Otoacoustic Estimates of Cochlear Tuning: Testing Predictions in Macaque.

Otoacoustic estimates of cochlear frequency selectivity suggest substantially sharper tuning in humans. However, the logic and methodology underlying these estimates remain untested by direct measurements in primates. We report measurements of frequency tuning in macaque monkeys, Old-World primates phylogenetically closer to humans than the small laboratory animals often taken as models of human hearing (e.

Vascular endothelium-specific overexpression of human catalase in cloned pigs.

The objective of this study was to develop transgenic Yucatan minipigs that overexpress human catalase (hCat) in an endothelial-specific manner. Catalase metabolizes hydrogen peroxide (H(2)O(2)), an important regulator of vascular tone that contributes to diseases such as atherosclerosis and preeclampsia. A large animal model to study reduced endothelium-derived H(2)O(2) would therefore generate valuable translational data on vascular regulation in health and disease.

Upregulation of cyclooxygenase-2 expression in porcine macula densa with chronic nitric oxide synthase inhibition.

The objective of this study was to investigate the effects of chronic inhibition of nitric oxide synthase (NOS) on cyclooxygenase-2 (COX-2) expression in the macula densa (MD) of swine, as well as the effects on expression of related proteins. Adult female Yucatan swine were given either tap water (control, n = 6) or water with N (G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/liter, n = 5) for a minimum of 30 days. Duplicate samples of kidney were fixed or snap frozen.

Increased brachial artery retrograde shear rate at exercise onset is abolished during prolonged cycling: role of thermoregulatory vasodilation.

Acute leg exercise increases brachial artery retrograde shear rate (SR), while chronic exercise improves vasomotor function. These combined observations are perplexing given the proatherogenic impacts of retrograde shear stress on the vascular endothelium and may be the result of brief protocols used to study acute exercise responses. Therefore, we hypothesized that brachial artery retrograde SR increases initially but subsequently decreases in magnitude during prolonged leg cycling.

Relationship between brachial and femoral artery endothelial vasomotor function/phenotype in pigs.

In humans, the measurement of brachial artery endothelial vasomotor function is used as a surrogate index of systemic endothelial health; however, the applicability of brachial artery findings to other vasculatures needs to be examined. The purpose of the present investigation was to test the following hypotheses: (1) brachial and femoral artery endothelium-dependent/independent relaxation is correlated; (2) endothelial expression of pro-/antiatherogenic proteins is correlated between brachial and femoral arteries; and (3) within vessel, there is a positive correlation between expression of antiatherogenic proteins and endothelium-dependent/independent relaxation, and an inverse correlation between expression of proatherogenic proteins and relaxation. In vitro endothelium-dependent (bradykinin [BK] and acetylcholine [Ach]) and -independent (sodium nitroprusside [SNP]) relaxation were evaluated in harvested brachial and femoral arteries of 96 Yucatan miniature swine.

Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection.

Methods: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo.

Epicardial fat gene expression after aerobic exercise training in pigs with coronary atherosclerosis: relationship to visceral and subcutaneous fat.

Epicardial adipose tissue (EAT) is contiguous with coronary arteries and myocardium and potentially may play a role in coronary atherosclerosis (CAD). Exercise is known to improve cardiovascular disease risk factors. The purpose of this study was to investigate the effect of aerobic exercise training on the expression of 18 genes, measured by RT-PCR and selected for their role in chronic inflammation, oxidative stress, and adipocyte metabolism, in peri-coronary epicardial (cEAT), peri-myocardial epicardial (mEAT), visceral abdominal (VAT), and subcutaneous (SAT) adipose tissues from a castrate male pig model of familial hypercholesterolemia with CAD.

Impact of chronic intermittent external compressions on forearm blood flow capacity in humans.

During dynamic exercise, the vasculature embedded within skeletal muscle intermittently collapses due to increased intramuscular pressure (IMP). The aim of this study was to ascertain whether oscillations in IMP during muscle contractions independently contribute to exercise training-induced increases in blood flow capacity (BFC). Based on IMP measurements during handgrip exercise, we attempted to mimic the action of repeated vascular compressions by using external inflatable cuffs.

Strategies to enhance umbilical cord blood stem cell engraftment in adult patients.

Umbilical cord blood (UCB) has been used successfully as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation in children and adults in the treatment of hematologic diseases. However, compared with marrow or mobilized peripheral blood stem cell grafts from adult donors, significant delays in the rates and kinetics of neutrophil and platelet engraftment are noted after UCB transplant. These differences relate in part to the reduced numbers of HSCs in UCB grafts.

Umbilical cord blood stem cells for myocardial repair and regeneration.

Cardiovascular disease remains a major cause of morbidity and mortality with substantial economic cost. There remains a need for therapeutic improvement for patients refractory to revascularization and those who redevelop occlusions following revascularization. Early evidence linked age-associated reductions in the levels of circulating marrow-derived hematopoietic stem cells (HSC), characterized by expression of early HSC markers CD133 and CD34, with the occurrence of cardiovascular events and associated death.

Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats.

Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk.

Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis.

Background: Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate.

Methods: We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia.

Effects of high-density lipoprotein on endothelium-dependent vasorelaxation.

Studies using cultured endothelial cells have shown that high-density lipoprotein (HDL) positively modulates endothelial nitric oxide synthase (eNOS). The purpose of this study was to test the hypotheses that positive modulation of eNOS by HDL occurs in whole vessels and that it augments endothelium-dependent vasorelaxation. To test these hypotheses, brachial arteries were obtained from swine.

Long-term exercise training does not alter brachial and femoral artery vasomotor function and endothelial phenotype in healthy pigs.

Although the beneficial effects of exercise training on conduit artery endothelial function are well-established in animals and humans with compromised basal function, whether exercise exerts favorable effects on a healthy endothelium is inconclusive. We sought to determine whether long-term exercise training enhances endothelial function in peripheral conduit arteries of healthy pigs. Using a retrospective analysis of data collected in our laboratory (n = 127), we compared in vitro brachial and femoral artery endothelium-dependent and -independent relaxation between a group of pigs that exercise-trained for 16-20 wk and a group that remained sedentary.

Factors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries.

A retrospective analysis was conducted to examine factors affecting early mortality after myeloablative, single-unit cord blood transplantation (CBT) for hematological malignancies in adolescents and adults. Data were collected from the three main CBT registries pooling 514 records of unrelated, single, unmanipulated, first myeloablative allogeneic CBTs conducted in North America or Europe from 1995 to 2005, with an HLA match ≥ 4/6 loci, in patients aged 12-55. Overall 100-day, 180-day and 1-year survival (Kaplan-Meier method) were 56, 46 and 37%, respectively, with no significant heterogeneity across registries.

Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex.

The complement cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemoattractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the bone marrow (BM). We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal-derived factor-1 (SDF-1)-independent manner because (i) plasma SDF-1 level does not correlate with mobilization efficiency; (ii) the chemotactic plasma gradient is not affected in the presence of AMD3100 and (iii) it is resistant to denaturation by heat.

The effects of acute and chronic exercise on the vasculature.

Regular physical activity (endurance training, ET) has a strong positive link with cardiovascular health. The aim of this review is to draw together the current knowledge on gene expression in different cell types comprising the vessels of the circulatory system, with special emphasis on the endothelium, and how these gene products interact to influence vascular health. The effect beneficial effects of ET on the endothelium are believed to result from increased vascular shear stress during ET bouts.

Intermittent pneumatic leg compressions acutely upregulate VEGF and MCP-1 expression in skeletal muscle.

Application of intermittent pneumatic compressions (IPC) is an extensively used therapeutic strategy in vascular medicine, but the mechanisms by which this method works are unclear. We tested the hypothesis that acute application (150 min) of cyclic leg compressions in a rat model signals upregulation of angiogenic factors in skeletal muscle. To explore the impact of different pressures and frequency of compressions, we divided rats into four groups as follows: 120 mmHg (2 s inflation/2 s deflation), 200 mmHg (2 s/2 s), 120 mmHg (4 s/16 s), and control (no intervention).

Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model.

Background & Aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.

Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).

Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.

Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat.

We tested the hypothesis that physical activity can attenuate the temporal decline of ACh-induced endothelium-dependent relaxation during type 2 diabetes mellitus progression in the Otsuka Long-Evans Tokushima fatty (OLETF) rat. Sedentary OLETF rats exhibited decreased ACh-induced abdominal aortic endothelium-dependent relaxation from 13 to 20 wk of age (20-35%) and from 13 to 40 wk of age (35-50%). ACh-induced endothelium-dependent relaxation was maintained in the physically active OLETF group and control sedentary Long-Evans Tokushima Otsuka (LETO) group from 13 to 40 wk of age.

Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats.

The temporal changes in skeletal muscle mitochondrial content and lipid metabolism that precede type 2 diabetes are largely unknown. Here we examined skeletal muscle mitochondrial fatty acid oxidation (MitoFAOX) and markers of mitochondrial gene expression and protein content in sedentary 20- and 40-wk-old hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF-SED) rats. Changes in OLETF-SED rats were compared with two groups of rats who maintained insulin sensitivity: age-matched OLETF rats given access to voluntary running wheels (OLETF-EX) and sedentary, nonobese Long-Evans Tokushima Otsuka (LETO-SED) rats.