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BackgroundNumerous studies in veterinary species have recently linked vitamin D status with non-skeletal health disorders. Previous studies have indicated that dogs cannot produce endogenous vitamin D via cutaneous production and rely solely on dietary intake of vitamin D. The seasonal variation of vitamin D seen in humans due to changes in UV exposure therefore is unlikely to be replicated in these animals.ObjectivesThe objective of this study was to investigate the natural variation in 25-hydroxyvitamin-D concentration in dogs subject to seasonal UV exposure.MethodsThis longitudinal study followed 18 healthy dogs fed a standardized diet over one year, with blood samples obtained monthly. Two key vitamin D metabolites, 25-hydroxyvitamin-D2 and 25-hydroxyvitamin-D3, were assessed by liquid chromatography tandem mass spectrometry in serum samples. Various other biochemical parameters were also measured. Seasonality was assessed using Cosinor statistical analysis.ResultsAlthough the dogs were subject to seasonally varying UV radiation, 25-hydroxyvitamin-D and related biomarkers (including calcium and parathyroid hormone) remained stable over time and did not follow a seasonal pattern. 25-hydroxyvitamin-D was not positively correlated to exposure to UV radiation. Nonetheless, variation in 25-hydroxyvitamin-D concentration between individual dogs was detected.ConclusionsGiven the standardization of diet, we concluded that the seasonal stability of 25-hydroxyvitamin-D concentration (vitamin D status) was likely a direct result of lack of cutaneous vitamin D production in this species and highlights the importance of dietary intake. The variation in 25-hydroxyvitamin-D concentration between animals warrants further investigatio

In view of the challenges of the current coronavirus (COVID-19) pandemic and to protect both patients and ultrasound providers (physicians, sonographers, allied professionals), ISUOG has compiled the following expert-opinion-based guidance for the performance of ultrasound investigations in pregnancy and for gynecological indications.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

INTRODUCTION: The availability of obstetric point‐of‐care ultrasound (PoCUS) services has been shown to improve pregnancy outcomes in regional and remote areas both in Australia and around the world. There is an increasing demand for efficient, cost‐effective PoCUS courses for monitoring the fetus in the third trimester of pregnancy. AIM: To compare the effectiveness of targeted PoCUS courses provided for health professionals that assess the fetus during the third trimester of pregnancy. METHOD: The skill‐teaching curriculum and competency outcomes of six obstetric PoCUS courses were compared. There were 55 learners with no prior ultrasound experience including 23 with English as a second language. Course duration ranged from 4 to 18 h, didactic lecture time up to 6 h and practical scanning sessions of 3–12 h. Learner/tutor ratio varied from 1:1 to 6:1. All courses included the teaching of knobology, image optimisation and probe manipulation. Practical sessions included supervised scanning of ultrasound phantoms and scanning women in the third trimester of pregnancy. The teaching outcomes that were assessed included image optimisation, determination of fetal lie, fetal heart rate, measuring the single deepest pocket of amniotic fluid, identifying the placental position and basic fetal biometry. The same pre‐ and post‐course multiple choice test and course evaluation forms were used for every programme. RESULTS: All participants achieved the limited course objectives, regardless of the differences in the course formats. CONCLUSION: This study confirms that obstetric PoCUS courses can provide the initial basic knowledge and scanning skills required to perform limited scope third‐trimester scanning.

Although the prevalence of incidental findings revealed during an obstetric ultrasound examination is low, the findings may include adnexal and cervical masses, uterine or urinary congenital malformations, free fluid in the pouch of Douglas or tortuous vessels (varices). Adnexal masses are the most common finding and vary in imaging characteristics. They are mainly unilateral, cystic masses with a low risk of malignancy that are treated conservatively. The International Ovarian Tumor Analysis scoring models may be helpful in differentiating benign from malignant masses. For those masses >5 cm, follow-up is recommended, and resection could be considered to avoid risk of torsion, rupture and hemorrhage, which may compromise pregnancy outcome. Uterine masses such as fibroids are commonly diagnosed early in the first trimester and should be followed up during pregnancy to evaluate any changes. Transabdominal and transvaginal ultrasound is the first-line test for the diagnosis of such incidentalomas; however, magnetic resonance ultrasound may have a useful role in excluding malignancy potential. As a result of their low frequency and the lack of good evidence, there are no specific guidelines on the management of incidentalomas detected at obstetric scans. Their management should follow the related general guidelines for ovarian, cervical and uterine masses, with individualized management depending on the pregnancy status.

The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.

Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma‐related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient‐derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons., The effect of pediatric glioma cells on the function of surrounding neurons during early development is unknown. We intrancranially injected patient‐derived pediatric glioma cells in young pups and examined on the function of peritumoral neurons. Pediatric glioma cells induced changes in the intrinsic properties of periturmoral neurons, lowered the threshold of hyperexcitability and exhibited an early onset of depolarization block.

Mini abstractWe tested usability, safety, and ability to manage elective surgery flow of a multidisciplinary pathway adopting the SWALIS-2020 model in an interhospital setting during the COVID-19 pandemic. This pilot included 295 adults. The pathway prioritized, monitored and scheduled surgery in an 840.000-inhabitants area. Using the COVID-19-GOA-Sur-MDT-SWALIS-2020 model may be warranted.Structured abstractThe COVID-19 outbreak burdens non-COVID elective surgery patients with figures similar to the SARS-Cov-2, by creating an overwhelming demand, increasing waiting times and costs. New tools are urgently needed to manage elective access. The study assesses the “SWALIS-2020” model’s ability to prioritize and optimize access to surgery during the pandemic.A 2020 March - May feasibility-pilot study, tested a software-aided, inter-hospital, multidisciplinary pathway. All specialties patients in the Genoa Departments referred for urgent elective surgery were included in a multidisciplinary pathway adopting a modified Surgical Waiting List InfoSystem (SWALIS) cumulative prioritization method (PAT-2020) based on waiting time and clinical urgency, in three subcategories: A1-15 days (certain rapid disease progression), A2-21 days (probable progression), and A3-30 days (potential progression).Following the feasibility study (N=55 patients), 240 referrals were evaluated in 4 weeks without major criticalities (M/F=73/167, Age=68.7±14.0). Waiting lists were prioritized and monitored, and theatres allocated based on demand. The SWALIS-2020 score (% of waited-against-maximum time) at operation was 88.7±45.2 at week 1 and then persistently over 100% (efficiency), over a controlled variation (equity), with a difference between A3 (153.29±103.52) vs. A1 (97.24 ± 107.93) (p The pathway has selected the very few patients with the greatest need, optimizing access even with +30% capacity weekly modifications. We will use the pathway to manage active, backlog, and hidden waiting lists throughout the further pandemic phases, and are looking for collaboration for multi-center research.https://www.isrctn.com/ISRCTN11384058.

Background Rett syndrome (RTT) is an X-linked neurodevelopmental disorder predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity. Although the gut microbiome has been previously characterized in humans with RTT, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated.Methods We evaluated the microbial community through 16S sequencing of fecal samples collected across postnatal development as behavioral symptoms appear and progress in a novel zinc-finger nuclease rat model of RTT. Additionally, we profiled fecal levels of fatty acids in MecP2 deficient rats. Lastly, we compared our results to predicted functional shifts in the microbiota of females with RTT compared to their mothers to further examine the translational potential of the current RTT rat model.Results We have identified microbial taxa that are differentially abundant across key timepoints in a zinc-finger nuclease rat model of RTT compared to WT. Furthermore, we have characterized functional categories of gut microbes that are similarly affected in females with RTT and female RTT rats, including similar alterations in pathways related to short chain fatty acid (SCFA) activity. Lastly, we have demonstrated that SCFA levels are decreased in the feces of RTT rats compared to WT.Limitations The current study is potentially limited by age related differences in the microbiome of RTT participants and controls as well as medication effects on the microbiome. Additionally, the current study did not assess male MeCP2-deficient rats, and it may be relevant in future studies to address potentially disparate microbial changes in male and female rats and humans with RTT.Conclusions The results of our studies establish distinct microbial community shifts that occur in RTT across developmental time points independently of diet or environmental factors. We identify p105 as a key translational timepoint at which microbial shifts most closely mirror reported microbiota communities in RTT patients. Overall, these results represent an important step in translational RTT research.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.

Introduction/Aims Australasia is witnessing a rapidly increasing use of diagnostic medical ultrasound in clinical practice with industry statistics giving a conservative estimate of ten million scans performed annually in Australia and New Zealand. Ultrasound practice has broadened from its traditional use in radiology, obstetrics and gynaecology, vascular and cardiology specialties to embrace emergency medicine, rheumatology, midwifery, physiotherapy, paramedics and other point of care practice. With this expansion of practice comes an increase in the potential risk for ultrasound transmitted bacterial or viral infection due to suboptimal cleaning habits of transducers, cords and keyboards. Results/Conclusion This study describes results of an Australasian survey on the disinfection and hygiene practice in medical ultrasound. Results highlighted a significant need for updated guidelines and education on infection prevention and control in medical ultrasound.

Background: Chronic Enteropathies (CE) are a common cause of morbidity in dogs. Chronic enteropathies are diagnosed in dogs with chronic gastrointestinal clinical signs (>3 weeks), inflammatory changes on intestinal biopsies and where no other underlying cause is determined based on a thorough, standardised diagnostic workup. Based on response to therapy, CE are sub-classified into food-responsive, antibiotic-responsive or steroid-responsive enteropathies. A significant proportion of dogs with a CE are food-responsive; however, there are limited peer-reviewed publications describing the clinical efficacy of the commercially available diets used to treat CE. Methods: In this study, we evaluated the response of 15 dogs with a CE to a commercially available dietetic food (Hill’s TM Prescription Diet TM i/d TM Sensitive Canine Dry). The dogs underwent a standard diagnostic evaluation, and did not receive concurrent anthelmintic, antibiotic, glucocorticoid or gastroprotectant therapies. The clinical efficacy of the dietary treatment was assessed by comparing the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) before and a median of 13 days after dietary therapy. Results: We found that the CIBDAI significantly decreased following the introduction of the dietetic food (median CIBDAI score pre treatment 9, post treatment 2 (p

Objective: Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)–approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc‐ (SXC) and decrease tumor‐associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs. Methods: Using in vitro cortical mouse brain slices, whole‐cell patch‐clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4‐aminopyridine (4‐AP) and magnesium‐free (Mg2+‐free) solution to determine the effect of SAS on epileptiform events. In addition, voltagesensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs. Results: SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg2+‐free–induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4‐AP–induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4‐AP. Co‐application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals. Significance: Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4‐AP–induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy. Foundation for the National Institutes of Health, Grant/Award Number: 5R01‐NS036692, R01‐NS052634 and R01CA227149

Idiopathic retinal detachment is a serious common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. Genetic correlations between retinal detachment and high myopia or cataract operation were high, respectively 0.46 (SE=0.08) and 0.44 (SE=0.07), in the UK Biobank dataset and in line with known epidemiological associations. Meta-analysis of genome-wide association studies using UK Biobank retinal detachment cases (N=3977) and two cohorts, each comprising ∼1000 rhegmatogenous retinal detachment patients, uncovered 11 genome-wide significant association signals, near or withinZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1andLOXL1.Replication in the 23andMe dataset, where retinal detachment is self-reported by participants, firmly establishes association at six lociFAT3, COL22A1, TYR, BMP3, ZC3H11BandPLCE1.The former two seem to particularly impact on retinal detachment, the latter three shed light on shared aetiologies with cataract, myopia and glaucoma.Author SummaryRetinal detachments are common conditions that may lead to permanent severe sight reduction or blindness; they are a major cause of emergency eye surgery. The most common type of retinal detachment follows a break in the retina and is thought to be in part genetically determined but little is known about the contributing individual genetic risk variants. The condition prevalence increases with age and with common eye conditions such as myopia, cataract or glaucoma. We showed that the retinal detachment cases derived from self-report or hospitalisation records in the large UK Biobank dataset show very similar characteristics to samples of carefully clinically evaluated retinal detachment with break cases and therefore could be used to perform genetic analysis of the condition. Association studies require large sample of cases and by pooling Biobank and clinical cases, this study identifies 11 novel significant associations, six of which were further replicated in an independent population-based dataset (23andMe). Two of the replicated findings seem to specifically underline retinal detachment risk while three others highlight shared genetic risk with myopia, cataract and/or glaucoma, paving the way to better understanding of these conditions and of their overlap.

Hypovitaminosis D and hypervitaminosis D are well recognised disorders in dogs. Hypovitaminosis D can occur following consumption of a diet inadequately supplemented with vitamin D or as a sequelae of severe intestinal disease. Hypervitaminosis D may occur as a result of consuming proprietary dog foods over-supplemented with vitamin D or through ingestion of vitamin D containing medicinal products or rodenticides. Consequently, there is a clear need to establish a methodology that can accurately quantify vitamin D metabolites across a broad dynamic range in dogs. The existence of C3-epimers of vitamin D metabolites has yet to be elucidated in dogs, yet are known to interfere with the analysis of vitamin D and have unknown biological activity in other species. Here, we describe the development and validation of a sensitive, specific and robust analytical liquid chromatography tandem mass spectrometry (LC–MS/MS) assay capable of separating and accurately measuring 25-hydroxyvitamin-D2/3 (25(OH)D2/3) and 3-epi-25-hydroxyvitamin-D2/3 (3-epi-25(OH)D2/3). We describe a simplified workflow utilising supported liquid extraction (SLE) without derivatization that provides good linearity (mean r > 0.996) and accuracy across a broad dynamic range of 4–500 nmol/L for D3 metabolites and 7.8–500 nmol/L for D2 metabolites. Upon application of this assay to 117 canine serum samples, 25(OH)D3 was detectable in all samples with a median concentration of 82.1 nmol/L (inter-quartile range (IQR) 59.7–101.8 nmol/L). 3-epi-25(OH)D3 could be detected in 87.2 % of the study population, with a median concentration of 5.2 nmol/L (2.4–8.1 nmol/L). However, 3-epi-25(OH)D3 was quantified below the LLOQ in 40.2 % of these samples. 3-epi-25(OH)D3 contributed on average 6.3 % to 25(OH)D3 status (contribution ranges from 0 to 23.8%) and a positive correlation was detected between 25(OH)D3 and 3-epi-25(OH)D3 concentrations. Free 25(OH)D was also measured using an immunoassay with a median concentration of 15.2 pmol/L (12.5–23.2 pmol/L), and this metabolite was also positively correlated to both 3-epi-25(OH)D3 and 25(OH)D3 concentrations. D2 metabolites were not detected in canine serum as expected. Vitamin D metabolite concentrations were variable between individuals, and research into the causes of this variation should include factors such as breed, age, sex and neuter status to determine the impact of genetic and hormonal factors. Given the clinical importance of vitamin D in dogs, and the immense potential for utilising this species as a model for human disease, further elucidation of the vitamin D pathway in this species would provide immense clinical and research benefit.

Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits., Brain tumours are associated with epilepsy. Here the authors show, using a mouse model, that the degradation of perineuronal nets around fast spiking interneurons near the tumour contribute to seizures by increasing their membrane capacitance and firing.

Fetal measurements have been a contentious issue in ultrasound departments worldwide for decades. With a plethora of literature on measuring planes, mathematical formulae, local charts, and differences in fetal size due to various factors, deciding which charts to use can be confusing. Australia has not been immune to this issue. In 2001, ASUM recommended the use of the Campbell Westerway charts for CRL, BPD, OFD, HC, AC, FL & HL, which were formulated from an Australian population. Despite this recommendation, there are currently at least eight fetal growth charts in clinical use around Australia. 1 Unfortunately, it is not uncommon to find different charts on different machines within the same department, which is confusing for follow‐up growth studies, and affects parents, clinicians and researchers alike. For example, a baby diagnosed as small for gestational age (SGA) by one practitioner is later that day found to be ‘normal’ with a different reference chart at the referral hospital. This makes counselling challenging: why does this difference exist? Is it due to the chart or the quality of scanning? Is the baby at risk or not? The issue illustrates the problem of a lack of uniform ultrasound reporting, which may be particularly noticeable in countries like Australia where scans are commonly performed in small private practices. In general terms, fetal growth can be assessed using charts that are: 1 Derived from the observed distributions of fetal size for gestational age in a defined population 2 Customised on the basis of maternal characteristics such as maternal parity, height and ethnicity including an estimate of fetal weight based on Hadlock's proportionality equation 3 Standards derived from a healthy population purposely selected to reflect optimal growth, based on observed measurements of fetuses that are free from adverse constraints on growth and which are independent of time or place. SGA is most commonly defined as the 10th centile of estimated fetal weight (EFW) or abdominal circumference (AC). It must be realised that the apparent ‘prevalence’ of SGA will always be close to the 10th centile when reference or customised charts are used. This is despite the fact that the prevalence of other perinatal conditions differs greatly around the world: for example, differences in rates of pre‐eclampsia or gestational diabetes are readily accepted, without a call for local definitions, demonstrating the illogical nature of insisting on an SGA prevalence that is “fixed” at 10%. So which fetal biometry charts should be used from the hundreds available around the world? After over five decades of obstetric ultrasound there has been no implementation of an international standard. Contrast this with the consensus on optimal growth in paediatrics. Since the 1970s, it has been observed that growth in children depends more on their environment and nutritional state, than ethnic origin. 2 In 1996, the WHO Multicentre Growth Reference Study (MGRS) was established to prove whether this hypothesis was indeed correct for babies born in diverse populations around the world. Across six countries, researchers followed the growth and development of 8406 healthy, breast‐fed babies until 5 years of age. 3 They demonstrated that, under such conditions, growth was remarkably similar in childhood. 4 This led to the release of the WHO Child Growth Standards in 2006 and these have subsequently been adopted in over 130 countries. 5 In Australia, national unification of child growth monitoring occurred in 2012, when the NHMRC recommended the WHO Child Growth Standards for use in all infants aged 0 to 2 years of age. 6 The current situation in fetal medicine Identifying babies experiencing poor or excessive growth in utero is challenging. Despite ASUM recommending the Campbell Westerway charts in 2000,7 there has been no consensus on fetal growth monitoring, no publication of an ‘Australian standard’, and consequently several charts have been used. For most practitioners, the choice of fetal growth chart is determined either by their institutional protocol, professional society, imaging software program, or the default chart installed by the ultrasound machine manufacturer. However, charts differ greatly not only in the centile thresholds and trajectories, but also the quality of the studies upon which they were based: two comprehensive systematic reviews evaluated the quality of published ultrasound charts for fetal dating with crown‐rump length 8 and fetal growth monitoring. 9 Across the 112 studies identified, there were several important potential sources of methodological bias including: failure to define gestational age accurately; inconsistent population definitions and inclusion and exclusion criteria; lack of image standardisation protocols, and retrospective analysis of images captured for clinical purposes. This resulted in a large amount of variation in centile thresholds when different charts were used: for example, the 10th centile for AC at 36 weeks' gestation ranged from 276 to 292 mm even among the best studies. Open in a separate window Figure 1 Abdominal circumference.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values

The elimination of this virus worldwide is a long way off and it is important for healthcare professionals to understand the symptoms. Susan Campbell outlines what to look for and the changes in UK legislation concerning pet quarantine A zoonotic disease, rabies is an encephalitis caused by the rabies virus. It is estimated that there are about 55,000 cases of rabies each year worldwide, almost all in developing countries (Health Protection Agency 2012). Rabies has the highest death rate of any type of viral infection, yet is almost 100 per cent preventable (Briggs 2010, NHS Choices 2011). This article explains recent changes in UK quarantine laws and discusses whether we are any closer to the eradication of rabies.

SUMMARY Purpose: Patients with gliomas frequently present with seizures, but the factors associated with seizure development are still poorly understood. In this study, we assessed peritumoral synaptic network activity in a glioma animal model and tested the contribution of aberrant glutamate release from gliomas on glioma-associated epileptic network activity. Methods: In vitro brain slices were made from gliomaimplanted mice. Using extracellular field recordings, we analyzed peritumoral epileptiform activity induced by Mg 2+ -free medium in slices from tumor-bearing animals and sham-operated controls. We assessed the effect of sulfasalazine (SAS), a blocker of system x c and glutamate release, on spontaneous and evoked activity in tumorassociated slices. Key Findings: Tumor-associated cortical networks were hyperexcitable. The onset latency of Mg 2+ -free‐induced epileptiform activity was significantly shorter in tumorbearing slices, and the incidence of Mg 2+ -free‐induced ictal-like events was higher. Block of glutamate release from system x c decreased the response area of evoked activity and completely blocked Mg 2+ -free‐induced ictallike, but not interictal-like events. Significance: Control of seizures in patients with gliomas is an essential component of clinical management; therefore, understanding the origin of seizures is vital. This work provides evidence that peritumoral synaptic network activity is disrupted by tumor masses resulting in network excitability. We show that blocking glutamate release via system x c with SAS, a drug already approved by the U.S. Food and Drug Administration (FDA), can inhibit Mg 2+ -free‐induced ictal-like epileptiform events similar to other chemicals used to decrease seizure activity. We, therefore, suggest that further studies should consider SAS a promising agent to aid in the treatment of seizures associated with gliomas.

Epileptic seizures are a common and poorly understood comorbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted human-derived glioma cells into severe combined immunodeficient mice. Within 14-18 d, glioma-bearing mice developed spontaneous and recurring abnormal electroencephalogram events consistent with progressive epileptic activity. Acute brain slices from these mice showed marked glutamate release from the tumor mediated by the system x(c)(-) cystine-glutamate transporter (encoded by Slc7a11). Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain tissue. We inhibited glutamate release from the tumor and the ensuing hyperexcitability by sulfasalazine (SAS), a US Food and Drug Administration-approved drug that blocks system x(c)(-). We found that acute administration of SAS at concentrations equivalent to those used to treat Crohn's disease in humans reduced epileptic event frequency in tumor-bearing mice compared with untreated controls. SAS should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans.

Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate −4.56 years; 95% CI −8.13, −1.00; p = 0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I 2 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.

Of all the insect-borne diseases, malaria is the most serious public health problem, even though deaths from malaria are generally preventable. Eradication was tried in the 1950s and 60s but was abandoned to a strategy of control. However, recent developments indicate that eradication could be reconsidered, given enough time and money. The three elements of control are case management of patients with malaria, prevention of infection through vector control and prevention of disease by administration of antimalarial drugs to particularly vulnerable population groups (Centers for Disease Control and Prevention (CDC) 2006).

An influenza pandemic can have many negative effects on a society, and nurses are at the frontline of treatment. This article explains how to prepare for a pandemic and discusses the implications for healthcare staff when it occurs.

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.

Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl−gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.

Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21–28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model. National Institute of Mental Health NIMH: R01 NS075062 NIMH: NS090041 NIMH:P30-NS047466

to examine the relationship between seven predictor variables (recorded on Day 3 of hospital admission) and discharge destination in non-elective medical patients aged 65+ years.prospective cohort.eight centres in six European countries.age, gender, living alone, physical function (three categories based on Barthel Index), cognition (Katzman's orientation-memory-concentration test), main body system affected (based on International Classification of Diseases), number of geriatric giants (GGs) involved in the referral (a GG being a problem with falling, mobility, continence or cognition).discharge destination (by Day 90) in three categories: 'HOMESAME' (return to previous residence), 'INSTIN90' (discharge to alternative residence or still in hospital at 90 days), 'DEADINHO' (death in hospital),in 1,626 patients, discharge destination was HOMESAME in 84.7%, DEADINHO in 8.9% and INSTIN90 in 6.4%. Mean duration of stay was 17.7 days, median 12. Univariate analyses showed a statistically significant relationship between all seven predictor variables and discharge destination. Physical function was the best single predictor with a seven-fold difference in adverse outcome rates between the best and worst categories. On multiple logistic regression, significant predictor variables were as follows. (i) For DEADINHO: physical function, cognition, gender; (ii) for INSTIN90: physical function, living alone, GGs, age, gender. Multiple linear regression identified physical function, GGs and living alone as predictors of loge length of stay.case-mix systems to compare risk-adjusted hospital outcome in older medical patients need to incorporate information about physical function, cognition and presenting problems in addition to diagnosis.

Objective: To compare rates of fetal macrosomia (birthweight >4000 g) and birth complications in both Chinese women immigrants and Caucasian women for two time periods: 1992 and 1999–2000. Population: Chinese women immigrants and Caucasian women attending the Royal North Shore Hospital and Hornsby Ku-Ring-Gai Hospital in Sydney's northern health region. Methods: Data used were extracted from the Northern Suburbs Area Health Service OBSTET database. Significance of trends were assessed using χ2 test. Results: The results show a rise in macrosomic babies born to Chinese immigrants from 4% of total Chinese births in 1992 to 9.8% in 1999–2000 (P = 0.02).There was no significant difference in the rate of macrosomia among Caucasian women with respective rates of 11 and 14% for the same periods. The incidence of post-partum haemorrhage increased significantly in both Chinese immigrants and Caucasian women (P

We conducted a survey of children with autism/pervasive developmental disorder who entered public school education settings following intensive behavioral treatment in a private center-based program. The survey included 27 children that had been discharged from the center to public schools over a nine-year period. Based on parent report, the survey revealed that 92.5% of children were attending public schools and that 96.0% of them were participating in inclusive education (instruction with typically developing peers). Children who were involved in inclusive classrooms required the support of an individual instructor from 0-100% of the time. The amount of time spent in inclusive education and the percent of individual support was unrelated to the years since discharge from the center-based program. Parents were uniformly satisfied with the services their children were receiving in the public schools independent of inclusion status or the provision of individual support. These findings illustrate ...

Although assessment is a critical component in the education and treatment of persons who have autism, there is insufficient information about the types of assessment instruments that are used routinely by practitioners. This brief report describes a survey of national service centers to determine their use of standardized instruments and the purposes of their assessment practices. Data from centers representing 30 states revealed that (a) the number of assessment instruments endorsed by centers increased as centers adopted a "multidisciplinary" approach to education and treatment, (b) the largest proportion of instruments fell within intellectual, motor, and language/communication domains, and (c) instruments were used most frequently for diagnostic and curriculum design purposes. Agreement among practitioners on the selection of instruments occurred most frequently in the domains of projective, adaptive behavior, and family assessment. The implications from these findings for assessment practices in autism are discussed.

Objective. The effectiveness of activities to promote routine prophylaxis to prevent thromboembolism is difficult to assess because information about the prevalence of prophylaxis is sparse. The aim of this study was to assess the prevalence of deep vein thrombosis (DVT) prophylaxis for patients at risk in general medicine, general surgery, orthopaedics and gynaecology in Scotland and the North of England. Design. Retrospective case note review of a random sample of episodes of care in a stratified random sample of directorates in Scotland and a convenience sample in England. Setting. Twenty acute hospital directorates in Scotland and eight in the North of England. Participants. Case notes of patients at risk of thrombosis and discharged from the selected directorates in a 12-month period (n=742). Main outcome measures. The proportion of patients receiving prophylaxis in each directorate. Results. Overall, 469/526 (89%) of patients in Scotland and 199/216 (92%) in England received prophylaxis.The proportion varied from 71% in general medicine to 100% in orthopaedics. The frequency of use of different forms of prophylaxis varied between directorates. Approximately 60% of the patients who received prophylaxis received more than one form. Conclusions. Prophylaxis for DVT is well established for procedures and conditions that are known to increase the risk of thrombosis and for which there are no contraindications. Additional efforts to promote prophylaxis for these conditions are unlikely to be cost effective. Further research is needed to establish whether rates are equally high in other conditions, and whether the high prophylaxis rates are due to clinical effectiveness initiatives.

Children with autism have complex learning and behavioural challenges which typically require comprehensive educational and therapeutic services. In recent years there have been many developments in the philosophy, methodology, and scope of intervention for this population. Factors such as early intervention, criterion‐referenced assessment, the combination of applied behaviour analysis and developmentally appropriate practices (DAP), parent training, and public school inclusive education have been noteworthy. This article describes a comprehensive continuum of services model for children with autism developed by a human services agency in Massachusetts which incorporates these and additional empirically‐based approaches. Service components, methodologies, and program objectives are described including representative summary data. The article concludes with a discussion of educational, therapeutic, and research issues which address “best practice” approaches toward children with autism.

Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.

Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Background. Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). Methods. Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. Results. Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 6 0.06 mg/dL and fractional excretion of UA was 89–150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. Conclusions. This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

Most chronic pain patients are treated in primary care and their management is often challenging. Secondary care- or private sector-based Pain Management Programmes (PMPs) offering intensive multidisciplinary approaches have been found to improve participants' physical performance and psychological well-being.We aimed to identify the components and perceived outcomes of multidisciplinary PMPs in the UK and to explore expert health care providers' opinions about important characteristics of an ideal yet practical PMP for delivery in primary care.All PMPs in the UK (n = 77), identified through the British Pain Society, were invited to participate. Each PMP was sent a postal questionnaire. We then conducted a modified Delphi survey with 18 pain management experts from a range of professional backgrounds.A representative from 54 (response rate 70.1%) PMPs completed a questionnaire. Most PMPs were delivered in National Health Service outpatient secondary care by physiotherapists (98%), psychologists (94%), pain specialists (61%), nurses (54%) and occupational therapists (52%). There was evidence of reasonably prolonged follow-up of participants and use of a range of clinical outcome measures. Consensus was reached on most components and outcomes of a potential primary care-based PMP. 'Necessary' components included training in, and information about, self-management, general fitness, posture and mobility. Input from a physiotherapist and clinical or health psychologist was identified as key to the PMP. Preferred patient outcome measures were related to emotional well-being, self-efficacy and coping and quality of life.Future research should look to design, deliver and evaluate a primary care-based intervention based on these findings.

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea 60 ml/min/1.73 m 2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P 5 × 10 8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. © 2010 Nature America, Inc. All rights reserved.

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 ± 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

DYT1 dystonia is caused by a trinucleotide deletion of GAG (DeltaGAG) in DYT1, which codes for torsinA. A previous epidemiologic study suggested an association of DYT1 DeltaGAG mutation with early-onset recurrent major depression. However, another study reported no significant association with depression, but instead showed an association with anxiety and dystonia. In this study, we analyzed these related behaviors in Dyt1 DeltaGAG heterozygous knock-in mice. The knock-in mice showed a subtle anxiety-like behavior but did not show depression-like behaviors. The mutant mice also displayed normal sensorimotor gating function in a prepulse inhibition test. While normal hippocampus-dependent contextual fear memory and hippocampal CA1 long-term potentiation (LTP) were observed, the knock-in mice exhibited an enhancement in the formation of cued fear memories. Anatomical analysis indicated that the number of c-fos positive cells was significantly increased while the size of the central nucleus of the amygdala (CE) was significantly reduced in the knock-in mice. These results suggest that the Dyt1 DeltaGAG mutation increased the activity of the CE and enhanced the acquisition of the cued fear memory.

While working in a rural hospital in The Gambia, I realized that some of my colleagues viewed traditional healers with some degree of scepticism. Some felt that it led to a delay in patients seeking treatment and, at times, could lead to death from herbal intoxication. However, despite the unscientific, and at times harmful, treatments it remains a popular choice of health care that is culturally acceptable and readily available in the rural communities. So important are culture and ethnicity to health outcomes that, even if structural constraints are removed in the health sector, desired results are unlikely to be achieved unless the cultures of communities are taken into consideration by health policymakers and planners and providers of health care. Indeed, increased attention to these issues by policymakers increases the chances of success in implementing policy. If this is done, providers will be less likely to display an ambivalence towards the use of traditional medicine and users will be less likely to vacillate between modern and traditional medicine (World Bank 1995). With an increase in chronic diseases (and new diseases such as AIDS) with no known cure, it seems that this valuable resource should be tapped safely and more effectively, with support and supervision, to improve the chances of health for all by the year 2000.

The ACMEplus project aims to devise a standardised system for measuring case-mix and outcome in older patients admitted to hospitals in different parts of Europe for primarily 'medical' (i.e. not surgical or psychiatric) reasons. As a first step in this project, a systematic review was carried out to identify factors which had a significant influence on outcome in such patients.The systematic search used Medline 1966-2000, Cinahl 1982-2000, Web of Science 1981-2000, reference lists of relevant papers and a hand search of Age and Ageing 1974-2000. A six-category grading system was devised to classify the 313 identified papers with regard to their relevance to the ACMEplus project, study design and power. The analysis of the 14 'category 1' papers is presented.The main areas of assessment of case-mix were function, cognition, depression, illness severity, nutrition, social elements, aspects of diagnosis and demographic details. Statistically significant predictors, for the four outcome measures, listed below were: For length of stay: functional status score, illness severity, cognitive score, poor nutrition, comorbidity score, diagnosis or presenting illness, polypharmacy, age and gender. For mortality: functional status score, illness severity, cognitive score, comorbidity score, diagnosis or presenting illness, polypharmacy, age and gender. For discharge destination: functional status score, cognitive score, diagnosis or presenting illness and age. For readmission rate: functional status score, illness severity, co-morbidity, polypharmacy, diagnosis or presenting illness and age.Factors affecting outcome in older medical patients are complex. When looking at outcomes of hospital admission in older people it is important not just to look at routinely available statistics such as age, gender and diagnosis but also to take into account multifaceted aspects such as functional status and cognitive function.

DYT1 early-onset generalized torsion dystonia (DYT1 dystonia) is an inherited movement disorder caused by mutations in one allele of DYT1 (TOR1A), coding for torsinA. The most common mutation is a trinucleotide deletion (DGAG), which causes a deletion of a glutamic acid residue (DE) in the C-terminal region of torsinA. Although recent studies using cultured cells suggest that torsinA contributes to protein processing in the secretory pathway, endocytosis, and the stability of synaptic proteins, the nature of how this mutation affects synaptic transmission remains unclear. We previously reported that thetaburst- induced long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not altered in Dyt1 DGAG heterozygous knock-in (KI) mice. Here, we examined short-term synaptic plasticity and synaptic transmission in the hippocampal slices. Field recordings in the hippocampal Schaffer collaterals (SC) pathway revealed significantly enhanced paired pulse ratios (PPRs) in Dyt1 DGAG heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell recordings from the CA1 neurons showed that Dyt1 DGAG heterozygous KI mice exhibited normal miniature excitatory post-synaptic currents (mEPSC), suggesting that action-potential independent spontaneous pre-synaptic release was normal. On the other hand, there was a significant decrease in the frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents (sEPSC) in Dyt1 DGAG heterozygous KI mice, suggesting that the action-potential dependent pre-synaptic release was impaired. Moreover, hippocampal torsinA was significantly reduced in Dyt1 DGAG heterozygous KI mice. Although the hippocampal slice model may not represent the neurons directly associated with dystonic symptoms, impaired release of neurotransmitters caused by partial dysfunction of torsinA in other brain regions may contribute to the pathophysiology of DYT1 dystonia. This work was supported by Tyler’s Hope for a Dystonia Cure, Inc., National Institutes of Health grants (NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72872, and NS 74423), Howard Hughes Med-Grad Graduate Fellowship (CCC), and startup funds from the Lucille P. Markey Charitable Trust (UIUC) and Department of Neurology (UAB). Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Objectives: There is no consensus on the best approach to cervical surveillance during pregnancy: should all women have a transvaginal (TV) scan or can this be restricted to women with a short cervix on initial transabdominal (TA) assessment? This study compares TA and TV assessment of cervical length at 16–41 weeks gestation. Methods: TA and TV ultrasound measurements of cervical length were made at 16–41 weeks gestation. Cervical length was measured from internal to external os using the landmarks described by the FMF. Bland-Altman plots and paired t-tests were used to look at differences in TA and TV measurement. The screening efficacy of initial TA assessment in defining a group for TV evaluation is also reported. Results: 367 women participated including 273, 84 and 10 presenting at 16–23, 24–35 and >36 weeks respectively. Overall, the TA method underestimated cervical length by 2.5 mm (95% CI 1.7–3.4 mm). Bland Altman plots showed an inverse trend with shorter cervixes after 24 weeks. 17 women had a cervix 36 weeks. The sensitivity and specificity of TA assessment of cervical length at 24–36 weeks gestation were 1/10 (0.10) and 70/74 (0.95) respectively; positive and negative predictive values were 1/5 (0.20) and 70/79 (0.89). At >36 weeks the sensitivity was 0/6 (0.0) and the specificity was 2/4 (0.5). Conclusions: TA measurements do not reflect TV assessment accurately, particularly if the cervix is short ( 24 weeks gestation. There is no value in TA assessment of the cervix >36 weeks.