Experimental and clinical pharmacology - Incretin mimetics and enhancers: mechanisms of action

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes, so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase

Proximity to Sports Facilities and Sports Participation for Adolescents in Germany

Objectives - To assess the relationship between proximity to specific sports facilities and participation in the corresponding sports activities for adolescents in Germany. Methods - A sample of 1,768 adolescents aged 11–17 years old and living in 161 German communities was examined. Distances to the nearest sports facilities were calculated as an indicator of proximity to sports facilities using Geographic Information Systems (GIS). Participation in specific leisure-time sports activities in sports clubs was assessed using a self-report questionnaire and individual-level socio-demographic variables were derived from a parent questionnaire. Community-level socio-demographics as covariates were selected from the INKAR database, in particular from indicators and maps on land development. Logistic regression analyses were conducted to examine associations between proximity to the nearest sports facilities and participation in the corresponding sports activities. Results - The logisitic regression analyses showed that girls residing longer distances from the nearest gym were less likely to engage in indoor sports activities; a significant interaction between distances to gyms and level of urbanization was identified. Decomposition of the interaction term showed that for adolescent girls living in rural areas participation in indoor sports activities was positively associated with gym proximity. Proximity to tennis courts and indoor pools was not associated with participation in tennis or water sports, respectively. Conclusions - Improved proximity to gyms is likely to be more important for female adolescents living in rural areas

Morphometric analyses of the visual pathways in macular degeneration

Introduction. Macular degeneration (MD) causes central visual field loss. When field defects occur in both eyes and overlap, parts of the visual pathways are no longer stimulated. Previous reports have shown that this affects the grey matter of the primary visual cortex, but possible effects on the preceding visual pathway structures have not been fully established. Method. In this multicentre study, we used high-resolution anatomical magnetic resonance imaging and voxel-based morphometry to investigate the visual pathway structures up to the primary visual cortex of patients with age-related macular degeneration (AMD) and juvenile macular degeneration (JMD). Results. Compared to age-matched healthy controls, in patients with JMD we found volumetric reductions in the optic nerves, the chiasm, the lateral geniculate bodies, the optic radiations and the visual cortex. In patients with AMD we found volumetric reductions in the lateral geniculate bodies, the optic radiations and the visual cortex. An unexpected finding was that AMD, but not JMD, was associated with a reduction in frontal white matter volume. Conclusion. MD is associated with degeneration of structures along the visual pathways. A reduction in frontal white matter volume only present in the AMD patients may constitute a neural correlate of previously reported association between AMD and mild cognitive impairment. Keywords: macular degeneration - visual pathway - visual field - voxel-based morphometryComment: appears in Cortex (2013

Lung dendritic cells and host immunity to infection

The lung is a portal of entry for numerous microbial pathogens, against which evolution has created an adequate innate and adaptive immune response. Dendritic cells (DCs) are central to the integration of innate and specific immunity. These cells are located within the epithelium and interstitium of the lung where they are influenced by the innate immune system. Upon recognition and internalization of microbial antigens, DCs migrate to the draining lymph nodes of the lung to initiate the specific cellular and humoral immune response. By their capacity to integrate stimuli derived from the pathogen, the host and the environment, they are specialized to induce a protective immune response while at the same time avoiding damage to the host. It is becoming increasingly clear that dendritic cells are involved in the induction of immunity to viruses, bacteria, mycobacteria and fungi. Some pathogens subvert the function of dendritic cells to escape immune recognition. Not surprisingly, if dendritic cell function fails, the consequence for the host is immunodeficiency

A conformational study of peptides with the general structure Ac-L-Xaa-Pro-D-Xaa-L-Xaa-NH_2: spectroscopic evidence for a peptide with significant β-turn character in water and in dimethyl sulfoxide

Several tetrapeptides, Ac-Val-Pro-D-Ser-His-NH_2, in particular, show significant type II β-turn character in water and in dimethyl sulfoxide. Evidence for this turn population is provided by 2D-rotating frame nuclear Overhauser effect (ROESY) spectroscopy, ^1H NMR amide temperature coefficients, and circular dichroism (CD) studies. To further investigate which residues specifically contribute to the integrity of the turn, studies on 10 tetrapeptides, having the general sequence AC-LXaa-Pro-D-Xaa-L-Xaa-NH_2, are described. The results show the effects of sequence variations on the type II β-turn forming propensity of these peptides in solution. Conclusions from these studies indicate that a cooperative effect between a sterically hindered, β-branched amino acid at the (i) position and a small, non-β-branched D-amino acid at the (i+2) position promotes turn formation. Implications for use of these sequences as structural nucleation elements in de novo protein design are discussed

RXTE observations of the dipping low-mass X-ray binary 4U 1624-49

We analyse ~ 360 ks of archival data from the Rossi X-Ray Timing Explorer (RXTE) of the 21 hr orbital period dipping low-mass X-ray binary 4U 1624-49. We find that outside the dips the tracks in the colour-colour and hardness-intensity diagrams (CDs and HIDs) are reminiscent of those of atoll sources in the middle and upper parts of the banana branch. The tracks show secular shifts up to ~ 10%. We study the power spectrum of 4U 1624-49 as a function of the position in the CD. This is the first time power spectra of this source are presented. No quasi-periodic oscillations (QPOs) are found. The power spectra are dominated by very low frequency noise (VLFN), characteristic for atoll sources in the banana state, and band limited noise (BLN) which is not reliably detected but may, uncharacteristically, strengthen and increase in frequency with spectral hardness. The VLFN fits to a power law, which becomes steeper when the source moves to the harder part of the CD. We conclude that 4U 1624-49 is an atoll source which in our observations is in the upper banana branch. Combining this with the high (0.5-0.7 L_Edd) luminosity, the long-term flux stability of the source as seen with the RXTE All-Sky Monitor (ASM), and with the fact that it is an X-ray dip source, we conclude that 4U 1624-49 is most likely a GX atoll source such as GX 3+1 and GX 9+9, but seen edge on.Comment: 8 pages, 5 figures, 2 tables, accepted for publication in A&A. This version: a few typos correcte

Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.

To evaluate the association between a vessel size index (VSIMRI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSIMRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSIMRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSIMRI = 13.67 μm and VSIHistology = 12.60 μm, with slight overestimation of VSIMRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSIMRI and VSIHistology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber

Seasonal diet changes in elephant and impala in mopane woodland

Elephant and impala as intermediate feeders, having a mixed diet of grass and browse, respond to seasonal fluctuations of forage quality by changing their diet composition. We tested the hypotheses that (1) the decrease in forage quality is accompanied by a change in diet from more monocots in the wet season to more dicots in the dry season and that that change is more pronounced and faster in impala than in elephant; (2) mopane (Colophospermum mopane), the most abundant dicot species, is the most important species in the elephant diet in mopane woodland, whereas impala feed relatively less on mopane due to the high condensed tannin concentration; and (3) impala on nutrient-rich soils have a diet consisting of more grass and change later to diet of more browse than impala on nutrient-poor soils. The phosphorus content and in vitro digestibility of monocots decreased and the NDF content increased significantly towards the end of the wet season, whereas in dicots no significant trend could be detected. We argue that this decreasing monocot quality caused elephant and impala to consume more dicots in the dry season. Elephant changed their diet gradually over a 16-week period from 70% to 25% monocots, whereas impala changed diets rapidly (2-4 weeks) from 95% to 70% monocots. For both elephants and impala, there was a positive correlation between percentage of monocots and dicots in the diet and the in vitro digestibility of these forage items. Mopane was the most important dicot species in the elephant diet and its contribution to the diet increased significantly in the dry season, whereas impala selected other dicot species. On nutrient-rich gabbroic soils, impala ate significantly more monocots than impala from nutrient-poor granitic soils, which was related to the higher in vitro digestibility of the monocots on gabbroic soil. Digestibility of food items appears to be an important determinant of diet change from the wet to the dry season in impala and elephants

X-ray time variability across the atoll source states of 4U 1636--53

We have studied the rapid X-ray time variability in 149 pointed observations with the \textit{Rossi X-ray Timing Explorer} (RXTE)'s Proportional Counter Array of the atoll source 4U~1636--53 in the banana state and, for the first time with RXTE, in the island state. We compare the frequencies of the variability components of 4U~1636--53 with those in other atoll and Z-sources and find that 4U~1636--53 follows the universal scheme of correlations previously found for other atoll sources at (sometimes much) lower luminosities. Our results on the hectohertz QPO suggest that the mechanism that sets its frequency differs from that for the other components, while the amplitude setting mechanism is common. A previously proposed interpretation of the narrow low-frequency QPO frequencies in different sources in terms of harmonic mode switching is not supported by our data, nor by some previous data on other sources and the frequency range that this QPO covers is found not to be related to spin, angular momentum or luminosity.Comment: 16 pages, 13 figures, accepted for publication in Ap