tbuckley/cabot-search huggingface dataset:
Role of p38 Mitogen-Activated Protein Kinase Activation in Podocyte Injury and Proteinuria in Experimental Nephrotic Syndrome
Authors: Masao Koshikawa, Masashi Mukoyama, Kiyoshi Mori, Takayoshi Suganami, Kazutomo Sawai, Tetsuro Yoshioka, Tetsuya Nagae, Hideki Yokoi, Hiroshi Kawachi, Fujio Shimizu, Akira Sugawara, Kazuwa Nakao
Journal: Journal of the American Society of Nephrology (2005)

Podocytes play an important role in maintaining normal glomerular function and structure, and podocyte injury leads to proteinuria and glomerulosclerosis. The family of mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase, and p38) may be implicated in the progression of various glomerulopathies, but the role of MAPK in podocyte injury remains elusive. This study examined phosphorylation of p38 MAPK in clinical glomerulopathies with podocyte injury, as well as in rat puromycin aminonucleoside (PAN) nephropathy and mouse adriamycin (ADR) nephropathy. The effect of treatment with FR167653, an inhibitor of p38 MAPK, was also investigated in rodent models. In human podocyte injury diseases, the increased phosphorylation of p38 MAPK was observed at podocytes. In PAN and ADR nephropathy, the phosphorylation of p38 MAPK and ERK was marked but transient, preceding overt proteinuria. Pretreatment with FR167653 (day -2 to day 14, subcutaneously) to PAN or ADR nephropathy completely inhibited p38 MAPK activation and attenuated ERK phosphorylation, with complete suppression of proteinuria. Electron microscopy and immunohistochemistry for nephrin and connexin43 revealed that podocyte injury was markedly ameliorated by FR167653. Furthermore, early treatment with FR167653 effectively prevented glomerulosclerosis and renal dysfunction in the chronic phase of ADR nephropathy. In cultured podocytes, PAN or oxidative stress induced the phosphorylation of p38 MAPK along with actin reorganization, and FR167653 inhibited such changes. These findings indicate that the activation of MAPK is necessary for podocyte injury, suggesting that p38 MAPK and, possibly, ERK should become a potential target for therapeutic intervention in proteinuric glomerulopathies.
Health Status Deterioration in Patients with Chronic Obstructive Pulmonary Disease
Authors: SALLY SPENCER, PETER M. A. CALVERLEY, P. SHERWOOD BURGE, PAUL W. JONES
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

This study examined health status decline in patients with chronic obstructive pulmonary disease (COPD). Data are from the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. After an 8-wk run-in, 751 patients (566 male), mean age 64 yr, were randomized to receive fluticasone propionate (FP) 500 μ g twice daily (376 patients) or placebo (375 patients). Mean baseline postbronchodilator FEV1 was 50 ± 15% predicted. Patients completed the St George's Respiratory Questionnaire (SGRQ) and the Short-Form 36 (SF-36) at baseline and every 6 mo for 3 yr. FEV1 and smoking status were assessed at baseline and at 3-mo intervals. A total of 387 (212 FP) patients completed the trial. All SGRQ components (p = 0.03 to 0.004) and Physical Function, Mental Health, Energy/ Vitality, and Physical Role Limitation scales of the SF-36 (p = 0.05 to 0.005) deteriorated faster in the placebo group. FEV1 and SGRQ scores correlated at baseline values (r = − 0.25, p < 0.0001), as did change in FEV1 and change in SGRQ ( Δ r = − 0.24, p < 0.0001). At baseline values smokers had worse SGRQ Total, Symptoms, and Impacts scores than ex-smokers. This difference was maintained throughout the study. Smoking status did not influence the rate of decline in health status. The SGRQ Total scores of FP-treated patients took 59% longer than placebo to deteriorate by a clinically significant amount. We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone.
Why glucocorticoids should be removed from the World Antidoping Agency's list of banned products
Authors: John W Orchard
Journal: British Journal of Sports Medicine (2007)

Sports medicine clinicians and researchers should all be familiar with the concepts of false positives and false negatives. Research to test a hypothesis about a link between, say, a risk factor and a disease can potentially be wrong in either of two ways. The findings might falsely show a link when in reality one does not exist (a type I or α error), or they might fail to show a link when there really is one (a type II or β error).1 2 Hopefully most of the time, if studies are well conducted, the likelihood of both of these errors is reduced.

Similar errors in both directions can potentially occur in drug testing in sport, although the nature of false positives and false negatives is somewhat different from that in other clinical testing. The rigorous methods of collection and the use of “A” and “B” samples mean that many sources of potential laboratory error are minimised. The false positive and false negative phenomena in doping may be better referenced to the athlete’s intent to cheat using performance-enhancing drugs. An athlete who takes a so-called “undetectable” anabolic steroid is a true “drug cheat”, but one who might produce a “false-negative” drug test because the structure of the undetectable drug is not yet known by the testing authorities. By comparison, the athlete who inadvertently takes a banned drug (particularly one with minimal performance-enhancing potential) not to cheat, but to treat a legitimate medical condition, may test positive in a doping test. Such a result may be considered a “false positive” with respect to intent to cheat using a performance-enhancing drug, even though the testing process was accurate in finding the drug in the athlete’s system.

Intent to cheat is so difficult to prove or disprove that WADA takes a pragmatic approach …
Therapeutic Drug Monitoring Facilitates Blood Pressure Control in Resistant Hypertension
Authors: Stephanie Brinker, Ambarish Pandey, Colby Ayers, Angela Price, Prafull Raheja, Debbie Arbique, Sandeep R. Das, Ethan A. Halm, Norman M. Kaplan, Wanpen Vongpatanasin
Journal: Journal of the American College of Cardiology (2013)
Increased Risk in Patients With High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention
Authors: Kevin P. Bliden, Joseph DiChiara, Udaya S. Tantry, Ashwani K. Bassi, Srivasavi K. Chaganti, Paul A. Gurbel
Journal: Journal of the American College of Cardiology (2007)
Connective Tissue Growth Factor CCN2 Interacts with and Activates the Tyrosine Kinase Receptor TrkA
Authors: Nadia Abdel Wahab, Benjamin S. Weston, Roger M. Mason
Journal: Journal of the American Society of Nephrology (2004)

Connective tissue growth factor (CTGF) is implicated as a factor promoting tissue fibrosis in several disorders, including diabetic nephropathy. However, the molecular mechanism(s) by which it functions is not known. CTGF rapidly activates several intracellular signaling molecules in human mesangial cells (HMC), including extracellular signal-related kinase 1/2, Jun NH2-terminal kinase, protein kinase B, CaMK II, protein kinase Cα, and protein kinase Cδ, suggesting that it functions via a signaling receptor. Treating HMC with CTGF stimulated tyrosine phosphorylation of proteins 75 to 80 and 140 to 180 kD within 10 min, and Western blot analysis of anti-phosphotyrosine immunoprecipitates identified the neurotrophin receptor TrkA (molecular weight approximately 140 kD). Cross-linking rCTGF to cell surface proteins with 3,3′-dithiobis(sulfosuccinimidylpropionate) revealed that complexes formed with TrkA and with the general neurotrophin co-receptor p75NTR. rCTGF stimulated phosphorylation of TrkA (tyr 490, 674/675). K252a, a known selective inhibitor of Trk, blocked this phosphorylation, CTGF-induced activation of signaling proteins, and CTGF-dependent induction of the transcription factor TGF-β-inducible early gene in HMC. It is concluded that TrkA serves as a tyrosine kinase receptor for CTGF.
Endometrial oestrogen and progesterone receptors and their relationship to sonographic appearance of the endometrium
Authors: Y Ohno
Journal: Human Reproduction Update (1998)

The rapid development of ultrasonographic equipment now permits instantaneous assessment of follicles and endometrium. The sonographic appearance of the endometrium has been discussed in relation to in-vitro fertilization (IVF) cycles. However, a generally agreed view of the relationship of the sonographic appearance to fecundity in IVF cycles has not emerged. We have studied the relationship between steroid receptors and the sonographic appearance of the preovulatory endometrium in natural cycles and ovulation induction cycles. Preovulatory endometrial thickness was not found to be indicative of fecundity, although a preovulatory endometrial thickness of <9 mm related to an elevated miscarriage rate. The preovulatory endometrial echo pattern did not predict fecundity. No relationships were found among endometrial appearance, endometrial steroid receptors and steroid hormone concentrations in serum. Oestrogen or progesterone receptor concentrations were not related to endometrial thickness or to concentrations of serum oestradiol, the only significant correlation being found between the endometrial concentrations of oestrogen and progesterone receptors. The ratio of progesterone:oestrogen receptor concentration was somewhat less in echo pattern B (not triple line) endometrium compared with pattern A (triple line) endometrium. Oestrogen and progesterone receptor concentrations appeared stable on gonadotrophin induction, though fewer numbers were found during clomiphene cycles than in natural cycles. With regard to the distribution of receptor concentration between clomiphene and natural cycles, most women using clomiphene had very low oestrogen receptor populations. Pregnancy rates were low, in spite of high ovulatory rates during clomiphene treatment and were mainly related to low oestrogen receptor concentrations in preovulatory endometrium.
CCR2 Signaling Contributes to Ischemia-Reperfusion Injury in Kidney
Authors: Kengo Furuichi, Takashi Wada, Yasunori Iwata, Kiyoki Kitagawa, Ken-ichi Kobayashi, Hiroyuki Hashimoto, Yoshiro Ishiwata, Masahide Asano, Hui Wang, Kouji Matsushima, Motohiro Takeya, William A. Kuziel, Naofumi Mukaida, Hitoshi Yokoyama
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase–positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion. E-mail: twada@medf.m.kanazawa-u.ac.jp
MiRNA-196 Is Upregulated in Glioblastoma But Not in Anaplastic Astrocytoma and Has Prognostic Significance
Authors: Yanlei Guan, Masahiro Mizoguchi, Koji Yoshimoto, Nobuhiro Hata, Tadahisa Shono, Satoshi O. Suzuki, Yukie Araki, Daisuke Kuga, Akira Nakamizo, Toshiyuki Amano, Xinlong Ma, Kenshi Hayashi, Tomio Sasaki
Journal: Clinical Cancer Research (2010)

MicroRNAs (miRNA) are short noncoding RNAs that can play critical roles in diverse biological processes. They are implicated in tumorigenesis and function both as tumor suppressors and as oncogenes. The clinical significance of miRNA expression profiles in malignant gliomas remains unclear.In this study, we examined the expression levels of 365 mature human miRNAs in 12 malignant gliomas, including 8 glioblastomas and 4 anaplastic astrocytomas, using TaqMan real-time quantitative PCR arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-196a, -196b, -21, and -15b, by analyzing 92 malignant gliomas by conventional real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 39 glioblastoma patients by Kaplan-Meier method and multivariate analysis.Expression profiles in glioblastomas and anaplastic astrocytomas suggested that 16 miRNAs were candidate markers associated with the malignant progression of gliomas. Among them, miR-196a showed the most significant difference (P = 0.0038), with miR-196b also having a high significance (P = 0.0371). Both miRNAs showed increased expression levels in glioblastomas relative to both anaplastic astrocytomas and normal brains in the validation study. Furthermore, patients with high miR-196 expression levels showed significantly poorer survival by the Kaplan-Meier method (P = 0.0073). Multivariate analysis showed that miR-196 expression levels were an independent predictor of overall survival in all 39 glioblastoma patients (P = 0.021; hazard ratio, 2.81).Our results suggest that miR-196 may play a role in the malignant progression of gliomas and may be a prognostic predictor in glioblastomas.
Four weeks of androstenedione supplementation diminishes the treatment response in middle aged men
Authors: S G Beckham, C P Earnest
Journal: British Journal of Sports Medicine (2003)

Objectives: To examine baseline hormonal concentrations and the pharmacokinetic response on day 0 and day 28 of 28 days of androstenedione supplementation. Methods: Eight men (mean (SD) age 44.1 (3.0) years (range 40–48), weight 76.3 (9.4) kg, and percentage body fat 20.6 (6.7)) participated in a randomised, double blind, cross over, 2 × 28 day placebo controlled study. Subjects were tested on day 0 and 28 days after receiving 200 mg/day oral androstenedione and a placebo treatment with a 28 day washout period between treatments. Serum hormone concentrations were examined at baseline (time 0) and then at 30 minute intervals for 180 minutes to measure day 0 and day 28 pharmacokinetic responses. Analytes included androstenedione, total testosterone, dehydroepiandrosterone sulfate (DHEAS), oestradiol, and sex hormone binding globulin (SHBG). Lipid concentrations, weight, body composition, resting heart rate, and blood pressure were also measured. Results: Analysis of integrated area under the curve (AUC) and time 0 hormonal concentrations by repeated measures multivariate analysis of variance (p&lt;0.05) and Fisher’s post hoc analysis showed a significant increase in AUC for serum androstenedione at day 0 (108.3 (27.6) nmol/l) in the supplemented condition as compared with day 28 (43.4 (13.1) nmol/l) and placebo (2.1 (0.8) nmol/l) conditions. No other significant AUC changes were noted. After 28 days of supplementation, DHEAS levels were significantly elevated (p = 0.00002) at time 0 (12.9 (1.3) μmol/l) compared with placebo (7.0 (0.8) μmol/l) with a trend (p = 0.08) toward elevation of time 0 androstenedione concentrations (16.4 (7.0) nmol/l) compared with placebo (5.6 (0.4) nmol/l). No changes were found for lipids, resting heart rate, or blood pressure, weight, or percentage body fat. Conclusion: Although supplementation with 200 mg/day androstenedione increases AUC for serum androstenedione in the day 0 condition, continued supplementation is characterised by a diminished treatment response, coupled with time 0 increases in testosterone precursors but not testosterone.
<i>Helicobacter pylori</i>infection in gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma: a re-evaluation
Authors: Larissa Sena Teixeira Mendes, Ayoma D Attygalle, Andrew C Wotherspoon
Journal: Gut (2014)

In 1991 Wotherspoon et al 1 showed a close association between Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML) with the organism present in 92% of cases. Other studies have shown this association to be varying between 42% and 100%. In vitro studies at that time showed that lymphoma cell proliferation was associated with the presence of H. pylori mediated through specific tumour infiltrating T cells in a contact dependant manner. In the light of this finding Wotherspoon et al 1 were able to demonstrate that eradication of H. pylori induced lymphoma regression. 

In a recent Gut article, Nakamura et al 2 demonstrated that H. pylori eradication therapy can result in durable lymphoma regression in the majority of cases. However, absence of H. pylori infection is a known predictive factor for eradication resistance.3 

Prevalence of H. pylori has shown signs of decrease especially among Western populations. A decline in the number of GML H. pylori -positive has also been reported.4–7 To address these issues, we performed a retrospective review to analyse the H. pylori infection status …
The life span of major histocompatibility complex-peptide complexes influences the efficiency of presentation and immunogenicity of two class I-restricted cytotoxic T lymphocyte epitopes in the Epstein-Barr virus nuclear antigen 4.
Authors: V Levitsky, Q J Zhang, J Levitskaya, M G Masucci
Journal: The Journal of Experimental Medicine (1996)

We have investigated the reactivity to two human histocompatibility leukocyte antigen (HLA) A11-restricted cytotoxic T lymphocyte (CTL) epitopes derived from amino acids 416-424 (IVTDFSVIK, designated IVT) and 399-408 (AVFDRKSVAK, designated AVF) of the Epstein-Barr virus (EBV) nuclear antigen (EBNA) 4. A strong predominance of CTL clones specific for the IVT epitope was demonstrated in polyclonal cultures generated by stimulation of lymphocytes from the EBV-seropositive donor BK with the autologous B95.8 virus-transformed lymphoblastoid cell line (LCL). This was not due to intrinsic differences of CTL efficiency since clones specific for the two epitopes lysed equally well A11-positive phytohemagglutinin blasts and LCLs pulsed with the relevant synthetic peptide. Irrespective of the endogenous levels of EBNA4 expression, untreated LCLs were lysed more efficiently by the IVT-specific effectors, suggesting that a higher density of A11-IVT complexes is presented at the cell surface. In accordance, 10-50-fold higher amounts of IVT peptides were found in high-performance liquid chromatography fractions of acid extracts corresponding to an abundance of about 350-12,800 IVT and 8-760 AVF molecules per cell. Peptide-mediated competition of CTL sensitization, transport assays in streptolysin-O permeabilized cells, and induction of A11 expression in the transporter associated with antigen presentation-deficient T2/A11 transfectant demonstrated that the IVT and AVF peptides bind with similar affinities to A11, are translocated with equal efficiency to the endoplasmic reticulum, and form complexes of comparable stability over a wide range of temperature and pH conditions. A rapid surface turnover of A11 molecules containing the AVF peptide was demonstrated in metabolically active T2/A11 cells corresponding to a half-life of approximately 3.5 as compared to approximately 2 h for molecules induced at 26 degrees C in the absence of exogenous peptides and &amp;gt;12 h for IVT-containing complexes. This difference in persistence is likely to determine the representation of individual class I-restricted CTL epitopes within the cell surface pool of molecules, and may be an important factor contributing to their immunogenicity.
Rare Coding Sequence Changes are Consistent with Ecdysozoa, not Coelomata
Authors: M. Irimia, I. Maeso, D. Penny, J. Garcia-Fernandez, S. W. Roy
Journal: Molecular Biology and Evolution (2007)

There is growing interest in the use of alternative, more slowly-evolving RGCs (rare genomic changes). Recently, Rogozin and coauthors (Rogozin et al. 2007) proposed a novel phylogenetic method employing rare amino acid changes, RGC-CAMs (rare genomic changes-conserved amino acids-multiple substitutions). They applied their method to 694 sets of eukaryotic orthologs in order to distinguish the relationship between nematodes, arthropods and deuterostomes. They concluded that such rare amino acid changes were consistent with the Coelomata hypothesis, which groups arthropods and deuterostomes to the exclusion of nematodes. Here we use newly available genomic sequences from Nematostella vectensis, a basal metazoan, and from Brugia malayi, an additional nematode. We show that the apparent support for Coelomata is likely to be the result of the rapid rate of evolution leading to Caenorhabditis nematodes. Including the additional species paints a very different picture, with 13 remaining characters consistent with Ecdysozoa versus only 1 consistent with Coelomata.
Single Lung Transplantation for Pulmonary Hypertension
Authors: Michael K. Pasque, Elbert P. Trulock, Joel D. Cooper, Anastasios N. Triantafillou, Charles B. Huddleston, Michael Rosenbloom, Sudhir Sundaresan, James L. Cox, G. Alexander Patterson
Journal: Circulation (1995)

The present study considered the uniformity and durability of the cardiopulmonary response to single lung transplantation in patients with severe pulmonary hypertension, as well as its effect on length and quality of survival.Thirty-four patients with pulmonary hypertension underwent evaluation, single lung transplantation, and follow-up assessment between November 1, 1989, and June 1, 1994. Operative survival for the entire group of patients was reasonable, with 91% (31 of 34 patients) surviving and being discharged from the hospital following transplantation. The actuarial survival for these 34 patients at 1-, 2-, and 3-year follow-up was 78%, 66%, and 61%, respectively. In the subgroup of 24 patients with primary pulmonary hypertension (PPH), 96% (23 of 24) were successfully discharged from the hospital after transplantation. The actuarial survival for this isolated PPH subgroup at 1-, 2-, and 3-year follow-up was 87%, 76%, and 68%, respectively. The uniform, early posttransplant normalization of pulmonary vascular resistance and right ventricular ejection fraction appears to persist throughout the 4-year follow-up period. Despite a high prevalence of bronchiolitis obliterans, the majority of survivors remain in New York Heart Association functional class I or II and are employed.Single lung transplantation can be performed in patients with end-stage pulmonary vascular disease with reasonable expectations for a relatively low operative mortality; immediate, complete, and durable amelioration of pulmonary hypertension and right ventricular failure; and optimal use of limited donor organ supply.