tbuckley/cabot-search huggingface dataset:
β-Cell Response During a Meal Test
Authors: Lawrence S. Cozma, Stephen D. Luzio, Gareth J. Dunseath, Paul M. Underwood, David R. Owens
Journal: Diabetes Care (2005)

OBJECTIVE—To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. RESEARCH DESIGN AND METHODS—Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA1c 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. RESULTS—The insulinogenic index (ΔI30/ΔG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC0–30) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) &amp;lt;9-mmol/l subgroup of subjects and not in the FPG &amp;gt;9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC120–240), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. CONCLUSIONS—Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.
Reactive Oxygen Species Mediate Amplitude-Dependent Hypertrophic and Apoptotic Responses to Mechanical Stretch in Cardiac Myocytes
Authors: David R. Pimentel, Jay K. Amin, Lei Xiao, Thomas Miller, Jason Viereck, Jennifer Oliver-Krasinski, Ragavendra Baliga, Jing Wang, Deborah A. Siwik, Krishna Singh, Patrick Pagano, Wilson S. Colucci, Douglas B. Sawyer
Journal: Circulation Research (2001)

Oxidative stress stimulates both growth and apoptosis in cardiac myocytes in vitro. We investigated whether oxidative stress mediates hypertrophy and apoptosis in cyclically stretched ventricular myocytes. Neonatal rat ventricular myocytes cultured on laminin-coated silastic membranes were stretched cyclically (1 Hz) at low (nominal 5%) and high (nominal 25%) amplitudes for 24 hours. Stretch caused a graded increase in superoxide anion production as assessed by superoxide dismutase (SOD)-inhibitable cytochrome c reduction or electron paramagnetic resonance spectroscopy. The role of reactive oxygen species (ROS) was assessed using the cell-permeable SOD/catalase mimetics Mn(II/III)tetrakis(1-methyl-4-peridyl) (MnTMPyP) and EUK-8. Stretch-induced increases in protein synthesis ( 3 H-leucine incorporation) and cellular protein content were completely inhibited by MnTMPyP (0.05 mmol/L) at both low and high amplitudes of stretch. In contrast, while MnTMPyP inhibited basal atrial natriuretic factor (ANF) mRNA expression, the stretch-induced increase in ANF mRNA expression was not inhibited by MnTMPyP. In contrast to hypertrophy, only high-amplitude stretch increased myocyte apoptosis, as reflected by increased DNA fragmentation on gel electrophoresis and an ≈3-fold increase in the number of TUNEL-positive myocytes. Similarly, only high-amplitude stretch increased the expression of bax mRNA. Myocyte apoptosis and bax expression stimulated by high-amplitude stretch were inhibited by MnTMPyP. Both low- and high-amplitude stretch caused rapid phosphorylation of ERK1/2, while high-, but not low-, amplitude stretch caused phosphorylation of JNKs. Activation of both ERK1/2 and JNKs was ROS-dependent. Thus, cyclic strain causes an amplitude-related increase in ROS, associated with differential activation of kinases and induction of hypertrophic and apoptotic phenotypes.
Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients
Authors: Ronald F van Vollenhoven, Paul Emery, Clifton O Bingham, Edward C Keystone, Roy M Fleischmann, Daniel E Furst, Nicola Tyson, Neil Collinson, Patricia B Lehane
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). <h3>Methods</h3> Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. <h3>Results</h3> As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had &gt;5 years' follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for &gt;5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. <h3>Conclusions</h3> This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.
Progesterone Regulates Cardiac Repolarization Through a Nongenomic Pathway
Authors: Hiroaki Nakamura, Junko Kurokawa, Chang-Xi Bai, Ken Asada, Jun Xu, Ronit V. Oren, Zheng I. Zhu, Colleen E. Clancy, Mitsuaki Isobe, Tetsushi Furukawa
Journal: Circulation (2007)

Female sex is an independent risk factor for torsade de pointes in long-QT syndrome. In women, QT interval and torsade de pointes risk fluctuate dynamically during the menstrual cycle and pregnancy. Accumulating clinical evidence suggests a role for progesterone; however, the effect of progesterone on cardiac repolarization remains undetermined.We investigated the effects of progesterone on action potential duration and membrane currents in isolated guinea pig ventricular myocytes. Progesterone rapidly shortened action potential duration, which was attributable mainly to enhancement of the slow delayed rectifier K+ current (I(Ks)) under basal conditions and inhibition of L-type Ca2+ currents (I(Ca,L)) under cAMP-stimulated conditions. The effects of progesterone were mediated by nitric oxide released via nongenomic activation of endothelial nitric oxide synthase; this signal transduction likely takes place in the caveolae because sucrose density gradient fractionation experiments showed colocalization of the progesterone receptor c-Src, phosphoinositide 3-kinase, Akt, and endothelial nitric oxide synthase with KCNQ1, KCNE1, and Ca(V)1.2 in the caveolae fraction. We used computational single-cell and coupled-tissue action potential models incorporating the effects of progesterone on I(Ks) and I(Ca,L); the model reproduces the fluctuations of cardiac repolarization during the menstrual cycle observed in women and predicts the protective effects of progesterone against rhythm disturbances in congenital and drug-induced long-QT syndrome.Our data show that progesterone modulates cardiac repolarization by nitric oxide produced via a nongenomic pathway. A combination of experimental and computational analyses of progesterone effects provides a framework to understand complex fluctuations of QT interval and torsade de pointes risks in various hormonal states in women.
Quality-of-Life Effects of Prophylactic Salpingo-Oophorectomy Versus Gynecologic Screening Among Women at Increased Risk of Hereditary Ovarian Cancer
Authors: Joanna B. Madalinska, Judith Hollenstein, Eveline Bleiker, Marc van Beurden, Heiddis B. Valdimarsdottir, Leon F. Massuger, Katja N. Gaarenstroom, Marian J.E. Mourits, René H.M. Verheijen, Eleonora B.L. van Dorst, Hans van der Putten, Ko van der Velden, Henk Boonstra, Neil K. Aaronson
Journal: Journal of Clinical Oncology (2005)

Recommendations for women at high risk of ovarian cancer include periodic gynecologic screening (GS) and prophylactic bilateral salpingo-oophorectomy (PBSO). The aim of the current study was to determine the quality-of-life (QOL) effects of PBSO versus GS.Questionnaire data were obtained from 846 high-risk women who had participated in this nationwide, cross-sectional, observational study. Forty-four percent of the women had undergone PBSO, and 56% had opted for GS. Topics addressed by the questionnaire included generic QOL, cancer-specific distress, endocrine symptoms, and sexual functioning.No statistically significant between-group differences were observed in generic QOL (Short Form-36), with women in both the PBSO and GS groups scoring similarly to the general population. Compared with GS, PBSO was associated with fewer breast and ovarian cancer worries (P < .001) and more favorable cancer risk perception (P < .05). However, the PBSO group reported significantly more endocrine symptoms (P < .001) and worse sexual functioning (P < .05) than the GS group. Eighty-six percent of women would choose PBSO again, and 63% would recommend it to a friend with familial risk of ovarian cancer.PBSO had no measurable adverse impact on generic QOL of high-risk women. The favorable effects of PBSO in terms of reduced cancer worries and low perceived cancer risk need to be weighed against the increase in endocrine and sexual symptoms. Balanced information will help clinicians and high-risk women to make informed decisions about the optimal preventive health strategy.
Increased Prevalence of Significant Coronary Artery Calcification in Patients With Diabetes
Authors: Richard K. Bernstein
Journal: Diabetes Care (2001)

Evidence of Macrovascular Complications Elevated plasma total homocysteine (tHcy) levels are a powerful risk factor for atherosclerotic vascular disease (1), but it is still unclear by which pathophysiological mechanisms tHcy may promote atherothrombosis.In both experimental animal and cell culture studies (2,3), acute hyperhomocysteinemia induces endothelial dysfunction, leading to a low-grade inflammatory state that results in increased leukocyte adher-
Maffucci's syndrome with oral and intestinal haemangioma
Authors: N H Lee, E H Choi, W K Choi, S H Lee, S K Ahn
Journal: British Journal of Dermatology (1999)

Journal Article Maffucci's syndrome with oral and intestinal haemangioma Get access N H Lee, N H Lee Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar E H Choi, E H Choi Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar W K Choi, W K Choi Paediatrics, Yonsei University Wonju College of Medicine, 162 Ilsan‐Dong, Wonju 220‐701, Korea,Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar S H Lee, S H Lee Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea Search for other works by this author on: Oxford Academic Google Scholar S K Ahn S K Ahn Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 140, Issue 5, 1 May 1999, Pages 968–969, https://doi.org/10.1046/j.1365-2133.1999.02840.x Published: 01 May 1999
6-minute walk test (6MWT) in patients with idiopathic pulmonary fibrosis (IPF): Confirmation of the minimal clinically important difference (MCID)
Authors: Steven Nathan, Carlo Albera, Roland du Bois, Williamson Bradford, Ulrich Costabel, Talmadge King, Paul Noble, Steven Sahn, Dominique Valeyre
Journal: European Respiratory Journal (2012)

Introduction:  The 6MWT is a practical measure of exercise tolerance in patients with IPF. MCID estimates for 6MWT distance (6MWD) in patients with IPF have ranged between 10–58 m [1-3]; we sought to confirm these estimates in an independent cohort of patients with IPF.   Methods:  All patients randomized to placebo in the CAPACITY studies were included in the analysis. Both distribution- and anchor-based methods were used to estimate the MCID for 6MWD. Distribution-based analyses included standard error of measurement (SEM) and effect size (ES); anchor-based analyses used criterion referencing to estimate the difference in 6MWD between those who did and did not experience significant health events.   Results:  A total of 345 patients were included in the analysis. The mean (SD) baseline 6MWD was 404.6 m (90.4). The estimated SEM for 6MWD was 37 m (95% CI, 34–40). The estimated ES was 0.32, based on a mean change of 29.2 m from baseline to Wk 48. 6MWD values were significantly different for those who experienced the composite endpoint of hospitalization or death vs. those who did not; the corresponding MCID was 21.7 m (p=0.047).  Conclusions:  Analysis of 6MWD data from a large cohort of IPF patients yielded an MCID estimate of 22–37 m. This finding is consistent with previous estimates which, taken together, provide a meaningful benchmark for assessing 6MWD in patients with IPF.
Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair
Authors: Steven Lu, Johnny Lam, Jordan E. Trachtenberg, Esther J. Lee, Hajar Seyednejad, Jeroen J.J.P. van den Beucken, Yasuhiko Tabata, Mark E. Wong, John A. Jansen, Antonios G. Mikos, F. Kurtis Kasper
Journal: Biomaterials (2014)
Subcellular electrolyte alterations during progressive hypoxia and following reoxygenation in isolated neonatal rat ventricular myocytes.
Authors: F T Thandroyen, D Bellotto, A Katayama, H K Hagler, J T Willerson, L M Buja
Journal: Circulation Research (1992)

This study characterizes the sequential alterations of, and relations between, multiple electrolytes in cytoplasm, mitochondria, and whole cells during hypoxia and on reoxygenation in isolated neonatal rat ventricular myocytes. Subcellular electrolyte content and distribution were measured by electron probe x-ray microanalysis, membrane phospholipid degradation by tritiated arachidonic acid release, and cell morphology by electron microscopy. At 1-2 hours of hypoxia, the myocyte population showed a loss of cytoplasmic potassium, magnesium, and chlorine without alteration of cytoplasmic sodium or calcium. Mitochondria showed increased potassium with unchanged magnesium content. There was no morphological evidence of cell injury or tritiated arachidonic acid release. At 3-5 hours of hypoxia, the myocyte population showed a further loss of cytoplasmic potassium and magnesium and an increase in cytoplasmic sodium, chlorine, and calcium. At a single-cell level, the increase in cytoplasmic sodium preceded the increase in cytoplasmic calcium. Mitochondria showed increased sodium and chlorine and decreased magnesium before increased calcium content; potassium loss was manifest only at 5 hours of hypoxia. At 3-5 hours of hypoxia, there was also tritiated arachidonic acid release and morphological evidence of cell injury. Reoxygenation for 1 hour after 5 hours of hypoxia partially reversed the mean alterations of all electrolytes, except calcium, in the cytoplasm of the myocyte population, whereas analysis was required at a single-cell level to show a partial reversal in calcium levels in cytoplasm of reoxygenated cells. Reoxygenation for 1 hour after 5 hours of hypoxia partially reversed the mean alterations of all electrolytes, including calcium, in the mitochondria of the myocyte population. Recovery of potassium in the cytoplasm correlated with reduction of mitochondrial calcium content on reoxygenation and best predicted recovery of cellular homeostasis of sodium, chlorine, magnesium, and calcium. This study demonstrates that in this experimental model of hypoxia 1) initial losses of cytoplasmic potassium and magnesium occur in the absence of cell injury; 2) increases of sodium, chlorine, and calcium occur in association with cell injury, with sodium increasing before calcium; 3) membrane phospholipid degradation and electrolyte derangement, including increased calcium, may contribute to reversible and irreversible phases of cell injury; 4) analysis of calcium at a subcompartmental level and at a single-cell level is required to correlate reduction of calcium on reoxygenation with recovery of cell homeostasis; 5) reduction of calcium content in mitochondria may predict recovery of cell homeostasis; and 6) recovery of potassium on reoxygenation best predicts recovery of cell membrane function and cell homeostasis.
Hunger in an Adult Patient Population
Authors: Karin Nelson
Journal: JAMA (1998)

Context.—Although clinical observations suggest that some patients experience hunger and food insecurity, there are limited data on the prevalence of hunger in adult patients.Objective.—To determine the prevalence of hunger and food insecurity in adult patients at an urban county hospital.Design.—Cross-sectional survey conducted in 1997.Patients.—The primary survey included all patients aged 18 years or older who were admitted to the medicine, surgery, and neurology services during a 2-week period, and all patients who attended the hospital's general medicine clinic during 1 week. A second survey included primary care patients who received insulin from the hospital pharmacy during a 1-month period.Main Outcome Measures.—Rates of hunger and food insecurity.Results.—Of 709 eligible patients, 567 (participation rate, 80%) were interviewed in either the clinic (n=281) or hospital (n=286). An additional 170 patients who received insulin were interviewed by telephone (response rate, 75%). Of the primary sample, 68 (12%) respondents reported not having enough food, 75 (13%) reported not eating for an entire day, and 77 (14%) reported going hungry but not eating because they could not afford food. A total of 222 (40%) had received food stamps in the previous year and of those, 113 (50%) had their food stamps reduced or eliminated. Recipients whose food stamps had been eliminated or reduced were more likely to report not having enough food (18% vs 13%,P=.006), not eating for a whole day (20% vs 16%, P=.01), going hungry but not eating (20% vs 16%, P=.08), and cutting down on the size of meals or skipping meals (33% vs 27%,P=.01). In multivariate analysis, independent predictors of hunger included an annual income of less than $10000 (odds ratio [OR], 7.55; 95% CI, 3.01-18.92), drug use (OR, 3.56; 95% CI, 1.46-8.66), and a reduction in food stamp benefits (OR, 1.73; 95% CI, 1.01-2.96). Predictors of food insecurity included an annual income of less than $10000 (OR, 4.12; 95% confidence interval [CI], 1.98-8.58), drug use (OR, 2.11; 95% CI, 1.66-5.08), and a reduction in food stamps (OR, 2.02; 95% CI, 1.23-3.32). In addition, 103 (61%) patients in the sample of diabetics reported hypoglycemic reactions; 32 (31%) of these were attributed to inability to afford food.Conclusion.—Hunger and food insecurity are common among patients seeking care at an urban county hospital.
REGIONAL PROTECTION IN CANCER CHEMOTHERAPY. I. INFUSIONS OF THYMIDINE INTO EXTERNAL CAROTID ARTERY OF PATIENTS RECEIVING SYSTEMIC 5-IODO-2′-DEOXYURIDINE*
Authors: Paul Calabresi
Journal: Journal of Clinical Investigation (1962)

The ability of an antimetabolite to interfere with the production of DNA is accompanied by mani- festations of cellular toxicity in rapidly proliferat- ing tissues.Attempts to achieve a more specific inhibition of rapidly dividing cells have focused attention on thymidine, since this pyrimidine nu- cleoside is required exclusively for the biosynthe- sis of mammalian DNA.Welch and Prusoff (1)
Simultaneous integrin αβ and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty
Authors: T SAKUMA, I SARI, C GOODMAN, J LINDNER, A KLIBANOV, S KAUL
Journal: Cardiovascular Research (2005)

We tested the hypothesis that simultaneous inhibition of the endothelial integrin alpha(v)beta(3) and the platelet glycoprotein IIb/IIIa receptor will substantially reduce infarct size in a model of acute coronary thrombosis and primary angioplasty.Dogs were subjected to thrombus formation in the left anterior descending coronary artery followed by primary angioplasty. Prior to angioplasty, they were randomized into 3 treatment groups. Group 1 (n=7) received saline; Group 2 (n=9) received MK-383 that inhibits only IIb/IIIa; and Group 3 (n=9) received CP-4715, that inhibits both IIb/IIIa and alpha(v)beta(3).There was a 59% reduction in infarct size in dogs receiving CP-4715 compared to controls (p=0.002) and a 37% reduction compared to the dogs receiving MK-383 (p=0.04). Myocardium microthrombi were seen to be reduced similarly with both drugs on post-mortem (99m)Tc-DMP444 autoradiography that reflects in vivo IIb/IIIa receptor activity. In vivo imaging using echistatin-conjugated and leukocyte-targeted microbubbles revealed significant alpha(v)beta(3) inhibition and reduction in active leukocyte recruitment only in Group 3 dogs. Myocardial blood flow and regional function after reperfusion were also significantly better in this group.Simultaneous inhibition of IIb/IIIa and alpha(v)beta(3) causes a marked reduction in infarct size in a model of acute coronary thrombosis and primary PTCA that is associated with reduced myocardial microthrombi and inflammation, as well as improved myocardial blood flow and regional function. These results may have important implications in the treatment of acute coronary syndromes.
Visualizing Tubular Lipid Peroxidation in Intact Renal Tissue in Hypertensive Rats
Authors: Sujata Bapat, Jan Andries Post, Branko Braam, Roel Goldschmeding, Hein A. Koomans, Arie J. Verkleij, Jaap A. Joles
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. An imbalance between production of reactive oxygen species (ROS) and antioxidant defense is involved in the pathogenesis of diverse chronic parenchymatous diseases. To identify the primary site of such increased oxidative stress, a lipophilic ROS-sensitive probe (C11-Bodipy 581/591) is introduced, which allows the visualization and quantification of oxidative injury using confocal fluorescence microscopy in living cells. The properties of this probe are such that its emission wavelength irreversibly shifts from red to green upon oxidation. This probe was used to identify the spatiotemporal distribution of lipid peroxidation in the rat kidney during chronic NOS inhibition, a model associated with hypertension and proteinuria. Chronic NOS inhibition resulted in increased lipid peroxidation in renal tubules but hardly any in glomeruli or blood vessels. This peroxidation preceded the loss of renal function characteristic of the model and was accompanied by parallel changes in thiobarbituric acid reactive substances in the renal cortex. Furthermore, the increase in oxidation was dependent on angiotensin II and NADPH oxidase and prevented by vitamin E. Induction of cytoprotective heat-shock protein 70 preceded lipid peroxidation, rise in BP, or proteinuria. These findings challenge the paradigm that the vascular wall is the source and target of oxidative stress in chronic parenchymatous renal disease associated with hypertension.