CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control.

BACKGROUND/OBJECTIVES: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. SUBJECTS/METHODS: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. RESULTS: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). CONCLUSIONS: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.

Acute increase of complexity in the neurocardiovascular dynamics following carotid stenting.

OBJECTIVE: Percutaneous carotid angioplasty and stenting (CAS) has been used to improve cerebral circulation and autoregulation. However, whether CAS ameliorates the autonomic regulatory dynamics remains unclear. This prospective study examines the neurocardiovascular dynamics following carotid stenting. METHODS: Thirty minutes electrocardiograms were recorded at three different time points (pre-operative, 1-h post-operative, 1-day post-operative) on twelve male patients (mean age 70.8 ± 9.6 years) receiving unilateral primary CAS. The HR data were analyzed by the conventional heart rate variability (HRV) and the multiscale entropy (MSE) methods; the former associates with autonomic activities and the latter quantifies the regulatory complexity of heart beat intervals. Loss of complexity at multiple scales has been associated with decoupled regulatory network in vivo. RESULTS: Conventional HRV indices showed no difference after CAS. Complexity indices increased significantly on scales 2-8 at 1-h and on scales 2-3 1-day post-treatment. The lower scale MSE (1-5) correlated with the frequency components of conventional HRV indices. The increased complexity could imply a restoration of the neurocardiovascular dynamics on the path to a healthier state. CONCLUSIONS: Primary CAS can induce a recovery in the neurocardiovascular regulatory dynamics in patients with high-grade carotid stenosis.

Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes.

The effect of CDKN2A, the major high-risk melanoma susceptibility gene, has been shown to be modified by host-related phenotypes and variants of MC1R gene. The glutathione S-transferase (GSTs) genes, implicated in detoxification of metabolites after UV exposure, are candidates for modulating CDKN2A penetrance. Few case-control studies have investigated the effect of GSTs on melanoma risk, and have led to controversial results while these genes have not yet been studied in CDKN2A melanoma-prone families. We examined the effect of GSTP1, GSTM1 and GSTT1 genotypes on melanoma risk in 25 multi-generational melanoma-prone families with CDKN2A mutations, in presence of MC1R gene variants, sun exposure, and host-related phenotypes. These data included 195 genotyped subjects for all studied genes. We applied the GEE (Generalized Estimating Equations) approach to test for the effect of GSTs while adjusting for age, sex and CDKN2A mutation status and including successively MC1R, sun exposure and host factors in the model. No significant effect of null GSTM1 allele and GSTP1 variants (p.I105V, p.A114V) on melanoma risk was found. However, a significant protective effect of carrying >or=1 null GSTT1 allele was shown: OR(adjusted for age,sex,CDKN2A ) = 0.41 (0.18-0.94) and OR(adjusted for age,sex,CDKN2A,MC1R ) = 0.24 (0.15-0.58). Altogether, the factors modifying significantly the melanoma risk associated with CDKN2A mutations (stepwise procedure) were: MC1R and dysplastic nevi (increasing the risk) and GSTT1 (decreasing the risk). This study shows that even when a high-risk gene (CDKN2A) has been identified, multiple genetic modifiers influence melanoma risk.

Localization of a susceptibility locus for hepatocellular carcinoma to chromosome 4q in a hepatitis B hyperendemic area.

Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3-28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3-28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned approximately 873 kb away from D4S3240 was associated with HCC, with P=0.0074.

Selenium: occurrence in foods and its toxicological significance--a review.

The occurrence of selenium (Se) in foods and the toxicological information relevant to it are reviewed. The estimated normal dietary daily intake for man in most parts of the world ranges from 4-35 microgram/person in infants to 60-250 microgram/person in adults. The current use of Se supplementation in animal feeds could elevate the Se content of meats by up to 30%, but this does not lead to a biologically relevant increase in the Se intake of man. Available metabolic data reveal that after ingestion Se is mostly absorbed. Up to 50% is excreted in the urine, and the portion retained in the body accumulates chiefly in the liver and kidneys. Recent epidemiological and animal studies show that Se is not a carcinogen, and in some cases may have anti-cancer properties. Neither the essentiality for man, nor the no-effect level of Se have been established. Human selenosis of food origin has not been reported in the literature, except those documented in the 1930s in the seleniferous areas.