Defining the Epsilon‐Sarcoglycan (SGCE) Gene Phenotypic Signature in Myoclonus‐Dystonia: A Reappraisal of Genetic Testing Criteria

Mutations or exon deletions of the epsilon‐sarcoglycan (SGCE) gene cause myoclonus‐dystonia (M‐D), but a subset of M‐D patients are mutation‐negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M‐D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M‐D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score (“new score”), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole‐gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9‐Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE‐positive from SGCE‐negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation‐dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes. © 2013 Movement Disorder Society     

Trans-tragal incision for improved exposure of diacapitular and condylar neck fractures

The authors present a modification of the preauricular approach that improves the exposure of the condyle whilst reducing diacapitular and condylar neck fractures. The incision is a combination of the hockey-stick and endaural incisions. Its inferior part runs within the ear on the posterior face of the tragus; the tragal cartilage is transected together with the retrotragal skin and included in the anterior skin flap. Between May 2009 and December 2010, 16 patients with diacapitular or condylar neck fractures were treated with this approach. All patients showed good occlusion postoperatively and satisfactory aesthetic results. No infection or cartilage necrosis was observed in this series. This approach improves the exposure of the condylar head during the reduction of diacapitular and condylar neck fractures, ensuring easier internal fixation and good cosmetic results.     

Six-month humoral response to BNT162b2 mRNA COVID-19 vaccine in people with multiple sclerosis treated with natalizumab

Neurological Sciences - Few studies investigated the immune response to SARS-CoV-2 vaccine in patients with multiple sclerosis (pwMS) treated with natalizumab (NTZ) and found a short-term efficient...     

Validation of the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire for the evaluation of dysphagia in ALS patients

Neurological Sciences - Dysphagia is a common symptom during the trajectory of ALS, and it can significantly impact on the quality of life and prognosis of patients. Nowadays, no specific tool for...     

Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone

The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans.     

Effects of repetitive transcranial magnetic stimulation on spike-and-wave discharges

Aim of this study was to evaluate the effect of 5Hz-suprathreshold repetitive transcranial magnetic stimulation (rTMS) on the duration of the spike-and-wave discharges (SWDs) in a patient presenting idiopathic absence seizures. At the moment of the study the patient presented a mild blunting of consciousness due to the high frequency of absences and EEG recordings showed sub-continuous, generalized, symmetrical and synchronous 3c/s SWDs, petit mal status. Trains of 10 stimuli (120% resting motor threshold) were delivered at 5Hz frequency at the beginning of the SWDs. 5Hz-rTMS trains significantly changed the EEG activity by reducing the duration of SWDs without changing the intervals between two consecutive discharges. rTMS had not significant after-effects on the epileptic activity and patient's clinical status. Despite the limitations of a single case report, our neurophysiological findings suggest that 5Hz-suprathreshold rTMS delivered in short trains induces a transitory interference of the ongoing epileptic activity.     

Management of early ankle osteoarthritis through anterior joint-preserving surgery: a retrospective evaluation at mid- to long-term follow-up

European Journal of Orthopaedic Surgery & Traumatology - Chronic anterior ankle pain is a recognized and straightforward characteristic of anterior impingement syndrome. This retrospective...     

Tumor Size Predicts Vascular Invasion and Histologic Grade Among Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC ≥5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: <3 cm, 3.6 %; 3–5 cm, 24.7 %; 5–7 cm, 38.3 %; 7–15 cm, 32.9 %, ≥15 cm, 55.6 %; (p?<?0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: <3 cm, 9.7 %; 3–5 cm, 19.8 %; 5–7 cm, 24.2 %; 7–15 cm, 21.1 %; >15 cm, 31.6 % (p?=?0.04). The presence of perineural invasion (odds ratio [OR]?=?2.98) and regional lymph node metastasis (OR?=?4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors ≥5 cm (both p?<?0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC.     

Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction

Background and Purpose

Altered glutamate exocytosis and cAMP production in cortical terminals of experimental autoimmune encephalomyelitis (EAE) mice occur at the early stage of disease (13 days post-immunization, d.p.i.). Neuronal defects were paralleled by overexpression of the central chemokine CCL5 (also known as RANTES), suggesting it has a role in presynaptic impairments. We propose that drugs able to restore CCL5 content to physiological levels could also restore presynaptic defects. Because of its efficacy in controlling CCL5 overexpression, desipramine (DMI) appeared to be a suitable candidate to test our hypothesis.

Experimental Approach

Control and EAE mice at 13 d.p.i. were acutely or chronically administered DMI and monitored for behaviour and clinical scores. Noradrenaline and glutamate release, cAMP, CCL5 and TNF-α production were quantified in cortical synaptosomes and homogenates. Peripheral cytokine production was also determined.

Key Results

Noradrenaline exocytosis and α₂-adrenoeceptor-mediated activity were unmodified in EAE mice at 13 d.p.i. when compared with control. Acute, but not chronic, DMI reduced CCL5 levels in cortical homogenates of EAE mice at 13 d.p.i., but did not affect peripheral IL-17 and TNF-α contents or CCL5 plasma levels. Acute DMI caused a long-lasting restoration of glutamate exocytosis, restored endogenous cAMP production and impeded the shift from inhibition to facilitation of the CCL5-mediated control of glutamate exocytosis. Finally, DMI ameliorated anxiety-related behaviour but not motor activity or severity of clinical signs.

Conclusions

We propose DMI as an add-on therapy to normalize neuropsychiatric symptoms in multiple sclerosis patients at the early stage of the disease.