Intramyocellular lipid stores increase markedly in athletes after 1.5 days lipid supplementation and are utilized during exercise in proportion to their content

Intramyocellular lipids (IMCL) and muscle glycogen provide local energy during exercise (EX). The objective of this study was to clarify the role of high versus low IMCL levels at equal initial muscle glycogen on fuel selection during EX. After 3 h of depleting exercise, 11 endurance-trained males consumed in a crossover design a high-carbohydrate (7 g kg(-1) day(-1)) low-fat (0.5 g kg(-1) day(-1)) diet (HC) for 2.5 days or the same diet with 3 g kg(-1) day(-1) more fat provided during the last 1.5 days of diet (four meals; HCF). Respiratory exchange, thigh muscle substrate breakdown by magnetic resonance spectroscopy, and plasma FFA oxidation ([1-(13)C]palmitate) were measured during EX (3 h, 50% W (max)). Pre-EX IMCL concentrations were 55% higher after HCF. IMCL utilization during EX in HCF was threefold greater compared with HC (P < 0.001) and was correlated with aerobic power and highly correlated (P < 0.001) with initial content. Glycogen values and decrements during EX were similar. Whole-body fat oxidation (Fat(ox)) was similar overall and plasma FFA oxidation smaller (P < 0.05) during the first EX hour after HCF. Myocellular fuels contributed 8% more to whole-body energy demands after HCF (P < 0.05) due to IMCL breakdown (27% Fat(ox)). After EX, when both IMCL and glycogen concentrations were again similar across trials, a simulated 20-km time-trial showed no difference in performance between diets. In conclusion, IMCL concentrations can be increased during a glycogen loading diet by consuming additional fat for the last 1.5 days. During subsequent exercise, IMCL decrease in proportion to their initial content, partly in exchange for peripheral fatty acids.

Functional imaging of the parotid glands using blood oxygenation level dependent (BOLD)-MRI at 1.5T and 3T

PURPOSE: To evaluate the function of the parotid glands before and during gustatory stimulation, using an intrinsic susceptibility-weighted MRI method (blood oxygenation level dependent, BOLD-MRI) at 1.5T and 3T. MATERIALS AND METHODS: A total of 10 and 13 volunteers were investigated at 1.5T and 3T, respectively. Measurements were performed before and during gustatory stimulation using ascorbate. Circular regions of interest (ROIs) were delineated in the left and right parotid glands, and in the masseter muscle for comparison. The effects of stimulation were evaluated by calculating the difference between the relaxation rates, DeltaR(2)*. Baseline and stimulation were statistically compared (Student's t-tests), merging both parotid glands. RESULTS: The averaged DeltaR(2)* values prestimulation obtained in all parotid glands were stable (-0.61 to 0.38 x 10(-3) seconds(-1)). At 3T, these values were characterized by an initial drop (to -2.7 x 10(-3) seconds(-1)) followed by a progressive increase toward the baseline. No significant difference was observed between baseline and parotid gland stimulation at 1.5T, neither for the masseter muscle at both field strengths. A considerable interindividual variability (over 76%) was noticed at both magnetic fields. CONCLUSION: BOLD-MRI at 3T was able to detect DeltaR(2)* changes in the parotid glands during gustatory stimulation, consistent with an increase in oxygen consumption during saliva production.

Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) corevalve revalving system: results from the multicentre, expanded evaluation registry 1-year following CE mark approval

AIMS: To describe the procedural performance and 30-day outcomes following implantation using the 18 Fr CoreValve Revalving System (CRS) as part of the multicentre, expanded evaluation registry, 1-year after obtaining CE mark approval. METHODS AND RESULTS: Patients with symptomatic severe aortic stenosis and logistic Euroscore > or =15%, or age > or =75 years, or age > or =65 years associated with pre-defined risk factors, and for whom a physician proctor and a clinical specialist were in attendance during the implantation and who collected the clinical data, were included. From April 2007, to April 2008, 646 patients with a mean age of 81 +/- 6.6 years, mean aortic valve area 0.6 +/- 0.2 cm2, and logistic EuroSCORE of 23.1 +/- 13.8% were recruited. After valve implantation, the mean transaortic valve gradient decreased from 49.4 +/- 13.9 to 3 +/- 2 mmHg. All patients had paravalvular aortic regurgitation < or = grade 2. The rate of procedural success was 97%. The procedural mortality rate was 1.5%. At 30 days, the all-cause mortality rate (i.e, including procedural) was 8% and the combined rate of death, stroke and myocardial infarction was 9.3%. CONCLUSIONS: The results of this study demonstrate the high rate of procedural success and a low 30-day mortality in a large cohort of high-risk patients undergoing transcatheter aortic valve implantation (TAVI) with the CRS.

Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues

The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst(1)) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA(1,4-6,10,12,13)-[DTyr(2),DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (25) was radio-iodinated ((125)I-25) and specifically labeled sst(1)-expressing cells and tissues. 3D NMR structures were calculated for des-AA(1,4-6,10,12,13)-[DPhe(2),DTrp(8),IAmp(9)]-SRIF-Thr-NH(2) (16), des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (23), and des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9),Tyr(11)]-SRIF-NH(2) (27) in DMSO. Though the analogues have the sst(1) pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst(1) binding of these novel, less constrained sst(1)-selective family members.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

SLR-derived terrestrial reference frame using the observations to LAGEOS-1/2, Starlette, Stella, and AJISAI

Currently, the contributions of Starlette, Stella, and AJISAI are not taken into account when defining the International Terrestrial Reference Frame (ITRF), despite the large amount of data collected in a long time-span. Consequently, the SLR-derived parameters and the SLR part of the ITRF are almost exclusively defined by LAGEOS-1 and LAGEOS-2. We investigate the potential of combining the observations to several SLR satellites with different orbital characteristics. Ten years of SLR data are homogeneously processed using the development version 5.3 of the Bernese GNSS Software. Special emphasis is put on orbit parameterization and the impact of LEO data on the estimation of the geocenter coordinates, Earth rotation parameters, Earth gravity field coefficients, and the station coordinates in one common adjustment procedure. We find that the parameters derived from the multi-satellite solutions are of better quality than those obtained in single satellite solutions or solutions based on the two LAGEOS satellites. A spectral analysis of the SLR network scale w.r.t. SLRF2008 shows that artifacts related to orbit perturbations in the LAGEOS-1/2 solutions, i.e., periods related to the draconitic years of the LAGEOS satellites, are greatly reduced in the combined solutions.

Assessing the paradox between transmitted and acquired HIV-1 drug resistance in the Swiss HIV Cohort Study from 1998 to 2012.

BACKGROUND  Transmitted HIV-1 drug-resistance mutations(TDR) are transmitted from treatment-failing or treatment-naïve patients. Although prevalence of drug-resistance in treatment-failing patients has declined in developed countries, TDR prevalence has not. Mechanisms causing this paradox are poorly explored. METHODS  We included recently-infected, treatment-naïve patients with genotypic-resistance-tests performed ≤1year post-infection and <2013. Potential risk factors for TDR were analyzed using logistic regression. Association of TDR prevalences with population viral load(PVL) from treatment-patients during 1997-2011 was estimated with Poisson regression for all TDR and individually for most frequent resistance-mutations against each drug class(M184V/L90M/K103N). RESULTS  We included 2421 recently-infected, treatment-naïve patients and 5399 treatment-failing patients. TDR prevalence fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in TDR(Odds Ratio[OR]=1.13,p=0.010), punctuated by sharp decreases when new drug-classes were introduced. Overall, TDR prevalence increased with decreasing PVL(Rate Ratio[RR]=0.91/1000Log10-PVL,p=0.033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with PVL of treatment-failing patients carrying M184V(RR=1.50/100Log10-PVL,p<0.001). Such association was absent and negative for K103N(RR-K103N=1.00/100Log10-PVL,p=0.99) and L90M(RR-L90M=0.75/100Log10-PVL,p=0.022), respectively. CONCLUSIONS  Transmission of antiretroviral drug-resistance is temporarily reduced by the introduction of new drug classes and driven by treatment-failing and treatment-naïve patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1-infection.

NGRIP CH4 concentration from 120 to 10 kyr before present and its relation to a δ15N temperature reconstruction from the same ice core

During the last glacial cycle, Greenland temperature showed many rapid temperature variations, the so-called Dansgaard–Oeschger (DO) events. The past atmospheric methane concentration closely followed these temperature variations, which implies that the warmings recorded in Greenland were probably hemispheric in extent. Here we substantially extend and complete the North Greenland Ice Core Project (NGRIP) methane record from the Preboreal Holocene (PB) back to the end of the last interglacial period with a mean time resolution of 54 yr. We relate the amplitudes of the methane increases associated with DO events to the amplitudes of the local Greenland NGRIP temperature increases derived from stable nitrogen isotope (δ15N) measurements, which have been performed along the same ice core (Kindler et al., 2014). We find the ratio to oscillate between 5 parts per billion (ppb) per °C and 18 ppb °C−1 with the approximate frequency of the precessional cycle. A remarkably high ratio of 25.5 ppb °C−1 is reached during the transition from the Younger Dryas (YD) to the PB. Analysis of the timing of the fast methane and temperature increases reveals significant lags of the methane increases relative to NGRIP temperature for DO events 5, 9, 10, 11, 13, 15, 19, and 20. These events generally have small methane increase rates and we hypothesize that the lag is caused by pronounced northward displacement of the source regions from stadial to interstadial. We further show that the relative interpolar concentration difference (rIPD) of methane is about 4.5% for the stadials between DO events 18 and 20, which is in the same order as in the stadials before and after DO event 2 around the Last Glacial Maximum. The rIPD of methane remains relatively stable throughout the full last glacial, with a tendency for elevated values during interstadial compared to stadial periods.