tbuckley/cabot-search huggingface dataset:
Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents.
Authors: Z Wang, B Fermini, S Nattel
Journal: Circulation Research (1993)

Depolarization of human atrial myocytes activates a transient outward current that rapidly inactivates, leaving a sustained outward current after continued depolarization. To evaluate the ionic mechanism underlying this sustained current (Isus), we applied whole-cell voltage-clamp techniques to single myocytes isolated from right atrial specimens obtained from patients undergoing coronary bypass surgery. The magnitude of Isus was constant for up to 10 seconds at +30 mV and was unaffected by 40 mmol/L tetraethylammonium, 100 nmol/L dendrotoxin, 1 mmol/L Ba2+, 0.1 mumol/L atropine, or removal of Cl- in the superfusate. Isus could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (Ito1) by differences in voltage-dependent inactivation (1000-millisecond prepulse to -20 mV reduced Ito1 by 91.7 +/- 0.1% [mean +/- SEM], P &lt; .001, versus 9.4 +/- 0.4% reduction of Isus) and 4AP sensitivity (IC50 for block of Ito1, 1.96 mmol/L; for Isus, 49 mumol/L). Isus activation had a voltage threshold near -30 mV, a half-activation voltage of -4.3 mV, and a slope factor of 8.0 mV. Isus was not inactivated by 1000-millisecond prepulses but was reduced by 16 +/- 8% (P &lt; .05) at a holding potential of -20 mV relative to values at a holding potential of -80 mV. Isus activated very rapidly, with time constants (tau) at 25 degrees C ranging from 18.2 +/- 1.8 to 2.1 +/- 0.2 milliseconds at -10 to +50 mV, two orders of magnitude faster than previously described kinetics of the rapid component of the delayed rectifier K+ current. At 16 degrees C, Isus activation was greatly slowed (tau at +10 mV, 46.7 +/- 4.1 milliseconds; tau at 25 degrees C, 7.1 +/- 0.8 milliseconds; P &lt; .01), and the envelope of tails test was satisfied. The reversal potential of Isus tail currents changed linearly with log [K+]o (slope, 55.3 +/- 2.9 mV per decade), and the fully activated current-voltage relation showed substantial outward rectification. Selective inhibition of Isus with 50 mumol/L 4AP increased human atrial action potential duration by 66 +/- 11% (P &lt; .01). In conclusion, Isus in human atrial myocytes is due to a very rapidly activating delayed rectifier K+ current, which shows limited slow inactivation, is insensitive to tetraethylammonium, Ba2+, and dendrotoxin, and is highly sensitive to 4AP. These properties resemble the characteristics of channels encoded by the Kv1.5 group of cardiac cDNAs and may represent a physiologically significant manifestation of such channels in human atrium.
Total and Allergen Specific IgE Antibody Levels During and After Pregnancy in Relation to Maternal Allergic Disease
Authors: M. Sandberg, A. Frykman, M. Persson, J. Ernerudh, G. Berg, L. Matthiesen, C. Ekerfelt, M.C. Jenmalm
Journal: Journal of Allergy and Clinical Immunology (2007)
Familial adult T‐cell leukemia/lymphoma
Authors: Lee Ratner, Nancy Vander Heyden, Elizabeth Paine, Debra Frei‐Lahr, Randy Brown, Paul Petruska, Satyanarayan Reddy, Michael D. Lairmore
Journal: American Journal of Hematology (1990)

Abstract Clinical and laboratory data are described for two siblings who both developed adult T‐cell leukemia/lymphoma resulting from infection by human T lymphotropic virus type I (HTLV‐I). These findings suggest that genetic factors or virus‐specific factors may determine which HTLV‐I‐infected individuals will develop leukemia.
Sorafenib for Older Patients With Renal Cell Carcinoma: Subset Analysis From a Randomized Trial
Authors: T. Eisen, S. Oudard, C. Szczylik, G. Gravis, H. Heinzer, R. Middleton, F. Cihon, S. Anderson, S. Shah, R. Bukowski, B. Escudier
Journal: JNCI Journal of the National Cancer Institute (2008)

The perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy. It is not known how older patients respond to targeted therapy. This retrospective subgroup analysis of data from the phase 3, randomized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older (age ≥70 years, n = 115) and younger patients (age <70 years, n = 787) who received treatment for advanced renal cell carcinoma. Patient demographics and progression-free survival were recorded. Best tumor response, clinical benefit rate (defined as complete response plus partial response plus stable disease), time to self-reported health status deterioration, and toxic effects were assessed by descriptive statistics. Health-related quality of life was assessed with a Cox proportional hazards model. Kaplan–Meier analyses were used to summarize time-to-event data. Median progression-free survival was similar in sorafenib-treated younger patients (23.9 weeks; hazard ratio [HR] for progression compared with placebo = 0.55, 95% confidence interval [CI] = 0.47 to 0.66) and older patients (26.3 weeks; HR = 0.43, 95% CI = 0.26 to 0.69). Clinical benefit rates among younger and older sorafenib-treated patients were also similar (83.5% and 84.3%, respectively) and were superior to those of younger and older placebo-treated patients (53.8% and 62.2%, respectively). Adverse events were predictable and manageable regardless of age. Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients (121 days with sorafenib vs 85 days with placebo; HR = 0.66, 95% CI = 0.43 to 1.03) and younger patients (90 days with sorafenib vs 52 days with placebo; HR = 0.69, 95% CI = 0.59 to 0.81) and improved quality of life over that time. Among patients with advanced renal cell carcinoma receiving sorafenib treatment, outcomes of older (≥70 years) and younger (<70 years) patients were similar.
The Shadow of Hiroshima: Two Diaries
Authors: M. Therese Southgate
Journal: JAMA (1984)

Although no longer recent, two little books, slim enough to be slipped into a pocket, deserve to be read—or reread, as the case may be—by all physicians. Both are diaries, both are written by physicians, and both concern Hiroshima in 1945. Both are timeless. The first,<i>Hiroshima Diary</i>,<sup>1</sup>covers two months in the life of Michihiko Hachiya, MD, from Aug 6, 1945, to Sept 30, 1945. The second,<i>Encounter With Disaster</i>,<sup>2</sup>picks up a little before the first ends and covers just under three months in the life of Averill Liebow, MD, from Sept 18, 1945, to Dec 10, 1945. At the time the accounts were written, Dr Hachiya was a civilian physician in charge of the Hiroshima Communications Hospital, a 125-bed hospital with a large outpatient population, which served workers in the postal, telegraph, and telephone services. Dr Liebow was a lieutenant colonel in the US Army
Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor δ from Peroxisome proliferator-activated receptor γ in the ob/ob mouse
Authors: Lee D Roberts, David G Hassall, Deborah A Winegar, John N Haselden, Andrew W Nicholls, Julian L Griffin
Journal: Genome Medicine (2009)

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPAR family consists of three members: PPARα, PPARγ, and PPARδ. PPARδ controls the transcription of genes involved in multiple physiological pathways, including cellular differentiation, lipid metabolism and energy homeostasis. The receptor is expressed almost ubiquitously, with high expression in liver and skeletal muscle. Although the physiological ligands of PPARδ remain undefined, a number of high affinity synthetic ligands have been developed for the receptor as a therapeutic target for type 2 diabetes mellitus, dyslipidemia and the metabolic syndrome. In this study, the metabolic role of PPARδ activation has been investigated in liver, skeletal muscle, blood serum and white adipose tissue from ob/ob mice using a high affinity synthetic ligand and contrasted with PPARγ activation. To maximize the analytical coverage of the metabolome, 1H-nuclear magnetic resonance (1H-NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS) were used to examine metabolites from tissue extracts. Analysis by multivariate statistics demonstrated that PPARδ activation profoundly affected glycolysis, gluconeogenesis, the TCA cycle and linoleic acid and α-linolenic acid essential fatty acid pathways. Although activation of both PPARδ and PPARγ lead to increased insulin sensitivity and glucose tolerance, PPARδ activation was functionally distinct from PPARγ activation, and was characterized by increased hepatic and peripheral fatty acid oxidative metabolism, demonstrating the distinctive catabolic role of this receptor compared with PPARγ.
The activin A antagonist follistatin inhibits asthmatic airway remodelling
Authors: Charles Linton Hardy, Hong-An Nguyen, Rohimah Mohamud, John Yao, Ding Yuan Oh, Magdalena Plebanski, Kate L Loveland, Craig A Harrison, Jennifer M Rolland, Robyn E O'Hehir
Journal: Thorax (2012)

<h3>Background</h3> Current pharmacotherapy is highly effective in the clinical management of the majority of patients with stable asthma, however severe asthma remains inadequately treated. Prevention of airway remodelling is a major unmet clinical need in the management of patients with chronic severe asthma and other inflammatory lung diseases. Accumulating evidence convincingly demonstrates that activin A, a member of the transforming growth factor (TGF)-β superfamily, is a key driver of airway inflammation, but its role in chronic asthmatic airway remodelling is ill-defined. Follistatin, an endogenously produced protein, binds activin A with high affinity and inhibits its bioactivity. The aim of this study was to test the potential of follistatin as a therapeutic agent to inhibit airway remodelling in an experimental model of chronic allergic airway inflammation. <h3>Methods</h3> BALB/c mice were systemically sensitised with ovalbumin (OVA), and challenged with OVA intranasally three times a week for 10 weeks. Follistatin was instilled intranasally during allergen challenge. <h3>Results</h3> Chronic allergen challenge induced mucus hypersecretion and subepithelial collagen deposition which persisted after cessation of challenge. Intranasal follistatin (0.05, 0.5, 5 µg) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-β1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-β1 and activin RIB immunostaining in airway epithelium which occurred following chronic allergen challenge. <h3>Conclusions</h3> These data demonstrate that follistatin attenuates asthmatic airway remodelling. Our findings point to the potential of follistatin as a therapeutic for prevention of airway remodelling in asthma and other inflammatory lung diseases.
The State of Federal Health Statistics on Racial and Ethnic Groups
Authors: Robert A. Hahn
Journal: JAMA (1992)

To examine assumptions underlying federal health statistics on racial and ethnic groups in the United States.Studies conducted by federal agencies and other investigators, and technical appendices of published vital statistics and census reports.Several assumptions underlying federal health statistics on racial and ethnic groups are not well supported. Conceptual (as opposed to operational) definitions of race and ethnicity are not available, and scientific grounds for definition are not considered. Procedures for the ascertainment of race and ethnicity vary within and among data-collection agencies. Miscounting and misclassification may vary by an order of magnitude between whites and other races. The responses of individuals to questions of racial and ethnic identity differ for different indicators, in different surveys, and at different times. As a result, counts, rates, and rate ratios may not be meaningful or accurate. Particularly for Hispanics and for races other than whites or blacks, there are inconsistencies in statistical information that may hinder health research and program development.Improvement of federal health statistics for racial and ethnic groups requires (1) clarification of goals for classification, (2) adoption of scientific principles for the validation and definition of the categories "race" and "ethnicity," (3) assessment of perceived social identity in the population, and (4) periodic evaluation.
A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells
Authors: Xinlai Cheng, Palvo Holenya, Suzan Can, Hamed Alborzinia, Riccardo Rubbiani, Ingo Ott, Stefan Wölfl
Journal: Molecular Cancer (2014)

Cancer cells in the advanced stage show aberrant antioxidant capacity to detoxify excessive ROS resulting in the compensation for intrinsic oxidative stress and therapeutic resistance. PDAC is one of the most lethal cancers and often associated with a high accumulation of ROS. Recent studies identified gold(I) NHC complexes as potent TrxR inhibitors suppressing cell growth in a wide spectrum of human malignant cell lines at the low micromolar concentration. However, the mechanism of action is not completely elucidated yet.To understand the biological function of gold(I) NHC complexes in PDAC, we used a recently published gold(I) NHC complex, MC3, and evaluated its anti-proliferative effect in four PDAC cell lines, determined by MTT and SRB assays. In further detailed analysis, we analyzed cellular ROS levels using the ROS indicator DHE and mitochondrial membrane potential indicated by the dye JC-1 in Panc1. We also analyzed cell cycle arrest and apoptosis by FACS. To elucidate the role of specific cell signaling pathways in MC3-induced cell death, co-incubation with ROS scavengers, a p38-MAPK inhibitor and siRNA mediated depletion of ASK1 were performed, and results were analyzed by immunoblotting, ELISA-microarrays, qRT-PCR and immunoprecipitation.Our data demonstrate that MC3 efficiently suppressed cell growth, and induced cell cycle arrest and apoptosis in pancreatic cancer cells, in particular in the gemcitabine-resistant cancer cells Panc1 and ASPC1. Treatment with MC3 resulted in a substantial alteration of the cellular redox homeostasis leading to increased ROS levels and a decrease in the mitochondrial membrane potential. ROS scavengers suppressed ROS formation and rescued cells from damage. On the molecular level, MC3 blocked the interaction of Trx with ASK1 and subsequently activated p38-associated signaling. Furthermore, inhibition of this pathway by using ASK1 siRNA or a p38 inhibitor clearly attenuated the effect of MC3 on cell proliferation in Panc1 and ASPC1.Our results confirm that MC3 is a TrxR inhibitor and show MC3 induced apoptosis in gemcitabine-resistant PDACs. MC3 mediated cell death could be blocked by using anti-oxidants, ASK1 siRNA or p38 inhibitor suggesting that the Trx-ASK1-p38 signal cascade played an important role in gold(I) NHC complexes-mediated cellular damage.
Osteoarthritis: New Insights. Part 2: Treatment Approaches
Authors: David T. Felson
Journal: Annals of Internal Medicine (2000)

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, estrogen use, and bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. These risk factors are particularly important in the weight-bearing joints, and modifying them may help prevent osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 2 of a two-part summary of a National Institutes of Health conference that brought together experts in osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 2 focuses on treatment approaches; evidence for the efficacy of commonly used oral therapies is reviewed and information on alternative therapies, including nutriceuticals and acupuncture, is presented. Biomechanical interventions, such as exercise and bracing, and behavioral interventions directed toward enhancing self-management are reviewed. Current surgical approaches are described and probable future biotechnology-oriented approaches to treatment are suggested.
Sagittal Abdominal Diameter as a New Predictor for Incident Diabetes
Authors: Pia Pajunen, Harri Rissanen, Maarit A. Laaksonen, Markku Heliövaara, Antti Reunanen, Paul Knekt
Journal: Diabetes Care (2012)

OBJECTIVE Obesity, particularly visceral adiposity, is a major risk factor for type 2 diabetes. The commonly used obesity indicators, BMI, waist girth, and waist-to-hip ratio (WHR), have limited ability to measure the visceral adipose tissue. Sagittal abdominal diameter (SAD) has been shown to predict the amount of visceral fat. So far no study has been published on its ability to predict diabetes occurrence. RESEARCH DESIGN AND METHODS We assessed and compared the prediction of the four obesity indicators for diabetes incidence in a prospective study based on 5,168 participants from the nationally representative Health 2000 study. RESULTS During a mean follow-up lasting 8.1 years, 222 incident diabetes cases occurred. In multivariate models adjusted for lifestyle factors, BMI, waist girth, WHR, and SAD were significant predictors of diabetes incidence. The relative risks (95% CI) between high and low levels were 15.0 (6.94–32.6), 11.4 (5.39–23.8), 12.5 (6.47–24.2), and 14.7 (6.89–31.2), respectively. Pairwise interaction analysis showed that the co-occurrence of high BMI and high SAD was associated with the highest diabetes incidence, with a relative risk of 37.0 (11.2–122). After adjustment for waist girth and the components of the metabolic syndrome, the relative risk was 9.88 (2.81–34.7). The corresponding population-attributable fraction estimate was 84% (49–95). CONCLUSIONS The combination of SAD and BMI measurements yields a new predictor of diabetes incidence.
A Preventive Intervention for Pregnant Women on Public Assistance at Risk for Postpartum Depression
Authors: Caron Zlotnick, Ivan W. Miller, Teri Pearlstein, Margaret Howard, Patrick Sweeney
Journal: American Journal of Psychiatry (2006)

Objective: Promising results were obtained in an earlier pilot study of a preventive intervention based on the principles of interpersonal psychotherapy to reduce the risk of postpartum major depressive disorder. In this study, the authors examined whether the intervention would reduce the risk of postpartum major depressive disorder in a larger sample of pregnant women. Method: Ninety-nine pregnant women on public assistance who were assessed to be at risk for postpartum depression were randomly assigned to receive standard antenatal care plus the intervention or standard antenatal care only. Diagnostic interviews were administered 3 months after delivery to assess for major depressive disorder. Results: Within 3 months after delivery, eight (20%) of the women in the standard antenatal care condition had developed postpartum major depressive disorder, compared with two (4%) in the intervention condition. Conclusions: This study provides further evidence for the efficacy of a brief intervention to reduce the occurrence of major depressive disorder among financially disadvantaged women during a postpartum period of 3 months.
Is the Mayo model for predicting survival useful after the introduction of ursodeoxycholic acid treatment for primary biliary cirrhosis?
Authors: M R Kilmurry, E J Heathcote, K Cauch-Dudek, K O’Rourke, R J Bailey, L M Blendis, C N Ghent, G Y Minuk, S C Pappas, L J Scully, U P Steinbrecher, L R Sutherland, C N Williams, L J Worobetz
Journal: Hepatology (1996)

Treatment of patients with primary biliary cirrhosis (PBC) using ursodeoxycholic acid (UDCA) leads to a reduction in serum bilirubin. The first objective of this study was to assess the performance of certain prognostic indicators for PBC after the introduction of treatment with UDCA. Serum bilirubin is an important prognostic indicator for PBC and an important component of the Mayo model for grading patients into risk categories. In an analysis of patients enrolled in the Canadian multicenter trial, the Mayo score was calculated before and after treatment with UDCA. After treatment, the Mayo score continued to divide patients with PBC into groups with varying risk. In addition, the serum bilirubin alone was shown to do the same even after the introduction of treatment with UDCA. A second objective was to establish whether UDCA had an effect on long-term (2- to 6-year) survival in patients with PBC.
Growth factors and apoptosis in neonatal ureteral obstruction.
Authors: R L Chevalier
Journal: Journal of the American Society of Nephrology (1996)

Renal insufficiency as a result of congenital obstructive nephropathy is a consequence of impaired renal growth: chronic unilateral ureteral obstruction (UUO) results in greater injury to the immature kidney than to the adult kidney. The neonatal kidney responds to UUO by marked activation of the renin-angiotensin system, which contributes to severe vasoconstriction and progressive interstitial fibrosis of the obstructed kidney. The latter results in part because of activation of transforming growth factor-beta 1 by angiotensin II. Chronic UUO in the neonatal rat delays maturation of the obstructed kidney, possibly in part through suppressed expression of epidermal growth factor. In addition to affecting growth factors, UUO stimulates apoptosis in the obstructed kidney, which is quantitatively greater in the neonate than in the adult. In contrast, expression of clusterin, a glycoprotein that may play a protective role in the response to UUO, is greater in the adult than in the neonatal obstructed kidney. The response of the developing kidney to UUO is similar in a number of respects to cystic kidney disease. This includes a reduction in epidermal growth factor, and increased apoptosis that may result from suppression of bcl-2, an oncoprotein that inhibits apoptosis. Improved knowledge of the cellular and molecular basis for cystic renal disorders should lead to specific intervention in fetuses and infants with congenital obstructive nephropathy, thereby improving renal growth and development.