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.

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.

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.

Human rabies postexposure prophylaxis and rabid terrestrial animals in Ontario, Canada: 2014-2016.

BACKGROUND: The number of rabid terrestrial animals in Ontario has decreased markedly since the 1970s and 1980s. However, the number of recommended rabies postexposure prophylaxis (RPEP) courses has not decreased proportionally. The decision to recommend RPEP for terrestrial animal exposures should be based on a risk assessment that considers the prevalence of rabies in these animals within a jurisdiction, among other factors. OBJECTIVE: To explore trends in RPEP recommendations for exposures to terrestrial animals in Ontario in relation to the recency of terrestrial animal rabies cases by public health unit (PHU) jurisdiction. METHODS: RPEP recommendation data for the 36 Ontario PHUs were obtained from the Ontario integrated Public Health Information System and animal rabies data by PHU were obtained from the Ministry of Natural Resources and Forestry. We calculated the annual RPEP recommendation rates for terrestrial animals by PHU for 2014 to 2016, and plotted the 2016 rates in relation to the year of the most recently identified rabid terrestrial animal in the PHU. RESULTS: Between 2014 and 2016, the annual RPEP recommendation rates for terrestrial animal exposures by PHU ranged from 3.0 to 35.2 per 100,000 persons, with a median of 11.9 RPEP recommendations per 100,000 persons. In 2016, ten PHUs had not identified a rabid terrestrial animal in their jurisdiction for more than15 years. Five of these PHUs had RPEP recommendation rates above the provincial median. CONCLUSION: Along with other factors, consideration of the occurrence of rabies in terrestrial animals in a jurisdiction can assist in the risk assessment of dogs, cats or ferrets that are not available for subsequent observation.

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.

Sex ratio in dementia with Lewy bodies balanced between Alzheimer's disease and Parkinson's disease dementia: a cross-sectional study.

BACKGROUND: Gender distribution varies across neurodegenerative disorders, with, traditionally, a higher female frequency reported in Alzheimer's disease (AD) and a higher male frequency in Parkinson's disease (PD). Conflicting results on gender distribution are reported concerning dementia with Lewy bodies (DLB), usually considered as an intermediate disease between AD and PD. The aim of the present study was to investigate gender differences in DLB in French specialized memory settings using data from the French national database spanning from 2010 to 2015 and to compare sex ratio in DLB with that in AD, Parkinson's disease dementia (PDD), and PD. Our hypothesis was that there is a balanced sex ratio in DLB, different from that found in AD and PD. METHODS: We conducted a repeated cross-sectional study. The study population comprised individuals with a DLB, AD, PDD, or PD diagnosis according to the International Classification of Diseases, Tenth Revision, in the French National Alzheimer Database between 2010 and 2015. Sex ratio and demographic data were compared using multinomial logistic regression and a Bayesian statistical model. RESULTS: From 2010 to 2015 in French specialized memory settings, sex ratios (female percent/male percent) were found as follows: 1.21 (54.7%/45.3%) for DLB (n = 10,309), 2.34 (70.1%/29.9%) for AD (n = 135,664), 0.76 (43.1%/56.9%) for PD (n = 8744), and 0.83 (45.4%/54.6%) for PDD (n = 3198). Significant differences were found between each group, but not between PDD and PD, which had a similar sex ratio. CONCLUSIONS: This large-sample prevalence study confirms the balanced gender distribution in the DLB population compared with AD and PD-PDD. Gender distribution and general demographic characteristics differed between DLB and PDD. This is consistent with the hypothesis that DLB is a distinct disease with characteristics intermediate between AD and PD, as well as with the hypothesis that DLB could have at least partially distinct neuropathological correlates.

Postpartum hemoptysis as presenting sign of longstanding vasculitis.

We present the case of a 26-year-old postpartum patient who presented with an episode of desaturation and hemoptysis on postpartum day three after an uncomplicated spontaneous vaginal delivery. The patient came to our attention in the postpartum area after she experienced massive hemoptysis and we were called by the obstetric team. The patient was subsequently intubated, mechanically ventilated, and underwent bronchoscopy, demonstrating diffuse alveolar hemorrhage. She was brought to the intensive care unit, placed on high-dose steroids and plasmapheresis was initiated. Her intensive care unit course was complicated by acute respiratory distress syndrome, acute kidney injury and a pulmonary embolism, but she recovered well and was discharged on postpartum day 23. This report describes a rare case of medium vessel vasculitis diagnosed in the peripartum period, and describes the diagnostic dilemmas underlying making a rare diagnosis, and the difficulties initiating appropriate therapy in a postpartum patient.

Influenza outbreaks in Ontario hospitals, 2012-2016.

BACKGROUND: Influenza outbreaks in hospital settings affect vulnerable patient populations and pose considerable risk of morbidity and mortality; however, key information regarding these outbreaks is limited. OBJECTIVE: To describe surveillance data on influenza outbreaks in Ontario hospitals between 2012-13 and 2015-16 and compare H3N2- and H1N1-dominant influenza seasons. METHODS: Hospital laboratory-confirmed influenza outbreaks occurring between September 1, 2012 and August 31, 2016 were analysed for indicators of outbreak duration and severity (case attack rate, pneumonia rate and fatality rate). Frequency, duration and severity of influenza A outbreaks were compared between H3N2- (2012-13, 2014-15) and H1N1-dominant seasons (2013-14, 2015-16). RESULTS: Over the four years, there were 256 hospital outbreaks involving 1,586 patients that included 91 cases of pneumonia and 40 deaths. The total number of outbreaks was lowest in the 2015-16 (n=36) and highest in the 2014-15 (n=117) influenza seasons. The 2014-15 season also had the highest number of influenza cases (n=753), pneumonia cases (n=46), fatalities (n=18) and hospital sites reporting ≥1 outbreak (n=72). Median outbreak duration ranged from 4.5 days in 2013-14 to 6.0 days in 2015-16. Comparisons of H3N2 and H1N1 seasons did not identify statistically significant differences in outbreak duration or severity; however, significantly more influenza A outbreaks than influenza B outbreaks were reported in H3N2 seasons compared with H1N1 seasons (p<0.05). CONCLUSION: While H3N2-dominant years contribute to influenza morbidity and mortality through an increased number of hospital outbreaks, the duration and severity of influenza A outbreaks are not significantly different in H3N2 and H1N1 seasons.

Olfactory disturbances in ageing with and without dementia: towards new diagnostic tools.

BACKGROUND: Olfactory disorders increase with age and often affect elderly people who have pre-dementia or dementia. Despite the frequent occurrence of olfactory changes at the early stages of neurodegenerative disorders such as Alzheimer's disease, olfactory disorders are rarely assessed in daily clinical practice, mainly due to a lack of standardised assessment tools. The aims of this review were to (1) summarise the existing literature on olfactory disorders in ageing populations and patients with neurodegenerative disorders; (2) present the strengths and weaknesses of current olfactory disorder assessment tools; and (3) discuss the benefits of developing specific olfactory tests for neurodegenerative diseases. METHODS: A systematic review was performed of literature published between 2000 and 2015 addressing olfactory disorders in elderly people with or without Alzheimer's disease or other related disorders to identify the main tools currently used for olfactory disorder assessment. RESULTS: Olfactory disorder assessment is a promising method for improving both the early and differential diagnosis of Alzheimer's disease. However, the current lack of consensus on which tests should be used does not permit the consistent integration of olfactory disorder assessment into clinical settings. CONCLUSION: Otolaryngologists are encouraged to use olfactory tests in older adults to help predict the development of neurodegenerative diseases. Olfactory tests should be specifically adapted to assess olfactory disorders in Alzheimer's disease patients.

Selective inhibition of metabotropic glutamate type 1 alpha receptor (mGluR1α) reduces cell proliferation and migration following status epilepticus in early development.

The present study examined whether a single or multiple episode(s) of status epilepticus induced with kainic acid (KA) during the first 3 weeks of postnatal (P) development would aberrantly stimulate proliferation zones that alters migration to potentially injured areas and whether they would be blocked by selective Group I mGluR antagonists. mGluR1α (LY367385) and mGluR5 (MPEP) antagonists were administered 2h following KA-induced status epilepticus and animals were examined after 7days. Proliferating cells of the subventricular zone (SVZ), third ventricle, hippocampus, amygdala cortical complex were analyzed with the proliferative marker, Ki67; and two complementary retrograde dye tracers. Proliferation increased in extrahippocampal limbic structures when KA was administered on P13 or P20 which correlated with number of injured cells at the older age. LY367385 post-treatment caused striking decreases in proliferation in all limbic structures in the presence and absence of injury, whereas a reduction with MPEP was observed only within the amygdala cortical complex (Amg/ERcx) in the presence of multiple seizures (3×KA). After 3×KA and LY367385 post-treatments, diminished co-staining of dye tracers with Ki67 was observed within the Amg/ERcx despite high levels of progenitors marked by the retrograde tracers in this region. This indicates that not only was local proliferation within the SVZ and distant structures inhibited, but also that migration itself was reduced indirectly since there were less cells to migrate from the SVZ. Co-labeling with biomarkers provided evidence for neuronal differentiation suggesting potential aberrant integration may occur in distant locations, and that targeting of mGluR1α receptors may be a potential therapeutic strategy for future development.

Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras.

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3'-OH kinase (PI3K)/Akt cascades. Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, Kras(D12) mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients.

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.

Increased abundance of translation machinery in stem cell-derived neural progenitor cells from four schizophrenia patients.

The genetic and epigenetic factors contributing to risk for schizophrenia (SZ) remain unresolved. Here we demonstrate, for the first time, perturbed global protein translation in human-induced pluripotent stem cell (hiPSC)-derived forebrain neural progenitor cells (NPCs) from four SZ patients relative to six unaffected controls. We report increased total protein levels and protein synthesis, together with two independent sets of quantitative mass spectrometry evidence indicating markedly increased levels of ribosomal and translation initiation and elongation factor proteins, in SZ hiPSC NPCs. We posit that perturbed levels of global protein synthesis in SZ hiPSC NPCs represent a novel post-transcriptional mechanism that might contribute to disease progression.

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.

Designing a standard for strain mapping: HR-EBSD analysis of SiGe thin film structures on Si.

Patterned SiGe thin film structures, heteroepitaxially deposited on Si substrates, are investigated as potential reference standards to establish the accuracy of high resolution electron backscattered diffraction (HR-EBSD) strain measurement methods. The proposed standards incorporate thin films of tetragonally distorted epitaxial Si1-xGex adjacent to strain-free Si. Six films of three different nominal compositions (x=0.2, 0.3, and 0.4) and various thicknesses were studied. Film composition and out-of-plane lattice spacing measurements, by x-ray photoelectron spectroscopy and x-ray diffraction, respectively, provided independent determinations of film epitaxy and predictions of tetragonal strain for direct comparison with HR-EBSD strain measurements. Films assessed to be coherent with the substrate exhibited tetragonal strain values measured by HR-EBSD identical to those predicted from the composition and x-ray diffraction measurements, within experimental relative uncertainties of order 2%. Such films thus provide suitable prototypes for designing a strain reference standard.

Efficacy of Retigabine on Acute Limbic Seizures in Adult Rats.

BACKGROUND AND PURPOSE: The efficacy of retigabine (RGB), a positive allosteric modulator of K+ channels indicated for adjunct treatment of partial seizures, was studied in two adult models of kainic acid (KA)-induced status epilepticus to determine it's toleratbility. METHODS: Retigabine was administered systemiclly at high (5 mg/kg) and low (1-2 mg/kg) doses either 30 min prior to or 2 hr after KA-induced status epilepticus. High (1 µg/µL) and low (0.25 µg/µL) concentrations of RGB were also delivered by intrahippocampal microinjection in the presence of KA. RESULTS: Dose-dependent effects of RGB were observed with both models. Lower doses increased seizure behavior latency and reduced the number of single spikes and synchronized burst events in the electroencephalogram (EEG). Higher doses worsened seizure behavior, produced severe ataxia, and increased spiking activity. Animals treated with RGB that were resistant to seizures did not exhibit significant injury or loss in GluR1 expression; however if stage 5-6 seizures were reached, typical hippocampal injury and depletion of GluR1 subunit protein in vulernable pyramidal fields occurred. CONCLUSIONS: RGB was neuroprotective only if seizures were significantly attenuated. GluR1 was simultaneously suppressed in the resistant granule cell layer in presence of RGB which may weaken excitatory transmission. Biphasic effects observed herein suggest that the human dosage must be carefully scrutinized to produce the optimal clinical response.

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.