Andrew W. Lyon

Promoting glutathione synthesis after spinal cord trauma decreases secondary damage and promotes retention of function

The study aimed to 1) quantify oxidative stress in spinal cord after crush injury at T6, 2) determine whether the administration of the procysteine compound L‐2‐oxothiazolidine‐4‐carboxylate (OTC) would up‐regulate glutathione (GSH) synthesis and decrease oxidative stress, and 3) determine whether decreased oxidative stress results in better tissue and function retention. We demonstrate that spinal cord compression (5 s with a 50 g aneurysm clip) at T6 in rats results in oxidative stress that is extensive (significant increases in oxidative stress seen at C3 and L4) and rapid in onset. Indices of oxidative stress used were GSH content, protein carbonyl content, and inactivation of glutathione reductase. Administration of OTC resulted in a marked decrease in oxidative stress associated with a sparing of white matter at T6 (1661.9% retained in OTC‐treated animals vs. less than 1% in saline‐treated). Behavioral indices in control, salinetreated, and OTC‐treated animals after 6 wk were respectively: angle board scores (59°, 32°, and 42°), modified Tarlov score (7, 2.4, and 4.1), and Basso‐ Beattie‐Bresnahan score (21, 5.3, and 12.9). We conclude that administration of OTC after spinal cord trauma greatly decreases oxidative stress and allows tissue preservation, thereby enabling otherwise paraplegic animals to locomote.—Kamencic, H., Griebel, R. W., Lyon, A. W., Paterson, P. G., Juurlink, B. H. J. Promoting glutathione synthesis after spinal cord trauma decreases secondary damage and promotes retention of function. FASEB J. 15, 243–250 (2001)

Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality

BackgroundModern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hills criteria.MethodsSystematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined.ResultsFifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis.ConclusionsA causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.

The All Our Babies pregnancy cohort: design, methods, and participant characteristics.

BackgroundThe prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization.MethodsWomen were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples.ResultsA total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign-born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data.ConclusionsThe extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children.

Strategies to promote rational clinical chemistry test utilization.

OBJECTIVE To critically review the elements of laboratory services that result in inappropriate ordering of clinical chemistry tests and the efficacy of corrective interventions. METHODS AND RESULTS In our experience, inappropriate use of laboratory services derives from multiple factors, including the use of multitest profiles, organ- or disease-specific test panels, indiscriminate ordering, standing orders, excessive reporting delays, poor audit trails of test requests, rigid group test ordering, failure to eliminate obsolete tests, and some features of computer software design. Educational strategies can be effective in modifying test-ordering patterns, provided there is sustained feedback to physicians. Careful design of requisitions and the use of disease-specific algorithms have also proven effective. CONCLUSION Limited resources must be directed to where they are most effective by optimizing laboratory work-flow from test ordering to reporting, to avoid practices that promote inappropriate laboratory use.

All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment

BackgroundPreterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a womens genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions.Methods/DesignCollaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses.DiscussionThe All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.

Autoimmunity and the pathogenesis of type 1 diabetes

Type 1 diabetes mellitus (TID) is an autoimmune genetic disease with unidentified environmental agents affecting its pathogenesis. Susceptibility is determined by the interaction of MHC and non-MHC genes in the thymus, primarily by the IDDM1 locus, which is extremely polymorphic and thus generates multitudes of predisposing and protective haplotypes for binding self-peptides. By presenting these peptide antigens to immature T-cells for activation and selection, most autoreactive cells will be deleted, but inefficient presentation and subsequent deficiencies of non-MHC genes allow some cells to escape to the periphery and to be eliminated by anergy or regulatory T-cells. T-cell dysregulation to a Th1 response with secretion of inflammatory cytokines promotes a self-perpetuating autoimmune cascade leading to overt disease unless blocked by suppressive cytokines from Th2-type cells. Since autoantibodies reflect target-cell destruction, early insulin autoantibodies may be transient due to benign insulitis induced by insulin or proinsulin. Multiple autoantibodies denote epitope spreading to cryptic autoantigens, likely involving posttranslational variants. Thus, the resulting T1D development requires coordinated abnormal variations, and this requirement limits its occurrence to a small minority of susceptible individuals.

A critical analysis of postulated pathogenetic mechanisms in amyloidogenesis.

This review has examined several of the major thrusts in amyloid research, past and present. The data concerning amyloid precursor quantity, primary protein and gene structure, and precursor proteolysis have shown that there are contradictions that must be resolved before these elements can be reamalgamated into a unified view of amyloidogenesis. One possibility is presented in Figure 2. A general hypothesis of amyloid formation that accounts for the uniformity of fibril structure, amyloid staining properties, and the specific selection of precursors and their specific anatomic localization in each form of amyloid has yet to be proposed. Some of these questions may be answered by an analysis of common structural constituents in amyloid deposits. Analyzing amyloid generation in the context of these common elements separates amyloid research into several specific areas (Figure 2). The first area concerns factors that govern the expression of amyloid precursor protein genes, thus providing adequate quantities of the precursor, if such a precursor pool does not already exist. Without such a pool, amyloid deposition clearly cannot occur. The second area concerns information as to where these precursors usually bind and/or exert their normal function. Once determined, this information will likely indicate the site or sites where the particular precursor may give rise to amyloid deposits. The last area concerns factors at these local sites that govern the interaction of the precursor with basement membrane or related extracellular matrix elements that would define both the site and the final common pathway for amyloid deposition.

Simulation of repetitive diagnostic blood loss and onset of iatrogenic anemia in critical care patients with a mathematical model

Anemia is prevalent among critical care patients and is attributed to pathologic and iatrogenic processes and bleeding. The extent that diagnostic blood loss contributes to anemia among adult critical care patients is controversial and multi-factorial. The aim of this study is to describe an erythrokinetic model that integrates rates of phlebotomy, erythropoiesis and red cell senescence with patient characteristics to predict the onset of iatrogenic anemia in an objective manner. Using sex-specific parameters, the model predicts that adults with (average body weight and average blood volume), initial hemoglobin concentration at mid-reference interval, active erythropoiesis and losing 53 mL of blood per day by phlebotomy would require 40-70 days to reach 70 g/L of hemoglobin. To mimic critical care patients with low initial hemoglobin and suppressed erythropoiesis, the influence of daily blood loss and total blood volume was predicted. Simultaneous lack of erythropoiesis, initial hemoglobin concentrations at the lower limit of the reference interval (110 g/L), low body weight and increased phlebotomy accelerated onset of ~70 g/L hemoglobin transfusion threshold to 9-14 days. This computer simulation depicts the extent that adult critical care patients with anemia risk factors could benefit from conservative test ordering practices and subsequent reduced diagnostic phlebotomy.

Variation in the Frequency of Hemoglobin A1c (HbA1c) Testing: Population Studies Used to Assess Compliance with Clinical Practice Guidelines and Use of HbA1c to Screen for Diabetes

Background: The volume of hemoglobin A1c (HbA1c) testing has increased dramatically over the past decade and few studies have attempted to determine how the test is used. The goals of this study were to evaluate the frequency of HbA1c testing in regional populations to assess the extent of screening for diabetes and to determine if the HbA1c testing intervals of known diabetic patients were consistent with clinical practice guidelines. Methods: Two years of HbA1c results were extracted from laboratory information systems in four regions of the province of Alberta that represent urban, mixed urban-rural, and rural populations. HbA1c testing frequencies and the proportions of nondiabetic patients undergoing HbA1c tests were derived. Results: Approximately 60% of HbA1c tests in each region were done on patients who had only a single test during the 2-year interval. Testing of nondiabetic patients accounted for 24% of HbA1c tests and varied by region. While the cumulative frequency distributions of HbA1c test intervals resembled each other, detailed analyses of the frequency distributions depicted broad multimodal peaks and regional variations that suggest a great deal of heterogeneity among practices. The most common HbA1c testing interval was 3 months ± 3 weeks in each region and is consistent with the 3-month test interval target in a clinical practice guideline. Conclusions: HbA1c testing is being performed on a substantial proportion of nondiabetic patients. On average, patients with diabetes in Alberta receive 1.5 HbA1c tests per year. However, we observed regional differences in the frequency of testing and variation in compliance with clinical practice guidelines.

Seasonal Variation in Hemoglobin A1c: Is It the Same in Both Hemispheres?

Introduction: There are several reports from locations in the northern hemisphere of seasonal variation in hemoglobin A1c (HbA1c) levels with higher values noted in the cooler months. The variation has been attributed to holiday seasons, temperature differences, and changes in diet. This article describes the seasonal variation in both hemispheres and in a country on the equator with minimal temperature variation. Methods: The mean and median HbA1c by month was calculated for a maximum of 2 years for HbA1c data from the different locations: Edmonton and Calgary, Canada; Singapore; Melbourne, Australia; and Marshfield, Wisconsin. The mean monthly temperature for each location was found from available meteorological information. Results: In both northern and southern hemispheres, the HbA1c was higher in cooler months and lower in the warmer months. In Singapore, where there is minimal temperature variation, there is also minimal variation in HbA1c values over the year. The difference in HbA1c over a year appears to be related to the difference in temperature. Conclusion: Hemoglobin A1c is higher in cooler months and lower in the warmer months in both hemispheres. In a country with minimal monthly temperature variation, there is only minimal variation in HbA1c values through the year. In all locations, the mean and median HbA1c declined over the study period, possibly due to better glycemic control of patients with diabetes or an increase in use of HbA1c as a screening test for diabetes or a combination of both.