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

Diagnostic Infant ABR Testing Via Telehealth: A Survey of Professional Opinions and Current Barriers

Purpose: To examine the barriers to Washington State audiologists adopting telehealth as a means of improving accessibility to diagnostic audiology for infants. Methods: A Qualtrics survey was distributed via e-mail and social media. Survey participants were required to be audiologists practicing in Washington State. The sixteen-question survey consisted of topics related to participant demographics, previous telehealth experience, and barriers to the use of telehealth for diagnostic infant auditory brainstem response (ABR) testing. A total of 17 participants completed the survey. Results: Survey responses indicated that Washington State audiologists are largely neutral or disagree with telehealth being an effective means of performing remote diagnostic ABRs. Participants primarily identified equipment cost as a barrier, and had varying opinions regarding insurance reimbursement, internet connection, privacy, and ability to counsel. Conclusions: This study identified several barriers to the implementation of remote diagnostic ABR testing in Washington State. The neutral and negative view of telehealth for diagnostic infant ABR points to the need for education among Washington State audiologists. Disseminating information on the efficacy of telehealth to audiologists is a likely next step in reframing the current attitude toward remote diagnostic ABR and working toward reducing loss to follow-up rates for rural families

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

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

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

Facilitated engraftment of human hematopoietic cells in severe combined immunodeficient mice following a single injection of Cl²MDP liposomes

Transplantation of normal and malignant human hematopoietic cells into severe combined immunodeficient (SCID) mice allows for evaluation of long-term growth abilities of these cells and provides a preclinical model for therapeutic interventions. However, large numbers of cells are required for successful engraftment in preirradiated mice due to residual graft resistance, that may be mediated by cells from the mononuclear phagocytic system. Intravenous (i.v.) injection of liposomes containing dichloromethylene diphosphonate (Cl2MDP) may eliminate mouse macrophages in spleen and liver. In this study outgrowth of acute myeloid leukemia (AML) cells and umbilical cord blood (UCB) cells in SCID mice conditioned with a single i.v. injection of Cl2MDP liposomes in addition to sublethal total body irradiation (TBI) was compared to outgrowth of these cells in SCID mice that had received TBI alone. A two- to 10-fold increase in outgrowth of AML cells was observed in four cases of AML. Administration of 107 UCB cells reproducibly engrafted SCID mice that had been conditioned with Cl2MDP liposomes and TBI, whereas human cells were not detected in mice conditioned with TBI alone. As few as 2 x 104 purified CD34+ UCB cells engrafted in all mice treated with Cl2MDP liposomes. In SCID mice treated with macrophage depletion unexpected graft failures were not observed. Histological examination of the spleen showed that TBI and Cl2MDP liposomes i.v. resulted in a transient elimination of all macrophage subsets in the spleen, whereas TBI had a minor effect. Cl2MDP liposomes were easy to use and their application was not associated with appreciable side-effects. Cl2MDP liposome pretreatment in combination with TBI allows for reproducible outgrowth of high numbers of human hematopoietic cells in SCID mice

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