Common cytokine receptor γ chain deficiency in dendritic cells: implications for immunity

X-linked Severe Combined Immunodeficiency (X-SCID) caused by mutations in the common cytokine receptor γ chain (γc) is a fatal disease in which the immune system is severely compromised as T and NK cells are absent or profoundly diminished. Although dendritic cells (DCs) are key antigen presenting cells and are crucial for the induction of normal immune responses, little is known about their function in this disease. This is of specific importance as the myeloid compartment, including DCs, frequently remains of host origin, and therefore γc-deficient, after bone marrow transplant or gene therapy for this form of SCID. Curiously, even after curative treatment, patients with X-SCID continue to have a long-term susceptibility to human papilloma virus infection. We hypothesised that this could be due to persistent myeloid defects. Using a murine model of X-SCID, we demonstrated that, in the absence of functional γc, DCs are less efficient at priming antigen-specific responses in γc-expressing CD4+ T cells. Despite the widely held view that IL-15Rα is the chain responsible for IL-15 transpresentation to NK and CD8+ T cells, here we have shown that expression of the γc by DCs is necessary for effective transpresentation to CD4+ T cells. In a novel system of supported planar bilayers mimicking the T cell interface, we demonstrated that DC-expressed γc colocalises with MHC II clusters and mediates IL-15Rα recruitment to the immunological synapse (IS). This depended on simultaneous TCR engagement with MHC-bound antigen, suggesting that IL-15 transpresentation may have important costimulatory function for T cell activation. Altogether, these data indicate that γc-deficiency impairs DC functions and reveal a novel mechanism for recruitment or stabilization of DC IL-15/IL-15Rα complexes at the IS leading to localized transpresentation of IL-15. The contribution of myeloid γc-deficiency to persistent immunodeficiency in transplanted X-SCID patients warrants further investigation

Early infant feeding and adiposity risk: from infancy to adulthood

Introduction: Systematic reviews suggest that a longer duration of breast-feeding is associated with a reduction in the risk of later overweight and obesity. Most studies examining breast-feeding in relation to adiposity have not used longitudinal analysis. In our study, we aimed to examine early infant feeding and adiposity risk in a longitudinal cohort from birth to young adulthood using new as well as published data. Methods: Data from the Western Australian Pregnancy Cohort (Raine) Study in Perth, W.A., Australia, were used to examine associations between breast-feeding and measures of adiposity at 1, 2, 3, 6, 8, 10, 14, 17, and 20 years. Results: Breast-feeding was measured in a number of ways. Longer breast-feeding (in months) was associated with reductions in weight z-scores between birth and 1 year (β = -0.027; p \u3c 0.001) in the adjusted analysis. At 3 years, breast-feeding for \u3c4 months increased the odds of infants experiencing early rapid growth (OR 2.05; 95% CI 1.43-2.94; p \u3c 0.001). From 1 to 8 years, children breast-fed for ≤4 months compared to ≥12 months had a significantly greater probability of exceeding the 95th percentile of weight. The age at which breast-feeding was stopped and a milk other than breast milk was introduced (introduction of formula milk) played a significant role in the trajectory of the BMI from birth to 14 years; the 4-month cutoff point was consistently associated with a higher BMI trajectory. Introduction of a milk other than breast milk before 6 months compared to at 6 months or later was a risk factor for being overweight or obese at 20 years of age (OR 1.47; 95% CI 1.12-1.93; p = 0.005). Discussion: Breast-feeding until 6 months of age and beyond should be encouraged and is recommended for protection against increased adiposity in childhood, adolescence, and young adulthood. Adverse long-term effects of early growth acceleration are fundamental in later overweight and obesity. Formula feeding stimulates a higher postnatal growth velocity, whereas breast-feeding promotes slower growth and a reduced likelihood of overweight and obesity. Biological mechanisms underlying the protective effect of breast-feeding against obesity are based on the unique composition and metabolic and physiological responses to human milk

Relationships between intrauterine fetal growth trajectories and markers of adiposity and inflammation in young adults

Background There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. Methods Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1–Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. Results Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (β = −1.45 kg/m2, 95% CI: −2.43 to −0.46, P = 0.004) and (β = −1.01 kg/m2, 95% CI: −1.96 to −0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9–73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5–33%, P = 0.011). Conclusion This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease

Modelling the effects of beverage substitution during adolescence on later obesity outcomes in early adulthood: results from the Raine study

High sugar-sweetened beverage (SSB) consumption has been linked with obesity. The present study examined the associations between adolescent SSB intake and body mass index (BMI), waist circumference (WC), and overweight status in early adulthood, and modelled the association of alternative beverage substitution with BMI and WC. Data of offspring from the Western Australian Pregnancy Cohort (Raine) Study at ages 14 and 22 years were used (n = 667). SSB intake at 14 years (100 g/day) was associated with higher BMI (β = 0.19 kg/m2, 95% CI 0.04, 0.33), WC (β = 0.41cm, 95% CI 0.04, 0.78), and being overweight at 22 years (OR 1.10, 95% CI 1.02, 1.18). Every 100g modelled substitution of SSB with milk at age 14 years was associated with lower BMI (-0.19 kg/m2) and WC (-0.52 cm) at age 22 years. Replacement of SSB with diet drink was associated with higher BMI and WC. No association was found for substitutions of SSB with water, tea/coffee, or 100% fruit juice with BMI or WC. SSB intake during adolescence was associated with higher BMI, WC, and being overweight in early adulthood. Milk as an alternative to SSB was associated with less adiposity. Caution is necessary in recommending diet drinks as a SSB alternative

A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly

Copyright © 2003 Massachusetts Medical Society. All rights reserved.Background Treatment of hypertension with diuretics, beta-blockers, or both leads to improved outcomes. It has been postulated that agents that inhibit the renin–angiotensin system confer benefit beyond the reduction of blood pressure alone. We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting–enzyme (ACE) inhibitors with the outcomes in those treated with diuretic agents. Methods We conducted a prospective, randomized, open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practices. Subjects were followed for a median of 4.1 years, and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models. Results At base line, the treatment groups were well matched in terms of age, sex, and blood pressure. By the end of the study, blood pressure had decreased to a similar extent in both groups (a decrease of 26/12 mm Hg). There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group (56.1 per 1000 patient-years) and 736 cardiovascular events or deaths from any cause in the diuretic group (59.8 per 1000 patient-years; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [95 percent confidence interval, 0.79 to 1.00]; P=0.05). Among male subjects, the hazard ratio was 0.83 (95 percent confidence interval, 0.71 to 0.97; P=0.02); among female subjects, the hazard ratio was 1.00 (95 percent confidence interval, 0.83 to 1.21; P=0.98); the P value for the interaction between sex and treatment-group assignment was 0.15. The rates of nonfatal cardiovascular events and myocardial infarctions decreased with ACE-inhibitor treatment, whereas a similar number of strokes occurred in each group (although there were more fatal strokes in the ACE-inhibitor group). Conclusions Initiation of antihypertensive treatment involving ACE inhibitors in older subjects, particularly men, appears to lead to better outcomes than treatment with diuretic agents, despite similar reductions of blood pressure.Lindon M.H. Wing, Christopher M. Reid, Philip Ryan, Lawrence J. Beilin, Mark A. Brown, Garry L.R. Jennings, Colin I. Johnston, John J. McNeil, Graham J. Macdonald, John E. Marley, Trefor O. Morgan, and Malcolm J. West, for the Second Australian National Blood Pressure Study Grou

Dynamic response of HTS composite tapes to pulsed currents

Dynamic voltage-current characteristics of an HTS Ag/BiSCCO composite tape are studied both experimentally and theoretically. The tape is subjected by pulsed currents with different shapes and magnitude and voltage traces are measured using the four-point method with different location of potential taps on the sample surface. Clockwise and anticlockwise hysteresis loops are obtained for the same sample depending on location of the potential taps. The dynamic characteristics deviate substantially from the DC characteristic, especially in the range of low voltages where a criterion for the critical current value is usually chosen (1-10 mkV/cm). The critical current determined from dynamic characteristics and its change with the pulse magnitude depend on location of the potential taps and on the curve branch chosen for the critical current determination (ascending or descending). The theoretical analysis is based on a model of the magnetic flux diffusion into a composite tape for a superconductor described by the flux creep characteristic. Numerical simulation based on this model gives the results in good agreement with the experimental ones and explains the observed peculiarities of the dynamic characteristics of HTS composite tapes. The difference between the magnetic diffusion into a tape and a slab is discussed.Comment: 18 pages, 13 figure

Instability and `Sausage-String' Appearance in Blood Vessels during High Blood Pressure

A new Rayleigh-type instability is proposed to explain the `sausage-string' pattern of alternating constrictions and dilatations formed in blood vessels under influence of a vasoconstricting agent. Our theory involves the nonlinear elasticity characteristics of the vessel wall, and provides predictions for the conditions under which the cylindrical form of a blood vessel becomes unstable.Comment: 4 pages, 4 figures submitted to Physical Review Letter

RANK/RANKL/OPG pathway: genetic associations with stress fracture period prevalence in elite athletes

Context: The RANK/RANKL/OPG signalling pathway is important in the regulation of bone turnover, with single nucleotide polymorphisms (SNPs) in genes within this pathway associated with bone phenotypic adaptations. Objective: To determine whether four SNPs associated with genes in the RANK/RANKL/OPG signalling pathway were associated with stress fracture injury in elite athletes. Design, Participants, and Methods: Radiologically confirmed stress fracture history was reported in 518 elite athletes, forming the Stress Fracture Elite Athlete (SFEA) cohort. Data were analysed for the whole group, and were sub-stratified into male and cases of multiple stress fracture group. Genotypes were determined using proprietary fluorescence-based competitive allele-specific PCR assays. Results: SNPs rs3018362 (RANK) and rs1021188 (RANKL) were associated with stress fracture injury (p<0.05). 8.1% of stress fracture group and 2.8% of the non-stress fracture group were homozygote for the rare allele of rs1021188. Allele frequency, heterozygotes and homozygotes for the rare allele of rs3018362 were associated with stress fracture period prevalence (p<0.05). Analysis of the male only group showed 8.2% of rs1021188 rare allele homozygotes to have suffered a stress fracture while 2.5% of the non-stress fracture group were homozygous. In cases of multiple stress fractures, homozygotes for the rare allele of rs1021188, and individuals possessing at least one copy of the rare allele of rs4355801 (OPG) were shown to be associated with stress fracture injury (p<0.05). Conclusions: The data support an association between SNPs in the RANK/RANKL/OPG signalling pathway and the development of stress fracture injury. The association of rs3018362 (RANK) and rs1021188 (RANKL) with stress fracture injury susceptibility supports their role in the maintenance of bone health, and offers potential targets for therapeutic interventions

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

BACKGROUND: The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. RESULTS: The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. CONCLUSIONS: As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required

Fat mass and obesity-associated obesity-risk genotype is associated with lower foetal growth: An effect that is reversed in the offspring of smoking mothers

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention. Copyrigh