BackgroundIsolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.Methodology/Principal FindingsThe study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits.Conclusions/SignificanceThe data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations.
Heart rate (HR) and oxygen uptake (VO2) at the mechanical power (W) corresponding to the capillary blood lactate ([la]cap) of 4 mmol.l-1 (Wlt) were measured in 34 healthy male subjects during incremental exercise (Winc). On the basis of these measurements, the subjects were asked to cycle at Wlt for 60 min (steady-state exercise, Wss). Twenty subjects could not reach the target time (mean exhaustion time, te, 38.2 min, SD 5.3), while 6 of the 14 remaining subjects declared themselves exhausted at the end of exercise. The final [la]cap if the two groups of exhausted subjects were 5.3 mmol.l-1, SD 2.3 and 4.3 mmol.l-1, SD 1.1, respectively. At the end of Wss, [la]cap and HR were significantly lower in the 8 unexhausted subjects than in the other subjects. This group also had a lower HR at Wlt during Winc. The HR and VO2 appeared to be higher during Wss than during Winc. When all subjects were ranked according to their te during Wss, Wlt (expressed per kilogram of body mass) was found to be negatively related to te. In conclusion, during Winc, measurements of physiological variables at fixed [la]cap give a poor prediction of their trends during Wss and of the relative te; at the same work load [la]cap can be quite different in the two experimental conditions. Furthermore, resistance to exercise fatigue at Wlt seems lower in the fitter subjects.
Objective: Osteoprotegerin (OPG), a glycoprotein belonging to the tumor necrosis factor receptor family, is an endogenous inhibitor of osteoclastogenesis produced by cells of the osteoblast lineage. OPG is a key cytokine involved in the regulation of osteoblast/osteoclast cross-talk. Since GH replacement therapy in GH deficiency (GHD) activates bone remodeling and increases bone mass, we investigated if short-term GH replacement therapy affects plasma OPG levels. Design and methods: Eighteen adults with GHD, ranging from 17 to 51 years (nine childhood-onset and nine adult-onset) were enrolled in the study. All subjects were on stable replacement therapy, especially sex hormones. The starting dose of GH replacement therapy was 4 mg/kg per day £ 7 days/week, and was progressively increased according to the serum IGF-I values. Biochemical parameters of bone and mineral metabolism were measured before and after 6 months of GH replacement therapy. Bone mass density (BMD) was monitored at three skeletal sites (lumbar vertebrae, femur, radius) by dual-energy X-ray absorptiometry. Results: After 6 months of therapy, ionized calcium, parathyroid hormone and 25-OH vitamin D did not change, whereas total serum calcium and urinary calcium excretion increased significantly ðP , 0:01Þ: Also osteocalcin and urinary deoxypyridinoline/24 h increased significantly (P , 0:02; P , 0:05 respectively). Mean basal T-scores of BMD values showed an osteopenic state, which remained unchanged after GH therapy. Plasma OPG increased significantly after 6 months of therapy ðP , 0:02Þ and this increase was significantly correlated with the increase of osteocalcin ðr ¼ 20:52; P ¼ 0:04Þ and deoxypyridinoline values ðr ¼ 20:64; P ¼ 0:011Þ: Conclusions: Our results suggest that the bone anabolic effect of GH replacement therapy could in part be mediated by a positive bone balance at each remodeling unit due to the inhibitory action of OPG on osteoclastogenesis.
Background: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is a known endocrine disruptor. In animal studies, TCDD exposure impairs bone metabolism and increases fragility. To our knowledge, no epidemiologic studies have examined this association.Objectives: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women’s Health Study, a retrospective cohort study of the health of the women. In 2008, we followed up the cohort. Here, we evaluated the association between TCDD exposure and bone structure and geometry in adulthood, and considered whether timing of TCDD exposure before achievement of peak bone mass (assumed to occur 2 years after onset of menarche) modified the association.Methods: Individual TCDD concentration was measured in archived serum collected soon after the explosion. In 2008, 350 women who were < 20 years old in 1976 underwent a dual-energy X-ray absorptiometry (DXA) bone scan. Bone mineral density was measured at the lumbar spine and hip, and hip geometry was extracted from hip DXA scans using the hip structural analysis method.Results: Among premenopausal women, TCDD serum levels were associated with some indexes indicating better bone structure in women exposed before peak bone mass (n = 219), with stronger associations in those exposed before 5 years of age (n = 46). In contrast, among postmenopausal women, TCDD levels were associated with evidence of better bone structure in women exposed after peak bone mass (n = 48) than in other women (n = 18).Conclusions: Our current results do not support the hypothesis that postnatal TCDD exposure adversely affects adult bone health. Continued follow-up of women who were youngest at exposure is warranted. Future studies should also focus on those exposed in utero.Citation: Eskenazi B, Warner M, Sirtori M, Fuerst T, Rauch SA, Brambilla P, Mocarelli P, Rubinacci A. 2014. Serum dioxin concentrations and bone density and structure in the Seveso Women’s Health Study. Environ Health Perspect 122:51–57; http://dx.doi.org/10.1289/ehp.1306788
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