tbuckley/cabot-search huggingface dataset:
Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
Authors: Andrea L. Hevener, Jerrold M. Olefsky, Donna Reichart, M.T. Audrey Nguyen, Gautam Bandyopadyhay, Ho-Yin Leung, Matthew J. Watt, Chris Benner, Mark A. Febbraio, Anh-Khoi Nguyen, Brian Folian, Shankar Subramaniam, Frank J. Gonzalez, Christopher K. Glass, Mercedes Ricote
Journal: Journal of Clinical Investigation (2007)

PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
Double echo steady state magnetic resonance imaging of knee articular cartilage at 3 Tesla: a pilot study for the Osteoarthritis Initiative
Authors: F Eckstein
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Quantitative magnetic resonance imaging (qMRI) may provide valuable measures of cartilage morphology in osteoarthritis (OA) but has been confined to sequences with relatively long acquisition times at 1.5 Tesla (T). <b>Objective:</b> To test the accuracy and precision of knee cartilage qMRI with a fast double echo, steady state (DESS) sequence with water excitation (we) at 3 T. <b>Methods:</b> As a pilot study for the Osteoarthritis Initiative, test-retest MR images were acquired in the knees of 19 participants with no OA to moderate degrees of clinical OA. Two double oblique coronal fast low angle shot (FLASHwe) sequences (1.5 mm slice thickness) were acquired at 3 T, and two sagittal DESSwe sequences (0.7 mm slice thickness). Double oblique coronal multiplanar reformats (MPR) were performed (1.5 mm slice thickness) from the sagittal DESSwe. Knee joint cartilage plates were quantified unpaired in random order with blinding to subject identification. <b>Results:</b> In the femorotibial joint, precision errors (root mean square coefficient of variation in % for unpaired analysis) for cartilage volume and thickness were 3.0–6.4% with coronal FLASHwe, 2.4–6.2% with coronal MPR DESSwe, and 2.3–8.2% with sagittal DESSwe. Correlation coefficients between DESSwe and FLASHwe ranged from <i>r</i> = 0.88 to 1.0. In the femoropatellar joint, precision errors (sagittal DESSwe) were 3.4–8.5%. <b>Conclusions:</b> DESSwe permits accurate and precise analysis of cartilage morphology in the femorotibial joint at 3 T. Further studies are needed to examine the accuracy of DESSwe in the femoropatellar joint and its ability to characterise sensitivity to longitudinal changes in cartilage morphology.
Regulation of human bone marrow-derived osteoprogenitor cells by osteogenic growth factors.
Authors: M W Long, J A Robinson, E A Ashcraft, K G Mann
Journal: Journal of Clinical Investigation (1995)

Human bone marrow contains a distinct cell population that expresses bone proteins and responds to transforming growth factor beta 1 (TGF-beta), but not to hematopoietic growth factors (Long, M. W., J. L. Williams, and K. G. Mann. 1990. J. Clin. Invest. 86:1387-1395). We now report the isolation, characterization, and growth factor responsiveness of these precursors to human osteoblasts and the identification of a human osteoprogenitor cell. Immunological separation of human bone marrow nonadherent low-density (NALD) cells results in a marked enrichment of cells that express osteocalcin, osteonectin, and bone alkaline phosphatase. Flow cytometric analyses show that distinct cell subpopulations exist among these isolated cells. The majority of the bone antigen-positive cells are approximately the size of a lymphocyte, whereas other, less frequent antibody-separated subpopulations consist of osteoblast-like cells and osteoprogenitor cells. In serum-free cultures, TGF-beta stimulates the small, antigen-positive cells to become osteoblast-like, as these cells both increase in size, and express increased levels of osteocalcin and alkaline phosphatase. Antibody-separated cells also contain a separate population of clonal progenitor cells that form colonies of osteoblast-like cells when cultured in serum-free, semi-solid media. Two types of human osteoprogenitor cells are observed: a colony-forming cell (CFC) that generates several hundred bone antigen-positive cells, and a more mature cluster-forming cell that has a lesser proliferative potential and thus generates clusters of 20-50 antigen-positive cells. Osteopoietic colony-forming cells and cluster-forming cells have an obligate but differential requirement for osteogenic growth factors. The CFCs respond to TGF-beta, basic fibroblast growth factor (bFGF), bone morphogenic protein-2 (BMP-2), and 1, 25-dihydroxy vitamin D3 (1,25-OH D3). In contrast to the colony-forming cells, cluster-forming cells are regulated predominantly by 1,25-OH D3 and TGF-beta, but fail to respond to bFGF. We conclude that human bone marrow contains a nonhematogenous, heterogeneous population of bone precursor cells among which exists a population of proliferating osteoprogenitor cells. Further characterization of these bone precursor cell populations should yield important information on their role in osteogenesis in both health and disease.
Erythropoietin and blood doping
Authors: N Robinson, S Giraud, C Saudan, N Baume, L Avois, P Mangin, M Saugy
Journal: British Journal of Sports Medicine (2006)

To outline the direct and indirect approaches in the fight against blood doping in sports, the different strategies that have been used and are currently being used to fight efficiently against blood doping are presented and discussed.The paper outlines the different approaches and diagnostic tools that some federations have to identify and target sports people demonstrating abnormal blood profiles. Originally blood tests were introduced for medical reasons and for limiting misuse of recombinant human erythropoietin (rHuEPO). In this way it became possible to prevent athletes with haematocrit levels well above normal, and potentially dangerous for their health, competing in sport. Today, with nearly a decade of blood testing experience, sports authorities should be familiar with some of the limitations and specially the ability of blood tests performed prior to competitions to fight efficiently against the misuse of rHuEPO, blood transfusion, and artificial haemoglobin.
Genotyping of immune-related genetic variants identifies<i>TYK2</i>as a novel associated locus for idiopathic inflammatory myopathies
Authors: M Jani, J Massey, L R Wedderburn, J Vencovský, K Danko, I E Lundberg, L Padyukov, A Selva-O'Callaghan, T Radstake, H Platt, R B Warren, C E Griffiths, A Lee, P K Gregersen, F W Miller, W E Ollier, R G Cooper, H Chinoy, J A Lamb
Journal: Annals of the Rheumatic Diseases (2014)

Idiopathic inflammatory myopathies (IIMs) may present as a primary autoimmune disorder, or overlap with other autoimmune/connective tissue diseases. The aetiology of IIM likely includes interactions between genetic and environmental factors. Several genetic variants common to multiple autoimmune disorders have been identified in recent genome-wide association studies (GWAS). A Myositis Genetics Consortium dermatomyositis (DM) GWAS also suggests genetic overlap with other autoimmune disorders.1 We sought to extend these findings to identify novel genetic risk factors in a large cohort of adult/juvenile patients with DM and polymyositis (PM), by genotyping immune-related single nucleotide polymorphisms (SNPs) not captured through the DM GWAS.1 

SNPs significantly associated (p<5×10−8) with 10 autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, coeliac disease, Crohn's disease, ulcerative colitis, psoriasis, type 1 diabetes, multiple sclerosis and systemic sclerosis) were identified from published GWAS or the National Human Genome Research Institute GWAS catalogue.2 Unique SNPs were identified (n=233), of which 99 had not been directly genotyped or captured (r2≥0.8 with genotyped SNPs) through our DM GWAS.1 These 99 SNPs were genotyped using Sequenom in 1001 European Caucasian individuals with …
Active kallikrein response to changes in sodium-chloride intake in essential hypertensive patients.
Authors: C Ferri, C Bellini, A Carlomagno, G Desideri, A Santucci
Journal: Journal of the American Society of Nephrology (1996)

To evaluate the behavior of active kallikrein excretion in salt-sensitive and salt-resistant hypertensive patients during changes in sodium-chloride (NaCl) intake, 61 male, nonobese, nondiabetic outpatients affected by uncomplicated essential hypertension were given a diet that contained 140 mmol NaCl per day for 2 wk. Patients then received either a low- (20 mmol NaCl/day) or a high- (320 mmol NaCl/day) sodium diet for 2 wk, according to a randomized, double-blind, cross-over protocol. Hypertensive patients were classified as salt sensitive when their diastolic blood pressure rose by at least 10 mm Hg after the high-sodium diet, and decreased by at least 10 mm Hg after the low-sodium diet, considering as baseline blood pressure values those that were taken at the end of the 140 mmol NaCl/day intake period. The remaining patients were classified as salt resistant or, when diastolic blood pressure increased by 10 mm Hg or more after low-sodium intake, as counter-regulating. Twenty-three patients were therefore classified as salt sensitive, 28 as salt resistant, and 10 as counter-regulating. The baseline active kallikrein excretion was significantly lower (P < 0.0001) in salt-sensitive (0.62 +/- 0.31 U/24 h) patients than in salt-resistant (1.39 +/- 0.44 U/24 h) and counter-regulating patients (1.27 +/- 0.38 U/24 h). Surprisingly, the kallikrein response to changes in sodium intake was similar in all subgroups, although enzyme excretion was always at the lowest level in salt-sensitive hypertensive patients. This latter group also showed the highest plasma atrial natriuretic peptide levels (28.2 +/- 8.5 fmol/mL, P < 0.0001 versus salt-resistant and counter-regulating patients), and the greatest peptide increment with sodium load (P < 0.0001 versus salt-resistant and counter-regulating patients). Counter-regulating patients showed the steepest increase in plasma renin activity (from 0.24 +/- 0.18 to 0.83 +/- 0.21 ng/L per s, P < 0.001) and decrease of plasma atrial natriuretic peptide (from 26.1 +/- 6.3 to 6.8 +/- 3.1 fmol/mL, P < 0.001) when switched from a high to a low-sodium intake. In conclusion, salt-sensitive hypertensive patients excrete less active kallikrein than do salt-resistant and counter-regulating patients, but maintain a normal enzyme response to changes in dietary sodium intake. The exaggerated response of atrial natriuretic peptide to high-sodium intake that was observed in the same patients could be compensating for an impaired renal capability to excrete a sodium load.
Effects of Anesthetics on Cancer Recurrence
Authors: Jonathan Moss, Robert J. Israel
Journal: Journal of Clinical Oncology (2009)

We read with great interest the recent article by Weckermann et al 1 on the perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.The authors postulate "unknown perioperatively acting triggers that stimulate outgrowth of DTCs" (disseminated tumor cells).Recent clinical and laboratory data suggest that anesthetic technique may play a role in tumor dissemination and recurrence.This issue has been highlighted in the anesthesia literature in a recent article of the Anesthesia Patient Safety Foundation Newsletter, which reviews the clinical and laboratory data for such an effect. 2In a retrospective study of prostate cancer, 3 there was a significant difference in the rate of tumor recurrence contingent on the type of anesthesia used.A small retrospective study in breast cancer had similar findings. 4A large, multicenter, prospective, randomized trial investigating the influence of type of anesthesia on breast cancer recurrence is currently underway. 5n addition to the clinical studies, there is also an evolving basic science literature suggesting that opiates affect tumor growth.Both we 6 and Gupta et al 7 have shown that clinically relevant concentrations of opiates can cause endothelial cell proliferation and migration in vitro.The proangiogenic effect of mu opioid agonists seems to be the result of reciprocal transactivation of the vascular endothelial growth factor receptor.We have also demonstrated that mu opioids induce a defect in barrier function, potentially allowing penetration of tumor cells. 8The effects of mu agonists on both angiogenesis and barrier function are reversed by tertiary opiate antagonists or by methylnaltrexone, a peripherally acting mu opioid receptor antagonist approved in the United States to treat opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxatives has not been sufficient. 9,10f these laboratory studies are confirmed clinically, then the selection of anesthetic technique used during the operative procedure and the possible use of peripheral mu opioid receptor antagonists in the perioperative period may be of potential importance.It would be particularly interesting if the authors were able to review the perioperative records of their patients to see which drugs were administered and what anesthetic techniques were used.We commend the authors for their diligent work and believe that their observations deserve additional investigation.
Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure
Authors: Alain P. Guerin, Jacques Blacher, Bruno Pannier, Sylvain J. Marchais, Michel E. Safar, Gérard M. London
Journal: Circulation (2001)

Background —Aortic pulse wave velocity (PWV) is a predictor of mortality in patients with end-stage renal failure (ESRF). The PWV is partly dependent on blood pressure (BP), and a decrease in BP can attenuate the stiffness. Whether the changes in PWV in response to decreases in BP can predict mortality in ESRF patients has never been investigated. Methods and Results —One hundred fifty ESRF patients (aged 52±16 years) were monitored for 51±38 months. From entry until the end of follow-up, the changes of PWV in response to decreased BP were measured ultrasonographically. BP was controlled by adjustment of “dry weight” and, when necessary, with ACE inhibitors, calcium antagonists, and/or β-blockers, in combination if necessary. Fifty-nine deaths occurred, including 40 cardiovascular and 19 noncardiovascular events. Cox analyses demonstrated that independent of BP changes, the predictors of all-cause and cardiovascular mortality were as follows: absence of PWV decrease in response to BP decrease, increased left ventricular mass, age, and preexisting cardiovascular disease. Survival was positively associated with ACE inhibitor use. After adjustment for all confounding factors, the risk ratio for the absence of PWV decrease was 2.59 (95% CI 1.51 to 4.43) for all-cause mortality and 2.35 (95% CI 1.23 to 4.41) for cardiovascular mortality. The risk ratio for ACE inhibitor use was 0.19 (95% CI 0.14 to 0.43) for all-cause mortality and 0.18 (95% CI 0.06 to 0.55) for cardiovascular mortality. Conclusions —These results indicate that in ESRF patients, the insensitivity of PWV to decreased BP is an independent predictor of mortality and that use of ACE inhibitors has a favorable effect on survival that is independent of BP changes.
Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes.
Authors: C Miller, J Stedra, G Kelsoe, J Cerny
Journal: The Journal of Experimental Medicine (1995)

The development of memory B cells takes place in germinal centers (GC) of lymphoid follicles where antigen-driven lymphocytes undergo somatic hypermutation and affinity selection, presumably under the influence of helper T cells. However, the mechanisms that drive this complex response are not well understood. We explored the relationship between GC formation and the onset of hypermutation in response to the hapten phosphorylcholine (PC) coupled to antigenic proteins in mice bearing different frequencies of CD4+ T cells. PC-reactive GC were identified by staining frozen splenic sections with peanut agglutinin (PNA) and with monoclonal Abs against AB1-2, a dominant idiotope of T15+ anti-PC antibody. The nucleotide sequences of rearranged T15 VH1 genes were determined from polymerase chain reaction amplifications of genomic DNA from microdissected GC B cells. T15+ GC became fully developed by day 6-7 after primary immunization of euthymic mice with either PC-keyhole limpet hemocyanin (KLH) or PC-chicken gamma globulin (CGG). Yet the VH1 gene segments recovered from the primary GC as late as day 10-14 had low numbers of mutations, in contrast to responses to the haptens nitrophenyl or oxazolone that sustain high levels of hypermutation after GC formation. PC-reactive B cells proliferate in histologically typical GC for considerable periods with no or little somatic hypermutation; the signals for GC formation are independent of those for the activation of hypermutation. We then examined GC 7 d after secondary immunization with PC-KLH in euthymic mice, in nu/nu mice reconstituted with limited numbers of normal CD4+ cells before priming (CD4(+)-nu/nu) and in nu/nu mice. All of these animals develop T15+ GC after antigen priming, however, the patterns of V gene mutations in the secondary GC reflected the levels of CD4+ cells present during the primary response. VDJ sequences from secondary GC of euthymic mice were heavily mutated, but most of these mutations were shared among all related (identical VDJ joints) sequences suggesting the proliferation of mutated, memory B cells, with little de novo somatic hypermutation. In contrast, the patterns of V gene diversity in secondary GC from CD4(+)-nu/nu mice suggested that there was ongoing mutation and clonal diversification during the first week after rechallenge. The secondary GC from T cell-deficient, nu/nu mice showed little evidence for mutational and/or recombinational diversity of T15+ B cells. We conclude that the participation of CD4+ helper cells is required for full activation of the mutator in GC and takes place in a dose-dependent fashion.
Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease
Authors: R. W. Schwenk, J. J.F.P. Luiken, A. Bonen, J. F.C. Glatz
Journal: Cardiovascular Research (2008)

Circulating long-chain fatty acids (LCFA) and glucose are the main sources for energy production in the heart. In the healthy heart the ratio of glucose and LCFA oxidation is sensitively balanced and chronic alterations in this substrate mix are closely associated with cardiac dysfunction. While it has been accepted for several years that cardiac glucose uptake is mediated by facilitated transport, i.e. by means of the glucose transport proteins GLUT1 and GLUT4, only in the last few years it has become clear that proteins with high-affinity binding sites to LCFA, referred to as LCFA transporters, are responsible for bulk LCFA uptake. Similar to the GLUTs, the LCFA transporters CD36 and FABPpm can be recruited from an intracellular storage compartment to the sarcolemma to increase the rate of substrate uptake. Permanent relocation of LCFA transporters, mainly CD36, from intracellular stores to the sarcolemma is accompanied by accumulation of lipids and lipid metabolites in the heart. As a consequence, insulin signalling and glucose utilization are impaired, leading to decreased contractile activity of the heart. These observations underline the particular role and interplay of substrate carriers for glucose and LCFA in modulating cardiac metabolism, and the development of heart failure. The signalling and trafficking pathways and subcellular machinery regulating translocation of glucose and LCFA transporters are beginning to be unravelled. More knowledge on substrate transporter recycling, especially the similarities and differences between glucose and LCFA transporters, is expected to enable novel therapies aimed at changing the subcellular distribution of glucose and LCFA transporters, thereby manipulating the substrate preference of the diseased heart to help restore cardiac function.
Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells.
Authors: J A Goss, R Pyo, M W Flye, J M Connolly, T H Hansen
Journal: The Journal of Experimental Medicine (1993)

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST &amp;gt; 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.
Clinical and cost-effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial
Authors: Rebecca L Ashby, Rhian Gabe, Shehzad Ali, Una Adderley, J Martin Bland, Nicky A Cullum, Jo C Dumville, Cynthia P Iglesias, Arthur R Kang'ombe, Marta O Soares, Nikki C Stubbs, David J Torgerson
Journal: The Lancet (2013)