Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy

Objective Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies. Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein. Design Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells. Results The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures. Conclusion The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient

An analysis of the relationship between being deaf and sexual offending

Female Genital Schistosomiasis (FGS) is a neglected disease affecting millions, however challenging to diagnose. This explorative descriptive study compares Schistosoma real-time PCR analysis of cervico-vaginal lavages (CVL) with corresponding urine and stool samples of 933 women from five different previously described study populations. Sampling included 310 women from an S. mansoni endemic region in Mwanza, Tanzania and 112 women from a nearby S. haematobium endemic region. Findings were compared with samples collected from S. haematobium endemic regions in South Africa from 394 women and from 117 women from Madagascar of which 79 were urine pre-selected microscopy positive cases from highly-endemic communities and 38 were urine microscopy negatives from a low-endemic community. As anticipated, urine and stool microscopy and gynecological investigations varied substantially between study populations; however, the same Schistosoma real-time PCR was performed in one reference laboratory. Schistosoma DNA was detected in 13% (120/933) of the CVL, ranging from 3% in the S. mansoni Tanzanian endemic region to 61% in the pre-selected Malagasy urine microscopy positive cases. Detectable Schistosoma DNA in CVL was associated with Schistosoma DNA in urine but not with microscopic detection of eggs in urine or by cytological examination. This study confirmed real-time PCR for the detection of Schistosoma DNA in gynecological samples to be a valuable diagnostic tool to study the distribution of FGS within schistosomiasis endemic areas.Host-parasite interactio

Mark correlations: relating physical properties to spatial distributions

Mark correlations provide a systematic approach to look at objects both distributed in space and bearing intrinsic information, for instance on physical properties. The interplay of the objects' properties (marks) with the spatial clustering is of vivid interest for many applications; are, e.g., galaxies with high luminosities more strongly clustered than dim ones? Do neighbored pores in a sandstone have similar sizes? How does the shape of impact craters on a planet depend on the geological surface properties? In this article, we give an introduction into the appropriate mathematical framework to deal with such questions, i.e. the theory of marked point processes. After having clarified the notion of segregation effects, we define universal test quantities applicable to realizations of a marked point processes. We show their power using concrete data sets in analyzing the luminosity-dependence of the galaxy clustering, the alignment of dark matter halos in gravitational $N$-body simulations, the morphology- and diameter-dependence of the Martian crater distribution and the size correlations of pores in sandstone. In order to understand our data in more detail, we discuss the Boolean depletion model, the random field model and the Cox random field model. The first model describes depletion effects in the distribution of Martian craters and pores in sandstone, whereas the last one accounts at least qualitatively for the observed luminosity-dependence of the galaxy clustering.Comment: 35 pages, 12 figures. to be published in Lecture Notes of Physics, second Wuppertal conference "Spatial statistics and statistical physics

Novel biomarkers to detect occult cancer in patients with unprovoked venous thromboembolism: Rationale and design of the PLATO-VTE study

Occult cancer is detected in about 5% of patients with unprovoked venous thromboembolism (VTE) in the 12 months following VTE diagnosis. Current guidance suggests conducting a ‘limited’ cancer screening in these patients, consisting of medical history taking, physical examination, routine blood tests, chest X-ray, and age- and gender-specific testing, over full-body imaging. However, almost half of underlying cancers remain undetected with this approach. Blood-based liquid biopsies may provide an attractive addition or alternative to current cancer screening strategies, with a potentially higher detection rate while avoiding radiation or invasive testing. The PLATO-VTE study is an ongoing, investigator-initiated, multinational, prospective, observational cohort study comparing the sensitivity of novel biomarkers for detecting cancer with that of limited cancer screening in the setting of unprovoked VTE. Patients older than 40 years with a first episode of unprovoked VTE are eligible, while those with major and minor transient provoking risk factors for VTE are excluded. Patients undergo standard-of-care ‘limited’ cancer screening and are followed for 12 months for the occurrence of cancer. A blood sample for biomarker analysis is drawn within 10 days; a second sample is taken at 3 months to assess test result consistency over time. Three biomarkers are assessed: platelet mRNA, circulating tumor DNA, and plasma proteomics analysis. The sensitivity and predictive value of the biomarkers at baseline will be compared with those of limited screening. The results from the PLATO-VTE study may lead to reconsider current approaches for cancer screening in patients with unprovoked VTE

Epidemiology of Plasmodium infections in Flores Island, Indonesia using real-time PCR

BACKGROUND:\ud DNA-based diagnostic methods have been shown to be highly sensitive and specific for the detection of malaria. An 18S-rRNA-based, real-time polymerase chain reaction (PCR) was used to determine the prevalence and intensity of Plasmodium infections on Flores Island, Indonesia.\ud METHODS:\ud Microscopy and real-time multiplex PCR for the detection of Plasmodium species was performed on blood samples collected in a population-based study in Nangapanda Flores Island, Indonesia.\ud RESULTS:\ud A total 1,509 blood samples were analysed. Real-time PCR revealed prevalence for Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae to be 14.5%, 13.2%, and 1.9% respectively. Sub-microscopic parasitaemia were found in more than 80% of all positive cases. The prevalence of P. falciparum and P. vivax was significantly higher in subjects younger than 20 years (p <= 0.01). In the present study, among non-symptomatic healthy individuals, anaemia was strongly correlated with the prevalence and load of P. falciparum infections (p <= 0.01; p = 0.02) and with the load of P. vivax infections (p = 0.01) as detected with real-time PCR. Subjects with AB blood group tend to have a higher risk of being infected with P. falciparum and P. vivax when compared to other blood groups.\ud CONCLUSION:\ud The present study has shown that real-time PCR provides more insight in the epidemiology of Plasmodium infections and can be used as a monitoring tool in the battle against malaria. The unsurpassed sensitivity of real-time PCR reveals that sub microscopic infections are common in this area, which are likely to play an important role in transmission and control.Trial registration: Trials number ISRCTN83830814

The capability set for work - correlates of sustainable employability in workers with multiple sclerosis

BACKGROUND: The aim of this study was to examine whether work capabilities differ between workers with Multiple Sclerosis (MS) and workers from the general population. The second aim was to investigate whether the capability set was related to work and health outcomes. METHODS: A total of 163 workers with MS from the MS@Work study and 163 workers from the general population were matched for gender, age, educational level and working hours. All participants completed online questionnaires on demographics, health and work functioning. The Capability Set for Work Questionnaire was used to explore whether a set of seven work values is considered valuable (A), is enabled in the work context (B), and can be achieved by the individual (C). When all three criteria are met a work value can be considered part of the individual's 'capability set'. RESULTS: Group differences and relationships with work and health outcomes were examined. Despite lower physical work functioning (U = 4250, p = 0.001), lower work ability (U = 10591, p = 0.006) and worse self-reported health (U = 9091, p ≤ 0.001) workers with MS had a larger capability set (U = 9649, p ≤ 0.001) than the general population. In workers with MS, a larger capability set was associated with better flexible work functioning (r = 0.30), work ability (r = 0.25), self-rated health (r = 0.25); and with less absenteeism (r = - 0.26), presenteeism (r = - 0.31), cognitive/neuropsychiatric impairment (r = - 0.35), depression (r = - 0.43), anxiety (r = - 0.31) and fatigue (r = - 0.34). CONCLUSIONS: Workers with MS have a larger capability set than workers from the general population. In workers with MS a larger capability set was associated with better work and health outcomes. TRIAL REGISTRATION: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. The study is registered at the Dutch CCMO register ( https://www.toetsingonline.nl ). This study is approved by the METC Brabant, 12 February 2014. First participants are enrolled 1st of March 2014

Cost-utility of medication withdrawal in older fallers: results from the improving medication prescribing to reduce risk of FALLs (IMPROveFALL) trial

Background: The use of Fall-Risk-Increasing-Drugs (FRIDs) has been associated with increased risk of falls and associated injuries. This study investigates the effect of withdrawal of FRIDs versus 'care as usual' on health-related quality of life (HRQoL), costs, and cost-utility in community-dwelling older fallers. Methods: In a prospective multicenter randomized controlled trial FRIDs assessment combined with FRIDs-withdrawal or modification was compared with 'care as usual' in older persons, who visited the emergency department after experiencing a fall. For the calculation of costs the direct medical costs (intramural and extramural) and indirect costs (travel costs) were collected for a 12 month period. HRQoL was measured at baseline and at 12 months follow-up using the EuroQol-5D and Short Form-12 version 2. The change in EuroQol-5D and Short Form-12 scores over 12 months follow-up within the control and intervention groups was compared using the Wilcoxon Signed Rank test for continuous variables and the McNemar test for dichotomous variables. The change in scores between the control and intervention groups were compared using a two-way analysis of variance. Results: We included 612 older persons who visited an emergency department because of a fall. The mean cost of the FRIDs intervention was €120 per patient. The total fall-related healthcare costs (without the intervention costs) did not differ significantly between the intervention group and the control group (€2204 versus €2285). However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant. Furthermore, the control group had a greater decline in EuroQol-5D utility score during the 12-months follow-up than the intervention group (p = 0.02). The change in the Short Form-12 Physical Component Summary and Mental Component Summary scores did not differ significantly between the two groups. Conclusions: Withdrawal of FRID's in older persons who visited an emergency department due to a fall, did not lead to reduction of total health-care costs. However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant in combination with less decline in HRQoL is an important result