Acute Effects of Kisspeptin Administration on Bone Metabolism in Healthy Men.

CONTEXT: Osteoporosis results from disturbances in bone formation and resorption. Recent nonhuman data suggest that the reproductive hormone kisspeptin directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. OBJECTIVE: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. METHODS: In vitro study: of Mono- and cocultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, 2-way crossover clinical study in 26 men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. Cells for the in vitro study were from 12 male blood donors and 8 patients undergoing hip replacement surgery. Twenty-six healthy eugonadal men (age 26.8 ±â€…5.8 years) were included in the clinical study. The intervention was Kisspeptin (vs placebo) administration. The main outcome measures were changes in bone parameters and turnover markers. RESULTS: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P = .0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P < .0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P = .021) and 24.3% maximal increase in carboxylated osteocalcin levels (P = .014). CONCLUSION: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis.

The effect of tenofovir on vitamin D metabolism in HIV-infected adults is dependent on sex and ethnicity.

BACKGROUND: Tenofovir has been associated with renal phosphate wasting, reduced bone mineral density, and higher parathyroid hormone levels. The aim of this study was to carry out a detailed comparison of the effects of tenofovir versus non-tenofovir use on calcium, phosphate and, vitamin D, parathyroid hormone (PTH), and bone mineral density. METHODS: A cohort study of 56 HIV-1 infected adults at a single centre in the UK on stable antiretroviral regimes comparing biochemical and bone mineral density parameters between patients receiving either tenofovir or another nucleoside reverse transcriptase inhibitor. PRINCIPAL FINDINGS: In the unadjusted analysis, there was no significant difference between the two groups in PTH levels (tenofovir mean 5.9 pmol/L, 95% confidence intervals 5.0 to 6.8, versus non-tenofovir; 5.9, 4.9 to 6.9; p = 0.98). Patients on tenofovir had significantly reduced urinary calcium excretion (median 3.01 mmol/24 hours) compared to non-tenofovir users (4.56; p<0.0001). Stratification of the analysis by age and ethnicity revealed that non-white men but not women, on tenofovir had higher PTH levels than non-white men not on tenofovir (mean difference 3.1 pmol/L, 95% CI 5.3 to 0.9; p = 0.007). Those patients with optimal 25-hydroxyvitamin D (>75 nmol/L) on tenofovir had higher 1,25-dihydroxyvitamin D [1,25(OH)(2)D] (median 48 pg/mL versus 31; p = 0.012), fractional excretion of phosphate (median 26.1%, versus 14.6; p = 0.025) and lower serum phosphate (median 0.79 mmol/L versus 1.02; p = 0.040) than those not taking tenofovir. CONCLUSIONS: The effects of tenofovir on PTH levels were modified by sex and ethnicity in this cohort. Vitamin D status also modified the effects of tenofovir on serum concentrations of 1,25(OH)(2)D and phosphate.

Single-center experience in systemic stress and short-term morbidity of single-incision cholecystectomy.

Single-incision laparoscopic surgery (SILS) aims to reduce the number and size of skin incisions. The authors compared systemic stress and perioperative outcome of SILS and laparoscopic (LAP) cholecystectomy. Twenty-nine subjects (8 males and 21 females; mean age = 47 years; mean body mass index = 27) were included in the study. There was no statistical difference in mean operative time (LAP = 89 minutes; SILS = 113 minutes; P = ns), and no intraoperative complications were reported. There were no statistically significant differences observed in white cell count, C-reactive protein, interleukin-6, and tumor necrosis factor-α between SILS and LAP groups. The mean hospital length of stay (LAP = 1.8 days; SILS = 1.4 days) and Visual Analogue Scale scores for pain at 6 hours (LAP = 5.14; SILS = 4.46) and 24 hours (LAP = 3.9; SILS = 2.815) were similar with no perioperative morbidity. These results suggest that the systemic stress response in LAP and SILS cholecystectomy does not appear to be significantly different. SILS cholecystectomy appears safe with no perioperative morbidity or complications encountered in this series.

Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis.

BACKGROUND: Human T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI) mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs), 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry. RESULTS: The concentrations of three plasma proteins--high [ß2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2]--were specifically associated with HAM, independently of proviral load. The plasma [ß2-microglobulin] was positively correlated with disease severity. CONCLUSIONS: The results indicate that monocytes are activated by contact with activated endothelium in HAM. Using ß2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM) in 81% of HTLV-1-infected subjects in the cohort.

MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages.

The activity of the pro-inflammatory cytokine IL (interleukin)-1 is closely regulated in vivo via a variety of mechanisms, including both the control of IL-1 production and secretion as well as naturally occurring inhibitors of IL-1 function, such as IL-1ra (IL-1 receptor antagonist). IL-1ra is homologous with IL-1, and is able to bind but not activate the IL-1 receptor. IL-1ra can be produced by a variety of cell types, and its production is stimulated by inflammatory signals. In the present study, we show that in macrophages the TLR (Toll-like receptor)-mediated induction of IL-1ra from both its proximal and distal promoters involves the p38 and ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) cascades. In addition, we show that MSK1 and 2 (mitogen- and stress-activated kinase 1 and 2), kinases activated by either ERK1/2 or p38 in vivo, are required for the induction of both IL-1ra mRNA and protein. MSKs regulate IL-1ra transcription via both IL-10-dependent and -independent mechanisms in cells. Consistent with this, knockout of MSK in mice was found to result in a decrease in IL-1ra production following LPS (lipopolysaccharide) injection. MSKs therefore act as important negative regulators of inflammation following TLR activation.

Quantifying visual field shape for improving accuracy of search performance prediction.

The current study calculated a set of 16 shape indices of six subjects (4 men and 2 women, 21-28 years old) for easy and precise quantification of visual lobe shapes using Visual Lobe Measurement System (VILOMS) software. The indices can be used in mathematical models of visual search for better understanding of search behaviour and higher accuracy of search performance prediction. General patterns in the shape indices showed that visual lobes of the subjects were slightly irregular, with low sphericity, a moderately rough boundary, horizontally elongated and slightly asymmetric along both axes. Given the complex relationships among visual lobe area, lobe shape, and search strategy, it seems that a more detailed analysis than hitherto attempted will be necessary. Quantifying lobe shape with the 16 shape indexes is a useful step to performing such analysis.

Visual performance on detection tasks with double-targets of the same and different difficulty.

This paper reports a study of measurement of horizontal visual sensitivity limits for 16 subjects in single-target and double-targets detection tasks. Two phases of tests were conducted in the double-targets task; targets of the same difficulty were tested in phase one while targets of different difficulty were tested in phase two. The range of sensitivity for the double-targets test was found to be smaller than that for single-target in both the same and different target difficulty cases. The presence of another target was found to affect performance to a marked degree. Interference effect of the difficult target on detection of the easy one was greater than that of the easy one on the detection of the difficult one. Performance decrement was noted when correct percentage detection was plotted against eccentricity of target in both the single-target and double-targets tests. Nevertheless, the non-significant correlation found between the performance for the two tasks demonstrated that it was impossible to predict quantitatively ability for detection of double targets from the data for single targets. This indicated probable problems in generalizing data for single target visual lobes to those for multiple targets. Also lobe area values obtained from measurements using a single-target task cannot be applied in a mathematical model for situations with multiple occurrences of targets.