What aspects of autism predispose to talent?

In this paper, we explore the question, why are striking special skills so much more common in autism spectrum conditions (ASC) than in other groups? Current cognitive accounts of ASC are briefly reviewed in relation to special skills. Difficulties in ‘theory of mind’ may contribute to originality in ASC, since individuals who do not automatically ‘read other minds’ may be better able to think outside prevailing fashions and popular theories. However, originality alone does not confer talent. Executive dysfunction has been suggested as the ‘releasing’ mechanism for special skills in ASC, but other groups with executive difficulties do not show raised incidence of talents. Detail-focused processing bias (‘weak coherence’, ‘enhanced perceptual functioning’) appears to be the most promising predisposing characteristic, or ‘starting engine’, for talent development. In support of this notion, we summarize data from a population-based twin study in which parents reported on their 8-year-olds'' talents and their ASC-like traits. Across the whole sample, ASC-like traits, and specifically ‘restricted and repetitive behaviours and interests’ related to detail focus, were more pronounced in children reported to have talents outstripping older children. We suggest that detail-focused cognitive style predisposes to talent in savant domains in, and beyond, autism spectrum disorders.     

Cognition in Males and Females with Autism: Similarities and Differences

The male bias in autism spectrum conditions (ASC) has led to females with ASC being under-researched. This lack of attention to females could hide variability due to sex that may explain some of the heterogeneity within ASC. In this study we investigate four key cognitive domains (mentalizing and emotion perception, executive function, perceptual attention to detail, and motor function) in ASC, to test for similarities and differences between males and females with and without ASC (n = 128 adults; n = 32 per group). In the mentalizing and facial emotion perception domain, males and females with ASC showed similar deficits compared to neurotypical controls. However, in attention to detail and dexterity involving executive function, although males with ASC showed poorer performance relative to neurotypical males, females with ASC performed comparably to neurotypical females. We conclude that performance in the social-cognitive domain is equally impaired in male and female adults with ASC. However, in specific non-social cognitive domains, performance within ASC depends on sex. This suggests that in specific domains, cognitive profiles in ASC are modulated by sex.     

Social cognitive impairment and autism: what are we trying to explain?

Early psychological theories of autism explained the clinical features of this condition in terms of perceptual and sensory processing impairments. The arrival of domain-specific social cognitive theories changed this focus, postulating a ‘primary’ and specific psychological impairment of social cognition. Across the years, evidence has been growing in support of social cognitive and social attention explanations in autism. However, there has also been evidence for general non-social cognitive impairments in representational understanding, attention allocation and sensory processing. Here, I review recent findings and consider the case for the specificity and primacy of the social cognitive impairment, proposing that we should focus more explicitly on clinically valid features for insights on the integration of ‘social’ and ‘non-social’ cognition.     

Can emotion recognition be taught to children with autism spectrum conditions?

Children with autism spectrum conditions (ASC) have major difficulties in recognizing and responding to emotional and mental states in others'' facial expressions. Such difficulties in empathy underlie their social-communication difficulties that form a core of the diagnosis. In this paper we ask whether aspects of empathy can be taught to young children with ASC. We review a study that evaluated The Transporters, an animated series designed to enhance emotion comprehension in children with ASC. Children with ASC (4–7 years old) watched The Transporters every day for four weeks. Participants were tested before and after intervention on emotional vocabulary and emotion recognition at three levels of generalization. The intervention group improved significantly more than a clinical control group on all task levels, performing comparably to typical controls at time 2. The discussion centres on how vehicles as mechanical systems may be one key reason why The Transporters caused the improved understanding and recognition of emotions in children with ASC. The implications for the design of autism-friendly interventions are also explored.     

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males.     

Why Are Autism Spectrum Conditions More Prevalent in Males?

Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC.     

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects

Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark''s roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean ± 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691–4090 g; length, 52.8–54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891–3290 g; 49.7–51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.     

Sensory Regulation of Neuroligins and Neurexin I in the Honeybee Brain

Background

Neurexins and neuroligins, which have recently been associated with neurological disorders such as autism in humans, are highly conserved adhesive proteins found on synaptic membranes of neurons. These binding partners produce a trans-synaptic bridge that facilitates maturation and specification of synapses. It is believed that there exists an optimal spatio-temporal code of neurexin and neuroligin interactions that guide synapse formation in the postnatal developing brain. Therefore, we investigated whether neuroligins and neurexin are differentially regulated by sensory input using a behavioural model system with an advanced capacity for sensory processing, learning and memory, the honeybee.

Methodology/Principal Findings

Whole brain expression levels of neuroligin 1–5 (NLG1–5) and neurexin I (NrxI) were estimated by qRT-PCR analysis in three different behavioural paradigms: sensory deprivation, associative scent learning, and lateralised sensory input. Sensory deprived bees had a lower level of NLG1 expression, but a generally increased level of NLG2–5 and NrxI expression compared to hive bees. Bees that had undergone associative scent training had significantly increased levels of NrxI, NLG1 and NLG3 expression compared to untrained control bees. Bees that had lateralised sensory input after antennal amputation showed a specific increase in NLG1 expression compared to control bees, which only happened over time.

Conclusions/Significance

Our results suggest that (1) there is a lack of synaptic pruning during sensory deprivation; (2) NLG1 expression increases with sensory stimulation; (3) concomitant changes in gene expression suggests NrxI interacts with all neuroligins; (4) there is evidence for synaptic compensation after lateralised injury.     

Hypoxia Enhances Proliferation of Human Adipose-Derived Stem Cells via HIF-1ɑ Activation

BackgroundAdipose tissue-derived stem cells (ASCs) have been recently isolated from human subcutaneous adipose tissue. ASCs may be useful in regenerative medicine as an alternative to bone marrow-derived stem cells. Changes in the oxygen concentration influence physiological activities, such as stem cell proliferation. However, the effects of the oxygen concentration on ASCs remain unclear. In the present study, the effects of hypoxia on ASC proliferation were examined.MethodsNormal human adipose tissue was collected from the lower abdomen, and ASCs were prepared with collagenase treatment. The ASCs were cultured in hypoxic (1%) or normoxic (20%) conditions. Cell proliferation was investigated in the presence or absence of inhibitors of various potentially important kinases. Hypoxia inducible factor (HIF)-1α expression and MAP kinase phosphorylation in the hypoxic culture were determined with western blotting. In addition, the mRNA expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 in hypoxic or normoxic conditions were determined with real-time RT-PCR. The effects of these growth factors on ASC proliferation were investigated. Chromatin immunoprecipitation (ChIP) of the HIF–1α-binding hypoxia responsive element in FGF–2 was performed. HIF–1α was knocked down by siRNA, and FGF–2 expression was investigated.ResultsASC proliferation was significantly enhanced in the hypoxic culture and was inhibited by ERK and Akt inhibitors. Hypoxia for 5–15 minutes stimulated the phosphorylation of ERK1/2 among MAP kinases and induced HIF–1α expression. The levels of VEGF and FGF–2 mRNA and protein in the ASCs were significantly enhanced in hypoxia, and FGF–2 increased ASC proliferation. The ChIP assay revealed an 8-fold increase in the binding of HIF–1α to FGF–2 in hypoxia. HIF–1α knockdown by siRNA partially inhibited the FGF–2 expression of ASCs induced by hypoxia.ConclusionASC proliferation was enhanced by hypoxia. HIF–1α activation, FGF–2 production, and the ERK1/2 and Akt pathway were involved in this regulatory mechanism.     

Medical Team Evaluation: Effect on Emergency Department Waiting Time and Length of Stay

Emergency Departments (ED) are trying to alleviate crowding using various interventions. We assessed the effect of an alternative model of care, the Medical Team Evaluation (MTE) concept, encompassing team triage, quick registration, redesign of triage rooms and electronic medical records (EMR) on door-to-doctor (waiting) time and ED length of stay (LOS). We conducted an observational, before-and-after study at an urban academic tertiary care centre. On July 17^th 2014, MTE was initiated from 9:00 a.m. to 10 p.m., 7 days a week. A registered triage nurse was teamed with an additional senior ED physician. Data of the 5-month pre-MTE and the 5-month MTE period were analysed. A matched comparison of waiting times and ED LOS of discharged and admitted patients pertaining to various Emergency Severity Index (ESI) triage categories was performed based on propensity scores. With MTE, the median waiting times improved from 41.2 (24.8–66.6) to 10.2 (5.7–18.1) minutes (min; P < 0.01). Though being beneficial for all strata, the improvement was somewhat greater for discharged, than for admitted patients. With a reduction from 54.3 (34.2–84.7) to 10.5 (5.9–18.4) min (P < 0.01), in terms of waiting times, MTE was most advantageous for ESI4 patients. The overall median ED LOS increased for about 15 min (P < 0.01), increasing from 3.4 (2.1–5.3) to 3.7 (2.3–5.6) hours. A significant increase was observed for all the strata, except for ESI5 patients. Their median ED LOS dropped by 73% from 1.2 (0.8–1.8) to 0.3 (0.2–0.5) hours (P < 0.01). In the same period the total orders for diagnostic radiology increased by 1,178 (11%) from 10,924 to 12,102 orders, with more imaging tests being ordered for ESI 2, 3 and 4 patients. Despite improved waiting times a decrease of ED LOS was only seen in ESI level 5 patients, whereas in all the other strata ED LOS increased. We speculate that this was brought about by the tendency of triage physicians to order more diagnostic radiology, anticipating that it may be better for the downstream physician to have more information rather than less.     

The central inflammasome adaptor protein ASC activates the inflammasome after transition from a soluble to an insoluble state

Apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) is a 22 kDa protein that functions as the central adaptor for inflammasome assembly. ASC forms insoluble specks in monocytes undergoing pyroptosis, and the polymerization of ASC provides a template of CARDs that leads to proximity-mediated autoactivation of caspase-1 in canonical inflammasomes. However, specks are insoluble protein complexes, and solubility is typically important for protein function. Therefore, we sought to define whether ASC specks comprise active inflammasome complexes or are simply the end stage of exhausted ASC polymers. Using a THP-1 cell–lysing model of caspase-1 activation that is ASC dependent, we compared caspase-1 activation induced by preassembled insoluble ASC specks and soluble monomeric forms of ASC. Unexpectedly, after controlling for the concentration dependence of ASC oligomerization, we found that only insoluble forms of ASC promoted caspase-1 autocatalysis. This link to insolubility was recapitulated with recombinant ASC. We show that purified recombinant ASC spontaneously precipitated and was functional, whereas the maltose-binding protein–ASC fusion to ASC (promoting enhanced solubility) was inactive until induced to insolubility by binding to amylose beads. This functional link to insolubility also held true for the Y146A mutation of the CARD of ASC, which avoids insolubility and caspase-1 activation. Thus, we conclude that the role of ASC insolubility in inflammasome function is inextricably linked to its pyrin domain–mediated and CARD-mediated polymerizations. These findings will support future studies into the molecular mechanisms controlling ASC solubility.     

Effect of Roux-en-Y Gastric Bypass on the NLRP3 Inflammasome in Adipose Tissue from Obese Rats

Objective

Obesity is associated with low-grade chronic inflammation. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery would reduce activation of the NLRP3 inflammasome in metabolically active adipose tissue (AT) of obese rats, and this change would be related to decreases in body weight and improved glycemic control.

Methods

Omental, mesenteric and subcutaneous fat depots were collected from Sprague-Dawley rats: Sham control and RYGB; 90-days after surgery. NLRP3, caspase–1, apoptosis-associated speck-like protein (ASC), IL–1β, IL–18, IL–6 and MCP–1 gene and protein expression were quantified. Glucose metabolism was assessed by oral glucose tolerance test (OGTT).

Results

Compared to Sham surgery controls, RYGB surgery decreased IL–6, MCP–1, NLRP3, IL–18, caspase–1 and ASC in omental fat, and decreased IL–6, MCP1, IL–1β, IL–18, caspase–1 and ASC gene expression in mesenteric fat. We observed differential gene expression between visceral and subcutaneous fat for IL–6 and IL–1β, both being downregulated by RYGB in visceral, and upregulated in subcutaneous depots. These changes in gene expression were accompanied by a decrease in NLRP3, ASC, IL–18, caspase–1 and IL–1β protein expression in omental tissue. We found a positive correlation between caspase–1, ASC, MCP–1, IL–18 and IL–6 gene expression following surgery and glucose AUC response in omental fat, while the change in glucose AUC response correlated with caspase–1 gene expression in subcutaneous fat.

Conclusion

This study demonstrates that bariatric surgery reverses inflammation in visceral adipose tissue by suppressing NLRP3 inflammasome activation. These are the first data to implicate the NLRP3 inflammasome in diabetes remission after RYGB surgery.     

The Effect of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) on Erectile Function: A Systematic Review and Meta-Analysis

Background

High prevalence of erectile dysfunction (ED) has been observed in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, whether or not CP/CPPS is a risk factor of ED remains unknown and controversial. Therefore, we conducted this systematic review and meta-analysis to evaluate the relationship between CP/CPPS and ED.

Methods

PubMed, Embase, Web of Science, and The Cochrane Library were searched up to November 11, 2014 to identify studies reporting the association between CP/CPPS and ED. Case–control, cohort and cross-sectional studies were included. Quality of the included studies was assessed. The odds ratio of ED and the mean difference of five-item International Index of Erectile Function (IIEF-5) score were pooled using a random effects model. Subgroup analysis and sensitivity analyses were performed.

Results

Three cross-sectional studies, two case–control studies, and four retrospective studies with 31,956 participants were included to calculate the pooled odds ratio of ED, and two studies with 1499 participants were included to calculate the pooled mean difference of IIEF-5 scores. A strong correlation was found between CP/CPPS and ED (pooled odds ratio: 3.02, 95% CI: 2.18–4.17, P < 0.01), with heterogeneity across studies (I ² = 65%; P < 0.01). A significant decrease in the IIFE-5 score was observed in the CP/CPPS group (pooled mean difference: −4.54, 95% CI: −5.11–−3.98; P < 0.01).

Conclusion

Our study indicates that patients with CP/CPPS have an increased risk of suffering from ED. Assessment of erectile function is necessary for the therapy of patients with CP/CPPS. Further evidence is necessary to confirm the relationship between CP/CPPS and ED.     

A Keller-Segel model for C elegans L1 aggregation

We describe a mathematical model for the aggregation of starved first-stage C elegans larvae (L1s). We propose that starved L1s produce and respond chemotactically to two labile diffusible chemical signals, a short-range attractant and a longer range repellent. This model takes the mathematical form of three coupled partial differential equations, one that describes the movement of the worms and one for each of the chemical signals. Numerical solution of these equations produced a pattern of aggregates that resembled that of worm aggregates observed in experiments. We also describe the identification of a sensory receptor gene, srh–2, whose expression is induced under conditions that promote L1 aggregation. Worms whose srh–2 gene has been knocked out form irregularly shaped aggregates. Our model suggests this phenotype may be explained by the mutant worms slowing their movement more quickly than the wild type.     

UVA Light-excited Kynurenines Oxidize Ascorbate and Modify Lens Proteins through the Formation of Advanced Glycation End Products: IMPLICATIONS FOR HUMAN LENS AGING AND CATARACT FORMATION*

Advanced glycation end products (AGEs) contribute to lens protein pigmentation and cross-linking during aging and cataract formation. In vitro experiments have shown that ascorbate (ASC) oxidation products can form AGEs in proteins. However, the mechanisms of ASC oxidation and AGE formation in the human lens are poorly understood. Kynurenines are tryptophan oxidation products produced from the indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway and are present in the human lens. This study investigated the ability of UVA light-excited kynurenines to photooxidize ASC and to form AGEs in lens proteins. UVA light-excited kynurenines in both free and protein-bound forms rapidly oxidized ASC, and such oxidation occurred even in the absence of oxygen. High levels of GSH inhibited but did not completely block ASC oxidation. Upon UVA irradiation, pigmented proteins from human cataractous lenses also oxidized ASC. When exposed to UVA light (320–400 nm, 100 milliwatts/cm², 45 min to 2 h), young human lenses (20–36 years), which contain high levels of free kynurenines, lost a significant portion of their ASC content and accumulated AGEs. A similar formation of AGEs was observed in UVA-irradiated lenses from human IDO/human sodium-dependent vitamin C transporter-2 mice, which contain high levels of kynurenines and ASC. Our data suggest that kynurenine-mediated ASC oxidation followed by AGE formation may be an important mechanism for lens aging and the development of senile cataracts in humans.     

Atypical Mismatch Negativity in Response to Emotional Voices in People with Autism Spectrum Conditions

Autism Spectrum Conditions (ASC) are characterized by heterogeneous impairments of social reciprocity and sensory processing. Voices, similar to faces, convey socially relevant information. Whether voice processing is selectively impaired remains undetermined. This study involved recording mismatch negativity (MMN) while presenting emotionally spoken syllables dada and acoustically matched nonvocal sounds to 20 subjects with ASC and 20 healthy matched controls. The people with ASC exhibited no MMN response to emotional syllables and reduced MMN to nonvocal sounds, indicating general impairments of affective voice and acoustic discrimination. Weaker angry MMN amplitudes were associated with more autistic traits. Receiver operator characteristic analysis revealed that angry MMN amplitudes yielded a value of 0.88 (p<.001). The results suggest that people with ASC may process emotional voices in an atypical fashion already at the automatic stage. This processing abnormality can facilitate diagnosing ASC and enable social deficits in people with ASC to be predicted.