The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is ...profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107,000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.
Key points
Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ...ablation confined to the periphery.
We employed juvenile and young adult Otof KO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO).
MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs.
Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types.
Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period.
Circuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super‐numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB–LSO circuit refinement after P20. Moreover, MNTB–LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10–12) and young adult (P27–49) otoferlin knockout (Otof KO) mice with respect to MNTB–LSO refinement. MNTB in vivo recordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealed Otof absence in the MNTB and LSO of wild‐types, Otof loss in KOs is specific to the periphery. Functional denervation impaired MNTB–LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB–LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB–LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild‐types. Collectively, we provide novel insights into functional MNTB–LSO circuit maturation governed by a cochlea‐specific protein. The central malfunctions in Otof KOs may have implications for patients with sensorineuronal hearing loss.
Key points
Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ablation confined to the periphery.
We employed juvenile and young adult Otof KO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO).
MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs.
Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types.
Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period.
The objective of the study was to investigate the associations among maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum disorders (ASDs) in children.
The study sample of 92 909 ...children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models.
At the end of follow-up on December 31, 2012, 419 children in the study sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder, and 154 with pervasive developmental disorder not otherwise specified. Maternal obesity (BMI ≥30) was only weakly associated with ASD risk, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07-2.82). For Asperger disorder, analyses were limited to children aged ≥7 years (n = 50 116). The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13-3.57). No associations were found for pervasive developmental disorder not otherwise specified.
Paternal obesity is an independent risk factor for ASDs in children. The associations should be investigated further in genetic and epigenetic studies.
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested ...the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.
In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.
A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).
Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).
Prenatal fever and autism risk Hornig, M; Bresnahan, M A; Che, X ...
Molecular psychiatry,
03/2018, Volume:
23, Issue:
3
Journal Article
Peer reviewed
Open access
Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence ...to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.
Experimental studies of nuclear fission induced by fusion, transfer, spallation, fragmentation, and electromagnetic reactions in combination with state-of-the-art calculations are successful to ...investigate the nuclear dissipation mechanism in normal nuclear matter, containing only nucleons. The dissipation mechanism has been widely studied by the use of many different fission observables and nowadays the dissipation coefficients involved in transport theories are well constrained. However, the existence of hypernuclei and the possible presence of hyperons in neutron stars make it necessary to extend the investigation of the nuclear dissipation coefficient to the strangeness sector. In this Letter, we use fission reactions of hypernuclei to constrain for the first time the dissipation coefficient in hypernuclear matter, observing that this coefficient increases a factor of 6 in the presence of a single Λ hyperon with respect to normal nuclear matter.
To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy.
Systematic review of relevant articles published between January 1985 and June 2007.
...It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7.
If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).
PDF
