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

Stem cell impairment at the host–microbiota interface in colorectal cancer

Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma–carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host– microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches

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

Carotid plaque imaging profiling in subjects with risk factors (diabetes and hypertension)

Carotid artery stenosis (CAS) due to the presence of atherosclerotic plaque (AP) is a frequent medical condition and a known risk factor for stroke, and it is also known from literature that several risk factors promote the AP development, in particular aging, smoke, male sex, hypertension, hyperlipidemia, smoke, diabetes type 1 and 2, and genetic factors. The study of carotid atherosclerosis is continuously evolving: even if the strategies of treatment still depends mainly on the degree of stenosis (DoS) determined by the plaque, in the last years the attention has moved to the study of the plaque components in order to identify the so called “vulnerable” plaque: features like the fibrous cap status and thickness, the volume of the lipid-rich necrotic core and the presence of intraplaque hemorrhage (IPH) are risk factors for plaque rupture, that can be studied with modern imaging techniques. The aim of this review is to give a general overview of the principle histological and imaging features of the subcomponent of carotid AP (CAP), focalizing in particular on the features of CAP of patients affected by hypertension and diabetes (in particular type 2 diabetes mellitus)

Therapeutic Use of Cerebellar Intermittent Theta Burst Stimulation (iTBS) in a Sardinian Family Affected by Spinocerebellar Ataxia 38 (SCA 38)

Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38

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