In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

Background: Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.

Methods: In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.

Results: In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).

Conclusions: Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.

Evidence of hantavirus in wild rodents in Northern Ireland

A survey of evidence of rodent hantavirus infection in County Down, Northern Ireland was carried out by using immunofluorescence to detect virus antigen and antibody. Antibodies to hantavirus (R22 strain of Seoul virus and Hantaan 76-118) were found in 11/51 (21.6%) brown rats (Rattus norvegicus), 1/31 (3.2%) field mice (Apodemus sylvaticus) and 17/59 (28.8%) house mice (Mus domesticus). Seven rodents had evidence of hantavirus antigen in lung tissues. Antibody positive animals were significantly more likely to be adults than juveniles (P = 0.04) but and there was no sex difference between antibody positive and negative animals. House mice were more likely to be antibody positive if captured inside farm outbuildings (P = 0.08). Attempts to culture virus from the rodent material were unsuccessful. This work demonstrates a substantial rodent reservoir for hantavirus in Northern Ireland.

Depression associates with Mini Nutritional Assessment (MNA), Vitamin B12 and Folate status::Findings from Belfast Elderly Longitudinal Free-Living Ageing STudy (BELFAST)

Introduction: An association between depression and folate has been found in clinical studies. Depression and dementia can contribute to nutritional deficiency. This study clinical depression in in octo/nonagenarians from the BELFAST study.
Method: In the BELFAST study, 38 free-living octo/nonagenarians (mean age 82 years), who apparently well and cognitively intact were followed up at 5 years and assessed using the Geriatric Depression Scale (GDS), Folstein (30 point), Mini Nutritional Assessment Tool (MNA) together with serum folate and vitamin B12 levels.
Results: Mean GDS was 3.4 (SD 2.5), serum folate 7.1 umol/l (SD 5.3) and B12 553 umol/l (458). With mean MNA and Folstein -25.8 (SD 2.7) and 27.6 (SD 2.7) respectively with no sex difference (p = 0.78; p = 0.36). 25% of subjects showed a GDS >5 indicating risk of mild depression and 21% had compromised nutritional status. MNA associated with GDS in male (r2 = 0.56 p = 0.01), but not in female elderly subjects (r2 = 0.01; p = 0.44). GDS score and lower serum folate were associated (r2 = -0.23; p = 0.01).
Conclusion: Overall there was the suggestion that nutritional status and depression might be linked in male subjects at 5 year follow-up in octo/nonagenarians from the BEFLAST study. The lower folate in subjects categorised at risk of mild depression might suggest vitamin supplementation could be useful.

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMSaveD pathogenesis.

Sex differences in fetal habituation

There is some evidence for sex differences in habituation in the human fetus, but it is unknown whether this is due to differences in central processing (habituation) or in more peripheral processes, sensory or motor, involved in the response. This study examined whether the sex of the fetus influenced auditory habituation at 33weeks of gestation, and whether this was due to differences in habituation or in the sensory or motor components using a set of four experiments. The first experiment found that female fetuses required significantly fewer stimulus presentations to habituate than males. The second experiment revealed no difference in the spontaneous motor behaviour of male and female fetuses. The third experiment examined auditory intensity thresholds for the stimuli used to habituate the fetus. No differences in thresholds were found between males and females, although there was inter-individual variability in thresholds. A final experiment, using stimuli individualized for that particular fetus' auditory intensity threshold, found that female fetuses habituated faster than males. In combination, the studies reveal that habituation in the human fetus is affected by sex and this is due to a difference in central 'information processing' of the stimuli rather than peripheral aspects of the response. It is argued that male and female fetuses present different neurobehavioural developmental trajectories, with females more advanced at 33weeks than males. This study suggests that research examining prenatal behaviour should consider the factor of fetal sex. This may be particularly pertinent where there is an intention to use the results diagnostically. © 2012 Blackwell Publishing Ltd.

Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

Influence of sex on the survival of patients with esophageal cancer

PURPOSE: The prognostic value of sex for esophageal cancer survival is currently unclear, and growing data suggest that hormonal influences may account for incidence disparities between men and women. Therefore, moving from the hypothesis that hormones could affect the prognosis of patients with esophageal cancer, we investigated the primary hypothesis that sex is associated with survival and the secondary hypotheses that the relationship between sex and survival depends, at least in part, on age, histology, and race/ethnicity.

PATIENTS AND METHODS: By using the SEER databases from 1973 to 2007, we identified 13,603 patients (34%) with metastatic esophageal cancer (MEC) and 26,848 patients (66%) with locoregional esophageal cancer (LEC). Cox proportional hazards model for competing risks were used for analyses.

RESULTS: In the multivariate analysis, women had longer esophageal cancer-specific survival (ECSS) than men in both MEC (hazard ratio [HR], 0.949; 95% CI, 0.905 to 0.995; P = .029) and LEC (HR, 0.920; 95% CI, 0.886 to 0.955; P < .001) cohorts. When age and histology were accounted for, there was no difference for ECSS between men and women with adenocarcinoma. In contrast, women younger than age 55 years (HR, 0.896; 95% CI, 0.792 to 1.014; P = .081) and those age 55 years or older (HR, 0.905; 95% CI, 0.862 to 0.950; P < .001) with squamous cell LEC had longer ECSS than men. In the squamous cell MEC cohort, only women younger than age 55 years had longer ECSS (HR, 0.823; 95% CI, 0.708 to 0.957; P = .011) than men.

CONCLUSION: Sex is an independent prognostic factor for patients with LEC or MEC. As secondary hypotheses, in comparison with men, women age 55 years or older with squamous cell LEC and women younger than age 55 years with squamous cell MEC have a significantly better outcome. These last two findings need further validation.

Biometric gonioscopy and the effects of age, race, and sex on the anterior chamber angle.

AIM:

To utilise a novel method for making measurements in the anterior chamber in order to compare the anterior chamber angles of people of European, African, and east Asian descent aged 40 years and over.

METHODS:

A cross sectional study on 15 people of each sex from each decade from the 40s to the 70s, from each of three racial groups-black, white, and Chinese Singaporeans. Biometric gonioscopy (BG) utilises a slit lamp mounted reticule to make measurements from the apparent iris insertion to Schwalbe's line through a Goldmann one mirror goniolens. The main outcome measures were BG measurements of the anterior chamber angle as detailed above.

RESULTS:

There was no significant difference in angle measurement between black, white, and Chinese races in this study. However, at younger ages people of Chinese race appeared to have deeper angles than white or black people, whereas the angles of older Chinese were significantly narrower (p = 0.004 for the difference in slope of BG by age between Chinese and both black and white people).

CONCLUSION:

The failure to detect a difference in angle measurements between these groups was surprising, given the much higher prevalence of angle closure among Chinese. It appears that the overall apparent similarity of BG means between Chinese and Western populations may mask very different trends with age. The apparently more rapid decline in angle width measurements with age among Chinese may be due to the higher prevalence of cataract or "creeping angle closure." However, longitudinal inferences from cross sectional data are problematic, and this may represent a cohort phenomenon caused by the increasing prevalence of myopia in the younger Singaporean population.

The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon Lefevre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early,onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p. V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 mu moles/mg/min vs. 1,678.7 +/- SD 527.2 mu moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS. (C) 2004 Wiley-Liss, Inc.

Difference equation approach to two-thermocouple sensor characterisation in constant velocity flow environments

Thermocouples are one of the most popular devices for temperature measurement due to their robustness, ease of manufacture and installation, and low cost. However, when used in certain harsh environments, for example, in combustion systems and engine exhausts, large wire diameters are required, and consequently the measurement bandwidth is reduced. This article discusses a software compensation technique to address the loss of high frequency fluctuations based on measurements from two thermocouples. In particular, a difference equation sDEd approach is proposed and compared with existing methods both in simulation and on experimental test rig data with constant flow velocity. It is found that the DE algorithm, combined with the use of generalized total least squares for parameter identification, provides better performance in terms of time constant estimation without any a priori assumption on the time constant ratios of the thermocouples.