tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Lixisenatide Once-Daily Morning or Evening Injections in Type 2 Diabetes Inadequately Controlled on Metformin (GetGoal-M)
Authors: Bo Ahrén, Aniceto Leguizamo Dimas, Patrick Miossec, Stéphane Saubadu, Ronnie Aronson
Journal: Diabetes Care (2013)

To examine the efficacy and safety of lixisenatide (20 μg once daily, administered before the morning or evening meal) as add-on therapy in patients with type 2 diabetes insufficiently controlled with metformin alone.This was a 24-week, randomized, double-blind, placebo-controlled study in 680 patients with inadequately controlled type 2 diabetes (HbA1c 7-10% [53-86 mmol/mol]). Patients were randomized to lixisenatide morning (n = 255), lixisenatide evening (n = 255), placebo morning (n = 85), or placebo evening (n = 85) injections.Lixisenatide morning injection significantly reduced mean HbA1c versus combined placebo (mean change -0.9% [9.8 mmol/mol] vs. -0.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo -0.5% [5.5 mmol/mol], P < 0.0001). HbA1c was significantly reduced by lixisenatide evening injection (mean change -0.8% [8.7 mmol/mol] vs. -0.4% [4.4 mmol/mol]; LS mean difference -0.4% [4.4 mmol/mol], P < 0.0001). Lixisenatide morning injection significantly reduced 2-h postprandial glucose versus morning placebo (mean change -5.9 vs. -1.4 mmol/L; LS mean difference -4.5 mmol/L, P < 0.0001). LS mean difference in fasting plasma glucose was significant in both morning (-0.9 mmol/L, P < 0.0001) and evening (-0.6 mmol/L, P = 0.0046) groups versus placebo. Mean body weight decreased to a similar extent in all groups. Rates of adverse events were 69.4% in both lixisenatide groups and 60.0% in the placebo group. Rates for nausea and vomiting were 22.7 and 9.4% for lixisenatide morning and 21.2 and 13.3% for lixisenatide evening versus 7.6 and 2.9% for placebo, respectively. Symptomatic hypoglycemia occurred in 6, 13, and 1 patient for lixisenatide morning, evening, and placebo, respectively, with no severe episodes.In patients with type 2 diabetes inadequately controlled on metformin, lixisenatide 20 μg once daily administered in the morning or evening significantly improved glycemic control, with a pronounced postprandial effect, and was well tolerated.
New Clues behind the Resilience of a Leading Sexually Transmitted Pathogen, Chlamydia
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2014)

Domman et al. (2014) have explored factors behind the resilience of the most common sexually transmitted disease in the United States, chlamydia, with an estimated 1 million infected. The research team sequenced four new strains of close genetic cousins of chlamydial pathogens and examined these with existing DNA data. They found that an extensive and robust shuffling of the genomic deck between chlamydia families has played a major role in the evolution of the pathogen, often serving to outwit and exploit its hosts. They also identified genomic hotspots that seem to play a key role in adaptation and survival, with many having an unknown function. Of note, these gene families were most commonly found to have specific protein features gained from their eukaryotic hosts. By combining their molecular analysis with cell-based assays, the authors demonstrated that these are thought to be secreted proteins that interfere with their hosts’ defenses. The authors argue that the evolutionary forces at work behind the diversity of chlamydiae are the result of a unique confluence of birth and death gene evolutionary cycles. In this cycle, new gene copies often arise by gene duplication, with the copies persisting or adapting
Computational Models for Neuromuscular Function
Authors: F.J. Valero-Cuevas, H. Hoffmann, M.U. Kurse, J.J. Kutch, E.A. Theodorou
Journal: IEEE Reviews in Biomedical Engineering (2009)

Computational models of the neuromuscular system hold the potential to allow us to reach a deeper understanding of neuromuscular function and clinical rehabilitation by complementing experimentation. By serving as a means to distill and explore specific hypotheses, computational models emerge from prior experimental data and motivate future experimental work. Here we review computational tools used to understand neuromuscular function including musculoskeletal modeling, machine learning, control theory, and statistical model analysis. We conclude that these tools, when used in combination, have the potential to further our understanding of neuromuscular function by serving as a rigorous means to test scientific hypotheses in ways that complement and leverage experimental data.
Induction of the Stem-like Cell Regulator CD44 by Rho Kinase Inhibition Contributes to the Maintenance of Colon Cancer–Initiating Cells
Authors: Hirokazu Ohata, Tatsuya Ishiguro, Yuki Aihara, Ai Sato, Hiroaki Sakai, Shigeki Sekine, Hirokazu Taniguchi, Takayuki Akasu, Shin Fujita, Hitoshi Nakagama, Koji Okamoto
Journal: Cancer Research (2012)

Abstract The difficulty in expanding cancer-initiating cells in vitro is one of major obstacles for their biochemical characterization. We found that Rho kinase (ROCK) inhibitors as well as blebbistatin, a myosin II inhibitor, greatly facilitated the establishment of spheroids from primary colon cancer. The spheroid cells expressed cancer stem cell markers, showed the ability to differentiate, and induced tumors in mice. The spheroids were composed of cells that express various levels of CD44, whereas CD44high cells were associated with increased sphere-forming ability, expression of the activating form of β-catenin, and elevated levels of glycolytic genes, CD44−/low cells showed increased levels of differentiation markers and apoptotic cells. The spheroid cells expressed variant forms of CD44 including v6, and the induction of the variants was associated with the activating phosphorylation of c-Met. As expected from the predicted hierarchy, CD44high cells differentiated into CD44−/low cells. Unexpectedly, a fraction of CD44−/low cells generated CD44high cells, and the ROCK inhibitor or blebbistatin primed the transition by inducing CD44 expression. We propose that the transition from CD44−/low to CD44high state helps to maintain a CD44high fraction and the tumorigenic diversity in colon cancer. Cancer Res; 72(19); 5101–10. ©2012 AACR.
Adenosine A <sub>3</sub> Receptor Deficiency Exerts Unanticipated Protective Effects on the Pressure-Overloaded Left Ventricle
Authors: Zhongbing Lu, John Fassett, Xin Xu, Xinli Hu, Guangshuo Zhu, Joel French, Ping Zhang, Jurgen Schnermann, Robert J. Bache, Yingjie Chen
Journal: Circulation (2008)

Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A(1) receptors (A(1)R) and A(3) receptors (A(3)R) is not known.To test the hypothesis that A(1)R and A(3)R can protect the heart against systolic overload, we exposed A(3)R gene-deficient (A(3)R knockout [KO]) mice and A(1)R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A(3)R KO attenuated 5-week TAC-induced left ventricular hypertrophy (ratio of ventricular mass/body weight increased to 7.6+/-0.3 mg/g in wild-type mice compared with 6.3+/-0.4 mg/g in KO mice), fibrosis, and dysfunction (left ventricular ejection fraction decreased to 43+/-2.5% and 55+/-4.2% in wild-type and KO mice, respectively). A(3)R KO also attenuated the TAC-induced increases of myocardial atrial natriuretic peptide and the oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal. In contrast, A(1)R KO increased TAC-induced mortality but did not alter ventricular hypertrophy or dysfunction compared with wild-type mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction and increased myocardial 3'-nitrotyrosine. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine reduced cell area, protein synthesis, atrial natriuretic peptide, and 3'-nitrotyrosine. Antagonism of A(3)R significantly potentiated the antihypertrophic effects of 2-chloroadenosine.Adenosine exerts protective effects on the overloaded heart, but the A(3)R acts counter to the protective effect of adenosine. The data suggest that selective attenuation of A(3)R activity might be a novel approach to treat pressure overload-induced left ventricular hypertrophy and dysfunction.
Plasma lipid, lipoprotein and apolipoprotein profiles in Nigerian university athletes and non-athletes.
Authors: O O Oyelola, M A Rufai
Journal: British Journal of Sports Medicine (1993)

The fasting plasma lipid, lipoprotein and apolipoprotein profiles were determined in 14 healthy Nigerian male athletes and controls matched for sex and anthropometric parameters. The mean levels of total cholesterol (P < 0.05), low-density lipoprotein (LDL) cholesterol, apolipoprotein (apo) AII and E were significantly lower (P < 0.01) in the athletes than in the controls. However, there were no statistically significant differences (P > 0.05) between the mean values of the plasma triglycerides, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL) cholesterol, apo AI, B, Lp(a), LpA1 and CIII:NonB respectively for the athletes and controls. A priori, the potential effect on cardiovascular disease (CVD) risk was also compared using three predictor ratios - total cholesterol: HDL cholesterol (TC:HDL), LDL cholesterol: HDL cholesterol and apo B:AI. The mean of the three ratios was lower in the athletes than in the controls; however, the differences were not statistically significant (P > 0.05). Based on our data, exercise appears to decrease the TC:HDL ratio in the athletes by lowering LDL-cholesterol, while the HDL-cholesterol is unaffected. We conclude that physical activity has salutary effects on the lipid, lipoprotein and apolipoprotein profiles of healthy Nigerian men.
Broad Consent for Research With Biological Samples: Workshop Conclusions
Authors: Christine Grady, Lisa Eckstein, Ben Berkman, Dan Brock, Robert Cook-Deegan, Stephanie M. Fullerton, Hank Greely, Mats G. Hansson, Sara Hull, Scott Kim, Bernie Lo, Rebecca Pentz, Laura Rodriguez, Carol Weil, Benjamin S. Wilfond, David Wendler
Journal: The American Journal of Bioethics (2015)

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Center's Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.
CENTRIFUGATION STUDIES ON PNEUMONIA VIRUS OF MICE (PVM)
Authors: Edward C. Curnen, Edward G. Pickels, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1947)

A technique has been devised for obtaining free or uncombined pneumonia virus of mice (PVM). Free PVM, liberated from infected mouse lungs by means of this technique, is infectious and causes hemagglutination directly. The results of quantitative studies carried out in the high speed angle centrifuge indicate that the free virus is relatively small, with dimensions of the order of 40 millimicrons. When it is in combination with lung tissue particles, PVM appears to be a relatively large virus with minimal dimensions of the order of 140 millimicrons. Non-infectious virus particles, released from combination with lung tissue particles by heating, are similar to the infectious free virus in size.
Stability of Renal Transplant Function With Alternate-Day Corticosteroid Therapy
Authors: Richard V. Breitenfield
Journal: JAMA (1980)

Fifty-three renal transplant recipients with good to excellent renal function, while receiving daily maintenance or near-maintenance doses of azathioprine and methylprednisolone, were gradually converted to alternate-day corticosteroid therapy. Stability of allograft glomerular filtration rate (GFR) in each patient was assessed by calculating the slope of a plot of the reciprocal of the serum creatinine concentration vs time. After conversion to alternate-day therapy, GFR was stable in 80% but deteriorated in 20% of patients. However, most of the patients who experienced deteriorating GFR during alternate-day therapy regained stable renal function when given the same total corticosteroid dose but on a daily basis. This suggests but does not prove that maintenance-level daily corticosteroid therapy is better than maintenance-level alternate-day therapy in stabilizing allograft function. We conclude that maintenance-level alternate-day corticosteroid therapy should be used cautiously until a long-term prospective study determines whether there is an increased risk of losing renal function with this schedule and whether this potential risk is offset by reduced corticosteroid toxicity. (<i>JAMA</i>244:151-156, 1980)
Is Immunohistochemistry for Epidermal Growth Factor Receptor Expression a Poor Predictor of Response to Epidermal Growth Factor Receptor-Targeted Therapy?
Authors: Mamoun Younes
Journal: Journal of Clinical Oncology (2005)

I read with interest the recently published article by Saltz et al 1 in which they reported poor correlation between the epidermal growth factor receptor (EGFr) score and response to cetuximab treatment in patients with refractory colorectal cancer.In that study, 1 one of 17 patients with 1ϩ EGFr status, four of 30 with EGFr 2ϩ status, and zero of 10 with EGFr 3ϩ status, were responders.The authors stated in the Discussion that immunohistochemistry for EGFr expression is a poor indicator of which tumors are most treatable by the EGFr-targeted therapy used in the study.Before accepting this conclusion, we need the authors to provide important methodological details that were lacking in their article.Answering the following questions will help us understand some possible reasons for the unexpected results they reported:(1) The authors should name the "single reference laboratory" who performed and measured the expression of EGFr by immunohistochemistry.This is a customary practice in most publications.(2) The authors need to clarify how EGFr status was scored.The grading method mentioned in their Methods section is certainly NOT according to the manufacturer's (DakoCytomation, Carpinteria, CA) instructions that are included in the recently released EGFrpharmDx kit.The product sheet recommends an "observational" approach to reporting the results of EGFr staining in which the overall percent of positive cancer cells, the percent of cancer cells with membranous staining, the percent of cancer cells with cytoplasmic staining, the intensity of the membranous staining, and the intensity of the cytoplasmic staining are all reported.There is no suggestion of a combined score.Therefore, the authors should explain how did they come up with the 0, 1ϩ, 2ϩ, and 3ϩ scores for EGFr expression, and what these scores mean.(3) It will be helpful to know what percent of cancer cells were positive for membranous EGFr expression, and whether or not there were correlation between this percentage and treatment response.(4) The instructions included with Dako EGFr pharmDx kit specifically state that "Only tissues preserved in neutral buffered formalin for routine processing and paraffin embedding are suitable for use."Unexpected results in previous studies on other markers were later found to be due to authors' using alcohol-based tissue fixatives or postfixation instead of neutral buffered formalin and routine processing.The authors did not pro-vide any information on the type of tissue fixatives used, whether postfixatives were used, or whether the same tissue fixatives, reagents, and processing protocols were used in all participating institutions.
Midterm Clinical and Echocardiographic Results With Patch Glue Repair of Left Ventricular Free Wall Rupture
Authors: Sergio J. Canovas, Eric Lim, Maria J. Dalmau, Maria Bueno, Jose Buendía, Fernando Hornero, Oscar Gil, Rafael Garcia, Rafael Paya, Jose Perez, Ildefonso Echanove, Jose Montero
Journal: Circulation (2003)

Background— Left ventricular free wall rupture (LVFWR) is a dramatic complication after myocardial infarction. We present our mid-term clinical and echocardiographic results of LVFWR with an epicardial patch without cardiopulmonary bypass. Methods— From February 1993 to May 2001, 17 patients underwent surgery for LVFWR. The mean age±SD of 12 males and 5 females was 68±10 years. All patients presented for emergency surgery with cardiac tamponade confirmed on echocardiography. After opening the chest and identification of the site of rupture, a Goretex patch was fashioned and applied with enbucrilate surgical glue. Results— Effective control of bleeding was achieved in all cases. There were no on-table deaths. The operative (30 day) mortality was 23.5% (4/17). One death occurred because of patch failure, two because of cardiogenic shock, and one from pneumonia. On follow-up at a median of 2.2 years (interquartile range, 1.1 to 4.3 years), two further deaths occurred, one from myocardial infarction and another of undetermined etiology. Echocardiography did not reveal any evidence of restriction to left ventricular free wall motion. Conclusions— Patch glue repair is expedient, simple and effective; with no adverse effects on mid-term ventricular dynamics. In view of superior published results to infarctectomy and repair with extra corporeal circulation, it should be considered to be the initial procedure of choice for the surgical repair of LVFWR.
Misrepresentation of carbohydrate for exercise: ‘It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet’
Authors: Patrick B Wilson
Journal: British Journal of Sports Medicine (2015)

The contention from Malhotra et al 1 regarding the unimportance of carbohydrate for exercise is misguided. First, the reference they provide is an editorial2 that should not be viewed as high-quality evidence. Several oft-cited exercise studies showing benefits with …
Optimization of the Rifampin Dosage to Improve the Therapeutic Efficacy in Tuberculosis Treatment Using a Murine Model
Authors: Jurriaan E. M. de Steenwinkel, Rob E. Aarnoutse, Gerjo J. de Knegt, Marian T. ten Kate, Marga Teulen, Henri A. Verbrugh, Martin J. Boeree, Dick van Soolingen, Irma A. J. M. Bakker-Woudenberg
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

The dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose.Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic parameters and pharmacokinetic/pharmacodynamic indices.A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. The maximum tolerated dosage, pharmacokinetic parameters, and pharmacokinetic/pharmacodynamic index were determined. Therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed.Maximum tolerated dosage of rifampin in the murine TB was 160 mg/kg/d. Pharmacokinetic measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a C(max) of 16.2 and 157.3 mg/L, an AUC(0-24h) of 132 and 1,782 h·mg/L, and AUC(0-24h)/minimum inhibitory concentration ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-week single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection.Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/d enabled a significant reduction in therapy duration without adverse effects.
Differing impact of the deletion of hemochromatosis‐associated molecules HFE and transferrin receptor‐2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin
Authors: Chloé Latour, Céline Besson‐Fournier, Delphine Meynard, Laura Silvestri, Ophélie Gourbeyre, Patricia Aguilar‐Martinez, Paul J. Schmidt, Mark D. Fleming, Marie‐Paule Roth, Hélène Coppin
Journal: Hepatology (2015)

Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor‐2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up‐regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2‐microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6 ‐deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv ‐deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6 ‐deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6 ‐deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. Conclusion : These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. (H epatology 2016;63:126–137)