Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?

BACKGROUND: The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D). METHODS: We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7. RESULTS: All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671. CONCLUSIONS: We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.

Force platform feedback for standing balance training after stroke.

BACKGROUND: Standing balance deficits are common in individuals after stroke. One way to address these deficits is to provide the individual with feedback from a force platform while balance activities are performed. The feedback can take visual and/or auditory form. OBJECTIVES: To determine if visual or auditory force platform feedback improves the clinical and force platform standing balance outcomes in clients with stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched December 2003), and the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to May 2003), EMBASE (1974 to May 2003), CINAHL (1982 to May 2003), PEDro (May 2003), CIRRIE (May 2003) and REHABDATA (May 2003). Reference lists of articles were reviewed and manufacturers of equipment were contacted. SELECTION CRITERIA: Randomized controlled trials comparing force platform with visual feedback and/or auditory feedback to other balance treatments. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion, methodological quality, and data extraction. Trials were combined for meta-analysis according to outcome and type of feedback. MAIN RESULTS: We included seven trials (246 participants). Force platform feedback did not improve clinical measures of balance when moving or walking (Berg Balance Scale and Timed Up and Go). Significant improvements in laboratory force platform indicators of stance symmetry were found for regimens using visual feedback (standardised mean difference (SMD) -0.68, 95% confidence interval (CI) -1.31 to -0.04, p = 0.04) and the concurrent visual and auditory feedback (weighted mean difference (WMD) -4.02, 95% CI -5.99 to -2.04, p = 0.00007). There were no significant effects on laboratory postural sway indicators, clinical outcomes or measures of function at follow-up assessment. REVIEWERS' CONCLUSIONS: Force platform feedback (visual or auditory) improved stance symmetry but not sway in standing, clinical balance outcomes or measures of independence.

Hepatitis B vaccination for patients with chronic renal failure.

BACKGROUND: Chronic renal failure patients are at particular risk of hepatitis B virus infection. Early studies have demonstrated that renal failure patients benefit from vaccination; however, not all studies have consistently shown benefit. OBJECTIVES: To determine the beneficial and harmful effects of hepatitis B vaccine and of a reinforced vaccination series in chronic renal failure patients. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Renal Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library (Issue 1, 2002),PubMed/MEDLINE (1966 to July 2003), EMBASE (1985 to November 2003), Current Clinical Practice Guidelines (Canadian Immunization Guide and Vaccine Preventable Diseases Surveillance Manual), and Science Citation Index as well as journals, published abstracts, and reference lists of articles. SELECTION CRITERIA: Randomised clinical trials comparing plasma vaccine with placebo, recombinant vaccine with placebo, recombinant vaccine with plasma vaccine, and a reinforced vaccination series (ie, more than three inoculations) with three inoculations of vaccine in chronic renal failure patients. DATA COLLECTION AND ANALYSIS: Primary outcome measures included incidence of patients developing hepatitis B virus antibodies and infections while secondary outcomes included adverse events, liver-related morbidity, and mortality. Random effects models were used and reported relative risks and 95% confidence intervals (RR and 95% CI). MAIN RESULTS: We included seven randomised clinical trials. None of them had high quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies (RR 23.0, 95% CI 14.39 to 36.76, 3 trials). We found no statistically significant difference between plasma vaccine or placebo regarding hepatitis B virus infections (RR 0.50, 95% CI 0.20 to 1.24). We found no statistically significant differences between recombinant vaccine and plasma vaccine in achieving hepatitis B antibodies (RR 0.65, 95% CI 0.28 to 1.53, 2 trials). Heterogeneity was significant and appeared to be attributable to the dose of vaccine. Two trials examined a reinforced recombinant vaccine strategy, which was not statistically more effective than three inoculations of recombinant vaccine regarding development of hepatitis B antibodies (RR 1.36, 95% CI 0.85 to 2.16). REVIEWERS' CONCLUSIONS: Plasma derived vaccines are more effective than placebo in achieving hepatitis B antibodies, while no statistically significant difference was found between recombinant and plasma vaccines. No statistically significant difference of effectiveness was observed between a reinforced vaccination series versus routine vaccinations of three inoculations of recombinant vaccine.

The effect of day care exposure on the risk of developing type 1 diabetes: a meta-analysis of case-control studies.

OBJECTIVE: Exposure to infections in infancy or childhood may be important in the pathogenesis of type 1 diabetes, but a protective role has also been suggested. We tested the hypothesis that increased early contact with infectious agents, measured by day care exposure, would decrease the risk of type 1 diabetes in childhood. RESEARCH DESIGN AND METHODS: We conducted a systematic review of case-control studies. Meta-analysis was performed to combine results, assess for heterogeneity, and explore variation in study design. RESULTS: Several generally well-designed case-control studies show a statistically significant protective effect of day care on type 1 diabetes. However, meta-analysis revealed too much heterogeneity to accept the overall synthesis results and none of the studies used prerecorded data. Day care does seem to have a protective effect in the subgroup of children who will be diagnosed with type 1 diabetes before the age of 5 years (odds ratio = 0.6, 95% CI 0.5-0.8); however, this result is based on only two studies. CONCLUSIONS: Recall bias is one alternate explanation for these data; confirmation using prerecorded data is required. Such data could be prospectively measured in cohort studies of children at risk. We also suggest that information about day care attendance be measured in randomized trials of agents for the prevention of type 1 diabetes, as day care exposure could potentially modify the effect of the preventive agent.

Pharmacological manipulation of height: qualitative review of study populations and designs.

OBJECTIVE: Various substances that can have an important effect on height are increasingly available. However, research into pharmacological manipulation of height in children has been criticized. There are concerns about diagnostic criteria; about the medical, ethical, and economic ramifications of modulating growth in children with no endocrinological abnormalities; and about biased results due to weak study designs. The authors reviewed articles published since Jan. 1, 1995, to characterize recent research into this area. METHODS: 70 peer-reviewed articles published in 18 journals in 1995 describing effects of hormonal interventions to affect height were reviewed. Study population, intervention, main purpose (safety, physiology, or therapeutic effect), and methodology were examined. The search was expanded after 1995 to list randomized controlled trials (RCTs) investigating pharmacological manipulation in children and its effect on ultimate height in adults. RESULTS: The inexpensive and brief androgen therapy for pubertal delay has been examined in RCTs, but expensive, long-term treatments to alter final adult height in children have rarely been subjected to RCTs. Some outcome reports pooled subjects with different causes of short stature. Documentation of growth hormone deficiency is problematic. CONCLUSIONS: There is a lack of RCTs in which target populations and growth outcomes are explicitly defined. Further research into overcoming barriers to relevant RCT studies is needed.

Does growth-hormone supplementation affect adult height in Turner's syndrome?

BACKGROUND: By comparison with historical controls, the effect of treatment with growth hormone on adult height in Turner's syndrome was initially reported as uniformly and strongly positive. Because randomised controlled trials are not near completion, we report our experiences in an open study. METHODS: We examined adult height, projected and attained, in 31 patients (17 treated with subcutaneous recombinant human growth hormone, up to 15 mg a week, outside of a controlled trial and 14 untreated contemporaries). FINDINGS: Contingency table analysis of attained versus projected height showed significantly higher values in treated patients although only 4 of 17 had final heights of 5 cm or more over projection. Patients' and treatment variables (height, bone-age delay, oestrogen replacement) that interfere with adult height projection confounded the analysis of adult height data. INTERPRETATION: Girls with Turner's syndrome should be counselled cautiously about the expectation of a strongly positive effect of treatment on adult height. Completion of the randomised controlled trials to adult height is needed to establish the effect of growth-hormone supplementation on adult height in Turner's syndrome and the psychological effect of treatment.

Mortality in Canadian children with growth hormone (GH) deficiency receiving GH therapy 1967-1992. The Canadian Growth Hormone Advisory Committee.

The objective of this study was to determine the risk of death and potential for prevention of mortality in a large population of children with growth hormone deficiency (GHD). The Canadian GH Advisory Committee registry was initiated in 1967 to include all persons in Canada treated with pituitary-derived GH (1967-1985). Since 1985, the registry has been maintained for continuous surveillance of those treated with biosynthetic GH. Thirty-seven children have died out of a total of 1366 children treated for GHD in the 25 years up to December 31, 1992. Individual cases were reviewed for circumstances before death and autopsy information. The likelihood of individual deaths being caused by potentially preventable endocrine causes was graded on a scale of 1-5. Survival curves were analyzed for the children with idiopathic GHD and craniopharyngioma. Age- and sex-specific mortality rates for children with idiopathic GHD were compared with those of the general population. The overall crude mortality rate was 2.7%. The most frequent cause of mortality was tumor recurrence (11/37). A surprisingly high proportion of deaths (9/37) were caused by the preventable endocrine complications of adrenal crisis and hypoglycemia. Children with idiopathic GHD receiving GH therapy had similar age- and sex-specific mortality rates compared with general population rates, except in a high-risk subgroup of males diagnosed with GHD before 2 yr of age. The highest mortality occurred in children with GHD secondary to craniopharyngioma. We concluded that preventable sudden deaths caused by adrenal crisis continue to occur in children with hypopituitarism. A high level of vigilance must be maintained in this population.