The environmental epidemiology of primary dystonia

Background: Dystonia is a movement disorder characterized by involuntary muscle contractions that cause twisting movements and abnormal postures. Primary dystonia is the most common form and is thought to be a multifactorial condition in which one or more genes combine with environmental factors to reach disease. Methods: We reviewed controlled studies on possible environmental risk factors for primary early‐ and late‐onset dystonia. Results: Environmental factors associated with primary early‐onset dystonia are poorly understood. Early childhood illnesses have been reported to be more frequent in patients with DYT1 dystonia than in subjects carrying the DYT1 mutation that did not manifest dystonia, thus raising the possibility that such exposures precipitate dystonia among DYT1 carriers. Conversely, several environmental factors have been associated with primary adult‐onset focal dystonias compared to control subjects. Namely, eye diseases, sore throat, idiopathic scoliosis, and repetitive upper limb motor action seem to be associated with blepharospasm (BSP), laryngeal dystonia (LD), cervical dystonia (CD), and upper limb dystonia, respectively. In addition, an inverse association between coffee drinking and BSP has been observed in both case‐unrelated control and family‐based case‐control studies. Additional evidence supporting a causal link with different forms of primary late‐onset dystonia is only available for diseases of the anterior segment of the eye, writing activity, and coffee intake. Conclusion: There is reasonable epidemiological evidence that some environmental factors are risk‐modifying factors for specific forms of primary adult‐onset focal dystonia

Damage-induced phosphorylation of Sld3 is important to block late origin firing.

Origins of replication are activated throughout the S phase of the cell cycle such that some origins fire early and others fire late to ensure that each chromosome is completely replicated in a timely fashion. However, in response to DNA damage or replication fork stalling, eukaryotic cells block activation of unfired origins. Human cells derived from patients with ataxia telangiectasia are deficient in this process due to the lack of a functional ataxia telangiectasia mutated (ATM) kinase and elicit radioresistant DNA synthesis after γ-irradiation(2). This effect is conserved in budding yeast, as yeast cells lacking the related kinase Mec1 (ATM and Rad3-related (ATR in humans)) also fail to inhibit DNA synthesis in the presence of DNA damage. This intra-S-phase checkpoint actively regulates DNA synthesis by inhibiting the firing of late replicating origins, and this inhibition requires both Mec1 and the downstream checkpoint kinase Rad53 (Chk2 in humans). However, the Rad53 substrate(s) whose phosphorylation is required to mediate this function has remained unknown. Here we show that the replication initiation protein Sld3 is phosphorylated by Rad53, and that this phosphorylation, along with phosphorylation of the Cdc7 kinase regulatory subunit Dbf4, blocks late origin firing in Saccharomyces cerevisiae. Upon exposure to DNA-damaging agents, cells expressing non-phosphorylatable alleles of SLD3 and DBF4 (SLD3-m25 and dbf4-m25, respectively) proceed through the S phase faster than wild-type cells by inappropriately firing late origins of replication. SLD3-m25 dbf4-m25 cells grow poorly in the presence of the replication inhibitor hydroxyurea and accumulate multiple Rad52 foci. Moreover, SLD3-m25 dbf4-m25 cells are delayed in recovering from transient blocks to replication and subsequently arrest at the DNA damage checkpoint. These data indicate that the intra-S-phase checkpoint functions to block late origin firing in adverse conditions to prevent genomic instability and maximize cell survival

Functional neurological disorders as seen by a cohort of general practitioners in northern italy: Evidence from an online survey

General practitioners (GPs) provide primary care and advise their patients on which diagnostic and therapeutic pathways they judge most appropriate. For patients with functional neurological disorders (FND), receiving a proper explanation of diagnosis by their GP from the very beginning may drastically improve prognosis. Novel approaches to the diagnosis and treatment of FND have important implications for effective management. The aim of this study was to investigate Italian GP opinion and knowledge about FND in light of new approaches to the illness. To do this, we evaluated the responses to a 13-item web-based survey completed by 133 GPs practicing in northern Italy. Psychological terms to describe FND were more frequently used than functional neurological disorder and mental illness was considered an important predictor of diagnosis. Referral to a neurologist rather than to a psychiatrist was largely preferred, while physiotherapy consultation was seldom recognized as a valuable approach to treating FND. Overall, the survey findings suggest that knowledge about novel approaches to FND is somewhat lacking. Currently, GPs appear to be transitioning from a classical psychological view of the disorder toward a more modern conceptualization, in which neurobiological, psychological, and social factors all play an important role. Professional education during this transition would be an advantageous way to optimize physician management of FND and to enhance diagnosis, explanation, and management across primary and secondary care pathways

Reshaping cortical connectivity in traumatic spinal cord injury: a novel effect of hyperbaric oxygen therapy

Introduction: Spinal cord injuries (SCIs) represent a severe neuro-traumatic occurrence and an excruciating social burden. Though the hyperbaric oxygen (HBO2) has been credited as a first line therapeutic resource for SCIs, its mechanism of action in the spine is only partially known, while the impingement upon other areas of the nervous system deserves additional investigation. In this study we deem to describe a novel effect of HBO2 in a subject affected by SCI who, along with the clinical improvement, showed a reshaped connectivity in cortical sensory-motor areas. Case presentation: A 45 years male presenting severe sensory-motor symptoms following a spinal lesion partially involving the C1 segment was successfully treated with HBO2 cycles. After the dramatic improvement reflected by an excellent optimization of the single performances, it has been investigated whether this result would reveal not only an intrinsic effect upon the spinal cord, but also a better connectivity strength in sensory-motor cortical regions. The results obtained by implementing EEG recordings with EEGLAB auto regressive vector plugins indeed suggest a substantial reshaping of cortico-cortical connectivity after HBO2. Discussion: These results show a correlation between positive clinical evolution and a new modulation of cortical connectivity. Though further clinical investigations would clarify as to whether HBO2 might be directly or epiphenomenally involved in this aspect of the network architecture, our report suggests that a comparison between clinical results and the study of brain connectivity represent a holistic approach in investigating the physiopathology of SCIs and in monitoring the treatment

The effect of stimulation frequency on transcranial evoked potentials

Introduction - Transcranial magnetic stimulation-evoked electroencephalography potentials (TEPs) have been used to study motor cortical excitability in healthy subjects and several neurological conditions. However, optimal recording parameters for TEPs are still debated. Stimulation rates could affect TEP amplitude due to plasticity effects, thus confounding the assessment of cortical excitability. We tested whether short interpulse intervals (IPIs) affect TEP amplitude.Methods - We investigated possible changes in TEP amplitude and global mean field amplitude (GMFA) obtained with stimulation of the primary motor cortex at IPIs of 1.1-1.4 s in a group of healthy subjects.Results - We found no differences in TEP amplitude or GMFA between the first, second and last third of trials.Discussion - Short IPIs do not affect TEP size and can be used without the risk of confounding effects due to short-term plasticity

Botulinum toxin A treatment for primary hemifacial spasm - A 10-year multicenter study

BACKGROUND: Botulinum toxin A (BTX) is the currently preferred symptomatic treatment for primary hemifacial spasm (HFS), but its long-term efficacy and safety are not known. OBJECTIVE: To assess the long-term effectiveness and safety of BTX in the treatment of primary HFS. DESIGN: Retrospective review of medical records of the 1st and 10th years of treatment. SETTING: Outpatient clinics of 4 Italian university centers in the Italian Movement Disorders Study Group. PARTICIPANTS: A series of 65 patients with primary HFS who had received BTX injections regularly for at least 10 years. MAIN OUTCOME MEASURES: Mean duration of improvement and quality of the effect induced by the preceding treatment (measured using a patient self-evaluation scale) and occurrence and duration of adverse effects in the 1st and 10th years of treatment. RESULTS: Using a mean BTX dose per treatment session similar to that used by others, we obtained a 95% response rate and an overall mean duration of improvement of 12.6 weeks during year 1. The effectiveness of BTX in relieving the symptoms of primary HFS, as measured by the response rate and average duration of improvement, remained unchanged in the 1st and 10th years. Patients needed statistically similar BTX doses in the 1st and 10th years. The rate of local adverse effects (including upper lid ptosis, facial weakness, and diplopia) diminished significantly in the 10th year of treatment. CONCLUSION: Treatment with BTX effectively induces sustained relief from symptoms of HFS in the long term, with only minimal and transient adverse reactions

Gait analysis and quantitative drug effect evaluation in Parkinson disease by jointly EEG-EMG monitoring

This work addresses the rising need for a diagnostic tool for the evaluation of the effectiveness of a drug treatment in Parkinson disease, allowing the physician to monitor of the patient gait at home and to shape the treatment on the individual peculiarity. In aim, we present a cyber-physical system for real-time processing EEG and EMG signals. The wearable and wireless system extracts the following indexes: (i) typical activation and deactivation timing of single muscles and the duty cycle in a single step (ii) typical and maximum co-contractions, as well as number of co-contraction/s. The indexes are validated by using Movement Related Potentials (MRPs). The signal processing stage is implemented on Altera Cyclone V FPGA. In the paper, we show in vivo measurements by comparing responses before and after the drug (Levodopa) treatment. The system quantifies the effect of the Levodopa treatment detecting: (i) a 17% reduction in typical agonist-antagonist co-contractions time (ii) 23.6% decrease in the maximum co-contraction time (iii) 33% decrease in number of critical co-contraction. Brain implications shows a mean reduction of 5% on the evaluated potentials

Tactile and proprioceptive temporal discrimination are impaired in functional tremor

Background and Methods: In order to obtain further information on the pathophysiology of functional tremor, we assessed tactile discrimination threshold and proprioceptive temporal discrimination motor threshold values in 11 patients with functional tremor, 11 age- and sex-matched patients with essential tremor and 13 healthy controls. Results: Tactile discrimination threshold in both the right and left side was significantly higher in patients with functional tremor than in the other groups. Proprioceptive temporal discrimination threshold for both right and left side was significantly higher in patients with functional and essential tremor than in healthy controls. No significant correlation between discrimination thresholds and duration or severity of tremor was found. Conclusions: Temporal processing of tactile and proprioceptive stimuli is impaired in patients with functional tremor. The mechanisms underlying this impaired somatosensory processing and possible ways to apply these findings clinically merit further research

Abstract: Analysis of acute skin rejection in non-human primate models of face and hand allotransplantation

Introduction: The incidence of acute rejection (AR) of the skin within the first year after hand or face transplantation is approximately 85% and up to 56% of patients experience multiple episodes1. Significant immunosuppression is required to prevent allograft loss, and recent studies suggest that repeated AR episodes can lead to VCA dysfunction and loss2. The mechanisms underlying variability in AR presentation remain poorly defined however. Materials and Methods: 8 cynomolgus monkeys received either an orthotopic hand (n=2) or heterotopic face VCA (n=6) from MHC-mismatched donors following induction with anti-thymocyte globulin. Post-operatively, triple immunosuppression – tacrolimus, mycophenolate mofetil, methylprednisolone – was maintained for up to 120 days before bone marrow transplantation (BMT) was performed. Protocol biopsies of VCA skin were performed at 30-day intervals for histopathology and flow cytometric analysis of resident skin leukocyte populations; VCA-resident cells were differentiated by H38 status (mouse antihuman HLA class I monoclonal antibody that cross reacts with cynomolgus monkeys) for donor or recipient derivation. Clinical AR was treated with steroids and further biopsies were taken for histologic confirmation; corresponding anti-donor responses were evaluated by mixed lymphocyte reaction (MLR) and allo-antibody formation. Results: Up to three episodes of AR (from POD 14, Banff I to II) developed while recipient animals were maintained on triple immunosuppression. Corresponding flow cytometric analyses demonstrate > 80% of skin-resident T lymphocytes (CD4+, CD8+) within VCA dermis were of recipient origin, suggesting rapid immigration of various lineages into the VCA. These observations coincided with the first episode of AR in fully mismatched recipients but haplomatched animals remained rejection-free. All but one episode of AR were successfully treated. No allo-antibodies were detected and anti-donor responses by MLR were comparable to that against third-party. Following BMT, mixed chimerism was detected and enabled immunosuppression withdrawal. However, this was transient and once lost, clinical AR developed and nearly 100% of both dermal and epidermal lymphocytes were recipient-derived. Conclusion: We report a clinically-relevant model for studying AR in VCA. Our results suggest that further understanding of the relative importance of MHC differences in transplant pairs may lead to differences in outcomes for VCA recipients maintained under standard immunosuppression. Immunosuppression-free tolerance of non-hematopoietic antigens in composite tissues can be achieved, but require additional strategies to achieve stable, rather than transient mixed chimerism following BMT