The influence of microsatellite polymorphisms in sex steroid receptor genes ESR1, ESR2 and AR on sex differences in brain structure.

The androgen receptor (AR), oestrogen receptor alpha (ESR1) and oestrogen receptor beta (ESR2) play essential roles in mediating the effect of sex hormones on sex differences in the brain. Using Voxel-based morphometry (VBM) and gene sizing in two independent samples (discovery n â€‹= â€‹173, replication â€‹= â€‹61), we determine the common and unique influences on brain sex differences in grey (GM) and white matter (WM) volume between repeat lengths (n) of microsatellite polymorphisms AR(CAG)n, ESR1(TA)n and ESR2(CA)n. In the hypothalamus, temporal lobes, anterior cingulate cortex, posterior insula and prefrontal cortex, we find increased GM volume with increasing AR(CAG)n across sexes, decreasing ESR1(TA)n across sexes and decreasing ESR2(CA)n in females. Uniquely, AR(CAG)n was positively associated with dorsolateral prefrontal and orbitofrontal GM volume and the anterior corona radiata, left superior fronto-occipital fasciculus, thalamus and internal capsule WM volume. ESR1(TA)n was negatively associated with the left superior corona radiata, left cingulum and left inferior longitudinal fasciculus WM volume uniquely. ESR2(CA)n was negatively associated with right fusiform and posterior cingulate cortex uniquely. We thus describe the neuroanatomical correlates of three microsatellite polymorphisms of steroid hormone receptors and their relationship to sex differences.

Safety and effectiveness of stoss therapy in children with vitamin D deficiency.

AIM: Paediatric vitamin D (25-hydroxyvitamin D (25OHD)) deficiency can lead to nutritional rickets and extra-skeletal complications. Compliance with daily therapy can be difficult, making high-dose, short-term vitamin D (stoss) therapy attractive to correct vitamin D deficiency. We compared the effectiveness and safety of standard versus stoss therapy in treating childhood 25OHD deficiency. METHODS: Children aged 2-16 years with 25OHD <50 nmol/L were randomised to either standard (5000 IU daily for 80 days) or stoss (100 000 IU weekly for 4 weeks) cholecalciferol. Participants underwent an evaluation of effectiveness and safety. The 25OHD level, random spot calcium: creatinine ratio (Ca:Cr) and compliance were measured at 12 weeks. RESULTS: A total of 151 children were enrolled in the study (68 standard and 83 stoss), median age 9 years (inter-quartile range (IQR): 6-12 years). Baseline 25OHD levels were 26 nmol/L (IQR: 19-35 nmol/L) and 32 nmol/L (IQR: 24-39 nmol/L) in the standard and stoss groups, respectively. At 12 weeks, the median 25OHD level was significantly greater in the standard versus stoss group (81 vs. 67 nmol/L; P = 0.005); however, >80% of participants in both groups achieved sufficiency (25OHD > 50 nmol/L) and had normal urinary Ca:Cr, with no significant difference seen between groups. Compliance was similar in the two groups. CONCLUSIONS: Compared to stoss, standard therapy achieved higher 25OHD levels at 12 weeks; however, in both groups, there was a similar proportion of participants who achieved 25OHD sufficiency, with no evidence of toxicity. Unlike other studies, simplifying the treatment regimen did not improve compliance. These results support stoss therapy as an effective and safe alternative therapy for the treatment of paediatric vitamin D deficiency.

The Parkinson's Disease Mendelian Randomization Research Portal.

BACKGROUND: Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.

Bioenergetic consequences of PINK1 mutations in Parkinson disease.

BACKGROUND: Mutations of the gene for PTEN-induced kinase 1 (PINK1) are a cause of familial Parkinson's disease (PD). PINK1 protein has been localised to mitochondria and PINK1 gene knockout models exhibit abnormal mitochondrial function. The purpose of this study was to determine whether cells derived from PD patients with a range of PINK1 mutations demonstrate similar defects of mitochondrial function, whether the nature and severity of the abnormalities vary between mutations and correlate with clinical features. METHODOLOGY: We investigated mitochondrial bioenergetics in live fibroblasts from PINK1 mutation patients using single cell techniques. We found that fibroblasts from PINK1 mutation patients had significant defects of bioenergetics including reduced mitochondrial membrane potential, altered redox state, a respiratory deficiency that was determined by substrate availability, and enhanced sensitivity to calcium stimulation and associated mitochondrial permeability pore opening. There was an increase in the basal rate of free radical production in the mutant cells. The pattern and severity of abnormality varied between different mutations, and the less severe defects in these cells were associated with later age of onset of PD. CONCLUSIONS: The results provide insight into the molecular pathology of PINK1 mutations in PD and also confirm the critical role of substrate availability in determining the biochemical phenotype--thereby offering the potential for novel therapeutic strategies to circumvent these abnormalities.

The natural history of vitamin D deficiency in African refugees living in Sydney.

OBJECTIVE: To describe the natural history of vitamin D deficiency in an at-risk population of African migrants living in Sydney. DESIGN, SETTING AND PARTICIPANTS: Opportunistic study of 25-hydroxyvitamin D [25(OH)D] concentrations over time in a community-based cohort of North African refugee families living in south-western Sydney. As part of a health-screening program, serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, phosphate (PO(4)) and alkaline phosphatase (ALP) were measured in September 2006 (end of winter, T1). Results for 25(OH)D were made available, and treatment was recommended as appropriate. In February-March 2007 (end of summer, T2), in the setting of a separate study of high-dose vitamin D (stoss) therapy, the same cohort was contacted, and measurements were repeated. MAIN OUTCOME MEASURES: Changes in 25(OH)D, PTH, ALP and PO(4) concentrations between T1 and T2 in those who had not received vitamin D supplementation in the intervening period. RESULTS: We collected data from 149 participants at T1; by T2, 58 participants (39%) had been excluded or lost to follow-up. Data from 91 participants (46% female), all of whom had Type VI (very dark) skin pigmentation, were included in the analysis. All 91 were 25(OH)D deficient at T1. Between T1 and T2, mean 25(OH)D serum concentration increased from 19 nmol/L (SD, 5.6 nmol/L) to 36 nmol/L (SD, 12.4 nmol/L) (P < 0.001). Of the 91 participants, 79 (87%) remained vitamin D deficient at T2. Serum PTH and ALP activity decreased between T1 and T2 (P < 0.05). CONCLUSION: Despite a significant increase in 25(OH)D serum concentration over the study period, most participants (87%) remained 25(OH)D deficient at the end of summer. Our results support the current consensus that recommends annual screening for vitamin D deficiency and routine vitamin D supplementation in at-risk populations, such as dark-skinned or veiled groups.

Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts.

OBJECTIVE: There are marked mitochondrial abnormalities in parkin-knock-out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in parkin-mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin-mutant human tissue. METHODS: We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous parkin mutations. RESULTS: Parkin-mutant cells had lower mitochondrial complex I activity and complex I-linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of parkin in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential. INTERPRETATION: Our study demonstrates marked abnormalities of mitochondrial function and morphology in parkin-mutant patients and provides proof-of-principle data for the potential usefulness of this new model system as a tool to screen for disease-modifying compounds in genetically homogenous parkinsonian disorders.

Establishment of a surveillance system (utilising Midwifes Data Collection Systems) for monitoring the impact of hepatitis B vaccination on the population prevalence of chronic hepatitis B virus infection in Australia.

OBJECTIVE: To examine how routine hepatitis B surface antigen (HBsAg) testing of antenatal women (as identified on the NT Midwifes Data Collection System) can be used to track the impact of hepatitis B (HBV) vaccination on the prevalence of chronic HBV infection in the Northern Territory (NT). METHODS: Women who gave birth between 01 July 2002 and 30 June 2004 were identified from the NT Midwives Data Collection System (MDCS). For each woman, the unique hospital record number (HRN) was linked to the information system of the NT Government pathology service to obtain the results of serological tests for hepatitis B. The prevalence of HBsAg was calculated by age, Indigenous status, and maternal country of birth. RESULTS: During the study period, 1061 records of women from the NT MDCS could be linked to HBsAg results. Overall, 33 (3.1%) were positive for HBsAg, of whom 29 were recorded as Indigenous and the remaining four were born outside Australia. CONCLUSIONS: Linking data from the NT MDCS and HBsAg results from government pathology service is a feasible means to monitor the impact of HBV vaccination policy. IMPLICATIONS: Routine inclusion of HBsAg results in all state and territory midwives data collections should be pursued.

Vaccination for the paediatrician.

In most of Australia, general practitioners manage routine childhood vaccination schedules. However, paediatricians have an important role and need to have a thorough understanding of vaccination, particularly as it interfaces with other medical care. This is challenging as the Australian Standard Vaccination Schedule has undergone some substantial changes over the past 4 years, with the addition of meningococcal C conjugate, 7 valent pneumococcal conjugate, varicella and inactivated polio vaccines. Paediatricians are frequently the first port of call for advice on vaccination schedules for children with special needs, in relation to either vaccine efficacy or the risk of side effects. Categories include children with a range of chronic diseases, immunosuppression, premature infants and immigrant children. Advice about specific vaccines such as varicella, inactivated polio, influenza or multivalent vaccines and revaccination after adverse events is also often sought. The aim of this article is to update paediatricians on vaccination recommendations and relevant reference sources. The first part of this article discusses groups with special vaccination requirements. The second part discusses the use of individual vaccines in these children.

Interspecies variation in yolk selenium concentrations among eggs of free-living birds: The effect of phylogeny.

Birds deposit the trace element selenium (Se) into their eggs because an adequate supply of this micronutrient is essential for embryonic development. Although there is considerable interest in egg Se with regard to topics as diverse as poultry nutrition and environmental pollution, data on the natural levels of Se in eggs of free-living avian species are currently very limited. To address this lack of information, we measured the yolk Se concentrations in eggs of 14 avian species collected in the wild. The concentrations (ng/g wet yolk) varied from 394 to 2238, with a mean value of 1040. Values (means+/-SD) for eggs from the UK, Canada and New Zealand were, respectively, 522+/-192 (3 species), 1194+/-584 (8 species) and 1147+/-200 (3 species). However, analysis by appropriate statistical models indicates that the effect of phylogenetic relatedness among these species is so significant that it removes any effect of geographical location. In particular, species belonging to the order Passeriformes displayed significantly higher yolk Se levels than Non-Passeriforme species. In marked contrast to the free-living species, our previously published data indicate that the Se concentration in egg yolk of the domestic chicken is only about 100 ng/g wet yolk when the birds are maintained on a basal commercial diet without supplementary Se. The results reveal an extensive interspecies variation in yolk Se (across a 6-fold range) for eggs collected from the wild. Nevertheless, the Se concentrations in the yolks of all the free-living species were far higher (4-21-fold) than that achieved in the yolk of the domestic chicken consuming a standard basal diet.