Breaking the cooperation between bystander T-cells and Natural Killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice
Nosocomial infections represent serious complications after traumatic or surgical injuries on intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th) cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-...
Source: Clinical Science - January 22, 2015 Category: Biomedical Science Authors: F Wirsdörfer, J Martin Bangen, E Pastille, W Hansen, S Barbara Flohé Source Type: research

Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma
TGF-β is cytostatic towards damage induced compensatory hepatocyte proliferation. This function is frequently lost during hepatocarcinogenesis, thereby switching the TGF-β role from tumor suppressor to tumor promoter. Here, we investigate Smad7 overexpression as pathophysiological mechanism for cytostatic TGF-β inhibition in liver damage and HCC. Transgenic hepatocyte specific Smad7 overexpression in damaged liver of fumarylacetoacetate hydrolase (FAH) deficient mice increased compensatory proliferation of hepatocytes. Similarly, modulation of Smad7 expression changed the sensitivity of Huh7, FLC-4, HLE and ...
Source: Clinical Science - January 20, 2015 Category: Biomedical Science Authors: T Feng, J Dzieran, X Gu, S Marhenke, A Vogel, K Machida, T S Weiss, P Rümmele, O Kollmar, P Hoffmann, F Graesser, H Allgayer, J Fabian, H Lei Weng, A Teufel, T Maass, C Meyer, U Lehmann, C Zhu, P R Mertens, C Gao, S Dooley, N M Meindl-Beinker Source Type: research

The Impact of Cryopreservation on Human Peripheral Blood Leukocyte Bioenergetics.
Conclusion: This study has demonstrated for the first time that cryopreservation of primary immune cells modified their metabolism in a time-dependent fashion, indicated by attenuated aerobic respiration and enhanced glycolytic activity. Taken together, we recommend caution in the interpretation of bioenergetic responses or BHI in cryopreserved samples. (Source: Clinical Science)
Source: Clinical Science - January 19, 2015 Category: Biomedical Science Authors: K N. Keane, E K. Calton, V F. Cruzat, M J Soares, P Newsholme Source Type: research

Circulating E3 ligases are novel and sensitive biomarkers for diagnosis of acute myocardial infarction
Ubiquitin ligase (E3) is a decisive element of the ubiquitin-proteasome system (UPS), which is the main pathway for intracellular protein turnover. Recently, circulating E3 ligases have been increasingly considered as cancer biomarkers. Here we aimed todetermine if cardiac-specific E3 ligases in circulation can serve as novel predictors for early diagnosis of acute myocardial infarction (AMI). By screening and verifying their tissue expression patterns with microarray and real-time PCR analysis, 6 of 261 E3 ligases, including cardiac-specific Rnf207 and cardiac- and muscle-enriched Fbxo32/atrogin-1, Trim54/MuRF3, Trim63/Mu...
Source: Clinical Science - January 19, 2015 Category: Biomedical Science Authors: Q Han, H Wang, X Liu, C Guo, Q Hua, X Yu, N Li, Y Yang, J Du, Y Xia, H Li Source Type: research

Interleukin-32{gamma} attenuates ethanol-induced liver injury by the inhibition of Cytochrome P450 2E1 expression and inflammatory responses
Alcohol abuse and alcoholism lead to alcoholic liver disease, which is a major type of chronic liver disease worldwide. Interleukin-32 (IL-32) is a novel cytokine involved in inflammation and cancer development. However, the role of IL-32 in chronic liver disease has not been reported. Here, we tested the effect of IL-32γ on ethanol-induced liver injury in IL-32γ-overexpressing transgenic mice (IL-32γ mice) after chronic ethanol feeding. Male C57BL/6 and IL-32γ mice (10–12 weeks old) were fed a Lieber-DeCarli diet containing 6.6% ethanol for 6 weeks. IL-32γ-transfected HepG2 and Huh7 cel...
Source: Clinical Science - January 13, 2015 Category: Biomedical Science Authors: D Lee, D Kim, C Hwang, S Song, S Han, Y Soo Kim, H Yoo, Y Jung, S Kim, D Yoon, J Tae Hong Source Type: research

Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and type 2 diabetes
In health, food carbohydrate is stored as glycogen in muscle and liver, preventing a deleterious rise in osmotically active plasma glucose after eating. Glycogen concentrations increase sequentially after each meal to peak in the evening, and fall to fasting levels thereafter. Skeletal muscle accounts for the larger part of this diurnal buffering capacity with liver also contributing.The effectiveness of this diurnal mechanism has not been previously studied in type 2 diabetes. We have quantified the changes in muscle and liver glycogen concentration with 13C magnetic resonance spectroscopy at 3.0 Tesla before and after 3 ...
Source: Clinical Science - January 13, 2015 Category: Biomedical Science Authors: M Macauley, F E Smith, P E Thelwall, K Grant Hollingsworth, R Taylor Source Type: research

Activated regulatory T cells attenuate myocardial ischemia/reperfusion injury through a CD39-dependent mechanism
In conclusion, our data validated a protective role of Tregs in MIRI. Moreover, in vitro–activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy. (Source: Clinical Science)
Source: Clinical Science - January 5, 2015 Category: Biomedical Science Authors: N Xia, J Jiao, T Tang, B Lv, Y Lu, K Wang, Z Zhu, X Mao, S Nie, Q Wang, X Tu, H Xiao, Y Liao, G Shi, X Cheng Source Type: research

Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation
Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for development of acute kidney injury (AKI). Although bone marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated TG-BMSCs from young, end organ disease-free rats with increased RAS act...
Source: Clinical Science - December 23, 2014 Category: Biomedical Science Authors: E Kankuri, E Mervaala, M Storvik, A J Ahola, J Levijoki, D N Muller, P Finckenberg, E M Mervaala Source Type: research

Epidermal Growth Factor Receptor Inhibitor Protects Abdominal Aortic Aneurysm in a Mouse Model
In conclusion, EGFR inhibition appears to protect mice from abdominal aortic aneurysm formation induced by angiotensin II plus β-aminopropionitrile. The mechanism seems to involve suppression of vascular EGFR and endoplasmic reticulum stress. (Source: Clinical Science)
Source: Clinical Science - December 22, 2014 Category: Biomedical Science Authors: T Obama, T Tsuji, T Kobayashi, Y Fukuda, T Takayanagi, Y Taro, T Kawai, S J. Forrester, K J Elliott, E T Choi, A Daugherty, V Rizzo, S Eguchi Source Type: research

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation.
In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect (Source: Clinical Science)
Source: Clinical Science - December 19, 2014 Category: Biomedical Science Authors: F H Greig, L Hutchison, C M Spickett, S Kennedy Source Type: research

Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunctionin in rodents
The gene ankyrin repeat domain 1 (Ankrd1) is known to upregulate in heart failure and acts as a co-activator of p53 and modulates its transcriptional activity, but it remains inconclusive whether this gene promotes or inhibits cell apoptosis. Here we attempted to investigate the role of Ankrd1 on angiotensin II- or pressure overload-induced cardiomyocyte apoptosis. In the failing hearts of mice with pressure overload or myocardial infarction, the protein expression of Ankrd1 termed cardiac ankyrin repeat protein (CARP) was significantly increased. In neonatal rat cardiomyocytes (NRCs), angiotensin II (Ang II) increased the...
Source: Clinical Science - December 16, 2014 Category: Biomedical Science Authors: L Shen, C Chen, X Wei, X Li, G Luo, J Zhang, J Bin, X Huang, S Cao, G Li, Y Liao Source Type: research

Ang 1-7 Prevents Systemic Hypertension, Attenuates Oxidative Stress and Tubulointerstitial Fibrosis, and Normalizes Renal Angiotensin-Converting Enzyme 2 and Mas Receptor Expression in Diabetic Mice
We investigated the relation between Ang 1-7 action, systolic hypertension (sHTN), oxidative stress, kidney injury, angiotensin converting enzyme-2 (Ace2) and angiotensin 1-7 receptor (MasR) expression in type 1 diabetic Akita mice. Ang 1-7 was administered daily (500 μg/kg body weight (BW)/day, subcutaneously) to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg BW/day). The animals were euthanized at 20 weeks of age. Age-matched wild type (WT) mice served as controls.Ang 1-7 administration prevented sHTN and attenuated kidney injury (reduced urinary alb...
Source: Clinical Science - December 12, 2014 Category: Biomedical Science Authors: Y Shi, C Lo, R Padda, S Abdo, I Chenier, J G Filep, J R Ingelfinger, S Zhang, J S D Chan Source Type: research

Generation of suppressive blood cells for control of allograft rejection
We describe here a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although, the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans. (Source: Clinical Science)
Source: Clinical Science - December 11, 2014 Category: Biomedical Science Authors: C Kleist, F Sandra-Petrescu, L Jiga, L Dittmar, E Mohr, J Greil, W Mier, L E. Becker, P Lang, G Opelz, P Terness Source Type: research

Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells
The presence of AT2 receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and the role in the induction of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high densities in mitochon...
Source: Clinical Science - December 9, 2014 Category: Biomedical Science Authors: Y Zhao, U Lützen, J Fritsch, M Zuhayra, S Schütze, U M Steckelings, C Recarti, P Namsoleck, T Unger, J Culman Source Type: research

Metabolic alterations, hfe gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.
Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small dense LDL levels, chemical composition of LDL and HDL particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures...
Source: Clinical Science - December 2, 2014 Category: Biomedical Science Authors: T Meroño, F Brites, C Dauteuille, M Lhomme, M Menafra, A Arteaga, M Castro, M Saez, E González Ballerga, P Sorroche, J Rey, P Lesnik, J Sordá, M Chapman, A Kontush, J Daruich Source Type: research

Macrophage CGI-58 deficiency promotes IL-1{beta} transcription by activating the SOCS3-FOXO1 pathway
Overnutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative Gene Identification-58 (CGI-58) is an intracellular lipolytic activator. Here we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes CGI-58 negatively and IL-1β positively correlate with obesity. Saturated free fatty acid (FFA) suppresses CGI-58 expression in macrophages, and this suppression activates FOXO1 through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL-1β promoter ...
Source: Clinical Science - November 28, 2014 Category: Biomedical Science Authors: H Miao, J Ou, X Zhang, Y Chen, B Xue, H Shi, L Gan, L Yu, H Liang Source Type: research

The Activation of mTOR is Required for Monocyte Proinflammatory Response in Patients with Coronary Artery Disease
Nuclear factor-κB (NF-κB) is a key regulator of systematic inflammation in atherosclerosis. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, has emerged as an important regulator of chronic inflammation. However, the relationship between mTOR and NF-κB remains poorly defined. The aim of this study was to investigate the role of mTOR in proinflammatory pathway of human monocytes (HMCs) in patients with coronary artery disease (CAD) and to determine the interaction between mTOR and NF-κB signaling under inflammatory state. HMCs were isolated from fasting blood samples of 68...
Source: Clinical Science - November 27, 2014 Category: Biomedical Science Authors: S Gao, W Liu, X Zhuo, L Wang, G Wang, T Sun, Z Zhao, J Liu, Y Tian, J Zhou, Z Yuan, Y Wu Source Type: research

Respiratory sinus arrhythmia in young men and women at different chest wall configurations
Respiratory sinus arrhythmia (RSA) is an acceleration of heart rate during inspiration and deceleration with expiration. We asked whether or not in humans some of the volume-related information necessary for RSA originated from the chest wall. Men and women, 19-20 years old, were breathing supine. Rib cage and abdomen displacement provided an index of tidal volume (VT) and RSA was computed breath-by-breath from the peak and trough of instantaneous heart rate. First, measurements were taken during breathing at rest (protocol a, 129 ♂ and 164 ♀). Then, in subgroups of the original subject population, measurements were co...
Source: Clinical Science - November 12, 2014 Category: Biomedical Science Authors: J P. Mortola, D Marghescu, R Siegrist-Johnstone Source Type: research

Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: Results from prospective and randomized study of treatment with renin-angiotensin system blockades
This study included 41 patients with CAD and 20 subjects without CAD (non-CAD).Plasma TLR4-responsive miRNA samples were analyzed using a microarray assay for 1,700 human miRNA. The candidate miRNAs were verified with real-time RT-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin (ARB) or enalapril and atorvastatin (ACEI). Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in 7 TLR4-responsive miRNAsbetween the CAD and non-CAD groups (P
Source: Clinical Science - November 10, 2014 Category: Biomedical Science Authors: M Satoh, Y Takahashi, T Tabuchi, M Tamada, K Takahashi, T Itoh, Y Morino, M Nakamura Source Type: research

Interval and Continuous Exercise Regimens Suppress Neutrophil-derived Microparticle Formation and Neutrophil-promoted Thrombin Generation under Hypoxic Stress
This study explicates the manner in which interval and continuous exercise regimens affect neutrophil-derived microparticle (NDMP) formation and neutrophil/NDMP-mediated thrombin generation (TG) under hypoxic condition. A total of 60 sedentary males were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80%VO2max) or moderate continuous training (MCT; sustained 60%VO2max) for 30 min/day, 5 days/week for 5 weeks, or to a control group who did not receive any form of training. At rest and immediately after hypoxic exercise test (HE, 100W under 12%O2 for 30 min), the NDMP characteristi...
Source: Clinical Science - November 5, 2014 Category: Biomedical Science Authors: Y Chen, C Ho, H Tsai, J Wang Source Type: research

Altered profile of circulating microparticles in Rheumatoid Arthritis patients
Microparticles (MPs) could be considered biomarkers of cell damage and activation as well as novel signaling structures. Since Rheumatoid Arthritis (RA) is characterized by immune and endothelial activation, the main aim of this study was to analyze MP counts in RA patients. Citrated-blood samples were obtained from 114 RA patients, 33 healthy controls (HC) and 72 individuals with marked cardiovascular (CV) risk without autoimmune manifestations (CVR). MPs were analyzed in platelet-poor plasma and different subsets were identified by their surface markers: platelet- (CD41+), endothelial- (CD146+), granulocyte- (CD66+), mon...
Source: Clinical Science - November 4, 2014 Category: Biomedical Science Authors: J Rodríguez-Carrio, M Alperi-López, P López, S Alonso-Castro, S Carro-Esteban, F Javier Ballina-García, A Suárez Source Type: research

Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: Role of Rac1/2-sensitive Nox-dependent pathways
Oxidative stress [increased bioavailaibility of reactive oxygen species (ROS)] plays a role in endothelial dysfunction and vascular inflammation, which underlie vascular damage in diabetes. Statins are cholesterol-lowering drugs that are vasoprotective in diabetes through unknown mechanisms. We tested the hypothesis that atorvastatin decreases NADPH oxidase (Nox)-derived ROS generation and associated vascular injury in diabetes. Leprdb/Leprdb (db/db) mice, a model of type 2 diabetes, and control Leprdb/Lepr+ (db/+) mice were administered atorvastatin (10 mg/kg/day, 2 weeks). Atorvastatin improved glucose tolerance in db/db...
Source: Clinical Science - October 31, 2014 Category: Biomedical Science Authors: T Bruder-Nascimento, G E Callera, A C Montezano, Y He, T T Antunes, A Nguyen Dinh Cat, R C Tostes R, R M Touyz Source Type: research

Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions
Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within individuals with age have not been fully addressed. Here, we report a longitudinal analysis of telomere length in PBMCs, lymphocytes and monocytes of two hundred and sixteen human subjects aged from 20s to 90s assessed at zero, five- and twelve- year follow-up. For the 5- and 12-year fo...
Source: Clinical Science - October 15, 2014 Category: Biomedical Science Authors: Y Lin, A Damjanovic, E Jeffrey Metter, H Nguyen, T Truong, K Najarro, C Morris, D L Longo, M Zhan, L Ferrucci, R J Hodes, N Weng Source Type: research

Neuromuscular electrical stimulation prevents muscle wasting in critically ill, comatose patients
Fully-sedated patients, being treated in the ICU, experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully-sedated ICU patients admitted for acute critical illness (n=3 males, n=3 females; age 63±6 y; APACHE II disease severity-score: 29±2). One leg was subjected to twice-daily NME...
Source: Clinical Science - October 8, 2014 Category: Biomedical Science Authors: M L. Dirks, D Hansen, A Van Assche, P Dendale, L J.C. Van Loon Source Type: research

Inter-relationships between proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III and plasma apolipoprotein B-48 transport in obese subjects: a stable isotope study in the postprandial state
Postprandial lipaemia, due to elevated plasma apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects.Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after intravenous d3-leucine administration using gas chromatography-mass spectrometry. Kinetic parameters, including secretion and fractional ...
Source: Clinical Science - October 7, 2014 Category: Biomedical Science Authors: D C Chan, A Y Wong, J Pang, P R Barrett, G F Watts Source Type: research

Angiotensin 1-7 Decreases Skeletal Muscle Atrophy induced by Angiotensin II through Mas Receptor Dependent Mechanism
Skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass, increase in myosin heavy chain (MHC) degradation, and the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. Angiotensin II (AngII) induces muscle atrophy. Angiotensin 1-7 (Ang (1-7)), through its receptor Mas, produces the opposite effects than AngII. We assessed the effects of Ang (1-7) on the skeletal muscle atrophy induced by AngII. Our results shows that Ang (1-7), through Mas, prevents the effects induced by AngII in muscle gastrocnemius: the decrease in the fibre diamet...
Source: Clinical Science - September 15, 2014 Category: Biomedical Science Authors: F Cisternas, M Morales, C Meneses, F Simon, E Brandan, J Abrigo, Y Vazquez, C Cabello-Verrugio Source Type: research

Chronic dehydration is associated with obstructive sleep apnoea syndrome
(Source: Clinical Science)
Source: Clinical Science - September 9, 2014 Category: Biomedical Science Authors: S N Thornton, M Trabalon Source Type: research

BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy
Bone morphogenetic protein 7 (BMP7) has been reported to confer renoprotective effects in acute and chronic kidney disease models, but its potential role in type 2 diabetic nephropathy remains unknown. In cultured human proximal tubular epithelial cells (PTECs), exposure to advanced glycation end products (AGEs) induced overexpression of intercellular adhesion molecule 1 (ICAM1), monocyte chemoattractant protein 1 (MCP1), interleukin 8 (IL-8) and interleukin 6 (IL-6), involving activation of p44/42 and p38 mitogen-activated protein kinase (MAPK) signaling. BMP7 dose-dependently attenuated AGE-induced upregulation of ICAM1,...
Source: Clinical Science - September 9, 2014 Category: Biomedical Science Authors: R Li, W Yiu, H Wu, D Wong, L Chan, M Lin, J Leung, K Lai, S CW Tang Source Type: research

Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signaling in healthy male subjects
Macrophage markers in skeletal muscle of obese subjects are elevated and inversely relate to insulin sensitivity. The present study aimed to investigate whether short-term high-fat high-calorie (HFHC) diet already increases macophage markers and affects glucose metabolism in skeletal muscle of healthy lean subjects. Muscle biopsies were obtained from 24 healthy lean young men before and after a 5-day HFHC-diet. mRNA expression levels of relevant genes in muscle and glucose, insulin, C-peptide and cholesteryl ester transfer protein (CETP) levels in plasma were measured. In addition, we assessed hepatic triglyceride content ...
Source: Clinical Science - August 22, 2014 Category: Biomedical Science Authors: M R. Boon, L E.H. Bakker, M C. Haks, E Quinten, G Schaart, L van Beek, Y Wang, L van Schinkel, V van Harmelen, A Edo Meinders, T H.M. Ottenhoff, K Willems van Dijk, B Guigas, I M. Jazet, P C.N. Rensen Source Type: research

Glycemic Regulation and Insulin Secretion Are Abnormal in Cystic Fibrosis Pigs Despite Sparing of Islet Cell Mass
Diabetes is a common and significant comorbidity in cystic fibrosis (CF). The pathogenesis of CF-related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal,newbornand older CF and non-CF pigsand assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and old...
Source: Clinical Science - August 21, 2014 Category: Biomedical Science Authors: A Uc, A K. Olivier, M A. Griffin, D K. Meyerholz, J Yao, M Abu-El-Haija, K Buchanan, O G Vanegas Calderón, M Abu-El-Haija, A A. Pezzulo, L R. Reznikov, M J. Hoegger, M V. Rector, L S. Ostedgaard, P J. Taft, N D. Gansemer, P S. Ludwig, E E. Hornick, D A. Source Type: research

Skeletal muscle work efficiency with age: the role of non-contractile processes
Although skeletal muscle work efficiency likely plays a key role in limiting mobility of the elderly, the physiological mechanisms responsible for this diminished function remain incompletely understood. Thus, in the quadriceps of young (n=9) and old (n=10) subjects, we measured the cost of muscle contraction (ATP cost) with 31P-magnetic resonance spectroscopy (31P-MRS) during 1) maximal intermittent contractions to elicit a metabolic demand from both cross-bridge cycling and ion pumping and 2) a continuous maximal contraction to predominantly tax cross-bridge cycling. The ATP cost of the intermittent contractions was sign...
Source: Clinical Science - August 19, 2014 Category: Biomedical Science Authors: G Layec, C R Hart, J Douglas Trinity, Y Le Fur, E Jeong, R S Richardson Source Type: research

The net clinical benefit of personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention
This was a prospective study comparing two groups: personalized and non-personalized treatment with P2Y12 receptor blockers during a 12-month follow-up. We aimed to investigate whether personalized antiplatelet treatment in patients with high on treatment platelet reactivity (HTPR) improves clinical outcome. Platelet reactivity was assessed by adenosine diphosphate induced aggregation using a multiple electrode aggregometry (MEA) in 798 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Patients with HTPR received up to four repeated loading doses of clopidogrel or prasugrel in the p...
Source: Clinical Science - August 15, 2014 Category: Biomedical Science Authors: J Maria Siller-Matula, C Gruber, M Francesconi, C Dechant, B Jilma, G Delle-Karth, K Grohs, A Podczeck-Schweighofer, G Christ Source Type: research

Autologous hematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis
Autologous hematopoietic stem cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to "reboot" the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify through a robust and unbiased transcriptomic analysis any changes of gene expression in T cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expressi...
Source: Clinical Science - August 13, 2014 Category: Biomedical Science Authors: A A.Sousa, K C. R. Malmegrim, R A. Panepucci, D S. Brum, A A. Barreira, A dos Santos, A G. Araujo, D T. Covas, M C. Oliveira, D A. Moraes, F Pieroni, G M Barros, B P. Simoes, R Nicholas, R K. Burt, J C. Voltarelli, P A. Muraro Source Type: research

CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients
In conclusion, the CXCL12/CXCR4 pathway contributes in both mice and patients to the enhanced recruitment of CD4+ T in NASH. An increased affinity of CXCL12 to CXCR4 rather than a higher expression of the chemokine or its receptors is involved in this process. (Source: Clinical Science)
Source: Clinical Science - July 30, 2014 Category: Biomedical Science Authors: H Boujedidi, O Robert, A Bignon, A Cassard-Doulcier, M Renoud, H Gary-Gouy, P Hemon, H Tharinger, S Prévot, F Bachelerie, S Naveau, D Emilie, K Balabanian, G Perlemuter Source Type: research

Prevention of oxidative stress, inflammation and mitochondrial dysfunction in the intestine by different cranberry phenolic fractions
Cranberry fruit has been reported to have high antioxidant effectiveness that is potentially linked to its richness in diversified polyphenolic content. The aim of the present study is to determine the role of cranberry polyphenolic fractions in oxidative stress, inflammation and mitochondrial functions using intestinal Caco-2/15 cells. The combination ofHPLC and UPLC-TDQ techniques allowed us to characterize the profile of low, medium and high molecular weight polyphenolic compounds in cranberry extracts. The medium molecular weight fraction was enriched with flavonoids and procyanidin dimers whereas procyanidin oligomers...
Source: Clinical Science - July 29, 2014 Category: Biomedical Science Authors: M C Denis, Y Desjardins, A Furtos, V Marcil, S Dudonné, A Montoudis, C Garofalo, E Delvin, A Marette, E Levy Source Type: research

Alveolar T-helper Type 2 Immunity in Atopic Asthma is Associated with Poor Clinical Control
Real-word evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). As conventional ICS have poor access to the peripheral airways, the aim of present study was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from poorly controlled asthmatics (n=12, Asthma Control Test (ACT) score
Source: Clinical Science - July 25, 2014 Category: Biomedical Science Authors: A Bergqvist, C K Andersson, M Mori, A F Walls, L Bjermer, J S Erjefält Source Type: research

Direct angiotensin AT2-receptor stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice
In this study we evaluated stimulation of the angiotensin AT2-receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunised with myelin-oligodendrocyte-peptide (MOG) and treated for 4 weeks with C21 (0.3mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures...
Source: Clinical Science - July 23, 2014 Category: Biomedical Science Authors: V Valero-Esquitino, K Lucht, P Namsolleck, F Monnet-Tschudi, T Stubbe, F Lucht, M Liu, F Ebner, C Brandt, L A. Danyel, D C Villela, L Paulis, C Thoene-Reineke, B Dahlöf, A Hallberg, T Unger, C Sumners, U Muscha Steckelings Source Type: research

Arginine infusion in septic shock patients increases nitric oxide production without hemodynamic instability
Arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state. On the other hand, excessive NO production has been related to global hemodynamic instability. Therefore, the aim of the present study was to investigate the dose-response effect of intravenous arginine supplementation in postabsorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional hemodynamics. Eight critically ill patients with a diagnosis of septic shock participated in this short-term (8h) dose-response study. L-arginine-HCl was continuously infused (IV)...
Source: Clinical Science - July 18, 2014 Category: Biomedical Science Authors: Y C Luiking, M Poeze, N EP Deutz Source Type: research

Cognitive Dysfunction in Postural Tachycardia Syndrome
This study provides evidence for deficits in selective attention and cognitive processing in patients with POTS, in the seated position when orthostatic stress is minimized. In contrast, other measures of cognitive function including memory assessments were not impaired in these patients, suggesting selectivity in these deficits. These findings provide new insight into the profile of cognitive dysfunction in POTS, and provide the basis for further studies to identify clinical strategies to better manage the mental clouding associated with this condition. (Source: Clinical Science)
Source: Clinical Science - July 8, 2014 Category: Biomedical Science Authors: A C Arnold, K Haman, E M Garland, V Raj, W D Dupont, I Biaggioni, D Robertson, S R Raj Source Type: research

Feasibility of global microRNA analysis from fine-needle biopsy FFPE material in patients with hepatocellular carcinoma treated with sorafenib.
Sorafenib is the standard of care in patients with advanced hepatocellular carcinoma (HCC). However, the median overall survival (OS) benefit is approximately three months, only, and sufficient biomarkers predicting treatment response are not available. Aim of the present study was to evaluate miRNA expression patterns from HCC tissue biopsies as potential biomarker in patients under sorafenib treatment. Nineteen patients with advanced HCC treated with sorafenib were included. RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) liver biopsies. MiRNA expression profiling of 818 mature miRNAs was performed using ...
Source: Clinical Science - June 24, 2014 Category: Biomedical Science Authors: J Peveling-Oberhag, C Döring, S Hartmann, N Filmann, A Mertens, A Piiper, E Herrmann, M Hansmann, S Zeuzem, J Trojan, M Welker Source Type: research

Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: Possible role of nuclear factor-{kappa}B
Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We hypothesized that the pro-inflammatory transcription factor nuclear factor κB (NF-κB) impairs EDD with sedentary aging and habitual aerobic exercise prevents this age-related suppression of EDD by NF-κB. To test this hypothesis, we inhibited NF-κB signaling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n=14, 58±2 years), older non-exercising adults (ON, n=16, 61±1 years) and young non-exercising controls (YN, n=8, 23±1 years). Salsalate...
Source: Clinical Science - June 20, 2014 Category: Biomedical Science Authors: A E Walker, R E Kaplon, G L Pierce, M J Nowlan, D R Seals Source Type: research

Upregulation of brain-enriched miR-107 promotes excitatory neurotoxicity through downregulation of glutamate transporter 1 expression following ischemic stroke
In this study, we screened the expressions of 9 brain-specific or brain-enriched miRNAs in a focal cerebral ischemia/reperfusion (I/R) injury rat model, which showed glutamate accumulation and down-regulated GLT-1 expression as expected, and uncovered miR-107 level was elevated in both brain tissue and plasma in the model. Next, we examined the functional relationship of miR-107 with GLT-1 expression in a nerve cell hypoxia/reoxygenation (H/R) injury model. H/R treatment increased apoptosis of the nerve cells concomitant with glutamate accumulation, miR-107 elevation and suppressed GLT-1 expression, mimicking our in vivo f...
Source: Clinical Science - June 19, 2014 Category: Biomedical Science Authors: Z Yang, Z Zhang, T Li, Z Lou, S Li, H Yang, J Yang, X Luo, J Peng Source Type: research

The inverse agonist propranolol confers no corticosteroid sparing activity in mild to moderate persistent asthma
The murine asthma model shows that switching off airway beta-2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low dose inhaled corticosteroid (ICS) versus higher dose ICS. A randomized, double-blind, placebo-controlled, crossover trial in mild-moderate persistent asthmatics was performed. After a run-in (2weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) 100μg/day, patients received randomised treatments (4weeks) with propranolol 80mg/day plus ...
Source: Clinical Science - June 18, 2014 Category: Biomedical Science Authors: W J Anderson, P M Short, P A Williamson, A Manoharan, B J Lipworth Source Type: research

NOD1 receptor is upregulated in diabetic human and murine myocardium
Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor, NOD1 (nucleotide-binding oligomerization domain 1), and the pathogenesis of diabetes in monocytes and hepatic and adipose tissues. The aim of this study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We measured NOD1 protein in cardiac tissue from type 2 diabetic mice (db). Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an upregulation of NF-kB and increased apoptosis. Heart tissu...
Source: Clinical Science - June 17, 2014 Category: Biomedical Science Authors: P Prieto, M Teresa Vallejo-Cremades, G Benito, P Gonzalez-Peramato, D E Francés, N Agra, V Terrón, S Gonzalez-Ramos, C Delgado, M Ruiz-Gayo, I Pacheco, J P Velasco-Martín, J Regadera, P Martín Sanz, E Lopez-Collazo, L Boscá, M Fernandez-Velasco Source Type: research

Curcumin exerted inhibitory effects on undifferentiated nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5p
Curcumin suppressed proliferation, migration, invasion, metastasis, and angiogenesis and induced apoptosis by regulating multiple signaling pathways and miRNAs in a wide variety of human malignancies. miRNAs play crucial roles in various steps of carcinogenesis in NPC, thus miRNAs could serve as critical therapeutic targets for NPC treatment. Curcumin could provide a novel strategy to block or introduce specific miRNAs for miRNA-based gene therapies. Nevertheless, there are no reports on the miRNAs regulated by curcumin in NPC yet. In the present study, we carried out a miRNA microarray to identify the miRNAs regulated by ...
Source: Clinical Science - June 4, 2014 Category: Biomedical Science Authors: W Gao, J Chan, T Wong Source Type: research

Physical Ischemia Induced by Isometric Exercise Facilitated Collateral Development in the Remote Ischemic Myocardium of Humans
The objective of the present study was to investigate the effects of isometric handgrip induced physical ischemia training (PIT) on remote coronary recruitment and growth. Methods: Seventy-four CAD patients were randomly assigned to either isometric handgrip (IHG) or non-exercise groups (NEG). Patients in the IHG group performed isometric handgrip exercises during one minute of coronary balloon occlusion, while patients in the NEG group remained sedentary. Collateral flow index (CFI), heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated prior to and at the end of occlusion. In a ...
Source: Clinical Science - June 3, 2014 Category: Biomedical Science Authors: S Lin, Y Chen, Y Li, J Li, X Lu Source Type: research

Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin producing cells
LRP1 is an endocytic and multifunctional type I cell surface membrane protein, which is known to be phosphorylated by the activated PDGF receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and c-Abl, and which has previously been reported to counteract beta-cell death and diabetes, has been suggested to ameliorate atherosclerosis by inhibiting PDGFR-induced LRP1 phosphorylation. The aim of this investigation was to study LRP1 function in beta-cells and to what extent imatinib modulates LRP1 activity. LRP1 and c-Abl gene knockdown was performed by RNAi using rat INS-1 832/13 and human EndoC1-bH1 c...
Source: Clinical Science - May 28, 2014 Category: Biomedical Science Authors: R Göran Fred, S Kumar Boddeti, M Lundberg, N Welsh Source Type: research

Activation of Lymphocyte Autophagy/Apoptosis Reflects Hemodynamic Inefficiency and Functional Aerobic Impairment in Patients with Heart Failure
This study investigated whether lymphocytopenia results from activated lymphocyte autophagy/apoptosis, which reflects hemodynamic inefficiency and functional aerobic impairment in the HF patients.One hundred twenty-seven HF patients were divided into three groups: HF with non-(lymphocytes≧2,000 cells/ml, n=45), mild-(1,500 cells/ml≧lymphocytes
Source: Clinical Science - May 27, 2014 Category: Biomedical Science Authors: T Weng, T Fu, C Wang, C Hsu, J Wang Source Type: research

Death-associated protein kinase3 mediates vascular structural remodeling via stimulating smooth muscle cell proliferation and migration
Death-associated protein kinase (DAPK)3 also known as zipper-interacting kinase is a serine/threonine kinase that mainly regulates cell death and smooth muscle contraction. We previously found that protein expression of DAPK3 increases in mesenteric artery from spontaneously hypertensive rats (SHR) and that DAPK3 mediates the development of hypertension in SHR partly through promoting reactive oxygen species-dependent vascular inflammation. However, it remains to be clarified how DAPK3 controls smooth muscle cells (SMCs) proliferation and migration that are also important processes for the hypertension development. We ther...
Source: Clinical Science - May 12, 2014 Category: Biomedical Science Authors: T Usui, T Sakatsume, R Nijima, K Otani, K Kazama, T Morita, S Kameshima, M Okada, H Yamawaki Source Type: research

Targeting mitochondrial 18kDa Translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype
The aim of this study was to establish mitochondrial cholesterol trafficking 18kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically, and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR, immunoblotting and radiolabelling, including [3H]cholesterol efflux to apoA-I, HDL and human serum. Induction of macrophage cholesterol deposition by acetylated LDL (AcLDL) increased expression of TSPO mRNA and pro...
Source: Clinical Science - May 12, 2014 Category: Biomedical Science Authors: J M W Taylor, A Marie Allen, A Graham Source Type: research