Predicted global climate change, including rising average temperatures, increasing airborne pollution, and ultraviolet radiation exposure, presents multiple environmental stressors contributing to ...increased morbidity and mortality. Extreme temperatures and more frequent and severe heat events will increase the risk of heat-related illness and associated complications in vulnerable populations, including infants and children. Historically, children have been viewed to possess inferior thermoregulatory capabilities, owing to lower sweat rates and higher core temperature responses compared to adults. Accumulating evidence counters this notion, with limited child-adult differences in thermoregulation evident during mild and moderate heat exposure, with increased risk of heat illness only at environmental extremes. In the context of predicted global climate change, extreme environmental temperatures will be encountered more frequently, placing children at increased risk. Thermoregulatory and overall physiological strain in high temperatures may be further exacerbated by exposure to/presence of physiological and environmental stressors including pollution, ultraviolet radiation, obesity, diabetes, associated comorbidities, and polypharmacy that are more commonly occurring at younger ages. The aim of this review is to revisit fundamental differences in child-adult thermoregulation in the face of these multifaceted climate challenges, address emerging concerns, and emphasize risk reduction strategies for the health and performance of children in the heat.
Oxytocin (OT) and vasopressin (AVP) regulate various social behaviors via activation of the OT receptor (OTR) and the AVP V1a receptor (V1aR) in the brain. Social behavior often differs across ...development and between the sexes, yet our understanding of age and sex differences in brain OTR and V1aR binding remains incomplete. Here, we provide an extensive analysis of OTR and V1aR binding density throughout the brain in juvenile and adult male and female rats, with a focus on regions within the social decision-making network. OTR and V1aR binding density were higher in juveniles than in adults in regions associated with reward and socio-spatial memory and higher in adults than in juveniles in key regions of the social decision-making network and in cortical regions. We discuss possible implications of these shifts in OTR and V1aR binding density for the age-specific regulation of social behavior. Furthermore, sex differences in OTR and V1aR binding density were less numerous than age differences. The direction of these sex differences was region-specific for OTR but consistently higher in females than in males for V1aR. Finally, almost all sex differences in OTR and V1aR binding density were already present in juveniles and occurred in regions with denser binding in adults compared to juveniles. Possible implications of these sex differences for the sex-specific regulation of behavior, as well potential underlying mechanisms, are discussed. Overall, these findings provide an important framework for testing age- and sex-specific roles of OTR and V1aR in the regulation of social behavior.
Regional variation in sweating over the body is widely recognised. However, most studies only measured a limited number of regions, with the use of differing thermal states across studies making a ...good meta-analysis to obtain a whole body map problematic. A study was therefore conducted to investigate regional sweat rates (RSR) and distributions over the whole body in male athletes. A modified absorbent technique was used to collect sweat at two exercise intensities 55% (I1) and 75% (I2)
in moderately warm conditions (25°C, 50% rh, 2 m s
−1
air velocity). At I1 and I2, highest sweat rates were observed on the central (upper and mid) and lower back, with values as high as 1,197, 1,148, and 856 g m
−2
h
−1
, respectively, at I2. Lowest values were observed on the fingers, thumbs, and palms, with values of 144, 254, and 119 g m
−2
h
−1
, respectively at I2. Sweat mapping of the head demonstrated high sweat rates on the forehead (1,710 g m
−2
h
−1
at I2) compared with low values on the chin (302 g m
−2
h
−1
at I2) and cheeks (279 g m
−2
h
−1
at I2). Sweat rate increased significantly in all regions from the low to high exercise intensity, with exception of the feet and ankles. No significant correlation was present between RSR and regional skin temperature (
T
sk
), nor did RSR correspond to known patterns of regional sweat gland density. The present study has provided detailed regional sweat data over the whole body and has demonstrated large intra- and inter-segmental variation and the presence of consistent patterns of regional high versus low sweat rate areas in Caucasians male athletes. This data may have important applications for clothing design, thermophysiological modelling and thermal manikin design.
Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk.
To evaluate the association of genetically proxied inhibition of ...3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers.
Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models.
Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels.
Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers).
The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio OR, 0.60 95% CI, 0.43-0.83; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 95% CI, 0.51-0.93; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 95% CI, 0.53-1.75; P = .91), PCSK9 (OR, 0.98 95% CI, 0.85-1.13; P = .80), or circulating LDL cholesterol (OR, 0.98 95% CI, 0.91-1.05; P = .55) with epithelial ovarian cancer.
Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.
Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with ...reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa.
Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging.
Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).
Abstract Under normothermic, resting conditions, humans dissipate heat from the body at a rate approximately equal to heat production. Small discrepancies between heat production and heat elimination ...would, over time, lead to significant changes in heat storage and body temperature. When heat production or environmental temperature is high the challenge of maintaining heat balance is much greater. This matching of heat elimination with heat production is a function of the skin circulation facilitating heat transport to the body surface and sweating, enabling evaporative heat loss. These processes are manifestations of the autonomic control of cutaneous vasomotor and sudomotor functions and form the basis of this review. We focus on these systems in the responses to hyperthermia. In particular, the cutaneous vascular responses to heat stress and the current understanding of the neurovascular mechanisms involved. The available research regarding cutaneous active vasodilation and vasoconstriction is highlighted, with emphasis on active vasodilation as a major responder to heat stress. Involvement of the vasoconstrictor and active vasodilator controls of the skin circulation in the context of heat stress and nonthermoregulatory reflexes (blood pressure, exercise) are also considered. Autonomic involvement in the cutaneous vascular responses to direct heating and cooling of the skin are also discussed. We examine the autonomic control of sweating, including cholinergic and noncholinergic mechanisms, the local control of sweating, thermoregulatory and nonthermoregulatory reflex control and the possible relationship between sudomotor and cutaneous vasodilator function. Finally, we comment on the clinical relevance of these control schemes in conditions of autonomic dysfunction.
Adolescence is a developmental period in which the mesolimbic dopaminergic "reward" circuitry of the brain, including the nucleus accumbens (NAc), undergoes significant plasticity. Dopamine D1 ...receptors (D1rs) in the NAc are critical for social behavior, but how these receptors are regulated during adolescence is not well understood. In this report, we demonstrate that microglia and complement-mediated phagocytic activity shapes NAc development by eliminating D1rs in male, but not female rats, during adolescence. Moreover, immune-mediated elimination of D1rs is required for natural developmental changes in male social play behavior. These data demonstrate for the first time that microglia and complement-mediated immune signaling (i) participate in adolescent brain development in a sex-specific manner, and (ii) are causally implicated in developmental changes in behavior. These data have broad implications for understanding the adolescent critical period of development, the molecular mechanisms underlying social behavior, and sex differences in brain structure and function.
We recently demonstrated that vasopressin (AVP) in the lateral septum modulates social play behavior differently in male and female juvenile rats. However, the extent to which different social ...contexts (i.e., exposure to an unfamiliar play partner in different environments) affect the regulation of social play remains largely unknown. Given that AVP and the closely related neuropeptide oxytocin (OXT) modulate social behavior as well as anxiety-like behavior, we hypothesized that these neuropeptides may regulate social play behavior differently in novel (novel cage) as opposed to familiar (home cage) social environments. Administration of the specific AVP V1a receptor (V1aR) antagonist (CH2)5Tyr(Me(2))AVP into the lateral septum enhanced home cage social play behavior in males but reduced it in females, confirming our previous findings. These effects were context-specific because V1aR blockade did not alter novel cage social play behavior in either sex. Furthermore, social play in females was reduced by AVP in the novel cage and by OXT in the home cage. Additionally, females administered the specific OXT receptor antagonist desGly-NH2,d(CH2)5-Tyr(Me)(2),Thr(4)OVT showed less social play in the novel as compared to the home cage. AVP enhanced anxiety-related behavior in males (tested on the elevated plus-maze), but failed to do so in females, suggesting that exogenous AVP alters social play and anxiety-related behavior via distinct and sex-specific mechanisms. Moreover, none of the other drug treatments that altered social play had an effect on anxiety, suggesting that these drug-induced behavioral alterations are relatively specific to social behavior. Overall, we showed that AVP and OXT systems in the lateral septum modulate social play in juvenile rats in neuropeptide-, sex- and social context-specific ways. These findings underscore the importance of considering not only sex, but also social context, in how AVP and OXT modulate social behavior.
Limited regional sweat rate (RSR) data are available for females, with only a small number of sites measured across the body. Similarly, sex differences in sweating concentrate on whole body values, ...with limited RSR data available.
A modified absorbent technique was used to collect sweat at two exercise intensities (60% (I1) and 75% (I2) V˙O2max) in 13 aerobically trained females (21 ± 1 yr, 59.5 ± 10 mL·min·kg V˙O2max) in moderately warm conditions (25°C, 45% relative humidity, 2 m·s air velocity). Females were compared with nine aerobically trained males (23 ± 3 yr, 70.2 ± 13 mL·min·kg V˙O2max) tested under the same conditions.
Female I1 RSR was highest at the central upper back, heels, and dorsal foot and between the breasts (223, 161, 139, and 139 g·m·h, respectively). Lowest values were over the breasts and the middle and lower outer back (<16 g·m·h). At I2, the central upper back, bra triangle, and lower back showed the highest RSR (723, 470, and 333 g·m·h, respectively). Regions of the breasts and palms had the lowest RSR at I2 (<82 g·m·h). Significantly greater gross sweat loss and thus RSR were observed in males versus females at both exercise intensities. For the same metabolic heat production (male I1 vs female I2), absolute and normalized RSR showed a significant region-sex interaction (P < 0.001), with a greater distribution toward the arms and hands in females versus males.
Despite some differences in distribution, both sexes showed highest RSR on the central upper back and the lowest toward the extremities. No correlation was observed between local skin temperature and RSR, failing to explain RSR variation observed. These data have important applications for sex-specific clothing design, thermophysiological modeling, and thermal manikin design.
Educated by initiative Smith, Daniel A; Tolbert, Caroline
2004., 20091112, 2004, c2004.
eBook
Educated by Initiative moves beyond previous evaluations of public policy to emphasize the educational importance of the initiative process itself. Since a majority of ballots ultimately fail or get ...overturned by the courts, Smith and Tolbert suggest that the educational consequences of initiative voting may be more important than the outcomes of the ballots themselves. The result is a fascinating and thoroughly-researched book about how direct democracy teaches citizens about politics, voting, civic engagement and the influence of special interests and political parties. Designed to be accessible to anyone interested in the future of American democracy, the book includes boxes (titled "What Matters") that succinctly summarize the authors' data into easily readable analyses.
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