Publications

Major depression is associated with adverse outcomes in patients who have coronary heart disease. How best to identify depression in busy cardiology practices is unknown. We compared the test characteristics of 4 depression screening instruments with an interview diagnosis of depression (Diagnostic Interview Schedule) in 1,024 outpatients who had coronary heart disease. Screening instruments were the 10-item Center for Epidemiologic Studies Depression Scale-10, the Patient Health Questionnaire-9, the Patient Health Questionnaire-2, and a simple 2-item instrument that asks (1) "During the past month, have you often been bothered by feeling down, depressed, or hopeless?" and (2) "During the past month, have you often been bothered by little interest or pleasure in doing things?" Of the 1,024 participants, 224 (22%) had major depression based on the Diagnostic Interview Schedule. Areas under the receiver-operating characteristic curves were similar for all instruments (range 0.84 to 0.87). In conclusion, a positive response to 1 of the 2 items was 90% sensitive and 69% specific for depression, with a negative likelihood ratio of 0.14. Thus, negative responses to the 2 items effectively ruled out depression. A score > or =10 on the Patient Health Questionnaire-9 was 54% sensitive and 90% specific, with a positive likelihood ratio of 5.4. Thus, a cutpoint > or =10 was virtually diagnostic for depression.

BACKGROUND

Ventricular assist devices (VADs) are important bridges to cardiac transplantation. VAD support may also function as a bridge to ventricular recovery (BTR); however, clinical predictors of recovery and long-term outcomes remain uncertain. We examined the prevalence, characteristics, and outcomes of BTR subjects in a large single center series.

METHODS AND RESULTS

We implanted VADs in 154 adults at the University of Pittsburgh from 1996 through 2003. Of these implants, 10 were BTR. This included 2/80 (2.5%) ischemic patients (supported 42 and 61 days, respectively). Both subjects had surgical revascularization, required perioperative left VAD support, and were alive and transplant-free at follow up (232 and 1319 days, respectively). A larger percentage of nonischemic patients underwent BTR (8/74, 11%; age 30+/-14; 88% female; left ventricular ejection fraction 18+/-6%; supported 112+/-76 days). Three had myocarditis, 4 had post-partum cardiomyopathy (PPCM), and 1 had idiopathic cardiomyopathy. Five received biventricular support. After explantation, ventricular function declined in 2 PPCM patients who then required transplantation. Ventricular recovery in the 6 nonischemic patients surviving transplant-free was maintained (left ventricular ejection fraction 54+/-5%; follow-up 1.5+/-0.9 years). Overall, 8 of 10 BTR patients are alive and free of transplant (follow-up 1.6+/-1.1 years).

CONCLUSIONS

In a large single center series, BTR was evident in 11% of nonischemic patients, and the need for biventricular support did not preclude recovery. For most BTR subjects presenting with acute inflammatory cardiomyopathy, ventricular recovery was maintained long-term. VAD support as BTR should be considered in the care of acute myocarditis and PPCM.

DNA microarrays may be used to identify microbial species present in environmental and clinical samples. However, automated tools for reliable species identification based on observed microarray hybridization patterns are lacking. We present an algorithm, E-Predict, for microarray-based species identification. E-Predict compares observed hybridization patterns with theoretical energy profiles representing different species. We demonstrate the application of the algorithm to viral detection in a set of clinical samples and discuss its relevance to other metagenomic applications.

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase-GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the -243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83-1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the -243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90-1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the -243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.

Alkaline incubation of NADH results in the formation of a very potent inhibitor of complex I (NADH:ubiquinone oxidoreductase). Mass spectroscopy (molecular mass equal to 696) and absorption spectroscopy suggest that the inhibitor is derived from attachment of two oxygen atoms to the nicotinamide moiety of NADH. The inhibitor is competitive with respect to NADH with a K(i) of about 10(-8)M. The inhibitor efficiently suppresses NADH-oxidase, NADH-artificial acceptor reductase, and NADH-quinone reductase reactions catalyzed by submitochondrial particles, as well as the reactions catalyzed by either isolated complex I or the three subunit flavoprotein fragment of complex I.

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.