tbuckley/cabot-search huggingface dataset:
The contractile properties of the elderly human diaphragm.
Authors: M I Polkey, M L Harris, P D Hughes, C H Hamnegärd, D Lyons, M Green, J Moxham
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

It has previously been reported that aging is associated with a substantial decrease in diaphragm strength. To test this hypothesis we studied 15 (10 male, 5 female) subjects with a mean age of 29 (range 21 to 40) and 15 elderly (10 male, 5 female) subjects, mean age 73 (range 67 to 81). We measured transdiaphragmatic pressure (Pdi) during a maximal sniff (Sniff Pdi) and during bilateral cervical magnetic stimulation (CMS) of the phrenic nerve roots (Tw Pdi). Additionally in 17 subjects (9 elderly and 8 young) the Pdi elicited by paired CMS (pTw Pdi) was obtained at interstimulus intervals ranging from 10 to 999 ms (1 to 100 Hz). There was considerable overlap between groups. Mean Sniff Pdi in the elderly was 119 cm H2O compared with 136 cm H2O for the young subjects; this represented a median reduction of 18 cm H2O or 13% (p = 0.05, 95% Cl of difference 0 to 33 cm H2O). Mean Twitch Pdi in the elderly was 26.8 cm H2O compared with 35.2 cm H2O, a median reduction of 8 cm H2O or 23% (p = 0.004, 95% Cl 3 to 13 cm H2O). At 10 Hz the elderly tended to generate a higher fraction of the Pdi obtained at 100 Hz than the young, but this trend did not achieve statistical significance (p = 0.11). We conclude that aging is associated with a reduction in diaphragm strength. However the magnitude of the reduction is small and may be offset by a leftward shift of the force-frequency relationship.
Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection
Authors: Ira M. Jacobson, John G. McHutchison, Geoffrey Dusheiko, Adrian M. Di Bisceglie, K. Rajender Reddy, Natalie H. Bzowej, Patrick Marcellin, Andrew J. Muir, Peter Ferenci, Robert Flisiak, Jacob George, Mario Rizzetto, Daniel Shouval, Ricard Sola, Ruben A. Terg, Eric M. Yoshida, Nathalie Adda, Leif Bengtsson, Abdul J. Sankoh, Tara L. Kieffer, Shelley George, Robert S. Kauffman, Stefan Zeuzem
Journal: New England Journal of Medicine (2011)

In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response).Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).
C6 Mediates Chronic Progression of Tubulointerstitial Damage in Rats with Remnant Kidneys
Authors: Masaomi Nangaku, Jeffrey Pippin, William G. Couser
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Although it was once considered only a marker of glomerular damage, accumulating evidence indicates that proteinuria per se is nephrotoxic and contributes to the progression of renal injury. Several studies have demonstrated that activation of complement in proteinuric urine results in tubular and interstitial damage. It was previously demonstrated that acute complement-mediated interstitial disease is induced by C5b-9. Here the role of C5b-9 in the progression of chronic proteinuric renal disease was investigated in a nonimmunologic remnant kidney model. Five-sixths nephrectomies were performed for normocomplementemic control and C6-deficient PVG rats. Tubulointerstitial injury was assessed by measurement of two independent markers of tubular injury (i.e., vimentin and osteopontin), interstitial accumulation of the extracellular matrix components collagen type I, collagen type IV, and laminin, interstitial macrophage infiltration, and renal function. The two groups developed similar levels of proteinuria and BP. Whereas C3 deposition on the brush border was equivalent for rats in the two groups, C5b-9 deposition was observed only for normocomplementemic rats. At day 35, the degrees of both tubulointerstitial injury and renal failure were the same for the two groups. Tubulointerstitial injury in normocomplementemic rats was still severe at day 70. In contrast, interstitial injury in C6-deficient rats had improved markedly at day 70, with improvements in renal function. In a rat model of chronic progressive renal disease secondary to nephron loss, the initial interstitial changes are complement-independent and largely reversible, whereas progressive interstitial fibrosis is mediated predominantly by C5b-9. Treatment to reduce C5b-9 attack in tubular cells may slow progression and facilitate recovery.
Electron Microscopy of Milk Secretion in the Mammary Gland of the C3H/Crgl Mouse. III. Cytomorphology of the Involuting Gland<xref ref-type="fn" rid="fn1">2</xref>
Authors: S. R. Wellings, K. B. Deome
Journal: JNCI Journal of the National Cancer Institute (1963)

The cytologic changes occurring during involution of the mouse mammary gland were studied by light and electron microscopy in tissue samples taken up to 15 days after the cessation of suckling. By light microscopy there was a marked decrease in the amount of epithelial tissue in the mammary glands, accompanied by a corresponding increase of stromal adipose tissue. By electron microscopy most of the epithelial cells of the alveoli and small ducts showed an intracellular accumulation of fat and protein droplets, vacuolization, the appearance of several types of intracellular inclusions, and the disappearance of portions of the ergastoplasmic and Golgi sacs. By the 5th day these changes culminated in cytolysis of the epithelial cells with the release of free nuclei, mitochondria, fat droplets, and other structures into the alveolar and ductal spaces bounded by intact basement membranes. By the 15th day after the termination of suckling, the process was complete, and remaining epithelial structures consisted mostly of small ducts lined by intact epithelial cells.
Impact of sleep in respiratory failure
Authors: WT McNicholas
Journal: European Respiratory Journal (1997)

Sleep has a physiological influence on respiration, which can have major adverse effects on gas exchange in patients with respiratory insufficiency. These effects relate largely to a reduction in various stimulant inputs to the brainstem respiratory centre. Conditions that may be associated with sleep-related respiratory insufficiency range from pulmonary disorders (such as chronic obstructive pulmonary disease (COPD)), to central respiratory insufficiency (such as central alveolar hypoventilation), neurological and neuromuscular disorders (such as polio and muscular dystrophy), and thoracic cage disorders (such as kyphoscoliosis). All these conditions have in common the finding of hypoxaemia and hypercapnia, which become more pronounced during sleep. The relative hypoventilation, which is common to each condition, is due to varying combinations of an inadequate respiratory drive and an increase in the work of breathing. Management of respiratory insufficiency during sleep should be directed first at optimizing the underlying disorder, then at correcting hypoxaemia with controlled low-flow supplemental oxygen. Pharmacological therapy may be effective in some instances, but the choice of agent varies with the underlying disorder. Assisted ventilation is an important part of the management of advanced cases, and the recent development of intermittent positive pressure ventilation by nasal mask (NIPPV) has been an important advance in this area. Use of NIPPV during the night is associated with beneficial effects during the day, particularly improved awake gas exchange and respiratory muscle strength, in addition to less dyspnoea and improved quality of life. Electrophrenic pacing of the diaphragm is helpful in highly selected cases, particularly patients with central respiratory insufficiency and high quadriplegia, but is frequently complicated by the development of obstructive sleep apnoea.
An antigen-specific pathway for CD8 T cells across the blood-brain barrier
Authors: Ian Galea, Martine Bernardes-Silva, Penny A. Forse, Nico van Rooijen, Roland S. Liblau, V. Hugh Perry
Journal: The Journal of Experimental Medicine (2007)

CD8 T cells are nature's foremost defense in encephalitis and brain tumors. Antigen-specific CD8 T cells need to enter the brain to exert their beneficial effects. On the other hand, traffic of CD8 T cells specific for neural antigen may trigger autoimmune diseases like multiple sclerosis. T cell traffic into the central nervous system is thought to occur when activated T cells cross the blood-brain barrier (BBB) regardless of their antigen specificity, but studies have focused on CD4 T cells. Here, we show that selective traffic of antigen-specific CD8 T cells into the brain occurs in vivo and is dependent on luminal expression of major histocompatibility complex (MHC) class I by cerebral endothelium. After intracerebral antigen injection, using a minimally invasive technique, transgenic CD8 T cells only infiltrated the brain when and where their cognate antigen was present. This was independent of antigen presentation by perivascular macrophages. Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti–MHC class I antibody. These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells. This has implications for a variety of diseases in which antigen-specific CD8 T cell traffic into the brain is a beneficial or deleterious feature.
Estrogen-Related Receptor α Is Critical for the Growth of Estrogen Receptor–Negative Breast Cancer
Authors: Rebecca A. Stein, Ching-yi Chang, Dmitri A. Kazmin, James Way, Thies Schroeder, Melanie Wergin, Mark W. Dewhirst, Donald P. McDonnell
Journal: Cancer Research (2008)

Abstract Expression of estrogen-related receptor α (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor α (ERα) and ERRα initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRα target genes, this study yielded the surprising result that most ERRα-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERα and ERRα led us to expand our study to the more aggressive and less clinically treatable ERα-negative class of breast cancers. In this setting, we found that ERRα expression is required for the basal level of expression of many known and novel ERRα target genes. Introduction of a small interfering RNA directed to ERRα into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRα expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRα in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor–negative breast cancer. [Cancer Res 2008;68(21):8805–12]
Comparison Between Laparoscopic and Open Radical Nephroureterectomy in a Contemporary Group of Patients: Are Recurrence and Disease-Specific Survival Associated with Surgical Technique?
Authors: Ricardo L. Favaretto, Shahrokh F. Shariat, Daher C. Chade, Guilherme Godoy, Matthew Kaag, Angel M. Cronin, Bernard H. Bochner, Jonathan Coleman, Guido Dalbagni
Journal: European Urology (2010)
Smoking habits in medical students and physicians in Groningen, The Netherlands
Authors: HJ Waalkens, J Cohen Schotanus, H Adriaanse, K Knol
Journal: European Respiratory Journal (1992)

Smoking habits and attitudes towards smoking of medical students (n = 725), house officers (n = 126) and consultants (n = 236) of the University Hospital of Groningen were studied, in 1989 by means of a World Health Organization (WHO) questionnaire. Overall response rate was 84%. Twenty seven percent of the medical students are current smokers, 28% of the house officers and 34% of the consultants. There is a remarkable difference among medical specialists i.e: smoking prevalence is highest among psychiatrists and lowest among paediatricians. The prevalence of smoking in medical students and house officers is lower than in the Dutch population. Smoking habits of the consultants are similar to those of the general population. About 75% of the doctors reported having no experience with smoking cessation programmes. Doctors report a need for more skills and knowledge on smoking cessation programmes.
Tobacco and Cancer: Recent Epidemiological Evidence
Authors: P. Vineis, M. Alavanja, P. Buffler, E. Fontham, S. Franceschi, Y. T. Gao, P. C. Gupta, A. Hackshaw, E. Matos, J. Samet, F. Sitas, J. Smith, L. Stayner, K. Straif, M. J. Thun, H. E. Wichmann, A. H. Wu, D. Zaridze, R. Peto, R. Doll
Journal: JNCI Journal of the National Cancer Institute (2004)
Brain and body in sport and exercise
Authors: T Wood
Journal: British Journal of Sports Medicine (2006)

Edited by Boria Blumenstein, Michael Bar-Eli, Gershon Tenenbaum. Published by John Wiley and Sons, 2002, £19.99, softcover, pp 133. ISBN 0471499072

Don’t be fooled by the initial title of a book. With Professor Noakes and his research team challenging the traditional model of peripheral fatigue in exercise, I was interested in how this book, Brain and body in sport and exercise , would complement his work. Unfortunately I …
Teplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients
Authors: Frank Waldron-Lynch, Octavian Henegariu, Songyan Deng, Paula Preston-Hurlburt, James Tooley, Richard Flavell, Kevan C. Herold
Journal: Science Translational Medicine (2012)

Humanized mice can be successfully used as a preclinical testing platform to identify the mechanism of action of immunotherapies in humans.
Patterns of contraceptive pill taking in an inner city practice.
Authors: I G Finlay, M G Scott
Journal: BMJ (1986)

A total of 161 patients completed a questionnaire about their pattern of taking the oral contraceptive pill. Only 28% (45) of patients were taking the pill according to the manufacturer's instructions, and in the event of the pill being missed only 26% of patients would use a sheath. A tenth of the patients believed that amenorrhoea always indicated pregnancy, but 35% believed that amenorrhoea was harmful to the body. This group did not differ in their pill taking from the remaining 65% of patients.
KCl Cotransporter-3 Down-regulates E-Cadherin/β-Catenin Complex to Promote Epithelial-Mesenchymal Transition
Authors: Yueh-Mei Hsu, Yih-Fung Chen, Cheng-Yang Chou, Ming-Jer Tang, Ji Hshiung Chen, Robert J. Wilkins, J. Clive Ellory, Meng-Ru Shen
Journal: Cancer Research (2007)

The potassium chloride cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. Here, we investigate if KCC is involved in the regulation of epithelial-mesenchymal transition (EMT), a critical cellular event of malignancy. E-cadherin and beta-catenin colocalize in the cell-cell junctions, which becomes more obvious in a time-dependent manner by blockade of KCC activity in cervical cancer SiHa and CaSki cells. Real-time reverse transcription-PCR on the samples collected from the laser microdissection indicates that KCC3 is the most abundant KCC isoform in cervical carcinoma. The characteristics of EMT appear in KCC3-overexpressed, but not in KCC1- or KCC4-overexpressed cervical cancer cells, including the elongated cell shape, increased scattering, down-regulated epithelial markers (E-cadherin and beta-catenin), and up-regulated mesenchymal marker (vimentin). Some cellular functions are enhanced by KCC3 overexpression, such as increased invasiveness and proliferation, and weakened cell-cell association. KCC3 overexpression decreases mRNA level of E-cadherin. The promoter activity assays of various regulatory sequences confirm that KCC3 expression is a potent negative regulator for human E-cadherin gene expression. The proteosome inhibitor restores the decreased protein abundance of beta-catenin by KCC3 overexpression. In the surgical specimens of cervical carcinoma, the decreased E-cadherin amount was accompanied by the increased KCC3 abundance. Vimentin begins to appear at the invasive front and becomes significantly expressed in the tumor nest. In conclusion, KCC3 down-regulates E-cadherin/beta-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of beta-catenin protein. The disruption of E-cadherin/beta-catenin complex formation promotes EMT, thereby stimulating tumor progression.
Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA
Authors: Hiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, Katsushi Tokunaga
Journal: Journal of Clinical Investigation (2014)

Polymorphisms within HLA gene loci are strongly associated with susceptibility to autoimmune disorders; however, it is not clear how genetic variations in these loci confer a disease risk. Here, we devised a cell-surface MHC expression assay to detect allelic differences in the intrinsic stability of HLA-DQ proteins. We found extreme variation in cell-surface MHC density among HLA-DQ alleles, indicating a dynamic allelic hierarchy in the intrinsic stability of HLA-DQ proteins. Using the case-control data for type 1 diabetes (T1D) for the Swedish and Japanese populations, we determined that T1D risk-associated HLA-DQ haplotypes, which also increase risk for autoimmune endocrinopathies and other autoimmune disorders, encode unstable proteins, whereas the T1D-protective haplotypes encode the most stable HLA-DQ proteins. Among the amino acid variants of HLA-DQ, alterations in 47α, the residue that is located on the outside of the peptide-binding groove and acts as a key stability regulator, showed strong association with T1D. Evolutionary analysis suggested that 47α variants have been the target of positive diversifying selection. Our study demonstrates a steep allelic hierarchy in the intrinsic stability of HLA-DQ that is associated with T1D risk and protection, suggesting that HLA instability mediates the development of autoimmune disorders.
The ratio of epidermal growth factor to monocyte chemotactic peptide-1 in the urine predicts renal prognosis in IgA nephropathy
Authors: D.D. Torres, M. Rossini, C. Manno, F. Mattace-Raso, C. D'Altri, E. Ranieri, P. Pontrelli, G. Grandaliano, L. Gesualdo, F.P. Schena
Journal: Kidney International (2007)
Racial Variation in Prostate Cancer Incidence and in Hormonal System Markers Among Male Health Professionals
Authors: E. A. Platz
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Racial variation in prostate cancer incidence in the United States is pronounced, with African-American men having the highest rates. Whether differences in the distribution of known or suspected risk factors among racial groups explain this variation is unknown. Methods: We evaluated prospectively the relation between prostate cancer and race among 45 410 U.S. male health professionals aged 40–75 years in 1986. We used multivariable, pooled logistic regression to adjust the rate ratio (RR) for potential dietary and lifestyle risk factors. We also measured circulating levels of steroid hormones, sex hormone-binding globulin, and vitamin D metabolites and length of the androgen receptor gene CAG repeat in a sample of African-American (n = 43), Asian (n = 52), and white (n = 55) participants and assessed variation by race in these possible prostate epithelial cell growth mediators by use of analysis of variance. Statistical tests were two-sided. Results: The age-adjusted RR for prostate cancer was 1.73 (95% confidence interval [CI] = 1.23–2.45) for African-American men compared with white men. After multivariate adjustment, the RR increased to 1.81 (95% CI = 1.27–2.58). The rate of prostate cancer did not differ between Asians and whites. Steroid hormone and 1,25-dihydroxyvitamin D levels did not vary appreciably by race. However, the mean number of androgen receptor gene CAG repeats was lower among African-Americans (mean ± standard deviation = 20.1 ± 3.5) than among whites (22.1 ± 3.1; P = .007) and Asians (22.1 ± 3.9; P = .009). Conclusions: Our results confirm the elevated incidence of prostate cancer among African Americans and show that it is not explained by differences in the distribution of possible dietary and lifestyle risk factors in this cohort. Racial variation in length of the androgen receptor gene CAG repeat may explain a small part of the excess risk of prostate cancer among African-American men in this cohort.