Upregulation of Heat-Shock Protein (hsp)-27 in a Patient with Heterozygous SPG11 c.1951C>T and SYNJ1 c.2614G>T Mutations Causing Clinical Spastic Paraplegia.

We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient's CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive. The patient's DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient's CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols. In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking.

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment.

BACKGROUND: Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. METHODS: This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. DISCUSSION: NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.

Possible Influence of the Route of Treatment Administration on Treatment Adherence in Patients With Multiple Sclerosis.

PURPOSE: Multiple sclerosis is a chronic, demyelinating, and degenerative disease of the central nervous system with an immune-based pathologic origin. The present pilot study aimed to assess whether the change in the route of treatment administration is associated with a variation in adherence and whether there is a change in quality of life, treatment satisfaction, and fatigue. METHODS: Patients with relapsing-remitting multiple sclerosis who were >18 years of age and who used to receive immunomodulatory parenteral treatment and were ready to change administration route were eligible for the study. Data were collected at baseline and 3 months later. Adherence, quality of life, treatment satisfaction, and fatigue were measured via the following questionnaires: Morisky-Green questionnaire on patient-reported medication adherence, Multiple Sclerosis Quality of Life Instrument, Treatment Satisfaction Questionnaire for Medication, and Modified Fatigue Impact Scale. FINDINGS: The study sample included 30 patients (mean age, 43.2 years; age range, 24-71 years; 60% female and 40% male). There was a significant improvement in adherence (p = 0.048). Mean (SD) physical and mental health quality-of-life summary scores varied from 52.50 (24.15) and 54.13 (21.24) to 67.55 (20.92) and 62.30 (21.75) (p < 0.001 and p = 0.001, d = -0.426 and d = -0.643, respectively). In the Treatment Satisfaction Questionnaire for Medication, an improvement of the score was observed in effectiveness of the medication (p = 0.0041, d = -0.563), adverse effects of the medication (p < 0.001, d = -0.976), convenience of the medication (p < 0.001, d = -1.235), and global satisfaction (p = 0.006, d = -0.725). Patients had a higher mean (SD) score (45.13 [26.7]) on the Modified Fatigue Impact Scale while receiving injectable treatment compared with that obtained with oral treatment (34.86 [23.16]; p = 0.009, d = 0.41). IMPLICATIONS: When the route of administration changed from injectable to oral, there was an increase in adherence, quality of life, and degree of patient satisfaction with their treatment and a decrease in the degree of fatigue.

Prevalencia de la esclerosis múltiple en la Región de Murcia / Prevalence of multiple sclerosis in the Region of Murcia

Introducción. La esclerosis múltiple (EM) es una enfermedad inflamatoria desmielinizante del sistema nervioso central con patogenia inmunomediada. Recientes estudios indican un aumento de su prevalencia, y numerosos trabajos relacionan el virus de Epstein-Barr (VEB) con su etiología. Objetivo. Análisis de prevalencia de la EM en la Región de Murcia, incluyendo la descripción de las características clínicas en el momento del inicio de la enfermedad, y del estado serológico del VEB de los pacientes con EM. Pacientes y métodos. Estudio epidemiológico retrospectivo, tomando como muestra la población residente en el área sanitaria centro-oeste de la Región de Murcia (257.865 habitantes). Se analizan datos clínicos y serológicos extraídos de diferentes fuentes. Resultados. Prevalencia de la EM en la población estudiada: 88 casos/100.000 habitantes. Prevalencia de la EM junto con el síndrome desmielinizante aislado: 98,4 casos/100.000 habitantes. Incidencia media de la EM: 5,8 casos/100.000 habitantes/año. En el inicio de la EM, el 67,8% eran mujeres, el 81,9% presentaba un curso recurrente-remitente, la edad media era de 31,4 años, el sistema funcional más frecuentemente afectado era el sensitivo (45,1%), el inicio fue monofocal en el 55,4% y el grado de discapacidad en la Expanded Disability Status Scale era de 2,1 puntos. La seroprevalencia del VEB fue del 99,3%. La reactivación de la infección por VEB se relacionó con actividad clínica de EM en 10 pacientes (45,4%). Conclusiones. Actualmente, la prevalencia de la EM en la Región de Murcia es similar a la estimada en otras comunidades autónomas españolas. El estudio confirma la tendencia de incremento de prevalencia observada en las últimas décadas (AU)

Introduction. Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system with immunemediated pathogenesis. Recent research points to an increase in its prevalence, and a number of studies relate EpsteinBarr virus (EBV) with its aetiology. Aims. This study seeks to analyse the prevalence of MS in the Region of Murcia, and includes a description of the clinical characteristics at the time of onset of the disease, and of the EBV serological status of patients with MS. Patients and methods. We conducted a retrospective epidemiological study based on a sample consisting of the population living within the central-west healthcare area of the Region of Murcia (257,865 inhabitants). Clinical and serological data extracted from different sources were analysed. Results. Prevalence of MS in the population under study: 88 cases/100,000 inhabitants. Prevalence of MS together with isolated demyelinating syndrome: 98.4 cases/100,000 inhabitants. Mean incidence of MS: 5.8 cases/100,000 inhabitants/ year. At the onset of MS, 67.8% were females, 81.9% presented a relapsing-remitting course, the mean age was 31.4 years, the sensory system was the most frequently compromised (45.1%), onset was monofocal in 55.4% and the degree of disability on the Expanded Disability Status Scale was 2.1 points. The seroprevalence of EBV was 99.3%. The reactivation of EBV infection was related to the clinical activity of MS in 10 patients (45.4%). Conclusions. Currently, the prevalence of MS in the Region of Murcia is similar to that estimated in other Spanish autonomous regions. The study confirms the trend of increased prevalence observed over the last few decades (AU)

Ictus trombótico en paciente de 35 años ¿criptogénico, malformación vascular o trombosis completa arterial? / Thrombotic stroke in a 35-year old patient. cryptogenic or vascular malformation or complete arterial thrombosis?

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[Usefulness of NTproBNP in the emergency management of patients with severe dyspnea and an uncertain heart failure diagnosis]. / Utilidad del NTproBNP en el manejo urgente del paciente con disnea severa y diagnóstico dudoso de insuficiencia cardíaca.

INTRODUCTION AND OBJECTIVES: Measurement of N-terminal pro-B-type natriuretic peptide (NTproBNP) helps in diagnosing heart failure (HF). The test's usefulness may be greatest in patients with severe dyspnea of uncertain origin. However, NTproBNP has not been evaluated specifically in this setting. PATIENTS AND METHOD: This prospective emergency department study included 70 patients with shortness of breath at rest as their chief complaint. In the attending physician's opinion, both HF and a non-cardiac cause were equally probable. Blinded NTproBNP measurement was carried out in blood samples collected on admission. Patients were monitored and their final diagnoses were based on clinical findings, therapeutic responses, and cardiac and noncardiac tests performed during hospitalization. RESULTS: The NTproBNP level was higher in the 49 patients (70%) with a final diagnosis of HF (P = .006); the area under the ROC curve was 0.72 (0.60-0.82). The optimum diagnostic cut-off value was 900 pg/mL, which had an accuracy of 87%, a sensitivity of 98%, and a negative predictive value of 92%. The NTproBNP level was significantly higher in the 6 patients (9%) who died during hospitalization (P = .009); the area under the ROC curve was 0.87 (0.76-0.93) and the optimum cut-off value for predicting death was 5500 pg/mL, which had an accuracy of 77%, a sensitivity of 100%, and a positive likelihood ratio of 4.2. CONCLUSIONS: In patients with severe dyspnea and an uncertain diagnosis of HF, an NTproBNP level < 900 pg/mL helps exclude the presence of HF, whereas a NTproBNP level > 5500 pg/mL identifies patients at an increased risk of death.

Utilidad del NTproBNP en el manejo urgente del paciente con disnea severa y diagnóstico dudoso de insuficiencia cardíaca / Usefulness of NTproBNP in the emergency management of patients with severe dyspnea and an uncertain heart failure diagnosis

Introducción y objetivos. El NTproBNP ayuda a identificar a los pacientes con insuficiencia cardíaca. Su utilidad podría ser máxima en pacientes con disnea severa de origen incierto; sin embargo, esta población no ha sido específicamente evaluada. Pacientes y método. Estudio prospectivo de 70 pacientes que acudieron a urgencias refiriendo disnea de reposo, cuyo diagnóstico clínico inicial fue establecido como dudoso, con probabilidad intermedia de insuficiencia cardíaca. A la llegada a urgencias se extrajeron las muestras analíticas y se determinó el valor de NTproBNP de forma ciega. Los pacientes fueron controlados y el diagnóstico final se estableció sobre la base de los hallazgos clínicos, la respuesta al tratamiento y las pruebas practicadas durante el curso hospitalario. Resultados. El NTproBNP fue mayor en los 49 pacientes (70%) con un diagnóstico final de insuficiencia cardíaca (p = 0,006), obteniendo un área bajo la curva ROC de 0,72 (0,60-0,82). El valor de corte diagnóstico óptimo fue 900 pg/ml, con una precisión del 87%, una sensibilidad del 98% y un valor predictivo negativo del 92%. En los 6 pacientes (9%) fallecidos durante la hospitalización, el NTproBNP fue significativamente mayor (p = 0,009), con un área bajo la curva ROC de 0,87 (0,76-0,93) y un valor de corte pronóstico óptimo de 5.500 pg/ml, con una precisión del 77%, una sensibilidad del 100% y una razón de probabilidad positiva de 4,2. Conclusiones. En una población con disnea severa que acude a urgencias con diagnóstico dudoso de insuficiencia cardíaca, un valor de NTproBNP 5.500 pg/ml identifica a los pacientes con un mayor riesgo de muerte hospitalaria

Introduction and objectives. Measurement of N-terminal pro-B-type natriuretic peptide (NTproBNP) helps in diagnosing heart failure (HF). The test's usefulness may be greatest in patients with severe dyspnea of uncertain origin. However, NTproBNP has not been evaluated specifically in this setting. Patients and method. This prospective emergency department study included 70 patients with shortness of breath at rest as their chief complaint. In the attending physician's opinion, both HF and a non-cardiac cause were equally probable. Blinded NTproBNP measurement was carried out in blood samples collected on admission. Patients were monitored and their final diagnoses were based on clinical findings, therapeutic responses, and cardiac and noncardiac tests performed during hospitalization. Results. The NTproBNP level was higher in the 49 patients (70%) with a final diagnosis of HF (P=.006); the area under the ROC curve was 0.72 (0.60-0.82). The optimum diagnostic cut-off value was 900 pg/mL, which had an accuracy of 87%, a sensitivity of 98%, and a negative predictive value of 92%. The NTproBNP level was significantly higher in the 6 patients (9%) who died during hospitalization (P=.009); the area under the ROC curve was 0.87 (0.76-0.93) and the optimum cut-off value for predicting death was 5500 pg/mL, which had an accuracy of 77%, a sensitivity of 100%, and a positive likelihood ratio of 4.2. Conclusions. In patients with severe dyspnea and an uncertain diagnosis of HF, an NTproBNP level 5500 pg/mL identifies patients at an increased risk of death

[Balloon rupture and alcohol leakage into the left anterior descending coronary artery during percutaneous septal ablation for hypertrophic obstructive cardiomyopathy]. / Rotura de balón y extravasación de alcohol hacia la arteria descendente anterior durante la ablación septal en paciente con miocardiopatía hipertrófica obstructiva.

We present a case of rupture of the balloon during percutaneous transluminal septal myocardial ablation with alcohol in a patient with hypertrophic obstructive cardiomyopathy. Rupture of the balloon caused reflux of alcohol into the left anterior descending artery. Angina, mild global hypokinesia of the left ventricle and advanced atrioventricular block were observed. Cardiac function recovered in a few minutes and peak creatine kinase was 526 U. Despite the restoration of sinus rhythm, there were episodes of complete atrioventricular block that made permanent pacemaker implantation necessary.

Rotura de balón y extravasación de alcohol hacia la arteria descendente anterior durante la ablación septal en paciente con miocardiopatía hipertrófica obstructiva / Balloon rupture and alcohol leakage into the left anterior descending coronary artery during percutaneous septal ablation for hypertrophic obstructive cardiomyopathy

Presentamos un caso de rotura del balón de oclusión septal durante el procedimiento de ablación con alcohol en un paciente con miocardiopatía hipertrófica obstructiva. La rotura causó reflujo de alcohol a la arteria descendente anterior y originó angina, leve hipocinesia global, transitoria de ventrículo izquierdo y bloqueo auriculoventricular avanzado. La función contráctil se recuperó en pocos minutos y el pico de creatincinasa fue de 526 U. A pesar de restaurarse el ritmo sinusal, hubo episodios de bloqueo auriculoventricular que obligaron al implante de marcapasos definitivo

We present a case of rupture of the balloon during percutaneous transluminal septal myocardial ablation with alcohol in a patient with hypertrophic obstructive cardiomyopathy. Rupture of the balloon caused reflux of alcohol into the left anterior descending artery. Angina, mild global hypokinesia of the left ventricle and advanced atrioventricular block were observed. Cardiac function recovered in a few minutes and peak creatine kinase was 526 U. Despite the restoration of sinus rhythm, there were episodes of complete atrioventricular block that made permanent pacemaker implantation necessary