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Abstract Background Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in ADIPOR2 predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS). Methods CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study. Results In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study. Conclusions Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT. Trial registration number ClinicalTrials.gov NCT00518167

Abstract Background Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits. Methods Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis. Results rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention. Conclusions These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM. Trial registration number ClinicalTrials.gov NCT00518167

Abstract Background It has been suggested that Plethodontid salamanders are excellent candidates for indicating ecosystem health. However, detailed, long-term data sets of their populations are rare, limiting our understanding of the demographic processes underlying their population fluctuations. Here we present a demographic analysis based on a 1996 - 2008 data set on an underground population of Speleomantes strinatii (Aellen) in NW Italy. We utilised a Bayesian state-space approach allowing us to parameterise a stage-structured Lefkovitch model. We used all the available population data from annual temporary removal experiments to provide us with the baseline data on the numbers of juveniles, subadults and adult males and females present at any given time. Results Sampling the posterior chains of the converged state-space model gives us the likelihood distributions of the state-specific demographic rates and the associated uncertainty of these estimates. Analysing the resulting parameterised Lefkovitch matrices shows that the population growth is very close to 1, and that at population equilibrium we expect half of the individuals present to be adults of reproductive age which is what we also observe in the data. Elasticity analysis shows that adult survival is the key determinant for population growth. Conclusion This analysis demonstrates how an understanding of population demography can be gained from structured population data even in a case where following marked individuals over their whole lifespan is not practical.

Abstract Background We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 ± 4.5 kg/m2, age: 55 ± 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group. Methods We analysed the data from the baseline and annual follow-up visits from years 1, 2 and 3. Measurements of anthropometry, plasma glucose and serum insulin in oral glucose tolerance test, serum total cholesterol, HDL-cholesterol and triglycerides were included. The median follow-up time for type 2 diabetes incidence was 7 years. Genetic variants were screened by restriction fragment length polymorphism or Illumina method. Results UCP3 gene variant rs3781907 was associated with increased serum total and LDL-cholesterol levels, at baseline and during the follow-up period. The same variant was associated with a higher risk of type 2 diabetes. Variants rs1726745, rs11235972 and rs1800849 in the UCP3 gene associated with serum total and LDL-cholesterol at baseline. Haploblock including variants rs659366, rs653529, rs15763, and rs1726745 was associated with measures of abdominal obesity at baseline and in the longitudinal analysis. The haplotype comprising alleles rs659366-G, rs653529-A, rs15763-G and rs1726745-A was associated with higher waist-to-hip ratio, and haplotype comprising alleles rs3781907-G, rs11235972-A, and rs1800849-T was associated with increased serum total and LDL-cholesterol concentrations. Conclusion Genetic variation in the UCP2-UCP3 gene cluster may act as a modifier increasing serum lipid levels and indices of abdominal obesity, and may thereby also contribute to the metabolic aberrations observed in obesity and type 2 diabetes.

Abstract Background Insulin resistance and diabetes are associated with increased oxidative stress and impairment of cellular defence systems. Our purpose was to investigate the interaction between glucose metabolism, antioxidative capacity and heat shock protein (HSP) defence in different skeletal muscle phenotypes among middle-aged obese subjects during a long-term exercise and dietary intervention. As a sub-study of the Finnish Diabetes Prevention Study (DPS), 22 persons with impaired glucose tolerance (IGT) taking part in the intervention volunteered to give samples from the vastus lateralis muscle. Subjects were divided into two sub-groups (IGTslow and IGTfast) on the basis of their baseline myosin heavy chain profile. Glucose metabolism, oxidative stress and HSP expressions were measured before and after the 2-year intervention. Results Exercise training, combined with dietary counselling, increased the expression of mitochondrial chaperones HSP60 and glucose-regulated protein 75 (GRP75) in the vastus lateralis muscle in the IGTslow group and that of HSP60 in the IGTfast group. In cytoplasmic chaperones HSP72 or HSP90 no changes took place. In the IGTslow group, a significant positive correlation between the increased muscle content of HSP60 and the oxygen radical absorbing capacity values and, in the IGTfast group, between the improved VO2max value and the increased protein expression of GRP75 were found. Serum uric acid concentrations decreased in both sub-groups and serum protein carbonyl concentrations decreased in the IGTfast group. Conclusion The 2-year intervention up-regulated mitochondrial HSP expressions in middle-aged subjects with impaired glucose tolerance. These improvements, however, were not correlated directly with enhanced glucose tolerance.

Diabetes mellitus is a chronic metabolic disease characterized by elevated blood glucose levels with associated disordered carbohydrate and lipid metabolism. Type 2 diabetes (T2D) specifically has been shown to cause a decrease in skeletal muscle mass due to oxidative stress. This study investigated a treatment option for T2D through thermotherapy on healthy (HSMM) and T2D (D-HSMM) human skeletal muscle cells. The goals were to determine the effects of thermotherapy, long-term (chronic) and short-term (acute), on HSMM and D-HSMM cell viabilities and oxidative stress. HSMM and D-HSMM cells were grown to confluency, harvested, and counted to determine density. Acute and chronic heat treatments were applied to both cell lines. The chronic treatment consisted of a 30-minute exposure to 40°C, three times a week for three weeks; the acute treatment was a one-time exposure. Oxidative stress assays and cell viabilities were tested 24 hours after heat treatments. Results indicated no significant effect on the cell viability of HSMM and D-HSMM cells. The acute treatment had a significant increase ( p ≤ 0.05) of MDA concentration compared to the chronic treatment. The chronic treatment had a significant increase ( p ≤ 0.05) in catalase activity compared to the acute treatment. The SOD activity had no significant change ( p > 0.05) between the chronic and acute treatments. In conclusion, acute thermotherapy may not be beneficial for skeletal muscle cells due to the observed increase in oxidative stress, especially in the D-HSMM cells., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Janette A. Lindstrom et al.)

Although systemic etanercept was approved in 2004 for adults, the Food and Drug Administration (FDA) denied approval for use in children with psoriasis in 2008. Revision of the FDA's risk-benefit assessment in response to understanding of disease burden, unmet medical need, and the effect of off-label use in children with psoriasis led to the 2016 approval as the first systemic biologic product for the treatment of children aged 4-17 with moderate to severe psoriasis. This article delineates the thinking that led to this reconsideration. The underlying thinking paved the way to inform current pediatric drug development as the FDA continues to bring needed medical products to children., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

To protect the public health and facilitate the safe and effective use of prescription drugs, the Food and Drug Administration (FDA) disseminates information through drug labeling, communication of safety issues, and the archiving of scientific reviews. The content and format requirements for professional labeling were revised in 2006 to improve the accessibility and usability of the information. New or emerging safety information is communicated using the formats of public health advisories (PHAs), information for heath care professional sheets, and early communications about ongoing safety reviews. The FDA analyses of approved drug marketing applications and Advisory Committee transcripts are posted on the FDA Web site. Prescribers can utilize these resources to inform the care that they provide to patients.

Minimising the public health burden of isotretinoin-induced teratogenicity has been a challenge for 24 years, the duration of availability of isotretinoin in the US for the treatment of severe, recalcitrant nodular acne. Although the teratogenicity of this drug is well known and risk-management programmes had been implemented, preventable fetal exposures continued to occur, largely as a result of the lack of sufficient controls within the programmes themselves. The manufacturers of isotretinoin implemented a new risk-management programme, iPLEDGE, in March 2006. iPLEDGE is a comprehensive distribution system that includes mandatory registration of patients, healthcare providers, pharmacies, and wholesalers. It allows real-time linkage of pregnancy-test results for verification prior to the dispensing of isotretinoin. Although the challenges of implementing a closed distribution system for a very widely used medication have been extensive, the potential public health benefits from preventing fetal exposure to isotretinoin are substantial.

Background: Reinfection, a common occurrence with gonorrhea, may result from a lack of protective immune response, or from the tremendous gonococcal strain variation., Goal: A two-phase study in human volunteers tested whether experimental infection with Neisseria gonorrhoeae MS11mkC would protect against reinfection with the same organisms., Study Design: In phase 1, an intraurethral inoculum of 57,000 piliated, transparent (opacity protein-negative [Opa-]) MS11mkC N gonorrhoeae infected 14 of 15 (93%) volunteers. The volunteers were encouraged to delay treatment for at least 5 days. In phase 2, which began 2 weeks after treatment for the initial infection, volunteers were inoculated with 7,100 piliated, Opa- MS11mkC., Results: The phase 2 challenge infected 6 of 14 (43%) previously infected volunteers and 5 of 10 (50%) naïve control subjects. Phase 1 volunteers who resisted reinfection were significantly more likely to have had a fourfold or greater increase in lipooligosaccharide immunoglobulin G during phase 1 than those who did not resist reinfection (P = 0.026)., Conclusions: Although infection did not provide protection from reinfection under the conditions used, the results suggest that immunity to reinfection is more complex than anticipated by the experimental design.

Causal heterogeneity of anencephaly and spina bifida has been demonstrated; in rare families the neural tube defect may be caused by a single gene. We report a family in which four cases of anencephaly or spina bifida may represent X-linked inheritance.

A rare ectodermal dysplasia with the acronym CHANDS (Curly Hair, Ankyloblepharon, Nail Dysplasia Syndrome) was described by Baughman (1971) as being a new autosomal dominant condition. Additional pedigree data obtained after the original report indicate that the mode of inheritance is more likely to be autosomal recessive, with an instance of quasi-dominant transmission as a result of multiple consanguineous matings in the family. These data are provided in this report.