Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations

Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-alpha -308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)(31) allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF -308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase "fast" allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.     

Early biomarkers of psychosis

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.     

Recall discriminability: utility of a new CVLT-II measure in the differential diagnosis of dementia.

Memory tests that are in a recall format have almost universally measured accuracy in terms of the number of target items reported by the examinee. However, this traditional scoring method can, in certain cases, result in artificially inflated memory accuracy scores. That is, just as a "yes" response bias and high false-positive rate on recognition testing can artificially inflate a patient's hit rate, so, too, a liberal response bias and high intrusion rate on recall testing can artificially inflate a patient's level of target recall. Recognition tests correct for this problem by using a discriminability measure that provides a single score of hit rate relative to false-positive rate; however, recall tests rarely provide a single score of recall accuracy that corrects for intrusion rate. In the present study, we examined the utility of a new recall discriminability measure that analyzes target recall relative to intrusion rate. Patients with Alzheimer's disease (AD) or Huntington's disease (HD) were administered the CVLT-II, which provides both the traditional measure of target recall and a new measure of recall discriminability. The results indicate that the new recall discriminability measure was superior to the traditional level of target recall measure in distinguishing the recall performance of AD and HD patients. Implications of these results for clinical practice and theories of memory disorder in dementia are discussed.     

CT perfusion cerebral blood flow imaging in neurological critical care

Computed tomography (CT) perfusion imaging is a technique for the measurement of cerebral blood flow, cerebral blood volume, and time-to-peak or mean transit time. The technique involves the administration of a single-bolus dose of iodinated contrast material, followed by spiral CT imaging during the passage of the contrast bolus through the cerebral vasculature. CT perfusion is a fast and inexpensive brain imaging modality for use in the management of patients with various neurological disorders, ranging from acute stroke to subarachnoid hemorrhage. This article reviews the technique of CT perfusion and presents several illustrative cases in which this imaging modality was used effectively in the critical care of patients with neurological disorders.     

Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project

OBJECTIVES: We sought to examine the independent predictive value of coronary artery calcium detection for coronary outcomes in a non-referred cohort of healthy men and women ages 40 to 50 years. BACKGROUND: Existing studies have suggested that coronary calcium might have incremental predictive value for coronary outcomes above standard coronary risk factors. However, additional data from non-referred and younger populations are needed. METHODS: Participants (n = 2,000; mean age 43 years) were evaluated with measured coronary risk variables and coronary calcium detected with electron beam tomography. Incident acute coronary syndromes and sudden cardiac death were ascertained via annual telephonic contacts, with follow-up (mean, 3.0 +/- 1.4 years; range, 1 to 6 years) in 99.2% of the cohort. RESULTS: Coronary calcium was found in 22.4% of men and 7.9% of women. A total of 9 acute events occurred in men at a mean age of 46 years, including 7 of 364 men with coronary calcium (1.95%) and 2 of 1,263 men without coronary calcium (0.16%; p < 0.0001 by log-rank). No events occurred in women. In these men, coronary calcium was associated with an 11.8-fold increased risk for incident coronary heart disease (CHD) (p = 0.002) in a Cox model controlling for the Framingham risk score. Among those with coronary artery calcification, the risk of coronary events increased incrementally across tertiles of coronary calcium severity (hazard ratio 4.3 per tertile). A family history of premature CHD was also predictive of incident events. The marginal cost effectiveness, assuming a 30% improvement in survival associated with primary prevention among at-risk men, was modeled to be 37,633 dollars per quality-adjusted life year saved. CONCLUSIONS: In young, asymptomatic men, the presence of coronary artery calcification provides substantial, cost-effective, independent prognostic value in predicting incident CHD that is incremental to measured coronary risk factors.     

Intermittent headaches as the presenting sign of subacute angle-closure glaucoma

Subacute angle closure causes intermittent episodes of transiently elevated intraocular pressure. Headache is often the chief complaint, which may lead to misdiagnosis. The authors examined headache characteristics and consequences of delayed diagnosis. Patients presenting with headaches have a substantial delay in diagnosis, contributing to permanent ocular damage and glaucoma. Patients with subacute angle closure misdiagnosed with migraine are older and have shorter-duration headaches than patients with typical migraine.     

Thrombophilia and pregnancy complications

OBJECTIVE: This systematic review examines the strength of the association between thrombophilia and recurrent pregnancy loss and other serious obstetric complications.Study design Electronic databases and manual bibliography searches were used to identify studies evaluating the association between thrombophilia and pregnancy loss, preeclampsia, fetal growth retardation, and placental abruption. RESULTS: Thrombophilic disorders are associated with an increased risk of fetal loss in the majority of case control and cohort studies. The risk is increased throughout pregnancy, but may be higher in the second and third trimester. The common pathologic finding of placental infarction suggests unexplained fetal loss may result from uteroplacental insufficiency and thrombosis. Thrombophilic disorders are not consistently associated with preeclampsia, fetal growth retardation, or placental abruption. Preliminary data suggest prophylactic anticoagulation may improve outcome in thrombophilic women with unexplained recurrent fetal loss. CONCLUSION: Women with thrombophilia have an increased risk of pregnancy loss and possibly other serious obstetric complications, although definition of the magnitude of risk will require prospective longitudinal studies. Preliminary data suggesting prophylactic anticoagulation may improve gestational outcome provide a rationale for prospective randomized trials in thrombophilic women with unexplained recurrent fetal loss.