Modulation of sensory function by high glucose-induced oxidative stress: Role of TRPV1 receptors

Diabetes can have a devastating effect on sensory nerves often leading to clinical symptoms of pain abnormalities termed diabetic sensory neuropathy (DSN). Converging evidence demonstrate that oxidative stress plays a pivotal role in DSN as a result of elevated reactive oxygen species (ROS) induced by hyperglycemia and lead to sensory neuron injury. However, the cellular and molecular mechanisms initiating neuronal dysfunction in DSN are still poorly understood. The present thesis investigated the effects of high glucose-induced oxidative stress on sensory function mediated by the activation of purinergic (P2X) and vanilloid (TRPV1) receptors expressed in nociceptive neurons from neonatal mouse dorsal root ganglion (DRG). Primary cultures of lumbar DRG neurons were prepared to characterize sensory function during control (5 mM glucose) and high glucose (25 mM glucose) conditions using electrophysiological, live imaging and biochemical techniques. Interesting, while characterizing TRPV1 channels following repetitive applications of capsaicin, I noticed two distinct responses in TRPV1 activity: a ‘monophasic’ response, commonly observed as a run-down of peak currents; and a ‘biphasic’ response characterized as a gradual potentiation followed by a run-down of peak currents. The latter response is a novel behaviour that had not been characterized under control condition, and this prompted further investigations. I revealed that the gradual potentiation was independent of calcium entry, and was mediated by PKC. Under the high glucose condition, the two responses remained unaffected; however, I observed an enhancement of TRPV1-mediated currents, while P2X-mediated currents seemed to be unaffected. Furthermore, I demonstrated that the enhancement of current can be prevented with the use of antioxidants. This suggests that the enhancement of TRPV1 activity by high glucose- induced oxidative stress may play an essential role in peripheral sensitization in diabetes

Family physician work force projections in Saskatchewan

This thesis applies the econometric projection approach to forecast the numbers of general practitioners (GPs) in Saskatchewan for the next 15 years at both provincial and the Regional Health Authorities (RHAs) levels. The projection results will provide the estimated level of GPs up to 2021 for policy makers to adjust their decision on health professionals’ planning. Three hypothesized scenarios, which include the changes in population proportion, average income for GPs and a combination of both, are used for projections based on the regression results. The projections suggest a 4.34% expected annual increase of GPs if the proportions of children and seniors increase or decrease according to prediction for the next 15 years for Saskatchewan. At the RHAs level, 4.5% to 10.7% expected annual rate of increase for numbers of GPs is projected for the northern RHAs and Saskatoon RHA, while the expected increase for other urban RHAs will experience less than 1.5% increases. The predicted changes in average income for GPs show insignificant effect for the expected changes in numbers of GPs. However, the second and third scenarios are not extended to the RHAs level due to lack of information, which requires additional data for both Saskatchewan physicians and population for further projection analysis

Szempontok és adatok a szellemi világ néprajzának keresztény értelmezéséhez

A dolgozat állást foglal és érveket sorakoztat fel a keresztény világkép alapján való tudományos elemzés létjogosultsága mellett, s megfogalmaz néhány szempontot az ilyen irányú kutatásokhoz

Sex- and Development-Dependent Responses of Rat Microglia to Pro- and Anti-inflammatory Stimulation

Addressing potential sex differences in pre-clinical studies is crucial for developing therapeutic interventions. Although sex differences have been reported in epidemiological studies and from clinical experience, most pre-clinical studies of neuroinflammation use male rodents; however, sexual dimorphisms in microglia might affect the CNS inflammatory response. Developmental changes are also important and, in rodents, there is a critical period of sexual brain differentiation in the first 3 weeks after birth. We compared rat microglia from sex-segregated neonates (P1) and at about the time of weaning (P21). To study transitions from a basal homeostatic state (untreated), microglia were subjected to a pro-inflammatory (IFNγ + TNFα) or anti-inflammatory (IL-4) stimulus. Responses were compared by quantifying changes in nitric oxide production, migration, and expression of nearly 70 genes, including inflammatory mediators and receptors, inflammasome molecules, immune modulators, and genes that regulate microglial physiological functions. No sex differences were seen in transcriptional responses in either age group but the IL-4-evoked migration increase was larger in male cells at both ages. Protein changes for the hallmark molecules, NOS2, COX-2, PYK2 and CD206 correlated with mRNA changes. P1 and P21 microglia showed substantial differences, including expression of genes related to developmental roles. That is, P21 microglia had a more mature phenotype, with higher basal and stimulated levels of many inflammatory genes, while P1 cells had higher expression of phagocytosis-related molecules. Nevertheless, cells of both ages responded to IL-4 and IFNγ + TNFα. We examined the Kv1.3 potassium channel (a potential target for modulating neuroinflammation) and the Kir2.1 channel, which regulate several microglia functions. Kv1.3 mRNA (Kcna3) was higher at P21 under all conditions and male P21 cells had higher mRNA and Kv currents in response to IFNγ + TNFα. Overall, numerous transcriptional and functional responses of microglia changed during the first 3 weeks after birth but few sex-dependent changes were seen

Ca2+ signaling modulates cytolytic T lymphocyte effector functions

Cytolytic T cells use two mechanisms to kill virally infected cells, tumor cells, or other potentially autoreactive T cells in short-term in vitro assays. The perforin/granule exocytosis mechanism uses preformed cytolytic granules that are delivered to the target cell to induce apoptosis and eventual lysis. FasL/Fas (CD95 ligand/CD95)–mediated cytolysis requires de novo protein synthesis of FasL by the CTL and the presence of the death receptor Fas on the target cell to induce apoptosis. Using a CD8+ CTL clone that kills via both the perforin/granule exocytosis and FasL/Fas mechanisms, and a clone that kills via the FasL/Fas mechanism only, we have examined the requirement of intra- and extracellular Ca2+ in TCR-triggered cytolytic effector function. These two clones, a panel of Ca2+ antagonists, and agonists were used to determine that a large biphasic increase in intracellular calcium concentration, characterized by release of Ca2+ from intracellular stores followed by a sustained influx of extracellular Ca2+, is required for perforin/granule exocytosis. Only the sustained influx of extracellular Ca2+ is required for FasL induction and killing. Thapsigargin, at low concentrations, induces this small but sustained increase in [Ca2+]i and selectively induces FasL/Fas-mediated cytolysis but not granule exocytosis. These results further define the role of Ca2+ in perforin and FasL/Fas killing and demonstrate that differential Ca2+ signaling can modulate T cell effector functions

Effects of physical activity on functional health of older adults: a systematic review

Reviews on the relationships between functional health and physical activity of general older adults have been well documented in literature. However, specific age range of older adults, in particular, older adults of 75 years or above, is currently under-examined. A systematic review was conducted to investigate the effects of physical activity on functional health older adults aged 75 years or above. The reviewed articles cover a variety range of functional health outcomes, including balance, muscle conditioning, joint range of motion, quadriceps strength, reaction time, gait speed, health-related quality of life, back and knee pain, muscle mass, and walking ability. In general, interventions of the reviewed articles had favourable effects on function health of older adults. While physical activity has been identified as an important determinant of functional health, the ways to engage in and accumulate sufficient daily physical activity warrant investigation. It is also important to explore interventions which enhance daily, self-driven physical activity of elderly, as normally supervised physical activity bears higher costs

How parents perceive and feel about participation in community activities: The comparison between parents of preschoolers with and without autism spectrum disorders

The present study compared how parents of preschoolers with and without Autism Spectrum Disorders (ASD) perceived and felt about participation in community activities. A questionnaire survey was conducted with 380 Hong Kong parents of preschoolers with ASD and 214 Hong Kong parents of preschoolers without ASD. The two groups were not different in their willingness and frequency of participation in community activities. However, the psychological processes underneath their willingness were very different. Among the parents of preschoolers with ASD, their willingness was associated with how they perceived the difficulty and importance of the participation and what emotions they experienced during the activities. This pattern of association was not evident among the parents of preschoolers without ASD. Copyright © The Author(s), 2010.published_or_final_versio

Effects of nutrients, salinity, pH and light:dark cycle on the production of reactive oxygen species in the alga Chattonella marina

Author Posting. © Elsevier B.V., 2007. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Experimental Marine Biology and Ecology 346 (2007): 76-86, doi:10.1016/j.jembe.2007.03.007.Experiments were carried out to investigate the effects of nutrients, salinity, pH and light:dark cycle on growth rate and production of reactive oxygen species (ROS) by Chattonella marina, a harmful algal bloom (HAB) species that often causes fish kills. Different nitrogen forms (organic-N and inorganic-N), N:P ratios, light:dark cycles and salinity significantly influenced algal growth, but not ROS production. However, iron concentration and pH significantly affected both growth and ROS production in C. marina. KCN (an inhibitor of mitochondrial respiration) and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (an inhibitor of photosynthesis) had no significant effects on ROS production. Vitamin K3 (a plasma membrane electron shuttle) enhanced ROS production while its antagonist, dicumarol, decreased ROS production. Taken together, our results suggest that ROS production by C. marina is related to a plasma membrane enzyme system regulated by iron availability but is independent of growth, photosynthesis, availability of macronutrients, salinity and irradiance.The work described in this paper was supported by a CERG grant from the University Grants Committee of the Hong Kong Special Administrative Region, China to RSSW (Project No. 9040864). Support for DMA is provided by U.S. National Science Foundation grant # OCE-0136861

Three versions of Perceived Stress Scale: validation in a sample of Chinese cardiac patients who smoke

<p>Abstract</p> <p>Background</p> <p>Smoking causes heart disease, the major cause of death in China and Hong Kong. Stress is one major trigger of smoking and relapse, and understanding stress among smoking cardiac patients can therefore help in designing effective interventions to motivate them to quit. The objective of this study was to examine the psychometric properties of the Perceived Stress Scale (PSS), and to compare the appropriateness of the three versions of the scale (PSS-14, PSS-10, and PSS-4) among Chinese cardiac patients who were also smokers.</p> <p>Methods</p> <p>From March 2002 to December 2004, 1860 cardiac patients who smoked were recruited at the cardiac outpatient clinics of ten acute hospitals in Hong Kong, and 1800 questionnaires were analysed. Participants completed a questionnaire including the PSS, nicotine dependence and certain demographic variables. The psychometric properties of the PSS were investigated: construct validity using confirmatory factor analysis, reliability using Cronbach's alpha and concurrent validity by examining the relationship with smoking- and health-related variables.</p> <p>Results</p> <p>For all the three versions of the PSS, confirmatory factor analyses corroborated the 2-factor structure of the scale, with the positive and negative factors correlating significantly and negatively to a moderate extent (<it>r </it>< -0.5), and high Cronbach's alpha values for the two subscales (alpha > 0.5). All the correlations of the two subscales and the smoking- and health-related variables were statistically significant and in the expected directions although of small magnitudes, except daily cigarette consumption.</p> <p>Conclusions</p> <p>The findings confirmed the satisfactory psychometric properties of all three Chinese versions of PSS. We recommend the use of PSS-10 for research which focuses on the two components of perceived stress, as it shows a higher reliability; and the use of PSS-4 if such partition is not essential and space for multiple measures is limited.</p

BING, a novel antimicrobial peptide isolated from Japanese medaka plasma, targets bacterial envelope stress response by suppressing cpxR expression

Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics. Although AMPs have previously been isolated in many organisms, efforts on the systematic identification of AMPs in fish have been lagging. Here, we collected peptides from the plasma of medaka (Oryzias latipes) fish. By using mass spectrometry, 6399 unique sequences were identified from the isolated peptides, among which 430 peptides were bioinformatically predicted to be potential AMPs. One of them, a thermostable 13-residue peptide named BING, shows a broad-spectrum toxicity against pathogenic bacteria including drug-resistant strains, at concentrations that presented relatively low toxicity to mammalian cell lines and medaka. Proteomic analysis indicated that BING treatment induced a deregulation of periplasmic peptidyl-prolyl isomerases in gram-negative bacteria. We observed that BING reduced the RNA level of cpxR, an upstream regulator of envelope stress responses. cpxR is known to play a crucial role in the development of antimicrobial resistance, including the regulation of genes involved in drug efflux. BING downregulated the expression of efflux pump components mexB, mexY and oprM in P. aeruginosa and significantly synergised the toxicity of antibiotics towards these bacteria. In addition, exposure to sublethal doses of BING delayed the development of antibiotic resistance. To our knowledge, BING is the first AMP shown to suppress cpxR expression in Gram-negative bacteria. This discovery highlights the cpxR pathway as a potential antimicrobial target