Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations

Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua, which often necessitate admission to the intensive care unit (ICU) and pose an important mortality risk. We describe two previously healthy unrelated teenage girls, who both were admitted with generalized tonic-clonic seizures and visual symptoms leading to a DNA-supported diagnosis of juvenile-onset Alpers' syndrome. Despite combined treatment with anti-epileptic drugs, both patients developed status epilepticus requiring admission to the ICU. Intravenous magnesium as anti-convulsant therapy was initiated, resulting in clinical and neurophysiological improvement and rapid extubation of both patients. Treating status epilepticus in juvenile-onset Alpers' syndrome with magnesium has not been described previously. Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered

Controlling epidemic spread by social distancing: Do it well or not at all

BACKGROUND: Existing epidemiological models have largely tended to neglect the impact of individual behaviour on the dynamics of diseases. However, awareness of the presence of illness can cause people to change their behaviour by, for example, staying at home and avoiding social contacts. Such changes can be used to control epidemics but they exact an economic cost. Our aim is to study the costs and benefits of using individual-based social distancing undertaken by healthy individuals as a form of control.METHODS: Our model is a standard SIR model superimposed on a spatial network, without and with addition of small-world interactions. Disease spread is controlled by allowing susceptible individuals to temporarily reduce their social contacts in response to the presence of infection within their local neighbourhood. We ascribe an economic cost to the loss of social contacts, and weigh this against the economic benefit gained by reducing the impact of the epidemic. We study the sensitivity of the results to two key parameters, the individuals' attitude to risk and the size of the awareness neighbourhood.RESULTS: Depending on the characteristics of the epidemic and on the relative economic importance of making contacts versus avoiding infection, the optimal control is one of two extremes: either to adopt a highly cautious control, thereby suppressing the epidemic quickly by drastically reducing contacts as soon as disease is detected; or else to forego control and allow the epidemic to run its course. The worst outcome arises when control is attempted, but not cautiously enough to cause the epidemic to be suppressed. The next main result comes from comparing the size of the neighbourhood of which individuals are aware to that of the neighbourhood within which transmission can occur. The control works best when these sizes match and is particularly ineffective when the awareness neighbourhood is smaller than the infection neighbourhood. The results are robust with respect to inclusion of long-range, small-world links which destroy the spatial structure, regardless of whether individuals can or cannot control them. However, addition of many non-local links eventually makes control ineffective.CONCLUSIONS: These results have implications for the design of control strategies using social distancing: a control that is too weak or based upon inaccurate knowledge, may give a worse outcome than doing nothing

Cognitive behavioural therapy versus supportive therapy for persistent positive symptoms in psychotic disorders: The POSITIVE Study, a multicenter, prospective, single-blind, randomised controlled clinical trial

Background: It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. Methods: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. Discussion: This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders. Trial Registration Current Controlled Trials ISRCTN2924287

Phylogeography of Supralittoral Rocky Intertidal Ligia Isopods in the Pacific Region from Central California to Central Mexico

Ligia isopods are widely distributed in the Pacific rocky intertidal shores from central California to central Mexico, including the Gulf of California. Yet, their biological characteristics restrict them to complete their life cycles in a very narrow range of the rocky intertidal supralittoral. Herein, we examine phylogeographic patterns of Ligia isopods from 122 localities between central California and central Mexico. We expect to find high levels of allopatric diversity. In addition, we expect the phylogeographic patterns to show signatures of past vicariant events that occurred in this geologically dynamic region.We sequenced two mitochondrial genes (Cytochrome Oxidase I and 16S ribosomal DNA). We conducted Maximum Likelihood and Bayesian phylogenetic analyses. We found many divergent clades that, in general, group according to geography. Some of the most striking features of the Ligia phylogeographic pattern include: (1) deep mid-peninsular phylogeographic breaks on the Pacific and Gulf sides of Baja peninsula; (2) within the Gulf lineages, the northern peninsula is most closely related to the northern mainland, while the southern peninsula is most closely related to the central-southern mainland; and, (3) the southernmost portion of the peninsula (Cape Region) is most closely related to the southernmost portion of mainland.Our results shed light on the phylogenetic relationships of Ligia populations in the study area. This study probably represents the finest-scale phylogeographic examination for any organism to date in this region. Presence of highly divergent lineages suggests multiple Ligia species exist in this region. The phylogeographic patterns of Ligia in the Gulf of California and Baja peninsula are incongruent with a widely accepted vicariant scenario among phylogeographers, but consistent with aspects of alternative geological hypotheses and phylo- and biogeographic patterns of several other taxa. Our findings contribute to the ongoing debate regarding the geological origin of this important biogeographic region

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

[This corrects the article DOI: 10.1186/s13601-016-0116-9.]