tbuckley/cabot-search huggingface dataset:
OBSERVATIONS ON A CASE OF CYCLIC ALBUMINURIA
Authors: Lafayette B. Mendel, Donald B. Hooker
Journal: The Journal of Experimental Medicine (1901)

The preceding observations record a new instance of the occurrence of cyclic albuminuria in an otherwise apparently healthy young man. The typical course of the proteid excretion from hour to hour under various conditions has been reviewed and its independence of the changes in diet or muscular work pointed out. No relationship between the volume of urine eliminated and the quantity of proteid excreted has been ascertained. The specific effect of the horizontal posture in dispelling the albuminuria is the most interesting feature observed. The attempt to refer this to attendant circulatory changes in the kidneys is, for the present, no more than an interesting speculation. See PDF for Structure See PDF for Structure.
Calcineurin Plays a Critical Role in the Development of Pressure Overload–Induced Cardiac Hypertrophy
Authors: Yunzeng Zou, Yukio Hiroi, Hiroki Uozumi, Eiki Takimoto, Haruhiro Toko, Weidong Zhu, Sumiyo Kudoh, Miho Mizukami, Masaki Shimoyama, Futoshi Shibasaki, Ryozo Nagai, Yoshio Yazaki, Issei Komuro
Journal: Circulation (2001)

Background —Although activation of the Ca 2+ -dependent phosphatase calcineurin has been reported to induce cardiomyocyte hypertrophy, whether calcineurin is involved in pressure overload–induced cardiac hypertrophy remains controversial. Methods and Results —We examined in the present study the role of calcineurin in pressure overload–induced cardiac hypertrophy using transgenic mice that overexpress the dominant negative mutant of calcineurin specifically in the heart. There were no significant differences in body weight, blood pressure, heart rate, heart weight, and the cardiac calcineurin activity between the transgenic mice and their littermate wild-type mice at basal state. The activity of calcineurin was markedly increased by pressure overload produced by constriction of the abdominal aorta in the heart of wild-type mice but less increased in the heart of the transgenic mice. Pressure overload induced increases in heart weight, wall thickness of the left ventricle, and diameter of cardiomyocytes; reprogramming of expressions of immediate early response genes and fetal-type genes; activation of extracellular signal–regulated protein kinases; and fibrosis. All these hypertrophic responses were more prominent in the wild-type mice than in the transgenic mice. Conclusions —These results suggest that calcineurin plays a critical role in the development of pressure overload–induced cardiac hypertrophy.
Hyper-IgM syndrome type 4 with a B lymphocyte–intrinsic selective deficiency in Ig class-switch recombination
Authors: Kohsuke Imai, Nadia Catalan, Alessandro Plebani, László Maródi, Özden Sanal, Satoru Kumaki, Vasantha Nagendran, Philip Wood, Catherine Glastre, Françoise Sarrot-Reynauld, Olivier Hermine, Monique Forveille, Patrick Revy, Alain Fischer, Anne Durandy
Journal: Journal of Clinical Investigation (2003)

Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome - which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 - do not account for all cases. We investigated the clinical and immunological characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2, these patients exhibited a slightly milder HIGM syndrome with residual IgG production. We found that B cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this new HIGM entity (HIGM4) occurs downstream of the AID activity, as the AID gene was induced normally and AID-induced DNA double-strand breaks in the switch micro region of the Ig heavy chain locus were detected during CSR as normal. Thus, HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells.
Development of mock circulation models for the assessment of counterpulsation systems
Authors: C. T Bowles, S. S Shah, K. Nishimura, C. Clark, D. V E Cumming, C. W Pattison, J. R Pepper, M. H Yacoub
Journal: Cardiovascular Research (1991)

Journal Article Development of mock circulation models for the assessment of counterpulsation systems Get access Christopher T Bowles, Christopher T Bowles Correspondence to: C Bowles Search for other works by this author on: Oxford Academic PubMed Google Scholar Samir S Shah, Samir S Shah Search for other works by this author on: Oxford Academic PubMed Google Scholar Kazunobu Nishimura, Kazunobu Nishimura Search for other works by this author on: Oxford Academic PubMed Google Scholar Colin Clark, Colin Clark Search for other works by this author on: Oxford Academic PubMed Google Scholar Deborah V E Cumming, Deborah V E Cumming Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles W Pattison, Charles W Pattison Search for other works by this author on: Oxford Academic PubMed Google Scholar John R Pepper, John R Pepper Search for other works by this author on: Oxford Academic PubMed Google Scholar Magdi H Yacoub Magdi H Yacoub Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 25, Issue 11, November 1991, Pages 901–908, https://doi.org/10.1093/cvr/25.11.901 Published: 01 November 1991 Article history Received: 10 April 1991 Accepted: 16 July 1991 Published: 01 November 1991
Geographic Variation in the Treatment of Acute Myocardial Infarction
Authors: Gerald T. O'Connor, Hebe B. Quinton, Neal D. Traven, Lawrence D. Ramunno, T. Andrew Dodds, Thomas A. Marciniak, John E. Wennberg
Journal: JAMA (1999)

Quality indicators for the treatment of acute myocardial infarction include pharmacologic therapy, reperfusion, and smoking cessation advice, but these therapies may not be administered to all patients who could benefit from them.To assess geographic variation in adherence to quality indicators for treatment of acute myocardial infarction.Inception cohort using data from the Health Care Financing Administration Cooperative Cardiovascular Project.Acute care hospitals in the United States.A total of 186800 Medicare beneficiaries hospitalized for treatment of confirmed acute myocardial infarction from February 1994 through July 1995.Adherence to quality indicators for pharmacologic therapy, reperfusion, and smoking cessation advice for patients judged to be ideal candidates for these therapies. The mean rates of adherence to these quality indicators for the entire United States were determined, and the 20th and 80th percentiles of the age- and sex-adjusted rates for each of 306 hospital referral regions were contrasted (mean rate [20th-80th percentiles]).Aspirin was used frequently both during hospitalization (86.2% [82.6%-90.1%]) and at discharge (77.8% [72.5% -83.9%]). Calcium channel blockers were withheld from most patients with impaired left ventricular function (81.9% [73.6%-90.8%]). Lower rates were seen in the use of angiotensin-converting enzyme inhibitors at discharge (59.3% [49.2%-69.2%]); reperfusion, using thrombolytic therapy or coronary angioplasty (67.2% [59.8%-75.1%]); prescription of beta-blockers at discharge (49.5% [35.8%-61.5%]); and for smoking cessation advice (41.9% [32.8%-51.3%]).Substantial geographic variation exists in the treatment of patients with acute myocardial infarction, and these gaps between knowledge and practice have important consequences. Therapies with proven benefit for AMI are underused despite strong evidence that their use will result in better patient outcomes.
T cell responses in calcineurin A alpha-deficient mice.
Authors: B W Zhang, G Zimmer, J Chen, D Ladd, E Li, F W Alt, G Wiederrecht, J Cryan, E A O'Neill, C E Seidman, A K Abbas, J G Seidman
Journal: The Journal of Experimental Medicine (1996)

We have created embryonic stem (ES) cells and mice lacking the predominant isoform (alpha) of the calcineurin A subunit (CNA alpha) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNA alpha -/- mice. CNA alpha -/- T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3 epsilon antibody). However, CNA alpha -/- mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNA alpha -/- ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNA alpha is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNA alpha -/- T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA beta or another CNA-like molecule can mediate the action of these immunosuppressive drugs. CNA alpha -/- mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.
Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002
Authors: Robert G. Maki, J. Kyle Wathen, Shreyaskumar R. Patel, Dennis A. Priebat, Scott H. Okuno, Brian Samuels, Michael Fanucchi, David C. Harmon, Scott M. Schuetze, Denise Reinke, Peter F. Thall, Robert S. Benjamin, Laurence H. Baker, Martee L. Hensley
Journal: Journal of Clinical Oncology (2007)

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.
Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway
Authors: Shehla Pervin, Rajan Singh, Estebes Hernandez, Guoyao Wu, Gautam Chaudhuri
Journal: Cancer Research (2007)

Nitric oxide (NO) in nanomolar (nmol/L) concentrations is consistently detected in tumor microenvironment and has been found to promote tumorigenesis. The mechanism by which NO enhances tumor progression is largely unknown. In this study, we investigated the possible mechanisms and identified cellular targets by which NO increases proliferation of human breast cancer cell lines MDA-MB-231 and MCF-7. DETA-NONOate, a long acting NO donor, with a half-life of 20 h, was used. We found that NO (nmol/L) dramatically increased total protein synthesis in MDA-MB-231 and MCF-7 and also increased cell proliferation. NO specifically increased the translation of cyclin D1 and ornithine decarboxylase (ODC) without altering their mRNA levels or half-lives. Critical components in the translational machinery, such as phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets, phosphorylated eukaryotic translation initiation factor and p70 S6 kinase, were up-regulated following NO treatment, and inhibition of mTOR with rapamycin attenuated NO induced increase of cyclin D1 and ODC. Activation of translational machinery was mediated by NO-induced up-regulation of the Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK (Raf/MEK/ERK) and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt signaling pathways. Up-regulation of the Raf/MEK/ERK and PI-3 kinase/Akt pathways by NO was found to be mediated by activation of Ras, which was cyclic guanosine 3',5'-monophosphate independent. Furthermore, inactivation of Ras by farnesyl transferase inhibitor or K-Ras small interfering RNA attenuated NO-induced increase in proliferation signaling and cyclin D1 and ODC translation, further confirming the involvement of Ras activation during NO-induced cell proliferation.
Natural killer cells and hepatitis C: action and reaction
Authors: K. Cheent, S. I. Khakoo
Journal: Gut (2010)

In 1989, hepatitis C virus (HCV) was first identified as the infectious agent responsible for human non-A, non-B hepatitis.1 Two decades later, HCV remains a global public health problem with a suboptimal response rate to treatment and the absence of a protective vaccine. Recent work has highlighted the influence of the innate immune system, and in particular natural killer cells, on the outcome and pathology of HCV infection. These cells are considerably more complex than was originally thought and their role in viral infections is currently being unravelled. This review summarises our emerging understanding of natural killer cells in HCV infection.
Parallel evolution of antibody variable regions by somatic processes: consecutive shared somatic alterations in VH genes expressed by independently generated hybridomas apparently acquired by point mutation and selection rather than by gene conversion.
Authors: L J Wysocki, M L Gefter, M N Margolies
Journal: The Journal of Experimental Medicine (1990)

We identified, in independently generated hybridoma antibodies, blocks of shared somatic alterations comprising four consecutive amino acid replacements in the CDR2s of their heavy chain variable regions. We found that the nucleotide sequences encoding the shared replacements differed slightly. In addition, we performed genomic cloning and sequencing analyses that indicate that no genomic sequence could encode the block of shared replacements in any one of the antibodies and thus directly serve as a donor by a recombinational process. Finally, in a survey of other somatically mutated versions of the same heavy chain variable gene, we found several examples containing one, two, or three of the shared CDR2 mutations in various combinations. We conclude that the shared somatic alterations were acquired by several independent events. This result, and the fact that the antibodies containing the four shared mutations were elicited in response to the same antigen and are encoded by the same VH and VK gene segments, suggests that an intense selection pressure has fixed the shared replacements by favoring the clonal expansion of B cells producing antibodies that contain them. The basis of this selection pressure is addressed elsewhere (Parhami-Seren, B., L. J. Wysocki, M. N. Margolies, and J. Sharon, manuscript submitted for publication).
Assessing the role of APNH, a gene encoding for a human amiloride-sensitive Na+/H+ antiporter, on the interindividual variation in red cell Na+/Li+ countertransport.
Authors: C R Dudley, L A Giuffra, A E Raine, S T Reeders
Journal: Journal of the American Society of Nephrology (1991)

The "reverse genetic" approach to essential hypertension is complicated by the fact that blood pressure is a heterogeneous, quantitative, complex trait. One strategy is to use "intermediate phenotypes" that are not only associated with hypertension but that also have a simple mode of inheritance, compatible with the action of a single gene. Red cell sodium-lithium countertransport (SLC) is one of the best characterized intermediate phenotypes for hypertension. The similarity in stoichiometry and kinetics between SLC and Na+/H+ exchange has led to the proposal that the gene encoding the Na+/H+ antiporter (APNH) may be responsible for the individual variance in SLC. We have tested this hypothesis by both an association study and Haseman and Elston's sib pair method of linkage analysis, by using a polymorphism at the APNH locus detected by denaturing gradient gel electrophoresis. Both analytical techniques were performed before and after correction of SLC values for known covariates. There was no significant association between mean SLC values and any of the three possible genotypes of the APNH locus either before or after regressing out covariates (F = 0.64 and P greater than 0.52; F = 0.63 and P greater than 0.53, respectively). Linkage analysis similarly failed to demonstrate a relationship between the squared difference in SLC values and the identity by descent status for APNH as well as other loci that map close to APNH (D1S57, RH, and ALPL). Taking these results together, we conclude that mutations at the APNH locus are not responsible for the observed variation in SLC values.
ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ
Authors: Kunihiro Hayakawa, Shotaro Nakajima, Nobuhiko Hiramatsu, Maro Okamura, Tao Huang, Yukinori Saito, Yasuhiro Tagawa, Minori Tamai, Shuhei Takahashi, Jian Yao, Masanori Kitamura
Journal: Journal of the American Society of Nephrology (2009)

Modest induction of endoplasmic reticulum (ER) stress confers resistance to inflammation in glomeruli. Recently, we found that ER stress leads to mesangial insensitivity to cytokine-induced activation of NF-κB, but the underlying mechanisms are incompletely understood. ER stress can trigger expression of CCAAT/enhancer-binding proteins (C/EBPs), which interact with transcription factors including NF-κB. Here, we investigated a role for C/EBPs in the ER stress–induced resistance to cytokines. Mesangial cells preferentially induced C/EBPβ after exposure to thapsigargin or tunicamycin; induction of C/EBPδ was modest and transient, and expression of C/EBPα was absent. The induction of C/EBPβ correlated with accumulation of C/EBPβ protein and enhanced transcriptional activity of C/EBP. Overexpression of C/EBPβ markedly suppressed TNF-α–induced activation of NF-κB, independent of its transacting potential. Knockdown of C/EBPβ by small interfering RNA reversed the suppressive effect of ER stress on NF-κB. In vivo, preconditioning of mice with ER stress induced renal C/EBPβ and suppressed NF-κB–dependent gene expression in response to LPS. Using dominant negative mutants and null mutants for individual branches of the unfolded protein response, we identified the RNA-dependent protein kinase–like ER kinase (PERK) and the inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) pathways as the unfolded protein response responsible for ER stress–induced C/EBPβ. These results suggest that ER stress blunts cytokine-triggered activation of NF-κB, in part through PERK- and IRE1-mediated preferential induction of C/EBPβ.
Mathematical Approaches to Understanding and Imaging Atrial Fibrillation
Authors: Natalia A. Trayanova
Journal: Circulation Research (2014)

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. The mechanisms that govern AF initiation and persistence are highly complex, of dynamic nature, and involve interactions across multiple temporal and spatial scales in the atria. This article aims to review the mathematical modeling and computer simulation approaches to understanding AF mechanisms and aiding in its management. Various atrial modeling approaches are presented, with descriptions of the methodological basis and advancements in both lower-dimensional and realistic geometry models. A review of the most significant mechanistic insights made by atrial simulations is provided. The article showcases the contributions that atrial modeling and simulation have made not only to our understanding of the pathophysiology of atrial arrhythmias, but also to the development of AF management approaches. A summary of the future developments envisioned for the field of atrial simulation and modeling is also presented. The review contends that computational models of the atria assembled with data from clinical imaging modalities that incorporate electrophysiological and structural remodeling could become a first line of screening for new AF therapies and approaches, new diagnostic developments, and new methods for arrhythmia prevention.
Developing a Comprehensive Pesticide Health Effects Tracking System for an Urban Setting: New York City’s Approach
Authors: Daniel E. Kass, Audrey L. Thier, Jessica Leighton, James E. Cone, Nancy L. Jeffery
Journal: Environmental Health Perspectives (2004)

In recent years, there have been substantial investments and improvements in federal and state surveillance systems to track the health effects from pesticide exposure. These surveillance systems help to identify risk factors for occupational exposure to pesticides, patterns in poisonings, clusters of disease, and populations at risk of exposure from pesticide use. Data from pesticide use registries and recent epidemiologic evidence pointing to health risks from urban residential pesticide use make a strong case for understanding better the sale, application, and use of pesticides in cities. In this article, we describe plans for the development of a pesticide tracking system for New York City that will help to elucidate where and why pesticides are used, potential risks to varied populations, and the health consequences of their use. The results of an inventory of data sources are presented along with a description of their relevance to pesticide tracking. We also discuss practical, logistical, and methodologic difficulties of linking multiple secondary data sources with different levels of person, place, and time descriptors.
Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail
Authors: James Pettitt, Larry Zeitlin, Do H. Kim, Cara Working, Joshua C. Johnson, Ognian Bohorov, Barry Bratcher, Ernie Hiatt, Steven D. Hume, Ashley K. Johnson, Josh Morton, Michael H. Pauly, Kevin J. Whaley, Michael F. Ingram, Ashley Zovanyi, Megan Heinrich, Ashley Piper, Justine Zelko, Gene G. Olinger
Journal: Science Translational Medicine (2013)

Ebola virus–infected macaques were successfully treated with a cocktail of monoclonals manufactured in plants.