tbuckley/cabot-search huggingface dataset:
Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes
Authors: Jens J. Holst, Filip K. Knop, Tina Vilsbøll, Thure Krarup, Sten Madsbad
Journal: Diabetes Care (2011)

Whereas glucose-tolerant individuals are capable of adjusting their insulin secretion to their actual insulin sensitivity, people with type 2 diabetes are incapable of doing so (1). β-Cell failure is therefore the hallmark of this disease, although failure may be precipitated by the development of insulin resistance, typically as a consequence of obesity. In healthy subjects, a considerable part of the postprandial insulin response is due to the actions of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, the two hormones are responsible for the so-called incretin effect, i.e., the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide identical plasma glucose concentrations (2).

Although frequently ignored, the effect strongly depends on the dose of glucose (3). A convenient way of describing the effect is to calculate the gastrointestinally mediated glucose disposal (GIGD) (4). Here the amount of glucose required by intravenous infusion to copy the glucose excursions after the oral load is related to the oral load. Thus, if 25 g is required to copy a 75-g oral glucose load, the GIGD amounts to 100 × (75 – 25)/75 = 66%. In other words, mechanisms associated with and activated by the oral ingestion resulted in a disposal of 75 – 25 = 50 g of the ingested glucose. In healthy subjects, most of the GIGD is accounted for by the actions of the incretin hormones, but inhibition of hepatic glucose production by suppression of glucagon secretion, hepatic uptake of glucose from the portal vein, and gut-brain or liver-brain reflex activity may also play a role. GIGD is particularly useful in the study of oral glucose handling in C-peptide–negative patients with type 1 diabetes, where the classical incretin definitions have no meaning (4). In a …
Epigenetic Regulation of <i>WTH3</i> in Primary and Cultured Drug-Resistant Breast Cancer Cells
Authors: Kegui Tian, Vladimir Jurukovski, Xue-Ping Wang, Mark H. Kaplan, Haopeng Xu
Journal: Cancer Research (2005)

Abstract Previous studies showed that the WTH3 gene functioned as a negative regulator during multidrug resistance (MDR) development in vitro. To understand whether this gene is also involved in clinical drug resistance, hypermethylation at its promoter region observed in cultured MDR MCF7/AdrR cells was examined in primary drug-resistant breast cancer epithelial cells isolated from effusions of breast cancer patients. The results showed that this event also occurred in drug-resistant breast cancer epithelial cells and a newly induced drug-resistant cell line, MCF7/inR. Interestingly, we found that a CpG (CpG 23) that was close to the TATA-like box was constantly methylated in the WTH3 promoter of drug-resistant breast cancer epithelial and cultured MDR cells. Mutagenic study suggested that this CpG site had a functional effect on promoter activity. We also discovered that MCF7/AdrR cells treated with trichostatin A, a histone deacetylase inhibitor, exhibited higher WTH3, but lower MDR1, expression. A reverse correlation between WTH3 and MDR1 gene expression was also observed in MCF7/AdrR, and its non-MDR parental cell line, MCF7/WT. This result indicated that both DNA methylation and histone deacetylase could act in concert to inhibit WTH3 and consequently stimulate MDR1 expression. This hypothesis was supported by data obtained from introducing the WTH3 transgene into MDR cell lines, which reduced endogenous MDR1 expression. Therefore, our studies suggested that the behavior of WTH3 in primary drug-resistant breast cancer epithelial cells was similar to that in a model system where epigenetic regulation of the WTH3 gene was linked to the MDR phenotype.
A6.6 The Role of Syndecan-4 in Experimental Colitis
Authors: Mareike Fröhling, Dominik Bettenworth, Peter Paruzel, Frank Echtermeyer, Andreas Lügering, Thomas Pap, Athanasios Stratis
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> The transmembrane heparan sulphate proteoglycan syndecan-4 (Scd4) has been implicated in cell-matrix adhesion, cell migration, differentiation, proliferation and plays an important role during inflammation in rheumatoid arthritis. Scd4 is a mediator and modulator of inflammatory signals, upon its binding of cytokines Scd4 acts either as a decoy receptor or through the initiation of Scd-dependend signalling, followed by the formation of a Scd4 complex. Cartilage damage is decreased in sdc4-deficient mice, but osteopontin-mediated liver damage is increased. Because of these dual effects we investigate the impact of sdc4 in murine experimental colitis. <h3>Materials and Methods</h3> We performed DSS-induced colitis in Scd4<sup>-/-</sup> and C57BL/6 WT mice. We used weight loss, colon length and histological scoring of colonic modifications to measure the course of colitis. Scd4<sup>-/-</sup> and WT mice were orally gavaged with 5 × 10<sup>8</sup> colony-forming units (CFU) of invasive bacterium <i>Citrobacter rhodentium</i> (<i>C. rhodentium</i>). The changes of body weight and faecal excretion of <i>C. rhodentium</i> were monitored for 21 days followed by evaluation of histological changes after infection. The permeability of the colon was examined in vitro by infection of colon samples from Scd4<sup>-/-</sup> and C57BL/6 WT mice with <i>C. rhodentium</i>. The migration behaviour of endothelial human cells (T-84) and scd4-siRNA T-84 knockdown cells was analysed by scratch assay. <h3>Results</h3> DSS-treated Scd4<sup>-/-</sup> mice lost dramatically more body weight compared to the WT mice and the histological damage according to the Dieleman-Score was markedly increased. At day 19 of post infection the clearance of <i>C. rhodentium</i> in Scd4<sup>-/-</sup> mice was markedly prolonged. In vitro infection of colon samples from Scd4<sup>-/-</sup> mice with <i>C. rhodentium</i> revealed a higher permeability for the bacterium compared to WT colon samples. The knockdown of Scd4 in human endothelial T-84 cells leads to delayed cell migration. <h3>Conclusions</h3> Like in inflammatory liver damage, Scd4 appears to play an important role in colitis and exerts protective effects in intestinal inflammation. The Scd4 deficiency leads to a higher permeability of the colon to<i> C. rhodentium</i> and a delayed cell migration. Further analysis are needed to explore the mechanisms of Sdc4-signalling in colitis.
Autoantibodies against alanyl-tRNA synthetase and tRNAAla coexist and are associated with myositis.
Authors: C C Bunn, R M Bernstein, M B Mathews
Journal: The Journal of Experimental Medicine (1986)

The sera of six patients with autoimmune disease, predominantly myositis with pulmonary fibrosis, contain antibodies of the PL-12 specificity. These autoantibodies react with both protein and RNA components of human cells. The protein has a subunit molecular mass of 110 kD, and the RNA comprises a group of bands in the tRNA size class. Aminoacylation experiments identify the antigens as alanyl-tRNA synthetase and its corresponding tRNAs, tRNAAla. Anti-tRNA antibody can be absorbed out without depleting antisynthetase activity, showing that the antigens are recognized independently by separable antibodies that coexist in these sera. The concurrence of separate antibodies to the two components suggests that the autoimmune response may be mounted against the charging enzyme-tRNA complex. However, the antisynthetase antibody fails to coprecipitate tRNA with the enzyme, suggesting that the antibody reacts with its target only when it is not complexed with tRNA.
Studies on Histamine Metabolism in Intrinsic Bronchial Asthma
Authors: O. Löwhagen, G. Granerus, H. Wetterqvist
Journal: Allergy (1979)

Histamine metabolism was investigated in patients with intrinsic asthma, during the acute phase and in remission, by determination of the urinary excretion of histamine metabolites. During acute attacks the excretion of methylhistamine (MeHi) and 1‐methyl‐4‐iniidazoleacetic acid (MeImAA) was significantly increased compared with healthy subjects. The excretion of MeHi was significantly increased during acute attacks compared with remission. The excretion of MeImAA was also increased, but the difference was not significant. The correlation between the excretion of MeHi and MeImAA was highly significant. Corticosteroids, given to some patients during remission, did not affect the excretion of histamine and its metabolites. Smoking and respirator’ infection during the acute attacks were both accompanied by increased excretion of MeHi. The results indicate that there is an increased histamine turnover in acute attacks of intrinsic bronchial asthma.
Experts call for greater transparency on safety of implants
Authors: A. O'Dowd
Journal: BMJ (2012)

The public wants and should receive much more information on implants as part of published data on the outcomes of surgical procedures, MPs have been told.

The desire for the NHS to offer more data on surgery and implants is growing and must be acknowledged, witnesses told MPs on the parliamentary science and technology committee.

The committee held its first evidence session on 23 May as part of its inquiry into regulation of medical implants.

The inquiry follows the scandal last year over discredited and now bankrupt French manufacturer Poly Implant Prosthese (PIP), which used non-medical grade silicone in breast implants that were given to around 47 000 women in the UK. 1 2

MPs asked the witnesses their …
Can Deleterious Mutations Explain the Time Dependency of Molecular Rate Estimates?
Authors: Michael Woodhams
Journal: Molecular Biology and Evolution (2006)

It has recently been observed by Ho et al. (Ho SYW, Phillips MJ, Cooper A, Drummond AJ. 2005. Time dependency of molecular rate estimates and systematic overestimation of recent divergence times. Mol Biol Evol. 22(7):1561-1568) that apparent rates of molecular evolution increase when measured over short timespans. I investigate whether the data are explainable purely by deleterious mutations. I derive an empirical approximation for the persistence of these mutations in a randomly mating population and, hence, derive lower limits on effective population sizes. These limits are high and get higher if additional reasonable assumptions are made. This casts doubt on whether deleterious mutations are able to explain the apparent rate acceleration.
Immunotoxin Treatment of Cancer
Authors: Ira Pastan, Raffit Hassan, David J. FitzGerald, Robert J. Kreitman
Journal: Annual Review of Medicine (2006)

Immunotoxins are proteins used to treat cancer that are composed of an antibody fragment linked to a toxin. The immunotoxin binds to a surface antigen on a cancer cell, enters the cell by endocytosis, and kills it. The most potent immunotoxins are made from bacterial and plant toxins. Refinements over many years have produced recombinant immunotoxins; these therapeutic proteins are made using protein engineering. Individual immunotoxins are designed to treat specific cancers. To date, most success has been achieved treating hematologic tumors. Obstacles to successful treatment of solid tumors include poor penetration into tumor masses and the immune response to the toxin component of the immunotoxin, which limits the number of cycles that can be given. Strategies to overcome these limitations are being pursued.
A prospective trial of plasma EBV DNA for the screening of nasopharyngeal carcinoma
Authors: K.C. Allen Chan, Emily C.W. Hung, Anita S.M. Cheng, Franco P.T. Lai, Andrew C. Van Hesselt, John K.S. Woo, Paul K.S. Chan, S.F. Leung, Anthony T.C. Chan, Y.M. Dennis Lo
Journal: Clinical Cancer Research (2010)

Abstract Nasopharyngeal carcinoma (NPC) is common in the southern part of China. Making use of the close relationship between Epstein-Barr virus (EBV) infection and NPC, our group has established plasma EBV DNA as a tumor marker for NPC. In this prospective trial, we have investigated the efficacy of plasma EBV DNA analysis for identifying asymptomatic NPC. We screened 1318 subjects with no NPC symptoms with plasma EBV DNA analysis. At recruitment, 69 subjects (5.2%) had detectable EBV DNA in their plasma and 19 of these 69 subjects (28%) had persistently positive results after a median of 16 days. As a comparison, 86 (6.5%) were positive for IgA against EBV viral capsid antigen (VCA). Nasal endoscopy was carried out for all subjects with either a positive EBV DNA or VCA-IgA result. Three subjects were subsequently diagnosed of having NPC. All of them were positive for plasma EBV DNA at recruitment and on follow-up. In contrast, only one of them was positive for EBV VCA-IgA. Interestingly, in one patient, the cancer was too small to be visible in endoscopic examination but was identified in a subsequent magnetic resonance imaging (MRI) examination because of an increasing EBV DNA level. In summary, our results show that plasma EBV DNA is useful for the screening of NPC in asymptomatic individuals and the repetition of the analysis in 2 weeks is useful for identifying individuals with false positive results. This study is supported by the Michael and Betty Kadoorie Cancer Genetics Research Program. This talk is also presented as Poster B3.
Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure
Authors: Yuko Yamada, Hideyuki Kinoshita, Koichiro Kuwahara, Yasuaki Nakagawa, Yoshihiro Kuwabara, Takeya Minami, Chinatsu Yamada, Junko Shibata, Kazuhiro Nakao, Kosai Cho, Yuji Arai, Shinji Yasuno, Toshio Nishikimi, Kenji Ueshima, Shiro Kamakura, Motohiro Nishida, Shigeki Kiyonaka, Yasuo Mori, Takeshi Kimura, Kenji Kangawa, Kazuwa Nakao
Journal: Cardiovascular Research (2014)

Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca2+ channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. We compared the effects of cilnidipine, a dual N- and L-type Ca2+ channel blocker, with those of nitrendipine, a selective L-type Ca2+ channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B+/− mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B+/+ mice. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
Psoriasis: dysregulation of innate immunity
Authors: J.D. Bos, M.A. de Rie, M.B.M. Teunissen, G. Piskin
Journal: British Journal of Dermatology (2005)

Journal Article Psoriasis: dysregulation of innate immunity Get access J.D. Bos, J.D. Bos Department of Dermatology, A0‐235, Academic Medical Center, University of Amsterdam, P.O.Box 22700, 1100 DE Amsterdam, the Netherlands Jan D. Bos MD, PhD, FRCP, Professor and Chairman. E‐mail: j.d.bos@amc.uva.nl Search for other works by this author on: Oxford Academic Google Scholar M.A. De Rie, M.A. De Rie Department of Dermatology, A0‐235, Academic Medical Center, University of Amsterdam, P.O.Box 22700, 1100 DE Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.B.M. Teunissen, M.B.M. Teunissen Department of Dermatology, A0‐235, Academic Medical Center, University of Amsterdam, P.O.Box 22700, 1100 DE Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar G. Piskin G. Piskin Department of Dermatology, A0‐235, Academic Medical Center, University of Amsterdam, P.O.Box 22700, 1100 DE Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 6, 1 June 2005, Pages 1098–1107, https://doi.org/10.1111/j.1365-2133.2005.06645.x Published: 01 June 2005 Article history Accepted: 25 December 2004 Published: 01 June 2005
Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events
Authors: Martin O'Donnell, Andrew Mente, Sumathy Rangarajan, Matthew J. McQueen, Xingyu Wang, Lisheng Liu, Hou Yan, Shun Fu Lee, Prem Mony, Anitha Devanath, Annika Rosengren, Patricio Lopez-Jaramillo, Rafael Diaz, Alvaro Avezum, Fernando Lanas, Khalid Yusoff, Romaina Iqbal, Rafal Ilow, Noushin Mohammadifard, Sadi Gulec, Afzal Hussein Yusufali, Lanthe Kruger, Rita Yusuf, Jephat Chifamba, Conrad Kabali, Gilles Dagenais, Scott A. Lear, Koon Teo, Salim Yusuf
Journal: New England Journal of Medicine (2014)

The optimal range of sodium intake for cardiovascular health is controversial.We obtained morning fasting urine samples from 101,945 persons in 17 countries and estimated 24-hour sodium and potassium excretion (used as a surrogate for intake). We examined the association between estimated urinary sodium and potassium excretion and the composite outcome of death and major cardiovascular events.The mean estimated sodium and potassium excretion was 4.93 g per day and 2.12 g per day, respectively. With a mean follow-up of 3.7 years, the composite outcome occurred in 3317 participants (3.3%). As compared with an estimated sodium excretion of 4.00 to 5.99 g per day (reference range), a higher estimated sodium excretion (≥ 7.00 g per day) was associated with an increased risk of the composite outcome (odds ratio, 1.15; 95% confidence interval [CI], 1.02 to 1.30), as well as increased risks of death and major cardiovascular events considered separately. The association between a high estimated sodium excretion and the composite outcome was strongest among participants with hypertension (P=0.02 for interaction), with an increased risk at an estimated sodium excretion of 6.00 g or more per day. As compared with the reference range, an estimated sodium excretion that was below 3.00 g per day was also associated with an increased risk of the composite outcome (odds ratio, 1.27; 95% CI, 1.12 to 1.44). As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a reduced risk of the composite outcome.In this study in which sodium intake was estimated on the basis of measured urinary excretion, an estimated sodium intake between 3 g per day and 6 g per day was associated with a lower risk of death and cardiovascular events than was either a higher or lower estimated level of intake. As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a lower risk of death and cardiovascular events. (Funded by the Population Health Research Institute and others.).
577 SYSTEMATIC ERROR IN MELD CALCULATION BY USING SERUM CREATININE AND CREATININE-BASED EQUATIONS IN PATIENTS WITH CIRRHOSIS
Authors: E. Tsochatzis, M. Garcovich, P. Manousou, G. Germani, G. Fede, E. Fatourou, G. Isgro, D. Georgiadis, P. Vasianopoulou, A.K. Burroughs
Journal: Journal of Hepatology (2011)
Simian virus 40 and human pleural mesothelioma
Authors: B. JASANI;, R M RUDD, C MULATERO
Journal: Thorax (1999)

We agree with Richard Coker 1 that the vast majority of non-compliant cases of tuberculosis can be dealt with by a mixture of directly observed therapy (DOT) and inducements.However, when DOT fails in a few cases each year, despite intensive team eVort and carrots such as housing or food vouchers, the Public Health Act may have to be invoked.We have had recourse to this measure four times in the past six months but, though providing valuable breathing space, it is extremely costly and proved ineVectual as a solution each time.Once the patient is admitted there are still potential problems.Treatment cannot be enforced and patients can abscond.There have also been instances of patients assaulting staV, physically and sexually, issuing death threats, breaking hospital property, and terrorising other patients, even interfering with others' oxygen therapy.Dealing with such patients puts hospital staV and patients under unacceptable pressure and requires extra staYng for security purposes.NHS hospitals were not designed for, nor are they staVed adequately for, custodial purposes.There is an urgent need to review the Public Health Act and make provisions for small specialist units staVed by nurses with training in and an aptitude for interpersonal skills.Admission to the unit would usually only be required for short periods of time until precipitating circumstances were resolved and alternative arrangements made.The threat of compulsory admission, or a short period thereof, may induce a behavioural change in the patient, allowing DOT to be successful after failing previously.In addition, a centrally based mobile unit of trained staV could be available to help tide teams over emergencies and could reduce the need for the specialist unit, enabling more non-adherent patients to be managed in the community.We call upon the Department of Health to examine and implement these proposals.
A pyogenic granuloma treated with topical timolol
Authors: M. Malik, R. Murphy
Journal: British Journal of Dermatology (2014)

Journal Article A pyogenic granuloma treated with topical timolol Get access M. Malik, M. Malik Department of Dermatology Queens Medical Centre Nottingham University Hospital Nottingham NG7 2UH U.K Correspondence Moona Malik. E‐mail: moona.malik@nuh.nhs.uk Search for other works by this author on: Oxford Academic Google Scholar R. Murphy R. Murphy Department of Dermatology Queens Medical Centre Nottingham University Hospital Nottingham NG7 2UH U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 171, Issue 6, 1 December 2014, Pages 1537–1538, https://doi.org/10.1111/bjd.13116 Published: 01 December 2014
Applied physiology of tennis performance
Authors: M S Kovacs
Journal: British Journal of Sports Medicine (2006)

Competitive tennis play requires a combination of the major physiological variables; however, the specifics of these variables have yet to be determined appropriately. General strength and flexibility training have been suggested as being beneficial for performance and injury prevention, yet specific guidelines are lacking. This paper provides a review of specific studies that relate to competitive tennis, and highlights the need for tennis-specific training as opposed to generalised physical training. It identifies specific studies that support the premise that tennis has physiological requirements which need to be understood when designing training and research programmes.