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Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.
A considerable body of evidence suggests that early caregiving may affect the short-term functioning and longer term development of the hypothalamic–pituitary–adrenocortical axis. Despite this, most research to date has been cross-sectional in nature or restricted to relatively short-term longitudinal follow-ups. More important, there is a paucity of research on the role of caregiving in low- and middle-income countries, where the protective effects of high-quality care in buffering the child's developing stress regulation systems may be crucial. In this paper, we report findings from a longitudinal study (N = 232) conducted in an impoverished periurban settlement in Cape Town, South Africa. We measured caregiving sensitivity and security of attachment in infancy and followed children up at age 13 years, when we conducted assessments of hypothalamus–pituitary–adrenocortical axis reactivity, as indexed by salivary cortisol during the Trier Social Stress Test. The findings indicated that insecure attachment was predictive of reduced cortisol responses to social stress, particularly in boys, and that attachment status moderated the impact of contextual adversity on stress responses: secure children in highly adverse circumstances did not show the blunted cortisol response shown by their insecure counterparts. Some evidence was found that sensitivity of care in infancy was also associated with cortisol reactivity, but in this case, insensitivity was associated with heightened cortisol reactivity, and only for girls. The discussion focuses on the potentially important role of caregiving in the long-term calibration of the stress system and the need to better understand the social and biological mechanisms shaping the stress response across development in low- and middle-income countries.
The alternate Mediterranean diet (aMED) score is an adaptation of the original Mediterranean diet score. Raw (aMED) and energy-standardised (aMED-e) versions have been used. How the diet scores and their association with health outcomes differ between the two versions is unclear. We examined differences in participants’ total and component scores and compared the association of aMED and aMED-e with all-cause, CVD and cancer mortality. As part of the Multiethnic Cohort, 193 527 men and women aged 45–75 years from Hawaii and Los Angeles completed a baseline FFQ and were followed up for 13–18 years. The association of aMED and aMED-e with mortality was examined using Cox’s regression, with adjustment for total energy intake. The correlation between aMED and aMED-e total scores was lower among people with higher BMI. Participants who were older, leaner, more educated and consumed less energy scored higher on aMED-e components compared with aMED, except for the red and processed meat and alcohol components. Men reporting more physical activity scored lower on most aMED-e components compared with aMED, whereas the opposite was observed for the meat component. Higher scores of both aMED and aMED-e were associated with lower risk of all-cause, CVD and cancer mortality. Although individuals may score differently with aMED and aMED-e, both scores show similar reductions in mortality risk for persons scoring high on the index scale. Either version can be used in studies of diet and mortality. Comparisons can be performed across studies using different versions of the score.
Consistently large differences occur in the calibrated 14C ages of stratigraphically associated shell and charcoal samples from Kilometer 4, an Archaic Period archaeological site located on the extreme south coast of Peru. A series of nine shell and charcoal samples were collected from a Late Archaic Period (~6000–4000 BP) sector of the site. After calibration, the intercepts of the charcoal dates were ~100–750 years older than the paired shell samples. Due to the hyper-arid conditions in this region that promote long-term preservation of organic material, we argue that the older charcoal dates are best explained by people using old wood for fuel during the Middle Holocene. Given this “old wood” problem, marine shell may actually be preferable to wood charcoal for dating archaeological sites in coastal desert environments as in southern Peru and Northern Chile.
We demonstrate variable radiocarbon content within 2 historic (AD 1936) and 2 prehistoric (about 8200 BP and 3500 BP) Mytilus californianus shells from the Santa Barbara Channel region, California, USA. Historic specimens from the mainland coast exhibit a greater range of intrashell variability (i.e. 180–240 14C yr) than archaeological specimens from Daisy Cave on San Miguel Island (i.e. 120 14C yr in both shells). δ13C and δ18O profiles are in general agreement with the up welling of deep ocean water depleted in 14C as a determinant of local marine reservoir correction (ΔR) in the San Miguel Island samples. Upwelling cycles are difficult to identify in the mainland specimens, where intrashell variations in 14C content may be a complex product of oceanic mixing and periodic seasonal inputs of 14C-depeleted terrestrial runoff. Though the mechanisms controlling ΔR at subannual to annual scales are not entirely clear, the fluctuations represent significant sources of random dating error in marine environments, particularly if a small section of shell is selected for accelerator mass spectrometry (AMS) dating. For maximum precision and accuracy in AMS dating of marine shells, we recommend that archaeologists, paleontologists, and 14C lab personnel average out these variations by sampling across multiple increments of growth.
Personalised nutrition (PN) has the potential to reduce disease risk and optimise health and performance. Although previous research has shown good acceptance of the concept of PN in the UK, preferences regarding the delivery of a PN service (e.g. online v. face-to-face) are not fully understood. It is anticipated that the presence of a free at point of delivery healthcare system, the National Health Service (NHS), in the UK may have an impact on end-user preferences for deliverances. To determine this, supplementary analysis of qualitative data obtained from focus group discussions on PN service delivery, collected as part of the Food4Me project in the UK and Ireland, was undertaken. Irish data provided comparative analysis of a healthcare system that is not provided free of charge at the point of delivery to the entire population. Analyses were conducted using the ‘framework approach’ described by Rabiee (Focus-group interview and data analysis. Proc Nutr Soc 63, 655-660). There was a preference for services to be led by the government and delivered face-to-face, which was perceived to increase trust and transparency, and add value. Both countries associated paying for nutritional advice with increased commitment and motivation to follow guidelines. Contrary to Ireland, however, and despite the perceived benefit of paying, UK discussants still expected PN services to be delivered free of charge by the NHS. Consideration of this unique challenge of free healthcare that is embedded in the NHS culture will be crucial when introducing PN to the UK.
To determine the prospective relationship between changes in sugar-sweetened beverage (SSB) intake and central adiposity in older children.
Dietary intakes of children were obtained by 3 d food records at ages 10 and 13 years. Waist circumference (WC) and weight and height to determine BMI were measured at 10 and 13 years and total body fat mass (TBFM) at 13 years by dual-energy X-ray absorptiometry. Analyses were conducted using multivariable linear regression. Reporting errors were measured and participants were categorized as under-, plausible and over-reporters of dietary intakes.
Community-based British cohort of children participating in the Avon Longitudinal Study of Parents and Children.
Among 2455 older children, increased SSB consumption from ages 10 to 13 years was associated with higher WC (standardized β=0·020, P=0·19), BMI (β=0·028, P=0·03) and TBFM (β=0·017, P=0·20) at 13 years. Effects were strengthened among plausible dietary reporters (n 1059): WC (β=0·097, P<0·001), BMI (β=0·074, P<0·001) and TBFM (β=0·065, P=0·003). The association between change in SSB and WC was weakened, but remained statistically significant after accounting for BMI (β=0·042, P=0·02) and TBFM (β=0·048, P=0·01).
Higher consumption of SSB from ages 10 to 13 years was associated with a larger WC at age 13 years independent of differences in total adiposity. Accounting for dietary reporting errors strengthened associations. Our findings further support recommendations to limit intakes of SSB to reduce excess weight gain in children and suggest that SSB have an additional deleterious effect on central adiposity.
Specific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound–protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.
The present study investigated whether whey (WH) protein, casein (CAS) protein or a carbohydrate placebo (PLA) consumed 30 min before sleep could acutely alter appetite or cardiometabolic risk the following morning. A total of forty-four sedentary overweight and obese women (BMI: 25·7–54·6 kg/m2) completed this stratified, randomised, double-blind, placebo-controlled study (WH: n 16, age 27·4 (sd 5·0) years; CAS: n 15, age 30·3 (sd 8·1) years; PLA: n 13, age 28·5 (sd 7·2) years). The participants came to the laboratory at baseline (visit 1) and again in the morning after night-time ingestion of either protein or PLA (visit 2). Visit 2 was conducted at least 48 h after visit 1. During visits 1 and 2, the following parameters were measured: appetite (hunger, satiety and desire to eat); resting metabolism; blood lipid and glucose levels; the levels of insulin, leptin, C-reactive protein, insulin-like growth factor-1, cortisol and adiponectin. Data were analysed using repeated-measures ANOVA. No group × time interactions were observed for the measured variables; however, a main effect of time was observed for increased satiety (P= 0·03), reduced desire to eat (P= 0·006), and increased insulin levels (P= 0·004) and homeostatic model assessment of insulin resistance values (P= 0·01) after the consumption of either protein or PLA. The results of the present study reveal that night-time consumption of protein or carbohydrate by sedentary overweight and obese women improves their appetite measures but negatively affects insulin levels. Long-term studies are needed to evaluate the effects of chronic consumption of low-energy snacks at night on body composition and cardiometabolic risk.
Significant new opportunities for astrophysics and cosmology have been identified at low radio frequencies. The Murchison Widefield Array is the first telescope in the southern hemisphere designed specifically to explore the low-frequency astronomical sky between 80 and 300 MHz with arcminute angular resolution and high survey efficiency. The telescope will enable new advances along four key science themes, including searching for redshifted 21-cm emission from the EoR in the early Universe; Galactic and extragalactic all-sky southern hemisphere surveys; time-domain astrophysics; and solar, heliospheric, and ionospheric science and space weather. The Murchison Widefield Array is located in Western Australia at the site of the planned Square Kilometre Array (SKA) low-band telescope and is the only low-frequency SKA precursor facility. In this paper, we review the performance properties of the Murchison Widefield Array and describe its primary scientific objectives.
Energy is essential for human development and energy systems are a crucial entry point for addressing the most pressing global challenges of the 21st century, including sustainable economic, and social development, poverty eradication, adequate food production and food security, health for all, climate protection, conservation of ecosystems, peace, and security. Yet, more than a decade into the 21st century, current energy systems do not meet these challenges.
In this context, two considerations are important. The first is the capacity and agility of the players within the energy system to seize opportunities in response to these challenges. The second is the response capacity of the energy system itself, as the investments are long-term and tend to follow standard financial patterns, mainly avoiding risks and price instabilities. This traditional approach does not embrace the transformation needed to respond properly to the economic, environmental, and social sustainability challenges of the 21st century.
A major transformation is required to address these challenges and to avoid potentially catastrophic consequences for human and planetary systems. The GEA identifies strategies that could help resolve the multiple challenges simultaneously and bring multiple benefits. Their successful implementation requires determined, sustained, and immediate action.
The industrial revolution catapulted humanity onto an explosive development path, whereby reliance on muscle power and traditional biomass was replaced mostly by fossil fuels. In 2005, approximately 78% of global energy was based on fossil energy sources that provided abundant and ever cheaper energy services to more than half the world's population.
Two longitudinal studies were used to examine the occurrence and consequences of peer deviancy training during childhood and the relative role of early covert antisocial behavior in risk for antisocial behavior in early adolescence. Peer deviancy training was apparent in a sample of at-risk first grade children, and it showed persistence and increased prevalence across the school year. Peer deviancy training, peer rejection, and unskilled parenting made additive contributions to the development of antisocial behavior during kindergarten and first grade and to antisocial behavior in fourth grade. Skilled parenting partially mitigated the association of peer deviancy training with antisocial behavior for boys. The appearance and growth of covert antisocial behavior was a predictor of fourth grade antisocial for boys and girls, more so than aggressive and overt antisocial behavior. Peer deviancy training and early covert antisocial behavior were key pathways to girls' antisocial behavior in fourth grade, and they complemented the roles of peer rejection and overt antisocial behavior for boys. The relationships of parenting and peer processes to trajectories of antisocial behavior were similar for boys and girls; but boys showed higher levels of antisocial behavior, were more involved in peer deviancy training, and were more likely to experience peer rejection.
Symptoms of obsessive–compulsive disorder (OCD) have been described in
neuropsychiatric syndromes associated with streptococcal infections. It
is proposed that antibodies raised against streptococcal proteins
cross-react with neuronal proteins (antigens) in the brain, particularly
in the basal ganglia, which is a brain region implicated in OCD
To test the hypothesis that post-streptococcal autoimmunity, directed
against neuronal antigens, may contribute to the pathogenesis of OCD in
Ninety-six participants with OCD were tested for the presence of
anti-streptolysin-O titres (ASOT) and the presence of anti-basal ganglia
antibodies (ABGA) in a cross-sectional study. The ABGA were tested for
with western blots using three recombinant antigens; aldolase C, enolase
and pyruvate kinase. The findings were compared with those in a control
group of individuals with depression (n = 33) and
schizophrenia (n = 17).
Positivity for ABGA was observed in 19/96 (19.8%) participants with OCD
compared with 2/50 (4%) of controls (Fisher's exact test
P = 0.012). The majority of positive OCD sera (13/19)
had antibodies against the enolase antigen. No clinical variables were
associated with ABGA positivity. Positivity for ASOT was not associated
with ABGA positivity nor found at an increased incidence in participants
with OCD compared with controls.
These findings support the hypothesis that central nervous system
autoimmunity may have an aetiological role in some adults with OCD.
Further study is required to examine whether the antibodies concerned are
pathogenic and whether exposure to streptococcal infection in vulnerable
individuals is a risk factor for the development of OCD.