tbuckley/cabot-search huggingface dataset:
Peak Oxygen Consumption as a Predictor of Death in Patients With Heart Failure Receiving β-Blockers
Authors: James O. O’Neill, James B. Young, Claire E. Pothier, Michael S. Lauer
Journal: Circulation (2005)

Background— Peak oxygen uptake (peak V̇ o 2 ) is a strong predictor of mortality and is commonly used in the evaluation of patients for cardiac transplantation. β-Blockers reduce mortality in patients with heart failure, without influencing peak V̇ o 2 , raising the possibility that peak V̇ o 2 is no longer suitable as an indicator of prognosis in these patients. Methods and Results— We analyzed prospectively gathered data on 2105 patients referred for cardiopulmonary testing for all-cause mortality and for occurrence of death or transplantation. Patients receiving β-blockers were younger, more likely to have coronary disease, and had a greater mean ejection fraction but had a similar peak V̇ o 2 . There were 555 deaths (26%) and 194 (9%) transplants during a median follow-up of 3.5 years. Peak V̇ o 2 was a predictor of mortality irrespective of β-blocker use; a decrease of 1 mL · kg −1 · min −1 resulted in an adjusted hazard ratio (HR) of 1.13 (95% CI 1.09 to 1.17, P &lt;0.0001) in patients not receiving β-blockers and 1.27 (95% CI 1.18 to 1.36, P &lt;0.0001) in patients receiving β-blockers. Similar findings were noted when considering death or transplantation as an end point. β-Blocker use was associated with better outcomes until peak V̇ o 2 values became very low (≈10 mL · kg −1 · min −1 ), at which level survival rates were equally poor. Conclusion— Peak V̇ o 2 is a determinant of survival in patients in heart failure even in the setting of β-blockade. Because of improved survival in patients treated with β-blockers, the cut point value of 14 mg · kg −1 · min −1 for referral for cardiac transplantation in these patients requires reevaluation, and a lower cut point may be more appropriate.
Cell volume increases of physiologic amplitude activate basolateral K and CI conductances in the rabbit proximal convoluted tubule.
Authors: S Breton, M Marsolais, J Y Lapointe, R Laprade
Journal: Journal of the American Society of Nephrology (1996)

The effects of increases in cell volume (CV) of physiologic amplitude, induced either hypotonically or isotonically, were studied on the three major basolateral conductances of rabbit isolated proximal convoluted tubules. CV increases were produced by a 40 mosmol/kg H2O hypotonic shock or by the isotonic replacement of mannitol by 40 mM glucose or alanine. The hypotonic shock led to an increase in CV of 17 +/- 3% (N = 8), whereas additions of glucose and alanine led to increases in CV of 22.6 +/- 2.5% (N = 7) and 28.3 +/- 3.5 (N = 5), respectively. Under all of these conditions, the absolute conductance mediated by the NaHCO3 cotransporter did not vary appreciably. This allowed determination of the variations of the absolute conductances to potassium (GK) and chloride (GCl) from their measured partial conductances. All three protocols induced significant increases in GK by factors of 2.37 +/- 0.3, 1.43 +/- 0.16, and 1.69 +/- 0.40, and in GCI by factors of 3.32 +/- 0.57, 3.68 +/- 0.75, and 3.90 +/- 1.0 during the hypotonic, glucose, and alanine protocols, respectively. These increases in GK and GCl occurred with a delay compared with the variations in CV, indicating a more elaborate signaling mechanism than stretch-activation of channels that are known to activate channels within seconds. Intracellular pH increased from 7.19 +/- 0.03 to 7.23 +/- 0.03, 7.17 +/- 0.02 to 7.20 +/- 0.02, and 7.13 +/- 0.01 to 7.16 +/- 0.01 after the hypotonic shock and the glucose and alanine additions, respectively. The study presented here demonstrates that there is a close relationship between CV and GK and GCl, independent of the means used (hypotonically or isotonically) to increase CV in rabbit proximal convoluted tubules. CV activation of GK is proposed to account for part of the increase in GK reported previously during activation of transepithelial transport.
Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model.
Authors: A W Nienhuis, R E Donahue, S Karlsson, S C Clark, B Agricola, N Antinoff, J E Pierce, P Turner, W F Anderson, D G Nathan
Journal: Journal of Clinical Investigation (1987)

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematopoietic reconstitution after autologous bone marrow transplantation was evaluated in a primate model. Animals were given a continuous intravenous infusion of recombinant human GM-CSF for several days both before and after transplantation or only after the transplant procedure. Marrow ablation was accomplished by total body irradiation. In both groups of animals, the neutrophil count reached 1,000/mm3 by 8-9 d posttransplant compared with an interval of 17 and 24 d for two concurrent controls. After withdrawal of GM-CSF, neutrophil counts fell to values comparable to those observed in untreated controls. Accelerated recovery of platelet production was also observed in four of the five animals. Two additional animals were initially given GM-CSF several weeks posttransplantation because of inadequate engraftment. Prompt and sustained increases in neutrophil and platelet counts were observed. We conclude that GM-CSF may be useful in accelerating bone marrow reconstitution.
Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma
Authors: Priscilla T.-Y. Law, Hao Qin, Arthur K.-K. Ching, Keng Po Lai, Ngai Na Co, Mian He, Raymond W.-M. Lung, Anthony W.-H. Chan, Ting-Fung Chan, Nathalie Wong
Journal: Journal of Hepatology (2013)
Epithelial-Specific Cre/lox Recombination in the Developing Kidney and Genitourinary Tract
Authors: Xinli Shao, Stefan Somlo, Peter Igarashi
Journal: Journal of the American Society of Nephrology (2002)

Ksp-cadherin is a unique, tissue-specific member of the cadherin family of cell adhesion molecules that is expressed in tubular epithelial cells in the kidney and developing genitourinary (GU) tract. It has recently been shown that a 1341-bp fragment of the 5' flanking region containing the Ksp-cadherin gene promoter can recapitulate the complete expression pattern of the gene in the developing kidney and GU tract. Similar to the endogenous Ksp-cadherin gene, transgenes containing 1341 bp of the 5' flanking region are expressed in developing nephrons, ureteric bud, mesonephric tubules, Wolffian duct, and Müllerian duct. In adult mice, the expression is restricted to renal tubules. In the current study, Ksp1.3/Cre transgenic mice carrying 1329 bp of the Ksp-cadherin 5' flanking region linked to the Cre recombinase gene were produced. Adult transgenic mice expressed Cre recombinase in renal tubules, especially collecting ducts and thick ascending limbs of Henle's loops. Transgenic embryos expressed Cre recombinase in the branching ureteric bud, developing renal tubules, and sex ducts. Ksp1.3/Cre transgenic mice were crossed with mice carrying a lacZ reporter gene that is activated by Cre/lox-mediated genetic recombination. Bitransgenic progeny expressed lacZ exclusively in renal tubules, mesonephric tubules, ureteric bud, developing ureter, and Wolffian duct. These results demonstrate that Ksp1.3/Cre transgenic mice express Cre recombinase exclusively in the kidney and developing GU tract and can mediate epithelial-specific Cre/lox recombination in these tissues. Ksp1.3/Cre transgenic mice should be useful for cell lineage studies and kidney-specific gene targeting.
A biomechanical comparison between the central one-third patellar tendon and the residual tendon.
Authors: M J Matava, W C Hutton
Journal: British Journal of Sports Medicine (1995)

The purpose of this study was to compare the tensile strength of the central one third patellar tendon--as used for reconstruction of the anterior cruciate ligament--to that of the residual patellar tendon. Ten matched pairs of human cadaveric knees were used for this study, each specimen consisting of an intact patella-patellar tendon-proximal tibial unit. One knee from each pair was randomly selected for removal of both the medial and lateral one third of the patellar tendon, leaving the central one third intact. The contralateral knee of each pair underwent removal of the central one third of the patellar tendon, leaving the residual two thirds intact. Each specimen was then mounted in a materials testing machine and tensile tested to failure at a strain rate of 100%.s-1. The most important result to emerge from these experiments was that there was no significant difference in maximum force to failure for the residual patellar tendon compared to the central one third. Thus any thought that removal of the central one third as a graft still leaves a tendon twice as wide and therefore twice as strong as a graft is dispelled by these experiments.
Making time stand still
Authors: L. Farrell
Journal: BMJ (2001)

I was being interviewed recently on radio about primary care groups. My voice, like my life, has an irritating nasal twang, but for once I was being impressive and articulate. “You obviously have a very clear understanding of this subject,” said the interviewer admiringly. “Yes,” I said, “and that's because I'm making it up as I go along.”

We seem to have been continuously reorganising over the past 10 years, and at this stage I have given …
Localization and cellular sources of activins in normal and fibrotic rat liver
Authors: P J De Bleser, T Niki, G Xu, V Rogiers, A Geerts
Journal: Hepatology (1997)

Activins are dimeric proteins, members of the transforming growth factor β (TGF-β) gene superfamily, consisting of the β-subunits of inhibin (β A and β B ). Recently, it was shown that activin A (β A :β A ) inhibits DNA replication and induces apoptosis in rat parenchymal cells in vitro and in vivo. Cryostat sections of normal livers and livers of rats treated with intraperitoneal injections of CCl 4 were stained for the different inhibin subunits and desmin, a marker for stellate cells (SC). Staining for inhibin-α was invariably negative, both in normal and fibrotic rat liver. In normal liver, inhibin-β A subunit immunoreactivity was localized in parenchymal cells (PC). Staining for inhibin-β B was weaker but similarly distributed. In fibrotic livers, connective tissue septa were strongly immunoreactive for inhibin-β A . Desmin-positive stellate cells (SC) accumulated in areas strongly immunoreactive for inhibin-β A and several cells were positive for both desmin and inhibin-β A . Staining for inhibin-β B was weaker but similarly distributed. As above data pointed to a possible role for PC and SC, we examined by Northern blot analysis, the expression of inhibin-α, -β A , and -β B messenger RNA (mRNA) in total RNA extracted from freshly isolated SC and PC of normal and CCl 4 -treated liver and in cultured SC. Inhibin-β A mRNA was predominantly expressed in PC of normal liver. Expression was lost in PC of CCl 4 -treated liver. Inhibin-β B mRNA expression was induced in SC of CCl 4 -treated liver. Inhibin-β A mRNA, and to a lesser extent, inhibin-β B mRNA expression was rapidly induced in cultured SC. The presence of activin A in conditioned media of cultured SC was shown by Western blotting. Apoptotic cells, identified by terminal deoxy-transferase mediated X-dUTP nick end labeling (TUNEL)-staining, were found predominantly in and near the fibrotic septa. In conclusion: 1) while activin A was constitutively expressed in PC of normal liver, its expression was lost in PC of fibrotic liver; 2) expression of activins was induced in activated SC; and 3) apoptotic cells were found predominantly near the septa, in support of the hypothesis that activin A, derived from activated SC in the septa, contributes to the induction of cell death in neighboring PC.
Coffee, Caffeine, and Risk of Type 2 Diabetes
Authors: Rob M. van Dam, Walter C. Willett, JoAnn E. Manson, Frank B. Hu
Journal: Diabetes Care (2006)

OBJECTIVE—High habitual coffee consumption has been associated with a lower risk of type 2 diabetes, but data on lower levels of consumption and on different types of coffee are sparse. RESEARCH DESIGN AND METHODS—This is a prospective cohort study including 88,259 U.S. women of the Nurses’ Health Study II aged 26–46 years without history of diabetes at baseline. Consumption of coffee and other caffeine-containing foods and drinks was assessed in 1991, 1995, and 1999. We documented 1,263 incident cases of confirmed type 2 diabetes between 1991 and 2001. RESULTS—After adjustment for potential confounders, the relative risk of type 2 diabetes was 0.87 (95% CI 0.73–1.03) for one cup per day, 0.58 (0.49–0.68) for two to three cups per day, and 0.53 (0.41–0.68) for four or more cups per day compared with nondrinkers (P for trend &amp;lt;0.0001). Associations were similar for caffeinated (0.87 [0.83–0.91] for a one-cup increment per day) and decaffeinated (0.81 [0.73–0.90]) coffee and for filtered (0.86 [0.82–0.90]) and instant (0.83 [0.74–0.93]) coffee. Tea consumption was not substantially associated with risk of type 2 diabetes (0.88 [0.64–1.23] for four or more versus no cups per day; P for trend = 0.81). CONCLUSIONS—These results suggest that moderate consumption of both caffeinated and decaffeinated coffee may lower risk of type 2 diabetes in younger and middle-aged women. Coffee constituents other than caffeine may affect the development of type 2 diabetes.
GSK and Roche tell MPs that more clinical trial data should be published
Authors: A. O'Dowd
Journal: BMJ (2013)

Two of the world’s largest drug companies have told MPs in parliament that they support a policy of publishing all clinical trial data.

A leading academic and clinician has, however, questioned their assertions and challenged them over how closely their promises would manifest into action.

MPs on the House of Commons Science and Technology Committee held an evidence session on 22 April for their inquiry into clinical trials. The inquiry is in the context of the European Commission’s proposal to revise the clinical trials directive that regulates trials in the United Kingdom and comes after concerns raised about transparency and disclosure of all trial data: drug companies are entitled to conduct numerous clinical trials on drugs but publish selectively.

MPs asked witnesses whether all clinical trials funded by …
Effects of steroid therapy on inflammatory cell subtypes in asthma
Authors: D. C. Cowan, J. O. Cowan, R. Palmay, A. Williamson, D. R. Taylor
Journal: Thorax (2009)

<h3>Rationale</h3> Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). <h3>Objectives</h3> To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). <h3>Methods</h3> Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 μg daily for 28+ days. Cut-off points were ≥/&lt;2% for sputum eosinophils and ≥/&lt;61% for neutrophils. <h3>Results</h3> After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p&lt;0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. <h3>Conclusions</h3> After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.
Smad7 inhibits angiotensin II-induced hypertensive cardiac remodelling
Authors: Li-Hua Wei, Xiao-Ru Huang, Yang Zhang, You-Qi Li, Hai-yong Chen, Bryan P. Yan, Cheuk-Man Yu, Hui Yao Lan
Journal: Cardiovascular Research (2013)

Smad7 plays a negative regulatory role in many inflammatory diseases, but its effect on hypertensive disease remains unknown. The present study tested the hypothesis that overexpression of Smad7 may have therapeutic potential for angiotensin II (Ang II)-mediated hypertensive cardiac remodelling. Hypertensive heart disease was induced in mice by subcutaneous infusion of Ang II for 28 days and treated with Smad7 by a non-invasive ultrasound-microbubble-mediated inducible Smad7 gene transfer. We found that cardiac Smad7 was largely reduced in the hypertensive heart and overexpression of cardiac Smad7 protected against the fall in the left ventricular (LV) ejection fraction (EF), an increase in LV mass, and cardiac inflammation and fibrosis such as up-regulation of pro-inflammatory cytokines (IL-1β, TNF-α) and fibrotic markers (collagen I, α-SMA), and infiltration of CD3+ T cells and F4/80+ macrophages. Further studies revealed that inactivation of the Sp1-TGF-β/Smad3-NF-κB (NF-κB, nuclear factor κB) pathways and prevention of cardiac miR-29 loss were mechanisms by which overexpression of Smad7 inhibited Ang II-mediated cardiac remodelling. Importantly, we also found that treatment with Smad7 when hypertensive cardiopathy established at day 14 halted the progression of cardiac injury by blunting the fall of EF and an increase in LV mass, and blocking TGF-β/Smad3-mediated cardiac fibrosis and NF-κB-driven inflammation. Smad7 plays a protective role in Ang II-induced cardiac remodelling via mechanisms involving the Sp1-TGF-β/Smad-NF-κB-miR-29 regulatory network. Thus, Smad7 may be a novel therapeutic agent for hypertensive cardiovascular diseases.
A Specific Splicing Variant of SVH, a Novel Human Armadillo Repeat Protein, Is Up-Regulated in Hepatocellular Carcinomas
Authors: Ruimin Huang, Zhigang Xing, Zhidong Luan, Tangming Wu, Xin Wu, Gengxi Hu
Journal: Cancer Research (2003)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. By representational difference analysis (RDA), a novel human gene designated SVH, up-regulated in the clinical HCC sample, was identified. The deduced SVH protein consisted of 343 amino acids with a transmembrane domain and an armadillo repeat. Northern blot revealed that SVH was expressed in most human adult tissues. Four variants of SVH, SVH-A, -B, -C, and -D, resulting from alternative splicing in the coding region of the SVH transcript, were observed and were all localized in endoplasmic reticulum (ER). Up-regulation of SVH-B, but not the other variants, was evident in about 60% (28 of 46) of HCC samples, detected by quantitative real-time PCR. Human liver cell line QSG-7701, transfected with SVH-B, acquired an accelerated growth rate and tumorigenicity in nude mice, whereas inhibition of SVH-B in hepatoma cell line BEL-7404, using antisense oligodeoxynucleotides, induced apoptosis. It is suggested that the splicing variants of SVH have distinct biological functions, and SVH-B may play an important role in hepatocarcinogenesis.
Nuclear factor-kappa B (NF-kappaB) inducing kinase is preferentially expressed in rheumatoid arthritis synovial tissue containing ectopic lymphoid neogenesis
Authors: A-R Noort, K P M van Zoest, M Modesti, S W Tas, P P Tak
Journal: Annals of the Rheumatic Diseases (2010)

Background and ObjectivesIn approximately 30% of patients with rheumatoid arthritis (RA), synovial infl ammation is characterised by ectopic lymphoid neogenesis (ELN) resulting in 'germinal centre-like' structures that contain dendritic cells (DC) and aggregates of B and T cells.This process does not defi ne a specifi c disease subset and also occurs in other types of chronic infl ammation.Nuclear factor-kappaB (NF-kappaB) transcription factors are not only essential for the expression of proinfl ammatory cytokines, but also induce regulatory circuits.These regulatory properties are thought to be governed at least in part by the non-canonical NF-kappaB pathway of which NF-kappaB-inducing kinase (NIK) is a key mediator.Non-canonical NF-kappaB signalling can be triggered by stimuli like CD40L and lymphotoxin α1β2 that are abundantly present in ELN.In addition, non-canonical NF-kappaB signalling is involved in indoleamine-2,3-dioxygenase (IDO) expression in DC that can suppress T cell responses and promote tolerance.Recently it was demonstrated that these cells may play an important role in the balance between regulatory T cells (Tregs) and Th17 cells.We investigated the presence of regulatory mechanisms in RA synovial tissue (ST) in relationship to ELN.We therefore studied the expression and distribution of NIK, IDO, Foxp3 (as a marker of Tregs) and interleukin 17 (IL17) expressing cells in ST with and without ELN.Methods Using immunohistochemistry, we analysed the expression of NIK, IDO, Foxp3 and IL17 in ST of 40 RA patients.ST was obtained via mini-arthroscopy of infl amed knee or ankle joints of RA patients with active disease.Expression was scored on a semiquantitative 5-point scale (0-4) by two independent observers.Foxp3 expression was quantifi ed by scoring the number of positive cells per HPF.Results ELN was present in 15 out of 40 RA ST.NIK expression was signifi cantly higher in ST with ELN and more abundantly present within lymphocyte aggregates (1.53 + 0.32 vs 0.62 + 0.19; p<0.05).We also observed more Foxp3 positive cells in ST containing ELN (6.02 + 1.37 vs 4.36 + 1.31).IDO and IL17-expressing cells were found in ST with and without ELN, but no signifi cant difference between the two types of synovial infl ammation was found.Conclusions NIK is preferentially expressed in RA ST containing ELN in association with a trend towards more Tregs.This may point towards a regulatory role for the non-canonical NF-kappaB pathway in RA synovial infl ammation, which could be exploited for the development of future new therapies.on July 17,