tbuckley/cabot-search huggingface dataset:
Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents
Authors: Ippei Shimizu, Tohru Minamino, Haruhiro Toko, Sho Okada, Hiroyuki Ikeda, Noritaka Yasuda, Kaoru Tateno, Junji Moriya, Masataka Yokoyama, Aika Nojima, Gou Young Koh, Hiroshi Akazawa, Ichiro Shiojima, C. Ronald Kahn, E. Dale Abel, Issei Komuro
Journal: Journal of Clinical Investigation (2010)

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload-induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.
Noninvasive pressure support ventilation in COPD patients with postextubation hypercapnic respiratory insufficiency
Authors: G Hilbert, D Gruson, L Portel, G Gbikpi-Benissan, JP Cardinaud
Journal: European Respiratory Journal (1998)

Patients with chronic obstructive pulmonary disease (COPD) who have been intubated and mechanically ventilated may prove difficult to wean. Noninvasive ventilation may be used in an attempt to avoid new endotracheal intubation. The efficacy of administration of noninvasive pressure support ventilation was evaluated in 30 COPD patients with postextubation hypercapnic respiratory insufficiency, compared with 30 historically matched control patients who were treated conventionally. Patients were included in the study if, within 72 h postextubation, they presented with respiratory distress, defined as the combination of a respiratory frequency >25 breaths x min(-1), an increase in the arterial carbon dioxide tension (Pa,CO2) of at least 20% compared with the value measured after extubation, and a pH <7.35. Noninvasive pressure support ventilation was effective in correcting gas exchange abnormalities. The use of noninvasive ventilation significantly reduced the need for endotracheal intubation: 20 of the 30 patients (67%) in the control group required endotracheal intubation, compared with only six of the 30 patients (20%) in the noninvasive-ventilation group (p<0.001). In-hospital mortality was not significantly different between the two groups, but the mean duration of ventilatory assistance for the treatment of the postextubation distress, and the length of intensive care unit stay related to this event, were both significantly shortened by noninvasive ventilation (p<0.01). In conclusion, noninvasive ventilation may be used in the management of patients with chronic obstructive pulmonary disease and postextubation hypercapnic respiratory insufficiency.
NI-42 * ALTERED STRUCTURAL CONNECTIVITY IN WIDELY DISTRIBUTED BILATERAL HEMISPHERIC NETWORKS OF PATIENTS WITH GLIOBLASTOMA
Authors: J.-W. Jeong, J. Lee, D. Kamson, N. Robinette, G. Barger, S. Mittal, C. Juhasz
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastomas (GBMs) typically involve the cerebral white matter and infiltrate well beyond the enhancing bulky tumor seen on MRI; thus, they can disrupt white matter fiber tracts. In this study, we evaluated how unilateral GBMs affect the structural organization of hemispheric networks. METHODS: Ten patients with newly-diagnosed unilateral GBM (age: 61 ± 11 years, 6 males, 4 left-sided, tumor size: 34.1 ± 22.7cm3) and 10 healthy controls (age: 67 ± 8 years, 5 males) underwent 3T diffusion-weighted MRI. Whole brain tractography was performed using a recently developed approach (independent component analysis with ball-and-stick model; Jeong et al., Magn Reson Med, 2013;70:441-53). In each subject, a total of 116 cortical regions of interest were generated by fitting a deformable template resulting in a 116x116 connectivity matrix where the elements quantify the pair-wise connectivity scores (i.e., fiber numbers connecting any two cortical regions which were normalized to the corresponding tract lengths). From this matrix we calculated three network properties in both hemispheres: global efficiency (characterizing structural integration), local efficiency (characterizing structural segregation), and clustering coefficient (characterizing structural complexity). RESULTS: GBM patients showed significantly reduced global efficiency, local efficiency, and clustering coefficients in both affected and contralateral hemispheres, as compared to the control group (p < 0.0001 in all comparisons). Larger tumor size was associated with more severely reduced global efficiency (p = 0.007 and p = 0.004 in affected and contralateral hemisphere, respectively), local efficiency (p = 0.02 and p = 0.003) and clustering coefficient (p = 0.04 and p = 0.006). Signs of intrahemispheric network reorganization were also observed in the affected hemisphere of individual patients. CONCLUSIONS: The structural organization is less efficient and less complex in both cerebral hemispheres of patients with unilateral GBM, although regional reorganization may occur on the affected side. Larger tumors are associated with more severe hemispheric network abnormalities. These alterations in widely-distributed neuronal networks may underlie some of the neurocognitive co-morbidities in these patients.
TGF-β1 induces bone marrow reticulin fibrosis in hairy cell leukemia
Authors: Medhat Shehata, Josef D. Schwarzmeier, Martin Hilgarth, Rainer Hubmann, Markus Duechler, Heinz Gisslinger
Journal: Journal of Clinical Investigation (2004)

The mechanisms that lead to reticulin fibrosis of bone marrow (BM) in hairy cell leukemia (HCL) are not fully understood. We therefore investigated the involvement of TGF-β1, a potent fibrogenic cytokine, in this process. Immunoassays revealed that TGF-β1 is present at higher concentrations in BM, serum, and plasma of HCL patients in comparison with healthy donors (P < 0.001). RT-PCR and immunofluorescence studies showed that TGF-β1 is overexpressed at the mRNA and protein levels in peripheral blood, spleen, and BM mononuclear cells and that hairy cells (HCs) are the main source of TGF-β1. Active TGF-β1 correlated significantly with grades of BM fibrosis, infiltration with HCs, and serum procollagen type III aminoterminal propeptide (PIIINP). Ex vivo studies demonstrated that TGF-β1 significantly enhances the production and deposition of reticulin and collagen fibers by BM fibroblasts. In addition, BM plasma of HCL patients increased the synthesis of type I and type III procollagens, the main components of reticulin fibers, at the mRNA and protein levels. This fibrogenic activity of BM plasma was abolished by neutralizing anti–TGF-β1 antibodies. These results show, for the first time to our knowledge, that TGF-β1 is highly expressed in HCs and is directly involved in the pathogenesis of BM reticulin fibrosis in HCL.
T-cell-based assays on cerebrospinal fluid and PBMCs for rapid diagnosis of TB meningitis in non-HIV patients
Authors: K.-H. Park, O.-H. Cho, E. M. Lee, S.-O. Lee, S.-H. Choi, Y. S. Kim, J. H. Woo, J. K. Kang, S.-A. Lee, S.-H. Kim
Journal: European Respiratory Journal (2012)

T-cell-based assays on cerebrospinal fluid and PBMCs for rapid diagnosis of TB meningitis in non-HIV patientsTo the Editors:Recently, two studies have shown that an ELISPOT assay using mononuclear cells (MCs) compartmentalised in the cerebrospinal fluid (CSF) is an accurate and rapid rule-out or rule-in test for tuberculosis meningitis (TBM) in conjunction with other rapid tests [1, 2].However, these two studies had limitations: the majority (94%) of enrolled patients were infected with HIV in one study [2], and the CSF-MC ELISPOT assay was performed on a relatively small number of patients in the other [1].This study builds on our earlier publication [1] and evaluates the clinical utility for the diagnosis of TBM of simultaneous testing with the peripheral blood mononuclear cell (PBMC) and CSF-MC ELISPOT assays in a larger number of non-HIV-infected patients, by using the standardised diagnostic criteria for TBM [3].Adult patients (aged o16 yrs) with suspected TBM admitted to Asan Medical Center, a 2,700-bed tertiary hospital in Seoul, Republic of Korea, were enrolled prospectively from April 2008 to October 2010.The results of the ELISPOT assays were concealed from the attending physicians to avoid bias because the results of the ELISPOT assays might have affected the attending physicians' decisions on empirical anti-tuberculosis therapy.
Effect of duration of regional myocardial ischemia and degree of reactive hyperemia on the magnitude of the initial thallium-201 defect.
Authors: T P Wharton, W A Neill, J M Oxendine, L N Painter
Journal: Circulation (1980)

Thallium-201 and microspheres were injected into the blood simultaneously during left circumflex (LC) occlusion in open chest dogs. The dogs were sacrificed 6-8 minutes later and regional myocardial (201)TI and microsphere concentrations determined. In dogs with permanent LC occlusion the myocardial (201)TI distribution approximated blood flow distribution as judged by the microsphere concentrations. Release of LC occlusion 45 seconds after (201)TI injection almost obliterated the myocardial (201)TI deficit in the area of the LC without changing the microsphere results, presumably a result of deposition of (201)TI during reactive hyperemia. Either delaying the onset of reflow until 3 minutes of attenuating the magnitude of reactive hyperemia by LC stenosis markedly decreased the change in (201)TI distribution due to reflow. We conclude that for a given degree of reversible regional myocardial ischemia at the time of (201)TI injection, the perfusion deficit observed on the initial scintigram will be influenced by the subsequent duration of ischemia and by the magnitude of postischemic reactive hyperemia.
Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis
Authors: Manish M. Patel, Andrew D. Clark, Colin F. B. Sanderson, Jacqueline Tate, Umesh D. Parashar
Journal: PLoS Medicine (2012)

Background To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur. Methods and Findings We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes. Conclusions Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary
Dairy Consumption, Type 2 Diabetes, and Changes in Cardiometabolic Traits: A Prospective Cohort Study of Middle-Aged and Older Chinese in Beijing and Shanghai
Authors: Geng Zong, Qi Sun, Danxia Yu, Jingwen Zhu, Liang Sun, Xingwang Ye, Huaixing Li, Qianlu Jin, He Zheng, Frank B. Hu, Xu Lin
Journal: Diabetes Care (2013)

OBJECTIVE To prospectively investigate associations of dairy consumption with risk of type 2 diabetes and changes of cardiometabolic traits. RESEARCH DESIGN AND METHODS In 2005, 2,091 middle-aged and older Chinese men and women were recruited and followed for 6 years. Baseline dairy consumption was assessed by a 74-item food frequency questionnaire. Erythrocyte fatty acids were analyzed by gas chromatography coupled with flame ion detector. Cardiometabolic traits were measured at both baseline and follow-up visits. RESULTS Only 1,202 (57.5%) participants reported any dairy consumption, with a median intake of 0.89 (interquartile range 0.19–1.03) serving/day. Compared with nonconsumers, the relative risks (RRs) of type 2 diabetes among those having 0.5–1 serving/day and &amp;gt;1 serving/day were 0.70 (95% CI 0.55–0.88) and 0.65 (0.49–0.85), respectively, after multivariate adjustment (Ptrend &amp;lt; 0.001), which were attenuated by further adjusting for changes in glucose during follow-up (Ptrend = 0.07). Total dairy consumption was associated with favorable changes in glucose, waist circumference, BMI, diastolic blood pressure (all Ptrend &amp;lt; 0.05), and systolic blood pressure (Ptrend = 0.05) after multivariate adjustment, including baseline values of dependent variables. Erythrocyte trans-18:1 isomers were significantly correlated with total dairy consumption (rs = 0.37, Ptrend &amp;lt; 0.001), and these dairy food biomarkers were associated with a lower risk of type 2 diabetes. The RR of type 2 diabetes comparing extreme quartiles of trans-18:1 isomers was 0.82 (0.65–1.04, Ptrend = 0.02), which was attenuated after adjustment for dairy consumption (Ptrend = 0.15). CONCLUSIONS Dairy consumption was associated with a significantly lower risk of type 2 diabetes and favorable changes of cardiometabolic traits in Chinese.
Possible Roles of Tumor-associated Carbohydrate Antigens
Authors: Minoru Fukuda
Journal: Cancer Research (1996)

Recent progress in the studies on the roles of carbohydrates has brought about critical discoveries, which allow us to have working hypotheses for understanding the roles of tumor-associated carbohydrate antigens. In this report, I focus my description on three different aspects of this progress. I discuss: (a) the immunological response to oligosaccharides aberrantly expressed under pathological conditions; (b) possible roles of carbohydrate-dependent cell adhesion during tumor metastasis; and (c) the roles of carbohydrates in modulating the functions of proteins that attach those carbohydrates. These three areas in the roles of carbohydrates will likely be the target for continuous research efforts to reveal the roles of tumor-associated carbohydrates.
Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4
Authors: Laia Caja, Patricia Sancho, Esther Bertran, Daniel Iglesias-Serret, Joan Gil, Isabel Fabregat
Journal: Cancer Research (2009)

Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-beta in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-beta-induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-beta-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-beta, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-beta and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.
Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis
Authors: J J Haringman
Journal: Annals of the Rheumatic Diseases (2005)

Chemokine receptors and chemokines have a crucial role in leucocyte recruitment into inflamed tissue.To examine the expression of an extensive number of chemokines and receptors in a unique bank of paired samples of synovial tissue (ST) and peripheral blood (PB) from patients with different forms of arthritis to assist in identifying suitable targets for therapeutic intervention.Synovial biopsy specimens were obtained from 23 patients with rheumatoid arthritis (RA), 16 with osteoarthritis, and 8 with reactive arthritis. ST chemokine (CCL2/MCP-1, CCL5/RANTES, CCL7/MCP-3, CCL8/MCP-2, CCL14/HCC-1, CCL15/HCC-2, CCL16/HCC-4), chemokine receptor (CCR1, CCR2b, CCR5, CXCR4), and CD13 expression was analysed by immunohistochemistry and two colour immunofluorescence. Chemokine receptor expression (CCR1, CCR3, CCR5, CCR6, CCR7) on PB cells was studied by flow cytometry. Non-parametric tests were used for statistical analysis.Abundant expression of CCR1, CXCR4, and CCR5 was found in all forms of arthritis, with a specific increase of CCL5 and CCL15 in RA. CCL7, CCL8, CCL14, CCL15, and CCL16 were detected for the first time in ST. The results for PB analysis were comparable among different arthritides. Interestingly, compared with healthy controls, significantly lower expression of CCR1 (p<0.005) and CCR5 (p<0.05) by PB monocytes in the patient groups was seen.A variety of chemokines and receptors might have an important role in several inflammatory joint disorders. Although other receptors are involved as well, migration of CCR1(+) and CCR5(+) cells towards the synovial compartment may play a part in the effector phase of various forms of arthritis.
Endoplasmic reticulum‐resident chaperones modulate the inflammatory and angiogenic responses of endothelial cells
Authors: R. Tsaryk, N.M. Bartholomä, N. Simiantonaki, L. Anspach, K. Peters, C. Heilmann, C.J. Kirkpatrick, F. Pröls
Journal: British Journal of Dermatology (2015)

Wound healing depends on a well-balanced regulation of inflammation and angiogenesis. In chronic wounds the healing process is disturbed and inflammation persists. Regulation of wound closure is controlled by transmembrane and extracellular proteins, the folding and maturation of which occur in the endoplasmic reticulum (ER) by ER-resident chaperone machinery.To study the role of the ER-resident chaperones BiP/Grp78, its cochaperone Mdg1/ERdJ4, and Grp94 in chronic, nonhealing wounds.Immunohistochemical staining of these chaperones in individual human biopsies and investigation of the possible role of BiP and Mdg1 in endothelial cells, focusing on their inflammatory response and angiogenic potential.In all chronic wounds investigated, the levels of these ER-resident chaperones were elevated in endothelial cells and leucocytes. The proangiogenic role of BiP has been shown in tumour growth studies before and was confirmed in this study. Proangiogenic activity of the cochaperone Mdg1 has been postulated before but could not be confirmed in this study. The chemokine tumour necrosis factor (TNF)-α was shown to trigger the presentation of proinflammatory adhesion molecules and the release of proinflammatory cytokines. Here we show that TNF-α does not affect endogenous chaperone levels, but that the ER-resident chaperones BiP and Mdg1 modulate the cellular TNF-α-induced proinflammatory response.According to the presented data we assume that in chronic wounds upregulated levels of ER-resident chaperones might contribute to persistent inflammation in chronic wounds. Therapies to downregulate chaperone levels might provide a tool that switches the imbalanced chronic wound microenvironment from inflammation to healing.