tbuckley/cabot-search huggingface dataset:
Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still's disease
Authors: D Y Chen, J L Lan, F J Lin, T Y Hsieh, M C Wen
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To determine the type 1 T helper (Th1)/type 2 T helper (Th2) balance in the peripheral blood (PB) and pathological tissues of patients with active untreated adult onset Still's disease (AOSD). <b>Methods:</b> The percentages of interferon γ (IFNγ)- and interleukin (IL)4-producing Th cells in the PB of 20 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls were determined by intracellular staining and flow cytometry. Serum levels of IL18 and soluble IL2 receptor were measured by enzyme linked immunosorbent assay. Levels of IFNγ and IL4 messenger (m) RNA expression were examined by real time quantitative polymerase chain reaction in biopsy specimens of evanescent rash and synovitis from 8 patients with AOSD. <b>Results:</b> Significantly higher IFNγ-producing Th cells and Th1/Th2 ratio in PB were found in patients with AOSD than in healthy controls. Percentages of IFNγ-producing Th cells and Th1/Th2 ratio in PB correlated significantly with clinical activity score and serum IL18 levels in patients with AOSD. Increased ratio of Th1/Th2 cytokine transcripts was seen in the biopsy specimens of evanescent rash and synovitis from patients with AOSD compared with normal skin controls and patients with OA. Th cell cytokine pattern in PB and cytokine mRNA expression in synovium were similar for patients with AOSD and with RA. After 3 months' treatment, clinical remission was associated with a marked decrease in the percentages of cytokine-producing Th1 cells, but not of the Th2 cells. <b>Conclusion:</b> A predominance of Th1 cytokine may precipitate the pathogenesis of AOSD.
Linagliptin Lowers Albuminuria on Top of Recommended Standard Treatment in Patients With Type 2 Diabetes and Renal Dysfunction
Authors: Per-Henrik Groop, Mark E. Cooper, Vlado Perkovic, Angela Emser, Hans-Juergen Woerle, Maximilian von Eynatten
Journal: Diabetes Care (2013)

OBJECTIVE Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials. RESEARCH DESIGN AND METHODS A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30−3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24. RESULTS UACR at week 24 was reduced by 32% (95% CI −42 to −21; P &amp;lt; 0.05) with linagliptin compared with 6% (95% CI −27 to +23) with placebo, with a between-group difference of 28% (95% CI −47 to −2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% (−6.7 mmol/mol) in favor of linagliptin (95% CI −0.88 to −0.34% [−9.6 to −3.7 mmol/mol]; P &amp;lt; 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment. CONCLUSIONS Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.
Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation
Authors: Adnan Sharif, Shazia Shabir, Sourabh Chand, Paul Cockwell, Simon Ball, Richard Borrows
Journal: Journal of the American Society of Nephrology (2011)

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39–0.96; P = 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58–0.92; P = 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08–1.90; P = 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80–0.98; P = 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.
Randomized Controlled Trial of Oral Antifungal Treatment for Severe Asthma with Fungal Sensitization
Authors: David W. Denning, B. Ronan O'Driscoll, Georgina Powell, Fiona Chew, Graham T. Atherton, Aashish Vyas, John Miles, Julie Morris, Robert M. Niven
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Some patients with severe asthma are immunologically sensitized to one or more fungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS responds to antifungal therapy.To evaluate the response of SAFS to oral itraconazole.Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testing were recruited. All had total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks.The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. Baseline mean AQLQ score was 4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group (-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group.SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.
Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.
Authors: R Bruno, D Hille, A Riva, N Vivier, W W ten Bokkel Huinnink, A T van Oosterom, S B Kaye, J Verweij, F V Fossella, V Valero, J R Rigas, A D Seidman, B Chevallier, P Fumoleau, H A Burris, P M Ravdin, L B Sheiner
Journal: Journal of Clinical Oncology (1998)

The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome.PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models.PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication.First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.
Sorbent Augmented Hemodialysis Systems
Authors: James F. Winchester, Claudio Ronco
Journal: Journal of the American Society of Nephrology (2009)

Recent publications have reintroduced the concept of using sorbent systems to augment the efficiency of the dialysis process, either by making stationary or compact wearable devices to regenerate dialysis fluid or to target larger molecules for removal by direct blood or plasma contact with sorbent particles. Many of the inherent problems associated with older sorbents have been overcome by designing sorbents with improved biocompatibility and potential for removing molecules beyond the limits of conventional dialysis membranes. One system is approved for use in acute renal failure in the United States, but other devices are not approved for use in humans and continue to be tested in animals and humans. A prototype wearable sorbent device under investigation is not yet able to meet acceptable small molecular weight solute removal, and the other sorbent devices that possess the ability to remove unconventional uremic toxins have not been studied sufficiently in dialysis patients to define their role as augmentation devices. That there is a renewal of interest in sorbents in augmentation of dialysis points to the dissatisfaction with current dialysis technology.
<i>In vitro</i> Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis
Authors: Elizabeth Gray, Mark R. Pett, Dawn Ward, David M. Winder, Margaret A. Stanley, Ian Roberts, Cinzia G. Scarpini, Nicholas Coleman
Journal: Cancer Research (2010)

An important event in the development of cervical squamous cell carcinoma (SCC) is deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly related to viral integration into host DNA. Mechanisms of development of the approximately 15% of SCCs that contain extrachromosomal (episomal) HR-HPV are poorly understood due to limited longitudinal data. We therefore used the W12 model to study mechanisms of cervical carcinogenesis associated with episomal HPV16. In vitro progression of W12 normally occurs through selection of cells containing integrated HPV16. However, in one long-term culture, keratinocytes developed a selective growth advantage and invasive phenotype while retaining HPV16 episomes at increased copy number in the absence of transcriptionally active integrants. Longitudinal investigations revealed similarities between the episome- and integrant-associated routes of neoplastic progression. Most notable were dynamic changes in viral early gene expression in episome-retaining cells, consistent with continually changing selective pressures. An early increase in viral transcription preceded elevated episome copy number and was followed by a reduction to near baseline after the development of invasiveness. Episomal transcriptional deregulation did not require selection of a specific sequence variant of the HPV16 upstream regulatory region, although increased levels of acetylated histone H4 around the late promoter implicated a role for altered chromatin structure. Interestingly, invasive episome-retaining cells showed high levels of HPV16 E2/E6 proteins (despite decreased transcript levels) and reduced expression of IFN-stimulated genes, adaptations that support viral persistence and cell survival. Our findings suggest a unified working model for events important in cervical neoplastic progression regardless of HR-HPV physical state.
Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies
Authors: T. C. Russ, E. Stamatakis, M. Hamer, J. M. Starr, M. Kivimaki, G. D. Batty
Journal: BMJ (2012)

<b>Objective</b> To quantify the link between lower, subclinically symptomatic, levels of psychological distress and cause-specific mortality in a large scale, population based study. <b>Design</b> Individual participant meta-analysis of 10 large prospective cohort studies from the Health Survey for England. Baseline psychological distress measured by the 12 item General Health Questionnaire score, and mortality from death certification. <b>Participants</b> 68 222 people from general population samples of adults aged 35 years and over, free of cardiovascular disease and cancer, and living in private households in England at study baseline. <b>Main outcome measures</b> Death from all causes (n=8365), cardiovascular disease including cerebrovascular disease (n=3382), all cancers (n=2552), and deaths from external causes (n=386). Mean follow-up was 8.2 years (standard deviation 3.5). <b>Results</b> We found a dose-response association between psychological distress across the full range of severity and an increased risk of mortality (age and sex adjusted hazard ratio for General Health Questionnaire scores of 1-3 <i>v</i> score 0: 1.20, 95% confidence interval 1.13 to 1.27; scores 4-6: 1.43, 1.31 to 1.56; and scores 7-12: 1.94, 1.66 to 2.26; P&lt;0.001 for trend). This association remained after adjustment for somatic comorbidity plus behavioural and socioeconomic factors. A similar association was found for cardiovascular disease deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels. <b>Conclusions</b> Psychological distress is associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress.
IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis
Authors: Christoph J. Binder, Karsten Hartvigsen, Mi-Kyung Chang, Marina Miller, David Broide, Wulf Palinski, Linda K. Curtiss, Maripat Corr, Joseph L. Witztum
Journal: Journal of Clinical Investigation (2004)

During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs). These epitopes are recognized by both adaptive T cell–dependent (TD) and innate T cell–independent type 2 (TI-2) immune responses. We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection. In addition, a PC-based immunization strategy that leads to a TI-2 expansion of innate B-1 cells and secretion of T15/EO6 clonotype natural IgM antibodies, which bind the PC of OxPLs within oxidized LDL (OxLDL), also reduces atherogenesis. T15/EO6 antibodies inhibit OxLDL uptake by macrophages. We now report that immunization with MDA-LDL, which does not contain OxPL, unexpectedly led to the expansion of T15/EO6 antibodies. MDA-LDL immunization caused a preferential expansion of MDA-LDL–specific Th2 cells that prominently secreted IL-5. In turn, IL-5 provided noncognate stimulation to innate B-1 cells, leading to increased secretion of T15/EO6 IgM. Using a bone marrow transplant model, we also demonstrated that IL-5 deficiency led to decreased titers of T15/EO6 and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specific to epitopes of OxLDL and protects from atherosclerosis, in part by stimulating the expansion of atheroprotective natural IgM specific for OxLDL.
Treatment and Outcome of 267 Patients with IgM-Related AL Amyloidosis
Authors: Murielle Roussel, Giovanni Palladini, Simon DJ Gibbs, Christopher P. Venner, Jean-Paul Fermand, Helen J Lachmann, Julian D Gillmore, Philip N Hawkins, Giampaolo Merlini, Arnaud Jaccard, Ashutosh Wechalekar
Journal: Blood (2012)
Genetic control of radiation leukemia virus-induced tumorigenesis. I. Role of the major murine histocompatibility complex, H-2.
Authors: D Meruelo, M Leiberman, N Ginzton, B Deak, H O McDevitt
Journal: The Journal of Experimental Medicine (1977)

Resistance to radiation leukemia virus-induced leukemogenesis is associated with the H-2D region of the H-2 complex, or with closely linked loci. The H-2Dd allele confers resistance ot the disease, while the H-2D-Q and H-2Ds alleles are associated with susceptibility. It is not clear whether Ir genes, or an alternative mechanism are responsible for the observed H-2-linked resistance to the disease.
Actin and agonist MHC–peptide complex–dependent T cell receptor microclusters as scaffolds for signaling
Authors: Gabriele Campi, Rajat Varma, Michael L. Dustin
Journal: The Journal of Experimental Medicine (2005)

T cell receptor (TCR) microclusters form within seconds of T cell contact with supported planar bilayers containing intercellular adhesion molecule-1 and agonist major histocompatibility complex (MHC)–peptide complexes, and elevation of cytoplasmic Ca2+ is observed within seconds of the first detectable microclusters. At 0–30 s after contact, TCR microclusters are colocalized with activated forms of Lck, ZAP-70, and the linker for activation of T cells. By 2 min, activated kinases are reduced in the older central microclusters, but are abundant in younger peripheral microclusters. By 5 min, TCR in the central supramolecular activation cluster have reduced activated kinases, whereas faint peripheral TCR microclusters efficiently generated activated Lck and ZAP-70. TCR microcluster formation is resistant to inhibition by Src family kinase inhibitor PP2, but is abrogated by actin polymerization inhibitor latrunculin A. We propose that Src kinase–independent formation of TCR microclusters in response to agonist MHC–peptide provides an actin-dependent scaffold for signal amplification.
MicroRNA-21 is a key determinant in IL-11/Stat3 anti-apoptotic signalling pathway in preconditioning of skeletal myoblasts
Authors: Khawaja Husnain Haider, Niagara Muhammad Idris, Ha Won Kim, Rafeeq P.H. Ahmed, Jiang Shujia, Muhammad Ashraf
Journal: Cardiovascular Research (2010)

AimsWe have previously shown that preconditioning of stem and progenitor cells promotes their survival post-engraftment in the infarcted heart. The present study was designed to (i) delineate the role of microRNA-21 (miR-21) in interleukin-11 (IL-11) signalling during preconditioning of skeletal myoblasts (MY) and (ii) study the long-term fate of preconditioned MY (PCMY) post-transplantation in the infarcted heart.
Effect of Dalteparin on Healing of Chronic Foot Ulcers in Diabetic Patients With Peripheral Arterial Occlusive Disease
Authors: Majid Kalani, Jan Apelqvist, Margareta Blombäck, Kerstin Brismar, Björn Eliasson, Jan W. Eriksson, Bengt Fagrell, Anders Hamsten, Ole Torffvit, Gun Jörneskog
Journal: Diabetes Care (2003)

OBJECTIVE—Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers. RESEARCH DESIGN AND METHODS—A total of 87 patients were investigated in a prospective, randomized, double-blind, placebo-controlled trial. Participants were randomized to treatment with subcutaneous injection of 5,000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1) who healed with intact skin; 2) in whom the study ulcer was improved, unchanged, or impaired; or 3) who were amputated above or below the ankle level, as compared with control subjects. RESULTS—Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided χ2 test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area ≥50% (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased ≥50%. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 ± 8 weeks in the dalteparin group compared with 16 ± 7 weeks in placebo group (NS). CONCLUSIONS—The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease.