Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics

Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). Conclusions-The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations

Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan

Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection

Identification of novel biomarker candidates by proteomic analysis of cerebrospinal fluid from patients with moyamoya disease using SELDI-TOF-MS

<p>Abstract</p> <p>Background</p> <p>Moyamoya disease (MMD) is an uncommon cerebrovascular condition with unknown etiology characterized by slowly progressive stenosis or occlusion of the bilateral internal carotid arteries associated with an abnormal vascular network. MMD is a major cause of stroke, specifically in the younger population. Diagnosis is based on only radiological features as no other clinical data are available. The purpose of this study was to identify novel biomarker candidate proteins differentially expressed in the cerebrospinal fluid (CSF) of patients with MMD using proteomic analysis.</p> <p>Methods</p> <p>For detection of biomarkers, CSF samples were obtained from 20 patients with MMD and 12 control patients. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) with an anion exchange chip in three different buffer conditions. After expression difference mapping was undertaken using the obtained protein profiles, a comparative analysis was performed.</p> <p>Results</p> <p>A statistically significant number of proteins (34) were recognized as single biomarker candidate proteins which were differentially detected in the CSF of patients with MMD, compared to the control patients (p < 0.05). All peak intensity profiles of the biomarker candidates underwent classification and regression tree (CART) analysis to produce prediction models. Two important biomarkers could successfully classify the patients with MMD and control patients.</p> <p>Conclusions</p> <p>In this study, several novel biomarker candidate proteins differentially expressed in the CSF of patients with MMD were identified by a recently developed proteomic approach. This is a pilot study of CSF proteomics for MMD using SELDI technology. These biomarker candidates have the potential to shed light on the underlying pathogenesis of MMD.</p

Internal Standard-Amplitude Modulated Multiplexed Flow Analysis

A new concept of flow analysis, internal standard-amplitude modulated multiplexed flow analysis, is proposed. A proof of concept was verified by applying it to the determination of ferrous ion (Fe2+) by 1,10-phenanthroline (o-Phen) spectrophotometry. The flow rates of sample solutions containing Methylene Blue (MB) as an internal standard substance were sinusoidally varied at different frequencies. The solutions were merged with a color reagent (o-Phen) solution, while the total flow rate was held constant. Downstream, analytical signals were monitored at the maximum absorption wavelengths of Fe2+-o-Phen complex and of MB (510 and 644 nm, respectively). The signals were respectively analyzed by fast Fourier transform. The concentrations of the analytes in respective samples were simultaneously determined from the amplitudes of the corresponding wave components. The precision, linearity of the calibration curve, limit of detection and robustness against deliberate fluctuation in flow rate were greatly improved by introducing the internal standard method. Good recoveries of around 100% were obtained for Fe2+ spiked into real water samples

Primary Pulmonary Synovial Sarcoma Showing a Prolonged Survival with Multimodality Therapy

A 54-year-old man was referred to our hospital due to a mass shadow noted on a chest X-ray. Thoracoscopic lobectomy yielded a diagnosis of primary pulmonary synovial sarcoma according to the histology and SYT-SSX1 gene analyses. Five months after the thoracic surgery, he developed brain metastasis; therefore, we performed resection of the brain metastatic focus followed by radiotherapy. As a local recurrence in the thoracic cavity concurrently emerged, systemic chemotherapy was also administered. These observations indicated that a multidisciplinary approach may be useful against primary pulmonary synovial sarcoma, although there is presently no established therapeutic strategy due to its rarity and highly aggressive nature

Corpus callosotomy in pediatric patients with non-lesional epileptic encephalopathy with electrical status epilepticus during sleep

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities