tbuckley/cabot-search huggingface dataset:
Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis
Authors: Yuji Oba, Siva T Sarva, Sofia Dias
Journal: Thorax (2015)

The place of long-acting β agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations in stable patients with COPD is not well defined. The purpose of this study was to systematically review the efficacy and safety of LABA/LAMA combinations.Several databases and manufacturers' websites were searched for relevant clinical trials. Randomised control trials, at least 12 weeks duration, comparing a LABA/LAMA combination with placebo and/or monotherapy were included. The data were pooled using a network as well as a traditional direct comparison meta-analysis.Twenty-three trials with a total of 27 172 patients were included in the analysis. LABA/LAMA combinations were associated with a greater improvement in lung function, St. George's Respiratory Questionnaire (SGRQ) score, and Transitional Dyspnoea Index (TDI) than monotherapies. LABA/LAMA combinations were associated with a significantly greater proportion of SGRQ and TDI responders than monotherapies (OR 1.23 (95% credible interval (CrI) 1.06-1.39), OR 1.34 (95% CrI 1.19-1.50) versus LABAs and OR 1.24 (95% CrI 1.11-1.36), OR 1.31 (95% CrI 1.18-1.46) versus LAMAs, respectively) and fewer moderate-to-severe exacerbations compared with LABAs (HR 0.82 (95% CrI 0.73-0.93)), but not when compared with LAMAs (HR 0.92 (95% CrI 0.84-1.00)). There were no statistically significant differences associated with LABA/LAMA combinations compared with monotherapies in safety outcomes as well as in severe exacerbations.The combination therapy was the most effective strategy in improving lung function, quality of life, symptom scores and moderate-to-severe exacerbation rates, and had similar effects on safety outcomes and severe exacerbations as compared with monotherapies.
T cell–mediated vascular dysfunction of human allografts results from IFN-γ dysregulation of NO synthase
Authors: Kian Peng Koh, Yinong Wang, Tai Yi, Stephen L. Shiao, Marc I. Lorber, William C. Sessa, George Tellides, Jordan S. Pober
Journal: Journal of Clinical Investigation (2004)

Allograft vascular dysfunction predisposes to arteriosclerosis and graft loss. We examined how dysfunction develops in transplanted human arteries in response to circulating allogeneic T cells in vivo using immunodeficient murine hosts. Within 7–9 days, transplanted arteries developed endothelial cell (EC) dysfunction but remained sensitive to exogenous NO. By 2 weeks, the grafts developed impaired contractility and desensitization to NO, both signs of VSMC dysfunction. These T cell–dependent changes correlated with loss of eNOS and expression of iNOS — the latter predominantly within infiltrating T cells. Neutralizing IFN-γ completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-γ production and partially prevented dysfunction. Inhibiting iNOS partially preserved responses to NO at 2 weeks and reduced graft intimal expansion after 4 weeks in vivo. In vitro, memory CD4+ T cells acted on allogeneic cultured ECs to reduce eNOS activity and expression of protein and mRNA. These effects required T cell activation by class II MHC antigens and costimulators (principally lymphocyte function-associated antigen–3, or LFA-3) on the ECs and were mediated by production of soluble mediators including IFN-γ and TNF. We conclude that IFN-γ is a central mediator of vascular dysfunction and, through dysregulation of NOS expression, links early dysfunction with late arteriosclerosis.
EFFECTIVENESS OF PACLITAXEL-ELUTING BALLOON CATHETER IN PATIENTS WITH CORONARY IN-STENT RESTENOSIS
Authors: Seiji Habara, Kazuaki Mitsudo, Kazushige Kadota, Tsuyoshi Goto, Naoki Oka, Yasushi Fuku, Shingo Hosogi, Hiroyuki Tanaka, Takeshi Tada, Yoshikazu Shigemoto, Daiji Hasegawa, Suguru Otsuru, Naoki Saito, Yuki Hayakawa
Journal: Journal of the American College of Cardiology (2011)
Do radiographic features of acute infection influence management of lower respiratory tract infections in the community?
Authors: JC Simpson, P Hulse, PM Taylor, M Woodhead
Journal: European Respiratory Journal (1998)

Community-acquired lower respiratory tract infection (LRTI) is a common clinical problem, and a chest radiograph is the most common investigation. This study investigated why general practitioners (GPs) request radiographs and whether radiographic features of LRTI affect management. The 12 month study included GP-requested chest radiographs performed at the Manchester Royal Infirmary. The GPs of patients with radiographic evidence of LRTI were sent a questionnaire. Radiographs (n=2,538) were performed in patients aged >15 yrs. One hundred and eleven (4.4%) chest radiographs showed evidence of LRTI, and 97 (87%) were included in the analysis. Fifty-six (62%) had their radiograph requested at the second or third visit. Forty-five (58%) radiographs were performed to confirm infection. In 47 (48%) of cases the GP felt the radiograph had affected treatment. An effect on treatment was significantly more common in patients not receiving antibiotics prior to the radiograph. Twenty-nine (32%) of GPs felt a normal radiograph would have affected management, most often with respect to antibiotic prescriptions (17 (58%)). Where the radiologist's report suggested a repeat radiograph or hospital referral, this was significantly more likely to have occurred. The commonest reason for a radiograph in patients with suspected lower respiratory tract infection is to confirm the infection. In the opinion of the general practitioner the results of the radiograph do affect patient treatment. The wording of the radiologists report is associated with patient management.
Peptide Nanofibers Preconditioned with Stem Cell Secretome Are Renoprotective
Authors: Yin Wang, Erica Bakota, Benny H.J. Chang, Mark Entman, Jeffrey D. Hartgerink, Farhad R. Danesh
Journal: Journal of the American Society of Nephrology (2011)

Stem cells may contribute to renal recovery following acute kidney injury, and this may occur through their secretion of cytokines, chemokines, and growth factors. Here, we developed an acellular, nanofiber-based preparation of self-assembled peptides to deliver the secretome of embryonic stem cells (ESCs). Using an integrated in vitro and in vivo approach, we found that nanofibers preconditioned with ESCs could reverse cell hyperpermeability and apoptosis in vitro and protect against lipopolysaccharide-induced acute kidney injury in vivo. The renoprotective effect of preconditioned nanofibers associated with an attenuation of Rho kinase activation. We also observed that the combined presence of follistatin, adiponectin, and secretory leukoprotease during preconditioning was essential to the renoprotective properties of the nanofibers. In summary, we developed a designer-peptide nanofiber that can serve as a delivery platform for the beneficial effects of stem cells without the problems of teratoma formation or limited cell engraftment and viability.
Normal Fasting Plasma Glucose and Risk of Type 2 Diabetes
Authors: Paolo Brambilla, Elisa La Valle, Rosanna Falbo, Giuseppe Limonta, Stefano Signorini, Fabrizio Cappellini, Paolo Mocarelli
Journal: Diabetes Care (2011)

To investigate the association of normal fasting plasma glucose (FPG) and the risk for type 2 diabetes.Data concerning 13,845 subjects, aged 40-69 years, who had their FPG measured at least three times between 1992 and 2008 were extracted from a database. Three FPG groups were defined (51-82, 83-90, and 91-99 mg/dL). A Cox proportional hazards analysis was applied to estimate the risk of incident diabetes adjusted for other risk factors.During 108,061 person-years of follow-up (8,110 women and 5,735 men), 307 incident cases of type 2 diabetes were found. The final model demonstrated a hazard ratio of 2.03 (95% CI 1.18-3.50) for 91-99 mg/dL and 1.42 (0.42-4.74) for 83-90 mg/dL.Our data suggest that FPG between 91 and 99 mg/dL is a strong independent predictor of type 2 diabetes and should be used to identify people to be further investigated and aided with preventive measures.
What are the roles of metalloproteinases in cartilage and bone damage?
Authors: G Murphy
Journal: Annals of the Rheumatic Diseases (2005)

A role for metalloproteinases in the pathological destruction in diseases such as rheumatoid arthritis and osteoarthritis, and the irreversible nature of the ensuing cartilage and bone damage, have been the focus of much investigation for several decades. This has led to the development of broad spectrum metalloproteinase inhibitors as potential therapeutics. More recently it has been appreciated that several families of zinc dependent proteinases play significant and varied roles in the biology of the resident cells in these tissues, orchestrating development, remodelling, and subsequent pathological processes. They also play key roles in the activity of inflammatory cells. The task of elucidating the precise role of individual metalloproteinases is therefore a burgeoning necessity for the final design of metalloproteinase inhibitors if they are to be employed as therapeutic agents.
Insulin-like growth factor-1 (IGF-1) enhances recovery from HgCl2-induced acute renal failure
Authors: M Friedlaender, M M Popovtzer, O Weiss, I Nefesh, J Kopolovic, I Raz
Journal: Journal of the American Society of Nephrology (1995)

Several growth factors have been found to play an important role in the recovery from acute renal failure (ARF). The effect of the continuous subcutaneous infusion of human recombinant insulin-like growth factor (IGF)-1 (125 micrograms daily by osmotic minipumps) in a rat model of mercuric chloride (HgCl2)-induced ARF was examined. HgCl2 (4 mg/kg) induced ARF with a mortality that was unaffected by IGF-1. However, IGF-1 significantly enhanced functional and histologic recovery in the survivors, as measured by serum creatinine and creatinine clearance and by histologic scoring. Solution hybridization RNAase protection assays showed that renal IGF-1 mRNA, IGF-1 receptor (IGF-1R) mRNA, and IGF-binding protein-1 (IGFBP-1) mRNA were unaffected by exogenous IGF-1, but this treatment significantly increased renal IGF-1 in ARF rats compared with normal rats and ARF rats not receiving IGF-1. After ARF renal mRNA for IGF-1 was decreased, IGF-1R was unchanged and IGFBP-1 was increased. Similar changes occurred in IGF-1-infused ARF rats. Thus, (1) IGF-1 enhances recovery from nephrotoxic ARF both functionally and histologically; (2) in nephrotoxic ARF, there is (a) a reduction in IGF-1 mRNA expression that is not prevented by IGF-1 infusion, and (b) an increase in renal IGFBP-1 mRNA. This may allow a significant increase in renal IGF-1 levels in IGF-1-infused ARF rats, despite the decrease in renal IGF-1 mRNA. A local increase in renal IGFBP-1 and IGF-1 may explain the accelerated recovery from ATN in this model. It was concluded that HgCl2-induced ARF is amenable to improvement by IGF-1 infusion and that the increase in renal IGFBP-1 mRNA may be an important modulator in the recovery of the kidney.
Proline and γ-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4
Authors: Yucheng Yao, Ani Shahbazian, Kristina I. Boström
Journal: Circulation Research (2008)

Arterial calcification is ubiquitous in vascular disease and is, in part, prevented by matrix Gla protein (MGP). MGP binds calcium ions through gamma-carboxylated glutamates (Gla residues) and inhibits bone morphogenetic protein (BMP)-2/-4. We hypothesized that a conserved proline (Pro)64 is essential for BMP inhibition. We further hypothesized that calcium binding by the Gla residues is a prerequisite for BMP inhibition. Site-directed mutagenesis was used to modify Pro64 and the Gla residues, and the effect on BMP-4 activity, and binding of BMP-4 and calcium was tested using luciferase reporter gene assays, coimmunoprecipitation, crosslinking, and calcium quantification. The results showed that Pro64 was critical for binding and inhibition of BMP-4 but not for calcium binding. The Gla residues were also required for BMP-4 binding but flexibility existed. As long as 1 Gla residue remained on each side of Pro64, the ability to bind and inhibit BMP-4 was preserved. Chelation of calcium ions by EDTA or warfarin treatment of cells led to loss of ability of MGP to bind BMP-4. Our results also showed that phenylalanine could replace Pro64 without loss of function and that zebrafish MGP, which lacks upstream Gla residues, did not function as a BMP inhibitor. The effect of MGP mutagenesis on vascular calcification was determined in calcifying vascular cells. Only MGP proteins with preserved ability to bind and inhibit BMP-4 prevented osteogenic differentiation and calcification. Together, our results suggest that BMP and calcium binding in MGP are independent but functionally intertwined processes and that the BMP binding is essential for prevention of vascular calcification.
Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Diabetes and Severe Aortic Stenosis at High Risk for Surgery
Authors: Brian R. Lindman, Philippe Pibarot, Suzanne V. Arnold, Rakesh M. Suri, Thomas C. McAndrew, Hersh S. Maniar, Alan Zajarias, Susheel Kodali, Ajay J. Kirtane, Vinod H. Thourani, E. Murat Tuzcu, Lars G. Svensson, Ron Waksman, Craig R. Smith, Martin B. Leon
Journal: Journal of the American College of Cardiology (2013)
Epidemiological study of respiratory disease in workers exposed to polyvinylchloride dust.
Authors: C A Soutar, L H Copland, P E Thornley, J F Hurley, J Ottery, W G Adams, B Bennett
Journal: Thorax (1980)

The respiratory health of workers exposed to polyvinylchloride (PVC) dust has been investigated in 818 men sampled from the work force of a factory manufacturing PVC. In a cross-sectional survey, the lung function and prevalences of respiratory symptoms and chest radiographic abnormalities were compared with estimates of individual PVC dust exposures based on detailed occupational histories and current measurements of respirable PVC dust. Complaints of slight exertional dyspnoea were associated with PVC dust exposure, though age and smoking effects were much stronger. The forced expired volume in one second (FEV1) and forced vital capacity (FVC) were inversely related to dust exposure after age, height, and smoking effects had been taken into account. This effect was seen principally in cigarette smokers, and there was suggestive evidence that PVC dust exposure and cigarette smoking interacted in the reduction of FEV1 and FVC. Gas transfer factor was not related to dust exposure. The chest radiographs were read according to the ILO U/C classification by three experienced readers. One reader recorded a low prevalence of small rounded opacities, and these were not related to age or dust exposure. Another reader recorded a higher prevalence of small rounded opacities category 0/1 or more, and these were related to age but not to dust exposure. The third reader recorded the highest prevalence of small rounded opacities (though none greater than category 1/1), and these were independently related both to age and to PVC dust exposure, indicating an effect of PVC dust on the appearance of the chest radiography. These appearances were so slight that only the higher sensitivity of this reader in the interpretation of profusion of small rounded opacities on the ILO U/C scale enabled detection of this effect of PVC dust. In conclusion, exposure to PVC dust is associated with some deterioration of lung function, slight abnormalities of the chest radiograph, and complaints of slight dyspnoea. The mean decline in FEV1 associated with the average dust exposure experienced in the study was small, though some of the men with higher dust exposures may have suffered clinically important loss of lung function as a result of their occupation.
A Genome-Wide Screen in <b> <i>Saccharomyces cerevisiae</i> </b> Reveals Altered Transport As a Mechanism of Resistance to the Anticancer Drug Bleomycin
Authors: Mustapha Aouida, Nicolas Pagé, Anick Leduc, Matthias Peter, Dindial Ramotar
Journal: Cancer Research (2004)

The potent DNA damaging agent bleomycin (BLM) is highly effective for treating various cancers, although, in certain individuals, the development of cellular resistance to the drug can severely diminish its antineoplastic properties. We performed two independent genome-wide screens using a Saccharomyces cerevisiae mutant collection to isolate variants exhibiting either sensitivity or resistance to BLM. This procedure reproducibly identified a relatively large collection of 231 BLM-hypersensitive mutants, representing genes belonging to diverse functional groups. In contrast, only five BLM-resistant mutants could be recovered by our screens. Among these latter mutants, three were deleted for genes involved in plasma membrane transport, including the L-carnitine transporter Agp2, as well as the kinases Ptk2 and Sky1, which are involved in regulating polyamine transport. We further showed that Agp2 acts as a transporter of BLM and that overexpression of this transporter significantly enhances BLM-induced cell killing. Our data strongly implicate membrane transport as a key determinant in BLM resistance in yeast. This finding is critical, given that very little is known about BLM transport in human cells. Indeed, characterization of analogous mechanisms in humans may ultimately lead to enhancement of the antitumor properties of BLM.
Prenatal Exposures and Glucose Metabolism in Adulthood
Authors: Claudia Thomas, Elina Hyppönen, Chris Power
Journal: Diabetes Care (2007)

Birth weight has been associated with the risk of type 2 diabetes in several studies. We investigated whether prenatal influences on birth weight (gestational age, parity, preeclampsia, prepregnancy BMI, smoking during pregnancy, and socioeconomic position [SEP]) were associated with glucose metabolism in midlife and the role of birth weight for gestational age (BGA) and adult adiposity in mediating these associations.Data from 7,518 participants of the 1958 British Birth Cohort with information on A1C at age 45 years were analyzed. Associations between prenatal exposures and A1C > or =6% were examined using a series of logistic regression models. The basic model consisted of all prenatal factors (except parity) adjusted for sex and family history of type 2 diabetes. Further adjustments included BGA only, concurrent adiposity only (BMI and waist circumference), and BGA plus adiposity.In the basic model, preeclampsia (odds ratio 1.78 [95% CI 1.14-2.80]), prepregnancy BMI > or =25 kg/m(2) (1.90 [1.45-2.47]), maternal smoking (1.33 [1.04-1.71]), and manual SEP (1.87 [1.36-2.58]) were independently associated with A1C at 45 years of age. Adjustment for BGA had little impact on the prenatal factors/A1C associations, whereas adjustment for adult adiposity at 45 years substantially reduced associations for prepregnancy BMI, smoking during pregnancy, and SEP.Prenatal exposures were related to blood glucose levels in mid-adulthood. Associations for several prenatal factors were largely mediated through adult adiposity but surprisingly not through birth weight. Prenatal exposures are likely to have the strongest effect on glucose metabolism indirectly through their influence on adiposity.
Quality of Life With Docetaxel Plus Cisplatin and Fluorouracil Compared With Cisplatin and Fluorouracil From a Phase III Trial for Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group
Authors: Jaffer A. Ajani, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Lucile Awad, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2007)

Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial.Four hundred forty-five patients randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plus fluorouracil 750 mg/m(2)/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m(2) on day 1 plus fluorouracil 1,000 mg/m(2)/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed.The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF.V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.
A decrease of the butyrate-producing species<i>Roseburia hominis</i>and<i>Faecalibacterium prausnitzii</i>defines dysbiosis in patients with ulcerative colitis
Authors: Kathleen Machiels, Marie Joossens, João Sabino, Vicky De Preter, Ingrid Arijs, Venessa Eeckhaut, Vera Ballet, Karolien Claes, Filip Van Immerseel, Kristin Verbeke, Marc Ferrante, Jan Verhaegen, Paul Rutgeerts, Séverine Vermeire
Journal: Gut (2013)

<h3>Objective</h3> Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohn9s disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites. <h3>Design</h3> The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography–mass spectrometry. <h3>Results</h3> Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of <i>Roseburia hominis</i> (p&lt;0.0001) and <i>Faecalibacterium prausnitzii</i> (p&lt;0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found. <h3>Conclusions</h3> The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in <i>R hominis</i> and <i>F prausnitzii,</i> both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.