Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis.

OBJECTIVE: Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis. METHODS: Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls. RESULTS: An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p-value<0.001). CONCLUSIONS: An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.

Crisis miasténica y síndrome de takotsubo: una relación no casual / Myasthenic crisis and Takotsubo syndrome: a non-chance relationship

Introducción. El síndrome de takotsubo (STT) es una rara entidad que simula un infarto agudo de miocardio. Asocia dolor precordial, elevación del segmento ST, ausencia de oclusión coronaria y deformación reversible ventricular izquierda por discinesia anteroapical que recuerda a un arte japonés de pescar pulpos (tako-tsubo). Se relaciona con estrés emocional y físico, y se piensa que está mediado por una liberación catecolaminérgica aguda. Caso clínico. Mujer de 83 años, hipertensa. Ingresó en la unidad coronaria con sospecha de síndrome coronario agudo e insuficiencia respiratoria, por lo que requirió ventilación mecánica. El ecocardiograma mostró disfunción ventricular grave con discinesia apical. El cateterismo cardíaco descartó enfermedad coronaria. La ventriculografía reveló una deformación ampulosa sistólica de los segmentos anterior y apical (STT). Se intentó retirar la ventilación sin éxito y se consultó con neurología. La anamnesis dirigida reveló un cuadro de meses de evolución de debilidad generalizada, disfagia y disnea progresivas. Un test de edrofonio fue positivo. El electromiograma de fibra aislada mostró jitter patológico. Los anticuerpos antirreceptor de acetilcolina fueron positivos. La paciente fue tratada con inmunoglobulinas, corticoides y piridostigmina. El ecocardiograma de control objetivó resolución del STT. Conclusiones. El STT debe contemplarse dentro de las complicaciones extraneurológicas de la crisis miasténica. El neurólogo debe tenerlo presente ante cualquier síntoma o signo de potencial origen cardíaco en la crisis miasténica y otros padecimientos neurocríticos (AU)

Introduction. Takotsubo syndrome (TTS) is a rare condition that mimics an acute myocardial infarction. It is associated with precordial pain, ST segment elevation, absence of coronary occlusion and reversible deformation of the left ventricle due to anteroapical dyskinesia that is reminiscent of a Japanese art of fishing octopuses (tako-tsubo). It is related with emotional and physical stress, and is thought to be mediated by an acute release of catecholamines. Case report. An 83-year-old woman with hypertension. She was admitted to the heart unit with a suspected acute coronary syndrome and respiratory failure, and thus required mechanical ventilation. An echocardiography scan showed severe ventricular dysfunction with apical dyskinesia. Cardiac catheterisation ruled out heart disease and a ventriculography scan revealed a bloated systolic deformation of the anterior and apical segments (TTS). Attempts to withdraw ventilation were unsuccessful and the neurology department was consulted. A directed medical history revealed that the patient had been suffering from generalised weakness, and progressive dysphagia and dyspnoea for several months. Results of an edrophonium test were positive. Single-fibre electromyography showed a pathological jitter and acetylcholine antireceptor antibodies were positive. The patient was treated with immunoglobulins, corticoids and pyridostigmine. A control echocardiogram showed resolution of the TTS. Conclusions. TTS must be considered within the extra-neurological complications arising from myasthenic crisis. The neurologist must take this into account when faced with any symptom or sign of a potentially cardiac origin in myasthenic crisis and other neurocritical conditions (AU)

[Spanish multi-centre observational study of the first attacks suggestive of multiple sclerosis: the PREM cohort]. / Estudio observacional multicentrico espanol de primeros episodios sugestivos de esclerosis multiple: cohorte PREM.

INTRODUCTION: Recent studies have shown the need to optimise the management of patients after a first attack suggestive of multiple sclerosis (MS). Our aim is to determine whether the results from follow-ups in these studies are reproducible within a Spanish multi-centre context. PATIENTS AND METHODS: The PREM study (observational prospective Spanish multi-centre study at 24 months) included patients in the first three months following a first event suggestive of MS with at least two typical lesions in a magnetic resonance scan. The Expanded Disability Status Scale (EDSS) was obtained and the presence of attacks was evaluated basally and at 3, 6, 9, 12, 18 and 24 months; a magnetic resonance scan was performed basally and at 6 and 24 months so as to be able to calculate the brain volume and the volumes of the lesions (T1, T2 and T1 after administering gadolinium). McDonald and Poser criteria were evaluated during the follow-up. A subgroup of patients was followed up for a total period of four years. RESULTS: Altogether 110 patients (67% females) with a mean age of 30.2 years were included in the study; 22 patients dropped out of the study before it finished. Poser criteria were met by 19% and 45% of patients at 6 months and 24 months, respectively; 63% and 71% satisfied McDonald criteria. The EDSS decreased significantly (-0.94; p < 0.001) and development of atrophy was observed (-1.2%; p < 0.001) at 24 months. CONCLUSIONS: Results of the follow-up of patients with first attacks suggestive of MS within a Spanish multi-centre context are wholly comparable with those from international clinical trials performed in these patients.