1. Bartkowski JP, Kohler J, Escude CL, Xu X, Bartkowski S. {{Evaluating the Impact of a Clinician Improvement Program for Treating Patients with Intellectual and Developmental Disabilities: The Challenging Case of Mississippi}}. {Healthcare (Basel, Switzerland)}. 2018; 6(1).
In recent years, people with intellectual and developmental disabilities (IDD) have moved from institutionalized settings to local community residences. While deinstitutionalization has yielded quality of life improvements for people with IDD, this transition presents significant health-related challenges. Community clinicians have typically not been trained to provide sound medical care to people with IDD, a subpopulation that exhibits unique medical needs and significant health disparities. This study reports the results of a comprehensive evaluation of an IDD-focused clinician improvement program implemented throughout Mississippi. DETECT (Developmental Evaluation, Training and Consultative Team) was formed to equip Mississippi’s physicians and nurses to offer competent medical care to people with IDD living in community residences. Given the state’s pronounced health disparities and its clinician shortage, Mississippi offers a stringent test of program effectiveness. Results of objective survey indicators and subjective rating barometers administered before and after clinician educational seminars reveal robust statistically significant differences in clinician knowledge and self-assessed competence related to treating people with IDD. These results withstand controls for various confounding factors. Positive post-only results were also evident in a related program designed specifically for medical students. The study concludes by specifying a number of implications, including potential avenues for the wider dissemination of this program and promising directions for future research.
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2. Bassler D, Shinwell ES, Hallman M, Jarreau PH, Plavka R, Carnielli V, Meisner C, Engel C, Koch A, Kreutzer K, van den Anker JN, Schwab M, Halliday HL, Poets CF. {{Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia}}. {The New England journal of medicine}. 2018; 378(2): 148-57.
BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .). Lien vers le texte intégral (Open Access ou abonnement)
3. Cortes HD, Wevrick R. {{Genetic analysis of very obese children with autism spectrum disorder}}. {Molecular genetics and genomics : MGG}. 2018.
Autism spectrum disorder (ASD) is defined by the triad of deficits in social interactions, deficits in communication, and repetitive behaviors. Common co-morbidities in syndromic forms of ASD include intellectual disability, seizures, and obesity. We asked whether very obese children with ASD had different behavioral, physical and genetic characteristics compared to children with ASD who were not obese. We found that very obese children with ASD had significantly poorer scores on standardized behavioral tests. Very obese boys with ASD had lower full scale IQ and increased impairments with respect to stereotypies, communication and social skills. Very obese girls with ASD had increased impairments with respect to irritability and oppositional defiant behavior. We identified genetic lesions in a subset of the children with ASD and obesity and attempted to identify enriched biological pathways. Our study demonstrates the value of identifying co-morbidities in children with ASD as we move forward towards understanding the biological processes that contribute to this complex disorder and prepare to design customized treatments that target the diverse genetic lesions present in individuals with ASD.
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4. Forsberg SL, Ilieva M, Maria Michel T. {{Epigenetics and cerebral organoids: promising directions in autism spectrum disorders}}. {Translational psychiatry}. 2018; 8(1): 14.
Autism spectrum disorders (ASD) affect 1 in 68 children in the US according to the Centers for Disease Control and Prevention (CDC). It is characterized by impairments in social interactions and communication, restrictive and repetitive patterns of behaviors, and interests. Owing to disease complexity, only a limited number of treatment options are available mainly for children that alleviate but do not cure the debilitating symptoms. Studies confirm a genetic link, but environmental factors, such as medications, toxins, and maternal infection during pregnancy, as well as birth complications also play a role. Some studies indicate a set of candidate genes with different DNA methylation profiles in ASD compared to healthy individuals. Thus epigenetic alterations could help bridging the gene-environment gap in deciphering the underlying neurobiology of autism. However, epigenome-wide association studies (EWAS) have mainly included a very limited number of postmortem brain samples. Hence, cellular models mimicking brain development in vitro will be of great importance to study the critical epigenetic alterations and when they might happen. This review will give an overview of the state of the art concerning knowledge on epigenetic changes in autism and how new, cutting edge expertise based on three-dimensional (3D) stem cell technology models (brain organoids) can contribute in elucidating the multiple aspects of disease mechanisms.
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5. Hayek J, Cervellati C, Crivellari I, Pecorelli A, Valacchi G. {{Lactonase Activity and Lipoprotein-Phospholipase A2 as Possible Novel Serum Biomarkers for the Differential Diagnosis of Autism Spectrum Disorders and Rett Syndrome: Results from a Pilot Study}}. {Oxidative medicine and cellular longevity}. 2017; 2017: 5694058.
Rett syndrome (RTT) and autism spectrum disorders (ASDs) are not merely expression of brain dysfunction but also reflect the perturbation of physiological/metabolic homeostasis. Accordingly, both disorders appear to be associated with increased vulnerability to toxicants produced by redox imbalance, inflammation, and pollution, and impairment of systemic-detoxifying agents could play a role in the exacerbation of these detrimental processes. To check this hypothesis, the activities of two mechanistically related blood-based enzymes, paraoxonase-1 (arylesterase, paraoxonase, and lactonase), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured in the serum of 79 ASD and 95 RTT patients, and 77 controls. Lactonase and Lp-PLA2 showed a similar trend characterized by significantly lower levels of both activities in ASD compared to controls and RTT (p < 0.001 for all pairwise comparisons). Noteworthy, receiving operator curve (ROC) analysis revealed that lactonase and, mostly, Lp-PLA2 were able to discriminate between ASD and controls (lactonase: area under curve, AUC = 0.660; Lp-PLA2, AUC = 0.780), and, considering only females, between ASD and RTT (lactonase, AUC = 0.714; Lp-PLA2, AUC = 0.881). These results suggest that lactonase and, especially, Lp-PLA2 activities might represent novel candidate biomarkers for ASD. Lien vers le texte intégral (Open Access ou abonnement)
6. Hutson RL, Thompson RL, Bantel AP, Tessier CR. {{Acamprosate rescues neuronal defects in the Drosophila model of Fragile X Syndrome}}. {Life sciences}. 2018.
AIMS: Several off-label studies have shown that acamprosate can provide some clinical benefits in youth with Fragile X Syndrome (FXS), an autism spectrum disorder caused by loss of function of the highly conserved FMR1 gene. This study investigated the ability of acamprosate to rescue cellular, molecular and behavioral defects in the Drosophila model of FXS. MAIN METHODS: A high (100muM) and low (10muM) dose of acamprosate was fed to Drosophila FXS (dfmr1 null) or genetic control (w(1118)) larvae and then analyzed in multiple paradigms. A larval crawling assay was used to monitor aberrant FXS behavior, overgrowth of the neuromuscular junction (NMJ) was quantified to assess neuronal development, and quantitative RT-PCR was used to evaluate expression of deregulated cbp53E mRNA. KEY FINDINGS: Acamprosate treatment partially or completely rescued all of the FXS phenotypes analyzed, according to dose. High doses rescued cellular overgrowth and dysregulated cbp53E mRNA expression, but aberrant crawling behavior was not affected. Low doses of acamprosate, however, did not affect synapse number at the NMJ, but could rescue NMJ overgrowth, locomotor defects, and cbp53E mRNA expression. This dual nature of acamprosate suggests multiple molecular mechanisms may be involved in acamprosate function depending on the dosage used. SIGNIFICANCE: Acamprosate may be a useful therapy for FXS and potentially other autism spectrum disorders. However, understanding the molecular mechanisms involved with different doses of this drug will likely be necessary to obtain optimal results.
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7. Kunnikova KI, Kotyusov AI, Lvova OA. {{[Specifics of visual perception in infants with familial risk of autism spectrum disorders]}}. {Vestnik oftalmologii}. 2017; 133(6): 83-9.
Preclinical prediction of autistic spectrum disorders (ASD) is one of the priorities of current research. Children at risk of ASD develop an atypical visual perception profile early in their lives, which influences their visual responsiveness, distribution of attention, and social orienting. In this study we have compared the oculomotor behavior in an infant at familial risk of ASD with data from two 10-month infants with typical development. The SMI RED500 eye tracker was used for acquisition. Most parameters of visual perception in the at-risk infant were found to differ significantly from these of the controls. The strategy of visual search in the at-risk infant was generally less successful (13% of attempts vs 31% and 56% in the controls) with a tendency to focus predominantly on social stimuli (50% of the total gaze time). The said changes together with longer fixation duration (576.41 ms vs 527.77 and 386.72 ms in the two controls), lower saccadic frequency (1.74 counts/ms vs 1.84 and 2.18 counts/ms), and shorter scan path length (2774.24 px vs 3612.58 and 3985.43 px) may result in difficulties in switching tasks and processing information.
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8. Little JA. {{Vision in children with autism spectrum disorder: a critical review}}. {Clinical & experimental optometry}. 2018.
Autism spectrum disorder (ASD) is a common neurodevelopmental condition with approximately 1-2 per cent prevalence in the population. The condition has lifelong effects for the individual and family, and early intervention and management helps maximise quality of life and outcomes. Many studies of vision in ASD have attempted to link the behavioural and sensory deficits in ASD with underlying visual processing. From this work, it is clear that individuals with ASD ‘see’ and process the world differently, but there remain gaps in our understanding. This review will summarise our current knowledge of key aspects of visual functions and the optometric profile of ASD. This includes findings regarding visual acuity and contrast sensitivity, refractive error, eye movements, binocular vision, near visual functions and retinal structure in ASD. From this, a pattern of knowledge emerges for children with ASD: we should expect normal visual acuity; there will likely be atypical eye movements and susceptibility for subtle visuo-motor deficits, there is an increased prevalence of strabismus; an increased likelihood of astigmatism and possibly other refractive errors; attention, crowding and task complexity will likely be problematic; and retinal structure and function may be compromised. Bringing this together, these findings highlight that further work is necessary, not only to understand how higher-level functions link to behaviours, but also to ensure there is a sound understanding of the building-blocks of vision to fully grasp the profile of visual processing as a whole in ASD. This review will give a translational viewpoint for clinicians, and underline the benefits of comprehensive vision care in ASD.
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9. Lubala TK, Lumaka A, Mbuyi-Musanzayi S, Kayembe T, Shongo MYP, Mukuku O, Lubala N, Malamba-Lez D, Luboya ON, Lukusa-Tshilobo P. {{Fragile X syndrome with mosaic size mutation in a Bantu patient from Central Africa}}. {Clinical dysmorphology}. 2018.
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10. Saeedan AS, Singh I, Ansari MN, Singh M, Rawat JK, Devi U, Gautam S, Yadav RK, Kaithwas G. {{Effect of early natal supplementation of paracetamol on attenuation of exotoxin/endotoxin induced pyrexia and precipitation of autistic like features in albino rats}}. {Inflammopharmacology}. 2018.
The present study was aimed to test the hypothesis that paracetamol (PCM) can precipitate autistic like features when used to counteract vaccine-induced fever using experimental rat pups. The pups were treated with measles mumps rubella (MMR) vaccine, diphtheria tetanus and pertussis (DPT) vaccines and lipopolysaccharide (LPS) with subsequent PCM treatment. The pups were evaluated for postnatal growth (weight gain, eye opening) and behavior alterations (swimming performance, olfactory discrimination, negative geotaxis, nociception, and locomotor activity) by performing battery of neurobehavioral test. Significant correlation was observed between social behavioral domains (nociception, anxiety and motor coordination) and pro-inflammatory load in the pups when treated with MMR/LPS along with PCM. A significant change in pro and anti-inflammatory (IL-4, IL-6, IL-10) markers were observed in rats treated with PCM, MMR, LPS, DPS alone or in combination with MMR, LPS and DPT (5128.6 +/- 0.000, 15,488 +/- 0.000(***), 9661.1 +/- 157.29(***a), 15,312 +/- 249.29 (***) , 10,471 +/- 0.00(***a), 16,789 +/- 273.34 (***) and 12,882 +/- 0.00(***a)). Pups were also scrutinized for the markers of oxidative stress, inflammation and histopathologically. All the treatment groups showed significant alteration in the behavioral changes, oxidative markers (TBARS-in control-4.33 +/- 0.02, PCM-9.42 +/- 0.18(***), MMR-5.27 +/- 0.15(***), MMR + PCM-8.57 +/- 0.18(*** a), LPS-6.84 +/- 0.10(***), LPS + PCM-4.51 +/- 0.30(***a), DPT-5.68 +/- 0.12(***), DPT + PCM-7.26 +/- 0.18(***a)) and inflammatory markers without following any specific treatment. These observation could be accorded to variable phenotypes of autistic spectrum disorders (ASDs).
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11. Subramanian D, Pralong E, Daniel RT, Chacko AG, Stoop R, Babu KS. {{Gamma oscillatory activity in vitro: a model system to assess pathophysiological mechanisms of comorbidity between autism and epilepsy}}. {Translational psychiatry}. 2018; 8(1): 16.
Autism spectrum disorder (ASD) and temporal lobe epilepsy exhibit remarkable comorbidity, but for reasons not clearly understood. To reveal a common pathophysiological mechanism, we here describe and characterize an in vitro epileptiform activity in the rat hippocampus that exhibits common features with in vivo activity in rodent ASD models. We discovered the development of this activity in the CA1 region of horizontal slices after prolonged interictal-like epileptiform activity in the CA3 region that was provoked by incubation in high potassium artificial cerebrospinal fluid. The CA1 epileptiform bursts were insensitive to blockers of glutamatergic transmission, and were carried by synaptic as well as extrasynaptic, tonically activated gamma-aminobutyric acid type A (GABA(A)) receptors. The bursts bear resemblance to in vivo gamma-oscillatory activity found in rat ASD models with respect to their gamma frequency spectrum, their origin (in the CA1), and their sensitivity to blockers of cation-chloride pumps (NKCC1 and KCC2), as well as to oxytocin. Considering this bursting activity as an in vitro model for studying comorbidity between epilepsy and ASD may help to disentangle the intricate interactions that underlie the comorbidity between both diseases and suggests that extrasynaptic tonic GABAergic transmission could represent a potential target for ASD.
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12. Valiente-Palleja A, Torrell H, Muntane G, Cortes MJ, Martinez-Leal R, Abasolo N, Alonso Y, Vilella E, Martorell L. {{Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability}}. {Hum Mol Genet}. 2018.
Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analyzed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.
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13. Wang P, Zhao D, Lachman HM, Zheng D. {{Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons}}. {Translational psychiatry}. 2018; 8(1): 13.
Autism spectrum disorder (ASD) is highly heritable but genetically heterogeneous. The affected neural circuits and cell types remain unclear and may vary at different developmental stages. By analyzing multiple sets of human single cell transcriptome profiles, we found that ASD candidates showed relatively enriched gene expression in neurons, especially in inhibitory neurons. ASD candidates were also more likely to be the hubs of the co-expression gene module that is highly expressed in inhibitory neurons, a feature not detected for excitatory neurons. In addition, we found that upregulated genes in multiple ASD cortex samples were enriched with genes highly expressed in inhibitory neurons, suggesting a potential increase of inhibitory neurons and an imbalance in the ratio between excitatory and inhibitory neurons in ASD brains. Furthermore, the downstream targets of several ASD candidates, such as CHD8, EHMT1 and SATB2, also displayed enriched expression in inhibitory neurons. Taken together, our analyses of single cell transcriptomic data suggest that inhibitory neurons may be a major neuron subtype affected by the disruption of ASD gene networks, providing single cell functional evidence to support the excitatory/inhibitory (E/I) imbalance hypothesis.
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14. Zhou HY, Cai XL, Weigl M, Bang P, Cheung EFC, Chan RCK. {{Multisensory temporal binding window in autism spectrum disorders and schizophrenia spectrum disorders: A systematic review and meta-analysis}}. {Neurosci Biobehav Rev}. 2018.
Multisensory temporal integration could be compromised in both autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) and may play an important role in perceptual and cognitive impairment in these two disorders. This review aimed to quantitatively compare the sensory temporal acuity between healthy controls and the two clinical groups (ASD and SSD). Impairment of sensory temporal integration was robust and comparable in both patients with SSD (Hedges’ g=0.91, 95%CI[0.62-1.19]; Z=6.21, p<.001) and ASD (Hedges' g=0.85, (95%CI[0.54-1.15]; Z=5.39, p<.001). By further separating studies into unisensory and multisensory (bimodal: audiovisual) ones, subgroup analysis indicated heterogeneous and unstable effects for unisensory temporal binding in the ASD group, but a more consistent and severe impairment in multisensory temporal integration represented by an enlarged temporal binding window in both clinical groups. Such multisensory dysfunction is associated with symptoms like hallucinations and impaired social communications. Future studies focusing on improving multisensory temporal functions may have important implications for the amelioration of schizophrenia and autistic symptoms. Lien vers le texte intégral (Open Access ou abonnement)
