tbuckley/cabot-search huggingface dataset:
Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model
Authors: A MORTON, N ARNOLD, J GUNN, R VARCOE, S FRANCIS, S DOWER, D CROSSMAN
Journal: Cardiovascular Research (2005)

To determine the influence of IL-1 on the arterial response to experimental injury in porcine models of percutaneous coronary intervention (PCI).An intravenous (i.v.) bolus of 0.5 mg/kg followed by a subcutaneous (s.c.) infusion of 2 mg/kg/24 h of human IL-1 receptor antagonist (IL-1ra) inhibited neutrophil recruitment in response to intradermal IL-1. Using this dose regimen, five groups of pigs were studied: Group 1, oversized balloon angioplasty of 2 coronary vessels (14-day infusion, 28th day sacrifice and analysis); Groups 2, 3, 4, and 5, oversized stenting of 2 coronary vessels (Group 2: 14-day infusion, 28th day analysis; Group 3: 14-day infusion, 14th day analysis; Group 4: 28-day infusion, 28th day analysis; Group 5: 28-day infusion, 90th day analysis). Neointimal area was quantified by standard means.In Group 1, IL-1ra resulted in a 23% decrease in neointimal area (p=0.04); in Group 2, a 34% increase (p=0.001); in Group 3, a 38% decrease (p<0.0001); in Group 4, a 34% decrease (p=0.0004); and in Group 5, a 41% decrease (p=0.00001).IL-1ra was associated with a sustained, significant reduction in neointima after vessel wall injury as long as it is given for the duration of the stimulation of the IL-1 system, in this case at least 28 days. This suggests that therapies based on the antagonism of IL-1 may modulate the coronary artery response to injury.
Combination Therapy With Nateglinide and a Thiazolidinedione Improves Glycemic Control in Type 2 Diabetes
Authors: Julio Rosenstock, Sharen G. Shen, Marjorie R. Gatlin, James E. Foley
Journal: Diabetes Care (2002)

OBJECTIVE—To compare the effects of monotherapy using nateglinide and the thiazolidinedione troglitazone with initial combination of the two agents on glycated hemoglobin (HbA1c) in patients with type 2 diabetes inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS—This study consisted of a 28-week, double-blind, randomized, multicenter study that included a 4-week, single-blind, placebo, run-in period and a 24-week (shortened to 16 weeks), double-blind, active treatment period. RESULTS—At the 16-week end point, nateglinide 120 mg, troglitazone 600 mg, and the combination of the agents achieved statistically significant decreases in HbA1c in comparison with placebo and a baseline HbA1c of 8.1–8.4% (P &amp;lt; 0.001). The reductions in HbA1c were similar in the nateglinide (0.6%) and troglitazone (0.8%) monotherapy groups. The reduction in HbA1c (1.7%) was greatest in the combination group; 79% of patients in the combination group achieved HbA1c levels of &amp;lt;7%. The combination group had a higher number of adverse events, primarily due to an increased incidence of mild hypoglycemia in this treatment group. CONCLUSIONS—Nateglinide and troglitazone are equally effective in decreasing HbA1c levels. However, these reductions from baseline HbA1c values of &amp;gt;8% are not adequate to achieve HbA1c levels of &amp;lt;7%. In contrast, the combination of nateglinide and of a thiazolidinedione shows an additive effect that is highly effective in reducing HbA1c levels to the target of &amp;lt;7% in 66% of patients, from a baseline HbA1c that is just above 8%.
Accurate measurement of intrinsic positive end-expiratory pressure: how to detect and correct for expiratory muscle activity
Authors: SG Zakynthinos, T Vassilakopoulos, E Zakynthinos, C Roussos
Journal: European Respiratory Journal (1997)

It has been shown that expiratory muscle contraction leads to an overestimation of intrinsic positive end-expiratory pressure (PEEPi). To quantify this overestimation, we compared PEEPi, measured during spontaneous breathing (SB) by the end-expiratory airway occlusion technique (PEEPi,occl) with static PEEPi (PEEPi,st). PEEPi,st was measured using end-expiratory airway occlusion during simulation of SB by the ventilator with the patient relaxed, and was considered to represent the "gold standard" for PEEPi,occl. Twelve ventilator-dependent patients were studied during SB (pressure support 5-7 cmH2O). Full mechanical ventilation was resumed when they were unable to sustain SB. Subsequently, by manipulating the variables of the ventilator, we simulated the pattern of SB and measured PEEPi,st, corresponding to PEEPi,occl. On the basis of the presence or absence of expiratory rise in gastric pressure (Pga) (rapid drop of end-expiratory Pga at the beginning of inspiration, Pga,exp,rise), and abdominal muscle electromyographic (EMG) activity, patients were subdivided into those either actively (Group 1) or passively expiring (Group 2). In Group 1 (8 patients), PEEPi,occl was higher than PEEPi,st (13.3+/-2.0 vs 6.8+/-1.1 cmH2O; p<0.01). PEEPi,occl-Pga,exp,rise (6.9+/-1.1 cmH2O) was quite similar to PEEPi,st; their mean difference was 0.03 cmH2O with limits of agreement -0.48 to +0.53 cmH2O. In Group 2, PEEPi,occl was similar to PEEPi,st. We conclude that, in actively expiring patients, an accurate estimation of the actual PEEPi,st can be obtained by subtracting Pga,exp,rise from PEEPi,occl.
Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials
Authors: Catherine J Minns Lowe, Karen L Barker, Michael Dewey, Catherine M Sackley
Journal: BMJ (2007)

<b>Objective</b> To evaluate the effectiveness of physiotherapy exercise after elective primary total knee arthroplasty in patients with osteoarthritis. <b>Design</b> Systematic review. <b>Data sources</b> Database searches: AMED, CINAHL, Embase, King9s Fund, Medline, Cochrane library (Cochrane reviews, Cochrane central register of controlled trials, DARE), PEDro, Department of Health national research register. Hand searches: <i>Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings</i>. <b>Review methods</b> Randomised controlled trials were reviewed if they included a physiotherapy exercise intervention compared with usual or standard physiotherapy care, or compared two types of exercise physiotherapy interventions meeting the review criteria, after discharge from hospital after elective primary total knee arthroplasty for osteoarthritis. <b>Outcome measures</b> Functional activities of daily living, walking, quality of life, muscle strength, and range of motion in the knee joint. Trial quality was extensively evaluated. Narrative synthesis plus meta-analyses with fixed effect models, weighted mean differences, standardised effect sizes, and tests for heterogeneity. <b>Results</b> Six trials were identified, five of which were suitable for inclusion in meta-analyses. There was a small to moderate standardised effect size (0.33, 95% confidence interval 0.07 to 0.58) in favour of functional exercise for function three to four months postoperatively. There were also small to moderate weighted mean differences of 2.9 (0.61 to 5.2) for range of joint motion and 1.66 (−1 to 4.3) for quality of life in favour of functional exercise three to four months postoperatively. Benefits of treatment were no longer evident at one year. <b>Conclusions</b> Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit.
Type 2 Diabetes and the Risk of Parkinson's Disease
Authors: Gang Hu, Pekka Jousilahti, Siamak Bidel, Riitta Antikainen, Jaakko Tuomilehto
Journal: Diabetes Care (2007)

OBJECTIVE—To evaluate whether type 2 diabetes at baseline is a risk factor for Parkinson's disease. RESEARCH DESIGN AND METHODS—We prospectively followed 51,552 Finnish men and women 25–74 years of age without a history of Parkinson's disease at baseline. History of diabetes and other study parameters were determined at baseline using standardized measurements. Ascertainment of the Parkinson's disease status was based on the nationwide Social Insurance Institution's drug register data. Hazard ratios of incident Parkinson's disease associated with the history of type 2 diabetes were estimated. RESULTS—During a mean follow-up period of 18.0 years, 324 men and 309 women developed incident Parkinson's disease. Age- and study year–adjusted hazard ratios of incident Parkinson's disease among subjects with type 2 diabetes, compared with those without it, were 1.80 (95% CI 1.03–3.15) in men, 1.93 (1.05–3.53) in women, and 1.85 (1.23–2.80) in men and women combined (adjusted also for sex). Further adjustment for BMI, systolic blood pressure, total cholesterol, education, leisure-time physical activity, smoking, alcohol drinking, and coffee and tea consumption affected the results only slightly. The multivariate adjusted association between type 2 diabetes and the risk of Parkinson's disease was also confirmed in stratified subgroup analysis. CONCLUSIONS—These data suggest that type 2 diabetes is associated with an increased risk of Parkinson's disease. Surveillance bias might account for higher rates in diabetes. The mechanism behind this association between diabetes and Parkinson's disease is not known.
National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5·4 million participants
Authors: Goodarz Danaei, Mariel M Finucane, John K Lin, Gitanjali M Singh, Christopher J Paciorek, Melanie J Cowan, Farshad Farzadfar, Gretchen A Stevens, Stephen S Lim, Leanne M Riley, Majid Ezzati
Journal: The Lancet (2011)
Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy
Authors: E. Terpos, E. Kastritis, D. Christoulas, M. Gkotzamanidou, E. Eleutherakis-Papaiakovou, N. Kanellias, A. Papatheodorou, M.A. Dimopoulos
Journal: Annals of Oncology (2012)
Ischaemic necrosis of the ilium complicating haemolytic anaemia due to an unstable haemoglobin.
Authors: N W McGill, P Warburton, H Kronenberg, J E Hassall, M A Rossleigh
Journal: Annals of the Rheumatic Diseases (1988)

A case of ischaemic necrosis of bone (INB) affecting the right hemipelvis in a 57 year old woman with an unstable haemoglobinopathy is presented. The rarity of INB in this site, the usefulness of nuclear scanning, and the relation between haemolytic anaemia and INB are discussed.
Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome
Authors: Daniel Kotlarz, Natalia Ziętara, Gulbu Uzel, Thomas Weidemann, Christian J. Braun, Jana Diestelhorst, Peter M. Krawitz, Peter N. Robinson, Jochen Hecht, Jacek Puchałka, E. Michael Gertz, Alejandro A. Schäffer, Monica G. Lawrence, Lela Kardava, Dietmar Pfeifer, Ulrich Baumann, Eva-Doreen Pfister, Eric P. Hanson, Axel Schambach, Roland Jacobs, Hans Kreipe, Susan Moir, Joshua D. Milner, Petra Schwille, Stefan Mundlos, Christoph Klein
Journal: The Journal of Experimental Medicine (2013)

Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21RArg201Leu mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21–induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.
Respiratory viral infections as promoters of allergic sensitization and asthma in animal models
Authors: J. Schwarze, E.W. Gelfand
Journal: European Respiratory Journal (2002)

Respiratory virus infections can trigger exacerbations of asthma and may also contribute to allergic sensitization to aeroallergens and the development of asthma. Conversely, atopy may predispose to more severe virus-induced airway disease. The animal models reviewed in this article support the hypothesis that respiratory virus infections can promote allergic sensitization and the development of asthma. Respiratory viruses can prevent induction of tolerance and enhance sensitization to inhaled allergens resulting in increased airway inflammation and airway hyperresponsiveness. Probable mechanisms involved in this enhanced sensitization are increased permeability of the airway mucosa to allergens and recruitment of dendritic cells to the respiratory epithelium during acute infection. Factors involved in augmenting the consequences of allergic airway sensitization appear to be T-cells, especially CD8+ T-cells as regulators of this process, interleukin-5 as a pivotal cytokine for eosinophilic airway inflammation and eosinophils themselves as effector cells triggering airway hyperresponsiveness. Depending on the timing of allergen exposure, respiratory virus infections which elicit a significant type 1 T-helper cell cytokine response may also downregulate allergic sensitization. Respiratory virus infections in animals previously sensitized to aeroallergens result in prolonged increases in inflammation and airway responsiveness, indicating that critical interactions between immune responses to allergen sensitization and the responses to infection can lead to more severe disease. Taken together, animal models have proved valuable in generating a number of plausible pathogenetic concepts, and can be used to address a host of unresolved questions regarding the immunology of respiratory virus infections, allergic sensitization and asthma.
Synovial Sarcoma: A Multivariate Analysis of Prognostic Factors in 112 Patients With Primary Localized Tumors of the Extremity
Authors: Jonathan J. Lewis, Cristina R. Antonescu, Denis H. Y. Leung, David Blumberg, John H. Healey, James M. Woodruff, Murray F. Brennan
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Synovial sarcoma is a high-grade tumor that is associated with poor prognosis. Previous studies analyzing prognostic factors are limited because of inclusion of heterogeneous cohorts of patients with nonextremity and recurrent tumors. The objective of this study was to determine independent prognostic factors of primary synovial sarcoma localized to the extremity. PATIENTS AND METHODS: Between July 1, 1982, and June 30, 1996, 112 patients underwent surgical resection for cure at our institution and then were followed-up prospectively. Clinical and pathologic factors examined for prognostic value included age, sex, tumor site and location, depth, size, microscopic status of surgical margins, invasion of bone or neurovascular structures, and monophasic or biphasic histology. The end points analyzed were the time to first local recurrence that was not preceded by a distant recurrence, time to any distant recurrence, and time to disease-related mortality. These end points were modeled using the method of Kaplan and Meier and analyzed by the log-rank test and Cox regression. RESULTS: The median duration of follow-up among survivors in this cohort of 112 patients was 72 months. The 5-year local-recurrence, distant-recurrence, and mortality rates were 12%, 39%, and 25%, respectively. Tumor size ≥ 5 cm (P = .001; relative risk [RR] = 2.7; 95% confidence interval [CI], 1.5 to 5.2) and the presence of bone or neurovascular invasion (P = .04; RR = 2.3; 95% CI, 1.0 to 5.3) were independent adverse predictors of distant recurrence. Tumor size ≥ 5 cm (P = .003; RR = 2.3; 95% CI, 1.4 to 6.3) and the presence of bone or neurovascular invasion (P = .03; RR = 2.7; 95% CI, 1.0 to 6.5) were also independent adverse predictors of mortality. CONCLUSION: The natural history of primary synovial sarcoma of the extremity is related to tumor size and invasion of bone and neurovascular structures.
Influences of Transporter Associated with Antigen Processing (TAP) on the Repertoire of Peptides Associated with the Endoplasmic Reticulum–resident Stress Protein gp96
Authors: Danièle Arnold, Claudia Wahl, Stefan Faath, Hans-Georg Rammensee, Hansjörg Schild
Journal: The Journal of Experimental Medicine (1997)

The endoplasmic reticulum (ER)-resident stress protein gp96 induces protective immunity and specific cytotoxic T lymphocyte (CTL) responses against antigens expressed in those cells it has been isolated from. This ability is based on peptides associated with gp96. Because gp96 is located inside the ER, our experiments address the question whether or not the repertoire of peptides associated with gp96 is influenced by the transporter associated with antigen processing (TAP). For this purpose, gp96 was isolated from cells with and without a TAP defect and used for immunization of mice. We found that for some antigens the association of peptides with gp96 required functional TAP molecules, whereas the association of peptides from other antigens was TAP independent. In the case of a TAP-dependent association of peptides with gp96, our results prove that peptide binding by gp96 in vivo occurs inside the ER and is not an artifact induced by cell lysis during the gp96 purification. The finding that some antigens can also associate with gp96 in the absence of functional TAP molecules indicates that the repertoire of peptides bound by gp96 truly reflects the entire repertoire of peptides present inside the ER and not only those peptides transported by TAP. These results, together with the earlier finding that the gp96 peptide repertoire is independent of the major histocompatibility complex molecules expressed by the cell gp96 is isolated from, give the theoretical foundation for the ability of gp96 to induce CTL responses against all kinds of intracellular antigens.
Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial
Authors: Nicola Longo, Cary O Harding, Barbara K Burton, Dorothy K Grange, Jerry Vockley, Melissa Wasserstein, Gregory M Rice, Alejandro Dorenbaum, Jutta K Neuenburg, Donald G Musson, Zhonghua Gu, Saba Sile
Journal: The Lancet (2014)
A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors
Authors: Marwan G. Fakih, Donald L. Trump, Josephia R. Muindi, Jennifer D. Black, Ronald J. Bernardi, Patrick J. Creaven, James Schwartz, Michael G. Brattain, Alan Hutson, Renee French, Candace S. Johnson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. Experimental Design: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. Results: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 μg/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 μg/wk calcitriol dose level. The relationship between calcitriol dose and peak serum calcitriol (Cmax) and systemic exposure (AUC) was linear. Mean (±SD) serum calcitriol Cmax at the MTD was 6.68 ± 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. Conclusions: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 μg calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.
Four-Year Analysis of Cardiovascular Disease Risk Factors, Depression Symptoms, and Antidepressant Medicine Use in the Look AHEAD (Action for Health in Diabetes) Clinical Trial of Weight Loss in Diabetes
Authors: Richard R. Rubin, Mark Peyrot, Sarah A. Gaussoin, Mark A. Espeland, Don Williamson, Lucy F. Faulconbridge, Thomas A. Wadden, Linda Ewing, Monika Safford, Gina Evans-Hudnall, Rena R. Wing, William C. Knowler
Journal: Diabetes Care (2013)

OBJECTIVE To study the association of depressive symptoms or antidepressant medicine (ADM) use with subsequent cardiovascular disease (CVD) risk factor status in the Look AHEAD (Action for Health in Diabetes) trial of weight loss in type 2 diabetes. RESEARCH DESIGN AND METHODS Participants (n = 5,145; age [mean ± SD] 58.7 ± 6.8 years; BMI 35.8 ± 5.8 kg/m2) in two study arms (intensive lifestyle [ILI], diabetes support and education [DSE]) completed the Beck Depression Inventory (BDI), reported ADM use, and were assessed for CVD risk factors at baseline and annually for 4 years. Risk factor–positive status was defined as current smoking, obesity, HbA1c &amp;gt;7.0% or insulin use, and blood pressure or cholesterol not at levels recommended by expert consensus panel or medicine to achieve recommended levels. Generalized estimating equations assessed within-study arm relationships of elevated BDI score (≥11) or ADM use with subsequent year CVD risk status, controlled for demographic variables, CVD history, diabetes duration, and prior CVD risk status. RESULTS Prior year elevated BDI was associated with subsequent CVD risk factor–positive status for the DSE arm (A1C [odds ratio 1.30 (95% CI 1.09–1.56)]; total cholesterol [0.80 (0.65–1.00)]; i.e., protective from high total cholesterol) and the ILI arm (HDL [1.40 (1.12–1.75)], triglyceride [1.28 (1.00–1.64)]). Prior year ADM use predicted subsequent elevated CVD risk status for the DSE arm (HDL [1.24 (1.03–1.50)], total cholesterol [1.28 (1.05–1.57)], current smoking [1.73 (1.04–2.88)]) and for the ILI arm (A1C [1.25 (1.08–1.46)], HDL [1.32 (1.11–1.58)], triglycerides [1.75 (1.43–2.14)], systolic blood pressure [1.39 (1.11–1.74)], and obesity [1.46 (1.22–2.18)]). CONCLUSIONS Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted.