Diet,cow's milk protein antibodies and the risk of IDDM in Finnish children

Summary Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date-and sex-matched population-based control children in the nationwide Childhood Diabetes in Finland study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabeticpopulation-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - BLG betalactoglobulin - BSA bovine serum albumin - ICA islet cell antibodies - IAA insulin autoantibodies - OR odds ratio - CI confidence interval     

Gut Microbiome Composition Is Predictive of Incident Type 2 Diabetes in a Population Cohort of 5,572 Finnish Adults

OBJECTIVETo examine the previously unknown long-term association between gut microbiome composition and incident type 2 diabetes in a representative population cohort.RESEARCH DESIGN AND METHODSWe collected fecal samples from 5,572 Finns (mean age 48.7 years; 54.1% women) in 2002 who were followed up for incident type 2 diabetes until 31 December 2017. The samples were sequenced using shotgun metagenomics. We examined associations between gut microbiome composition and incident diabetes using multivariable-adjusted Cox regression models. We first used the eastern Finland subpopulation to obtain initial findings and validated these in the western Finland subpopulation.RESULTSAltogether, 432 cases of incident diabetes occurred over the median follow-up of 15.8 years. We detected four species and two clusters consistently associated with incident diabetes in the validation models. These four species were Clostridium citroniae (hazard ratio [HR] 1.21; 95% CI 1.04–1.42), C. bolteae (HR 1.20; 95% CI 1.04–1.39), Tyzzerella nexilis (HR 1.17; 95% CI 1.01–1.36), and Ruminococcus gnavus (HR 1.17; 95% CI 1.01–1.36). The positively associated clusters, cluster 1 (HR 1.18; 95% CI 1.02–1.38) and cluster 5 (HR 1.18; 95% CI 1.02–1.36), mostly consisted of these same species.CONCLUSIONSWe observed robust species-level taxonomic features predictive of incident type 2 diabetes over long-term follow-up. These findings build on and extend previous mainly cross-sectional evidence and further support links between dietary habits, metabolic diseases, and type 2 diabetes that are modulated by the gut microbiome. The gut microbiome can potentially be used to improve disease prediction and uncover novel therapeutic targets for diabetes.     

Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.     

Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.     

Peroral lynestrenol and arterial disease in mentally retarded women. A case-control study based on autopsy findings

Autopsy findings from 170 non-smoking and mentally retarded women aged 12-51 years were analysed for any epidemiological association between the use of peroral lynestrenol for inducing therapeutic amenorrhea (TA) and arterial disease. Eighty-six women had received lynestrenol continuously for an average of 81 months (range 2-220 months) and the other 84 had not. After exclusion of 6 cases with known risk factors (diabetes, hypertension) predisposing to arterial disease, pathological arterial changes were found in 16 patients, 10 of them belonging to the TA group and 5 to the non-lynestrenol group. The incidence of arterial disease at autopsy at the age of 35 or more was 8/19 in TA patients and 1/15 in non-lynestrenol patients (p = 0.078). The benefits of prolonged TA induced by lynestrenol in this group of patients must be weighed very carefully against the possible risks involved.     

Healing of subcapital femoral osteotomies fixed with self-reinforced poly-L-lactide screws: an experimental long-term study in sheep

Subcapital femoral osteotomies of ten young adult sheep were fixed with two bioabsorbable, self-reinforced, poly- L-lactide (SR-PLLA) lag screws of 4.5 mm in diameter. At 3 weeks radiographs were taken to check the reduction and fixation achieved. After follow-up periods of 12 weeks, 1 year and 3 years with three sheep in each group, and of 7 years and 4 months with one sheep, the sheep were killed, and the healing of the osteotomies, degradation and tissue response of the implants were examined radiographically, histologically and microradiographically. All osteotomies healed with a firm bony union. There was no dislocation or wound infection. Histologically, there was no marked tissue response in the bone tissue. At 12 weeks the implants were grossly intact, at 1 year granulation tissue and new bone formation had started to penetrate into the implant, and at 3 years the implant area was mostly replaced by connective tissue and new bone, but implant material was still seen as little islands surrounded by some lymphocytes. At 7 years and 4 months, the implant material had been degraded and replaced by tight bone. Self-reinforced poly- L-lactide lag screws seem to possess adequate mechanical properties and good biocompatibility for this demanding fixation.