Utility of ambulatory electrocardiographic monitoring for predicting recurrence of sustained ventricular tachyarrhythmias in patients receiving amiodarone

The prognostic implications of changes in ventricular ectopic activity on serial 24 hour ambulatory electrocardiographic (Holter) recordings were prospectively evaluated in 107 patients with a history of sustained ventricular tachyarrhythmias treated with amiodarone for at least 30 days. Twenty-seven patients (25%) had insufficient ventricular ectopic activity < 10 ventricular premature complexes/h and no repetitive forms) on baseline Holter recordings for serial statistical analysis. In 53 (66%) of the remaining 80 patients, serial 24 hour Holter monitor recordings showed efficacy of treatment, defined as a 75% decrease in ventricular premature complexes, a 95% decrease in ventricular couplets and absence of ventricular tachycardia. During a mean followup period of 14.2 ± 9.9 months, 34 (32%) of the 107 patients had recurrence of a sustained ventricular tachyarrhythmia. Holter recording correctly predicted nine recurrences and correctly identified 37 patients who did not experience a recurrence. Holter efficacy failed to predict recurrence of a sustained ventricular tachyarrhythmia in 16 patients, and 18 patients remained free of recurrence despite failure to achieve Holter efficacy. The positive predictive value of Holter monitoring efficacy was 33% and the negative predictive value was 70%; however, these differences were not statistically significant by chi-square analysis. Similar results were obtained using Holter recordings performed relatively early in therapy (6 weeks and 4 months).Of the 27 patients without significant ventricular ectopic activity on the baseline Holter recording, 9 had an arrhythmia recurrence despite continued infrequent ventricular premature complexes and no repetitive forms on subsequent recordings. The recurrence rate in this group (33%) was similar to the overall recurrence rate.Therefore, among patients taking amiodarone for sustained ventricular tachyarrhythmias: 1) 25% will have insufficient ventricular ectopic activity on 24 hour Holter recordings for serial statistical analysis; and 2) in the remaining 75%, data obtained from serial Holter recordings are not predictive of arrhythmia recurrence

West Nile Virus Risk Assessment and the Bridge Vector Paradigm

In the northeast United States, control of West Nile virus (WNV) vectors has been unfocused because of a lack of accurate knowledge about the roles different mosquitoes play in WNV transmission. We analyzed the risk posed by 10 species of mosquitoes for transmitting WNV to humans by using a novel risk-assessment measure that combines information on the abundance, infection prevalence, vector competence, and biting behavior of vectors. This analysis suggests that 2 species (Culex pipiens L. and Cx. restuans Theobald [Diptera: Cilicidae]) not previously considered important in transmitting WNV to humans may be responsible for up to 80% of human WNV infections in this region. This finding suggests that control efforts should be focused on these species which may reduce effects on nontarget wetland organisms. Our risk measure has broad applicability to other regions and diseases and can be adapted for use as a predictive tool of future human WNV infections

On Quality Control Measures in Genome-Wide Association Studies: A Test to Assess the Genotyping Quality of Individual Probands in Family-Based Association Studies and an Application to the HapMap Data

Allele transmissions in pedigrees provide a natural way of evaluating the genotyping quality of a particular proband in a family-based, genome-wide association study. We propose a transmission test that is based on this feature and that can be used for quality control filtering of genome-wide genotype data for individual probands. The test has one degree of freedom and assesses the average genotyping error rate of the genotyped SNPs for a particular proband. As we show in simulation studies, the test is sufficiently powerful to identify probands with an unreliable genotyping quality that cannot be detected with standard quality control filters. This feature of the test is further exemplified by an application to the third release of the HapMap data. The test is ideally suited as the final layer of quality control filters in the cleaning process of genome-wide association studies. It identifies probands with insufficient genotyping quality that were not removed by standard quality control filtering

Sour Ageusia in Two Individuals Implicates Ion Channels of the ASIC and PKD Families in Human Sour Taste Perception at the Anterior Tongue

BACKGROUND:The perception of sour taste in humans is incompletely understood at the receptor cell level. We report here on two patients with an acquired sour ageusia. Each patient was unresponsive to sour stimuli, but both showed normal responses to bitter, sweet, and salty stimuli. METHODS AND FINDINGS:Lingual fungiform papillae, containing taste cells, were obtained by biopsy from the two patients, and from three sour-normal individuals, and analyzed by RT-PCR. The following transcripts were undetectable in the patients, even after 50 cycles of amplification, but readily detectable in the sour-normal subjects: acid sensing ion channels (ASICs) 1a, 1beta, 2a, 2b, and 3; and polycystic kidney disease (PKD) channels PKD1L3 and PKD2L1. Patients and sour-normals expressed the taste-related phospholipase C-beta2, the delta-subunit of epithelial sodium channel (ENaC) and the bitter receptor T2R14, as well as beta-actin. Genomic analysis of one patient, using buccal tissue, did not show absence of the genes for ASIC1a and PKD2L1. Immunohistochemistry of fungiform papillae from sour-normal subjects revealed labeling of taste bud cells by antibodies to ASICs 1a and 1beta, PKD2L1, phospholipase C-beta2, and delta-ENaC. An antibody to PKD1L3 labeled tissue outside taste bud cells. CONCLUSIONS:These data suggest a role for ASICs and PKDs in human sour perception. This is the first report of sour ageusia in humans, and the very existence of such individuals ("natural knockouts") suggests a cell lineage for sour that is independent of the other taste modalities

DNA Methylation Causes Predominant Maternal Controls of Plant Embryo Growth

The parental conflict hypothesis predicts that the mother inhibits embryo growth counteracting growth enhancement by the father. In plants the DNA methyltransferase MET1 is a central regulator of parentally imprinted genes that affect seed growth. However the relation between the role of MET1 in imprinting and its control of seed size has remained unclear. Here we combine cytological, genetic and statistical analyses to study the effect of MET1 on seed growth. We show that the loss of MET1 during male gametogenesis causes a reduction of seed size, presumably linked to silencing of the paternal allele of growth enhancers in the endosperm, which nurtures the embryo. However, we find no evidence for a similar role of MET1 during female gametogenesis. Rather, the reduction of MET1 dosage in the maternal somatic tissues causes seed size increase. MET1 inhibits seed growth by restricting cell division and elongation in the maternal integuments that surround the seed. Our data demonstrate new controls of seed growth linked to the mode of reproduction typical of flowering plants. We conclude that the regulation of embryo growth by MET1 results from a combination of predominant maternal controls, and that DNA methylation maintained by MET1 does not orchestrate a parental conflict

Down-Regulation of ZnT8 Expression in INS-1 Rat Pancreatic Beta Cells Reduces Insulin Content and Glucose-Inducible Insulin Secretion

The SLC30A8 gene codes for a pancreatic beta-cell-expressed zinc transporter, ZnT8. A polymorphism in the SLC30A8 gene is associated with susceptibility to type 2 diabetes, although the molecular mechanism through which this phenotype is manifest is incompletely understood. Such polymorphisms may exert their effect via impacting expression level of the gene product. We used an shRNA-mediated approach to reproducibly downregulate ZnT8 mRNA expression by >90% in the INS-1 pancreatic beta cell line. The ZnT8-downregulated cells exhibited diminished uptake of exogenous zinc, as determined using the zinc-sensitive reporter dye, zinquin. ZnT8-downregulated cells showed reduced insulin content and decreased insulin secretion (expressed as percent of total insulin content) in response to hyperglycemic stimulus, as determined by insulin immunoassay. ZnT8-depleted cells also showed fewer dense-core vesicles via electron microscopy. These data indicate that reduced ZnT8 expression in cultured pancreatic beta cells gives rise to a reduced insulin response to hyperglycemia. In addition, although we provide no direct evidence, these data suggest that an SLC30A8 expression-level polymorphism could affect insulin secretion and the glycemic response in vivo

Parental Genome Dosage Imbalance Deregulates Imprinting in Arabidopsis

In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2) and FLOWERING WAGENINGEN (FWA) controlled by DNA methylation, and MEDEA (MEA) and PHERES1 (PHE1) controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis

Replicating genotype-phenotype associations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62757/1/447655a.pd