Sensory Neurons and Schwann Cells Respond to Oxidative Stress by Increasing Antioxidant Defense Mechanisms

Abstract Elevated blood glucose is a key initiator of mechanisms leading to diabetic neuropathy. Increases in glucose induce acute mitochondrial oxidative stress in dorsal root ganglion (DRG) neurons, the sensory neurons normally affected in diabetic neuropathy, whereas Schwann cells are largely unaffected. We propose that activation of an antioxidant response in DRG neurons would prevent glucose-induced injury. In this study, mild oxidative stress (1 μM H2O2) leads to the activation of the transcription factor Nrf2 and expression of antioxidant (phase II) enzymes. DRG neurons are thus protected from subsequent hyperglycemia-induced injury, as determined by activation of caspase 3 and the TUNEL assay. Schwann cells display high basal antioxidant enzyme expression and respond to hyperglycemia and mild oxidative stress via further increases in these enzymes. The botanical compounds resveratrol and sulforaphane activate the antioxidant response in DRG neurons. Other drugs that protect DRG neurons and block mitochondrial superoxide, identified in a compound screen, have differential ability to activate the antioxidant response. Multiple cellular targets exist for the prevention of hyperglycemic oxidative stress in DRG neurons, and these form the basis for new therapeutic strategies against diabetic neuropathy. Antioxid. Redox Signal. 11, 425-438.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78129/1/ars.2008.2235.pd

Patient-provider communication about medication use at the community pharmacy counter

Objective: The objectives of this study were to, first, describe the information exchanged between pharmacy staff and patients about prescribed medication at the community pharmacy counter, and second, to investigate to what extent this met professional medication counselling guidelines. Methods: Pharmaceutical encounters were videotaped in four community pharmacies in the Netherlands. Patients were included if they collected a prescription for their own use. An observation protocol, including the MEDICODE checklist, was used to analyse the video recordings. A distinction was made between first and repeat prescriptions. Key findings: One hundred fifty-three encounters were videotaped. When dispensing first prescriptions, pharmacy staff provided most information on instructions how to use the medication (83.3%), form of the medication (71.4%) and treatment duration (42.9%). Topics for repeat prescriptions (such as the effects of the medication and the incidence of observed adverse effects) were rarely discussed. Pharmacy staff rarely encouraged patients to ask questions. Conclusions: Pharmacy staff members provided little medication-related information at the counter, especially for repeat prescriptions, did not encourage active patient participation, and thereby did not adhere to the guidelines of their professional organisation. Further research is needed to understand the reasons for this

Schistosomiasis transmission at high altitude crater lakes in Western Uganda

<p>Abstract</p> <p>Background</p> <p>Contrary to previous reports which indicated no transmission of schistosomiasis at altitude >1,400 m above sea level in Uganda, in this study it has been established that schistosomiasis transmission can take place at an altitude range of 1487–1682 m above sea level in western Uganda.</p> <p>Methods</p> <p>An epidemiological survey of intestinal schistosomiasis was carried out in school children staying around 13 high altitude crater lakes in Western Uganda. Stool samples were collected and then processed with the Kato-Katz technique using 42 mg templates. Thereafter schistosome eggs were counted under a microscope and eggs per gram (epg) of stool calculated. A semi-structured questionnaire was used to obtain demographic data and information on risk factors.</p> <p>Results</p> <p>36.7% of the pupils studied used crater lakes as the main source of domestic water and the crater lakes studied were at altitude ranging from 1487–1682 m above sea level. 84.6% of the crater lakes studied were infective with over 50% of the users infected.</p> <p>The overall prevalence of <it>Schistosoma mansoni </it>infection was 27.8% (103/370) with stool egg load ranging from 24–6048 per gram of stool. 84.3%( 312) had light infections (<100 eggs/gm of stool), 10.8%( 40) had moderate infections (100–400 eggs/gm of stool) and 4.9% (18) had heavy infections (>400 egg/gm of stool). Prevalence was highest in the age group 12–14 years (49.5%) and geometric mean intensity was highest in the age group 9–11 years (238 epg). The prevalence and geometric mean intensity of infection among girls was lower (26%; 290 epg) compared to that of boys (29.6%; 463 epg) (t = 4.383, p < 0.05). Though 61%(225) of the pupils interviewed were aware of the existence of the disease, 78% (290)didn't know the mode of transmission and only 8% (30) of those found infected were aware of their infection status. In a multivariate logistic regression model, altitude and water source (crater lakes) were significantly associated with infection.</p> <p>Conclusion and recommendations</p> <p>The altitudinal threshold for <it>S. mansoni </it>transmission in Uganda has changed and use of crater water at an altitude higher than 1,400 m above sea level poses a risk of acquiring <it>S. mansoni </it>infection in western Uganda. However, further research is required to establish whether the observed altitudinal threshold change is as a result of climate change or other factors. It is also necessary to establish the impact this could have on the epidemiology of schistosomiasis and other vector-borne diseases in Uganda. In addition, sensitisation and mass treatment of the affected community is urgently required.</p

Association between tissue hypoxia and elevated non-protein sulphydryl concentrations in human cervical carcinoma xenografts

A double staining technique was developed for the simultaneous measurement of tissue hypoxia and the concentration of non-protein sulphydryls (NPSH), based on the fluorinated nitroimidazole EF5 and the fluorescent histochemical NPSH stain 1-(4-chloromercuriphenoylazo)-naphthol-2 (mercury orange). Cryostat sections of tumour tissue were examined by fluorescence image analysis, using a computer-controlled microscope stage to generate large tiled field images of the cut tumour surface. This method was applied to the human cervical squamous cell carcinoma lines ME180 and SiHa, grown as xenografts in severe combined immunodeficient (SCID) mice, in order to determine if there is a systematic relationship between tissue hypoxia and NPSH levels. Hypoxic regions of the tumours, defined by EF5 labelling, were found to show greater NPSH concentrations relative to better oxygenated regions. This is probably due to increases in glutathione, since the ME180 and SiHa xenografts contained low levels of cysteine and metallothionein; the other major cellular thiols that can bind to mercury orange. Because the effects of glutathione on radiation and chemotherapy resistance are likely to be greater under hypoxic conditions, these results have potentially important implications for the study of resistance mechanisms in solid tumours. © 1999 Cancer Research Campaig

Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency

Recommendations for Nanomedicine Human Subjects Research Oversight: An Evolutionary Approach for an Emerging Field

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96363/1/j.1748-720X.2012.00703.x.pd