Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion

Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes.     

Longer term follow up of aerobic capacity in children affected by severe acute respiratory syndrome (SARS)

BACKGROUND: A study was undertaken to investigate the aerobic capacity and pulmonary function of children 6 and 15 months after the diagnosis of severe acute respiratory syndrome (SARS). METHODS: Thirty four patients of mean age 14.7 years completed both pulmonary function and maximal aerobic capacity tests at 6 months. All had normal clinical examination and were asymptomatic. Their exercise responses were compared with a group of healthy controls. Complete data were collected on 27 of the original 34 cases at 15 months. RESULTS: Compared with normal controls, the patient group had significantly lower absolute and mass related peak oxygen consumption (peak V o(2) (p<0.01)), higher ventilatory equivalent for oxygen (p<0.01), lower oxygen pulse (p<0.01), and a lower oxygen uptake efficiency slope (p<0.01) at 6 months. This impairment was unexpected and out of proportion with the degree of lung function abnormality. Residual high resolution computed tomography of thorax (HRCT) abnormalities were present in 14 patients. Those with abnormal HRCT findings had significantly lower mass related peak V o(2) than subjects with normal radiology (p<0.01). Absolute and mass related peak V o(2) in the patient group remained impaired at 15 months despite normalisation of lung function in all patients. CONCLUSIONS: The mechanism for the reduced aerobic capacity in children following SARS is not fully understood, but it is probably a consequence of impaired perfusion to the lungs at peak exercise and deconditioning.     

Different faecal sampling methods alter the acceptability of faecal occult blood testing: a cross sectional community survey

BackgroundA bowel cancer screening programme is being introduced in the UK. The programme will screen men and women aged 60–69 using faecal occult blood testing (FOBt). Uptake rates in the pilot evaluation were <60%. This study aimed to determine whether the acceptability of FOBt is associated with the sampling method or previous exposure to FOBt.MethodsPostal questionnaire assessing the perceived acceptability of three potential methods of FOBt sampling: (1) sterile transport swab; (2) smear card [as used in the national screening roll-out]; (3) faecal specimen pot [routinely used in the NHS for stool samples]. Study population comprised those aged 50–69.ResultsResponse rate was 63%. FOBt was reported as acceptable by 94.5%. Acceptability fell significantly when sampling methods were detailed. The swab was rated more acceptable than the card or the pot (90.2% versus 62.9% versus 63.0%, p < 0.0005). FOBt acceptability did not vary with previous experience of FOBt.ConclusionsThe acceptability of FOBt varied by the sampling method described. The smear card, such as that used in the national screening programme, was the least preferred method. To increase the uptake of screening, alternative methods of faecal sampling should be considered.     

A cell-sparing electric field stimulation technique for high-throughput screening of voltage-gated ion channels

The Trans Cell Layer Electrical Field Stimulation (TCL-EFS) system has been developed for high-throughput screening (HTS) of voltage-gated ion channels in microplate format on a Voltage-Ion Probe Reader (VIPR) platform. In this design, a wire electrode is placed above the cell layer of each filter well, and a whole plate perimeter electrode resides beneath the filter layer. This configuration allows the electrodes to be placed away from the cell layer to minimize the near electrode field effects on cell function and dye bleaching observed with other existing designs. Mathematical simulation indicates that the electric field at the cell layer becomes uniform as the top electrode is raised to a position near the surface of the solution in the well. Using the TCL-EFS system and membrane potential fluorescence resonance energy transfer (FRET) dyes, the sensitivity of voltage-gated sodium channels to tetrodotoxin and other channel inhibitors was found to be similar to those determined by established electrophysiological and more conventional VIPR techniques. A good correlation was also observed with the TCL-EFS system for inhibition of Cav2.2 by omega-conotoxin-GVIA and for block of Cav1.2 by known small molecule inhibitors. Thus, the TCLEFS system is suitable for both quantitative analysis and HTS of voltage-gated sodium and calcium channels, without the liabilities of previously reported EFS methodologies.     

Validation of an instrument for injury data collection in rugby union

OBJECTIVE: To provide the basis for collecting rugby union injury data using a rigorously validated injury report form. METHODS: Seven stages were used to assess face, content, and criterion validity of the rugby union injury report form. A 22 member panel plus four sporting bodies assessed the form for face validity, and an expert panel assessed it for content and criterion validity. Panel members were consulted until consensus was reached. A yardstick developed by an expert panel using the Delphi technique was used to assess the reliability of the form. An independent panel of 10 viewed a series of five videotaped injuries, three times over a five week period to assess inter-rater and intrarater reliability. The form was then trialed by 40 people in situ during four games. RESULTS: The rugby union injury report form for games and training was developed, and the face, content, and criterion validity successfully assessed. A seven step protocol to create a yardstick was also developed to assist in the validation process. Both inter-rater and intrarater reliability results indicated a 98% agreement. The 40 trialists who completed forms in situ during four games were found to have an inter-rater reliability agreement of 98% for nine injuries. CONCLUSIONS: A measurement instrument for injury data collection in rugby union was successfully developed and validated, providing researchers with a basis for future studies in this area. A procedure to develop future injury data collection instruments in other sports was also developed.     

Accelerated healing with a mesh autograft/allodermal composite skin graft treated with silver nylon dressings with and without direct current in rats

PURPOSE: Evaluation of the healing and persistence of a meshed composite skin graft applied without immunosuppression. METHODS: The contraction of wounds grafted with 9:1 split-thickness autograft/1.5:1 allodermal mesh composite skin grafts (auto/allo MCSGs) was investigated. No immunosuppressive agent was applied. Male ACI rats and female Lewis rats reciprocally served as allodermis graft donors and recipients. Autograft/dermal autograft and allograft/dermal allograft MCSGs were the controls. RESULTS:AT 3 months after grafting, when epithelized auto/allo MCSG wounds were measured by computerized morphometric analysis, the silver nylon (SN) dressing group displayed less contraction than the Vaseline (petroleum jelly) dressing group (p < 0.003), and direct current treatment (SNDC) was more effective than SN (p < 0.005). The histologic structures of the hair follicles appear to confine the rejection process to the allogeneic follicles of the graft. The focal nature of the rejection process and the relatively low antigenicity of the dermal matrix allowed the survival of the allodermis layer. Although direct current significantly enhanced MCSG healing, SN and SNDC were not the immunosuppressive agents that were confirmed. CONCLUSION: This type of MCSG can heal without immunosuppressive treatment.     

Differential induction of chemokines in human microglia by type I and II interferons

Chemokines are secreted proteins that function as chemoattractants, mediating the recruitment of specific subsets of leukocytes to sites of tissue damage and immunological reactions. Chemokines may also function as antiviral agents, since viruses such as human immunodeficiency virus type 1 (HIV-1) use chemokine receptors as co-receptors for viral entry. This study examines whether virus-induced interferon, IFNbeta, or immune-related interferon, IFNgamma, affects the production of beta-chemokines by CNS microglia and peripheral monocytes. When IFNbeta was used as the stimulus, induction of MIP-1alpha, MIP-1beta, MCP-1, and RANTES mRNA and protein was observed within 12 h of stimulation in microglia. By contrast, when IFNgamma was used as the stimulus, only MCP-1 was induced. IFNbeta stimulation of blood monocytes resulted in upregulation of MIP-1alpha, MIP-1beta, and MCP-1. Thus, type I and II interferons differentially regulate beta-chemokines in human fetal microglia and peripheral blood monocytes. These observations may have relevance for the therapeutic activity of IFNbeta in multiple sclerosis and for the antiviral effects of IFNbeta for HIV-1 infection of monocytes and microglia.     

Adolescent care: reducing risk and promoting resilience

In summary adolescence is a crucial period in the chronology of health. Most lifelong health choices are decided at this stage and clinicians can help adolescents make healthy choices to ensure a safe, secure future. They also develop skills for the rest of their lives to cope with stress, take care of their bodies, and decide whom to spend time with in meaningful relationships. Preventive health for adolescence stems from the relationship the provider cultivates with the patient and the power that comes from that dynamic relationship to respond to patient needs and promote health throughout the life cycle.