Dysfunction In Later Life Research Articles

Early-life injury produces lifelong neural hyperexcitability, cognitive deficit and altered defensive behaviour in the squid Euprymna scolopes.

Injury occurring in the neonatal period in mammals is known to induce plasticity in pain pathways that may lead to pain dysfunction in later life. Whether these effects are unique to the mammalian nervous system is not well understood. Here, we investigate whether similar effects of early-life injury are found in a large-brained comparative model, the cephalopod Euprymna scolopes. We show that the peripheral nervous system of E. scolopes undergoes profound and permanent plasticity after injury of peripheral tissue in the early post-hatching period, but not after the same injury given in the later juvenile period. Additionally, both innate defensive behaviour and learning are impaired by injury in early life. We suggest that these similar patterns of nervous system and behavioural remodelling that occur in squid and in mammals indicate an adaptive value for long-lasting plasticity arising from early-life injury, and suggest that injuries inflicted in very early life may signal to the nervous system that the environment is highly dangerous. Thus, neonatal pain plasticity may be a conserved pattern whose purpose is to set the developing nervous system's baseline responsiveness to threat. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function

Preterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction in later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial and learning deficits and hippocampal shrinkage. We hypothesized that the underlying mechanism was the induction of hippocampal mitochondrial dysfunction by neonatal hyperoxia. C57BL/6J mouse pups were exposed to 85% oxygen or room air from P2–P14. Hippocampal proteomic analysis was performed in young adult mice (14 weeks). Mitochondrial bioenergetics were measured in neonatal (P14) and young adult mice. We found that hyperoxia exposure reduced mitochondrial ATP-linked oxygen consumption and increased state 4 respiration linked proton leak in both neonatal and young adult mice while complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that hyperoxia exposure decreased complex I NDUFB8 and NDUFB11 and complex IV 7B subunits, but increased complex III subunit 9 in young adult mice. In conclusion, neonatal hyperoxia permanently impairs hippocampal mitochondrial function and alters complex I function. These hippocampal mitochondrial changes may account for cognitive deficits seen in children and adolescents born preterm and may potentially be a contributing mechanism in other oxidative stress associated brain disorders.

Arterial stiffness relates to executive dysfunction in later life

ABSTRACTCardiovascular disease in older people is often linked with cognitive impairment, particularly in domains of executive function and processing speed. Our aims examined whether carotid-femoral pulse wave velocity (PWV) related to subtle changes of executive function and processing speed. Fifty-six individuals with subjective mood and/or cognitive concerns underwent PWV and neuropsychological assessments of processing speed (Trail Making Test Part A) and executive functioning (Delis Kaplan Executive Function System Stroop Task; Trail Making Test Part B, TMT-B). Individuals with high PWV (≥12.0m/s) had poorer performance on TMT-B, compared to low PWV (<12.0m/s), and a moderate negative correlation (r = −0.38, p = .004) between PWV and TMT-B performance. Our results confirm that in older adults at-risk for cognitive decline, early markers of CVD are associated with subtle decrements in rapid set-shifting (executive function), supporting efforts towards early detection of CVD as a secondary prevention strategy for older individuals with cognitive decline.

Interleukin-1β Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide.

Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1β (IL-1β) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1β and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP+) astrocytes and decreased numbers of neuronal nuclei positive (NeuN+) cells. The numbers of sex-determining region Y-box 2 positive (SOX2+) and doublecortin positive (DCX+) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2+ cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1β administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1β for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1β administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1β in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.

Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress.

Perinatal iron deficiency (ID) alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal ID causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet. Pregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for 6 weeks prior to experimentation at 6 months of age. Blood pressure (BP) was assessed via indwelling catheters in anaesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic BP due to ID (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by ID (P < 0.05). The combination of perinatal ID and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal ID increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal ID and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or ID. Perinatal ID causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.

Breastfeeding Greater Than 6 Months Is Associated with Smaller Maternal Waist Circumference Up to One Decade After Delivery.

Abdominal obesity is an important indicator of cardiometabolic dysfunction in later life. Prior studies have observed an inverse association between breastfeeding and maternal waist circumference (WC) in the years after pregnancy, but this may be due to bias resulting from systematic differences in women who do and do not breastfeed. A total of 678 women enrolled in the Pregnancy Outcomes and Community Health (POUCH) cohort also participated in the POUCHmoms Study 7-15 years after delivery. Multivariable linear regression models and propensity scores were used to assess the relationship between WC measured at follow-up and self-reported history of breastfeeding duration of >6 months versus ≤6 months. After a mean follow-up period of 11.0 (standard deviation = 1.4) years, breastfeeding was significantly associated with smaller WC. A threshold effect was detected for women who reported breastfeeding >6 months; their adjusted mean WC was 3.5 cm (95% confidence interval [CI]: -5.7 to -1.2) smaller compared with women who breastfed ≤6 months. The use of two propensity score approaches, weighted and matched, produced similar results; adjusted mean WC difference was -3.6 cm (95% CI: -5.6 to -1.6) and -3.1 cm (95% CI: -5.5 to -0.7), respectively. This study extends conventional observational study methods to incorporate propensity score approaches that make it possible to separate the study design from the study analysis to account for systematic differences in women who did and did not breastfeed. After reducing potential bias, breastfeeding for greater than 6 months was independently associated with smaller WC in the decade after delivery.

Impaired fetal growth in mothers with inadequate gestational weight gain: a retrospective study in Japanese uncomplicated pregnancy

Introduction: The average birth weight in Japan has gradually decreased and the number of low birth weight infant has increased over the last 30 years. Japanese pregnant women are characterized with lower prevalence of obesity than those in other developed countries, and maternal underweight before pregnancy is independently associated with low birth weight. However, the association between maternal inadequate gestational weight gain (GWG) and the risk of small for gestational age (SGA) in Japanese uncomplicated pregnant women has not been fully understood. This study aimed to examine the effect of maternal inadequate GWG on the risk of SGA in Japanese uncomplicated pregnancies.Methods: We retrospectively analyzed uncomplicated Japanese singleton pregnancies that delivered at term gestation in our institution from 2006 to 2016. The association between GWG and birth weight was analyzed by multiple linear regression. Potential confounding factors included maternal age, parity, prepregnancy BMI, and neonatal sex. The association between inadequate GWG and SGA was also examined by logistic regression.Results: A total of 3837 mother–neonate dyads were analyzed. Maternal GWG was 10.1 ± 3.7 kg (mean ± SD), and 2529 (66%) had inadequate GWG. After adjusting for confounding factors, GWG significantly correlated with birth weight (standardized β = 0.199, p < .001). Inadequate GWG increased the risk of delivering SGA neonate (adjusted odds ratio (aOR) = 1.97 [1.45–2.68], p < .001). This association was particularly pronounced in underweight (aOR = 2.95 [1.38–6.29], p = .005) and normal weight mothers (aOR = 1.79 [1.27–2.52], p = .001), and not in overweight/obese mothers (p = .115).Conclusion: Maternal GWG is associated with birth weight in Japanese women with uncomplicated singleton pregnancies. Inadequate GWG is an important risk factor of SGA, particularly in non-obese women. The present finding would potentially provide further evidence that promoting adequate gestational weight gain in Japanese underweight and normal weight mothers would reduce SGA, as well as metabolic dysfunction in later life.

Impact of birth weight and postnatal diet on the gut microbiota of young adult guinea pigs.

BackgroundThe gastrointestinal tract (GIT) microbiota is essential to metabolic health, and the prevalence of the Western diet (WD) high in fat and sugar is increasing, with evidence highlighting a negative interaction between the GIT and WD, resulting in liver dysfunction. Additionally, an adverse in utero environment such as placental insufficiency resulting in low birth weight (LBW) offspring, contributes to an increased risk of metabolic diseases such as fatty liver infiltration and liver dysfunction in later life. We sought to understand the potential interactive effects of exposure to a WD upon growing LBW offspring. We postulated that LBW offspring when challenged with a poor postnatal diet, would display an altered microbiota and more severe liver metabolic dysfunction.MethodsThe fecal microbiota of normal birth weight (NBW) and LBW young guinea pig offspring, weaned onto either a control diet (CD) or WD was determined with 16S rRNA gene next generation sequencing at young adulthood following the early rapid growth phase after weaning. A liver blood chemistry profile was also performed.ResultsThe life-long consumption of WD following weaning into young adulthood resulted in increased total cholesterol, triglycerides and alanine aminotransferase levels in association with an altered GIT microbiota when compared to offspring consuming CD. Neither birth weight nor sex were associated with any significant changes in microbiota alpha diversity, by measuring the Shannon’s diversity index. One hundred forty-eight operational taxonomic units were statistically distinct between the diet groups, independent of birth weight. In the WD group, significant decreases were detected in Barnesiella, Methanobrevibacter smithii and relatives of Oscillospira guillermondii, while Butyricimonas and Bacteroides spp. were increased.DiscussionThese results describe the GIT microbiota in a guinea pig model of LBW and WD associated metabolic syndrome and highlight several WD specific GIT alterations associated with human metabolic disease.

The Need for Longitudinal Studies on Co-occurring Alcohol Use and Anxiety Disorders among Older Adults

Co-occurring alcohol use and anxiety disorders is common in older adults and contributes to poor health&#x0D; outcomes, higher health care utilization, heightened mortality, and social dysfunction in later life. Although&#x0D; there are several proposed theoretical explanations for the association between drinking and mental health&#x0D; disorders (e.g., the precipitation model, the self-medication model, and the mutual maintenance model), few&#x0D; studies have tested the longitudinal time-dependent relationship between alcohol use and anxiety disorders&#x0D; in later life, in part, because longitudinal studies are limited. Better understanding of the temporal sequence&#x0D; of the relationship between alcohol use and anxiety disorders will have implications for improving&#x0D; prevention and treatment programs for at-risk drinking and anxiety in the older population.

Prevention-based approaches to social policy: the case of early childhood development

This article reviews the Australian evidence concerning interventions in early childhood aimed at promoting children’s psychological well-being and preventing social and psychological dysfunction in later life. Two kinds of research are surveyed. One is the Australian social science literature that has emerged in the last twenty years from five major research programs. The other is the evaluation studies that, more recently, have assessed the effectiveness of various early childhood preventive interventions. Together these studies provide an evidentiary platform for reviewing current policy in this field. A full analysis of ‘what works’ would need to include relevant international evidence, which is outside the scope of this article. However, the Australian evidence does support the current policy focus on good parenting programs, while also suggesting that a number of other factors matter in promoting children’s well-being.

Timing of Maternal Exposure and Foetal Sex Determine the Effects of Low-level Chemical Mixture Exposure on the Foetal Neuroendocrine System in Sheep.

We have shown that continuous maternal exposure to the complex mixture of environmental chemicals (ECs) found in human biosolids (sewage sludge), disrupts mRNA expression of genes crucial for development and long‐term regulation of hypothalamic‐pituitary gonadal (HPG) function in sheep. The present study investigated whether exposure to ECs only during preconceptional period or only during pregnancy perturbed key regulatory genes within the hypothalamus and pituitary gland and whether these effects were different from chronic (life‐long) exposure to biosolid ECs. The findings demonstrate that the timing and duration of maternal EC exposure influences the subsequent effects on the foetal neuroendocrine system in a sex‐specific manner. Maternal exposure prior to conception, or during pregnancy only, altered the expression of key foetal neuroendocrine regulatory systems such as gonadotrophin‐releasing hormone and kisspeptin to a greater extent than when maternal exposure was ‘life‐long’. Furthermore, hypothalamic gene expression was affected to a greater extent in males than in females and, following EC exposure, male foetuses expressed more ‘female‐like’ mRNA levels for some key neuroendocrine genes. This is the first study to show that ‘real‐life’ maternal exposure to low levels of a complex cocktail of chemicals prior to conception can subsequently affect the developing foetal neuroendocrine system. These findings demonstrate that the developing neuroendocrine system is sensitive to EC mixtures in a sex‐dimorphic manner likely to predispose to reproductive dysfunction in later life.

Early-Life Exposure to Perfluoroalkyl Substances and Childhood Metabolic Function

Background:Perfluoroalkyl substances (PFASs) are synthetic chemicals that may persist in the environment and in humans. There is a possible association between early-life PFAS exposure and metabolic dysfunction in later life, but data are limited.Methods:We studied 665 mother–child pairs in Project Viva, a Boston, Massachusetts-area cohort recruited 1999–2002. We quantified concentrations of PFASs [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA)] in maternal plasma collected at the first prenatal visit (median, 9.6 weeks gestation) and in child plasma from the mid-childhood research visit (median, 7.7 years). We assessed leptin, adiponectin, and homeostatic model assessment of insulin resistance (HOMA-IR) in mid-childhood. We fit covariate-adjusted linear regression models and conducted stratified analyses by child sex.Results:Children with higher PFAS concentrations had lower HOMA-IR [e.g., –10.1% (95% CI: –17.3, –2.3) per interquartile range increment in PFOA]. This inverse association between child PFAS and HOMA-IR was more pronounced in females [e.g., PFOA: –15.6% (95% CI: –25.4, –4.6) vs. –6.1% (95% CI: –16.2, 5.2) for males]. Child PFAS plasma concentrations were not associated with leptin or adiponectin. Prenatal PFAS plasma concentrations were not associated with leptin, adiponectin, or HOMA-IR in offspring.Conclusions:We found no evidence for an adverse effect of early-life PFAS exposure on metabolic function in mid-childhood. In fact, children with higher PFAS concentrations had lower insulin resistance.Citation:Fleisch AF, Rifas-Shiman SL, Mora AM, Calafat AM, Ye X, Luttmann-Gibson H, Gillman MW, Oken E, Sagiv SK. 2017. Early-life exposure to perfluoroalkyl substances and childhood metabolic function. Environ Health Perspect 125:481–487; http://dx.doi.org/10.1289/EHP303

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth

Background: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined.Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype.Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed “recuperated”). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase–polymerase chain reaction.Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01).Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.

Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats.

ABSTRACT‘Developmental programming’, which occurs as a consequence of suboptimal in utero and early environments, can be associated with metabolic dysfunction in later life, including an increased incidence of cardiovascular disease and type 2 diabetes, and predisposition of older men to sarcopenia. However, the molecular mechanisms underpinning these associations are poorly understood. Many conditions associated with developmental programming are also known to be associated with the aging process. We therefore utilized our well-established rat model of low birth weight and accelerated postnatal catch-up growth (termed ‘recuperated’) in this study to establish the effects of suboptimal maternal nutrition on age-associated factors in skeletal muscle. We demonstrated accelerated telomere shortening (a robust marker of cellular aging) as evidenced by a reduced frequency of long telomeres (48.5-8.6 kb) and an increased frequency of short telomeres (4.2-1.3 kb) in vastus lateralis muscle from aged recuperated offspring compared to controls. This was associated with increased protein expression of the DNA-damage-repair marker 8-oxoguanine-glycosylase (OGG1) in recuperated offspring. Recuperated animals also demonstrated an oxidative stress phenotype, with decreased citrate synthase activity, increased electron-transport-complex activities of complex I, complex II-III and complex IV (all markers of functional mitochondria), and increased xanthine oxidase (XO), p67phox and nuclear-factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Recuperated offspring also demonstrated increased antioxidant defense capacity, with increased protein expression of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase and heme oxygenase-1 (HO1), all of which are known targets of NF-κB and can be upregulated as a consequence of oxidative stress. Recuperated offspring also had a pro-inflammatory phenotype, as evidenced by increased tumor necrosis factor-α (TNFα) and interleukin-1β (IL1β) protein levels. Taken together, we demonstrate, for the first time to our knowledge, an accelerated aging phenotype in skeletal muscle in the context of developmental programming. These findings may pave the way for suitable interventions in at-risk populations.

EVALUATION OF MUSCULOSKELETAL PAIN, SERUM VISFATIN, LEPTIN LEVEL AND BLOOD PRESSURE IN OBESE CHILD AND NON OBESE CHILD

Background: The increasing prevalence of obesity is becoming an important public health problem in childhood and presents numerous problems. Similarly to the risks of obesity in adulthood, childhood obesity is also a leading cause of pediatric hypertension associated with type 2 diabetes mellitus, and increases the risk of cardiovascular diseases. Objective :This study was designed to compare the anthropometric measurements (height, weight, BMI, waist circumference) systolic and diastolic blood pressure, lipid profile (T.C, TG, HDL-C, LDL-C), fasting blood glucose, leptin level , visfatin level and correlation between musculoskeletal pain and weight, waist, BMI ,leptin an Visfatin level within obese children and non obese children. Patients and methods The study included two groups. Group (1) thirty age and sex-matched non-obese children were included as the control group. Group (2) sixty healthy obese children aged 11–15 years. The case-control observational study was evaluated from December 2013 to December 2014 with informed consent. A careful history and physical examination included anthropometric measurements in all subjects. Body weight, height and waist circumference were measured, body mass index (BMI) was calculated (kg/m) as an index of overall adiposity. Children with BMI over their age- and sex-specific 95th percentile values were defined as obese children, and those with BMI <85 percentiles were considered non-obese . Joint site model was used in order to account for correlations between musculoskeletal pain and weight, waist, BMI, leptin an Visfatin level within obese children and non obese children. Results: The obese children showed higher significant difference in fasting blood glucose, TG, LDL-C, T.C, diastolic and systolic blood pressure and they had lower HDL-C compared with non obese children. The study showed that no significant correlations between anthropometric indices (weight, height, BMI, and waist circumference), age ,systolic and diastolic blood pressure with visfatin in the obese group . There was no significant correlations were found between leptin, fasting blood sugar, total cholesterol, HDL-C and LDL-C with visfatin in the obese group , however positive correlation was found between visfatin and Triglycerides . There was no significant correlations between anthropometric indices , systolic, diastolic blood pressure and age with leptin in the obese group . There was no significant correlations were found between FBS, Total cholesterol, Triglycerides, HDL-C, and LDL-C with leptin in the obese group Significant correlations of hip pain, knee pain, feet pain and back pain with weight, waist and BMI were found . Conclusion: Obesity has a significant impact on the health and well-being of these children and may contribute to ongoing health problems such as musculoskeletal pain and bone/joint dysfunction in later life.

Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) – a network implicated in AD and other brain disorders – in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β=−0.063, 95% CI: −0.106, −0.020), anterior cingulate (β=−0.055, 95% CI: −0.101, −0.010), and medial frontal lobe (β=−0.050, 95% CI: −0.092, −0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β=−0.024, 95% CI: −0.062, 0.014) and the hippocampus (β=−0.006, 95% CI: −0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

Effects of moderate global maternal nutrient reduction on fetal baboon renal mitochondrial gene expression at 0.9 gestation.

Early life malnutrition results in structural alterations in the kidney, predisposing offspring to later life renal dysfunction. Kidneys of adults who were growth restricted at birth have substantial variations in nephron endowment. Animal models have indicated renal structural and functional consequences in offspring exposed to suboptimal intrauterine nutrition. Mitochondrial bioenergetics play a key role in renal energy metabolism, growth, and function. We hypothesized that moderate maternal nutrient reduction (MNR) would adversely impact fetal renal mitochondrial expression in a well-established nonhuman primate model that produces intrauterine growth reduction at term. Female baboons were fed normal chow diet or 70% of control diet (MNR). Fetal kidneys were harvested at cesarean section at 0.9 gestation (165 days gestation). Human Mitochondrial Energy Metabolism and Human Mitochondria Pathway PCR Arrays were used to analyze mitochondrially relevant mRNA expression. In situ protein content was detected by immunohistochemistry. Despite the smaller overall size, the fetal kidney weight-to-body weight ratio was not affected. We demonstrated fetal sex-specific differential mRNA expression encoding mitochondrial metabolite transport and dynamics proteins. MNR-related differential gene expression was more evident in female fetuses, with 16 transcripts significantly altered, including 14 downregulated and 2 upregulated transcripts. MNR impacted 10 transcripts in male fetuses, with 7 downregulated and 3 upregulated transcripts. The alteration in mRNA levels was accompanied by a decrease in mitochondrial protein cytochrome c oxidase subunit VIc. In conclusion, transcripts encoding fetal renal mitochondrial energy metabolism proteins are nutrition sensitive in a sex-dependent manner. We speculate that these differences lead to decreased mitochondrial fitness that contributes to renal dysfunction in later life.

Ultrasound imaging of the pelvic floor: changes in anatomy during and after first pregnancy

To describe changes in the absolute values of levator hiatal dimensions and in the contractility and distensibility of the levator hiatus during pelvic floor contraction and Valsalva maneuver, using three/four-dimensional (3D/4D) transperineal ultrasound in women during and after their first pregnancy. Two-hundred and eighty nulliparous pregnant women underwent ultrasound examination at 12 and 36 weeks' gestation and 6 months postpartum. Hiatal dimensions were measured at rest, on pelvic floor contraction and on Valsalva maneuver. The contractility and distensibility were determined by the difference between hiatal dimensions at rest and those on contraction or Valsalva, respectively. After exclusions, there were 231 datasets from women at rest, 199 for pelvic floor contraction and 230 for Valsalva maneuver. Data at 36 weeks' gestation and 6 months postpartum were compared with data at 12 weeks' gestation. At 36 weeks' gestation, the absolute values of hiatal dimensions and the contractility and distensibility of the levator hiatus were significantly increased compared with those at 12 weeks' gestation. Women who delivered vaginally showed a persistent significant increase in hiatal dimensions on Valsalva, whereas women who delivered by prelabor or first-stage Cesarean section showed no significant changes in hiatal dimensions on Valsalva. After both vaginal and Cesarean section delivery, there was a persistent increase in the distensibility of the hiatus during Valsalva compared with in early pregnancy. During first pregnancy, the absolute values of levator hiatal dimensions and the contractility and distensibility of the levator hiatus increase. Regardless of delivery mode, increased distensibility of the levator hiatus during Valsalva persists after childbirth. This increased pelvic floor distensibility may play a role in the development of pelvic floor dysfunction in later life.

IPLA2β knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology.

Calcium-independent phospholipase A2 group VIa (iPLA2β) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4months, PLA2G6 knockout mice (iPLA2β(-/-)) show minimal neuropathology but altered brain DHA metabolism. By 1year, they develop motor disturbances, cerebellar neuronal loss, and striatal α-synucleinaccumulation. We hypothesized that older iPLA2β(-/-) mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2β(-/-) or wild-type (WT) mice. These older iPLA2β(-/-) mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-α messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2γ expression was unchanged. iPLA2β deficient mice show evidence ofneuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation.

Investigation of Genetic Variants, Birthweight and Hypothalamic-Pituitary-Adrenal Axis Function Suggests a Genetic Variant in the SERPINA6 Gene Is Associated with Corticosteroid Binding Globulin in the Western Australia Pregnancy Cohort (Raine) Study

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents.MethodsMorning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method.ResultsThe penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons.ConclusionsOur study suggests that genetic variation in the SERPINA6 gene may be associated with altered CBG levels during adolescence. Replication of these findings is required.