Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Movement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a critical postsynaptic signaling pathway in medium spiny neurons. Here, we review the clinical presentation, genetic findings, and disease mechanisms that characterize these genetic postsynaptic movement disorders

Computational modelling in source space from scalp EEG to inform presurgical evaluation of epilepsy

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordObjective: The effectiveness of intracranial electroencephalography (iEEG) to inform epilepsy surgery depends on where iEEG electrodes are implanted. This decision is informed by noninvasive recording modalities such as scalp EEG. Herein we propose a framework to interrogate scalp EEG and determine epilepsy lateralization to aid in electrode implantation. Methods: We use eLORETA to map source activities from seizure epochs recorded from scalp EEG and consider 15 regions of interest (ROIs). Functional networks are then constructed using the phase-locking value and studied using a mathematical model. By removing different ROIs from the network and simulating their impact on the network’s ability to generate seizures in silico, the framework provides predictions of epilepsy lateralization. We consider 15 individuals from the EPILEPSIAE database and study a total of 62 seizures. Results were assessed by taking into account actual intracranial implantations and surgical outcome. Results: The framework provided potentially useful information regarding epilepsy lateralization in 12 out of the 15 individuals (p=0.02, binomial test). Conclusions: Our results show promise for the use of this framework to better interrogate scalp EEG to determine epilepsy lateralization. Significance: The framework may aid clinicians in the decision process to define where to implant electrodes for intracranial monitoring.Medical Research CouncilEpilepsy Research UKEngineering and Physical Sciences Research Council (EPSRC)Wellcome TrustEngineering and Physical Sciences Research Council (EPSRC)Innovate UKEuropean Union’s Horizon 2020Alzheimer's SocietyMedical Research Counci

Pelvic actinomycosis presenting as a malignant pelvic mass: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pelvic actinomycosis constitutes 3% of all human actinomycosis infections. It is usually insidious, and is often mistaken for other conditions such as diverticulitis, abscesses, inflammatory bowel disease and malignant tumors, presenting a diagnostic challenge pre-operatively; it is identified post-operatively in most cases. Here we present a case that presented as pelvic malignancy and was diagnosed as pelvic actinomycosis post-operatively.</p> <p>Case presentation</p> <p>A 48-year-old Caucasian Turkish woman presented to our clinic with a three-month history of abdominal pain, weight loss and difficulty in defecation. She had used an intra-uterine device for 16 years, however it had recently been removed. The rectosigmoidoscopy revealed narrowing of the lumen at 12 cm due to a mass lesion either in the wall or due to an extrinsic lesion that prevented the passage of the endoscope. On examination, there was no gynecological pathology. Magnetic resonance imaging showed a mass, measuring 5.5 × 4 cm attached to the rectum posterior to the uterus. The ureter on that side was dilated. Surgically there was a pelvic mass adhered to the rectum and uterine adnexes, measuring 10 × 12 cm. It originated from uterine adnexes, particularly ones from the left side and formed a conglomerated mass with the uterus and nearby organs; the left ureter was also dilated due to the pelvic mass. Because of concomitant tubal abscess formation and difficulty in dissection planes, total abdominal hysterectomy and bilateral salphingo-oophorectomy was performed (our patient was 48 years old and had completed her childbearing period). The cytology revealed inflammatory cells with aggregates of <it>Actinomyces</it>. Penicillin therapy was given for six months without any complication.</p> <p>Conclusions</p> <p>Pelvic actinomycosis should always be considered in patients with a pelvic mass especially in ones using intra-uterine devices, and who have a history of appendectomy, tonsillectomy or dental infection. Surgeons should be aware of this infection in order to avoid excessive surgical procedures.</p

Hyperlipidemia and Atherosclerotic Lesion Development in Ldlr-Deficient Mice on a Long-Term High-Fat Diet

BACKGROUND: Mice deficient in the LDL receptor (Ldlr(-/-) mice) have been widely used as a model to mimic human atherosclerosis. However, the time-course of atherosclerotic lesion development and distribution of lesions at specific time-points are yet to be established. The current study sought to determine the progression and distribution of lesions in Ldlr(-/-) mice. METHODOLOGY/PRINCIPAL FINDINGS: Ldlr-deficient mice fed regular chow or a high-fat (HF) diet for 0.5 to 12 months were analyzed for atherosclerotic lesions with en face and cross-sectional imaging. Mice displayed significant individual differences in lesion development when fed a chow diet, whereas those on a HF diet developed lesions in a time-dependent and site-selective manner. Specifically, mice subjected to the HF diet showed slight atherosclerotic lesions distributed exclusively in the aortic roots or innominate artery before 3 months. Lesions extended to the thoracic aorta at 6 months and abdominal aorta at 9 months. Cross-sectional analysis revealed the presence of advanced lesions in the aortic sinus after 3 months in the group on the HF diet and in the innominate artery at 6 to 9 months. The HF diet additionally resulted in increased total cholesterol, LDL, glucose, and HBA1c levels, along with the complication of obesity. CONCLUSIONS/SIGNIFICANCE: Ldlr-deficient mice on the HF diet tend to develop site-selective and size-specific atherosclerotic lesions over time. The current study should provide information on diet induction or drug intervention times and facilitate estimation of the appropriate locations of atherosclerotic lesions in Ldlr(-/-) mice

Planck scale effects in neutrino physics

We study the phenomenology and cosmology of the Majoron (flavon) models of three active and one inert neutrino paying special attention to the possible (almost) conserved generalization of the Zeldovich-Konopinski-Mahmoud lepton charge. Using Planck scale physics effects which provide the breaking of the lepton charge, we show how in this picture one can incorporate the solutions to some of the central issues in neutrino physics such as the solar and atmospheric neutrino puzzles, dark matter and a 17 keV neutrino. These gravitational effects induce tiny Majorana mass terms for neutrinos and considerable masses for flavons. The cosmological demand for the sufficiently fast decay of flavons implies a lower limit on the electron neutrino mass in the range of 0.1-1 eV.Comment: 24 pages, 1 figure (not included but available upon request), LaTex, IC/92/196, SISSA-140/92/EP, LMU-09/9

Intraplaque haemorrhages as the trigger of plaque vulnerability

Atherothrombosis remains one of the main causes of morbidity and mortality in the western countries. Human atherothrombotic disease begins early in life in relation to circulating lipid retention in the inner vascular wall. Risk factors enhance the progression towards clinical expression: dyslipidaemia, diabetes, smoking, hypertension, ageing, etc. The evolution from the initial lipid retention in the arterial wall to clinical events is a continuum of increasingly complex biological processes. Current strategies to fight the consequences of atherothrombosis are orientated either towards the promotion of a healthy life style1 and preventive treatment of risk factors, or towards late interventional strategies.2 Despite this therapeutic arsenal, the incidence of clinical events remains dramatically high,3 dependent, at least in part, on the increasing frequency of type 2 diabetes and ageing. But some medical treatments, focusing only on prevention of the metabolic risk, have failed to reduce cardiovascular mortality, thus illustrating that our understanding of the pathophysiology of human atherothrombosis leading to clinical events remain incomplete. New paradigms are now emerging which may give rise to novel experimental strategies to improve therapeutic efficacy and prediction of disease progression. Recent studies strengthen the concept that the intraplaque neovascularization and bleeding (Figure 1, upper panel) are events that could play a major role in plaque progression and leucocyte infiltration, and may also serve as a measure of risk for the development of future events. The recent advances in our understanding of IntraPlaque Hemorrhage as a critical event in triggering acute clinical events have important implications for clinical research and possibly future clinical practice. Figure 1Macroscopic view and schematic representation of the detrimental consequences of intraplaque haemorrhages on plaque biology and stability

Towards screening Barrett’s Oesophagus: current guidelines, imaging modalities and future developments

Barrett’s oesophagus is the only known precursor to oesophageal adenocarcinoma (OAC). Although guidelines on the screening and surveillance exist in Barrett’s oesophagus, the current strategies are inadequate. Oesophagogastroduodenoscopy (OGD) is the gold standard method in screening for Barrett’s oesophagus. This invasive method is expensive with associated risks negating its use as a current screening tool for Barrett’s oesophagus. This review explores current definitions, epidemiology, biomarkers, surveillance, and screening in Barrett’s oesophagus. Imaging modalities applicable to this condition are discussed, in addition to future developments. There is an urgent need for an alternative non-invasive method of screening and/or surveillance which could be highly beneficial towards reducing waiting times, alleviating patient fears and reducing future costs in current healthcare services. Vibrational spectroscopy has been shown to be promising in categorising Barrett’s oesophagus through to high-grade dysplasia (HGD) and OAC. These techniques need further validation through multicentre trials

A brief early intervention for adolescent depression that targets emotional mental images and memories: protocol for a feasibility randomised controlled trial (IMAGINE trial)

This is the final version of the article. Available from BioMed Central via the DOI in this record.Background: Adolescent depression is common and impairing. There is an urgent need to develop early interventions to prevent depression becoming entrenched. However, current psychological interventions are difficult to access and show limited evidence of effectiveness. Schools offer a promising setting to enhance access to interventions, including reducing common barriers such as time away from education. Distressing negative mental images and a deficit in positive future images, alongside overgeneral autobiographical memories, have been implicated in depression across the lifespan, and interventions targeting them in adults have shown promise. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This feasibility randomised controlled trial will test the feasibility and acceptability of delivering this imagery-based cognitive behavioural intervention in schools. Methods/design: Fifty-six adolescents (aged 16-18) with high symptoms of depression will be recruited from schools. Participants will be randomly allocated to the imagery-based cognitive behavioural intervention (ICBI) or the control intervention, non-directive supportive therapy (NDST). Data on feasibility and acceptability will be recorded throughout, including data on recruitment, retention and adherence rates as well as adverse events. In addition, symptom assessment will take place pre-intervention, post-intervention and at 3-month follow-up. Primarily, the trial aims to establish whether it is feasible and acceptable to carry out this project in a school setting. Secondary objectives include collecting data on clinical measures, including depression and anxiety, and measures of the mechanisms proposed to be targeted by the intervention. The acceptability of using technology in assessment and treatment will also be evaluated. Discussion: Feasibility, acceptability and symptom data for this brief intervention will inform whether an efficacy randomised controlled trial is warranted and aid planning of this trial. If this intervention is shown in a subsequent definitive trial to be safe, clinically effective and cost-effective, it has potential to be rolled out as an intervention and so would significantly extend the range of therapies available for adolescent depression. This psychological intervention draws on cognitive mechanism research suggesting a powerful relationship between emotion and memory and uses imagery as a cognitive target in an attempt to improve interventions for adolescent depression. Trial registration: ISRCTN85369879.This study represents independent research from a Clinical Doctoral Research Fellowship (Dr Victoria Pile, ICA-CDRF-2015-01-007) supported by the National Institute for Health Research and Health Education England

In Search of HPA Axis Dysregulation in Child and Adolescent Depression

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression