Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene ...interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes:
GABRG1, GABRA2,GABRA4, and
GABRB1 on chromosome 4p12;
GABRB2, GABRA6, GABRA1, GABRG2, and
GABRP on 5q34-q35.1;
GABRR1 and
GABRR2 on 6q15; and
GABRA5, GABRB3, and
GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis—with the pedigree disequilibrium test and the family-based association test—and for genotypic and haplotypic association analysis—with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers
RS1912960 (in
GABRA4;
P = .01) and
HCV9866022 (in
GABRR2;
P = .04). The geno-PDT found significant genotypic association for
HCV8262334 (in
GABRA2),
RS1912960 and
RS2280073 (in
GABRA4), and
RS2617503 and
RS12187676 (in
GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at
RS1912960 (in
GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving
RS1912960 in
GABRA4 and
RS2351299 in
GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between
GABRA4 and
GABRB1 (odds ratio = 2.9 for interaction term;
P = .002). Through the convergence of all analyses, we conclude that
GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with
GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.
Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene ...reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.
Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic ...heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)—derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview–Revised—was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the
GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the γ-aminobutyric acid–receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.
Proteorhodopsins (PRs) are retinal-containing proteins that catalyze light-activated proton efflux across the cell membrane. These photoproteins are known to be globally distributed in the ocean's ...photic zone, and they are found in a diverse array of Bacteria and Archaea. Recently, light-enhanced growth rates and yields have been reported in at least one PR-containing marine bacterium, but the physiological basis of light-activated growth stimulation has not yet been determined. To describe more fully PR photosystem genetics and biochemistry, we functionally surveyed a marine picoplankton large-insert genomic library for recombinant clones expressing PR photosystems in vivo. Our screening approach exploited transient increases in vector copy number that significantly enhanced the sensitivity of phenotypic detection. Two genetically distinct recombinants, initially identified by their orange pigmentation, expressed a small cluster of genes encoding a complete PR-based photosystem. Genetic and biochemical analyses of transposon mutants verified the function of gene products in the photopigment and opsin biosynthetic pathways. Heterologous expression of six genes, five encoding photopigment biosynthetic proteins and one encoding a PR, generated a fully functional PR photosystem that enabled photophosphorylation in recombinant Escherichia coli cells exposed to light. Our results demonstrate that a single genetic event can result in the acquisition of phototrophic capabilities in an otherwise chemoorganotrophic microorganism, and they explain in part the ubiquity of PR photosystems among diverse microbial taxa.
Rice (Oryza sativa L.) cultivated with the direct‐seeded, delayed‐flood production system relies heavily on post‐emergence aerial application of N. The availability of a controlled‐release N ...fertilizer suitable for preplant application would offer rice growers an alternative N‐fertilization method and reduce the aerial application costs of N fertilization. Our objectives were to determine grain yield and N uptake of rice receiving preplant incorporated polymer‐coated urea (PCU) compared with urea applied preflood at the five‐leaf stage and characterize the N release of two PCUs. Field trials were conducted at five site‐years to evaluate rice performance when fertilized with preplant‐applied Environmentally Smart Nitrogen (ESN) and Duration Type 5 (D5) and preflood‐applied urea across N rates ranging from 0 to 168 kg N ha−1 Nitrogen release from PCU was evaluated in field incubations using a buried‐bag method at two site‐years. Nitrogen release was nonlinear across time and similar between site‐years but different between PCUs. The nonlinear relationships predicted that 75% of PCU N content was released by 36 d for D5 and 25 d for ESN. Nitrogen recovery at panicle differentiation averaged 30% for D5, 26% for ESN, and 72% for urea and at heading averaged 47% for D5, 37% for ESN, and 101% for urea. As the N rate increased, yields increased nonlinearly for rice receiving D5 preplant and urea preflood and linearly for rice receiving ESN preplant. Yield predictions for D5 were always lower than for urea at the same N rates. Results suggest that the N release from D5 and ESN is too rapid for rice cultivated in the direct‐seeded, delayed‐flood method.
OBJECTIVES
We sought to develop national benchmarks for valve replacement surgery by developing statistical risk models of operative mortality.
BACKGROUND
National risk models for coronary artery ...bypass graft surgery (CABG) have gained widespread acceptance, but there are no similar models for valve replacement surgery.
METHODS
The Society of Thoracic Surgeons National Cardiac Surgery Database was used to identify risk factors associated with valve surgery from 1994 through 1997. The population was drawn from 49,073 patients undergoing isolated aortic valve replacement (AVR) or mitral valve replacement (MVR) and from 43,463 patients undergoing CABG combined with AVR or MVR. Two multivariable risk models were developed: one for isolated AVR or MVR and one for CABG plus AVR or CABG plus MVR.
RESULTS
Operative mortality rates for AVR, MVR, combined CABG/AVR and combined CABG/MVR were 4.00%, 6.04%, 6.80% and 13.29%, respectively. The strongest independent risk factors were emergency/salvage procedures, recent infarction, reoperations and renal failure. The c-indexes were 0.77 and 0.74 for the isolated valve replacement and combined CABG/valve replacement models, respectively. These models retained their predictive accuracy when applied to a prospective patient population undergoing operation from 1998 to 1999. The Hosmer-Lemeshow goodness-of-fit statistic was 10.6 (p = 0.225) for the isolated valve replacement model and 12.2 (p = 0.141) for the CABG/valve replacement model.
CONCLUSIONS
Statistical models have been developed to accurately predict operative mortality after valve replacement surgery. These models can be used to enhance quality by providing a national benchmark for valve replacement surgery.
Summary
Background Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin.
Objectives The ...ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin‐depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ).
Methods The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays.
Results dA and its second‐generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver–Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate.
Conclusions Thus, dA and its second‐generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post‐translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin.
Exercise testing is useful in the assessment of symptomatic patients for diagnosis of significant or extensive coronary disease and to predict their future risk of cardiac events. The Duke treadmill ...score (DTS) is a composite index that was designed to provide survival estimates based on results from the exercise test, including ST-segment depression, chest pain, and exercise duration. However, its usefulness for providing diagnostic estimates has yet to be determined.
A logistic regression model was used to predict significant (>/=75% stenosis) and severe (3-vessel or left main) coronary artery disease, and a Cox regression analysis was used to predict cardiac survival. After adjustment for baseline clinical risk, the DTS was effectively diagnostic for significant (P<0.0001) and severe (P<0.0001) coronary artery disease. For low-risk patients (score >/=+5), 60% had no coronary stenosis >/=75% and 16% had single-vessel >/=75% stenosis. By comparison, 74% of high-risk patients (score <-11) had 3-vessel or left main coronary disease. Five-year mortality was 3%, 10%, and 35% for low-, moderate-, and high-risk DTS groups (P<0.0001).
The composite DTS provides accurate diagnostic and prognostic information for the evaluation of symptomatic patients evaluated for clinically suspected ischemic heart disease.
Recent subgroup analyses of randomized trials have suggested that percutaneous intervention in diabetic patients with multivessel disease results in higher mortality than coronary artery bypass graft ...surgery (CABG). We studied the relationship between diabetes and survival after revascularization in a large prospective cohort of patients with multivessel coronary artery disease.
By analyzing data for 3220 patients (24% diabetic) with symptomatic two- or three-vessel coronary disease who were undergoing percutaneous transluminal coronary angioplasty (PTCA) or CABG at Duke University Medical Center between 1984 and 1990, we found that at 5 years, unadjusted survival in the group of patients undergoing CABG was 74% in diabetics and 86% in nondiabetics. Similarly, 5-year survival among PTCA patients was 76% in diabetics and 88% in patients without diabetes. After adjustment for baseline characteristics, diabetic patients receiving either PTCA or CABG had significantly poorer survival than nondiabetics (chi2=43.56, P<.0001). Unlike previous studies, however, there was no significant differential effect of diabetes on outcome between patients treated with PTCA and those treated with CABG (chi2=0.01, P=.91).
Although diabetes was associated with a worse long-term outcome after both PTCA and CABG in patients with multivessel coronary artery disease, the effect of diabetes on prognosis was similar in both treatment groups. Thus, our findings support the concept that the choice of initial revascularization strategy should not be based exclusively on a history of diabetes but rather should rely on other factors, such as angiographic suitability and clinical status.
Numerous studies have reported racial differences in the use of cardiac procedures.
1
–
15
These studies have often relied on medical-claims data, however, which do not contain important clinical ...information needed to identify patients with coronary artery disease accurately and adjust for differences in the severity of disease.
16
For instance, if blacks had less extensive coronary disease, fewer symptoms, or fewer coexisting illnesses, then lower rates of coronary-revascularization procedures would be expected.
In addition, these studies generally could not determine the effect of differences in treatment on outcomes in patients. The potential benefits of coronary revascularization can be measured in terms . . .
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