tbuckley/cabot-search huggingface dataset:
CD4+CD25+ T Regulatory Cells Dependent on ICOS Promote Regulation of Effector Cells in the Prediabetic Lesion
Authors: Ann E. Herman, Gordon J. Freeman, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2004)

CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69− cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4+CD25+CD69− cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory–specific profile. Thus, CD4+CD25+69− Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.
Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice
Authors: Charlotte Bonnard, Annie Durand, Simone Peyrol, Emilie Chanseaume, Marie-Agnes Chauvin, Béatrice Morio, Hubert Vidal, Jennifer Rieusset
Journal: Journal of Clinical Investigation (2008)

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.
Haplotype Effect of the Matrix Metalloproteinase-1 Gene on Risk of Myocardial Infarction
Authors: Eve Pearce, David-Alexandre Tregouet, Ann Samnegård, Angharad R. Morgan, Charles Cox, Anders Hamsten, Per Eriksson, Shu Ye
Journal: Circulation Research (2005)

Myocardial infarction (MI) is commonly caused by atherosclerotic plaque rupture following excessive degradation of collagen fibers in the atherosclerotic lesion. We investigated whether interindividual variability in risk of MI was related to polymorphisms in the gene encoding matrix metalloproteinase (MMP)-1, a key fibrillar collagen–degrading enzyme. Several single nucleotide polymorphisms in the MMP1 gene promoter were identified following sequencing DNA samples from 30 individuals. An analysis of the polymorphisms in a cohort of British whites with coronary atherosclerosis, including 639 patients with MI and 538 non-MI subjects, revealed a haplotype effect of the −519A&gt;G and −340T&gt;C polymorphisms on risk of MI, with the A −519 -C −340 and G −519 -T −340 haplotypes being protective (odds ratio=0.70 [0.57 to 0.86]; P =0.0007), whereas the G −519 -C −340 haplotype increased MI risk (odds ratio=1.94 [1.15 to 3.28]; P =0.013). This finding was replicated in a subsequent analysis of 387 Swedish MI patients and 387 healthy controls (odds ratio=0.70 [0.55 to 0.89], P =0.003, for A −519 -C −340 and G −519 -T −340 ; odds ratio=1.54 [0.97 to 2.46], P =0.07, for G −519 -C −340 ). In vitro assays showed that compared with the A −519 -T −340 haplotype, the A −519 -C −340 and G −519 -T −340 haplotypes had lower promoter activity, whereas the G −519 -C −340 haplotype had greater promoter strength, in driving gene expression in human macrophages. Haplotype-specific differences in MMP1 mRNA level in atherosclerotic tissues were also detected. The data indicate that MMP1 gene variation is a genetic factor contributing to interindividual differences in MI risk.
Systemic lupus erythaematosus in a multiethnic US cohort (LUMINA) LIII: disease expression and outcome in acute onset lupus
Authors: A M Bertoli, L M Vilá, J D Reveille, G S Alarcón
Journal: Annals of the Rheumatic Diseases (2007)

Objective: To determine the features associated with acute onset systemic lupus erythaematosus (SLE). Methods: A total of 631 SLE patients from LUMINA (for “lupus in minority populations: nature vs nurture”), a multiethnic (Hispanics, African–Americans and Caucasians) cohort, were studied. Acute disease onset was defined as the accrual of ⩾4 American College of Rheumatology (ACR) criteria for the classification of SLE in ⩽4 weeks. Socioeconomic demographic features, clinical manifestations, disease activity, damage accrual, mortality, autoantibodies, HLA class II and FCGR alleles, behavioural/psychological variables were compared between patients with acute and insidious disease onset by univariable (χ 2 and Student t test) and multivariable (stepwise logistic regression) analyses. Results: A total of 94 (15%) patients had acute disease onset. In the multivariable analysis, patients with acute onset lupus had more renal involvement (odds ratio (OR) = 1.845, 95% CI 1.076–3.162; p = 0.026) and higher disease activity (OR = 1.057, 95% CI 1.005–1.112; p = 0.030). By contrast, age (OR = 0.976, 95% CI 0.956–0.997; p = 0.025), education (OR = 0.901, 95% CI 0.827–0.983, p = 0.019), health insurance (OR = 0.423, 95% CI 0.249–0.718; p = 0.001) and skin involvement (OR = 0.346, 95% CI 0.142–0.843; p = 0.019) were negatively associated with acute onset lupus. No differences were found regarding the serological, genetic and behavioural/psychological features; this was also the case for damage accrual and mortality. Conclusions: Patients with acute onset lupus seem to be younger, have a lower socio-economic status and display more severe disease in terms of clinical manifestations and disease activity. However, intermediate (damage) and long-term (mortality) outcomes appear not to be influenced by the type of disease onset in SLE.
Evaluation of the residual antigenicity and allergenicity of cow's milk substitutes by <i>in vitro</i> tests
Authors: G. Docena, P. Rozenfeld, R. Fernández, C. A. Fossati
Journal: Allergy (2002)

Background: This study aimed the to investigate presence of residual allergenic cow's milk proteins (CMP) in some milk substitutes employed in the treatment of cow's milk allergy (CMA). These allergens may interfere with the treatment, and elicit allergic reactions in sensitized individuals. Methods: The protein composition of the different extracts was evaluated by Lowry's method and tricine SDS‐PAGE. Different immunoenzymatic methods were used (ELISA, EAST and immunoblotting) to quantify total serum IgE and specific serum IgE, as well as to detect the presence of antigenic and allergenic components. Results: The results showed a higher protein content in mammalian milks (cow, sheep, mare, goat, and human) than in hydrolyzed substitutes (partially or extensively hydrolyzed casein or whey proteins). Residual native, processed, or contaminant polypeptides have been identified in the moderate hydrolysates, whereas extensive hydrolysates did not show the presence of residual components by immunoblotting. However, specific antibodies with capacity to bind to peptides have been detected by EAST and ELISA, suggesting that extensive hydrolysates contain residual peptides that preserve immunoreactive epitopes. We were unable to demonstrate either residual antigenicity or allergenicity in an amino‐acid‐based formula. Conclusions: Immunoenzymatic methods were used to detect the presence of cross‐reactive components in mammalian milks. Residual allergenic components from cow's milk could be identified in both the moderate and extensive hydrolysates analyzed. This information may be relevant to the treatment of CMA.
Mineralocorticoids in the Heart and Vasculature: New Insights for Old Hormones
Authors: Achim Lother, Martin Moser, Christoph Bode, Ross D. Feldman, Lutz Hein
Journal: The Annual Review of Pharmacology and Toxicology (2014)

The mineralocorticoid aldosterone is a key regulator of water and electrolyte homeostasis. Numerous recent developments have advanced the field of mineralocorticoid pharmacology—namely, clinical trials have shown the beneficial effects of aldosterone antagonists in chronic heart failure and post–myocardial infarction treatment. Experimental studies using cell type–specific gene targeting of the mineralocorticoid receptor (MR) gene in mice have revealed the importance of extrarenal aldosterone signaling in cardiac myocytes, endothelial cells, vascular smooth cells, and macrophages. In addition, several molecular pathways involving signal transduction via the classical MR as well as the G protein–coupled receptor GPER mediate the diverse spectrum of effects of aldosterone on cells. This knowledge has initiated the development of new pharmacological ligands to specifically interfere with targets on different levels of aldosterone signaling. For example, aldosterone synthase inhibitors such as LCI699 and the novel nonsteroidal MR antagonist BAY 94-8862 have been tested in clinical trials. Interference with the interaction between MR and its coregulators seems to be a promising strategy toward the development of selective MR modulators.
Maximising the effect of combination HIV prevention through prioritisation of the people and places in greatest need: a modelling study
Authors: Sarah-Jane Anderson, Peter Cherutich, Nduku Kilonzo, Ide Cremin, Daniela Fecht, Davies Kimanga, Malayah Harper, Ruth Laibon Masha, Prince Bahati Ngongo, William Maina, Mark Dybul, Timothy B Hallett
Journal: The Lancet (2014)
The mTOR signaling pathway as a treatment target for intracranial neoplasms
Authors: D. Pachow, W. Wick, D. H. Gutmann, C. Mawrin
Journal: Neuro-Oncology (2014)

Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors.
Definitions and types of work-related asthma: a nosological approach
Authors: O. Vandenplas, J-L. Malo
Journal: European Respiratory Journal (2003)

The workplace can trigger or induce asthma and cause the onset of different types of work-related asthma. Analysis of previous definitions of occupational asthma (OA) led to the conclusion that evidence of a direct causal relationship between workplace exposure and the development of asthma remains the key element for defining OA. Based on clinical features and pathophysiological mechanisms, the following conditions should be distinguished in the spectrum of work-related asthma: 1) immunological OA characterised by a latency period necessary to acquire immunologically induced sensitisation; 2) nonimmunological OA characterised by the rapid onset of asthma following single or multiple exposures to high concentrations of irritant compounds; 3) work-related asthma defined by exacerbation of symptoms in workers with pre-existing or coincident asthma; and 4) variant syndromes including eosinophilic bronchitis, potroom asthma, and asthma-like disorders caused by organic dusts. The issues and controversies relating to this approach are critically reviewed in order to stimulate the consensus development of operational definitions of work-related asthma.
Detection of testosterone administration based on the carbon isotope ratio profiling of endogenous steroids: international reference populations of professional soccer players
Authors: E Strahm, C Emery, M Saugy, J Dvorak, C Saudan
Journal: British Journal of Sports Medicine (2009)

The determination of the carbon isotope ratio in androgen metabolites has been previously shown to be a reliable, direct method to detect testosterone misuse in the context of antidoping testing. Here, the variability in the 13C/12C ratios in urinary steroids in a widely heterogeneous cohort of professional soccer players residing in different countries (Argentina, Italy, Japan, South Africa, Switzerland and Uganda) is examined.
Effect of acupuncture on experimentally induced itch
Authors: T. LUNDEBERG, L. BONDESSON, M. THOMAS
Journal: British Journal of Dermatology (1987)

The effect of acupuncture on experimentally induced itch was studied in 10 healthy volunteers. Itching was induced by intradermal injections of histamine on the upper arm. ‘Placebo‐acupuncture’, acupuncture and electro‐acupuncture at 2 Hz or 80 Hz were applied over the injection site, proximal to the injection site (in the same dermatome) or extrasegmentally (ipsilateral to the injected arm) for a period of 5 min following induction of itch. In addition, the effect of a 5 min period and a 20 min period of stimulation of the skin area prior to the induction of itch were studied. The same periods of stimulation were also applied to extrasegmental points prior to the induction of itch on the arm. Acupuncture and 2 Hz and 80 Hz electro‐acupuncture significantly reduced subjective itch intensity when applied intrasegmentally. No significant effects were obtained when stimulation was applied extrasegmentally. The results suggest that acupuncture or electro‐acupuncture could be tried in clinical conditions associated with pruritus.
Short-term impact of the smokefree legislation in England on emergency hospital admissions for asthma among adults: a population-based study
Authors: Michelle Sims, Roy Maxwell, Anna Gilmore
Journal: Thorax (2013)

Comprehensive smokefree laws have now been introduced in several jurisdictions. Few studies have examined the association between smokefree laws and asthma in adults and these have limitations, such as lacking appropriate adjustment for long-term trends or having limited statistical power due to small study populations. This study addresses these limitations and evaluates the short-term impact of smokefree legislation in England. It aims to investigate whether the introduction of smokefree legislation on 1 July 2007 was associated with an immediate reduction in emergency hospital admissions for asthma in the adult population, and whether any association differs across regions.We identified monthly numbers of emergency admissions for asthma (primary diagnosis, 10th revision of the International Classification of Diseases code J45 and J46) in the nine Government Office Regions from April 1997 to December 2010 in the population aged 16 and over. A generalised additive model was fitted that adjusted for seasonality, variation in population size and region-specific, non-linear, long-term trends.Smokefree legislation was associated with an immediate 4.9% (95% CI 0.6% to 9.0%) reduction in emergency admissions for asthma in the adult population. This implies that approximately 1900 emergency admissions for asthma were prevented in each of the first 3 years after legislation was introduced. The reduction in admissions did not vary significantly across regions.Our findings add to the expanding body of evidence that smokefree policies are associated with positive health outcomes. Further research evaluating the impact of legislation in other jurisdictions is needed to support these findings.
Effect of a bed covering system in children with asthma and house dust mite hypersensitivity
Authors: JM Frederick, JO Warner, WJ Jessop, I Enander, JA Warner
Journal: European Respiratory Journal (1997)

Allergen avoidance is regarded as an important approach to management of atopic asthma. The effect of Intervent bed covering systems on house dust mite (HDM) allergen exposure, asthma symptoms and markers of inflammation was investigated in 31 HDM sensitive asthmatic children. Dust concentrations of Dermatophagoides pteronyssinus allergen 1 (Der p 1) were monitored before and after covering the mattress, duvet and pillow with active and placebo covers for 3 months, in a single-blind, cross-over trial. Twice daily peak expiratory flow rate (PEFR), daily symptom scores and treatment schedule were recorded. Bronchial hyperresponsiveness was monitored by histamine challenge (provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20)), and inflammation by measuring eosinophil cationic protein (ECP), eosinophil protein X (EPX), eosinophil peroxidase (EPO), and soluble interleukin-2 receptor (sIL-2R) in serum. There was a significant reduction in Der p 1 when the mattress, duvet and pillow were covered with the active bedding. There was no significant improvement in symptoms of asthma, PEFR, bronchodilator usage of PC20. Also, ECP, EPX, sIL-2R concentrations did not change for either treatment. EPO concentrations were significantly lower in the active compared to the placebo period. The active bed covers reduced retrievable Dermatophagoides pteronyssinus allergen 1 (Der p 1) from the bedding, with short term clinical benefit.
Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group
Authors: Mark T. Jennings, Richard Sposto, James M. Boyett, L. Gilbert Vezina, Emi Holmes, Mitchell S. Berger, Carol S. Bruggers, Janet M. Bruner, Ka-Wah Chan, Kathryn E. Dusenbery, Lawrence J. Ettinger, Charles R. Fitz, Deborah Lafond, David E. Mandelbaum, Vicky Massey, Warren McGuire, Lee McNeely, Thomas Moulton, Ian F. Pollack, Violet Shen
Journal: Journal of Clinical Oncology (2002)

PURPOSE: This Children’s Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent ± 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% ± 9% of patients improved. The neuroradiographic response rate for regimen B was 19% ± 8% for chemotherapy and 23% ± 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% ± 5% (estimate ± SE) at 1 year and 6% ± 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P &lt; .05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.
hzAnalyzer: detection, quantification, and visualization of contiguous homozygosity in high-density genotyping datasets
Authors: Todd A Johnson, Yoshihito Niimura, Hiroshi Tanaka, Yusuke Nakamura, Tatsuhiko Tsunoda
Journal: Genome biology (2011)

Abstract The analysis of contiguous homozygosity (runs of homozygous loci) in human genotyping datasets is critical in the search for causal disease variants in monogenic disorders, studies of population history and the identification of targets of natural selection. Here, we report methods for extracting homozygous segments from high-density genotyping datasets, quantifying their local genomic structure, identifying outstanding regions within the genome and visualizing results for comparative analysis between population samples.
Training programs in blood diseases: Mayo Clinic Rochester Hematology–Oncology Fellowship Program
Authors: Cheng E. Chee, Tow S. Tan, Timothy J. Moynihan, Alexandra P. Wolanskyj
Journal: American Journal of Hematology (2010)

The Hematology fellowship program at Mayo Clinic Rochester began in 1965 followed by the Oncology fellowship program in 1973.The two programs later merged in 1990 and since that time, 115 fellows have completed training (Table I).Mayo Clinic Jacksonville followed shortly thereafter in 1996 and most recently, Mayo Clinic Scottsdale started its program in 2006.Mayo Clinic is known for excellence in its three shields: clinical practice, education, and research, all of which are emphasized during the training program.Indeed, our fellowship combines well-rounded clinical training with opportunities to work with world-class faculty in a collegial environment.We believe that the 4-
Reply to A. Stang et al, J.T. Rowley et al, and F. Samkange-Zeeb et al
Authors: Seung-Kwon Myung, Woong Ju, Diana D. McDonnell, Yeon Ji Lee, Gene Kazinets, Chih-Tao Cheng, Joel M. Moskowitz
Journal: Journal of Clinical Oncology (2010)
Diurnal variations in myocardial metabolism
Authors: M. S. Bray, M. E. Young
Journal: Cardiovascular Research (2008)

The heart is challenged by a plethora of extracellular stimuli over the course of a normal day, each of which distinctly influences myocardial contractile function. It is therefore not surprising that myocardial metabolism also oscillates in a time-of-day dependent manner. What is becoming increasingly apparent is that the heart exhibits diurnal variations in its intrinsic properties, including responsiveness to extracellular stimuli. This article summarizes our current knowledge regarding the mechanism(s) mediating diurnal variations in myocardial metabolism. Particular attention is focused towards the intramyocardial circadian clock, a cell autonomous molecular mechanism that appears to regulate myocardial metabolism both directly (e.g. triglyceride and glycogen metabolism) and indirectly (through modulation of the responsiveness of the myocardium to workload, insulin, and fatty acids). In doing so, the circadian clock within the cardiomyocyte allows the heart to anticipate environmental stimuli (such as changes in workload, feeding status) prior to their onset. This synchronization between the myocardium and its environment is enhanced by regular feeding schedules. Conversely, loss of synchronization may occur through disruption of the circadian clock and/or diurnal variations in neurohumoral factors (as observed during diabetes mellitus). Here, we discuss the possibility that loss of synchronization between the heart and its environment predisposes the heart to metabolic maladaptation and subsequent myocardial contractile dysfunction.