The role of family factors in the association between early adulthood BMI and risk of cardiovascular disease. An intergenerational study of BMI in early adulthood and cardiovascular mortality in parents, aunts and uncles.

BACKGROUND: High body mass index (BMI) in childhood and adolescence is related to cardiovascular disease (CVD). Causality is not established because common genetic or early life socioeconomic factors (family factors) may explain this relationship. We aimed to study the role of family factors in the association between BMI and CVD by investigating if early adulthood BMI in conscripts and CVD mortality in their parents/aunts/uncles are related. METHODS: Data from the Armed Forces Personnel Database (including height and weight among conscripts) were linked with data from the Norwegian Population Registry, generational data from the Norwegian Family Based Life Course Study, the National Educational Registry and the Cause of Death Registry using unique personal identification numbers. The study sample (N = 369,464) was Norwegian males born 1967-1993, who could be linked to both parents and at least one maternal and one paternal aunt or uncle. Subsamples were identified as conscripts whose parents/aunts/uncles had data on cardiovascular risk factors available from Norwegian health surveys. Cox proportional hazards regression models were used to estimate hazard ratios (HR) of CVD mortality in the parental generation according to BMI categories of conscripts. RESULTS: Parents of conscripts with obesity or overweight had a higher hazard of CVD death (fathers HR obese: 1.99 (1.79, 2.21), overweight: 1.33 (1.24, 1.42) mothers HR obese: 1.65 (1.32, 2.07), overweight: 1.23 (1.07, 1.42)) than parents of normal- or underweight conscripts. Aunts and uncles of conscripts with obesity and overweight had an elevated hazard of CVD death, but less so than parents. Adjustment for CVD risk factors attenuated the results in parents, aunts and uncles. CONCLUSIONS: Family factors may impact the relationship between early adulthood overweight and CVD in parents. These can be genes with impact on BMI over generations and genes with a pleiotropic effect on both obesity and CVD, as well as shared environment over generations.

Embryo culture at a reduced oxygen concentration of 5%: a mini review.

The optimum oxygen tension for culturing mammalian embryos has been widely debated by the scientific community. While several laboratories have moved to using 5% as the value for oxygen tension, the majority of modern in vitro fertilization (IVF) laboratory programmes still use 20%. Several in vivo studies have shown the oxygen tension measured in the oviduct of mammals fluctuates between 2% and 8% and in cows and primates this values drops to <2% in the uterine milieu. In human IVF, a non-physiological level of 20% oxygen has been used in the past. However, several studies have shown that atmospheric oxygen introduces adverse effects to embryo development, not limited to numerous molecular and cellular physiology events. In addition, low oxygen tension plays a critical role in reducing the high level of detrimental reactive oxygen species within cells, influences embryonic gene expression, helps with embryo metabolism of glucose, and enhances embryo development to the blastocyst stage. Collectively, this improves embryo implantation potential. However, clinical studies have yielded contradictory results. In almost all reports, some level of improvement has been identified in embryo development or implantation, without any observed drawbacks. This review article will examine the recent literature and discusses ongoing efforts to understand the benefits that low oxygen tension can bring to mammal embryo development in vitro.

Slow and steady cell shrinkage reduces osmotic stress in bovine and murine oocyte and zygote vitrification.

STUDY QUESTION: Does the use of a new cryoprotectant agent (CPA) exchange protocol designed to minimize osmotic stress improve oocyte or zygote vitrification by reducing sublethal cryodamage? SUMMARY ANSWER: The use of a new CPA exchange protocol made possible by automated microfluidics improved oocyte and zygote vitrification with superior morphology as indicated by a smoother cell surface, higher sphericity, higher cytoplasmic lipid retention, less cytoplasmic leakage and higher developmental competence compared with conventional methods. WHAT IS KNOWN ALREADY: The use of more 'steps' of CPA exposure during the vitrification protocol increases cryosurvival and development in the bovine model. However, such an attempt to eliminate osmotic stress is limited by the practicality of performing numerous precise pipetting steps in a short amount of time. STUDY DESIGN, SIZE, DURATION: Murine meiotically competent germinal vesicle intact oocytes and zygotes were harvested from the antral follicles in ovaries and ampulla, respectively. Bovine ovaries were obtained from a local abattoir at random stages of the estrous cycle. A total of 110 murine oocytes, 802 murine zygotes and 52 bovine oocytes were used in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Microfluidic devices were fabricated using conventional photo- and soft-lithography. CPAs used were 7.5% ethylene glycol (EG) and 7.5% dimethyl sulfoxide (DMSO) for equilibration solution and 15% EG, 15% DMSO and 0.5 M sucrose for vitrification solution. End-point analyses include mathematical modeling using Kedem-Katchalsky equations, morphometrics assessed by conventional and confocal microscopy, cytoplasmic lipid quantification by nile red staining, cytoplasmic leakage quantification by fluorescent dextran intercalation and developmental competence analysis by 96 h embryo culture and blastomere quantification. MAIN RESULTS AND THE ROLE OF CHANCE: The automated microfluidics protocol decreased the shrinkage rate of the oocyte and zygote by 13.8 times over its manual pipetting alternative. Oocytes and zygotes with a lower shrinkage rate during CPA exposure experienced less osmotic stress resulting in better morphology, higher cell quality and improved developmental competence. This microfluidic procedure resulted in murine zygotes with a significantly smoother cell surface (P < 0.001), more spherical cellular morphology (P < 0.001), increased cytoplasmic lipid retention in vitrified and warmed bovine oocytes (P < 0.01), decreased membrane perforations and cytoplasmic leakage in CPA-exposed murine zygotes (P < 0.05) and improved developmental competence of vitrified and warmed murine zygotes (P < 0.05) than CPA exposure using the current clinically used manual pipetting method. LIMITATIONS, REASONS FOR CAUTION: It is necessary to design the microfluidic device to be more user-friendly for widespread use. WIDER IMPLICATIONS OF THE FINDINGS: The theory and approach of eliminating osmotic stress by decreasing shrinkage rate is complementary to the prevalent osmotic stress theory in cryobiology which focuses on a minimum cell volume at which the cells shrink. The auto-microfluidic protocol described here has immediate applications for improving animal and human oocyte, zygote and embryo cryopreservation. On a fundamental level, the clear demonstration that at the same minimum cell volume, cell shrinkage rate affects sublethal damage should be broadly useful for cryobiology. STUDY FUNDING/COMPETING INTERESTS: This project was funded by the National Institutes of Health and the University of Michigan Reproductive Sciences Program. The authors declare no conflicts of interest.

Longitudinal target-spin asymmetries for deeply virtual compton scattering.

A measurement of the electroproduction of photons off protons in the deeply inelastic regime was performed at Jefferson Lab using a nearly 6 GeV electron beam, a longitudinally polarized proton target, and the CEBAF Large Acceptance Spectrometer. Target-spin asymmetries for ep→e^{'}p^{'}γ events, which arise from the interference of the deeply virtual Compton scattering and the Bethe-Heitler processes, were extracted over the widest kinematics in Q^{2}, x_{B}, t, and ϕ, for 166 four-dimensional bins. In the framework of generalized parton distributions, at leading twist the t dependence of these asymmetries provides insight into the spatial distribution of the axial charge of the proton, which appears to be concentrated in its center. These results also bring important and necessary constraints for the existing parametrizations of chiral-even generalized parton distributions.

Measurement of resilience in Chinese older people.

BACKGROUND: Resilience has been identified as a personal construct that may contribute to the process of healthy ageing in older people. To date, no measurement instrument has been tested to evaluate resilience in Chinese older people. AIM: To examine the psychometric testing and clinical application of the Chinese version of the Resilience Scale (RS) in Chinese older people. METHODS: A descriptive cross-sectional study design was used. Forward and backward translation procedures were used to obtain semantic equivalence of the original English version of the RS. Content validity was examined by identified experts, followed by exploratory factor analysis, item-to-total correlation, Cronbach's α coefficients and test-retest reliability. RESULTS: The 25-item Chinese version of Resilience Scale (RS-CN) was fully completed by 461 Chinese older people. Cronbach's α for the total Chinese version of the Revised Resilience Scale was 0.95, with a range of 0.85-0.89 for the sub-scales. Item-to-total correlation coefficients ranged from 0.51 to 0.75 and items were excluded with item-to-total correlations coefficients lower than 0.4. The test-retest reliability of the total scale was 0.80, sub-scale test-retest reliability ranged from 0.61 to 0.620. The exploratory principal component analysis with varimax rotation revealed RS-CN to have a four-factor structure. CONCLUSION: The RS-CN is a valid and reliable instrument for the measurement of the concept of resilience in Chinese older people. The results of this study provide cross-cultural evidence for the potential application of this scale in Chinese older people. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Greater insight into the psychological constructs of resilience in Chinese older people can lead to international comparisons and to the potential development of interventions for this population around the world.

The association of birth order with later body mass index and blood pressure: a comparison between prospective cohort studies from the United Kingdom and Brazil.

BACKGROUND: Previous studies have found greater adiposity and cardiovascular risk in first born children. The causality of this association is not clear. Examining the association in diverse populations may lead to improved insight. METHODS: We examine the association between birth order and body mass index (BMI), systolic and diastolic blood pressure (SBP/DBP) in the 2004 Pelotas cohort from southern Brazil and the Avon Longitudinal Study of Parents and Children (ALSPAC) from Bristol, south-west England, restricting analysis to families with two children in order to remove confounding by family size. RESULTS: No consistent differences in BMI, SBP or DBP were observed comparing first and second born children. Within the Pelotas 2004 cohort, first born females were thinner, with lower SBP and DBP; for example, mean difference in SBP comparing first with second born was -0.979 (95% confidence interval -2.901 to 0.943). In ALSPAC, first born females had higher BMI, SBP and DBP. In both cohorts, associations tended to be in the opposite direction in males, although no statistical evidence for gender interactions was found. CONCLUSIONS: The findings do not support an association between birth order and BMI or blood pressure. Differences to previous studies may be explained by differences in populations and/or confounding by family size in previous studies.

Socio-economic position and cardiovascular risk in rural Indian adolescents: evidence from the Andhra Pradesh children and parents study (APCAPS).

OBJECTIVES: This study examined association between socio-economic position and cardiovascular risk factors in adolescents to investigate whether childhood socio-economic position is a risk factor for future cardiovascular disease, independently of adult behaviours. STUDY DESIGN AND METHODS: Participants (n = 1128, 46% girls, aged 13-18 years) were members of a birth cohort (Andhra Pradesh Children and Parents Study or APCAPS) established to investigate long-term effects of a pregnancy and childhood nutritional supplementation trial conducted in 29 villages near Hyderabad in South India. Cross-sectional associations between socio-economic position and cardiovascular risk factors were examined using linear regression models. RESULTS: The mean BMI was 16.7 kg/m(2) for boys and 17.8 kg/m(2) for girls. Socio-economic position was positively associated with fat mass index (0.15 kg/m(2); 95% CI: 0.05-0.25) and inversely associated with central-peripheral skinfold ratio (-0.04; 95% CI: -0.06 to -0.01) and, in boys, fasting triglycerides (-0.05; 95% CI: -0.09 to -0.01). Association of socio-economic position with other risk factors (blood pressure, arterial stiffness, fasting glucose, insulin and cholesterol) was weak and inconsistent, and did not persist after adjustment for potential confounders, including age, sex, pubertal stage, height, adiposity and nutrition supplementation. CONCLUSIONS: The study thus showed that lower socio-economic position may be associated with greater central adiposity and higher triglyceride levels in these settings. Socio-economic gradient in cardiovascular risk may strengthen in future with later economic and lifestyle changes. Cardiovascular disease prevention strategies should therefore focus on the youth from the low income group.

Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs.

AIMS/HYPOTHESIS: Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-ß), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population. METHODS: We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits. RESULTS: The risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with ß values of 0.007 (p = 0.05), 0.01 (p = 0.01), 0.007 (p = 0.05), 0.01 (p = 0.003) and 0.08 (p = 0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with ß values of -0.06 (p = 0.04), 0.05 (p = 0.05), -0.08 (p = 0.01) and -0.08 (p = 0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with ß values of 0.05 (p = 0.04), -0.07 (p = 0.03) and -0.08 (p = 0.02), respectively. We also found significant associations of ADAM30 (ß = -0.05; p = 0.01) and CDKN2A/B (ß = -0.05; p = 0.03) with HOMA-ß. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p = 0.03). CONCLUSIONS/INTERPRETATION: We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.

Microdrop preparation factors influence culture-media osmolality, which can impair mouse embryo preimplantation development.

Because media osmolality can impact embryo development, the effect of conditions during microdrop preparation on osmolality was examined. Various sizes of microdrops were prepared under different laboratory conditions. Drops were pipetted directly onto a dish and covered by oil (standard method) or pipetted on the dish, overlaid with oil before removing the underlying media and replaced with fresh media (wash-drop method). Drops were made at 23°C or on a heated stage (37°C) and with or without airflow. Osmolality was assessed at 5 min and 24h. The biological impact of osmolality change was demonstrated by culturing 1-cell mouse embryos in media with varying osmolality. Reduced drop volume, increased temperature and standard method were associated with a significant increase in osmolality at both 5 min and 24h (P-values <0.001, <0.0001 and <0.0001, respectively). There was a significant interaction between airflow, decreased volume, increased temperature and standard method that caused a significant increase in osmolality (40mOsm/kg) compared with controls (P<0.04). There was no significant change in osmolality over time. Mouse embryo development was significantly reduced in media with elevated osmolality (>310mOsm/kg; P<0.05). Procedures in the IVF laboratory can alter osmolality and impact embryo development.

Atom probe trajectory mapping using experimental tip shape measurements.

Atom probe tomography is an accurate analytical and imaging technique which can reconstruct the complex structure and composition of a specimen in three dimensions. Despite providing locally high spatial resolution, atom probe tomography suffers from global distortions due to a complex projection function between the specimen and detector which is different for each experiment and can change during a single run. To aid characterization of this projection function, this work demonstrates a method for the reverse projection of ions from an arbitrary projection surface in 3D space back to an atom probe tomography specimen surface. Experimental data from transmission electron microscopy tilt tomography are combined with point cloud surface reconstruction algorithms and finite element modelling to generate a mapping back to the original tip surface in a physically and experimentally motivated manner. As a case study, aluminium tips are imaged using transmission electron microscopy before and after atom probe tomography, and the specimen profiles used as input in surface reconstruction methods. This reconstruction method is a general procedure that can be used to generate mappings between a selected surface and a known tip shape using numerical solutions to the electrostatic equation, with quantitative solutions to the projection problem readily achievable in tens of minutes on a contemporary workstation.

Management of Fibro-adipose Vascular Anomalies (FAVA) in Paediatric Practice.

Fibro-adipose vascular anomaly (FAVA) is a discrete type of vascular anomaly. We describe our experience managing FAVA at a tertiary level paediatric hospital and offer a treatment algorithm. METHODS: A retrospective review of 27 patients with proven FAVA was undertaken. All patients had undergone MRI and USS evaluation. Patient demographics, presenting concerns, treatment methods, and outcomes were recorded and evaluation with the paediatric outcomes data collection instrument (PODCI) completed a minimum of 12 months after definitive treatment. RESULTS: Mean age at presentation was 8.9 years (range: 9 m-17.4 y) and mean post-treatment follow-up was 7.4 y (range: 2 y-11.6 y). Twenty of 27 lesions affected the lower limb. Severe neurogenic-type pain was present in 23 cases and contractures across joints in 11 cases. Sclerotherapy with sodium tetradecyl sulphate was used in 11 cases, with no improvement in symptoms. Cryoablation provided pain relief in 3/4 cases, but contracture subsequently increased in one patient and pain recurred in another.Fourteen cases underwent surgery (four surgical excisions alone, 10 in combination with other procedures). Three patients required four further surgical procedures that include one amputation for intractable pain and poor function.PODCI evaluations suggest overall good function, with surgical management and interventional radiology that provide comparable results. Surgery did correct deformity. CONCLUSION: If conservative measures or cryoablation fail to achieve symptomatic control, surgical excision should be considered, combined with adjunctive procedures, to correct contractures and balance muscle forces.Relief of pain may compensate for the loss of muscle mass and overall improves function. Multidisciplinary team working is essential.

Dynamic microfunnel culture enhances mouse embryo development and pregnancy rates.

BACKGROUND: Despite advances in in vitro manipulation of preimplantation embryos, there is still a reduction in the quality of embryos produced leading to lower pregnancy rates compared with embryos produced in vivo. We hypothesized that a dynamic microfunnel embryo culture system would enhance outcomes by better mimicking the fluid-mechanical and biochemical stimulation embryos experience in vivo from ciliary currents and oviductal contractions. METHODS AND RESULTS: Mouse embryos were cultured in microdrop-static control, microfunnel-static control or microfunnel-dynamic conditions with microfluidics. All groups tested had greater than 90% total blastocyst development from zygotes after 96 h culture. Blastocyst developmental stage was significantly enhanced (P < 0.01) under dynamic microfunnel culture conditions as evidenced by an increased percentage of hatching or hatched blastocysts (Microdrop-control 31%; Microfunnel-control 23%; Microfunnel-pulsatile 71%) and significantly higher (P < 0.01) average number of cells per blastocyst (Microdrop-control 67 +/- 3; Microfunnel-control 60 +/- 3; Microfunnel-pulsatile 109 +/- 5). Blastocyst cell numbers in dynamic microfunnel cultures (109 +/- 5) more closely matched numbers obtained from in vivo grown blastocysts (144 +/- 9). Importantly, dynamic microfunnel culture significantly improved embryo implantation and ongoing pregnancy rates over static culture to levels approaching that of in utero derived preimplantation embryos. CONCLUSIONS: The improved pregnancy outcomes along with the simple and user-friendly design of the microfluidic/microfunnel system has potential to alleviate many inefficiencies in embryo production for biomedical research, genetic gain in domestic species and assisted reproductive technologies in humans.

Structure of pressinoic acid: the cyclic moiety of vasopressin.

Arginine vasopressin consists of a 20-membered, disulfide-linked macrocyclic ring system called pressinoic acid to which is attached a COOH-terminal tripeptide. The molecular conformation of pressinoic acid has been determined from single crystal x-ray diffraction data. The 20-membered macrocyclic ring, stabilized by two intramolecular hydrogen bonds, has a type I beta-bend centered on Gln4 and Asn5 and a highly distorted type II' bend centered on Phe3 and Gln4. In vasopressin the Asn5 side chain extends away from the macrocyclic ring system and hydrogen bonds to the terminal tripeptide, but in pressinoic acid the Asn5 side chain lies over the molecule and forms a strong hydrogen bond to the nitrogen of Tyr2. The absence of pressor activity in pressinoic acid may be a result of both the loss of the COOH-terminal tripeptide and the incorrect orientation of the Asn5 side chain. Whether this class of hormones has pressor or oxytocic activity is determined by the orientation of the Tyr2 side chain, that is, whether it is extended away from or over the ring system, respectively. In pressinoic acid, the Tyr2 side chain is in the expected "pressor conformation," that is, extended away from the ring system, and is stabilized through a hydrophobic interaction with the Phe3 side chain. Thus, the conformation of the pressinoic acid molecule partly explains the activity of vasopressin-like hormones.

Methadone conformation and opioid activity.

The inactive methadone analog threo-5-methylmethadone has a solid-state conformation in which the nitrogen is antiperiplanar to the tertiary carbon C(4). Since threo-5-methylmethadone exhibits no opioid agonism either in vivo or in vitro, methadone analogs probably do not have this conformation when bound to an opioid receptor. The potent agonist (-)-erythro-5-methylmethadone has a solid-state conformation in which the nitrogen atom is rotated back toward the phenyl rings on the quarternary carbon, suggesting that this unusual conformation is the active one.

Determining the composition of small features in atom probe: bcc Cu-rich precipitates in an Fe-rich matrix.

Aberrations in the ion trajectories near the specimen surface are an important factor in the spatial resolution of the atom probe technique. Near the boundary between two phases with dissimilar evaporation fields, ion trajectory overlaps may occur, leading to a biased measurement of composition in the vicinity of this interface. In the case of very small second-phase precipitates, the region affected by trajectory overlaps may extend to the centre of the precipitate prohibiting a direct measurement of composition. A method of quantifying the aberrant matrix contribution and thus estimating the underlying composition is presented. This method is applied to the Fe-Cu-alloy system, where the precipitation of low-nanometre size Cu-rich precipitates is of considerable technical importance in a number of materials applications. It is shown definitively that there is a non-zero underlying level of Fe within precipitates formed upon thermal ageing, which is augmented and masked by trajectory overlaps. The concentration of Fe in the precipitate phase is shown to be a function of ageing temperature. An estimate of the underlying Fe level is made, which is at lower levels than commonly reported by atom probe investigations.

Surface segregation of Au-Pd alloys in UHV and reactive environments: quantification by a catalytic atom probe.

The surface composition of an Au-62at%Pd alloy has been studied by means of a catalytic atom probe (CAP) before and after exposures to nitric oxide (NO) at temperatures ranging from 300 to 573K for 20min. Subsequent CAP analysis at 100K revealed a considerable surface enrichment in Pd (to approximately 80at%) after exposure at 573K. This is correlated with the occurrence of NO dissociation, and the formation of strong Pd-O bonds at the surface. Blank experiments in ultra-high vacuum reflect the surface composition of the bulk material, in excellent agreement with electron microprobe analysis. At 573K, no detectable surface segregation occurs in the absence of NO adsorption for the times and temperatures studied. However, classical Metropolis Monte-Carlo simulations performed with a semi-empirical potential on the Au(40)Pd(60) (111), (110) and (100) systems show surface enrichment of gold at equilibrium. This suggests that the temperatures of the clean surface segregation experiments are too low to reach equilibrium within times of the order of hours.

Cold Tolerance of Mountain Pine Beetle (Coleoptera: Curculionidae) Pupae.

Determining the cold tolerance of mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae), is critical for assessing its long-term persistence and eruptive potential in its new habitat, as well as the risk of continued range expansion across Canada's boreal forest. We used supercooling points (SCPs) and mortality assessments with exposure to different temperatures to determine the cold tolerance of pupae. Mountain pine beetle pupae cold tolerance did not increase with chilling and there was little change in the lethal temperature regardless of treatment or sample time. SCPs were reflective of expected mortality due to freezing: the lethal temperature for 50% mortality was -19.3°C and the mean SCP was -18.7°C. However, significant mortality occurred over time at much warmer temperatures (0 and -9°C), indicating that this life stage suffers significant prefreeze mortality. On the basis of our results, it is unlikely that pupae would be able to successfully overwinter in most regions in Canada. This study is part of a larger project aimed at producing a comprehensive assessment of the cold tolerance of all life stages of the mountain pine beetle to feed population models, climatic suitability indices, and spread assessments.