Background: Variants in CLCN4 are implicated in neurodevelopmental disorder, X-linked intellectual disability, and epileptic encephalopathy. CLCN4 encodes ClC-4, which is hypothesized to play a role in ion homeostasis and intracellular trafficking. ClC-4 relies on its formation of heterodimers with ClC-3, which possesses signals for target organelles. Methods: Case-Series. Then, we performed heterologous expression, patch-clamp electrophysiology, confocal microscopy, and protein biochemistry experiments to characterize our patients’ ClC-4 variants. Results: All three male patients had developmental and epileptic encephalopathy. Patients #1 and #2 had normal-appearing brains on MRI and no dysmorphic features. Patient #3 had: microcephaly, microsomia, complete agenesis of the corpus-callosum; and, cerebellar and brainstem hypoplasia. Patient #1 had recurrent status epilepticus separated by months of seizure freedom, while Patient #2 and #3 had brief, daily seizures. The p.Gly342Arg variant impaired the heterodimerization capability of ClC-4. The p.Ile549Leu and p.Asp89Asn variants exhibited early transport-activation, with p.Asp89Asn favouring higher transport-activity of ClC-4. Conclusions: We extend the phenotypic spectrum of CLCN4 variants and demonstrate the pathological functional-consequences of three previously unclassified variants. The p.Gly342Arg variant lead to a loss-of-function phenotype; however, the p.Ile549Leu and p.Asp89Asn variants likely caused gain-of-function phenotypes. Targeted animal or induced pluripotent stem-cell models are needed to further understand epileptogenic mechanisms of CLCN4 variants.

Environmental conditions during the early life stages of birds can have significant effects on the quality of sexual signals in adulthood, especially song, and these ultimately have consequences for breeding success and fitness. This has wide-ranging implications for the rehabilitation protocols undertaken in wildlife hospitals which aim to return captive-reared animals to their natural habitat. Here we review the current literature on bird song development and learning in order to determine the potential impact that the rearing of juvenile songbirds in captivity can have on rehabilitation success. We quantify the effects of reduced learning on song structure and relate this to the possible effects on an individual's ability to defend a territory or attract a mate. We show the importance of providing a conspecific auditory model for birds to learn from in the early stages post-fledging, either via live- or tape-tutoring and provide suggestions for tutoring regimes. We also highlight the historical focus on learning in a few model species that has left an information gap in our knowledge for most species reared at wildlife hospitals.

This study aimed to identify behaviours that could be used to assess post-operative pain and analgesic efficacy in male rabbits. In consideration of the ‘Three Rs’, behavioural data were collected on seven male New Zealand White rabbits in an ethically approved experiment requiring abdominal implantation of a telemetric device for purposes other than behavioural assessment. Prior to surgery, rabbits were anaesthetised using an isoflurane/oxygen mix and given Carprofen (2 mg kg−1) as a peri-operative analgesic. Rabbits were housed individually in standard laboratory cages throughout. Data were collected at three time periods: 24-21 h prior to surgery (T1) and, post-surgery, 0-3 h (T2) and 3-6 h (T3). Behavioural changes were identified using Observer XT, significance of which was assessed using a Friedman's test for several related samples. The frequency or duration of numerous pre-operative behaviours was significantly reduced in T2 and T3, as compared to T1. Conversely, novel or rare behaviours had either first occurrence or significant increase in T2 into T3 as compared to T1, these include ‘full-body-flexing’, ‘tight-huddling’, ‘hind-leg-shuffling’. We conclude that reduced expression of common pre-operative behaviours and the appearance of certain novel post-operative behaviours may be indicative of pain in rabbits. Behaviours identified as increased in T2 as compared to T1 but not consistently elevated into T3 were considered separately due to the potentially confounding effect of anaesthesia recovery. These included lateral lying, ‘drawing-back’, ‘staggering’ and ‘closed eyes’. We postulate that for effective application of best-practice post-operative care, informed behavioural observation can provide routes by which carers may identify requirements for additional post-operative analgesia. Additionally, improvement of the peri-operative pain management regimen may be required to ameliorate the immediate effects of abdominal surgery. Comparisons with other studies into post-operative pain expression in rabbits suggest behavioural indicators of pain may differ, depending on housing and surgical procedure.

Background: Sotos syndrome is a genetic condition caused by NSD1 alterations, characterized by overgrowth, macrocephaly, dysmorphic features, and learning disability. Approximately half of children with Sotos syndrome develop seizures. We investigated the spectrum of seizure phenotypes in these patients. Methods: Patients were recruited from clinics and referral from support groups. Those withclinical or genetic diagnosis of Sotos syndrome and seizures were included. Phenotyping data was collected via structured clinical interview and medical chart review. Results: 25 patients with typical Sotos syndrome features were included. Of 14 tested patients, 64% (n=9) had NSD1 alterations. Most had developmental impairment (80%, n=20) and neuropsychiatric comorbidities (68%, n=17). Seizure onset was variable (2 months to 12 years). Febrile and absence seizures were the most frequent types (64%, n=16). Afebrile generalized tonicclonic (40%, n=10) and atonic (24%, n=6) seizures followed. Most patients (60%, n=15) had multiple seizure types. The majority (72%, n=18) was controlled on a single antiepileptic, or none; 4% (n=1) remained refractory to antiepileptics. Conclusions: The seizure phenotype in Sotos syndrome most commonly involves febrile convulsions or absence seizures. Afebrile tonic-clonic or atonic seizures may also occur. Seizures are typically well-controlled with antiepileptics. The rate of developmental impairment and neuropsychiatric comorbidities is high.

The 9th meeting of the African Society of Human Genetics, in partnership with the Senegalese Cancer Research and Study Group and the Human Heredity and Health in Africa (H3Africa) Consortium, was held in Dakar, Senegal. The theme was Strengthening Human Genetics Research in Africa. The 210 delegates came from 21 African countries and from France, Switzerland, UK, UAE, Canada and the USA. The goal was to highlight genetic and genomic science across the African continent with the ultimate goal of improving the health of Africans and those across the globe, and to promote the careers of young African scientists in the field. A session on the sustainability of genomic research in Africa brought to light innovative and practical approaches to supporting research in resource-limited settings and the importance of promoting genetics in academic, research funding, governmental and private sectors. This meeting led to the formation of the Senegalese Society for Human Genetics.

Background: Epileptic encephalopathy (EE) is a severe condition in which epileptic activity itself may contribute to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology alone. Next generation sequencing technologies such as whole exome sequencing (WES) can detect underlying genetic causes of in EE. Methods: This report describes genotype-phenotype correlation of 29 subjects with unexplained epileptic encephalopathy, in whom WES, targeting a list of 557 epilepsy-associated genes was performed. Epilepsy phenotyping was done according to current ILAE recommendations. Results: Median age at seizure onset was 14 months (range 1-48). Electroclinical syndromes were applicable for 16/29, 8/16 had a definite/likely diagnosis. 6/8 subjects with West syndrome had variants in ALG13, STXBP1, PAFAH1B1, SLC35A2, CDKL5 and ADSL. 2 patients with Dravet syndrome had variants in SCN1A and PCDH19 respectively. 4/29 had unspecified EE and definite/likely diagnosis due to STXBP1, POLG, and KCNQ2 (2) variants. 4/29 had a possible diagnosis involving GABRB3, ARHGEF9, PCDH19 and SCN3A variants. Conclusions: The high diagnostic yield (definite/likely diagnosis in 11/29 = 38%), involving a broad variety of epilepsy-associated genes in different electroclinical syndromes justifies the diagnostic approach of early onset EE by next generation sequencing.

Extended abstract of a paper presented at Microscopy and Microanalysis 2010 in Portland, Oregon, USA, August 1 – August 5, 2010.

Extended abstract of a paper presented at Microscopy and Microanalysis 2010 in Portland, Oregon, USA, August 1 – August 5, 2010.

The nonlinear stability of two-phase core-annular flow in a cylindrical pipe is studied. A constant pressure gradient drives the flow of two immiscible liquids of different viscosities and equal densities, and surface tension acts at the interface separating the phases. Insoluble surfactants are included, and we assess their effect on the flow stability and ensuing spatio-temporal dynamics. We achieve this by developing an asymptotic analysis in the limit of a thin annular layer – which is usually the relevant regime in applications – to derive a coupled system of nonlinear evolution equations that govern the dynamics of the interface and the local surfactant concentration on it. In the absence of surfactants the system reduces to the Kuramoto–Sivashinsky (KS) equation, and its modifications due to viscosity stratification (present when the phases have unequal viscosities) are derived elsewhere. We report on extensive numerical experiments to evaluate the effect of surfactants on KS dynamics (including chaotic states, for example), in both the absence and the presence of viscosity stratification. We find that chaos is suppressed in the absence of viscosity differences and that the new flow consists of successive windows (in parameter space) of steady-state travelling waves separated by time-periodic attractors. The intricate structure of the travelling pulses is also explained physically. When viscosity stratification is present we observe a transition from time-periodic dynamics, for instance, to steady-state travelling wave pulses of increasing amplitudes and speeds. Numerical evidence is presented that indicates that the transition occurs through a reverse Feigenbaum cascade in phase space.

Frontal and basal ganglia infarcts and executive dysfunction are thought to be involved in the pathophysiology of poststroke emotional incontinence (PSEI). The study examined whether patients with PSEI have more frontal and/or basal ganglia infarcts and impairment in executive function. A total of 516 Chinese patients with acute ischemic stroke consecutively admitted to the acute stroke unit of a university-affiliated regional hospital in Hong Kong were screened for PSEI 3 months after the index stroke. According to Kim’s criteria, 39 (7.6%) had PSEI. Thirty-nine stroke patients without PSEI served as matched control group. The PSEI group had significantly more frontal and/or basal ganglia infarcts, had lower Chinese Frontal Assessment Battery scores, required more time to complete the Stroop Test, and made more omission and commission errors in the Go–NoGo test. There was no significant correlation between frontal or basal ganglia infarcts and executive function. The correlation between frontal infarct and severity of PSEI was .420. Further follow-up and functional imaging studies are warranted to explore the relationship between PSEI, brain infarcts, and executive dysfunction. (JINS, 2009, 15, 62–68.)

Background. The global toll of suicide is estimated to be one million lives per year, which exceeded the number of deaths by homicide and war combined. A key step to suicide prevention is to prevent less serious suicidal behaviour to preclude more lethal outcomes. Although 61% of the world's suicides take place in Asia and the suicide rates among middle age groups have been increasing since the economic crisis in many Asian countries, population-based studies of suicidal behaviour among working-age adults in non-western communities are scarce.

Method. Data from a population-based survey with 2015 participants were used to estimate the prevalence of suicidal ideation and behaviour among the working-age population in Hong Kong, and to study the associated socio-economic and psychological correlates. We focused particularly on potential modulating factors between life-event-related factors and suicidal ideation.

Results. Six per cent of the Hong Kong population aged 20–59 years considered suicide in the past year, while 1·4% attempted suicide. Hopelessness, reasons for living, and reluctance to seek help from family and friends had direct association with past-year suicidal ideation. Reasons for living were found to moderate the effect of perceived stress on suicidal ideation.

Conclusions. Suicidality is a multi-faceted problem that calls for a multi-sectored, multi-layered approach to prevention. Prevention programmes can work on modulating factors such as reasons for living to reduce suicidal risk in working-age adults.

China is the only country in which the suicide rate is higher among women than men. We provide a demographic perspective on the gender differential in suicide in China. This shows that the male/female ratio of suicide increased between 1991 and 2001 and there is reason to believe this trend will continue. Among the population subgroups, only young women living in rural areas had much higher suicide rates than their male counterparts. It is argued that consideration of the gender ratio of suicide in China must take age-, gender- and region-specific suicide patterns and the population structure into account. The increasing urbanisation of China is likely to be associated with more male suicides and we predict that before long the male suicide rate will overtake that of females.