tbuckley/cabot-search huggingface dataset:
Metformin attenuates cardiac fibrosis by inhibiting the TGFβ1–Smad3 signalling pathway
Authors: Han Xiao, Xiaowei Ma, Wei Feng, Yongnan Fu, Zhizhen Lu, Ming Xu, Qiang Shen, Yi Zhu, Youyi Zhang
Journal: Cardiovascular Research (2010)

The mechanism of the cardioprotective action of metformin is incompletely understood. We determined the role of metformin in cardiac fibrosis and investigated the mechanism. Ten-week-old male mice (C57BL/6) were subjected to left ventricular pressure overload by transverse aortic constriction. Mice received metformin (200 mg/kg/day) or normal saline for 6 weeks. Metformin inhibited cardiac fibrosis (fibrosis area/total heart area: 0.6 ± 0.3 vs. 3.6 ± 0.9%, P < 0.01) induced by pressure overload and improved cardiac diastolic function (left ventricular end-diastolic pressure: 5.2 ± 0.9 vs. 11.0 ± 1.6 mmHg, P < 0.05). Metformin inhibited the pressure overload-induced transforming growth factor (TGF)-β1 production in mouse hearts and the TGF-β1-induced collagen synthesis in cultured adult mouse cardiac fibroblasts (CFs). Metformin suppressed the phosphorylation of Smad3 in response to TGF-β1 in CFs. Metformin also inhibited the nuclear translocation and transcriptional activity of Smad3 in CFs. Metformin inhibited cardiac fibrosis induced by pressure overload in vivo and inhibited collagen synthesis in CFs probably via inhibition of the TGF-β1–Smad3 signalling pathway. These findings provide a new mechanism for the cardioprotective effects of metformin.
Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials.
Authors: E F Juniper, G H Guyatt, R S Epstein, P J Ferrie, R Jaeschke, T K Hiller
Journal: Thorax (1992)

BACKGROUND: In the past only physiological and clinical outcomes have been used to assess the effect of asthma interventions and the effect of the intervention on the lives of the patients has not been determined. The objective of this study was to assess health related impairment of quality of life in adult asthmatic patients and to develop a questionnaire for measuring quality of life in clinical trials in asthma. METHODS: Impairment of quality of life in adults with asthma was evaluated from structured interviews in which patients were asked to identify the parts of their daily lives affected by asthma. On the basis of these results, an asthma quality of life questionnaire was developed in an interviewer and self administered form and tested for comprehension and acceptability. A total of 150 adults with asthma and with a wide range of airway hyperresponsiveness were enrolled from previous clinical trials, local asthma clinics, and notices in the media. RESULTS: Areas of quality of life impairment included symptoms classically associated with asthma, responses to environmental stimuli, the need to avoid these stimuli, limitation of activities, and emotional dysfunction. Areas of impairment were similar across strata of airway hyperresponsiveness, age, and treatment requirements and between sexes, thus allowing a single questionnaire suitable for all adults with asthma to be developed. The questionnaire contains 32 items and takes 5-10 minutes to administer; in the pretesting it was shown to be acceptable to a wide range of patients. CONCLUSIONS: The questionnaire includes areas of quality of life impairment that are important to adult asthmatic patients. It has been designed to be responsive to within subject change and therefore may be used as a measure of outcome in clinical trials in asthma.
Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. Department of Veterans Affairs Implantable Insulin Pump Study Group
Authors: Christopher D. Saudek, William C. Duckworth, Anita Giobbie-Hurder, William G. Henderson, Robert R. Henry, David E. Kelley, Steven V. Edelman, Franklin J. Zieve, Robert A. Adler, James W. Anderson, Robert J. Anderson, Bruce P. Hamilton, Thomas W. Donner, M. Sue Kirkman, Nancy A. Morgan
Journal: JAMA (1996)

Objective.  —To determine whether implantable insulin pump (IIP) therapy and multiple daily insulin (MDI) injections could equally attain improved blood glucose control, and to compare the 2 treatments with respect to reducing daily blood glucose fluctuations, reducing serious hypoglycemic insulin reactions, and improving patients' quality of life.  Design.  —Randomized clinical trial.  Setting.  —Seven Veterans Affairs medical centers.  Patients.  —One hundred twenty-one male type II diabetic patients between the ages of 40 and 69 years, receiving at least 1 injection of insulin per day and having hemoglobin A1c(HbA1c) levels of 8% or above.  Intervention.  —Intensive therapy (IIP or MDI) for 1 year.  Main Outcome Measures.  —Hemoglobin A1cand blood glucose levels.  Results.  —Blood glucose levels declined to 7.96±1.08 mmol/L (143.4±19.5 mg/dL) and 8.30±1.52 mmol/L (149.6±27.4 mg/dL) (mean ± SD) for IIP and MDI, respectively (P=.57). Hemoglobin A1clevels improved in both groups (time effectP  Conclusions.  —Intensive insulin therapy with IIP and MDI is effective in controlling non—insulin-dependent diabetes mellitus. IIP has significant advantages in reducing glycemic variability, clinical hypoglycemia, and weight gain, while improving aspects of quality of life.
Characterizing the Microenvironment Surrounding Phosphorylated Protein Sites
Authors: Shi-Cai Fan, Xue-Gong Zhang
Journal: Genomics Proteomics & Bioinformatics (2005)

Protein phosphorylation plays an important role in various cellular processes. Due to its high complexity, the mechanism needs to be further studied. In the last few years, many methods have been contributed to this field, but almost all of them investigated the mechanism based on protein sequences around protein sites. In this study, we implement an exploration by characterizing the microenvironment surrounding phosphorylated protein sites with a modified shell model, and obtain some significant properties by the rank-sum test, such as the lack of some classes of residues, atoms, and secondary structures. Furthermore, we find that the depletion of some properties affects protein phosphorylation remarkably. Our results suggest that it is a meaningful direction to explore the mechanism of protein phosphorylation from microenvironment and we expect further findings along with the increasing size of phosphorylation and protein structure data.
Echocardiographic assessment of left ventricular function in aortic valve disease.
Authors: I G McDonald
Journal: Circulation (1976)

Echocardiography was used to study left ventricular size and contraction in 128 patients with isolated aortic valve disease -45 patients with aortic stenosis, 25 with mixed aortic valve disease and 58 with aortic regurgitation. Left ventricular measurements included the end-diastolic internal dimension (LVIDd), mural thickness (PWTd), an index of circumferential myocardial contraction-fractional shortening (FS=[(LVIDd-LVIDs)/LVIDd] X 100)--and stroke volume (LVSV). In the absence of left ventricular failure, measurements in aortic stenosis were characteristic of pressure overload with normal LVIDd and FS and an increase in PWTd related to the severity of stenosis; in aortic regurgitation, there was volume overload with increases in LVIDd and PWTd which were related to the severity of regurgitation, while FS was slightly reduced. In mixed aortic valve disease there was evidence of both pressure and volume overload. When left ventricular failure was associated with aortic stenosis, mixed aortic valve disease and chronic aortic regurgitation, FS was usually reduced. By contrast, in a recent patient with acute severe aortic regurgitation, FS was normal despite left ventricular failure, suggesting pump rather than myocardial failure.
Cardiovascular and Hematopoietic Defects Associated With Notch1 Activation in Embryonic Tie2-Expressing Populations
Authors: Deepak A. Venkatesh, Kyung-Sook Park, Anne Harrington, Laura Miceli-Libby, Jeong K. Yoon, Lucy Liaw
Journal: Circulation Research (2008)

Notch signaling is critical for the development and maintenance of the cardiovasculature, with loss-of-function studies defining roles of Notch1 in the endothelial/hematopoietic lineages. No in vivo studies have addressed complementary gain-of-function strategies within these tissues to define consequences of Notch activation. We developed a transgenic model of Cre recombinase–mediated activation of a constitutively active mouse Notch1 allele (N1ICD + ) and studied transgene activation in Tie2-expressing lineages. The in vivo phenotype was compared to effects of Notch1 activation on endothelial tubulogenesis, paracrine regulation of smooth muscle cell proliferation, and hematopoiesis. N1ICD + embryos showed midgestation lethality with defects in angiogenic remodeling of embryonic and yolk sac vasculature, cardiac development, smooth muscle cell investment of vessels, and hematopoietic differentiation. Angiogenic defects corresponded with impaired endothelial tubulogenesis in vitro following Notch1 activation and paracrine inhibition of smooth muscle cells when grown with Notch1-activated endothelial cells. Flow cytometric analysis of hematopoietic and endothelial precursor populations demonstrated a significant loss of CD71 + /Ter119 + populations with an active N1ICD + allele and a corresponding increase in c-Kit + /CD71 and Flk1 + populations, suggesting a developmental block during the transition between c-Kit– and Ter119-expressing erythroblasts. Cardiovascular lineages are sensitive to an imbalance in Notch signaling, with aberrant activation reflecting a vascular phenotype comparable to a loss-of-function Notch1 mutation.
Bone marrow transplantation improves hepatic fibrosis in<i>Abcb4</i><sup>−/−</sup>mice via Th1 response and matrix metalloproteinase activity
Authors: Martin Roderfeld, Timo Rath, Sravanthi Pasupuleti, Marc Zimmermann, Caterina Neumann, Yuri Churin, Christian Dierkes, Robert Voswinckel, Peter J Barth, Daniel Zahner, Jürgen Graf, Elke Roeb
Journal: Gut (2011)

Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4-/- mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4-/- mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon γ was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.
Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think
Authors: Camille Lobry, Philmo Oh, Iannis Aifantis
Journal: The Journal of Experimental Medicine (2011)

Notch signaling is often considered a model hematopoietic proto-oncogene because of its role as the main trigger of T cell acute lymphoblastic leukemia (T-ALL). Although its role in T-ALL is well characterized and further supported by a high frequency of activating NOTCH1 mutations in T-ALL patients, it still remains an open question whether the effects of Notch signaling are causative in other types of cancer, including solid tumors. Growing evidence supported by recent studies unexpectedly shows that Notch signaling can also have a potent tumor suppressor function in both solid tumors and hematological malignancies. We discuss the intriguing possibility that the pleiotropic functions of Notch can be tumor suppressive or oncogenic depending on the cellular context.
Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump
Authors: Michael D. Aleo, Yi Luo, Rachel Swiss, Paul D. Bonin, David M. Potter, Yvonne Will
Journal: Hepatology (2014)

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs. Conclusion : These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI. (Hepatology 2014;60:1015–1022)
An in situ molecular signature to predict early recurrence in hepatitis B virus-related hepatocellular carcinoma
Authors: Jing Xu, Tong Ding, Qi He, Xing-Juan Yu, Wen-Chao Wu, Wei-Hua Jia, Jing-Ping Yun, Ying Zhang, Ming Shi, Chun-Kui Shao, Wei-Dong Pan, Xiao-Yu Yin, Jun Min, Shi-Mei Zhuang, Limin Zheng
Journal: Journal of Hepatology (2012)
Bcl-2 and Bax in congenital naevi
Authors: C. Stefanaki, C. Antoniou, K. Stefanaki, G. Petrikos, T. Argyrakos, C.V-V. Constantinidou, O. Karentzou, A. Stratigos, A. Katsambas
Journal: British Journal of Dermatology (2006)

Melanocytes represent a static component of the epidermis, and the role of apoptosis in basal melanocyte function and melanocytic tumour formation has not been fully elucidated.The aim of this study was to investigate the expression of Bcl-2 anti-apoptotic and Bax apoptotic proteins in congenital naevi in correlation with p-27 protein and Ki-67 proliferative index.Our material comprised 30 congenital naevi (eight giant) excised from children aged from 15 days to 14 years old. The immunohistochemical streptavidin-biotin method was performed on paraffin sections for the detection of Bcl-2 (cl100/D5), Bax (cl2D2) , Ki-67 (MIB-1) and p-27 (1B4) proteins with monoclonal antibodies.Bcl-2 protein was detected in all cases showing a strong diffuse cytoplasmic expression in >70% of the naevocytes and was preserved in the deeper parts of the naevi. On the other hand, Bax was detected in 13 of the cases, showing a fainter cytoplasmic expression in 40-50% of the naevocytes without any particular topographic distribution. Ki-67 was detected in all cases showing a limited expression in 1-2% of the nuclei mainly in the junctional and upper dermal components. p-27 protein showed a broad diffuse nuclear expression (>70% of the nuclei) in all cases with a particular increase in the deeper parts of the naevi. Bcl-2 expression showed a parallel correlation with p-27 protein.Broad Bcl-2 expression in congenital naevi suggests that suppression of apoptosis may play an important role in the maintenance of naevocytes despite the low proliferative activity.
Donor Hepatitis C Seropositivity
Authors: Jay R. Bucci, Cal S. Matsumoto, S. John Swanson, Lawrence Y. C. Agodoa, Kent C. Holtzmuller, Thomas G. Peters, Kevin C. Abbott
Journal: Journal of the American Society of Nephrology (2002)

The impact of hepatitis C virus–positive donor kidneys on patient survival has not been analyzed in a national study. This study analyzed 20,111 adult (age, ≥16 yr) recipients having solitary cadaveric kidney transplants from adult donors with valid donor hepatitis C serologies from July 1, 1994, to June 30, 1998, in an historical cohort study (the 2000 United States Kidney Data System) of patient survival. Analysis was by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. Of 484 kidneys positive for hepatitis C virus serology, 165 (34%) were given to recipients with confirmed negative hepatitis C serologies. Unadjusted 3-yr patient survival was 93% in all recipients of donor hepatitis C–negative kidneys versus 85% in all recipients of donor hepatitis C–positive kidneys ( P = 0.01). Among hepatitis C–positive recipients, those who received hepatitis C–positive kidneys had worse survival than recipients of hepatitis C–negative kidneys. Among elderly hepatitis C–negative recipients, those who received hepatitis C–positive kidneys also had worse survival; in fact, all recipients of donor hepatitis C–positive kidneys had increased risk of mortality ( P = 0.028). There were no significant interactions between donor hepatitis C positivity and either recipient hepatitis C positivity or older recipient age. The use of hepatitis C–positive kidneys in recipients who were hepatitis C–negative was fairly common and contrary to some current recommendations. Recipients of donor hepatitis C–positive kidneys were at independently increased risk of mortality, with no evidence that any subgroups were less affected.
Temporal changes in he sympathetic-parasympathetic interactions that occur in the perfused canine atrium.
Authors: Y Furukawa, M N Levy
Journal: Circulation Research (1984)

In the isolated, blood-perfused, canine right atrium, stimulation of the intramural autonomic nerves evoked negative chronotropic and inotropic responses. The responses were not maintained at a constant level during tonic neural stimulation, but they tended to drift back toward their control levels. These time-dependent changes in the cardiac responses were more pronounced the higher the frequency of stimulation. After the beta-adrenergic receptors were blocked in half of the preparations, the negative cardiac responses to autonomic neural stimulation were more pronounced, but the time dependency of those responses was less. After the muscarinic receptors were blocked in the other half of the preparations, only positive responses to neural stimulation were observed. These responses faded significantly at a high stimulation frequency (30 Hz), but not at a lower frequency (5 Hz). The cardiac responses to combined autonomic neural stimulation were substantially more negative than the algebraic sum of the individual responses to sympathetic and parasympathetic stimulation. The extent of this interaction was most pronounced near the beginning of stimulation, but it became less pronounced as the stimulation progressed. Hence, the cardiac sympathetic-parasympathetic interactions change appreciably with time during a continuous train of autonomic neural stimulation.
Radiographic features of staphylococcal pneumonia in adults and children.
Authors: J. Macfarlane, D. Rose
Journal: Thorax (1996)

BACKGROUND: Clinical and laboratory features do not accurately correlate with the cause of community acquired pneumonia. A study was performed to examine whether the radiographic features of staphylococcal pneumonia are sufficiently distinct to aid early diagnosis. METHODS: The chest radiographs of 34 patients (including eight children) with proven staphylococcal pneumonia were reviewed by two experienced observers using methods described previously. Features on presentation and follow up were noted. RESULTS: The most striking features were the presence of multilobar consolidation on presentation, cavitation, pneumatocoeles and spontaneous pneumothorax, together with a tendency to radiographic deterioration after admission in both adults and children. Some of these features are much less common with other causes of community acquired pneumonia. However, most of the cases did not have these classic features. CONCLUSIONS: The presence of certain radiographic features, including multilobar shadowing, cavitation, pneumatocoeles, and spontaneous pneumothorax, are seen with staphylococcal pneumonia in adults and children, but their absence does not exclude the diagnosis.