Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects.

To determine the role of dietary sodium intake in the reduction in beta-adrenergic sensitivity in hypertension, lymphocyte beta-receptors from 8 borderline hypertensive and 16 normotensive subjects were studied after 5 d on a high sodium diet (400 meq/d) and also following a low sodium diet (10 meq/d). During the high sodium diet, lymphocyte beta-receptor-stimulated adenylate cyclase activity, expressed as the relative increase over basal levels stimulated by the beta-agonist isoproterenol, was significantly (P less than 0.025) decreased in hypertensive (24 +/- 5%, mean +/- SE) compared with normotensive (42 +/- 4%) subjects. Neither beta-receptor density nor the proportion of nonsequestered beta-receptors differed between groups. A low sodium diet significantly increased beta-receptor-stimulated adenylate cyclase activity in hypertensives (low sodium, 51 +/- 7%; high sodium, 24 +/- 5%, P less than 0.025) to a level not different than that of normotensives (46 +/- 5%). Thus, reduced lymphocyte beta-receptor responsiveness in hypertensive subjects is not due to beta-receptor sequestration and is corrected on a low sodium diet. Dietary sodium may be an important factor in the beta-receptor defect in early hypertension.

DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.

Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.

Opioid peptides in human adrenal: partial characterization and presence of adrenal peptide E.

Evaluation of hypotheses concerning the role of opioid peptides in the human adrenal is handicapped by the lack of information concerning the nature of these peptides. We studied the content of opioid peptides in whole adrenal tissue using several RIAs, including one which cross-reacts with all opioid peptides tested. Opioid peptides were localized to granules which behaved like chromaffin granules on crude sucrose density separation. beta-Endorphin immunoreactivity was a minor component, which was found principally in the form of beta-endorphin-(1-31). The majority of the remaining peptides probably were products of proenkephalin. The human postmortem tissue differed from bovine tissue in that the major accumulating products of this precursor were the size of the enkephalins and their small congeners, and not the intermediate-sized (mol wt, approximately 1500-4000) peptides that predominated in bovine tissue. We also found evidence of the presence of the 25-amino acid complex opioid, peptide E, in human tissue.

Breakdown of small enkephalin derivatives and adrenal peptide E by human plasma.

To provide information concerning the fate of opioid peptides introduced into the circulation of man, we have investigated the breakdown of the following peptides when incubated in human plasma: [Met]enkephalin, [Met]enkephalyl-Arg6-Phe7, [Met]enkephalyl-Arg6-Gly7-Leu8, [Met]enkephalyl-Arg6-Arg7-Val8-NH2 and the complex opioid, peptide E. We used a radioimmunoassay recognizing the amino-terminus of opioid peptides (assay for total opioid peptide-like immunoreactivity). The three small enkephalin derivatives were broken down considerably faster than the enkephalins themselves. The rate of loss of immunoreactivity was considerably reduced by bacitracin. When peptide E was incubated in human plasma, a relatively sustained level of opioid peptide-like immunoreactivity was seen. This was shown to be due, not only to the relatively slow aminopeptidase attack of the larger peptide, but also to the generation during breakdown of peptide E of [Leu]enkephalin and [Met]-enkephalin.

Thermal and metabolic responses to cold-water immersion at knee, hip, and shoulder levels.

To examine the effect of cold-water immersion at different depths on thermal and metabolic responses, eight men (25 yr old, 16% body fat) attempted 12 tests: immersed to the knee (K), hip (H), and shoulder (Sh) in 15 and 25 degrees C water during both rest (R) or leg cycling [35% peak oxygen uptake; (E)] for up to 135 min. At 15 degrees C, rectal (Tre) and esophageal temperatures (Tes) between R and E were not different in Sh and H groups (P > 0.05), whereas both in K group were higher during E than R (P < 0.05). At 25 degrees C, Tre was higher (P < 0.05) during E than R at all depths, whereas Tes during E was higher than during R in H and K groups. Tre remained at control levels in K-E at 15 degrees C, K-E at 25 degrees C, and in H-E groups at 25 degrees C, whereas Tes remained unchanged in K-E at 15 degrees C, in K-R at 15 degrees C, and in all 25 degrees C conditions (P > 0.05). During R and E, the magnitude of Tre change was greater (P < 0.05) than the magnitude of Tes change in Sh and H groups, whereas it was not different in the K group (P > 0.05). Total heat flow was progressive with water depth. During R at 15 and 25 degrees C, heat production was not increased in K and H groups from control level (P > 0.05) but it did increase in Sh group (P < 0.05). The increase in heat production during E compared with R was smaller (P < 0.05) in Sh (121 +/- 7 W/m2 at 15 degrees C and 97 +/- 6 W/m2 at 25 degrees C) than in H (156 +/- 6 and 126 +/- 5 W/m2, respectively) and K groups (155 +/- 4 and 165 +/- 6 W/m2, respectively). These data suggest that Tre and Tes respond differently during partial cold-water immersion. In addition, water levels above knee in 15 degrees C and above hip in 25 degrees C cause depression of internal temperatures mainly due to insufficient heat production offsetting heat loss even during light exercise.

Characterisation of Met-enkephalin(Arg6,Phe7) immunoreactivity in human adrenal and human phaeochromocytoma.

The molecular forms of opioid peptides in human adrenal have not been well characterised. These peptides are predominantly derived from the proenkephalin A precursor, which has the sequence of Met-enkephalin(Arg6,Phe7) as its carboxyl terminus. We have looked in the present study at the subcellular distribution and the molecular form of immunoreactivity to this sequence in post-mortem human adrenal medulla and in phaeochromocytoma. In the human adrenal homogenates, the immunoreactivity distributes on a sucrose gradient in a manner consistent with localisation in chromaffin granules. On chromatography, the immunoreactivity from adrenal medulla is predominantly in the heptapeptide form; the intermediate (3000-4000) molecular weight material is only a minor component of immunoreactivity, in contrast to bovine tissue extracts where this is the major form of immunoreactivity. In the phaeochromocytoma extracts, the heptapeptide sequence again predominates over a minor amount of intermediate sized material. The results are discussed in terms of post-mortem changes, precursor processing and the function of the adrenal medulla.

Metorphamide, a C-terminally amidated opioid peptide, in human adrenal and human phaeochromocytoma.

There appears to be only one possible site for the production of an amidated peptide in the human proenkephalin sequence; this will give rise to the peptide named metorphamide. Since amidation of peptides is commonly an activation step in the synthesis of regulatory peptides, we have examined the levels and form of immunoreactivity to metorphamide in human post-mortem adrenal and phaeochromocytoma extracts. In three out of four post-mortem adrenal extracts, and in each of the two phaeochromocytoma extracts examined, there was 3-4 times more immunoreactivity to the carboxy-terminus of pro-enkephalin, Met-enkephalin(Arg6,Phe7), than to metorphamide. The metorphamide immunoreactivity was shown in each extract to measure only the amidated octapeptide according to gel exclusion and reverse-phase chromatography data. The implications for processing of proenkephalin in human adrenal are indicated.

Cardiorespiratory responses to ballet exercise and the VO2max of elite ballet dancers.

Physiologic responses to ballet exercise and VO2max during treadmill running were studied in elite professional ballet dancers (7 men, 8 women; age 20-30 yr) from American Ballet Theatre. Ten dancer were studied during standard 1-h ballet classes consisting of 28 min of barre and 32 min of center floor exercise. Eight dancers performed maximal treadmill running tests yielding VO2max values (ml . min-1 . kg-1) of 48.2 (range 43.8-51.9) for men and 43.7 (range 40.9-50.1) for women. Mean VO2 (ml . min-1 . kg-1) during barre exercise was 18.5 (38% VO2max) for men and 16.5 (38% VO2max) for women; during center floor exercise 26.3 (55% VO2max) for men and 20.1 (46% VO2max) for women, with a peak of 77% VO2max for a male dancer. Mean caloric output values (kcal . kg-1 . min-1) during barre exercise were 0.09 and 0.08 for men and women, respectively, and during center floor exercise 0.13 for men and 0.10 for women, with a peak of 0.18 for one male dancer. Estimated net caloric outputs for the entire ballet class averaged 200 kcal . h-1 for women and 300 kcal . h-1 for men. During barre exercise, HR was below the training sensitive zone (70% HR max) for significant periods of time. Peak HR (beats . min-1) was relatively high during allegro center floor exercise, averaging 178 (92% HR max) and 158 (85% HR max) for men and women, respectively. However, these were maintained for only brief durations similar to sprint or burst activities. We conclude that these physiologic data obtained during ballet class represent only a relatively modest stimulus for augmenting aerobic (VO2max). In conjunction with the strong isometric component in ballet exercise, along with the sprint or burst component of ballet exercise, these factors would produce in elite ballet dancers VO2max values in the range of non-endurance athletes.

Cardiovascular adjustments to exercise distributed between the upper and lower body.

The present study examined the hemodynamic differences between upper- and lower-body exercise where the total power output (PO) was proportionally distributed between the upper and lower body. Six males completed five combinations of arm-leg exercise at maximal and three submaximal intensities. The ratio of arm PO to total PO for each exercise combination was 0, 25, 50, 75, and 100%. At each submaximal intensity, VO2 and cardiac output (Q) were not different (P greater than 0.05) across exercise combinations. Likewise, heart rate (HR) responses were not different for 0, 25, 50, and 75% at level 1 (mean = 102, 102, 106, 106 beats.min-1, respectively), level 2 (mean = 114, 110, 119, 118 beats.min-1, respectively), and level 3 (mean = 127, 124, 132, 131 beats.min-1, respectively). However, HR for 100% (arm-only exercise) tended to be higher than 0% at level 1 (delta HR = 10 beats.min-1; P less than 0.10), level 2 (delta HR = 12 beats.min-1, P less than 0.06) and level 3 (delta HR = 10 beats.min-1; P less than 0.06). At level 1, stroke volume (SV) remained essentially unchanged from 0-75%, while SV at 100% (108 ml) was slightly though not significantly lower (P less than 0.10) than 0% (125 ml). At exercise levels 2 and 3, SV remained unchanged for 0 and 25%; however, SV at 50, 75, and 100% were generally lower (P less than 0.05) compared with 0%. These results indicate that involving the leg musculature to varying degrees during arm-leg exercise attenuates the hemodynamic differences observed during strict upper body versus strict lower body exercise.

Specificity of arm training on aerobic power during swimming and running.

The specificity of aerobic training for upper-body exercise requiring differing amounts of muscle mass was evaluated in 25 college-aged male recreational swimmers who were randomly assigned to either a non-training control group (N = 9), a 10-wk swim(S)-training group (N = 9), or a group that trained with a standard swim-bench pulley system (SB; N = 7). For all subjects prior to training, tethered-swimming peak VO2 averaged 19% below treadmill values (P less than 0.01), while SB-ergometry peak VO2 was 50% and 39% below running and swimming values, respectively (P less than 0.01). Significant (P less than 0.01) increases of peak VO2 in tethered swimming (11%) and SB (21%) were observed for the SB-trained group, while the S-trained group improved (P less than 0.01) 18% and 19% on the tethered swimming and SB tests, respectively. No changes were observed during treadmill running, and the control subjects remained unchanged on all measures. Comparisons between training groups indicated that although both groups improved to a similar extent when measured on the swim bench, the 0.53 l X min-1 improvement in tethered-swimming peak VO2 for the S-trained group was greater (P less than 0.05) than the 0.32 l X min-1 increase noted for the SB-trained group. The comparisons between SB and S exercise vs treadmill exercise support the specificity of aerobic improvement with training and suggest that local adaptations contribute significantly to improvements in peak VO2. Furthermore, the present data indicate that SB exercise activates a considerable portion of the musculature involved in swimming, and that aerobic improvements with SB training are directly transferred to swimming.

Lipid and lipoprotein profiles relate to peak aerobic power in spinal cord injured men.

The relationship between peak VO2 and serum lipids, lipoproteins, and apolipoproteins was assessed in nine traumatic spinal cord injured (SCI), active, male volunteers. Mean (SD) age, height, and weight were 30.6 (11.6) yr, 171.1 (11.3) cm, and 74.2 (12.5) kg, respectively. Peak VO2 (X = 2.13 l.min-1) was assessed by a graded arm-crank test to maximum, percent body fat (X = 28.7%) by densitometry, and lipid profile by measures of serum triglycerides, total cholesterol (TC), high and low density lipoprotein cholesterol (HDL-C and LDL-C, respectively), apolipoproteins (apoA-1, apoB), and various ratios of lipids, lipoproteins, and apolipoproteins. Significant inverse relationships emerged between peak VO2 and TC/HDL-C (r = -0.86; P less than 0.01), apoB/apoA-1 (r = -0.75; P less than 0.05), triglycerides (r = -0.73; P less than 0.05), and LDL-C/HDL-C (r = -0.72; P less than 0.05). Direct correlations (P less than 0.05) were demonstrated between peak VO2 and apoA-1/apoB (r = 0.71) and HDL-C/apoA-1 (r = 0.64). The present results indicate that, for active, mid-to-lower thoracic SCI men, the putative atherogenic and antiatherogenic lipid, lipoprotein, and apolipoprotein indices are significantly related to peak VO2 in a manner similar to that described for the able-bodied. These findings indicate the relevance of aerobic fitness assessment in planning CHD prevention strategies for the SCI.

Temporomandibular joint repositioning and exercise performance: a double-blind study.

In the present study, the effects of temporomandibular joint (TMJ) repositioning by use of an acrylic appliance on maximum and submaximum physiologic and performance measures were evaluated in seven male and four female volunteers with documented TMJ malalignment. In an attempt to remove design inadequacies of previous research in this area, a double-blind strategy was utilized. Subjects were randomly assigned to each of four conditions: 1) normal, without a bite splint, 2) with a placebo splint with no occlusal contact so as to maintain normal jaw position, 3) with a splint that optimized jaw position, and 4) with a splint that magnified the subjects normal degree of malocclusion. Measurements were taken of visual reaction time and movement time, muscular strength of the grip, elbow flexors, and leg extensors, submaximal and maximal oxygen uptake, perceived exertion, anaerobic power output, and all-out working capacity in both arm and leg exercise on a cycle ergometer. Analysis of variance for repeated measures indicated that in no instance were the differences in mean scores on physiologic and performance measures with TMJ repositioning or placebo statistically significant when compared with the normal condition. This was the case for the group as a whole or when the five subjects with the greatest TMJ dysfunction were analyzed separately. These findings strongly support the contention that the beneficial effects of short-term TMJ repositioning on exercise performance noted in previous reports may be the result of inadequacies in research design and evaluation rather than the true effects of the bite splint.

Polymorphisms in the PTPN22 region are associated with psoriasis of early onset.

BACKGROUND: Psoriasis, a chronic inflammatory skin disease, affects approximately 2% of the population worldwide. Although the aetiology of psoriasis is poorly understood, patients with disease of early onset (Type I, age of onset