Characterising the social interaction style of autism in young adult males with fragile X syndrome.

BACKGROUND: The characterisation of autism in fragile X syndrome (FXS) has been a source of controversy due to the complexity of disentangling autism traits from common features of the FXS phenotype. Autism in FXS is significantly underdiagnosed in the community, which may be partly due to insufficient clinical description of the social interaction profile of autism within the FXS phenotype. In this study, we applied a classic framework for characterising social interaction styles in autism to a sample of young adult males with FXS and co-occurring autism to enhance understanding of how the social challenges associated with autism manifest within FXS. METHODS: Participants were 41 males (M age = 18 years) with FXS and co-occurring autism. Interaction samples were coded for expression of predominately 'active' (characterised by a desire to make social approaches) or 'passive' (characterised by lack of initiation of social approach towards others) interaction profiles. Differences in the expression of phenotypic features of FXS, including anxiety, attention-deficit/hyperactivity disorder, cognitive, adaptive and language impairments and autism symptom severity, were examined across those with passive and active interaction styles. RESULTS: Approximately half of the sample was classified as active and half as passive, demonstrating diversity in the social phenotype of autism associated with FXS. The two subtypes did not differ in autism severity, anxiety or attention-deficit/hyperactivity disorder symptoms or in cognitive, adaptive or language abilities. CONCLUSIONS: This study enhances understanding of FXS-associated autism by documenting phenotypic variability in the social interaction profile in this group, with active and passive social interaction styles represented. The two social interaction styles were not associated with differential expression of common phenotypic features of FXS, suggesting similar support needs.

Exposing immature hippocampal neurons to excitotoxins reveals distinct transcriptome and protein regulation with induction of common survival signaling pathways.

Early life traumas lead to neuroprotection by preconditioning mechanisms. To determine which genes and pathways are most likely involved in specific adaptive effects, immature hippocampal cultures were exposed to a single high dose of glutamate (250 µM), NMDA (100 µM), or KA (300 µM) for 48 h (5-7 DIV) based on our prior "two hit" in vitro model of preconditioning. Transcriptome profiling and immunocytochemistry of gene candidates were performed 7 days later when cultured neurons mature (14 DIV). Many genes were up- and down- regulated involving distinct Ca2+-binding protein families, G-coupled proteins, various growth factors, synaptic vesicle docking factors, certain neurotransmitter receptors, heat shock, oxidative stress, and certain anti-apoptotic Bcl-2 gene members that influence neuronal survival. Immunohistochemistry showed a marked decrease in the number of Calb1 and Calm2 positive neurons following NMDA but not after glutamate exposure whereas ryanodine and Cav1.2 voltage gated channel expression was less affected. Survivors had marked increases in Calm2 immunostaining; however, high-density neural clusters observed in controls, were depleted after NMDA and partly diminished after glutamate. While NR1 mRNA expression was decreased in the microarray, specific antibodies revealed selective loss of the NR1C1 splice variant. Calm2 which can inactivate NMDA receptors by binding to C1 but not C2 regions of its NR1 subunit suggests that loss of the C1 splice variant will reduce co-regulation with Calm2 and alter NR1 trafficking, phosphorylation, and NMDA currents following early life NMDA exposure. A dramatic reduction in the density of GABAAα5 and GABAB receptor expressing neurons was observed after NMDA exposure but immunodensity measurements were unchanged as was the expression of the GABA synthesizing enzyme, GAD, suggesting that fast inhibitory neurotransmission and response to benzodiazepines and GABAB-mediated IPSPs may be preserved in matured survivors. Selective upregulation of Chat and CNRIP was detected after glutamate treatment suggesting this condition would decrease cholinergic and excitatory neurotransmission by decreasing Ach content and CB1 interacting protein function. This decrease likely contributes to memory and attention tasks deficits that follow a single early neurological insult. Diverse changes that follow overactivation of excitatory networks of immature neurons appear long-lasting or permanent and are expected to have profound effects on network function and adaptive responses to further insult.

Role of supportive maintenance therapy on implant survival: a university-based 17 years retrospective analysis.

OBJECTIVE: The objective of this study was to determine whether professional maintenance appointments were related to a decrease on dental implant loss. METHODS: We performed a retrospective review (1995-2012) of 1020 patient dental charts to collect data including a cadre of different variables such as age, gender, race, diabetes, osteoporosis, jaw location, implant dimensions and professional maintenance therapy. As a patient may have multiple implants which are correlated, we selected one random implant per patient to assure independence of observations assumption of the Cox proportional hazards regression model. Data analysis was performed using Kaplan-Meier survival curves and multivariate analysis using Cox proportional hazards regression analysis. RESULTS: Our results demonstrate that subjects with no maintenance had the lowest cumulative survival rate as compared to subjects with regular maintenance. In a multivariate Cox regression model, regular maintenance patients had the dental implant failure rate reduced by 90% as compared to no maintenance (P = 0.001). If patients had less than one maintenance visit per year, the failure rate was reduced by 60% as compared to no maintenance, but the difference was not statistically significant (P = 0.08). CONCLUSION: From this research, we conclude that a professional administered periodontal maintenance at least on an annual basis is a critical factor for implant survival.

Hippocampal volume change relates to clinical outcome in childhood-onset schizophrenia.

BACKGROUND: Fixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients. METHOD: We prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume). RESULTS: Fewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043). CONCLUSIONS: These results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

Retigabine calms seizure-induced behavior following status epilepticus.

In adult rats, intraperitoneal injection of kainate (KA) results in sustained status epilepticus and persistent behavioral comorbidities such as hyperexcitability, anxiety, and altered response to environmental cues. Intrahippocampal KA also results in sustained status epilepticus and continuous high frequency oscillations in the electroencephalograph (EEG), although subsequent behavioral side effects are unknown. We hypothesized that retigabine, a recently discovered anticonvulsant and potent positive modulator of Kv7 channels, may attenuate seizure-induced behavioral abnormalities. Status epilepticus was induced by administration of KA either intraperitoneally (15 mg/kg) or by single intrahippocampal injection (1.0 µg/0.5 µL). After 24 h, half of systemically KA-treated animals that reached stage 6 seizures were injected once daily with retigabine (5 mg/kg) for 14 continuous days. All groups underwent three behavioral tests--capture and handling, open field, and elevated plus maze--24 h following the last retigabine treatment and were sacrificed at 25-28 days. In the capture and handling test, systemic KA treatment resulted in frisky behavior and resistance to capture with wild attempts to escape during the 1st, 2nd, and 3rd weeks of the observation period. In contrast, these behaviors were attenuated in KA+retigabine-treated animals. In the open-field test, KA-treated animals spent more time in the center zone, but KA+retigabine-treated rats had greater overall activity compared with those having vehicle, KA, or retigabine-only treatment. In the elevated plus maze, KA+retigabine-treated animals traveled greater distances in open and closed arms (proximal and distal) compared with controls, also signifying anxiety reduction. Retigabine-only-treated rats traveled more in the open proximal arms compared with controls, indicating increased hyperlocomotion in normotensive rats. Although treatment with KA+retigabine resulted in anxiolytic-like effects in all three behavioral tasks compared with vehicle, this group did not significantly differ from systemically KA-treated rats in most measurements in open-field and elevated plus maze tasks, suggesting that retigabine may also cause hyperlocomotion unrelated to anxiety level. Despite that intrahippocampal KA-treated rats displayed comparable seizure behavior, epileptiform activity, and hippocampal injury, their behavior resembled the controls, suggesting that molecular and subsequent cellular changes are also partially responsible for anxiolytic-like effects and that these results are likely independent of the hippocampus.

Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy.

Injury of the CA1 subregion induced by a single injection of kainic acid (1 × KA) in juvenile animals (P20) is attenuated in animals with two prior sustained neonatal seizures on P6 and P9. To identify gene candidates involved in the spatially protective effects produced by early-life conditioning seizures we profiled and compared the transcriptomes of CA1 subregions from control, 1 × KA- and 3 × KA-treated animals. More genes were regulated following 3 × KA (9.6%) than after 1 × KA (7.1%). Following 1 × KA, genes supporting oxidative stress, growth, development, inflammation and neurotransmission were upregulated (e.g. Cacng1, Nadsyn1, Kcng1, Aven, S100a4, GFAP, Vim, Hrsp12 and Grik1). After 3 × KA, protective genes were differentially over-expressed [e.g. Cat, Gpx7, Gad1, Hspa12A, Foxn1, adenosine A1 receptor, Ca(2+) adaptor and homeostasis proteins, Cacnb4, Atp2b2, anti-apoptotic Bcl-2 gene members, intracellular trafficking protein, Grasp and suppressor of cytokine signaling (Socs3)]. Distinct anti-inflammatory interleukins (ILs) not observed in adult tissues [e.g. IL-6 transducer, IL-23 and IL-33 or their receptors (IL-F2 )] were also over-expressed. Several transcripts were validated by real-time polymerase chain reaction (QPCR) and immunohistochemistry. QPCR showed that casp 6 was increased after 1 × KA but reduced after 3 × KA; the pro-inflammatory gene Cox1 was either upregulated or unchanged after 1 × KA but reduced by ~70% after 3 × KA. Enhanced GFAP immunostaining following 1 × KA was selectively attenuated in the CA1 subregion after 3 × KA. The observed differential transcriptional responses may contribute to early-life seizure-induced pre-conditioning and neuroprotection by reducing glutamate receptor-mediated Ca(2+) permeability of the hippocampus and redirecting inflammatory and apoptotic pathways. These changes could lead to new genetic therapies for epilepsy.

Which older adults maintain benefit from cognitive training? Use of signal detection methods to identify long-term treatment gains.

BACKGROUND: Cognitive training has been shown to improve memory in older adults; however, little is known about which individuals benefit from or respond best to training in the long term. Identification of responders' characteristics would help providers match cognitive interventions to individuals to improve their effectiveness. Signal detection methods may prove more informative than more commonly used analytic methods. The goal of the current study is to identify baseline characteristics of long-term treatment responders and of those able to maintain their initial benefit from cognitive training. METHODS: Participants were 120 non-demented, community-dwelling older adults who had participated in a cognitive training intervention. Tested predictors included both demographic and neurocognitive variables. Primary outcome variables were performance on measures of memory at one-year follow-up. RESULTS: Results of the signal detection analysis indicated that different neurocognitive performances predicted long-term effects of memory training and maintenance of initial treatment response according to different types of to-be-remembered material. Higher baseline scores on tests of associative memory, delayed verbal memory, attention, episodic memory, and younger age were found predictive of long-term response one year later. Higher associative memory scores and lower initial gains at the end of treatment (week 14) predicted successful maintenance of training gains at week 52. CONCLUSIONS: To derive long-term benefit from particular cognitive training programs, it appears necessary for older adults to have specific neurocognitive profiles. Further, inclusion of booster sessions to cognitive training programs may assist in maintenance of initial treatment gains.

Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.

Breast cancer in men is about a hundredfold less common than in women and this has hindered research into its genetic basis. We have examined 22 families with at least one case of male breast cancer for linkage to the hereditary breast and ovarian cancer locus, BRCA1, on chromosome 17q. We found strong evidence against linkage to BRCA1 (lod score-16.63) and the best estimate of the proportion of linked families was 0% (95% CI 0-18%). Our results indicate that there is a gene(s) other than BRCA1 which predisposes to early-onset breast cancer in women and which confers a higher risk of male breast cancer. Identification of additional pedigrees that include cases of male breast cancer may therefore facilitate the mapping and isolation of this gene.

Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.

We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.

Sex differences in behavioral pathology induced by subconvulsive stimulation during early postnatal life are overcome by epileptic activity in the pre-juvenile weanling period.

Chronic subconvulsive activity in early life leads to sex-related autistic-like deficits in handling, object recognition, and social performance in pre-pubertal rats. Since autism and epilepsy are common neurodevelopmental disorders with high coincidence, we tested whether early-life chronic subconvulsive activity compared to convulsive activity alters handling, spatial memory, lateralization, coping strategy and the seizure threshold in a sex-dependent manner. A hypothesis is that convulsive seizures may alter sex differences induced by subconvulsive (SC) activity. Serial subconvulsive doses of kainic acid (KA) were administered postnatally (0.25-1 mg/kg) for 15 days to induce the chronic subconvulsive phenotype (SC group). Age-matched controls and a subset of SC pups were exposed to a convulsive dose of KA (KA and SC + KA groups; 7.5 mg/kg) or flurothyl vapors. In our open handling test, controls and the ASD groups escaped to a similar degree whereas after convulsive seizures, the pups exhibited freezing behavior; no escapes occurred. In the spontaneous alternating T-Maze control males and females entered the left arm with higher frequency. The SC males but not SC females entered left and right arms to a similar degree; alternation rates were reduced to chance revealing a sex difference. However, in KA and SC + KA groups, there was a sharp loss of spontaneous alternation rates. The rapid repetitive entries shifted to the right in both sexes possibly be due to hippocampal injury and changes in network activity induced by status epilepticus. In the forced swim test (FST), control and CS females were more active than corresponding males. After convulsions, immobility was reduced and vertical mobility was increased in SC and SC + KA males suggesting an elevated coping strategy compared to females. Onset and severity of KA induced status epilepticus was delayed in SC males and females possibly due to desensitization of KA receptors. Following flurothyl exposure, control males had faster onset of twitches and clonic seizures than control females which disappeared after the sub-convulsive pre-treatment. Data suggest that behavioral manifestations are more readily detectable between males and females when low levels of hyperexcitation are present chronically in early postnatal development but diminished after tonic-clonic convulsions persist. Therefore, therapeutic interventions may benefit patients if initiated upon the initial onset of sex-related autistic pathologies, particularly in males, which may reduce subsequent vulnerability to seizures.

Cannabidiol reduces lesion volume and restores vestibulomotor and cognitive function following moderately severe traumatic brain injury.

Despite the high incidence of traumatic brain injury (TBI), there is no universal treatment to safely treat patients. Blunt brain injuries destroy primary neural tissue that results in impaired perfusion, excessive release of glutamate, inflammation, excitotoxicity, and progressive secondary neuronal cell death. We hypothesized that administration of cannabidiol (CBD) directly to a brain contusion site, will optimize delivery to the injured tissue which will reduce local neural excitation and inflammation to spare neural tissue and improve neurological outcome following TBI. CBD was infused into a gelfoam matrix forming an implant (CBDi), then applied over the dura at the contusion site as well as delivered systemically by injection (CBD.IP). Post-injury administration of CBDi+IP greatly reduced defecation scores, lesion volume, the loss of neurons in the ipsilateral hippocampus, the number of injured neurons of the contralateral hippocampus, and reversed TBI-induced glial fibrillary acidic protein (GFAP) upregulation which was superior to either CBD.IP or CBDi treatment alone. Vestibulomotor performance on the beam-balance test was restored by 12 days post-TBI and sustained through 28 days. CBDi+IP treated rats exhibited preinjury levels of spontaneous alternation on the spontaneous alternation T-maze. In the object recognition test, they had greater mobility and exploration of novel objects compared to contusion or implant alone consistent with reduced anxiety and restored cognitive function. These results suggest that dual therapy by targeting the site of injury internally with a CBD-infused medical carrier followed by systemic supplementation may offer a more effective countermeasure than systemic or implant treatment alone for the deleterious effects of penetrating head wounds.

The histopathology of the humeral head in glenohumeral osteoarthritis.

Objective: The histopathologic wear patterns in glenohumeral osteoarthritis (GOA) have not been described. The aims of the study were to a) describe the histopathology of humeral head wear patterns in patients with end-stage GOA and b) identify clinical and radiographic parameters that correlate with observed histopathological wear patterns. Methods: Eighteen humeral heads from patients undergoing anatomic total shoulder arthroplasty for end-stage osteoarthritis were divided radially into eight wedge-shaped zones. Each zone was subdivided into central and peripheral regions. Histologic analysis included measurements of cartilage and subchondral bone plate thickness, subchondral bone area, and cartilage structure was scored using the Osteoarthritis Research Society (OARSI) and modified Mankin systems. Clinical variables including patient history, physical exam, functional evaluation, and radiographic assessments were evaluated for correlations with humeral head characteristics. Results: Overall, humeral heads demonstrated a pattern of central and inferior cartilage damage, loss, and subchondral bone changes. However, within the group, composite maps of individual patient wear patterns demonstrated a sub-group of patients with a more focal inferior cartilage lesion. Overall, these more focal inferior lesions were associated with greater pre-operative range of motion (in both upper extremities), higher pre-operative SANE and ASES scores, female sex, non-dominant extremity, concentric wear patterns, and smaller inferior osteophytes. Conclusion: Humeral head cartilage wear patterns in GOA include central and inferior cartilage damage and loss. A histopathological distinction was identified between patients with more focal versus diffuse wear, which may manifest clinically with preservation of function and range of motion, and with less profound radiographical changes.

Evaluation of a stroma-free hemoglobin solution for use as a plasma expander.

The preparation of large quantities of a stable, stroma-free hemoglobin solution without coagulant activity is described. Following infusion of this solution into phlebotomized dogs, there is no methemoglobin formation, no adverse effects on vital signs, and no demonstrable activation of blood coagulation. The hemoglobin maintains its oxygen-carrying capacity and liberates oxygen into tissues. Acute and chronic effects on renal function following infusion of this preparation were also studied and no effect on clearance of urea, creatinine, or P.A.H. could be demonstrated. There was no change in urinary output and histological sections revealed no lesions attributable to hemoglobin toxicity. It is concluded that a stroma-free hemoglobin solution may have use as a plasma expander.

Glutamatergic and morphological alterations associated with early life seizure-induced preconditioning in young rats.

Postnatal day (P)20 rats are sensitive to CA1 injury following a single injection of kainic acid (KA) but are resistant to this injury when animals have a history of two neonatal seizures. We hypothesized that the two earlier seizures led to neuroprotection by a preconditioning mechanism. Therefore, morphology, [Ca(2+)](i) and NMDA subunit proteins of the hippocampus were examined after KA was administered once (1 × KA, on P6, P9, P13 or P20), twice (2 × KA, on P6 and P9) or three times (3 × KA, on P6, P9, P13 or P20). After 1 × KA on P20, the Golgi method revealed marked decreases in spine densities and aborization of CA1 and CA3 apical dendrites. After 3 × KA, morphological alterations were attenuated in CA1 neurons and were similar to pruning observed after 1 × KA on P6 or 2 × KA. After 1 × KA at P13, baseline [Ca(2+)](i) was elevated within pyramidal and dentate granule cells. N-methyl-D-aspartate (NMDA) responses were simultaneously enhanced. After 3 × KA, Ca(2+) elevations were attenuated. Immunohistochemistry revealed selective depletion of the NR2A/B subunit modulator in the same areas. NR1 subunit expression was downregulated in the subiculum and increased in the CA3, causing a significant shift in the NR1:NR2A/B ratio throughout the hippocampus. After 1 × KA or 3 × KA at P20, reduced expression was only observed in areas of cell injury. Results indicate that different changes in morphology and excitatory responses occur depending upon when seizures begin. Partial pruning and persistent shift in the NR1:NR2A/B ratio among excitatory synapses of the hippocampus early in life may produce epileptic tolerance and protect against subsequent insults.

The efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancer.

The aim of the study is to evaluate the efficacy of sertraline for controlling hot flashes in women with or at high risk of breast cancer. This was a randomized, double-blind, placebo-controlled study. All participants were asked to complete hot flash diaries. Participants reporting weekly hot flash scores >15 during baseline week underwent a 1-week single-blind placebo run-in. Those reporting hot flash score reductions >50% following placebo run-in were excluded. The remaining women received an assigned treatment for 4 weeks. Both groups' demographic and clinical characteristics were similar with a greater decline, but not statistically significant, in hot flash frequencies and scores in the sertraline-treated group compared with the placebo (P = 0.13 and P = 0.15, respectively). Emotional well-being improved significantly in the sertraline group (P = 0.041). The study failed to demonstrate effectiveness of sertraline in attenuating hot flashes in women with or at high risk of developing breast cancer who were not recommended to take hormone replacement therapy.

Variations in the isotopic composition of carbon in urban atmospheric carbon dioxide.

Measurement of the abundance of atmospheric carbon dioxide as an indicator of air pollution has been of very limited value because of variations in urban areas in the substantial concentration of natural carbon dioxide produced from combustion and noncombustion (natural) sources. A solution to this problem is the use of precise isotopic assay of ratios of carbon-13 to carbon-12 in atmospheric carbon dioxide. There is very little variation of carbon isotopic composition in samples taken over rural or urban areas where rapid mixing and diffusion of gaseous combustion products is possible. Significant differences in this composition in samples taken at centrally located points at street level in the lower Manhattan business district show an increase in concentration of atmospheric carbon dioxide of roughly 20 percent produced primarily by automobile exhaust.

Odor incongruity and chirality.

The enantiomers R-(-)- and S-(+)-carvone are the organoleptic constituents in oil of spearmint and caraway, respectively. Their odor distinctiveness has been unambiguously demonstrated by chemical interconversion, independent synthesis, and resolution. Odor differences between other chiral isomers were also firmly established.

The stability of DNA in human cerebellar neurons.

Human tissues have carbon-isotope ratios (13C/12C) that reflect dietary ratios. This observation has been used to determine the extent of metabolic turnover of DNA in cells of the adult human cerebellum (90 percent of which are neuronal). If adult human neuronal DNA were metabolically stable, its 13C/12C would reflect that in the maternal diet during fetal development as nearly all neurons are formed during maturation of the fetal brain and do not undergo cell division thereafter. The 13C/12C ratios in the food chains and body tissues of Europeans differ from corresponding American ratios by about 50 parts per million on the average. Therefore, turnover was studied by comparing 13C/12C ratios in cerebellar DNA of American-born Americans, European-born Americans, and European-born Europeans. The 13C/12C ratios in cerebellar DNA from European-born Americans were closer to 13C/12C ratios in cerebellar DNA from European-born Europeans than from American-born Americans, indicating that there was little or no turnover of neuronal DNA.

Chronic subconvulsive activity during early postnatal life produces autistic behavior in the absence of neurotoxicity in the juvenile weanling period.

The diagnosis of autism spectrum disorder (ASD) varies from very mild to severe social and cognitive impairments. We hypothesized that epigenetic subconvulsive activity in early postnatal life may contribute to the development of autistic behavior in a sex-related manner. Low doses of kainic acid (KA) (25-100 µg) were administered to rat pups for 15 days beginning on postnatal (P) day 6 to chronically elevate neuronal activity. A battery of classical and novel behavioral tests was used, and sex differences were observed. Our novel open handling test revealed that ASD males nose poked more often and ASD females climbed and escaped more frequently with age. In the social interaction test, ASD males were less social than ASD females who were more anxious in handling and elevated plus maze (EPM) tasks. To evaluate group dynamics, sibling and non-sibling control and experimental animals explored 3 different shaped novel social environments. Control pups huddled quickly and more frequently in all environments whether they socialized with littermates or non-siblings compared to ASD groups. Non-sibling ASD pups were erratic and huddled in smaller groups. In the object recognition test, only ASD males spent less time with the novel object compared to control pups. Data suggest that chronic subconvulsive activity in early postnatal life leads to an ASD phenotype in the absence of cell death. Males were more susceptible to developing asocial behaviors and cognitive pathologies, whereas females were prone to higher levels of hyperactivity and anxiety, validating our postnatal ASD model apparent in the pre-juvenile period.