gene was inactivated by Cre-loxP–mediated recombination in vivo. Macrophages lacking c-raf-1 are hypersensitive towards pathogen-induced apoptosis. Surprisingly, activation of the antiapoptotic mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) and nuclear factor κB pathways is normal in Raf-1–deficient macrophages, and mitochondrial fragility is not increased. Instead, pathogen-mediated activation of caspase-1 is enhanced selectively, implying that Raf-1 antagonizes stimulus-induced caspase-1 activation and apoptosis.