tbuckley/cabot-search huggingface dataset:
Chronic Alcoholism Enhances Hepatocarcinogenicity of Diethylnitrosamine in Rats Fed A Marginally Methyl–Deficient Diet
Authors: Eduardo A. Porta, Nalani Markell, Russell D. Dorado
Journal: Hepatology (1985)

To determine whether the chronic consumption of ethanol was capable of enhancing the hepatocarcinogenic activity of diethylnitrosamine per se, or through the accentuation of a methyl deficiency, two groups (A and B) of Sprague-Dawley female rats were fed for 10 months either a 20% casein basal diet marginally deficient in methyl, or the same diet supplemented with choline (1 gm per 100 gm) and folic acid (0.54 mg per 100 gm). Both groups were offered a drinking ethanol solution, while two other nonalcohol control groups (C and D) were isocalorically pair-fed to Groups A and B, and received diets in which the alcohol consumed by the corresponding groups was replaced by isocaloric amounts of sucrose. A baseline nonalcohol Group E, isocalorically pair-fed to Group A, received the intact basal diet of Group A and water. One day before the initiation of the experiment, and again 2 months later, all rats from the five groups were injected with a single i.p. dose of diethylnitrosamine (100 mg per kg). The growth attained by all groups was statistically similar. Hepatic triglycerides in Group A were significantly higher than in all the other groups. While in Group A primary hepatocellular carcinomas and renal tumors were encountered at the end of the experiment in 3 of 6 and in 2 of 6 rats, respectively, no malignancies were observed in any of the other groups. These results indicate that chronic ethanol consumption enhances the hepatocarcinogenic and renal tumorigenic activity of diethylnitrosamine, and strongly suggest that this action is mediated through the accentuation of methyl deficiency.
Altered DNA Methylation Profile in Idiopathic Pulmonary Fibrosis
Authors: Yan Y. Sanders, Namasivayam Ambalavanan, Brian Halloran, Xiangyu Zhang, Hui Liu, David K. Crossman, Molly Bray, Kui Zhang, Victor J. Thannickal, James S. Hagood
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).To determine the DNA methylation changes in IPF and their effects on gene expression.Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
Fast, sensitive and specific diagnosis of infections with<i>Leishmania</i>spp. in formalin-fixed, paraffin-embedded skin biopsies by cytochrome b polymerase chain reaction
Authors: M. Gebhardt, B. Ertas, T.M. Falk, N. Blödorn-Schlicht, D. Metze, A. Böer-Auer
Journal: British Journal of Dermatology (2015)

Northern spread of sandflies and Leishmania spp. has been observed in Europe. Diagnosis can be difficult owing to the various clinical manifestations. Species identification is important for patient management and therapy. Molecular diagnostics is increasingly used for pan-Leishmania detection but species identification remains challenging in formalin-fixed material.To apply cytochrome b (cytb) polymerase chain reaction (PCR) and sequencing for identification of Leishmania species on formalin-fixed, paraffin-embedded (FFPE) skin biopsies; and to identify species-specific histological patterns.Sixty-nine biopsies (48 patients) diagnosed with leishmaniasis based on the presence of amastigotes in the tissue (n = 41) or granulomatous infiltrates with positive pan-Leishmania real-time PCR (n = 28) were analysed with cytb PCR, sequencing and phylogenetic analysis. Histological sections were analysed; epidemiological data were collected.Cytb PCR identified Leishmania in all specimens: L. infantum (79%), L. major (8%), L. panamensis (4%), L. tropica (4%), L. killicki (2%) and L. aethiopica (2%). Of the detected species 95% were endemic to the country in which the infection was acquired. Amastigotes were found in 59%. Infiltrates were mainly tuberculoid granulomatous (65%), interstitial (15%) and sarcoidal (10%). Pseudolymphomatous features and pseudocarcinomatous hyperplasia were more common in L. major infections than in L. infantum (P < 0·01).Cytb PCR and sequencing is a fast, reliable and sensitive assay for identification of Leishmania spp. in FFPE biopsies. Leishmania infantum is the main cause of cutaneous leishmaniasis in Germany. Tuberculoid granulomas, other types of granulomas and pseudolymphomatous infiltrates may be encountered; the latter being indicative of infection with L. major.
Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies
Authors: Christina Ellervik, Thomas Mandrup-Poulsen, Anne Tybjærg-Hansen, Børge G. Nordestgaard
Journal: Diabetes Care (2013)

Mortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown.In two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346).The cumulative survival rate was reduced in individuals with diabetes with TS ≥50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ≥50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P = 0.0001), with an HR for TS ≥70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ≥50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype.Individuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death.
Technical and clinical assessment of oxygen concentrators.
Authors: G A Gould, W Scott, M D Hayhurst, D C Flenley
Journal: Thorax (1985)

One membrane oxygen enricher (Oxygen Enrichment Company OE-4E) and four molecular sieve (MS) concentrators (Mountain Medical Econo2, De Vilbiss MINI DeVO2, Cryogenic Roomate III, and Mountain Medical Mini O2) have been studied to assess technical and clinical performance. During four weeks of continuous operation at a flow rate of 2 l min-1 (6 l min-1 for OE-4E) consistent oxygen levels were delivered by all machines (mean greater than 93% for MS concentrators, 36.5% for OE-4E). At flow rates of up to 21 mm-1 all four MS machines delivered oxygen concentrations greater than 92%, but at 3 l min-1 (Econo2 89.6%, MINI DeVO2 93.9%, Roomate III 92.0%, Mini O2 85.0%) and at 4 l min-1 (Econo2 78.0%, Mini DeVO2 84.7%, Roomate III 83.3%, Mini O2 69.1%) the two newer machines gave higher oxygen concentrations. In 20 hypoxic patients the mean oxygen saturation levels achieved when they were breathing oxygen from the MS concentrators at a flow rate of 2 l min-1 were similar (Econo2 92.6%, MINI DeVO2 92.5%, Roomate II 92.6%), but the level achieved when they were breathing from the OE-4E, at the equivalent flow rate of 6 l min-1, was lower (91.0%, p less than 0.005). The performance of concentrators in service (Econo2, MINI DeVO2, Mini O2) was satisfactory when judged by patients9 oxygen saturation levels and delivered oxygen concentrations. The OE-4E may be indicated for a small number of patients who require oxygen with high humidification. The four MS concentrators studied are all suitable for domiciliary use, but the MINI DeVO2 and Roomate III have advantages in terms of better performance at high flow rates and reduced size and weight.
Phase II Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Either Receiving or Not Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study
Authors: Timothy F. Cloughesy, Patrick Y. Wen, H. Ian Robins, Susan M. Chang, Morris D. Groves, Karen L. Fink, Larry Junck, David Schiff, Lauren Abrey, Mark R. Gilbert, Frank Lieberman, John Kuhn, Lisa M. DeAngelis, Minesh Mehta, Jeff J. Raizer, W.K. Alfred Yung, Ken Aldape, John Wright, Kathleen R. Lamborn, Michael D. Prados
Journal: Journal of Clinical Oncology (2006)

A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG).Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety.Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups.Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.
A Comparison of the Role of the Bronchial Arteries in Bronchiectasis and in Experimental Ligation of the Pulmonary Artery
Authors: F. B. Cockett, C. C. N. Vass
Journal: Thorax (1951)

The hypertrophy of the bronchial arteries in bronchiectasis has been known to surgeons ever since resection of the lung had been practised for this condition.Histologists have noticed and commented upon the extreme vascularity of the tissue round the bronchiectatic sacs, and have tried to explain this as part of the general inflammatory change.The physiological importance and significance of this bronchial artery hypertrophy have only recently been appreciated.By means of perfusion experiments, followed by the preparation of complete vascular casts in neoprene, it has been possible to demonstrate accurately the anatomical extent of this hypertrophy, and to show that an extensive anastomosis develops between the bronchial arteries and the pulmonary arteries in these lungs.Moreover, the vascular pathology is comparable to that which occurs in the experimental dog after liga- tion of the pulmonary artery.This is a surprising observation, as the stimulus to the development of the bronchial collateral circulation appears to be so dissimilar in the two cases.EXPERIMENTAL WORKThe original reason for beginning the experimental work was to show that if the pulmonary artery to a lung were tied, a collateral blood supply could be directed into it by creating adhesions between it and the chest wall.It was found that branches from the intercostals entered the adhesions and anastomosed with the hypertrophied subpleural capillary network, which was supplied mainly by the enlarged bronchial arterial system within the lung.It was while studying this collateral circulation that our attention was drawn to the hypertrophy of these bronchial vessels, and to the fact that they ramified throughout the lung as large tortuous channels almost as big as the original pulmonary arteries.Moreover, it was evident that communications had developed between these enlarged bronchial arteries and the pulmonary arteries, which were precapillary in situation.No such precapillary anastomosis between bronchial arteries and pulmonary veins could be on July 26, 2023 by guest.
PWE-184 The Effect Of Fibre On Chronic Constipation In Adults: A Systematic Review
Authors: S Christodoulides, E Dimidi, KC Fragkos, PG McLean, Q Aziz, K Whelan, SM Scott
Journal: Gut (2014)

Introduction Symptoms of chronic constipation are common, with a prevalence of ~14% in adults worldwide. Although increasing fibre intake is universally accepted as a first-line treatment, patient dissatisfaction is common. A systematic review is thus required in order to evaluate the quality of scientific evidence behind this management approach. The aim was to assess the effect of fibre on chronic constipation and IBS-C in adults via a systematic review of randomised controlled trials (RCTs). Methods Following Cochrane and PRISMA recommendations, references were identified by searching 5 electronic databases, hand-searching abstracts of 3 annual conferences, as well as scanning reference lists. Two reviewers independently assessed all studies identified, and performed data extraction and risk of bias assessment. Only RCTs reporting administration of fibre (carbohydrate polymers with ≥3 monomers that are not hydrolysed by endogenous enzymes in the small intestine) in adults with either chronic constipation or IBS-C were included. Results Of 916 records identified, only 9 RCTs were eligible (495 patients). Fibre supplements, administered in the form of powder, granules, yoghurt or milk, were: psyllium (n = 3), galacto-oligosaccharides (GOS: n = 2), wheat bran (n = 1), inulin (n = 1), and mixtures of inulin/ resistant maltodextrin (n = 1), and inulin/partially hydrolysed guar gum (n = 1). Outcomes measured included stool frequency (n = 9), stool consistency (n = 6), stool weight (n = 5), faecal microbiota (n = 3) and adverse events (n = 3). Four out of 9 RCTs demonstrated a significant increase in stool frequency following fibre consumption compared to placebo. Stool consistency significantly improved following fibre consumption in 2 RCTs, while 4 RCTs failed to show an effect. Three RCTs demonstrated a significant increase in stool weight, but 2 RCTs did not. Bifidobacteria significantly increased in 2 out of 3 RCTs (inulin and one GOS intervention). No side effects were observed and no patient withdrew because of adverse events. Attrition bias was high amongst trials, while selection bias and performance bias were unclear due to inadequate reporting. Outcome data will undergo meta-analysis. Conclusion Current guidelines recommend the use of fibre as first-line treatment for constipation. However, this review shows that not all studies support its use in adults. Most studies suffer from small sample sizes and poor design with high risk of bias. The paucity of high quality data highlights the need for further large, methodologically rigorous RCTs. Disclosure of Interest S. Christodoulides Grant/research support from: Nestec Ltd, E. Dimidi Grant/research support from: Nestec Ltd, K. Fragkos: None Declared, P. McLean Employee of: Nestec Ltd, Q. Aziz: None Declared, K. Whelan: None Declared, S. M. Scott: None Declared.
Alteration of Cellular and Humoral Immunity by Mutant p53 Protein and Processed Mutant Peptide in Head and Neck Cancer
Authors: Marion E. Couch, Robert L. Ferris, Joseph A. Brennan, Wayne M. Koch, Elizabeth M. Jaffee, Michael S. Leibowitz, Gerald T. Nepom, Henry A. Erlich, David Sidransky
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine if serologic recognition of p53 mutations at the protein level depends upon the ability of mutant p53 to express new peptide epitopes that bind to human leukocyte antigen (HLA) class II molecules, we used anti-p53 antibody production as a marker for HLA class II–restricted T-cell involvement in head and neck cancer. Experimental Design: An anti-p53 antibody response was correlated with specific p53 mutations and the patients' HLA class II alleles and haplotypes. HLA binding studies and in vitro stimulation (IVS) of peripheral blood mononuclear cells were done using a mutant versus wild-type HLA-DQ7-binding p53 peptide. Results: Certain HLA-DQ and HLA-DR alleles were frequently present in p53 seropositive patients who produced serum anti-p53 antibodies. Selected mutated p53 peptides fit published allele-specific HLA class II binding motifs for the HLA-DQ7 or HLA-DR1 molecules. Moreover, a mutant p53 peptide bound with a 10-fold greater affinity than the wild-type p53 peptide to HLA-DQ7 molecules. IVS of CD4+ T cells from seven healthy HLA-DQ7+ donors using this mutant p53 peptide (p53220C) was associated with a partial T helper type 2 phenotype compared with IVS using the wild-type p53210-223 peptide. Conclusions: Our results support the hypothesis that mutated p53 neoantigens can bind to specific HLA class II molecules, leading to a break in tolerance. This may lead to skewing of the CD4+ T lymphocyte response toward a tumor-permissive T helper type 2 profile in head and neck cancer patients, as manifested by seropositivity for p53.
Renal Vasodilatory Action of Carvedilol in the Dog
Authors: Toshiaki Tamaki, Kouichi Hasui, Akira Yamamoto, Yasuharu Aki, Tetsuo Shoji, Akio Nakamura, Shoji Kimura, Kiyoshi Fukui, Hiroshi Iwao, Youichi Abe
Journal: Drugs (1988)
Serum Extracellular Superoxide Dismutase in Patients With Type 2 Diabetes
Authors: Fumiaki Kimura, Goji Hasegawa, Hiroshi Obayashi, Tetsuo Adachi, Hirokazu Hara, Mitsuhiro Ohta, Michiaki Fukui, Yoshihiro Kitagawa, Hyohun Park, Naoto Nakamura, Koji Nakano, Toshikazu Yoshikawa
Journal: Diabetes Care (2003)

The aim of this study was to determine the distribution of serum extracellular superoxide dismutase (EC-SOD) concentrations in patients with type 2 diabetes and to assess whether increased EC-SOD concentration is associated with the development of diabetic vascular complications.Serum EC-SOD concentrations were determined in 222 patients with type 2 diabetes and 75 healthy control subjects by an enzyme-linked immunosorbent assay. All subjects had the EC-SOD domain genotyped.The serum EC-SOD concentrations showed a distinct bimodal distribution in both patients with diabetes and control subjects. All subjects with the high-level phenotype carried the Arg213Gly mutation. The frequency of this variant was similar in the diabetes and control groups. Within the group of subjects with the common EC-SOD phenotype, the serum EC-SOD concentration (mean +/- SE) was significantly higher in patients with type 2 diabetes (99.3 +/- 1.3 ng/ml) compared with the control subjects (68.4 +/- 2.3 ng/ml, P < 0.01). Stepwise multiple regression analysis of the data from the diabetic common phenotype group showed a significant relationship between serum EC-SOD concentration and duration of diabetes (F = 5.31), carotid artery intimal-media thickness (F = 8.24), and severity of nephropathy (F = 16.05) and retinopathy (F = 4.43).We observed a strong relationship between the serum concentration of EC-SOD and the severity of both micro- and macrovascular diabetic complications. These findings suggest that serum EC-SOD concentration levels may be a marker of vascular injury, possibly reflecting hyperglycemia-induced oxidative injury to the vascular endothelium and decreased binding of EC-SOD to the vascular wall.
Symptoms, lactate and exercise limitation at peak cycle ergometry in adults with cystic fibrosis
Authors: A. J. Moorcroft, M. E. Dodd, J. Morris, A. K. Webb
Journal: European Respiratory Journal (2005)

The purpose of this study was to investigate symptoms, lactate accumulation and limiting factors at peak exercise in cystic fibrosis (CF) patients. In total, 104 CF adults attending an adult CF centre and 27 controls performed progressive cycle ergometry to a symptom-limited maximum. Measurements taken at peak exercise included: heart rate, ventilation, oxygen uptake, carbon dioxide output, oxygen saturation and blood lactate. Symptom scores of perceived breathlessness and muscle effort were recorded using Borg scales. The CF subjects had a lower mean body mass index, forced expiratory volume in one second (FEV 1 ) and peak oxygen uptake than controls. Peak lactate concentrations were very similar to controls (mean± sd 6.8±2.0 mmol·L −1 versus 7.4±1.0 mmol·L −1 ). Symptom scores were no different to controls for either breathlessness (4.5±2.0 versus 4.3±1.0) or perceived muscle effort (6.1±2.0 versus 6.5±1.0), with higher scores for muscle effort than breathlessness in both groups. In addition, peak ventilation was lower than the predicted maximum, and high peak heart rates were recorded supporting nonpulmonary factors as important in limiting peak exercise. Peak oxygen uptake was correlated with FEV 1 . Comparison of CF subjects with mild or moderate pulmonary disease and controls revealed similar exercise responses. In contrast, those CF patients with severe lung disease (FEV 1 &lt;40% predicted) had significantly higher breathlessness, lower muscle effort scores, lower peak lactate, lower peak heart rate and a mean ventilation exceeding predicted, thus confirming that ventilation was the major factor limiting exercise. In conclusion, cystic fibrosis subjects have a reduced peak exercise capacity, but their exercise response is similar to controls in generating high blood-lactate concentrations and symptoms of muscle effort in excess of dyspnoea. Nonpulmonary factors influence peak performance more in those without severe disease.