The IL-6 -174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans

Chronic low-grade elevations in circulating levels of interleukin (IL)-6 act as a marker of subclinical cardiovascular diseases (CVD) and provide an independent predictor of increased mortality in elderly populations. The purpose of the present study was to test the hypothesis that the IL-6 -174G>C promoter polymorphism was associated with a high prevalence of CVD and acted as an independent predictor of mortality in a longitudinal study of 324 relatively healthy 80-year-old people with a history of CVD in 18% of the cases. The C allele was associated with elevated serum levels of IL-6 at baseline and the CC genotype had a high prevalence of CVD. A Cox regression model was used to explore the effect of the polymorphism on survival in the following six years. A significant interaction was found between smoking status and the polymorphism. Thus, C allele carrier status was associated with increased all-cause mortality risk in non-smokers independently of sex, body mass index, co-morbidity, and low-grade elevations in serum levels of IL-6. This effect was not detected among smokers. We conclude that the IL-6 -174G>C polymorphism was an independent predictor of all-cause mortality in octogenarians but the effect was complex and interacted with the smoking status.     

Interleukin-6 markedly decreases skeletal muscle protein turnover and increases nonmuscle amino acid utilization in healthy individuals

CONTEXT: IL-6 is a key modulator of immune function and suggested to be involved in skeletal muscle wasting as seen in sepsis. OBJECTIVE: Our objective was to determine the role of IL-6 in human in vivo systemic and skeletal muscle amino acid metabolism and protein turnover. SUBJECTS AND METHODS: There were 12 healthy men infused for 3 h with saline (saline, n = 6) or recombinant human IL (rhIL)-6 (n = 6). Systemic and muscle protein turnover was determined with a combination of tracer dilution methodology, primed constant infusion of L-[ring-(2)H(5)]phenylalanine, and femoral arterial-venous blood differences and m. vastus lateralis biopsies after 2-h basal, 3-h infusion, and 3 h after infusion. RESULTS: The IL-6 concentration after 30-min infusion was approximately 4 (saline) and 140 pg/ml (rhIL-6). Three-hour rhIL-6 infusion caused an approximate 50% decrease in muscle protein turnover, albeit synthesis was more suppressed than breakdown, causing a small increase in net muscle protein breakdown. Furthermore, rhIL-6 decreased arterial amino acid concentration with 20-40%, despite the increase net release from muscle. CONCLUSIONS: We demonstrated that IL-6 profoundly alters amino acid turnover. A substantial decrease in plasma amino acids was observed with a concomitant 50% decrease in muscle protein turnover, however, modest increase in net muscle degradation. We hypothesize that the profound reduction in muscle protein turnover and modest increase in net degradation are primarily caused by the reduced plasma amino acid availability and not directly mediated by IL-6.     

Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.Studies in human and rodent models have revealed deleterious effects of excess lipid availability on peripheral insulin sensitivity (1,2). Intracellular increases in fatty acid metabolites, such as diacylglycerol (DAG) and ceramide, may play critical roles in mediating lipid-induced insulin resistance by inducing serine phosphorylation of insulin-receptor substrate 1 (IRS-1) (3–6) and consequently inhibiting downstream signaling to GLUT4 translocation. However, recent reports challenge such causality. These studies revealed unaltered signal transduction at the level of IRS-1, IRS-1–associated phosphatidylinositol-3-kinase (PI3K) activity, Akt, and TBC1 domain family member 4 (TBC1D4) phosphorylation (phospho-Akt-substrate [PAS] an unspecific antibody recognizing phosphorylated Akt substrate motifs), after 2–7 h of lipid infusion (7–11). When DAG and/or ceramide levels were reported, no changes in skeletal muscle DAG or ceramide levels were found after lipid infusion (7,11).We recently showed that lactate release in human skeletal muscle is augmented along with reduced respiratory exchange ratio (RER) values during lipid infusion (11). This could indicate suppressed activity of the pyruvate dehydrogenase (PDH) complex, which in turn could lead to a reduction in glucose uptake according to the Randle cycle (12). Here, we wished to investigate whether this increase in leg lactate release and reduced RER values were accompanied by altered regulation of PDH, measured by site-specific phosphorylation.Exercise increases peripheral insulin sensitivity (13–15). After an acute bout of exercise, the ability for insulin to stimulate glucose uptake in skeletal muscle is increased several hours into recovery (14,16). This effect can be ascribed to adaptations in the exercised muscle rather than changes in systemic factors (13,17,18) and is observed in both healthy and insulin-resistant states (e.g., obesity) (19) and type 2 diabetes (20). A recent study has shown that a single bout of exercise can prevent subsequent lipid-induced impairments in whole-body glucose tolerance assessed by an intravenous glucose tolerance test (IVGTT) (2). It was hypothesized that repartitioning fatty acids toward intramuscular triacylglycerol (IMTG) synthesis and storage rather than DAG or ceramide might be a primary mediator of the beneficial effects of exercise on lipid-induced impairments in glucose tolerance (2). Enhanced insulin sensitivity after a bout of exercise is associated with increased GLUT4 recruitment to the plasma membrane (21) and not with altered protein synthesis (e.g., GLUT4 protein) (22), but has not been associated with altered signal transduction through the insulin receptor, IRS-1, PI3K, or Akt (13,22,23). Recently, the hypothesis was put forward (24) that the guanosine triphosphatase (GTPase) activating proteins TBC1 domain family member 1 (TBC1D1) and 4 (TBC1D4) might serve as points of convergence for insulin dependent and independent signaling pathways to GLUT4 translocation. In agreement with this hypothesis, PAS phosphorylation of TBC1D4 is elevated along with insulin-stimulated glucose uptake for up to 27 h after exercise in skeletal muscle of rats (25), and we recently showed that phosphorylation of TBC1D4 on specific residues was elevated 4 h after a single bout of exercise in human skeletal muscle (26).TBC1D4/D1 are multikinase substrates proposed to be involved in contraction- and insulin-stimulated glucose uptake in mice (27,28), and exercise and insulin both substantially increase TBC1D4/D1 phosphorylation in human skeletal muscle (29,30). TBC1D4/D1 contain several phosphorylation sites distinctly phosphorylated by various kinases, including Akt and 5′AMP-activated protein kinase (AMPK) (28,31–33). Phosphorylation of TBC1D4/D1 and subsequent 14-3-3 binding is proposed to lead to inactivation of the GTPase-activating proteins, decreasing their inhibitory function on the GLUT4 translocation process and thus, potentially, increasing the GLUT4 capacity of the surface membrane.In the current study we tested the hypothesis that prior exercise prevents subsequent lipid-induced insulin resistance in human skeletal muscle through regulation of the signaling molecules TBC1D4/TBC1D1.     

Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross‐sectional study we compared patients with type I OI to age‐ and gender‐matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21–77) years, and 39 controls, aged 53 (range, 21–77) years, were included in the study. Twenty‐seven of the patients had been treated with bisphosphonates. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and dual‐energy X‐ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1–L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age‐ and gender‐matched controls. © 2012 American Society for Bone and Mineral Research.     

Test-retest reliability of joint position and kinesthetic sense in the elbow of healthy subjects

Proprioception is an important effect measure in neuromuscular function training in physiotherapy. Reliability studies of methods for measuring proprioception are few on joint position sense (JPS) and threshold to detection of a passive movement (TDPM) on the elbow. The aim was to study test-retest reliability of elbow-JPS and elbow-TDPM. A total of 45 healthy subjects participated in the study (mean age 33 years, range 18–57 years). In the active-active test-retest of JPS 26 subjects and in test-retest of TDPM 19 subjects participated. The duration between test and retest was approximately 30 minutes. There was no significant difference (p<0.05) between test and retest. The intraclass correlation coefficients, (ICC, model 2.1) of test-retest on absolute error were 0.59 and 0.69 for JPS and TDPM, respectively, indicating a fair to good reliability. ICCs of variable error were 0.45 for TDPM, indicating a fair to good reliability, whereas for JPS it was 0.007, indicating poor reliability. TDPM can be recommended as an examination tool for absolute error, but to a minor degree for consistency of error. JPS can only be recommended to a minor degree for absolute error, but for consistency of error it is not reliable and can therefore not be recommended.     

Tetracycline-resistant micro-organisms recovered from patients with refractory periodontal disease

Abstract Tetracycline in combination with scaling and root planing is frequently used to treat refractory periodontal disease. This study examined tetracycline resistance in bacteria recovered from periodontal pockets of patients with refractory periodontitis. Bacterial isolates resistant to 10 μg/ml of tetracycline were isolated from plaque samples of 17 patients, of whom 6 had received tetracycline within 8 weeks prior to sampling. Minimal inhibitory concentrations (MICs) of tetracycline and minocycline were determined by agar dilution. In the 6 patients who had received tetracycline, a mean of 22.9% (±38.2) of the total cultivable subgingival flora were resistant to tetracycline, compared with a mean of 7.2% (±8.5) in the untreated group. Although various organisms were isolated, in most patients, the tetracycline-resistant organisms were dominated by Streptococcus spp. Overgrowth of Candida was found in one patient, and of Enterobacteriaceae in another patient, while small numbers of yeast or Staphylococcus spp. were isolated from the plaque samples of 9 others. 3 out of 4 patients who did not respond to tetracycline treatment had a variety of tetracycline-resistant anaerobic Gram-negative rods present. No correlation was found between increased proportions of tetracycline resistance in the whole bacterial sample and the presence of resistant periodontal pathogens.     

Prevention of mouse-rat brain xenograft rejection by a combination therapy of cyclosporin A,prednisolone and azathioprine

Embryonic mouse hippocampal tissue was grafted as tissue blocks to the hippocampal region of adult rats and the effect of two different immunosuppressive treatments compared. Immunosuppression with cyclosporin A, prednisolone and azathioprine or with cyclosporin A alone was compared with placebo treatment. Eight weeks' postgrafting medication with cyclosporin A, prednisolone and azathioprine had resulted in survival of 14 out of 15 grafts (93%), compared with 11 out of 14 (79%) in the group treated with cyclosporin A alone. Only 2 out of 13 grafts (15%) survived in placebo-treated animals. Transplants in the trimedication group displayed distinct cell and neuropil layers and only minimal cellular infiltration by leukocyte common antigen-expressing cells, whereas grafts in cyclosporin A- and placebo-treated groups were densely infiltrated. The results are discussed in relation to the need for extended immunosuppressive and antiinflammatory therapies after intracerebral grafting of histoincompatible tissues.     

GABAA and GABAB receptor agonists, partial agonists, antagonists and modulators: design and therapeutic prospects

A large number of highly selective GABA_A and, more recently, GABA_B receptor ligands have been developed and used for receptor characterization. Whereas full agonists and antagonists at GABA_A receptors, for different reasons, may be difficult to use therapeutically, partial GABA_A agonists may have therapeutic interest. The efficacious partial GABA_A agonist, THIP, shows analgesic and anxiolytic effects in man, but THIP is ineffective as an antiepileptic agent, and PET studies have disclosed that THIP increases glucose metabolism in epileptic patients and human volunteers. In principle, GABA_A antagonists may be used therapeutically in Alzheimer's disease and schizophrenia, but low-efficacy partial GABA_A agonists may have particular interest in these disorders. Using the nonannulated THIP analogue, 4-PIOL, as a lead, a series of partial GABA_A agonists showing a broad spectrum of relative efficacies have been developed.