David W. Kinniburgh

Protection against Recurrent Stroke with Resveratrol: Endothelial Protection

Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro ‘ischemia’ resulting in improved viability against oxygen and glucose deprivation (39.6±6.6% and 81.3±9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.

Phenytoin binding to partially purified albumin in renal disease

Drug binding to protein is known to be altered in renal disease. Explanations include hypoproteinemia, competitive or noncompetitive inhibition, and basic functional defects in the binding protein. Albumin, the primary binding protein for phenytoin (DPH), was isolated from the plasma of patients with severe renal failure as well as from normal controls. DPH binding was not different between the albumin preparations isolated from the two sources, although some differences were detected in the apparent affinity constant and the number of binding sites. It would appear that the significant defect in DPH binding in renal disease cannot be attributed to a basic functional defect in the drug‐binding protein albumin.

Determination of plasma octopamine and its level in renal disease.

A radioenzymatic assay method for the estimation of octopamine levels in plasma was developed. Preparation of the enzyme, phenylethanolamine-N-methyl transferase, dilution of the plasma sample, preparation of a suitable blank, and the assay conditions were found to have a significant effect on the sensitivity of the assay. Plasma octopamine levels were measured in a population of 33 normal individuals ranging in age from 19 to 94 years. Significantly higher plasma octopamine levels were found in the age group 70-90 years. Excluding those individuals over the age of 70 years, no significant differences in plasma octopamine levels were found for males or females, the range of values was 0 to 0.68 ng per ml, with a mean value of 0.23 ng per ml (n = 25). Examination of plasma octopamine levels in patients with severe renal disease requiring hemoperfusion dialysis, revealed a significantly higher level of plasma octopamine in renal disease (1.9 ng per ml), and an increase in plasma octopamine during dialysis; the mean level post dialysis being 2.7 ng per ml.

An ORS-ICP-MS method for monitoring trace levels of cobalt and chromium in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses.

OBJECTIVE To develop a rapid and reliable method, using an octopole reaction system (ORS) ICP-MS, capable of monitoring trace levels of Co and Cr in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses. DESIGN AND METHOD Whole blood is diluted 10-fold with an alkaline diluent and analyzed using an Agilent 7500 CE ORS-ICP-MS. RESULTS Limit of quantification of 0.03 μg/L Co and 0.20 μg/L Cr in patient samples. <6% covariance obtained for quality control materials analyzed over 10 runs. CONCLUSION This method is capable of monitoring trace levels of Co and Cr in diluted whole blood samples with a vial to vial run time of approximately 2 min. Results are comparable to those obtained using high resolution (HR) ICP-MS with sample digestion.

Canadian family physician knowledge and attitudes toward laboratory utilization management.

OBJECTIVES Mitigation of unnecessary and redundant laboratory testing is an important quality assurance priority for laboratories and represents an opportunity for cost savings in the health care system. Family physicians represent the largest utilizers of laboratory testing by a large margin. Engagement of family physicians is therefore key to any laboratory utilization management initiatives. Despite this, family physicians have been largely excluded from the planning and implementation of such initiatives. Our purposes were to (1) assess the importance of lab management issues to family physicians, and (2) attempt to define the types of initiatives most acceptable to family physicians. DESIGN AND METHODS We invited all Alberta family practice residents and practicing physicians to participate in a self-administered online electronic survey. Survey questions addressed the perceived importance of lab misutilization, prevalence of various types of misutilization, acceptability of specific approaches to quality control, and responsibility of various parties to address this issue. RESULTS Of 162 respondents, 95% considered lab misutilization to be either important or very important. Many physicians placed the responsibility for addressing lab misutilization issues on multiple parties, including patients, but most commonly the ordering physician (97%). Acceptability for common strategies for quality improvement in lab misutilization showed a wide range (35%-98%). CONCLUSIONS These responses could serve as a framework for laboratories to begin discussions on this important topic with primary care groups.

Evaluation of a kinetic assay for angiotensin converting enzyme.

We have verified the analytical reliability of a Sigma reagent kit, which is a modified method of Holmquist et al. (1) for the determination of angiotensin-converting enzyme (ACE) on the Abbott ABA-100 analyzer. The reaction was linear up to 160 U/L. Correlation with a radiometric method (Ventrex Laboratories) was good except for a negative constant bias and loss of linearity with the radiometric method at high levels. The reconstituted reagent was determined by atomic absorption spectroscopy to contain 5.6 mumol/L of zinc. An increase in zinc content up to 45.6 mumol/L had little or no effect on enzyme activities of preparations from three mammalian species: rabbit, guinea pig and human. Neither was ACE activity inhibited by preincubating each of two serum pools with any of four corticosteroids for up to 8 d. Enzyme activity in samples remained stable at 5 degrees C for 8 d.

European Starlings (Sturnus vulgaris) As Sentinels of Urban Air Pollution: A Comprehensive Approach from Noninvasive to Post Mortem Investigation

Urban, traffic-related air pollution remains a concern to health-care and environmental professionals, with mounting evidence connecting diverse disease conditions with exposure. Wildlife species such as European starlings (Sturnus vulgaris) cohabit urban neighborhoods and may serve as sentinels for these contaminants. In this novel approach, we use passive, personal-type air samplers to provide site-specific measurements of nitrogen dioxide (NO2), sulfur dioxide (SO2) and volatile organic compounds (VOCs, such as benzene, toluene, ethylbenzene, and xylenes, or BTEX), and account for the effects of confounding environmental factors when teasing out the responses to exposure. This study examines biomarkers of exposure to predominately traffic-related, urban air contaminants in European starlings, including morphometric measurements, immunotoxicology, oxidative stress and hepatic detoxification, and analyses responses in the context of multilayered factors including year, hatch date, weather and location, confirming that this experimental approach and the selected health indicators can be used for comparing locations with different levels of contaminants.

Enclosure design for flock-level, chronic exposure of birds to air contaminant mixtures

Abstract The objective of this study was to design an enclosure suitable for studying the ecotoxicological effects of vehicle emissions on groups of wild birds without compromising welfare. Two, adjacent enclosures sheltered from sunlight, wind and rain, were bird-proofed and wrapped with thick polyethylene sheeting. Emissions were directed into the treatment enclosure from the exhaust of a light-duty gasoline truck, using flexible, heat-proof pipe, with joins sealed to prevent leakage. During active exposure, the engine was idled for 5 h/day, 6 days/week for 4 weeks. Fans maintained positive pressure (controls) and negative pressure (treatment), preventing cross-contamination of enclosures and protecting investigators. Four sets of passive, badge-type samplers were distributed across each enclosure, measuring nitrogen dioxide, sulfur dioxide and volatile organic compounds (NO2, SO2 and VOCs, respectively), and were complemented by active monitors measuring VOCs and particulate matter (2.5 µm diameter, PM2.5). We found that the concentrations of NO2, SO2 and PM2.5 were not different between treatment and control enclosures. Volatile organic compounds (e.g. benzene, toluene, ethylbenzene and xylenes) were approximately six times higher in the treatment enclosure than control (13.23 and 2.13 µg m−1, respectively). In conclusion, this represents a successful, practical design for studying the effects of sub-chronic to chronic exposure to realistic mixtures of vehicle exhaust contaminants, in groups of birds. Recommended modifications for future research include a chassis dynamometer (vehicle treadmill), to better replicate driving conditions including acceleration and deceleration.

Concentrations of Trace Elements and Clinical Outcomes in Hemodialysis Patients: A Prospective Cohort Study

BACKGROUND AND OBJECTIVES Deficiency of essential trace elements and excess of potentially toxic trace elements are common in patients on hemodialysis. Whether these abnormalities are associated with poor outcomes is unknown but worth investigating, because they are potentially treatable. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We did a prospective longitudinal study of 1278 patients on incident hemodialysis, assessing blood concentrations of 25 trace elements at baseline. We used adjusted logistic regression to evaluate the association between trace element status and four outcomes (death, cardiovascular events, systemic infection, and hospitalization). A priori hypotheses concerned (1) deficiency of zinc, selenium, and manganese and (2) excess of lead, arsenic, and mercury. Concentrations of the other 19 elements were tested in hypothesis-generating analyses. RESULTS Over 2 years of follow-up, 260 (20%) patients died, 285 (24%) experienced a cardiovascular event, 117 (10%) were hospitalized for systemic infection, and 928 (77%) were hospitalized for any cause. Lower concentrations of zinc or manganese and higher concentrations of lead, arsenic, or mercury were not independently associated with higher risk of clinical outcomes. Lower concentrations of selenium were strongly and independently associated with death (odds ratio, 0.86 per decile; 99.2% confidence interval, 0.80 to 0.93) and all-cause hospitalization (odds ratio, 0.92 per decile; 99.2% confidence interval, 0.86 to 0.98). In exploratory analyses, higher copper concentrations were significantly associated with higher risk of death (odds ratio, 1.07 per decile; 99.2% confidence interval, 1.00 to 1.15), and cadmium levels in the highest decile were associated with higher risk of death (odds ratio, 1.89; 99.2% confidence interval, 1.06 to 3.38). CONCLUSIONS Lower levels of zinc or manganese and higher concentrations of lead, arsenic, or mercury were not associated with higher risk of clinical outcomes, but lower concentrations of selenium were strongly and independently associated with the risks of death and hospitalization.