tbuckley/cabot-search huggingface dataset:
Effect of Cardiac Resynchronization Therapy on Reverse Remodeling and Relation to Outcome
Authors: Scott D. Solomon, Elyse Foster, Mikhail Bourgoun, Amil Shah, Esperanza Viloria, Mary W. Brown, W. Jackson Hall, Marc A. Pfeffer, Arthur J. Moss
Journal: Circulation (2010)

Background— Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function. Methods and Results— A total of 1820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (−26.2 versus −7.4 mL/m 2 ), left ventricular end-systolic volume index (−28.7 versus −9.1 mL/m 2 ), left ventricular ejection fraction (11% versus 3%), left atrial volume index (−11.9 versus −4.7 mL/m 2 ), and right ventricular fractional area change (8% versus 5%; P &lt;0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk ( P &lt;0.001). Conclusions— CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
Theoretical Impact of the Injection of Material Into the Myocardium
Authors: Samuel T. Wall, Joseph C. Walker, Kevin E. Healy, Mark B. Ratcliffe, Julius M. Guccione
Journal: Circulation (2006)

Background— To treat cardiac injuries created by myocardial infarcts, current approaches seek to add cells and/or synthetic extracellular matrices to the damaged ventricle to restore function. Because definitive myocardial regeneration remains undemonstrated, we propose that cardiac changes observed from implanted materials may result from altered mechanisms of the ventricle. Methods and Results— We exploited a validated finite element model of an ovine left ventricle with an anteroapical infarct to examine the short-term effect of injecting material to the left ventricular wall. The model’s mesh and regional material properties were modified to simulate expected changes. Three sets of simulations were run: (1) single injection to the anterior border zone; (2) therapeutic multiple border zone injections; and (3) injection of material to the infarct region. Results indicate that additions to the border zone decrease end-systolic fiber stress proportionally to the fractional volume added, with stiffer materials improving this attenuation. As a potential therapy, small changes in wall volume (≈4.5%) reduce elevated border zone fiber stresses from mean end-systole levels of 28.2 kPa (control) to 23.3 kPa (treatment), similar to levels of 22.5 kPA computed in remote regions. In the infarct, injection improves ejection fraction and the stroke volume/end-diastolic volume relationship but has no effect on the stroke volume/end-diastolic pressure relationship. Conclusions— Simulations indicate that the addition of noncontractile material to a damaged left ventricular wall has important effects on cardiac mechanics, with potentially beneficial reduction of elevated myofiber stresses, as well as confounding changes to clinical left ventricular metrics.
TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis
Authors: Ning Lu, Yi-Hong Wang, Yui-Hsi Wang, Kazuhiko Arima, Shino Hanabuchi, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2009)

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.
Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase
Authors: Tony C. Lee, Yidan D. Zhao, David W. Courtman, Duncan J. Stewart
Journal: Circulation (2000)

Background —Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS. Methods and Results —We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo. Conclusions —These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality.
Hemodynamic study during transdermal application of nitroglycerin tape in patients with cirrhosis
Authors: Tadashi Iwao, Atsushi Toyonaga, Michihiro Sumino, Kohsuke Takagi, Kazunori Ohkubo, Rintaroh Inoue, Kyuichi Tanikawa
Journal: Hepatology (1991)

We studied 14 patients with portal hypertension and cirrhosis using portal and hepatic vein catheterizations to determine the effects of transdermal application of nitroglycerin tape (containing 10 mg of nitroglycerin and capable of releasing 6 to 7 mg of nitroglycerin in 12 hr) on splanchnic hemodynamics. Patients randomly received nitroglycerin (n = 7) or a placebo (n = 7). No significant changes were observed after the administration of the placebo. In contrast, transdermal nitroglycerin caused a significant reduction in portal pressure, as evaluated by measurements of the portal venous pressure gradient (-22%, p less than 0.01). The reduction of portal pressure was due to a decrease in the portal venous pressure, with no changes in the free hepatic venous pressure. Despite the fall in portal pressure, the hepatic blood flow was maintained. These findings suggest that transdermal nitroglycerin could be potentially useful in the treatment of portal hypertension associated with cirrhosis.
Mouse Models of <i>Kras</i>-Mutant Colorectal Cancer: Valuable GEMMs for Drug Testing?
Authors: Federica Di Nicolantonio, Alberto Bardelli
Journal: Clinical Cancer Research (2013)

Abstract The development of effective therapies for colorectal cancer depends on the ability of preclinical models to faithfully recapitulate the molecular and biologic behavior of human tumors. This study reports on the characterization of colorectal genetically engineered mouse models and their derivative cell lines carrying wild-type or oncogenic Kras with concomitant Apc and p53 loss. Clin Cancer Res; 19(11); 2794–6. ©2013 AACR.
Thioredoxin is Positively Associated with Eosinophils in Induced Sputum from Patients with Asthma
Authors: J.M. Hartman, A. Hastie, W.C. Moore, B. Rector, S.P. Peters, E.R. Bleecker, M.S. Dykewicz
Journal: Journal of Allergy and Clinical Immunology (2012)
Results of Two Open-Label, Multicenter Phase II Studies of Docetaxel, Platinum Salts, and Trastuzumab in HER2-Positive Advanced Breast Cancer
Authors: M. D. Pegram, T. Pienkowski, D. W. Northfelt, W. Eiermann, R. Patel, P. Fumoleau, E. Quan, J. Crown, D. Toppmeyer, M. Smylie, A. Riva, S. Blitz, M. F. Press, D. Reese, M.-A. Lindsay, D. J. Slamon
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Preclinical data indicate that docetaxel, platinum salts, and the combination of both drugs are highly synergistic with the anti-HER2 antibody trastuzumab. The University of California at Los Angeles-Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG) have conducted two phase II studies to evaluate docetaxel and trastuzumab in combination with either cisplatin or carboplatin for the treatment of women with advanced breast cancer that overexpresses HER2. Methods: Each study enrolled 62 patients with HER2-overexpressing tumors. Patients received a median of six cycles of docetaxel at 75 mg/m2 of body surface area and cisplatin (BCIRG 101 study) at 75 mg/m2 or carboplatin (UCLA-ORN study) at AUC = 6 mg/mL · min given on day 1 and then every 21 days. Trastuzumab was given on day 1, cycle 1 (4 mg/kg) and then continued weekly at 2 mg/kg for 1 year or until disease progression. Tumor measurements were obtained at baseline, after three cycles of chemotherapy, and then every 3 months. HER2 gene amplification was determined by fluorescence in situ hybridization. Results: Patient characteristics were comparable between trials with the exception that 15% of the patients in the UCLA-ORN study had received previous adjuvant taxane therapy. Both regimens were well tolerated, with manageable toxicities. Hematologic toxicities were more frequent in patients in the UCLA-ORN study than in patients in the BCIRG 101 study, whereas the reverse pattern was observed for non-hematologic toxicities. One patient in each study developed reversible congestive heart failure. Responses were observed in 49 of 62 patients in the BCIRG 101 study (overall response rate = 79%, 95% confidence interval [CI] = 66% to 89%) and in 34 of 59 evaluable patients in the UCLA-ORN study (overall response rate = 58%, 95% CI = 44% to 70%). Median times to progression were 9.9 months (95% CI = 8.3 to 13.1 months) and 12.7 months (95% CI = 8.6 to 15.5 months) for patients in the BCIRG 101 and UCLA-ORN studies, respectively. Overall response rates were higher and median time to progression was longer in the subset of patients whose tumors harbored HER2 gene amplification. Conclusion: Combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2. The BCIRG is conducting ongoing randomized studies of the three-drug combination in both the metastatic and adjuvant settings.
The New Case for Exercise
Authors: Henry E. Robson
Journal: British Journal of Sports Medicine (1988)

Williams et al (1987) have demonstrated that maximal motor unit activation, defined as the integral of the electromyogram during maximal contraction, was not significantly increased by caffeine ingestion.Thus it appears that caffeine ingestion resulted in plasma concentrations which were too low to elicit effects on performance and/or that any caffeine-induced effects were masked by the response to the exercise bout.In summary, these results that acute caffeine ingestion does not appear to increase one's maximal ability to generate power during short-term cycling exercise.Further, caffeine does not alter the rate or magnitude of fatigue during high intensity, dynamic exercise.
Are common, harmful, heritable mental disorders common relative to other such non-mental disorders, and does their frequency require a special explanation?
Authors: Oliver Mayo, Carolyn Leach
Journal: Behavioral and Brain Sciences (2006)

Keller &amp; Miller's (K&amp;M's) conclusion appears to be correct; namely, that common, harmful, heritable mental disorders are largely maintained at present frequencies by mutation-selection balance at many different loci. However, their “paradox” is questionable.
The Scientific Basis for the Current Treatment of Parkinson's Disease
Authors: C. Warren Olanow
Journal: Annual Review of Medicine (2004)

Parkinson's disease (PD) is an age-related neurodegenerative disease that affects approximately one million people in the United States. The introduction of levodopa revolutionized the treatment for this disorder, but the long-term utility of the drug is limited by motor complications, the development of features such as postural instability and dementia that do not respond to treatment, and continued disease progression. Insights into the organization of the basal ganglia in the normal and PD conditions has permitted the design of new treatment strategies that reduce the risk of developing motor complications. Additionally, increased knowledge of the mechanisms responsible for cell death in PD has permitted the development of putative neuroprotective drugs that might slow or stop disease progression. No drug has yet been established to alter the rate of disease progression, but the rapid pace of research offers reason for optimism.
Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan
Authors: Haruhiko Yoshida, Yasushi Shiratori, Mitsuhiko Moriyama, Yasuyuki Arakawa, Tatsuya Ide, Michio Sata, Osami Inoue, Michitami Yano, Motohiko Tanaka, Shigetoshi Fujiyama, Shuhei Nishiguchi, Tetsuo Kuroki, Fumio Imazeki, Osamu Yokosuka, Shingo Kinoyama, Gotaro Yamada, Masao Omata
Journal: Annals of Internal Medicine (1999)

Background: Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma. Objective: To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis. Design: Retrospective cohort study. Setting: Seven university hospitals and one regional core hospital in Japan. Patients: 2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490were untreated. Measurements: The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional-hazards regression. Results: Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis(P = 0.0128) and for those with stage F3 fibrosis(P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% CI, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [CI, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [CI, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [CI, 0.206 to 0.622]). Conclusions: Interferon therapy significantly reduces the risk for hepatocellular carcinoma, especially among virologic or biochemical responders.
The Electrophysiological Properties of Diphenylhydantoin Sodium as Compared to Procaine Amide in the Normal and Digitalis-Intoxicated Heart
Authors: RICHARD H. HELFANT, BENJAMIN J. SCHERLAG, ANTHONY N. DAMATO
Journal: Circulation (1967)

The effects of diphenylhydantoin sodium (Dilantin) on ventricular automaticity, intraventricular conduction, atrioventricular (A-V) conduction, and sinus rate have been determined in the digitalis-intoxicated and normal heart. These effects have been compared with procaine amide. Diphenylhydantoin sodium depresses ventricular automaticity and enhances A-V conduction while having little or no effect on intraventricular conduction or sinus rate. Procaine amide differed from diphenylhydantoin sodium in that it caused depression of both A-V and the intraventricular conduction, as well as slowing of the sinus rate. The results indicate that the electrophysiological properties of diphenylhydantoin sodium make it superior to procaine amide in the treatment of digitalis toxicity. Both diphenylhydantoin sodium and procaine amide can suppress digitalis arrhythmias due to enhanced automaticity, but procaine amide may promote "re-entry" arrhythmias by potentiating the intraventricular conduction defect caused by the glycoside. In addition, diphenylhydantoin sodium appears to antagonize the action of digitalis on the A-V node, while procaine amide increases the digitalis-induced A-V block. It is concluded that the electrophysiological properties of diphenylhydantoin sodium make it an excellent agent in treating digitalis-induced arrhythmias.
Regulated Expression of Human Histocompatibility Leukocyte Antigen (HLA)-DO During Antigen-dependent and Antigen-independent Phases of B Cell Development
Authors: Xinjian Chen, Oskar Laur, Taku Kambayashi, Shiyong Li, Robert A. Bray, Dominique A. Weber, Lars Karlsson, Peter E. Jensen
Journal: The Journal of Experimental Medicine (2002)

Human histocompatibility leukocyte antigen (HLA)-DO, a lysosomal resident major histocompatibility complex class II molecule expressed in B cells, has previously been shown to be a negative regulator of HLA-DM peptide loading function. We analyze the expression of DO in human peripheral blood, lymph node, tonsil, and bone marrow to determine if DO expression is modulated in the physiological setting. B cells, but not monocytes or monocyte-derived dendritic cells, are observed to express this protein. Preclearing experiments demonstrate that ∼50% of HLA-DM is bound to DO in peripheral blood B cells. HLA-DM and HLA-DR expression is demonstrated early in B cell development, beginning at the pro-B stage in adult human bone marrow. In contrast, DO expression is initiated only after B cell development is complete. In all situations, there is a striking correlation between intracellular DO expression and cell surface class II–associated invariant chain peptide expression, which suggests that DO substantially inhibits DM function in primary human B cells. We report that the expression of DO is markedly downmodulated in human germinal center B cells. Modulation of DO expression may provide a mechanism to regulate peptide loading activity and antigen presentation by B cells during the development of humoral immune responses.
STDs: To Clap, Add Leak, Coolant, and Bore
Authors: Rose Jones
Journal: JAMA (1992)

<h3>To the Editor.</h3> —Fleisher et al<sup>1</sup>recently pointed out that a generic question inadequately assesses a prior history of STDs because people may not recognize that a specific disease is sexually transmitted. The communication issue they identify may be more complex in specific cultures or subcultures. People may apply alternative, ethnomedical labels to diseases they don't recognize as sexually transmitted but which biomedicine does. They also may apply ethnomedical labels to STDs without recognizing equivalence between ethnomedical and biomedical labels. For example, research undertaken during 1989 through 1991 revealed that people on the West Indian islands of Barbados and St Lucia use a variety of labels for illnesses that biomedical practice recognizes as STDs. Some are identical to biomedical labels, like syphilis, herpes, gonorrhea, and chlamydia. Other labels, like "clap," "leak," "coolant," and "bore," apply to symptoms commonly produced by STDs. Some people comment that labels like clap
Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse
Authors: David Morgan, Lee Turnpenny, Judith Goodship, Weilie Dai, Kumud Majumder, Lucy Matthews, Alison Gardner, Gaby Schuster, Long Vien, Wilbur Harrison, Frederick F.B. Elder, Miranda Penman-Splitt, Paul Overbeek, Tom Strachan
Journal: Nature Genetics (1998)
Ischemic Stroke Activates Hematopoietic Bone Marrow Stem Cells
Authors: Gabriel Courties, Fanny Herisson, Hendrik B. Sager, Timo Heidt, Yuxiang Ye, Ying Wei, Yuan Sun, Nicolas Severe, Partha Dutta, Jennifer Scharff, David T. Scadden, Ralph Weissleder, Filip K. Swirski, Michael A. Moskowitz, Matthias Nahrendorf
Journal: Circulation Research (2014)

Rationale: The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. Objective: To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. Methods and Results: Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke ( P &lt;0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO ( P &lt;0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system’s myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 ( P &lt;0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose ( P &lt;0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the β 3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P =0.51). Conclusions: Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C high monocytes and neutrophils.