A novel mtDNA point mutation in tRNAVal is associated with hypertrophic cardiomyopathy and MELAS

Background. Pathological mutations of mitochondrial (mt) DNA may cause specific diseases such as cardiomyopathies or hearing loss, or syndromes such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. We describe a novel mtDNA mutation in a patient with severe hypertrophic cardiomyopathy associated with MELAS. The familial phenotype included 1) hypertrophic cardiomyopathy and MELAS, 2) clinically mild cardiac hypertrophy, and 3) deafness. Methods. The proband and her first degree relatives underwent echo and electrocardiograms, and biochemical tests. Magnetic resonance imaging of the brain was performed in the proband. mtDNA was fully analyzed by sequencing. DNA purification, polymerase chain reaction and direct automated sequencing were performed following standard procedures. Heteroplasmy of the novel mutation was quantified by densitometric analysis. Results. A novel G1644A transition affecting the tRNAVal was identified in the proband and maternal relatives. The mutation has been interpreted as pathological because the G at the 1644 position is a highly conserved base, is heteroplasmic with higher levels of mutant DNA in the proband than in the relatives, is located in the unique tRNAVal, is very close to a mutation described as causative of MELAS, and finally has not been found in 100 healthy controls. Conclusions. Although it is rare for patients with MELAS to be referred to cardiological evaluation because of coexisting cardiomyopathy, cardiologists should be aware of this association as well as of the non cardiac signs that may address the diagnosis to mtDNA defect-related disease in families with a variable phenotype. © 2004 CEPI Srl

Usability of a Hybrid System Combining P300-Based Brain-Computer Interface and Commercial Assistive Technologies to Enhance Communication in People With Multiple Sclerosis

Brain-computer interface (BCI) can provide people with motor disabilities with an alternative channel to access assistive technology (AT) software for communication and environmental interaction. Multiple sclerosis (MS) is a chronic disease of the central nervous system that mostly starts in young adulthood and often leads to a long-term disability, possibly exacerbated by the presence of fatigue. Patients with MS have been rarely considered as potential BCI end-users. In this pilot study, we evaluated the usability of a hybrid BCI (h-BCI) system that enables both a P300-based BCI and conventional input devices (i.e., muscular dependent) to access mainstream applications through the widely used AT software for communication "Grid 3." The evaluation was performed according to the principles of the user-centered design (UCD) with the aim of providing patients with MS with an alternative control channel (i.e., BCI), potentially less sensitive to fatigue. A total of 13 patients with MS were enrolled. In session I, participants were presented with a widely validated P300-based BCI (P3-speller); in session II, they had to operate Grid 3 to access three mainstream applications with (1) an AT conventional input device and (2) the h-BCI. Eight patients completed the protocol. Five out of eight patients with MS were successfully able to access the Grid 3 via the BCI, with a mean online accuracy of 83.3% (+/- 14.6). Effectiveness (online accuracy), satisfaction, and workload were comparable between the conventional AT inputs and the BCI channel in controlling the Grid 3. As expected, the efficiency (time for correct selection) resulted to be significantly lower for the BCI with respect to the AT conventional channels (Z = 0.2, p < 0.05). Although cautious due to the limited sample size, these preliminary findings indicated that the BCI control channel did not have a detrimental effect with respect to conventional AT channels on the ability to operate an AT software (Grid 3). Therefore, we inferred that the usability of the two access modalities was comparable. The integration of BCI with commercial AT input devices to access a widely used AT software represents an important step toward the introduction of BCIs into the AT centers' daily practice

Circulating thyrotropin is upregulated by estradiol

After encountering two women with serum thyrotropin (TSH) levels greater in periovulatory phase than in other days of the menstrual cycle, we hypothesized that TSH levels could be sensitive to changes in circulating estrogens in women. The objective of this study was to evaluate whether serum TSH increases after an induced acute increase of serum estradiol, and compare serum TSH increase with that of prolactin (PRL) which is a classic estradiol-upregulated pituitary hormone. In this retrospective study, we resorted to stored frozen sera from 55 women who had undergone the GnRH agonist (buserelin)-acute stimulation test of ovarian steroidogenesis. This test, that is preceded by dexamethasone administration to suppress adrenal steroidogenesis, had been performed to show an increased buserelin-stimulated response of 17-hydroxyprogesterone, a response that is frequent in polycystic ovary syndrome. Fifty-five women had enough serum volume at pertinent times (first observation early in the follicular phase and all times of the test) to permit assay of serum estradiol, TSH and PRL. Before dexamethasone administration, estradiol averaged 26.4 ± 15.5 pg/ml (reference range 23–139, follicular phase), TSH 1.78 ± 0.86 mU/L (reference range 0.3–4.2) and PRL 409.4 ± 356 mU/L (reference range 70.8–556) (mean ± SD). Serum estradiol, TSH and PRL averaged 47.2 ± 27 pg/ml, 0.77 ± 0.48 mU/L and 246.4 ± 206.8 mU/L just prior to the buserelin injection, but they peaked at 253.4 ± 113.5 pg/ml (nv 83–495, midcycle), 3.30 ± 1.65 mU/L and 540.3 ± 695.2 mU/L after injection. The responses to buserelin of estradiol, TSH and PRL were of wide magnitude. There was a significant correlation between TSH peak and serum estradiol peak, betweeen AUC0-24 h-TSH and AUC0-24 h-estradiol, or between PRL peak and estradiol peak and AUC0-24 h -PRL and AUC0-24 h-estradiol in only a subgroup of women. Therefore, women with estradiol-dependent increase in serum TSH do exist. Reference bands of serum TSH dependent on the phases of the menstrual cycle should be available

Study protocol on advance care planning in multiple sclerosis (ConCure-SM): intervention construction and multicentre feasibility trial

Multiple sclerosis (MS) is the most common cause of progressive neurological disability in young adults. The use of advance care planning (ACP) for people with progressive MS (pwPMS) remains limited. The ConCure-SM project aims to assess the effectiveness of a structured ACP intervention for pwPMS. The intervention consists of a training programme on ACP for healthcare professionals caring for pwPMS, and a booklet to be used during the ACP conversation. Herein, we describe the first two project phases

An 8-week rehabilitation training using the HBP exoskeleton improves cognitive brain functions in multiple sclerosis patients

It has been showed that a single application of the exoskeleton (HBP) in multiple sclerosis patients is able to improve mobility and ambulation. These effects have been associated with brain changes in high-level executive functions decisive for improving patients’ motor control [1]. We applied an 8-weeks rehabilitation protocol in 12 MS patients, half of them randomly assigned to a standard protocol (control group, CG) and the other half to a protocol based on the HBP use (experimental group, EG). Patients were evaluated before and after rehabilitation training using multiple neurological, physiotherapeutic and cognitive testing. During the cognitive task, high-resolution EEG was also recorded for ERP analysis. Results showed that both groups improved their performance in the Barthel, Rivermead, 2-WT, 25-FWT, Tinetti and BBS tests. Only in the EG, other positive treatment effects were observed as measured by the EDSS disability scale and the FSS. Accordingly, in cognitive testing, only the EG showed significant benefits in response time (RT) and accuracy. At brain level the EG showed enhancement in task-related preparatory activity in frontal and prefrontal cortices and stronger post-stimulus activity in the anterior Insula, whose activity is related to more efficient decision making. The CG didn’t show enhanced performance in the cognitive task but only large activity in visual areas, as observed in EG. Concluding, both rehabilitation protocols brought substantial neurophysiological benefits to MS patients, however, the HBP protocol was particularly effective, boosting cognitive functions in prefrontal and frontal brain areas, it allowed improvements in RT and accuracy. The integration of HBP with standard rehabilitation procedure may considerably reduce disability in MS patients

The effects of transcutaneous spinal direct current stimulation on neuropathic pain in multiple sclerosis: clinical and neurophysiological assessment

Background: Central neuropathic pain represents one of the most common symptoms in multiple sclerosis (MS) and it seriously affects quality of life. Spinal mechanisms may contribute to the pathogenesis of neuropathic pain in MS. Converging evidence from animal models and neurophysiological and clinical studies in humans suggests a potential effect of transcranial direct current stimulation (tc-DCS) on neuropathic pain. Spinal application of DCS, i.e., transcutaneous spinal DCS (ts-DCS), may modulate nociception through inhibition of spinal reflexes. Therefore, ts-DCS could represents an effective, safe and well-tolerated treatment for neuropathic pain in MS, a largely unexplored topic. This study is a pilot randomized double-blind sham-controlled trial to evaluate the efficacy of ts-DCS on central neuropathic pain in MS patients. Methods: Thirty-three MS patients with central neuropathic pain were enrolled and randomly assigned to two groups in a double-blind sham-controlled design: anodal ts-DCS group (n = 19, 10 daily 20-min sessions, 2 mA) or sham ts-DCS group (n = 14, 10 daily 20-min sessions, 0 mA). The following clinical outcomes were evaluated before ts-DCS treatment (T0), after 10 days of treatment (T1) and 1 month after the end of treatment (T2): neuropathic pain symptoms inventory (NPSI), Ashworth Scale (AS) for spasticity and Fatigue Severity Scale (FSS). A subgroup of patients treated with anodal ts-DCS (n = 12) and sham ts-DCS (n = 11) also underwent a parallel neurophysiological study of the nociceptive withdrawal reflex (NWR) and the NWR temporal summation threshold (TST), two objective markers of pain processing at spinal level. Results: Anodal ts-DCS group showed a significant improvement in NPSI at T1, which persisted at T2, while we did not detect any significant change in AS and FSS. Sham ts-DCS group did not show any significant change in clinical scales. We observed a non-significant trend towards an inhibition of NWR responses in the anodal ts-DCS group at T1 and T2 when compared to baseline. Conclusions: Anodal ts-DCS seems to have an early and persisting (i.e., 1 month after treatment) clinical efficacy on central neuropathic pain in MS patients, probably through modulation of spinal nociception. Clinical Trial Registration: www.ClinicalTrials.gov, identifier #NCT02331654

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis

Clinical staff work sampling in a neurorehabilitation hospital and its relationship to severity of disease

AIM: Study aimed to analyse how rehabilitation staff spends working time on specific activities in a neurorehabilitation hospital and to determine the number of direct activities received by patients with different levels of disease severity. BACKGROUND: Few studies have investigated how clinical staff spends their time on activities in rehabilitation hospitals without considering at the same time all working categories and without reporting the number of direct activities received by patients with respect to their disease severity. DESIGN: Self-reported observational study. METHOD: Work Sampling Technique was used to record direct, indirect, unit-related and personal activities every 5 min for 2 days. RESULTS: Total of 6,974 activities were recorded over 581 working hours. Physiotherapists and nurses spent 75.2% and 54.8% of their time in direct activities and medical doctors only 25.4%. Total time of direct activities was significantly different among worker categories (p = 0.001) and depended on patients' disease severity (p = 0.020) in a different manner among worker categories (interaction: p = 0.010). This time ranged from almost 4 hr up to 6\ubd hr for the most severely affected patients. CONCLUSION: Type of work differed among professionals. Workload greatly depended on degree of patients' disability. IMPLICATIONS FOR NURSING MANAGEMENT: Nurses and therapists spent most of their time in direct activities with patients. Economic burden of neurorehabilitation may vary greatly depending on disease severity

Applying multidimensional computerized adaptive testing to the MSQOL-54: a simulation study

Background: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. Methods: Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at < 0.01 for both the general and the group factors. Performance of the MCAT was assessed by the number of administered items, root mean square difference (RMSD), and correlation. Results: Eight items were removed due to local dependency. The simulation with SE set to 0.32 (general factor), and no SE thresholds (group factors) provided satisfactory performance: the median number of administered items was 24, RMSD was 0.32, and correlation was 0.94. Conclusions: Compared to the full-length MSQOL-54, the simulated MCAT required fewer items without losing precision for the general HRQOL factor. Further work is needed to add/integrate/revise MSQOL-54 items in order to make the calibration and MCAT performance efficient also on group factors, so that the MCAT version may be used in clinical practice and research

Viability of a MSQOL-54 general health-related quality of life score using bifactor model

Background MSQOL-54 is a multidimensional, widely-used, health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). Findings from the validation study suggested that the two MSQOL-54 composite scores are correlated. Given this correlation, it could be assumed that a unique total score of HRQOL may be calculated, with the advantage to provide key stakeholders with a single overall HRQOL score. We aimed to assess how well the bifactor model could account for the MSQOL-54 structure, in order to verify whether a total HRQOL score can be calculated. Methods A large international database (3669 MS patients) was used. By means of confirmatory factor analysis, we estimated a bifactor model in which every item loads onto both a general factor and a group factor. Fit of the bifactor model was compared to that of single and two second-order factor models by means of Akaike information and Bayesian information criteria reduction. Reliability of the total and subscale scores was evaluated with Mc Donald's coefficients (omega, and omega hierarchical). Results The bifactor model outperformed the two second-order factor models in all the statistics. All items loaded satisfactorily (>= 0.40) on the general HRQOL factor, except the sexual function items. Omega coefficients for total score were very satisfactory (0.98 and 0.87). Omega hierarchical for subscales ranged between 0.22 to 0.57, except for the sexual function (0.70). Conclusions The bifactor model is particularly useful when it is intended to acknowledge multidimensionality and at the same time take account of a single general construct, as the HRQOL related to MS. The total raw score can be used as an estimate of the general HRQOL latent score