Robust Evaluation of Ultraviolet-C Sensitivity for SARS-CoV-2 and Surrogate Coronaviruses.

UV light, more specifically UV-C light at a wavelength of 254 nm, is often used to disinfect surfaces, air, and liquids. In early 2020, at the cusp of the COVID-19 pandemic, UV light was identified as an efficient means of eliminating coronaviruses; however, the variability in published sensitivity data is evidence of the need for experimental rigor to accurately quantify the effectiveness of this technique. In the current study, reliable and reproducible UV techniques have been adopted, including accurate measurement of light intensity, consideration of fluid UV absorbance, and confirmation of uniform dose delivery, including dose verification using an established biological target (T1UV bacteriophage) and a resistant recombinant virus (baculovirus). The experimental results establish the UV sensitivity of SARS-CoV-2, HCoV-229E, HCoV-OC43, and mouse hepatitis virus (MHV) and highlight the potential for surrogate viruses for disinfection studies. All four coronaviruses were found to be easily inactivated by 254 nm irradiation, with UV sensitivities of 1.7, 1.8, 1.7, and 1.2 mJ/cm2/log10 reduction for SARS-CoV-2, HCoV-229E, HCoV-OC43, and MHV, respectively. Similar UV sensitivities for these species demonstrate the capacity for HCoV-OC43, HCoV-229E, and MHV to be considered surrogates for SARS-CoV-2 in UV-inactivation studies, greatly reducing hazards and simplifying procedures for future experimental studies. IMPORTANCE Disinfection of SARS-CoV-2 is of particular importance due to the global COVID-19 pandemic. UV-C irradiation is a compelling disinfection technique because it can be applied to surfaces, air, and water and is commonly used in drinking water and wastewater treatment facilities. UV inactivation depends on the dose received by an organism, regardless of the intensity of the light source or the optical properties of the medium in which it is suspended. The 254 nm irradiation sensitivity was accurately determined using benchmark methodology and a collimated beam apparatus for four coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-OC43, and MHV), a surrogate indicator organism (T1UV), and a resistant recombinant virus (baculovirus vector). Considering the light distribution across the sample surface, the attenuation of light intensity with fluid depth, the optical absorbance of the fluid, and the sample uniformity due to mixing enable accurate measurement of the fundamental inactivation kinetics and UV sensitivity.

Individualized PK-based prophylaxis in severe haemophilia.

Over the past decades, haemophilia management has continually evolved, with prophylaxis now considered the treatment of choice. Prophylaxis primarily seeks to prevent bleeding and haemarthrosis episodes from occurring and avert the otherwise inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain. These concern dose levels, dosing intervals, ways of integrating variability in bleeding phenotype, patient age, joint status, lifestyle, physical activity, treatment adherence and individual responses to FVIII or FIX concentrates. Individualized prophylaxis may thus be paramount. One crucial tool that may allow more accurate prophylaxis regimens to be implemented is the individual pharmacokinetic (PK) study. Therefore, physicians in charge of managing those living with haemophilia must be comfortable with PK profiling in order to be in a position to tailor patients' treatment, taking into account PK data, while minimizing patients' inconvenience, discomfort, as well as, possibly, treatment costs. For optimization of prophylaxis, recent development of recombinant molecules with more attractive PK properties, such as prolonged elimination half-life, increases the choice of dosing regimens, enabling decreased frequency of dosing for some, if deemed appropriate. For each patient, PK parameters can be determined, including trough levels, AUC, and time spent under a predefined threshold, with additional pharmacodynamic (PD) parameters possibly established by means of a global coagulation test like the thrombin generation test. Most importantly, target PK/PD parameters will need to consider clinical variables like patient age, body weight, joint status, treatment adherence, number of bleeding episodes, activity index or lifestyle.

Abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions in cervical dystonia.

The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway. Previous TMS studies showed that cerebellar cortex excitation can block the increase in M1 excitability induced by a paired-associative stimulation (PAS), while cerebellar cortex inhibition would enhance it. Since cerebellum is known to be affected in many types of dystonia, this bidirectional modulation was assessed in 22 patients with cervical dystonia and 23 healthy controls. Exactly opposite effects were found in patients: cerebellar inhibition suppressed the effects of PAS, while cerebellar excitation enhanced them. Another experiment comparing healthy subjects maintaining the head straight with subjects maintaining the head turned as the patients found that turning the head is enough to invert the cerebellar modulation of M1 plasticity. A third control experiment in healthy subjects showed that proprioceptive perturbation of the sterno-cleido-mastoid muscle had the same effects as turning the head. We discuss these finding in the light of the recent model of a mesencephalic head integrator. We also suggest that abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions of the integrator in cervical dystonia.

The reliability of commonly used electrophysiology measures.

BACKGROUND: Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. OBJECTIVE/HYPOTHESIS: To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. METHODS: Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. RESULTS: Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. CONCLUSIONS: Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.

Study of six patients with complete F9 deletion characterized by cytogenetic microarray: role of the SOX3 gene in intellectual disability.

Essentials Some hemophilia B (HB) patients with complete F9 deletion present with intellectual disability (ID). We delineate six F9 complete deletions and investigate genotype/phenotype correlation. We identify SOX3 as a candidate gene for ID, acting through haploinsufficiency, in HB patients. All complete F9 deletions in ID patients should be explored with cytogenetic microarrays. SUMMARY: Background Large deletions encompassing both the complete F9 gene and contiguous genes have been detected in patients with severe hemophilia B (HB). Some of these patients present other clinical features, such as intellectual disability (ID). Objectives/Methods In this study, we characterized six unrelated large deletions encompassing F9, by cytogenetic microarray analysis (CMA), to investigate genotype/phenotype correlation. Results Five of the six patients included in this study presented with ID associated with HB. CMA showed that the six large deletions, ranging in size from approximately 933 kb to 9.19 Mb, were located within the Xq26.3 to Xq28 bands. In all cases, the complete deletion of F9 was associated with the loss of various neighboring genes (5-28 other genes). The smallest region of overlap for ID was a 1.26-Mb region encompassing seven OMIM genes (LOC389895, SOX3, LINC00632, CDR1, SPANXF1, LDOC1, SPANXC). SOX3, our candidate gene for ID, encodes an early transcription factor involved in pituitary development. All of the patients studied who had both HB and ID had deletion of the SOX3 gene. Conclusions All HB patients with an atypical phenotype, especially if complete deletion of F9 is suspected, should be referred to a geneticist for possible pangenomic assessment, because haploinsufficiency of genes flanking F9, such as SOX3 in particular, may result in a broader phenotype, including ID. Such assessment would be of particular value for the genetic counseling of female carriers with F9 deletions, as it would facilitate analysis of the risk of transmitting HB associated with ID.

[Chemistry approach for therapeutic education of children with hemophilia and their parents: Representation of complex phenomena related to treatment]. / La chimie au service de l'éducation thérapeutique des enfants atteints d'hémophilie et de leurs parents : représentation de phénomènes complexes liés au traitement.

INTRODUCTION: The therapeutic management of hemophilia is based on replacement therapy by clotting factor concentrates and may require several injections per week. In teenagers, non-compliance with treatment may be responsible for major orthopedic complications. The aim of this study was to develop and assess an educational intervention for children with hemophilia and their parents, thus illustrating the complex phenomena related to treatment and its adhesion. METHODS: The construction of the educational workshop and tools was based on the concrete, visual, and playful representation of the following concepts: pathophysiology, the replacement therapy's mechanism of action, drug elimination requiring repeated administrations, and inhibitor development. The procedure was then assessed by a sample of children and parents using a questionnaire. RESULTS: A 60- to 90-min workshop was developed. The different tools used to illustrate the severity of the disease, the effect of the injected drug, drug elimination, and the inhibitor effect were: a blue-to-transparent colorimetric scale in bottles, a weekly timeline, Muppets, and a slow redox reaction. Five children and eight parents assessed this educational intervention with a rating of 3.75/4 (±0.10) and 3.60/4 (±0.45), respectively. CONCLUSION: The intervention developed could be transposed to other chronic diseases with similar therapeutic characteristics (including replacement mechanism of action and pharmacokinetics). Understanding the transmitted pharmacological concepts in a playful way is a major challenge to encourage treatment adhesion during adolescence.

Effects of maternal stress and perinatal fluoxetine exposure on behavioral outcomes of adult male offspring.

UNLABELLED: Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. METHODS: C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25 mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12 days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. RESULTS: Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive abilities, memory, sensorimotor information processing, or risk assessment behaviors. These results demonstrate that maternal exposure to stress and Flx have a number of sustained effects on the male offspring.

Glycaemic control and self-management behaviours in Type 2 diabetes: results from a 1-year longitudinal cohort study.

AIM: To better understand the associations between changes in self-management behaviours and glycaemic control. METHODS: We conducted a prospective observational study of 295 adult patients with Type 2 diabetes evaluated at baseline, 6 and 12 months. Four self-management behaviours were evaluated using the Summary of Diabetes Self-Care Activities instrument, which assesses healthy diet, physical activity, medication taking and self-monitoring of blood glucose. Using hierarchical linear regression models, we tested whether changes in self-management behaviours were associated with short-term (6-month) or long-term (12-month) changes in glycaemic control, after controlling for demographic and clinical characteristics. RESULTS: Improved diet was associated with a decrease in HbA1c level, both at 6 and 12 months. Improved medication taking was associated with short-term improvement in glycaemic control, while increased self-monitoring of blood glucose frequency was associated with a 12-month improvement in HbA1c . Completely stopping exercise after being physically active at baseline was associated with a rise in HbA1c level at 6-month follow-up. Interaction analysis indicated that a healthy diet benefitted all participant subgroups, but that medication taking was associated with glycaemic control only for participants living in poverty and more strongly for those with lower educational levels. Finally, a higher self-monitoring of blood glucose frequency was associated with better glycaemic control only in insulin-treated participants. CONCLUSIONS: Even after adjusting for potential confounders (including baseline HbA1c ), increased frequency of healthy diet, medication taking and self-monitoring of blood glucose were associated with improved HbA1c levels. These self-management behaviours should be regularly monitored to identify patients at risk of deterioration in glycaemic control. Barriers to optimum self-management should be removed, particularly among socio-economically disadvantaged populations.

International cross-cultural validation study of the Canadian haemophilia outcomes: kids' life assessment tool.

Health-related quality of life (HRQoL) assessment is recognized as an important outcome in the evaluation of different therapeutic regimens for persons with haemophilia. The Canadian Haemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) is a disease-specific measure of HRQoL for 4 to 18-year-old boys with haemophilia. The purpose of this study was to extend this disease-specific, child-centric, outcome measure for use in international clinical trials. We adapted the North American English CHO-KLAT version for use in five countries: France, Germany, the Netherlands, Spain and the United Kingdom (UK). The process included four stages: (i) translation; (ii) cognitive debriefing; (iii) validity assessment relative to the PedsQL (generic) and the Haemo-QoL (disease-specific) and (iv) assessment of inter and intra-rater reliability. Cognitive debriefing was performed in 57 boys (mean age 11.4 years), validation was performed in 144 boys (mean age 11.0 years) and reliability was assessed for a subgroup of 64 boys (mean age 12.0 years). Parents also participated. The mean scores reported by the boys were high: CHO-KLAT 77.0 (SD = 11.2); PedsQL 83.8 (SD = 11.9) and Haemo-QoL 79.6 (SD = 11.5). Correlations between the CHO-KLAT and PedsQL ranged from 0.63 in Germany to 0.39 in the Netherlands and Spain. Test-retest reliability (concordance) for child self-report was 0.67. Child-parent concordance was slightly lower at 0.57. The CHO-KLAT has been fully culturally adapted and validated for use in five different languages and cultures (in England, the Netherlands, France, Germany and Spain) where treatment is readily available either on demand or as prophylaxis.

Broca's area damage is necessary but not sufficient to induce after-effects of cathodal tDCS on the unaffected hemisphere in post-stroke aphasia.

BACKGROUND: The inter-individual variability of behavioral effects after tDCS applied to the unaffected right hemisphere in stroke may be related to factors such as the lesion location. OBJECTIVE/HYPOTHESIS: We investigated the effect of left Broca's area (BA) damage on picture naming in aphasic patients after cathodal tDCS applied over the right BA. METHODS: We conducted a study using pre-interventional diffusion and resting state functional MRI (rsfMRI) and two cross-over tDCS sessions (TYPE: sham and cathodal) over the right homologous BA in aphasic stroke patients with ischemic lesions involving the left BA (BA+) or other left brain areas (BA-). Picture naming accuracy was assessed after each session. Inter-hemispheric (IH) functional balance was investigated via rsfMRI connectivity maps using the right BA as a seed. Probabilistic tractography was used to study the integrity of language white matter pathways. RESULTS: tDCS had different effects on picture naming accuracy in BA+ and BA- patients (TYPE × GROUP interaction, F(1,19): 4.6, P: 0.04). All BA- patients except one did not respond to tDCS and demonstrated normal IH balance between the right and left BA when compared to healthy subjects. BA+ patients were improved by tDCS in 36% and had decreased level of functional IH balance. Improvement in picture naming after cathodal tDCS was associated with the integrity of the arcuate fasciculus in BA+ patients. CONCLUSIONS: Behavioral effects of cathodal tDCS on the unaffected right hemisphere differ depending on whether BA and the arcuate fasciculus are damaged. Therefore, IH imbalance could be a direct consequence of anatomical lesions.

Diagnosis and management challenges in patients with mild haemophilia A and discrepant FVIII measurements.

Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one-stage clotting and two-stage chromogenic assays. It is, therefore, a real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty-six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time-based one-stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one-stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.

Connectivity between right inferior frontal gyrus and supplementary motor area predicts after-effects of right frontal cathodal tDCS on picture naming speed.

BACKGROUND: Cathodal transcranial direct current stimulation (tDCS) of the right frontal cortex improves language abilities in post-stroke aphasic patients. Yet little is known about the effects of right frontal cathodal tDCS on normal language function. OBJECTIVE/HYPOTHESIS: To explore the cathodal tDCS effects of the right-hemispheric homologue of Broca's area on picture naming in healthy individuals. We hypothesized that cathodal tDCS improves picture naming and that this effect is determined by the anatomical and functional connectivity of the targeted region. METHODS: Cathodal and sham tDCS were applied to the right inferior frontal gyrus in 24 healthy subjects before a picture-naming task. All participants were studied with magnetic resonance imaging at pre-interventional baseline. Probabilistic tractography and dynamic causal modeling of functional brain activity during a word repetition task were applied to characterize anatomical and functional connectivity. RESULTS: Subjects named pictures faster after cathodal relative to sham tDCS. The accelerating effect of tDCS was explained by a reduced frequency of very slow responses. tDCS-induced acceleration of picture naming correlated with larger volumes of the tract connecting the right Broca's area and the supplementary motor area (SMA) and greater functional coupling from the right SMA to the right Broca's area. CONCLUSIONS: The results support the notion that the after-effects of tDCS on brain function are at least in part determined by the anatomical and functional connectivity of the targeted region.

Cerebellar rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: an open label trial.

BACKGROUND: Cerebello-thalamo-cortical (CTC) pathways dysfunction is involved in pathological oscillations causing tremor in essential tremor (ET). Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can effectively modulate the cerebellar output. OBJECTIVE: As one session of rTMS can induce a brief improvement, we hypothesized that repeated sessions might have a cumulative and potentially long-term therapeutic effect on ET. We assessed, in an open label trial, the efficacy of one-week rTMS treatment on tremor and on the motor-CTC dysfunction in ET patients. METHODS: Resting-state fMRI functional connectivity was used as an indicator of CTC network integrity in 11 ET patients and 11 healthy subjects. Resting-state fMRI connectivity was quantified at baseline in patients and control subjects between the cerebellum and the motor network, and between the cerebellum and the default brain network (DBN) taken as control. The fMRI study was repeated in patients after 5 days of bilateral 1 Hz rTMS applied to the posterior cerebellar cortex. Tremor was assessed clinically (Fahn-Tolosa-Marin scale) and quantified using electromyographic and accelerometric recordings at baseline (day 1, before the cerebellar stimulation) and after the end of the cerebellar stimulation period at day 5, day 12 and day 29. RESULTS: Repeated rTMS over the cerebellum significantly improved total and specific (tremor, drawing, functional disability) scores, and reduced tremor amplitude (P < 0.006). It also re-established the defective information processing in the CTC network (P(Δ|y) > 0.909), but not in the DBN. The effects persisted for 3 weeks after the last session. CONCLUSION: Cerebellar stimulation could be an effective treatment option for patients with severe essential tremor.

Cerebellar processing of sensory inputs primes motor cortex plasticity.

Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations.

[Varicella-associated purpura fulminans and deep vein thrombosis: a pediatric case report]. / Purpura fulminans post-varicelleux et thrombose veineuse : à propos d'un cas pédiatrique.

Purpura fulminans (PF) and deep vein thrombosis are rare complications secondary to chicken pox disease. The presence of antibodies reflects an ongoing immunological process and requires specialized management. The present study reports a 4-year-old boy with no medical history who presented with purpura on the legs 10 days after chicken pox eruption. Laboratory tests showed a disseminated intravascular coagulation associated with low plasma protein C and S activities, and the presence of anti-protein S antibodies. A replacement therapy with protein C infusions and fresh frozen plasma was prescribed. The patient also underwent regular sessions of hyperbaric oxygen followed by the surgery. Fourteen days after the beginning of the purpuric lesions, he presented deep vein thrombosis (DVT) of the lower limbs and was treated with unfractionated heparin. This case report illustrates the pathophysiology of DVT occurring in a patient with chicken pox disease (i.e., acquired protein C and S deficiencies and anti-protein S autoantibodies) and emphasizes the utility of thrombophilia testing in order to better adapt treatment.

A novel DCC mutation and genetic heterogeneity in congenital mirror movements.

OBJECTIVE: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. METHODS: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. RESULTS: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. CONCLUSION: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity.

TENS is harmful in primary writing tremor.

OBJECTIVE: It is unclear whether primary writing tremor (PWT) is a tremulous form of dystonia or a tremor per se. Transcutaneous electrical nerve stimulation (TENS) at 50 Hz applied for 2 weeks was reported to improve the writing capabilities of patients with writer's cramp (WC). We explored whether such a beneficial effect can be obtained in patients with a PWT. METHODS: In a cross-over, double-blinded randomized study we tested whether 2-week periods of 5, 25 or 50 Hz TENS applied to wrist flexor muscles, improved the score of the Fahn-Tolosa-Marin scale of nine patients with PWT. Excitability of neurons and of various intracortical circuits in the motor cortex were also tested before and after TENS by using transcranial magnetic stimulation. RESULTS: TENS at 5 and 25 Hz did not have any effect while TENS at 50 Hz worsened the clinical condition and the cortical excitability. CONCLUSIONS: TENS is not a new treatment alternative for PWT. SIGNIFICANCE: The beneficial effect in WC and the harmful one in PWT of TENS stresses that the two disorders are likely different nosological entities.

Both L-DOPA and HFS-STN restore the enhanced group II spinal reflex excitation to a normal level in patients with Parkinson's disease.

OBJECTIVE: To investigate the contribution of group II spinal pathways in Parkinsonian upper limb rigidity and the modulation of spinal excitability of group I and group II pathways by L-DOPA and subthalamic nucleus-high-frequency stimulation (STN-HFS). METHODS: The effect of ulnar nerve electrical stimulation on Flexor Carpi Radialis Electromyogram (FCR EMG) was investigated in two groups of patients: patients receiving medication (MED group) and chronically surgically implanted patients (DBS group). Results were compared in patients ON and OFF treatment, and between patients and control subjects. RESULTS: The resulting long-lasting facilitation in FCR EMG had similar characteristics in all groups, and surface area was assessed in analysis windows corresponding to the parts supposed to be mediated by non-monosynaptic spinal pathways to FCR motoneurones, fed by hand muscle group I and group II afferents (Lourenço et al., 2006). In both the MED and DBS groups, the group I excitation was not altered but the group II excitation was particularly enhanced when OFF treatment, compared to controls, and both L-DOPA and STN-HFS restored the group II spinal excitation to normal level. CONCLUSION: Both L-DOPA and STN-HFS influence the metabolism of monoamines in the midbrain, and restore the descending neuromodulation on group II spinal reflex. SIGNIFICANCE: These results further support a group II contribution to the enhanced long latency response (LLR) to muscle stretch observed in wrist muscles of rigid Parkinson's disease (PD) patients.

Long-lasting inhibition of cerebellar output.

OBJECTIVE: The cerebellar influence on the motor cortex output is exerted mostly though the cerebellothalamocortical pathway (CTC). One way to explore this pathway is by the means of transcranial magnetic stimulation (TMS). A single-pulse conditioning magnetic stimulation delivered over the lateral cerebellum was shown to diminish the excitability of the contralateral motor cortex 5 milliseconds later (cerebellocortical inhibition [CBI]), most likely through transynaptic activation of cerebellar Purkinje cells, which in turn inhibit the tonic activity of the CTC. Repetitive TMS (rTMS) delivered over the lateral cerebellum was shown to induce a long-lasting change of the cortical excitability, as well, but the mechanism and time course of this effect are still debated. METHODS: We tested the time course of the effects of rTMS on the CBI in five paradigms: (1) 1 Hz rTMS, (2) continuous theta burst stimulation (cTBS), and (3) intermittent TBS (iTBS) over the right cerebellum, (4) 1 Hz rTMS over the cervical nerve roots, and (5) 1 Hz rTMS over the left cerebellum. Surface electromyography was recorded from the right first dorsal interosseous (FDI) and adductor digiti minimi. A double-cone coil was used for single-pulse cerebellar stimulation, whereas a figure-of-eight coil was used for the rTMS. The stimulus intensity was set at 90% of the M1 resting motor threshold for 1 Hz rTMS, and at 80% of the M1 active motor threshold for TBS. Both types of cerebellar stimulation were performed under magnetic resonance image (MRI)-guided neuronavigation centered over the right VIII B lobule, and stimulation intensities were adjusted for cerebellar cortex depth. A figure-of-eight coil was used for left motor cortex stimulation. RESULTS: There was significant CBI suppression to the left motor cortex up to 30 minutes after the 900 stimuli of 1 Hz rTMS over either cerebellar hemisphere, and after 600 stimuli of cTBS over the right cerebellum, but not after 600 stimuli of iTBS over the right cerebellum, or after 900 of 1 Hz rTMS stimuli delivered over the cervical nerve roots. The 1 Hz rTMS over the left cerebellum significantly reduced the CBI in the right FDI 10 minutes after the end of the intervention. The amplitudes of the unconditioned cortical motor-evoked potentials were not significantly changed. CONCLUSIONS: Our findings suggest that repetitive cerebellar stimulation operate at a cerebellar level, rather then at a cortical level.

Patient resources in the therapeutic education of haemophiliacs in France: their skills and roles as defined by consensus of a working group.

The activities of 'expert patients' or 'patient tutors', who help educate their peers, are gaining recognition in the health care system. This study investigates the role played by such patients in therapeutic education programmes organized by caregivers to validate the role of patients in implementing the therapeutic education of haemophilic patients and to define the skills required for such activities. This study employs the consensus methodology recommended by France's National Authority for Health. The working group includes seven caregivers from Hemophiliac Treatment Centers (HTCs) and three patients from the French Association of Hemophiliacs (FAH). The role of patients in haemophilia education is recognized. Patients participating in the education of their peers are referred to as 'patient resources'. A patient resource should be an adult, a volunteer and live in the same region as his peers. Candidates are chosen by the FAH and the HTCs to serve based on their motivation to facilitate the education of other patients as well as on their psychological and pedagogical aptitudes. A patient resource participates in the conception and administration of therapeutic education programmes. He also mediates between the caregivers and the patients. He ensures that the patients understand the material and are able to apply their knowledge in daily life. His activities are governed by professional ethics. Seven categories of skills were defined, permitting the group to determine precisely which skills are required to function as a patient resource. Supervision of the patients is planned to reinforce reflexive practices in the patients. Evolution of the health care system has led patients to become involved in therapeutic education. This phenomenon calls for a framework to be developed and an evaluation of its eventual effects.