Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations

OBJECTIVE: Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Na(v)1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS. METHODS: Four male patients with typical BrS ST-segment elevation in V1-V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. The sodium currents (I(Na)) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments. RESULTS: Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Na(v)1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 degrees C, we observed a pronounced acceleration of Na(v)1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced I(Na), fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever. CONCLUSIONS: The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specific.     

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Background

Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism.

Methods

Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated.

Results

The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients.

Conclusion

Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option.

     

Safety and outcome using endoscopic dilatation for benign esophageal stricture without fluoroscopy

AIM:To investigate the use of Savary-Gilliard marked dilators in tight esophageal strictures without fluoros-copy. METHODS:Seventy-two patients with signif icant dysphagia from benign strictures due to a variety of causes were dilated endoscopically. Patients with achalasia, malignant lesions or external compression were excluded. The procedure consisted of two parts. First, a guide wire was placed through video endoscopy and then dilatation was performed without fluoroscopy. In general, "the rule of three" was followed. Effective treatment was defi ned as the ability of patients, with or without repeated dilatations, to maintain a solid or semisolid diet for more than12mo. RESULTS: Six hundred and sixty two dilatations in a total of72patients were carried out. The success rate for placement of a guide wire was100%and for dilatation97%,without use of fluoroscopy, after6mo to4years of follow-up.The number of sessions per patient was between1and7,with an average of2sessions.The ability of patients, after 1 or more sessions of dilatation, to maintain a solid or semisolid diet for more than 12mo was obtained in70patients(95.8%).For very tight esophageal strictures, all patients improved clinically without complications after the endoscopic procedure without fluoroscopy, but we noted3failures. CONCLUSION:Dilatation using Savary-Gilliard dilators without fluoroscopy is safe and effective in the treatment of very tight esophageal strictures if performed with care.     

Comparison of the BASDAI and the miniBASDAI in assessing disease activity in patients with ankylosing spondylitis

The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) is the most widely used instrument for the assessment of disease activity in ankylosing spondylitis (AS). Objective. The aims to investigate whether the alternative BASDAI, here termed as the miniBASDAI [(Question (Q) 1 fatigue + Q2 spinal pain) + mean of (Q5 strength morning stiffness + Q6 duration morning stiffness)] / 3], measures disease activity more accurately in the subgroup of AS patients without peripheral manifestations. One hundred and ten patients were included in this cross-sectional study according to the modified New York criteria for AS. Clinical and biological parameters were evaluated. The disease activity was evaluated by the BASDAI. We calculated the miniBASDAI by omitting both the peripheral joints and the enthesitis questions: questions 3 and 4. Patients were dichotomized into a “P+” group if peripheral manifestations were present (at least arthritis or enthesitis) and a “P−” group, the subgroup without peripheral involvement (with either arthritis or enthesitis). Correlation of the BASDAI and miniBASDAI with other disease parameters were examined with the Spearman's rank correlation analysis. One hundred and ten patients were recruited. The percentage of patients with pure axial disease manifestation without peripheral involvement “P − group” was 42.7%. We found a similarly good correlation of the miniBASDAI with patient global, physician on disease activity, BASFI, ESR and CRP if compared to the correlation of the original BASDAI with these disease parameters, also in the group without peripheral involvement. Our study suggests that the BASDAI remains valid in assessing disease activity in AS patients with and without peripheral manifestations.     

Maternal knowledge of acute seizures

Objective:

To study maternal knowledge -of, and behavior during acute seizures.

Methods:

A cross sectional study conducted from September 2013 to January 2014 included consecutive mothers presenting at the Pediatric Neurology Clinics of King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. A structured 30-item questionnaire was designed to examine their demographics, knowledge, and behavior on acute seizures.

Results:

A total of 92 mothers were interviewed and 41% witnessed at least one acute seizure in their affected child (range 1-15 years, mean 4.5). Up to 26% felt not knowledgeable at all regarding the acute care and management of seizure. Mothers with higher education (college or university degree) were more likely to feel very knowledgeable (19% versus 11%, p=0.02). Only 10% were aware of an antiepileptic drug that could be used at home to stop prolonged seizures, and 35% mentioned that they would wait for 15 minutes before taking the child to the emergency department. Most mothers (93%) wanted more information. Those who felt strongly regarding that (66%), were more likely to be younger (<27 years) (p=0.01), and have at least 3 out of 7 mismanagement decisions (p=0.003).

Conclusion:

Maternal level of knowledge and behavior during acute seizures needs improvement. Many mothers have significant misinformation, negative behavior, and poor management practices. Increased awareness and educational programs are needed.Seizures are the most common pediatric neurological emergency.1,2 Adequate education is important for their proper identification, intervention, and management.3,4 Parents’ behavior during an acute seizure is influenced by their knowledge and experience. Although parents generally feel informed about epilepsy and its management, many still have significant misconceptions and misinformation.5 Such misconceptions should be identified and corrected for optimal care and management. In a recent Saudi study,6 although most parents stated that they know what to do in an acute seizure situation, up to 14% performed unnecessary procedures, such as sprinkling water to the face, shaking, or carrying the child around. This behavior was less likely if the parents achieved college or university education. More inappropriate or potentially harmful procedures related to mythical concepts were reported from other developing countries, such as forcing liquids by mouth, pressure over body to restrain convulsive movements, or putting some object to force the teeth open.7 Our objectives were to study maternal knowledge -of and behavior during acute seizures, and identify correlating and contributing factors to their negative behavior and actions. These may include their personal and social experiences, as well as, their socio-economic and educational levels. These issues have received limited study in our region. We hypothesize that many families in Saudi Arabia are not properly informed on what to do during an acute seizure. Some are misinformed from unreliable sources leading to negative management decisions and practices.     

Evaluation of Biocompatibility and Osteogenic Potential of Tricalcium Silicate–based Cements Using Human Bone Marrow–derived Mesenchymal Stem Cells

Introduction

The success of endodontic regeneration lies in the appropriate combination of stem cells and bioactive materials. Several novel dental materials are available on the market in this regard. Hence, the current study aimed to evaluate the proliferation, differentiation, and osteogenic potential of human bone marrow–derived mesenchymal stem cells (hBMSCs) onto biomaterials like ProRoot MTA (MTA; Dentsply Tulsa Dental, Tulsa, OK), Biodentine (BD; Septodont, Saint Maur de Fosses, France), and EndoSequence Root Repair Material (ERRM; Brasseler USA, Savannah, GA).

Cytokine patterns in maternal blood after premature rupture of membranes.

OBJECTIVE: To compare two types of cytokines, type 1, which activate cell-mediated reactions and are important in cytotoxic and delayed-type hypersensitivity reactions, and type 2, which encourage vigorous antibody production and are commonly found in association with humoral immune responses, in blood of women with premature rupture of membranes (PROM). METHODS: Forty-four women with histories of at least three successful pregnancies and who currently delivered normally served as controls. The PROM group consisted of 30 women with spontaneous rupture of fetal membranes at term. Peripheral blood mononuclear cells were stimulated separately with a mitogen, placental cells, and a trophoblast antigen extract, and the supernatants examined for type 1 and type 2 cytokines. RESULTS: Mitogen-stimulated blood cells produced significantly higher levels of type 1 cytokines in PROM women than in normal controls. Higher levels of the type 1 cytokine interferon-gamma were produced by PROM samples stimulated with autologous placental cells and with trophoblast antigens. Ratios of type 1 to type 2 cytokines were higher in PROM compared with normal pregnancy, and in some cases as much as 25-fold higher. CONCLUSION: Women in the PROM group had a stronger type 1 reactivity whereas normal women were more predisposed to type 2 immunity; thus, PROM appears to be associated with a maternal type 1 bias.