A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.

Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone.

BACKGROUND: There are limited long-term randomized controlled trials of growth hormone (GH) supplementation to adult height and few published reports of the health-related quality of life (HRQOL) following treatment. The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome (TS) yielded data to examine whether GH supplementation resulted in a higher HRQOL (either due to taller stature or from the knowledge that active treatment and not placebo had been received) or alternatively a lower HRQOL (due to medicalization from years of injections). METHODS: The original trial randomized 154 Canadian girls with TS aged 7-13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections; estrogen prescription for induction of puberty was standardized. Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up. The instrument used to study HRQOL was the SF-36, summarized into physical and mental component scales (PCS and MCS); higher scores indicate better HRQOL. RESULTS: Thirty-four of the 48 eligible participants (71%) consented to participate; data were missing for one patient. Both groups (GH and no treatment) had normal HRQOL at this post-treatment assessment. The GH group had a (mean ± SD) PCS score of 56 ± 5; the untreated group 58 ± 4; mean score for 16-24 year old females in the general population 53.5 ± 6.9. The GH group had a mean MCS score of 52 ± 6; the untreated group 49 ± 13; mean score for 16-24 year old females in the general population 49.6 ± 9.8. Secondary analyses showed no relationship between HRQOL and height. CONCLUSIONS: We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term randomized controlled trial, confirming larger observational studies. We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height. Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00191113.

Blastomycosis of the central nervous system in a child: a rare cause of hypopituitarism.

Blastomyces dermatitidis is a dimorphic fungus that can cause granulomatous lesions. Typically, children present with respiratory symptoms. Central nervous system involvement is unusual, and almost always associated with involvement of other organs. This case report, to our knowledge, is the first published case of an adolescent male presenting with panhypopituitarism secondary to a blastomycosis infection.

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.

BACKGROUND: Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function. OBJECTIVES: To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance. DATA COLLECTION AND ANALYSIS: Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model. MAIN RESULTS: The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded. AUTHORS' CONCLUSIONS: Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.

WITHDRAWN: Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years.

BACKGROUND: Gastro-esophageal reflux (GER) is the refluxing of gastric contents into the esophagus. Fifty per cent of all infants 0 to 3 months regurgitate at least once a day. This drops to 5% once infants are 10 to 12 months old. Three per cent of parents of 10 to 12 month old infants view this as a problem. OBJECTIVES: To investigate the effectiveness of thickened feeds, positioning, and metoclopramide as compared to placebo in improving the outcome of GER in developmentally normal infants aged one month to two years. SEARCH STRATEGY: Trials were identified by searching Cochrane Central Register of Controlled Trials (The Cochrane Library 2003), MEDLINE (January 1966 to 23 January 2003), EMBASE (January 1985 to 27 January 2003), and reference lists of articles. Searches in all databases were updated in April 2009. SELECTION CRITERIA: Randomised studies (parallel or cross over) which evaluated thickened feeds, positional alternations or metoclopramide for the treatment of GER in children between the age of one month and two years who were developmentally normal. DATA COLLECTION AND ANALYSIS: All three reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twenty trials involving 771 children met the inclusion criteria: eight dealt with thickened feeds, five with positioning, and seven with metoclopramide. Few comparisons could be made, and so summary measures were often made with two or three studies. Thickened feeds reduce the regurgitation severity score (standardized mean difference (SMD) -0.94;95% confidence interval -1.35 to -0.52), as well as the frequency of emesis (SMD -0.91; confidence interval -1.22 to -0.61). The reflux index was not reduced (weighted mean difference (WMD) 0.48%; 95% confidence interval -3.27 to 4.23). All five positioning studies utilized esophageal pH monitoring as their outcome measure. Elevating the head of the crib for treating reflux in the supine position is not justifiable. The seven metoclopramide studies used a variety of outcomes. Compared to placebo, metoclopramide appears to reduce daily symptoms ( SMD -0.73; 95% confidence interval -1.16 to -0.30), and reduce the reflux index (WMD -2.80%; 95% confidence interval -5.58 to -0.01). It does increase side effects. AUTHORS' CONCLUSIONS: Thickened feeds are helpful in reducing the symptoms of GER. Elevating the head of the crib in the supine position does not have any effect. Metoclopramide may have some benefit in comparison to placebo in the symptomatic treatment for GER, but that must be weighed against possible side effects. .

Propofol for sedation during colonoscopy.

BACKGROUND: Propofol is increasingly used for sedation during colonoscopy, with many recent reports of randomized controlled trials (RCTs) and large non-randomized case series. OBJECTIVES: The primary objective was to identify, analyze and summarize RCTs comparing the relative effectiveness, patient acceptance and safety of propofol for colonoscopy, to traditional sedatives (narcotics and/or benzodiazepines).The secondary objective was to synthesize the studies comparing propofol administration by anesthesiologists to that by non-anesthesiologists for sedation during colonoscopy. SEARCH STRATEGY: We searched Medline, Cancerlit, EMBASE, CINAHL, LILACS, Biological Abstracts, Web of Science and the Cochrane Controlled Trials Registry database between January 1980 and June 2007; and conference proceeding abstracts for DDW, EUGW and ACG between 1990 and June 2007. There were no language restrictions. SELECTION CRITERIA: Randomized controlled trials comparing use of propofol and traditional agents or administration of propofol by anesthesiologists to that by non-anesthesiologists for sedation during colonoscopy. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data. The data were pooled using the Cochrane Collaborations' methodology and statistical software RevMan 4.2.10. MAIN RESULTS: Twenty studies met the inclusion criteria for the primary objective. Most studies included only healthy out-patients. Recovery and discharge times were shorter with use of propofol. There was higher patient satisfaction with use of propofol (OR for dissatisfaction 0.35, 95% CI 0.23, 0.53). There was no difference in procedure time, cecal intubation rate or complications. There was no difference in pain control with non- patient controlled sedation (PCS) use of propofol as compared to the traditional agents (OR 0.90; 95% CI 0.58, 1.39). Although there was higher patient satisfaction (OR for dissatisfaction 0.42, 95% CI 0.20, 0.89), the pain control was inferior with use of PCS use of propofol as compared to the use of traditional agents (OR 3.09; 95% CI 2.15, 4.46).There was only one study comparing administration of propofol by anesthesiologists to that by non-anesthesiologists for sedation during colonoscopy, with no difference in procedure time or patient satisfaction. AUTHORS' CONCLUSIONS: Propofol for sedation during colonoscopy for generally healthy individuals can lead to faster recovery and discharge times, increased patient satisfaction without an increase in side-effects. More studies with standardized end-points are needed to compare propofol administration by anesthesiologists to that by non-anesthesiologists.

Feasibility of a type 1 diabetes primary prevention trial using 2000 IU vitamin D3 in infants from the general population with increased HLA-associated risk.

Recent epidemiologic, immunologic, and NOD mouse studies suggest that intervention in the vitamin D system may be a successful method to prevent type 1 diabetes. Newborns at increased HLA-associated risk are randomized to receive either 400 or 2000 IU vitamin D3 by 1 month of age. We show that recruitment of babies from the general population for identification of HLA-associated risk status followed by enrollment to a randomized controlled prevention trial is feasible in Canada.

Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native canadians.

BACKGROUND: Type 2 diabetes mellitus is increasingly being observed among children and youth, including the Native population of Canada. Only one study has investigated prenatal and early infancy risk factors for the disease. METHODS: A case-control study was conducted; 46 patients younger than 18 years were recruited from the only clinical center for the treatment of diabetes serving the province of Manitoba, and 92 age- and sex-matched controls were recruited from a pediatric ambulatory clinic serving a large Native population in Winnipeg, Manitoba. Information on exposure to prenatal and early infancy risk factors was obtained through questionnaires administered by a Native nurse-interviewer. RESULTS: Multiple logistic regression modeling identified preexisting diabetes (odds ratio [OR], 14.4; 95% confidence interval [CI], 2.86-72.5), gestational diabetes (OR, 4.40; 95% CI, 1.38-14.1), and breastfeeding longer than 12 months (OR, 0.24; 95% CI, 0.13-0.99) as significant independent predictors of diabetic status. Other factors, such as low (<2500 g) and high (>4000 g) birth weight and maternal obesity, were also associated with diabetes in our population, but the elevated risks were not statistically significant. CONCLUSION: Breastfeeding reduces the risk of type 2 diabetes among Native Canadian children and should be promoted as a potential intervention to control the disease.

Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes.

OBJECTIVE: Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject-parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals. RESEARCH DESIGN AND METHODS: From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects. RESULTS: Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 x 10(-8)) and BACH2 (1.13; combined P = 1.25 x 10(-6)). CONCLUSIONS: Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.

A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study.

OBJECTIVE: In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 x 10(-10)) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance. RESEARCH DESIGN AND METHODS: Two independent cohorts were studied. The Type 1 Diabetes Genetics Consortium replication cohort consisted of 549 families with at least one child diagnosed with diabetes (946 total affected) and DNA from both parents. The Canadian replication cohort consisted of 364 nuclear family trios with one type 1 diabetes-affected offspring and two parents (1,092 individuals). RESULTS: One locus at 12q13, with the highest statistical significance among the 23, was confirmed. It involves type 1 diabetes association with the minor allele of rs1701704 (P = 9.13 x 10(-10), OR 1.25 [95% CI 1.12-1.40]). CONCLUSIONS: We have discovered a type 1 diabetes locus at 12q13 that is replicated in an independent cohort of type 1 diabetic patients and confers a type 1 diabetes risk comparable with that of the 16p13 locus we recently reported. These two loci are identical to two loci identified by the whole-genome association study of the Wellcome Trust Case-Control Consortium, a parallel independent discovery that adds further support to the validity of the GWA approach.

Bone density in a population-based cohort of premenopausal adult women with early onset inflammatory bowel disease.

OBJECTIVE: We aimed to determine the bone mineral density (BMD) using dual energy x-ray absorptiometry in a population-based sample of women with inflammatory bowel disease who were diagnosed before age 20 yr and who are currently premenopausal and less than 45 yr. METHODS: The University of Manitoba Inflammatory Bowel Disease Epidemiology Research Registry was accessed to find eligible women. Of 171 eligible subjects, 82 agreed to participate, and 70 appeared for dual energy x-ray absorptiometry. All subjects completed demographic, clinical, and lifestyle questionnaires and underwent dual energy x-ray absorptiometry with analyses for both areal and volumetric BMD. RESULTS: The mean areal T scores at the lumbar spine, femoral neck, total hip, and total body were -0.14 +/- 1.05, -0.15 +/- 1.04, -0.25 +/- 1.17, and +0.09 +/- 1.04, respectively. Forty-five subjects had normal BMD, and 25 had a T score < -1. There were no significant differences between these groups for predictive variables. Only three (4%) had osteoporosis (T score < -2.5 at any site). There were 12 with disease onset before puberty and 58 after puberty. There were no differences between these groups for BMD. Volumetric BMD was slightly higher than areal BMD at the lumbar spine (p < 0.0002), femoral neck (p < 0.01), and total hip (p < 0.001). CONCLUSIONS: In a population-based sample of women diagnosed with IBD before 20 yr of age and who are currently premenopausal, their average BMD is normal and the prevalence of osteoporosis is very low. Despite the potential for children with IBD to develop osteoporosis, their BMD as adults is generally normal.