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Background: Population-level administrative data provides a cost-effective means of monitoring health outcomes and service needs of clinical populations. This study aimed to present a method for case identification of non-traumatic brain injury in population-level data and to examine the association with sociodemographic factors. Methods: An estimated resident population of youth aged 0-24 years was constructed using population-level datasets within the New Zealand Integrated Data Infrastructure. A clinical consensus committee reviewed the International Classification of Diseases Ninth and Tenth Editions codes and Read codes for inclusion in a case definition. Cases were those with at least one non-traumatic brain injury code present in the five years up until 30 June 2018 in one of four databases in the Integrated Data Infrastructure. Rates of non-traumatic brain injury were examined, both including and excluding birth injury codes and across age, sex, ethnicity, and socioeconomic deprivation groups. Results: Of the 1 579 089 youth aged 0-24 years on 30 June 2018, 8154 (0.52%) were identified as having one of the brain injury codes in the five-years to 30 June 2018. Rates of non-traumatic brain injury were higher in males, children aged 0-4 years, Māori and Pacific young people, and youth living with high levels of social deprivation. Conclusion: This study presents a comprehensive method for case identification of non-traumatic brain injury using national population-level administrative data. [ABSTRACT FROM AUTHOR]

Background: Akt and mTOR are aberrantly activated in cancers and targeting these proteins are interesting for cancer drug discovery. Napabucasin (NB), a phytochemical compound, has been reported as potential anti-cancer agent, however, Akt and mTOR targeting mechanisms remain unclear. Method: Apoptosis induction was investigated by Hoechst 33342/PI double staining and annexin V/PI staining with flowcytometry. Autophagy was evaluated by monodansylcadaverine staining and Western blot analysis. Binding affinity of NB and essential signaling proteins (PI3K, Akt, and mTOR) was investigated using molecular docking and confirmed by Western blot analysis. Result: A structure modification from changing methyl moiety of acetyl group of NB to hydroxyl moiety of carboxyl group of NB derivative (napabucasin-acid or NB-acid) greatly affected the compound activities. NB showed more potent anti-cancer activity. NB reduced cell viability with an approximately 20 times lower IC50 and inhibited the colony formation capacity much more than NB-acid treated cells. NB induced cell apoptosis, which was accompanied by decrease Bcl‑2 and Mcl-1 and clevage of PARP, while NB-acid show lesser effect on Mcl-1. NB was found to strongly induce autophagy indicated by acidic vesicle staining and the LC3B conversion. Interestingly, computational molecular docking analysis further demonstrated that NB directly bound to Akt and mTOR (complex 1 and 2) proteins at their critical sites indicating that NB targets the upstream regulators of apoptosis and autophagy. The docking results were confirmed by decrease of p-Akt/Akt, p-mTOR/mTOR, and c-Myc a downstream target of Akt protein levels. Conclusion: Results show for the first time that NB exerts an anti-cancer activity through the direct interaction to Akt and mTOR proteins. The methyl moiety of acetyl group of NB is required for its potent anti-cancer activities. These data encourage further development of NB compounds for Akt and mTOR driven cancers. [ABSTRACT FROM AUTHOR]

Background: Approximately 70% of Alzheimer's disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3× more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD.Methods: Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet from 3 to 7 months of age. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain.Results: In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, AD/MxD females had more amyloid beta plaques and hippocampal levels of insoluble amyloid beta 40 and 42 than AD/MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis.Conclusions: High-fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women. [ABSTRACT FROM AUTHOR]

Background: Microglia are highly motile phagocytic cells in the healthy brain with surveillance and clearance functions. Although microglia have been shown to engulf cellular debris following brain insult, less is known about their phagocytic function in the absence of injury. Propofol can inhibit microglial activity, including phagocytosis. Milk fat globule epidermal growth factor 8 (MFG-E8), as a regulator of microglia, plays an essential role in the phagocytic process. However, whether MFG-E8 affects the alteration of phagocytosis by propofol remains unknown.Methods: Microglial BV2 cells were treated with propofol, with or without MFG-E8. Phagocytosis of latex beads was evaluated by flow cytometry and immunofluorescence. MFG-E8, p-AMPK, AMPK, p-Src, and Src levels were assessed by western blot analysis. Compound C (AMPK inhibitor) and dasatinib (Src inhibitor) were applied to determine the roles of AMPK and Src in microglial phagocytosis under propofol treatment.Results: The phagocytic ability of microglia was significantly decreased after propofol treatment for 4 h (P < 0.05). MFG-E8 production was inhibited by propofol in a concentration- and time-dependent manner (P < 0.05). Preadministration of MFG-E8 dose-dependently (from 10 to 100 ng/ml) reversed the suppression of phagocytosis by propofol (P < 0.05). Furthermore, the decline in p-AMPK and p-Src levels induced by propofol intervention was reversed by MFG-E8 activation (P < 0.05). Administration of compound C (AMPK inhibitor) and dasatinib (Src inhibitor) to microglia blocked the trend of enhanced phagocytosis induced by MFG-E8 (P < 0.05).Conclusions: These findings reveal the intermediate role of MFG-E8 between propofol and microglial phagocytic activity. Moreover, MFG-E8 may reverse the suppression of phagocytosis induced by propofol through the regulation of the AMPK and Src signaling pathways. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke poses a severe risk to human health worldwide, and currently, clinical therapies for the disease are limited. Delta opioid receptor (DOR)-mediated neuroprotective effects against ischemia have attracted increasing attention in recent years. Our previous studies revealed that DOR activation by [d-Ala2, d-Leu5] enkephalin (DADLE), a selective DOR agonist, can promote hippocampal neuronal survival on day 3 after ischemia. However, the specific molecular and cellular mechanisms underlying the DOR-induced improvements in ischemic neuronal survival remain unclear. Results: We first detected the cytoprotective effects of DADLE in an oxygen–glucose deprivation/reperfusion (OGD/R) model and observed increased viability of OGD/R SH-SY5Y neuronal cells. We also evaluated changes in the DOR level following ischemia/reperfusion (I/R) injury and DADLE treatment and found that DADLE increased DOR levels after ischemia in vivo and vitro. The effects of DOR activation on postischemic autophagy were then investigated, and the results of the animal experiment showed that DOR activation by DADLE enhanced autophagy after ischemia, as indicated by elevated LC3 II/I levels and reduced P62 levels. Furthermore, the DOR-mediated protective effects on ischemic CA1 neurons were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Moreover, the results of the cell experiments revealed that DOR activation not only augmented autophagy after OGD/R injury but also alleviated autophagic flux dysfunction. The molecular pathway underlying DOR-mediated autophagy under ischemic conditions was subsequently studied, and the in vivo and vitro data showed that DOR activation elevated autophagy postischemia by triggering the AMPK/mTOR/ULK1 signaling pathway, while the addition of the AMPK inhibitor compound C eliminated the protective effects of DOR against I/R injury. Conclusion: DADLE-evoked DOR activation enhanced neuronal autophagy through activating the AMPK/mTOR/ULK1 signaling pathway to improve neuronal survival and exert neuroprotective effects against ischemia. [ABSTRACT FROM AUTHOR]

Background: The amniotic fluid (AF) cell-free transcriptome is modulated by physiologic and pathologic processes during pregnancy. AF gene expression changes with advancing gestation reflect fetal development and organ maturation; yet, defining normal expression and splicing patterns for biomarker discovery in obstetrics requires larger heterogeneous cohorts, evaluation of potential confounding factors, and novel analytical approaches. Methods: Women with a normal pregnancy who had an AF sample collected during midtrimester (n = 30) or at term gestation (n = 68) were included. Expression profiling at exon level resolution was performed using Human Transcriptome Arrays. Differential expression was based on moderated t-test adjusted p < 0.05 and fold change > 1.25; for differential splicing, a splicing index > 2 and adjusted p < 0.05 were required. Functional profiling was used to interpret differentially expressed or spliced genes. The expression of tissue-specific and cell-type specific signatures defined by single-cell genomics was quantified and correlated with covariates. In-silico validation studies were performed using publicly available datasets. Results: 1) 64,071 genes were detected in AF, with 11% of the coding and 6% of the non-coding genes being differentially expressed between midtrimester and term gestation. Expression changes were highly correlated with those previously reported (R > 0.79, p < 0.001) and featured increased expression of genes specific to the trachea, salivary glands, and lung and decreased expression of genes specific to the cardiac myocytes, uterus, and fetal liver, among others. 2) Single-cell RNA-seq signatures of the cytotrophoblast, Hofbauer cells, erythrocytes, monocytes, T and B cells, among others, showed complex patterns of modulation with gestation (adjusted p < 0.05). 3) In 17% of the genes detected, we found differential splicing with advancing gestation in genes related to brain development processes and immunity pathways, including some that were missed based on differential expression analysis alone. Conclusions: This represents the largest AF transcriptomics study in normal pregnancy, reporting for the first time that single-cell genomic signatures can be tracked in the AF and display complex patterns of expression during gestation. We also demonstrate a role for alternative splicing in tissue-identity acquisition, organ development, and immune processes. The results herein may have implications for the development of fetal testing to assess placental function and fetal organ maturity. [ABSTRACT FROM AUTHOR]

Background: CAD-31 is an Alzheimer's disease (AD) drug candidate that was selected on the basis of its ability to stimulate the replication of human embryonic stem cell-derived neural precursor cells as well as in APPswe/PS1ΔE9 AD mice. To move CAD-31 toward the clinic, experiments were undertaken to determine its neuroprotective and pharmacological properties, as well as to assay its therapeutic efficacy in a rigorous mouse model of AD. Results: CAD-31 has potent neuroprotective properties in six distinct nerve cell assays that mimic toxicities observed in the old brain. Pharmacological and preliminary toxicological studies show that CAD-31 is brain-penetrant and likely safe. When fed to old, symptomatic APPswe/PS1ΔE9 AD mice starting at 10 months of age for 3 additional months in a therapeutic model of the disease, there was a reduction in the memory deficit and brain inflammation, as well as an increase in the expression of synaptic proteins. Small-molecule metabolic data from the brain and plasma showed that the major effect of CAD-31 is centered on fatty acid metabolism and inflammation. Pathway analysis of gene expression data showed that CAD-31 had major effects on synapse formation and AD energy metabolic pathways. Conclusions: All of the multiple physiological effects of CAD-31 were favorable in the context of preventing some of the toxic events in old age-associated neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: The standard of care for neovascular age-related macular degeneration (nAMD) involves ongoing intravitreal injections of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF). The most commonly used anti-VEGF drugs are ranibizumab, bevacizumab and aflibercept. The main objective of the STAR trial is to determine if stereotactic radiotherapy can reduce the number of anti-VEGF injections that patients with nAMD require. Methods/design: STAR is a multicentre, double-masked, randomised, sham-controlled clinical trial. It evaluates a new device (manufactured by Oraya, Newark, CA, USA) designed to deliver stereotactic radiotherapy (SRT) to nAMD lesions. The trial enrols participants with chronic, active nAMD. Participants receive a single SRT treatment (16 Gy or sham) with a concomitant baseline intravitreal injection of 0.5 mg ranibizumab. Thereafter, they attend every month for 24 months, and ranibizumab is administered at the visit if retreatment criteria are met. The primary outcome is the number of pro re nata ranibizumab injections during the first 24 months. Secondary outcomes include visual acuity, lesion morphology, quality of life and safety. Additional visits occur at 36 and 48 months to inspect for radiation retinopathy. The target sample size of 411 participants (randomised 2:1 in favour of radiation) is designed to detect a reduction of 2.5 injections against ranibizumab monotherapy, at 90% power, and a significance level (alpha) of 0.025 (onesided two-sample t test). This gives 97% power to detect non-inferiority of visual acuity at a five-letter margin. The primary analyses will be by intention to treat. Discussion: The safety and efficacy outcomes will help determine the role of SRT in the management of chronic, active nAMD. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors.Methods: To dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6 (lpr/lpr) mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment.Results: Despite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity.Conclusions: Chimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity. [ABSTRACT FROM AUTHOR]

Background: The case definition for traumatic brain injury (TBI) often includes ‘unspecified injury to the head' diagnostic codes. However, research has shown that the inclusion of these codes leads to false positives. As such, it is important to determine the degree to which inclusion of these codes affect the overall numbers and profiles of the TBI population. The objective of this paper was to profile and compare the demographic and clinical characteristics, intention and mechanism of injury, and discharge disposition of hospitalized children and youth aged 19 years and under using (1) an inclusive TBI case definition that included ‘unspecified injury to the head' diagnostic codes, (2) a restricted TBI case definition that excluded ‘unspecified injury to the head ‘diagnostic codes, and (3) the ‘unspecified injury to the head' only case definition. Methods: The National Ambulatory Care Reporting System and the Discharge Abstract Database from Ontario, Canada, were used to identify cases between fiscal years 2003/04 and 2009/10. Results: The rate of TBI episodes of care using the inclusive case definition for TBI (2,667.2 per 100,000) was 1.65 times higher than that of the restricted case definition (1,613.3 per 100,000). ‘Unspecified injury to the head' diagnostic codes made up of 39.5 % of all cases identified with the inclusive case definition. Exclusion of ‘unspecified injury to the head' diagnostic code in the TBI case definition resulted in a significantly higher proportion of patients in the intensive care units (p < .0001; 18.5 % vs. 22.2 %) and discharged to a non-home setting (p < .0001; 9.9 % vs. 11.6 %). Conclusion: Inclusion of ‘unspecified injury to the head' diagnostic codes resulted in significant changes in numbers, healthcare use, and causes of TBI. Careful consideration of the inclusion of ‘unspecified injury to the head' diagnostic codes in the case definition of TBI for the children and youth population is important, as it has implications for the numbers used for policy, resource allocation, prevention, and planning of healthcare services. This paper can inform future work on reaching consensus on the diagnostic codes for defining TBI in children and youth. [ABSTRACT FROM AUTHOR]

Introduction: Despite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the ADrelevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models. Methods: Four different groups of mice ranging across the lifespan of this model (test groups: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze). Results: There were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed. Conclusion: This is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required. Methods: To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1ΔE9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included. Results: Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory. Conclusion: J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies. [ABSTRACT FROM AUTHOR]

Background: In Germany, hospitals can deliver data from patients with pelvic fractures selectively or twofold to two different trauma registries, i.e. the German Pelvic Injury Register (PIR) and the TraumaRegister DGUW (TR). Both registers are anonymous and differ in composition and content. We describe the methodological approach of linking these registries and reidentifying twofold documented patients. The aim of the approach is to create an intersection set that benefit from complementary data of each registry, respectively. Furthermore, the concordance of data entry of some clinical variables entered in both registries was evaluated. Methods: PIR (4,323 patients) and TR (34,134 patients) data from 2004-2009 were linked together by using a specific match code including code of the trauma department, dates of admission and discharge, patient's age, and sex. Data entry concordance was evaluated using haemoglobin and blood pressure levels at emergency department arrival, Injury Severity Score (ISS), and mortality Results: Altogether, 420 patients were identified as documented in both data sets. Linkage rates for the intersection set were 15.7% for PIR and 44.4% for TR. Initial fluid management for different Tile/OTA types of pelvic ring fractures and the patient's posttraumatic course, including intensive care unit data, were now available for the PIR population. TR is benefiting from clinical use of the Tile/OTA classification and from correlation with the distinct entity "complex pelvic injury." Data entry verification showed high concordance for the ISS and mortality, whereas initial haemoglobin and blood pressure data showed significant differences, reflecting inconsistency at the data entry level. Conclusions: Individually, the PIR and the TR reflect a valid source for documenting injured patients, although the data reflect the emphasis of the particular registry. Linking the two registries enabled new insights into care of multiple-trauma patients with pelvic fractures even when linkage rates were poor. Future considerations and development of the registries should be done in close bilateral consultation with the aim of benefiting from complementary data and improving data concordance. It is also conceivable to integrate individual modules, e.g. a pelvic fracture module, into the TR likewise a modular system in the future. [ABSTRACT FROM AUTHOR]

Background: The aims of this retrospective analysis were to evaluate the effect of combined superficial and deep groin dissection on disease-free and melanoma-specific survival, and to identify the most important factors for predicting the involvement of deep nodes according to clinically or microscopically detected nodal metastases. Methods: Between January 1996 and December 2005, 133 consecutive patients with groin lymph node metastases underwent superficial and deep dissection at the National Cancer Institute, Naples. Lymph node involvement was clinically evident in 84 patients and detected by sentinel node biopsy in 49 cases. Results: The 5-year disease-free survival was significantly better for patients with superficial lymph node metastases than for patients with involvement of both superficial and deep lymph nodes (34.9% vs. 19.0%; P = 0.001). The 5-year melanoma-specific survival was also significantly better for patients with superficial node metastases only (55.6% vs. 33.3%; P = 0.001). Conclusions: Metastasis in the deep nodes is the strongest predictor of both disease-free and melanoma-specific survival. Deep groin dissection should be considered for all patients with groin clinical nodal involvement, but might be spared in patients with a positive sentinel node. Prospective studies will clarify the issue further. [ABSTRACT FROM AUTHOR]

The article examines the factors associated with discharge destination after acquired brain injury in a publicly insured population with the use of the Anderson Behavioral Model as a framework in Ontario, Canada. A retrospective cohort design has been utilized and multinomial logistic regression showed that need factors were strongly correlated with discharge destinations. It concludes that the results show that need factors are vital in terms of discharge destination.

Background: Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. Methods: In this study, we utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results (P <0.001) for expression quantitative trait loci present in the parietal lobe (GSE35977), cerebellum (GSE35974) and lymphoblastoid cell lines (GSE7761). We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome-wide association study. Results: Our findings show a global enrichment of brain expression quantitative trait loci, but not lymphoblastoid cell line expression quantitative trait loci, among top single nucleotide polymorphisms from an autism genome-wide association study. Additionally, the data implicates individual genes SLC25A12, PANX1 and PANX2 as well as pathways previously implicated in autism. Conclusions: These findings provide supportive rationale for the use of annotation-based approaches to genome-wide association studies. [ABSTRACT FROM AUTHOR]

Background: SLC25A12 was previously identified by a linkage-directed association analysis in autism. In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R). Methods: We used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). We examined associations in our University of Illinois at Chicago-University of Florida (UIC-UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families). Results: In the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025-0.040). The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202-rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset. Conclusions: This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD. Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 originates from the mother in more than 90% of cases, the incidence increases with maternal age and there is a high recurrence in young women. In a previous report we have presented data to indicate that maternal trisomy 21 (T21) ovarian mosaicism might provide the major causative factor underlying these patterns of DS inheritance. One important outstanding question concerns the reason why the extra chromosome 21 in DS rarely originates from the father, i.e. in less than 10% of T21 DS cases. We here report data indicating that one reason for this parental sex difference is a very much lower degree of fetal testicular in comparison to ovarian T21 mosaicism. Results: We used fluorescence in situ hybridisation (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in fetal testicular cell nuclei from four male fetuses, following termination of pregnancy for a non-medical/social reason at gestational age 14-19 weeks. The cells studied were selected on the basis of their morphology alone, pending immunological specification of the relevant cell types. We could not detect any indication of testicular T21 mosaicism in any of these four male fetuses, when analysing at least 2000 cells per case (range 2038-3971, total 11.842). This result is highly statistically significant (p < 0.001) in comparison to the average of 0.54% ovarian T21 mosaicism (range 0.20-0.88%) that we identified in eight female fetuses analysing a total of 12.634 cells, as documented in a previous report in this journal. Conclusion: Based on these observations we suggest that there is a significant sex difference in degrees of fetal germ line T21 mosaicism. Thus, it would appear that most female fetuses are T21 ovarian mosaics, while in sharp contrast most male fetuses may be either very low grade T21 testicular mosaics or they may be non-mosaics. We further propose that this sex difference in germ line T21 mosaicism may explain the much less frequent paternal origin of T21 DS than maternal. The mechanisms underlying the DS cases, where the extra chromosome 21 does originate from the father, remains unknown and further studies in this respect are required. [ABSTRACT FROM AUTHOR]

Background: Trisomy of chromosome 21 (T21; Down syndrome, DS) is the most common aneuploidy in live births. Though its etiology has been intensively studied for a half of century, there are surprisingly many problems awaiting their elucidation. Some of the open questions are related directly to germ line mosaicism for T21, other problems include the prevalence of males with non-mosaic trisomy over females (skewed sex ratio, SR), the genetic predisposition to non-disjunction, etc. Studies in families of gonadal mosaicism (GM) carriers might help resolving some of these problems. Results: 80 families of carriers of GM, in which the sex of the offspring had been specified, were identified in the literature and in logbooks of two local genetic units. Mothers in these families were relatively young: only 8% of mothers were 35 years old and older at the time of delivery of their first affected offspring while the proportion of grandmothers on the GM carrier's side aged 35 years old and older was significantly higher (39%). Postzygotic rescue of T21 due to error in the meiosis I had been proposed as a mechanism of parental GM formation in 78% of the families with known origin of the T21. For the other 22%, rescue of errors in the meiosis II or postzygotic mitotic non-disjunction was assumed. Mosaicism for T21 in successive generations was reported in at least 12 families. The proportion of mosaics among affected female offspring (14%) is significantly higher compared to that among affected male offspring (0%). Male preponderance (SR = 1.5) is found in non mosaic liveborn offspring with either maternally- or paternally transmitted T21. Among unaffected offspring of male carriers of GM there is a notable excess of females (SR = 0.27). Conclusion: Both direct (results of cytogenetic and molecular study of the origin of trisomic line) and indirect (advanced grandmaternal age on the side of GM carrier) evidences allow to assume that significant proportion of the mosaic parents had been conceived as trisomics. Female-specific trisomy rescue and genetic predisposition to postzygotic non-disjunction has been suggested as mechanisms of formation of both GM and somatic mosaicism. Typical male preponderance in affected non mosaic offspring with either maternally- or paternally transmitted trisomy 21, indicates than meiotic events are not responsible for the skewed sex ratio in DS. However a female excess among unaffected offspring of male carriers of GM might be the result of meiotic non homologous coorientation of chromosomes 21 and X in spermatogenesis. [ABSTRACT FROM AUTHOR]