Future of genetics of mood disorders research.

This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.     

Intraprocedural volume imaging of the left atrium and pulmonary veins with rotational X-ray angiography: implications for catheter ablation of atrial fibrillation

Introduction: The use of preprocedural CT or MR imaging to generate patient-specific cardiac anatomy greatly facilitates catheter ablation of the left atrium and pulmonary veins (LA-PVs) to treat atrial fibrillation (AF). This report details the accuracy and utility of an intra procedural means to generate 3-D volumetric renderings of the LA-PV anatomy: contrast-enhanced rotational X-ray angiography (3DRA).
Methods and Results: Preprocedural CT or MR imaging and intraprocedural rotational angiography was performed in 42 patients undergoing AF ablation procedures. Initially, pulmonary artery (PA) bolus-chase contrast injections were performed (20 mL, 20 mL/s) to establish pulmonary transit time and cardiac isocentering. Depending on cardiac size, either a single PA injection (80–100 mL, 20 mL/s) or two separate dedicated left/right PA branch injections were performed (60 mL each, 20 mL/s). For the latter, the two volumes of the left/right portions of the LA-PVs were registered and fused. LA-PV 3DRA images were assessed qualitatively and quantitatively in comparison with CT/MR images. The majority of the 3DRA acquisitions (71%) were deemed at least "useful" in delineating the LA-PV anatomy. The LA appendage was delineated in 57% of the cases. A blinded quantitative comparison of PV ostial diameters resulted in an absolute difference of only 2.7 ± 2.3 mm, 2.2 ± 1.8 mm, 2.4 ± 2.2 mm, and 2.2 ± 2.3 mm for the left-superior, left-inferior, right-superior, and right-inferior PVs, respectively. The feasibility for registering the 3DRA image with real-time electroanatomical mapping was also demonstrated.
Conclusion: Intraprocedural contrast-enhanced rotational angiography provides volumetric 3-D images of the LA-PVs of comparable diagnostic value to dedicated preprocedural CT/MR imaging.     

A static handgrip method for distal quantitative sweat measurements

The quantitative sudomotor axon reflex test (QSART) measures sympathetic C fibre function when iontophoresed acetylcholine (Ach) evokes a measurable reliable sweat response. This study tests a novel, simplified method of sweat stimulation which accompanies hand dynamometry. In 34 healthy subjects we compared the standard sudomotor axon reflex test with a simplified method using static handgrip as sweat stimulus and recorded from the distal forearm, thumb and little finger tips. The standard method failed on technical grounds beyond the forearm. At the distal forearm, sweat rates were 313+/-140nl/min, representing a four-fold increase from baseline. Static handgrip induced sweat rates of 339+/-156 (thumb) and 296+/-139 (little finger)nl/min, representing a 1.7 and 1.6 fold increase from baseline. Static handgrip did not significantly alter distal forearm sweat secretion, and in females handgrip induced significantly less sweating over the thumb than in males. After dynamometry or Ach stimulation, over the three sites (thumb, little finger and forearm), the stimulated sweat secretion volumes were measured at 0.0278+/-0.021microl/cm(2)/min (thumb), 0.0204+/-0.020microl/cm(2)/min (little finger), and 0.0503+/-0.0283microl/cm(2)/min (forearm) after correction. Our study suggests the static handgrip method can be used to stimulate distal sweat production and may be of particular significance in investigating length-dependant neuropathies and assessing distal C fiber function.     

Comparison of plaque- and flow cytometry-based methods for measuring dengue virus neutralization

As dengue vaccines enter clinical trials, there is a need for rapid and quantitative assays to measure neutralization. We have developed flow-based neutralization assays which generated results similar to those generated by the established, plaque reduction neutralization test. The flow assays are an improvement, as they use human cells and allow for high-throughput screening.     

Cell transplantation for treatment of left-ventricular dysfunction due to ischemic heart failure: from bench to bedside

Cell transplantation is an innovative technology that involves the implantation of a variety of myogenic and angiogenic cell types. The transplanted cells proliferate and augment left ventricular performance and therein ameliorate the heart failure symptoms. The concept of cell transplantation has followed the footsteps of angiogenesis starting as bench side research. The latter half of the decade saw the transformation of this potential mechanism to a promising therapy for ischemic heart failure. More than 150 patients have been treated with cellular transplantation worldwide. This novel application has the potential to revolutionize alternative therapeutic approaches to management of heart failure.     

Percutaneous management of chronic critical limb ischemia

Critical limb ischemia (CLI) is primarily a disease of advanced atherosclerosis but may occur in the setting of other causes. It is essential for the treating physician to understand the complexity of patients with CLI and the appropriate and emerging treatment approaches in this patient population. The authors provide a comprehensive review of the percutaneous endovascular management of CLI in this article.     

Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.     

Genetic diversity of Plasmodium vivax Duffy Binding Protein II (PvDBPII) under unstable transmission and low intensity malaria in Sri Lanka

Elucidating the genetic diversity of the Duffy Binding Protein II (PvDBPII), a leading vaccine candidate for vivax malaria, in different geographical settings is vital. In Sri Lanka malaria transmission is unstable with low intensity. A relatively high level of allelic diversity, with 27 polymorphic nucleotides and 33 (aa) haplotypes was detected among the PvdbpII gene in 100 local Plasmodium vivax isolates collected from two hypoendemic areas, and from a non endemic area of the country. Mutations, recombination and balancing selection seem to maintain the observed local allelic diversity of PvdbpII. Lack of gene flow was evidenced by high Fst values between the two endemic study sites. Some of the aa polymorphisms may alter the binding and expression capacity of predicted T cell epitopes in PvDBPII. Of the 8 binding inhibitory linear B cell epitopes, 2 (H2 and M1) in the vicinity of the exact binding region of PvDBPII appeared to be highly conserved in Sri Lankan, Iran and Colombian isolates, while H3, M2, M3 and L3 neutralizing epitopes seem to be polymorphic globally, with H1 and L2 conserved in Colombian, South Korean and Iran isolates. In comparison to the reference Sal-1 strain, among 402 world-wide isolates (302 global and 100 local), 121 aa polymorphisms and 138 haplotypes were recorded of which 3 aa polymorphisms and 21 haplotypes seem to be unique to Sri Lanka. PvdbpII phylogeny suggests that local P. vivax parasites represent a sample of the global population. The ubiquitous presence of some PvDBPII aa haplotypes among both local and global P. vivax isolates may aid future vaccination strategies based on PvDBPII.     

Variation in the ciliary neurotrophic factor gene and muscle strength in older Caucasian women

OBJECTIVES: To determine whether genetic variants in the ciliary neurotrophic factor (CNTF) gene are associated with muscle strength in older women. DESIGN: Cross-sectional analysis of baseline data from the Women's Health and Aging Studies I (1992) and II (1994), complementary population-based studies. SETTING: Twelve contiguous ZIP code areas in Baltimore, Maryland. PARTICIPANTS: Three hundred sixty-three Caucasian, community-dwelling women aged 70 to 79. MEASUREMENTS: Participants were genotyped at the CNTF locus for eight single nucleotide polymorphisms (SNPs), including the null allele rs1800169. The dependent variables were grip strength and the frailty syndrome, identified as presence of three or more of five frailty indicators (weakness, slowness, weight loss, low physical activity, exhaustion). In addition to genotypes, independent variables of body mass index (BMI) and osteoarthritis of the hands were included. RESULTS: Using multivariate linear regression, single SNP analysis identified five SNPs significantly associated with grip strength (P<.05), after adjusting for age, BMI, and osteoarthritis. Haplotype analysis was performed, and a single haplotype associated with grip strength was identified (P<.01). The rs1800169 null allele fully explained the association between this haplotype and grip strength under a recessive model, with individuals homozygous for the null allele exhibiting a 3.80-kg lower (95% confidence interval=1.01-6.58) grip strength. No association was seen between the CNTF null allele and frailty. CONCLUSION: Individuals homozygous for the CNTF null allele had significantly lower grip strength but did not exhibit overt frailty. Larger prospective studies are needed to confirm this finding and extend it to additional populations.