Functional Characterization of a Novel Frameshift Mutation in the C-terminus of the Nav1.5 Channel Underlying a Brugada Syndrome with Variable Expression in a Spanish Family.

INTRODUCTION We functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) found in a proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry the mutation and showed a Brugada syndrome with an incomplete and variable expression. The mutation (p.D1816VfsX7) resulted in a severe truncation (201 residues) of the Nav1.5 C-terminus. METHODS AND RESULTS Wild-type (WT) and mutated Nav1.5 channels together with hNavβ1 were expressed in CHO cells and currents were recorded at room temperature using the whole-cell patch-clamp. Expression of p.D1816VfsX7 alone resulted in a marked reduction (≈90%) in peak Na(+) current density compared with WT channels. Peak current density generated by p.D1816VfsX7+WT was ≈50% of that generated by WT channels. p.D1816VfsX7 positively shifted activation and inactivation curves, leading to a significant reduction of the window current. The mutation accelerated current activation and reactivation kinetics and increased the fraction of channels developing slow inactivation with prolonged depolarizations. However, late INa was not modified by the mutation. p.D1816VfsX7 produced a marked reduction of channel trafficking toward the membrane that was not restored by decreasing incubation temperature during cell culture or by incubation with 300 μM mexiletine and 5 mM 4-phenylbutirate. CONCLUSION Despite a severe truncation of the C-terminus, the resulting mutated channels generate currents, albeit with reduced amplitude and altered biophysical properties, confirming the key role of the C-terminal domain in the expression and function of the cardiac Na(+) channel.

Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies.

Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated animals. The success rate of cornea graft transplantation was 73% in treated animals against 25% for the control group. This result was as good as observed for a systemic CsA treatment in the same animal model. This new formulation has the same efficacy like a systemic treatment but without the serious CsA systemic side effects. Ocular drug levels of transplanted and healthy rat eyes were dosed by UPLC/MS and showed a high CsA value in the cornea (11710 ± 7530 ng(CsA)/g(tissue) and 6470 ± 1730 ng(CsA)/g(tissue), respectively). In conclusion, the applied formulation has the capacity to overcome the ocular surface barriers, the micelles formed a drug reservoir in the cornea from, where a sustained release of CsA can take place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection.

Tratamiento ambulatorio de la diverticulitis aguda no complicada: impacto sobre los costes sanitarios

OBJETIVOS: Se ha demostrado previamente que el tratamiento ambulatorio de la diverticulitis aguda no complicada es seguro, eficaz y aplicable en la mayoría de los pacientes que toleran la dieta oral y que tienen un adecuado apoyo familiar. El objetivo de este estudio es cuantificar el impacto que el tratamiento ambulatorio tiene en la reducción de costes sanitarios. MATERIAL Y MÉTODOS: Estudio comparativo retrospectivo realizado sobre una base de datos mantenida de forma prospectiva. Periodo de estudio: enero del 2005 hasta junio del 2011. Grupo de estudio: pacientes diagnosticados de diverticulitis aguda no complicada tratados con antibióticos vía oral de forma ambulatoria (7-10 días). Grupo control: pacientes diagnosticados de diverticulitis aguda no complicada que cumplían criterios de tratamiento ambulatorio pero que fueron ingresados con tratamiento antibiótico endovenoso (7-10 días). El diagnóstico se confirmó mediante TC abdominal. Se han analizado las características de los pacientes y los motivos del ingreso así como el resultado del tratamiento. El análisis de costes se ha realizado mediante el sistema “full costing”, sumación de todos los costes variables (costes directos) más el conjunto de costes generales repartidos por actividad (costes indirectos) y que incluye los gastos en urgencias, unidad de hospitalización, laboratorio, radiología y farmacia. Se ha añadido el coste del tratamiento ambulatorio tanto en el grupo de estudio (tratamiento completo) como en el grupo control, cuando completaron el tratamiento una vez dados de alta. Se ha realizado el análisis comparativo según intención de tratamiento. RESULTADOS: Se incluyeron 136 pacientes, 90 en el grupo de estudio y 46 en el grupo control. No hubo diferencias en la edad, sexo, número de episodios anteriores, fiebre o leucocitosis entre los dos grupos. Los motivos de tratamiento hospitalario más frecuentes fueron: ingreso en la fase inicial del protocolo, decisión del médico de guardia o negativa del paciente al tratamiento ambulatorio. Cinco de los 90 pacientes del grupo de estudio precisaron ingreso por persistencia del dolor o vómitos mientras que 2 de los pacientes del grupo control reingresaron por recurrencia de la sintomatología (5,5% vs. 4,3%; p=0,7). Ninguno de estos pacientes precisó cirugía urgente. El coste global por episodio fue de 882±462 euros en el grupo de estudio frente a 2376±830 euros en el grupo control (p=0,0001). CONCLUSION El tratamiento ambulatorio de la diverticulitis agua no sólo es seguro y eficaz sino que también reduce más de un 50% los costes sanitarios. Palabras clave: Diverticulitis aguda. Tratamiento ambulatorio. Impacto sobre coste sanitario

Artroplastia total de cadera tipo Charnley: Estudio retrospectivo descriptivo de 595 casos de prótesis primarias durante 25 años.

L’artroplastia total de maluc cimentada, descrita per Charnley, és reconeguda per ser una de les intervencions més exitoses. Analitzem retrospectivament 595 artroplasties primàries tipus Charnley del nostre centre, durant 1986 i 2011. Com a punt final de supervivencia considerem el recanvi protèsic (afluixament asèptic, infecció o luxació), èxitus o pèrdua de seguiment. Els anàlisis de supervivència a llarg plaç, han sigut similars als obtinguts per altres autors. Aquest estudi identifica grups poblacionals que podrien beneficiar-se dels nous implants i tècniques que millorin aquesta exitosa pròtesi, i reafirma els bons resultats d’aquesta cirurgia, inclús a hospitals generals.

Association of 25-hydroxyvitamin D with metabolic syndrome in patients with psoriasis: a case-control study.

Vitamin D deficiency is associated with higher cardiovascular risk and metabolic syndrome (MeS) criteria. The main objective of this study was to analyse the association of 25-hydroxyvitamin D (25-OHD) serum levels with MeS (National Cholesterol Education Program-Adult Treatment Panel-III criteria) in 46 Spanish patients with psoriasis, but without arthritis and systemic treatment, and 46 control subjects, matched by sex and age. The patients with psoriasis showed significantly lower level of 25-OHD than controls (30.5 vs. 38.3 ng/ml; p = 0.0001). Patients with MeS had significantly lower serum levels of 25-OHD than those without MeS (24.1 ± 7.5 vs. 32.8 ± 8.9, p = 0.007), and a negative correlation was found between 25-OHD and waist circumference, diastolic blood pressure, fasting glucose, and triglyceridaemia. In the control group no significant correlation between 25-OHD and MeS was found. Al-though the sample was small, our results suggest a potential protective role for 25-OHD in the metabolic profile of patients with psoriasis without arthritis.

Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the β-isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.

25 Aniversario de la convención de los derechos del niño

Boletín semanal para profesionales sanitarios de la Secretaría General de Calidad, Innovación y Salud Pública de la Consejería de Igualdad, Salud y Políticas Sociales

Détermination spécifique d'individus vivants des deux espèces jumelles Sorex araneus et S. coronatus, par deux techniques biochimiques (Insectivora, Soricidae)

As the morphological determination of living individuals of the two sibling species S. araneus and S. coronatus is not possible, we have tested two biochemical methods to determine these shrews in ecological studies. After producing specific antibodies by rabbits, we performed an immunological test on 25 individuals. With this first method, a correct determination was achieved in 76% of the cases only. The second method proved very successful: a polyacrylamide gel electrophoresis showed a systematic difference for albumin (73 individuals analyzed). According to our experience, the necessary blood sampling (10-20 μl) seems harmless for the shrews

Estudio del síndrome metabólico y de la obesidad en pacientes en hemodiálisis.

INTRODUCTION: The metabolic syndrome (MS) consists of a set of clinical and biochemical changes. It is very common among chronic hemodialysis patients, being the leading cause of death in these patients, 44% of all patients undergoing this therapy. AIMS: The aim of this study was to investigate the prevalence of MS and risk factors associated with its development, as well as the prevalence of obesity in HD patients. METHODS: This study has followed 90 patients of both sexes with chronic renal failure (CRF) who were treated with hemodialysis periodically in our unit for ten years. All patients were performed quarterly measurements of plasma albumin (A1b) and other biochemical analysis; besides, they underwent some anthropometric measurements like weight, height and body mass index (BMI). This was calculated using weight / size2 formula and grouped in BMI values according to WHO criteria. The data concerning hypertension and glucose were also considered. RESULTS: The prevalence of MS was 25% and obesity was presented as follows: 45% with type I overweight; 30.8% with type II overweight and 12 patients (2%) were obese. Being statistically significant as risk factors, BMI, overweight, triglycerides, total cholesterol, HDL cholesterol as well as hypertension and elevated glucose levels were obtained. CONCLUSIONS: The metabolic syndrome compromises the patient survival causing a high prevalence in these patients. The principal risk factors in MS are monitoring weight, BMI, triglycerides, HDL cholesterol, hypertension and diabetes.