DEPDC5 mutations in familial and sporadic focal epilepsy.

BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized. MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing. RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene. DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

Trends in the susceptibility of methicillin-resistant Staphylococcus aureus to nine antimicrobial agents, including ceftobiprole, nemonoxacin, and tyrothricin: results from the Tigecycline In Vitro Surveillance in Taiwan (TIST) study, 2006-2010.

This study investigated the in vitro susceptibilities of methicillin-resistant Staphylococcus aureus (MRSA) to nine antimicrobial agents in Taiwan. A total of 1,725 isolates were obtained from 20 hospitals throughout Taiwan from 2006 to 2010. The minimum inhibitory concentrations (MICs) of the nine agents were determined by the agar dilution method. The MICs of mupirocin and tyrothricin were determined for 223 MRSA isolates collected from 2009 to 2010. For vancomycin, 99.7 % were susceptible; however, 30.0 % (n = 517) exhibited MICs of 2 µg/ml and 0.3 % (n = 6) demonstrated intermediate susceptibility (MICs of 4 µg/ml). Nearly all isolates (≥ 99.9 %) were susceptible to teicoplanin, linezolid, and daptomycin. The MIC90 values were 2 µg/ml for ceftobiprole and 1 µg/ml for nemonoxacin. The MIC90 values of mupirocin and tyrothricin were 0.12 and 4 µg/ml, respectively. MIC creep was noted for daptomycin during this period, but not for vancomycin, teicoplanin, linezolid, or tigecycline. For isolates with vancomycin MICs of 2 µg/ml, the MIC90 values were 2 µg/ml for teicoplanin, 0.5 µg/ml for daptomycin, and 0.5 µg/ml for tigecycline. Those values were four- to eight-fold higher than those among isolates with vancomycin MICs of 0.5 µg/ml (2, 0.06, and 0.12 µg/ml, respectively). Of the nine MRSA isolates exhibiting non-susceptibility to vancomycin (n = 6), teicoplanin (n = 1), daptomycin (n = 2), or tigecycline (n = 1), all had different pulsotypes, indicating the absence of intra-hospital or inter-hospital spread. The presence of a high proportion of MRSA isolates with elevated MICs (2 µg/ml) and MIC creep of daptomycin might alert clinicians on the therapy for serious MRSA infections in Taiwan.

Limits on spin-independent couplings of WIMP dark matter with a p-type point-contact germanium detector.

We report new limits on a spin-independent weakly interacting massive particle (WIMP)-nucleon interaction cross section using 39.5 kg days of data taken with a p-type point-contact germanium detector of 840 g fiducial mass at the Kuo-Sheng Reactor Neutrino Laboratory. Crucial to this study is the understanding of the selection procedures and, in particular, the bulk-surface events differentiation at the sub-keV range. The signal-retaining and background-rejecting efficiencies were measured with calibration gamma sources and a novel n-type point-contact germanium detector. Part of the parameter space in the cross section versus WIMP-mass implied by various experiments is probed and excluded.

Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells.

BACKGROUND: A T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 16189 can generate a variable length polycytosine tract (poly-C). This tract variance has been associated with disease. A suggested pathogenesis is that it interferes with the replication process of mtDNA, which in turn decreases the mtDNA copy number and generates disease. METHODS: In this study, 837 healthy adults' blood samples were collected and determined for their mtDNA D-loop sequence. The mtDNA copy number in the leucocytes and serum levels of oxidative thiobarbituric acid reactive substance (TBARS) and antioxidative thiols were measured. All subjects were then categorised into three groups: wild type or variant mtDNA with presence of an interrupted/uninterrupted poly-C at 16180-16195 segment. RESULTS: A step-wise multiple linear regression analysis identified factors affecting expression of mtDNA copy number including TBARS, thiols, age, body mass index and the mtDNA poly-C variant. Subjects harbouring a variant uninterrupted poly-C showed lowest mean (SD) mtDNA copy number (330 (178)), whereas an increased copy number was noted in subjects harbouring variant, interrupted poly-C (420 (273)) in comparison with wild type (358 (215)). The difference between the three groups and between the uninterrupted poly-C and the composite data from the interrupted poly-C and wild type remained consistent after adjustment for TBARS, thiols, age and body mass index (p=0.001 and p=0.011, respectively). A trend for decreased mtDNA copy number in association with increased number of continuous cytosine within the 16180-16195 segment was noted (p(trend)<0.006). CONCLUSIONS: Our results substantiate a previous suggestion that the mtDNA 16189 variant can cause alteration of mtDNA copy number in human blood cells.

Random forest can predict 30-day mortality of spontaneous intracerebral hemorrhage with remarkable discrimination.

BACKGROUND AND PURPOSE: Risk-stratification models based on patient and disease characteristics are useful for aiding clinical decisions and for comparing the quality of care between different physicians or hospitals. In addition, prediction of mortality is beneficial for optimizing resource utilization. We evaluated the accuracy and discriminating power of the random forest (RF) to predict 30-day mortality of spontaneous intracerebral hemorrhage (SICH). METHODS: We retrospectively studied 423 patients admitted to the Taichung Veterans General Hospital who were diagnosed with spontaneous SICH within 24 h of stroke onset. The initial evaluation data of the patients were used to train the RF model. Areas under the receiver operating characteristic curves (AUC) were used to quantify the predictive performance. The performance of the RF model was compared to that of an artificial neural network (ANN), support vector machine (SVM), logistic regression model, and the ICH score. RESULTS: The RF had an overall accuracy of 78.5% for predicting the mortality of patients with SICH. The sensitivity was 79.0%, and the specificity was 78.4%. The AUCs were as follows: RF, 0.87 (0.84-0.90); ANN, 0.81 (0.77-0.85); SVM, 0.79 (0.75-0.83); logistic regression, 0.78 (0.74-0.82); and ICH score, 0.72 (0.68-0.76). The discriminatory power of RF was superior to that of the other prediction models. CONCLUSIONS: The RF provided the best predictive performance amongst all of the tested models. We believe that the RF is a suitable tool for clinicians to use in predicting the 30-day mortality of patients after SICH.

Prevalence and accessory gene regulator (agr) analysis of vancomycin-intermediate Staphylococcus aureus among methicillin-resistant isolates in Taiwan--SMART program, 2003.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in nosocomial staphylococcal infections in Taiwan has exceeded 50% since 2000. However, little relevant data has been available concerning vancomycin-intermediate S. aureus (VISA) and heteroresistant VISA (hVISA). We collected 1,000 MRSA isolates from ten medical center hospitals in Taiwan during 2003. All were initially screened for reduced susceptibility to vancomycin on brain heart infusion (BHI) agar containing 5 mg/L vancomycin. Among 34 MRSA isolates that grew on the screening plates, two VISA isolates (0.2%) and seven hVISA isolates (0.7%) were evident. Vancomycin-resistant S. aureus was not detected. The accessory gene regulator (agr) typing of all 1,000 MRSA strains were typed by multiplex polymerase chain reaction (PCR); 919 strains (91.9%) including the VISA and hVISA isolates belonged to agr group I, 78 strains (7.8%) were agr group II, two strains (0.2%) were agr group III, and one isolate (0.1%) was agr group IV. There was no relationship between sample sites and agr typing. In 2003, the incidence of hVISA and VISA in Taiwan was low. Continued surveillance is recommended, given the implementation of new Clinical and Laboratory Standards Institute (CLSI) criteria for S. aureus and the increasing clinical use of glycopeptides.

Sporadic and outbreak cases of melioidosis in southern Taiwan: clinical features and antimicrobial susceptibility.

BACKGROUND: Melioidosis has been well known to be endemic in Thailand and Northern Australia, and was reported sporadically in Taiwan before 2005. METHODS: We retrospectively analyzed 58 patients with melioidosis in southern Taiwan from 2000 to 2005, including 40 clustered and 18 sporadic cases, for clinical characteristics and antimicrobial susceptibility. RESULTS: Fifty-one (88%) cases were found during the rainy season, and there was a significant correlation between the average monthly rainfalls and the case number (r = 0.37; p = 0.001). Diabetes mellitus was the most common underlying disease (35 cases, 60%). The majority (52 cases, 90%) had never traveled abroad before illness, indicating indigenous acquisition of Burkholderia pseudomallei. In comparison, clustered cases were older, less often had underlying diabetes mellitus and had a shorter duration of clinical symptoms before admission than sporadic cases. Acute form of melioidosis predominated, and shock at admission was independently associated with a grave prognosis. Overall, 22% of 58 patients died in hospitals. Ceftazidime, imipenem, meropenem, amoxicillin/clavulanic acid, co-trimoxazole, and doxycycline, as previously recommended, were the potentially therapeutic choices. The role of piperacillin/ tazobactam for melioidosis remains undefined. CONCLUSIONS: Melioidosis can occur sporadically or in a cluster in diabetic patients during rainy seasons in Taiwan.

Factors associated with gender difference in the intima-media thickness of the common carotid artery.

AIM: To investigate the gender differences associated with a thinner intima-media thickness (IMT) of the common carotid artery (CCA) in women. MATERIALS AND METHODS: In a sample of 218 consecutive healthy volunteers comprising 110 men and 108 women, the IMT of the CCA was measured using B-mode ultrasonography. Blood pressure, fasting blood sugar, body mass index (BMI), blood lipid profile, homocysteine, folic acid, uric acid, high sensitive C-reactive protein, and thiobarbituric acid reactive substances (TBARS) levels were measured and compared with each other in both genders. RESULTS: The IMT of the CCA was significantly thinner in women than in men (p=0.012). Blood pressure, fasting plasma glucose, BMI, low-density lipoprotein cholesterol, triglycerides, homocysteine, uric acid, and TBARS were significantly (p<0.05) lower, folic acid and high-density lipoprotein cholesterol (HDL-C) were significantly (p<0.0001) higher in women compared with men. Multivariable logistic regression analysis revealed that higher serum levels of homocysteine, uric acid, and TBARS, and lower serum levels of HDL-C were significantly (p<0.05) associated with male sex. Multiple linear regression analysis further revealed that age, sex, and BMI were independently associated with CCA IMT. CONCLUSIONS: The IMT of the CCA was thinner in women than in men. Traditional vascular risk factors explain only a small amount of variance in multivariate regression models supporting the hypothesis that other behavioural, sex hormone-related or genetic factors, which have not been sufficiently explored so far, may play a role in the gender differences of IMT.

Cerebrospinal fluid 14-3-3-gamma protein level in eight HIV-negative cryptococcal meningitis adults.

The clinical data and cerebrospinal fluid (CSF) 14-3-3-gamma protein detection of eight adult HIV-negative cryptococcal meningitis (CM) cases were examined. The eight cases included six males and two females aged 35-70 years (mean = 49.8 years). The duration between the onset of CM symptoms and the first CSF study ranged from 1 to 60 days. Initial neuroimaging study was abnormal in 87.5% (7/8) of the cases. All the eight had positive initial and subsequent follow-up CSF 14-3-3-gamma protein detection. The densitometric values of CSF 14-3-3-gamma protein were not correlated with either the CSF white blood cell counts or the therapeutic results. The therapeutic results showed that three cases died and five survived. Significant neurologic deficits were shown in 60% (3/5) of the survivors. This study revealed that HIV-negative CM patients have elevated CSF 14-3-3-gamma protein levels, and that this level is not changed with a short-term treatment.

Updates in heart transplantation.

Heart transplantation (HTx) has been a successful therapy for patients with end-stage heart failure. Since 1987, we have performed 288 HTx. Thirty-six subjects needed mechanical support prior to HTx. We use anti-thymocyte globulin (ATG) as induction therapy and low-dose immunosuppressive agents for maintenance treatment. In June 1996, we performed combined heart and kidney transplantation after bridging for 14 days with an indigenous total artificial heart (TAH). The patient is still well. Our actuarial survival rates at 1, 5, and 10 years are 86%, 76%, and 61%, respectively. One recipient who voluntarily discontinued all treatment at 4 years after HTx is still alive and free of rejection in his ninth posttransplantation year. The longest surviving recipient is in her 18th posttransplantation year. We also have used many suboptimal donor hearts, most with satisfactory outcomes. A 14-year-old boy had full recovery of heart function after receiving a donor heart after 13 hours of ischemia in 2003. Standard biatrial anastomotic technique is still our first choice. The incidence of tricuspid regurgitation (TR) and conduction disturbances is not higher than the bicaval technique reported by others. With low-dose therapy, our short-term and long-term results of HTx are satisfactory. The use of suboptimal donor hearts may expand the donor pool and save more patients' lives. A biatrial anastomosis remains our surgical technique.

Cardiac transplantation for congenitally corrected transposition of the great arteries: a case report.

Orthotopic heart transplantation (HTx) was successfully performed in a 46-year-old man with congenitally corrected transposition of the great arteries. Because of the need for an extraordinary length of aorta, we preserved the aortic arch during harvesting of the donor organ. The allograft was implanted using a biatrial technique, but the heart might have to be rotated clockwise due to the posteriorlyy located pulmonary artery. The patient was well at 4 years after HTx. HTx in corrected transposition of the great arteries is technically feasible. Preservation of the aortic arch of the donor's heart may be necessary to achieve a good anatomic correction. The long-term results of such an operation are as good as other HTx procedures.

Cardiac transplantation in situs inversus: two cases reports.

The challenge of heart transplantation in patients with situs inversus is reconstruction of the systemic venous return. Herein we have presented 2 cases of complex congenital heart disease with atriovisceral situs inversus. Both of the patients shared many common cardiac anomalies, such as a single ventricle, a single AV valve with severe regurgitation, and severe pulmonary stenosis. We completed the venous connection in 2 different ways. In the first case, the donor inferior vena cava (IVC) was anastomosed to the recipient left-sided IVC directly, making the heart slightly counterclockwise rotated. In the second case, the IVC venous reconnection was accomplished by a composite conduit made of recipient right atrium.

Successful treatment of aortic root aneurysm after orthotopic heart transplantation: case report.

Aortic root aneurysm after orthotopic heart transplantation (HTx) is rare. It may originate from cystic medial necrosis of the donor heart aorta. Herein we have reported a 64-year-old man who received an orthotopic HTx due to dilated cardiomyopathy. Although asymptomatic, follow-up echocardiography revealed dilatation of the aortic root and severe aortic regurgitation at 3 years after the transplantation. He underwent a Bentall procedure with a prosthetic valved conduit. The post-operative course was uneventful. This case demonstrated that a heart-transplant recipient with a late aortic root aneurysm can be successfully treated with an excellent outcome.

Tricuspid valve regurgitation and endomyocardial biopsy after orthotopic heart transplantation.

OBJECTIVE: Tricuspid valve regurgitation (TR) after heart transplantation (HTx) has been reported to be caused by endomyocardial biopsy (EMB), acute cellular rejection (ACR), or atrial anastomosis. We performed a prospective study of this problem among our HTx cohort. METHODS: From 1988 to 2006, we performed 274 HTx. Excluding cases within 1 year (2006), there were 178 patients in whom we had records of EMB dates, ACR grades (International Society for Heart and Lung Transplantation [ISHLT], 1990), echocardiography-measured TR, and time-to-TR. Statistical analyses were performed using nonparametric comparisons, Spearman correlation, Kaplan-Meier time to failure curves, and Cox regression model. RESULTS: All 178 patients underwent a biatrial anastomosis and underwent 2631 EMB (median, 15 times per patient; range, 0-42). The median follow-up duration was 66 months (range 2 days-194 months). Up to December 31, 2006, there were 47 patients (47/178 = 26.4%) who developed moderate-to-severe TR, which differed significantly from the prevalence rate (24/39 = 61.5%) reported by another cardiac team (P = .001) that performed bicaval anastomoses in half of the cases (20/39 = 51%). Our 1-, 3-, and 10-year Kaplan-Meier incidence rates of remarkable TR were 14.7% (10.2%-20.8%), 19.4% (14.2%-26.2%), and 36.3% (27.2%-47.3%), respectively. A positive correlation was shown between each patient's EMB times and ACR but not TR grades, in terms of mean, maximum, or minimum over time (all P < .001 for null hypothesis of noncorrelation). Each patient's EMB times and number of definite ACRs (> or = ISHLT grade II) did not differ significantly between the two groups of remarkable versus nonremarkable TR. Remarkable TR was negatively predicted by each patient's EMB times (hazard ratio = 0.93; P = .010) but not by the ACR grades or the numbers of definite ACRs. CONCLUSION: Our cohort demonstrated that biatrial anastomosis, ACR, or EMB were not associated with the risk of remarkable TR. The protective effect of EMB on remarkable TR needs further investigation.

Measurement of human erythrocyte C4d to erythrocyte complement receptor 1 ratio in cardiac transplant recipients with acute symptomatic allograft failure.

BACKGROUND: Complement activation has been recognized as a contributing factor to cardiac allograft dysfunction. Combined measurement of erythrocyte C4d (E-C4d) and complement receptor 1 (E-CR1) are potential biomarkers to monitor complement activity in patients with autoimmune diseases. We conducted a prospective study using CR1-2B11 monoclonal antibody to detect the E-C4d to E-CR1 ratio among our cardiac transplant recipients with acute symptomatic allograft failure. MATERIALS AND METHODS: Eight recipients with acute cardiac allograft failure and 72 healthy controls were included in this study. Levels of E-C4d and E-CR1 were measured by indirect immunofluorescence and flow cytometry. The results were utilized to determine the association between patient C4d staining, histological features, and clinical outcomes. RESULTS: Eight patients with nine episodes of sudden onset of graft failure and suspected antibody-mediated rejection (AMR) were included in this study. One patient who received emergent mechanical circulatory support was treated with plasmapheresis for his unstable hemodynamic status. The mean pretreatment left ventricular ejection fraction was 30.3%. No histological study demonstrated cellular rejection or AMR in any patient. There were two patients with positive C4d immunostaining. Three patients had four episodes of acute rejection with sudden death at home. The mean E-C4d/E-CR1 ratio in the study group (n = 9) was 0.22 +/- 0.07, and 0.12 +/- 0.10 in the control group (n = 72). As comparing both groups, we found the ratios were significant higher in the study group (P = .0003). CONCLUSIONS: Measurement of the E-C4d/E-CR1 ratio may be a noninvasive method for detecting acute rejection after cardiac transplantation.