Objective

To examine how genes and environments contribute to relationships among Trail Making test conditions and the extent to which these conditions have unique genetic and environmental influences.

Method

Participants included 1237 middle-aged male twins from the Vietnam-Era Twin Study of Aging (VESTA). The Delis-Kaplan Executive Function System Trail Making test included visual searching, number and letter sequencing, and set-shifting components.

Results

Phenotypic correlations among Trails conditions ranged from 0.29 – 0.60, and genes accounted for the majority (58–84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set-shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities.

Conclusions

A common genetic factor, most likely representing a combination of speed and sequencing accounted for most of the correlation among Trails 1–4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set-shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in non-patient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes.

Understanding the genetic and environmental contributions to measures of brain structure such as surface area and cortical thickness is important for a better understanding of the nature of brain-behavior relationships and changes due to development or disease. Continuous spatial maps of genetic influences on these structural features can contribute to our understanding of regional patterns of heritability, since it remains to be seen whether genetic contributions to brain structure respect the boundaries of any traditional parcellation approaches. Using data from magnetic resonance imaging scans collected on a large sample of monozygotic and dizygotic twins in the Vietnam Era Twin Study of Aging, we created maps of the heritability of areal expansion (a vertex-based area measure) and cortical thickness and examined the degree to which these maps were affected by adjustment for total surface area and mean cortical thickness. We also compared the approach of estimating regional heritability based on the average heritability of vertices within the region to the more traditional region-of-interest (ROI)-based approach. The results suggested high heritability across the cortex for areal expansion and, to a slightly lesser degree, for cortical thickness. There was a great deal of genetic overlap between global and regional measures for surface area, so maps of region-specific genetic influences on surface area revealed more modest heritabilities. There was greater inter-regional variability in heritabilities when calculated using the traditional ROI-based approach compared to summarizing vertex-by-vertex heritabilities within regions. Discrepancies between the approaches were greatest in small regions and tended to be larger for surface area than for cortical thickness measures. Implications regarding brain phenotypes for future genetic association studies are discussed.

The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.

Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles—perhaps the most reliably measured brain regions of interest—are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and re-interpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32-35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging.

Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition. Nine cognitive domains and general cognitive ability were assessed in a sample of 1237 male twins aged 51–60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability (p=0.013) and episodic memory (p=0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect.

Studies comparing young and older adults suggest a deficit in processing context information as a key mechanism underlying cognitive aging. However, the genetic architecture of context processing has not been examined. Consistent with previous results, we found evidence of functionally dissociable components of context processing accuracy in 1127 late middle-aged twins ages 51–60. One component emphasizes use of context cues to prepare responses (proactive cognitive control); the other emphasizes adjustment of responses after probes are presented (reactive control). Approximately one-quarter of the variance in each component was accounted for by genes. Multivariate twin analysis indicated that genetic factors underlying two important components of context processing were independent of one another, thus implicating more than one underlying mechanism. Slower reaction time (RT) on non-context processing trials was positively correlated with errors on the strongly proactive control component on which young adults outperform older adults, but RT was negatively correlated with errors on the strongly reactive control component on which older adults perform better. Although this RT measure was uncorrelated with chronological age in our age-homogeneous sample, slower RT was associated with performance patterns that were more like older adults. However, this did not generalize to other processing speed measures. Genetic correlations, which reflect shared genetic variance, paralleled the phenotypic correlations. There was also a positive genetic correlation between general cognitive ability and accuracy on the proactive control component, but there were still mostly distinct genetic influences underlying these measures. In contrast, the reactive control component was unrelated to general cognitive ability.

Summary

Animal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. “Marching seeds” and a data-driven, hypothesis-free, fuzzy clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in non-human mammalian models. Broad similarities in genetic patterning between rodents and humans may suggest a conservation of cortical patterning mechanisms while dissimilarities might reflect the functionalities most essential to each species.

Background

Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials.

Methods

Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples.

Results

Tamoxifen downregulated ets-oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis.

Conclusions

A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. Multipotential progenitor cap cells of terminal end buds may be the primary target.

Cortical surface area measures appear to be functionally relevant and distinct in etiology, development, and behavioral correlates compared with other size characteristics, such as cortical thickness. Little is known about genetic and environmental influences on individual differences in regional surface area in humans. Using a large sample of adult twins, we determined relative contributions of genes and environment on variations in regional cortical surface area as measured by magnetic resonance imaging before and after adjustment for genetic and environmental influences shared with total cortical surface area. We found high heritability for total surface area and, before adjustment, moderate heritability for regional surface areas. Compared with other lobes, heritability was higher for frontal lobe and lower for medial temporal lobe. After adjustment for total surface area, regionally specific genetic influences were substantially reduced, although still significant in most regions. Unlike other lobes, left frontal heritability remained high after adjustment. Thus, global and regionally specific genetic factors both influence cortical surface areas. These findings are broadly consistent with results from animal studies regarding the evolution and development of cortical patterning and may guide future research into specific environmental and genetic determinants of variation among humans in the surface area of particular regions.

Background

Influenza infection may be more serious in human immunodeficiency virus (HIV)-infected individuals, therefore, vaccination against seasonal and pandemic strains is highly advised. Seasonal influenza vaccines have had no significant negative effects in well controlled HIV infection, but the impact of adjuvanted pandemic A/California/07/2009 H1N1 influenza hemaglutinin (HA) vaccine, which was used for the first time in the Canadian population as an authorized vaccine in autumn 2009, has not been extensively studied.

Objective

Assess vaccine-related effects on CD4+ T cell counts and humoral responses to the vaccine in individuals attending the Newfoundland and Labrador Provincial HIV clinic.

Methods

A single dose of ArepanrixTM split vaccine including 3.75 μg A/California/07/2009 H1N1 HA antigen and ASO3 adjuvant was administered to 81 HIV-infected individuals by intramuscular injection. Plasma samples from shortly before, and 1–5 months after vaccination were collected from 80/81 individuals to assess humoral anti-H1N1 HA responses using a sensitive microbead-based array assay. Data on CD4+ T cell counts, plasma viral load, antiretroviral therapy and patient age were collected from clinical records of 81 individuals.

Results

Overall, 36/80 responded to vaccination either by seroconversion to H1N1 HA or with a clear increase in anti-H1N1 HA antibody levels. Approximately 1/3 (28/80) had pre-existing anti-H1N1 HA antibodies and were more likely to respond to vaccination (22/28). Responders had higher baseline CD4+ T cell counts and responders without pre-existing antibodies against H1N1 HA were younger than either non-responders or responders with pre-existing antibodies. Compared to changes in their CD4+ T cell counts observed over a similar time period one year later, vaccine recipients displayed a minor, transient fall in CD4+ T cell numbers, which was greater amongst responders.

Conclusions

We observed low response rates to the 2009 pandemic influenza vaccine among HIV-infected individuals without pre-existing antibodies against H1N1 HA and a minor transient fall in CD4+ T cell numbers, which was accentuated in responders. A single injection of the ArepanrixTM pandemic A/California/07/2009 H1N1 HA split vaccine may be insufficient to induce protective immunity in HIV-infected individuals without pre-existing anti-H1N1 HA responses.

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs, and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings do provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

Objective

Although episodic memory is often conceptualized as consisting of multiple component processes, there is a lack of understanding as to whether these processes are influenced by the same or different genetic determinants. The aim of the present study was to utilize multivariate twin analyses in order to elucidate the degree to which learning and delayed recall, two critical measures of episodic memory performance, have common or different genetic and environmental influences.

Method

Participants from the Vietnam Era Twin Study of Aging (314 monozygotic twin pairs, 259 dizygotic twin pairs, and 47 unpaired twins) were assessed using the second edition of the California Verbal Learning Test (CVLT-2). Mean age at the time of the evaluation was 55.4 years (sd = 2.5).

Results

Model fitting revealed the presence of a higher-order latent factor influencing learning, short- and long-delay free recall, with a heritability of .36. The best-fitting model also indicated specific genetic influences on learning, which accounted for 10% of the overall variance. Given that learning involves the acquisition and retrieval of information, whereas delayed recall involves only retrieval, we conclude that these specific effects are likely to reflect genes that are specific to acquisition processes.

Conclusion

These results demonstrate that even in non-clinical populations, it is possible to differentiate component processes in episodic memory. These different genetic influences may have implications for gene association studies, as well as other genetics studies of cognitive aging and disorders of episodic memory such as Alzheimer’s disease or mild cognitive impairment.

Objective

To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association; to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife.

Methods

Design

35-year longitudinal and cross-sectional twin study of cognitive aging.

Setting

Large multicenter study in the United States.

Participants

1237 male twins ages 51 to 60.

Measurements

At age 20 and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual-spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale prior to cognitive testing and provided health and lifestyle information during a medical history interview.

Results

Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 (r=−.16, p<.001). In bivariate twin modeling, 77% of the correlation between early cognitive ability and midlife depressive symptoms was due to shared genetic influences. Controlling for current age, age 20 AFQT, and non-independence of observations, depressive symptoms were associated with worse midlife AFQT scores and poorer performance in all cognitive domains except verbal memory

Conclusion

Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Cross-sectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.

The enzyme APOBEC3G (A3G) mutates the human immunodeficiency virus (HIV) genome by converting deoxycytidine (dC) to deoxyuridine (dU) on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G’s standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation.

The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer’s disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51–59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status.

Background

Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally-specific sets of genes.

Methods

We mapped the heritability of cortical thickness throughout the brain using 3D structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface.

Results

There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions, but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions.

Conclusions

These results provide strong evidence of regionally-specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly-defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally-defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders, and normal and pathological cognitive aging.

Marriage is considered one of the most important sources of social support that an individual receives as an adult. Although hypotheses have been formulated as to why individuals may dissolve a marriage, the determinants of marital success or failure are still relatively unknown. Behavioral geneticists have found that both marriage and divorce are, in part, genetically influenced. The goal of this research was to determine the degree of shared genetic and environmental variance between the two marital statuses. Participants were 6,225 twin pairs from the Vietnam Era Twin Registry. Data were obtained on marital history, and if the individual was no longer married, how the marriage ended. Univariate analyses were performed to determine the extent of genetic and environmental influences each of the marital statues (i.e., marriage and divorce), followed by a novel bivariate analysis to test the shared variance between marriage and divorce. Results from this analysis revealed that the two different marital statuses were influenced by entirely distinct genetic and environmental factors.

Background

Virtually all adult studies of APOE genotypes and cognition have included individuals over 60. In older adults, ε4 carriers may manifest greater cognitive asymmetries than non-ε4 carriers even in the absence of overall mean differences. General cognitive ability may also be affected by aging and APOE genotype, but most studies have inadequately addressed this potential confound. The goals of this study were to examine, in middle age, the relationship of APOE genotype with episodic memory and verbal-visuospatial episodic memory asymmetries, after accounting for prior general cognitive ability.

Method

We compared ε4+ and ε4- individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members.

Results

Compared with ε4- individuals, ε4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, ε4 carriers had higher general cognitive ability than ε4- individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability.

Conclusions

Small, but significant, APOE-ε4-related memory deficits do appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-ε4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.

We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male–male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.

Adult romantic attachment styles reflect ways of relating in close relationships and are associated with depression and negative emotionality. We estimated the extent to which dimensions of romantic attachment and negative emotionality share genetic or environmental risk factors in 1,237 middle-aged men in the Vietnam Era Twin Study of Aging (VETSA). A common genetic factor largely explained the covariance between attachment-related anxiety, attachment-related avoidance, depressive symptoms, and two measures of negative emotionality: Stress-Reaction (anxiety), and Alienation. Multivariate results supported genetic and environmental differences in attachment. Attachment-related anxiety and attachment-related avoidance were each influenced by additional genetic factors not shared with other measures; the genetic correlation between the attachment measure-specific genetic factors was 0.41, indicating some, but not complete overlap of genetic factors. Genetically informative longitudinal studies on attachment relationship dimensions can help to illuminate the role of relationship-based risk factors in healthy aging.

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51–59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

Objectives

Less-invasive options are available for surgical treatment of multivessel coronary artery disease. We hypothesized that stenting combined with grafting of the left anterior descending artery with the left internal thoracic artery through a minithoracotomy (hybrid procedure) would provide the best outcome.

Methods

Patients with equivalent numbers of coronary lesions (2.8 ± 0.4) underwent either hybrid (n = 15) or off-pump coronary artery bypass through a sternotomy (n = 30). Early and 1-year outcomes were compared. Blood drawn from the aorta and coronary sinus immediately postoperatively was analyzed for activation of coagulation (prothrombin fragment 1.2 and activated Factor XII), myocardial injury (myoglobin), and inflammation (interleukin 8) by using an enzyme-linked immunosorbent assay. Target-vessel patency was determined by means of computed tomographic angiographic analysis.

Results

The hybrid procedure was associated with significantly shorter lengths of intubation and stays in the intensive care unit and hospital and perioperative morbidity (P < .05). Intraoperative costs were increased but postoperative costs were reduced for the hybrid procedure compared with off-pump coronary artery bypass through a sternotomy. As a result, overall total costs were not significantly different between the groups. After adjusting for potential confounders, assignment to the hybrid group was an independent predictor of shortened time to return to work (t = −2.12, P = .04). Patient satisfaction after the hybrid procedure, as judged on a 6-point scale, was greater versus that after off-pump coronary artery bypass through a sternotomy. Finally, the hybrid procedure showed significantly reduced transcardiac gradients of markers of coagulation, myocardial injury, and inflammation and a trend toward significant improvement in target-vessel patency.

Conclusions

Perhaps because of reduced myocardial injury, inflammation, and activation of coagulation, patients undergoing the hybrid procedure had better perioperative outcomes and satisfaction, with excellent patency at 1 year’s follow-up. These promising preliminary findings warrant further investigation of this procedure.

Background

Declines in hearing acuity, especially in the high frequency range, often appear in middle age. The objective of this study was to characterize genetic and environmental influences that may underlie this pattern.

Methods

One hundred seventy-nine monozygotic and 150 dizygotic twin pairs, ranging in age from 52 to 60 years, were selected from the Vietnam Era Twin Registry and individually tested for hearing acuity in the frequency range from 500 to 8000 Hz. Biometrical modeling was used to quantify genetic and environmental influences.

Results

For individuals’ better ears, approximately two-thirds (65%–70%, 95% confidence interval [CI], 46%–75%) of the variance in hearing acuity in the middle and high frequency ranges could be accounted for by genetic factors. For the individuals’ poorer ear, which would be expected to show lower heritability, approximately one-half (41%–54%, 95% CI, 11%–67%) of the variance in the middle and high frequency ranges could be accounted for by genetic influences. Within a given frequency range, the same genetic factors influenced both the better and poorer ears. In contrast, although there was some overlap of genetic influences on the middle and high frequencies within a given ear, there were also some genetic influences that were specific to each frequency.

Conclusions

Results suggest that genetic effects play an important role in the level of hearing loss that often appears in late middle age. These data have important implications for identifying persons who may be especially vulnerable to environmental risk factors such as noise exposure and medications with ototoxic properties.

Previous research has demonstrated stability of cognitive ability and marked heritability during adulthood, but questions remain about the extent to which genetic factors account for this stability. We conducted a 35-year longitudinal assessment of general cognitive ability using the Armed Forces Qualification Test administered to 7,232 male twins in early adulthood and readministered to a subset of 1,237 twins during late middle age. The proportion of variance in cognitive functioning explained by genetic factors in young adulthood was .49 and it was .57 in late middle age. The correlation between the two administrations was .74 with a genetic correlation of 1.0, indicating that the same genetic influences operated at both times. Genetic factors were primarily responsible for stability and nonshared environmental factors for change. The genetic factors influencing cognition may change across other eras, but the same genetic influences are operating from early adulthood to late middle-age.

Background

The radial artery’s (RA) tendency to spasm when used as a bypass graft may relate to features of the RA itself. We imaged RA conduits before and after CABG in order to characterize intimal abnormalities that might relate to the risk of spasm.

Methods

RA conduits from thirty-two CABG patients were imaged intraoperatively using catheter-based optical coherence tomography (OCT) and again on day 5 using 64-channel MDCT angiography. The change in luminal diameter between timepoints was measured in the proximal, mid and distal RA. “Spasm” was defined as focal or diffuse luminal narrowing to a diameter less than the target coronary. Lipid content in the RA was quantified by the degree of light attenuation on the OCT image.

Results

Postoperative spasm was diagnosed in 18 of 32 (56%) RA grafts with the distal RA showing the most severe change versus the mid and proximal portions (−24.1±43.2% vs. −15.3±40.7%, −9.0±42.5% change in diameter respectively, p<0.01). The degree of attenuation of the OCT signal produced by the RA was strongly correlated with % diameter change (R=0.64, p=0.0005) and was significantly more pronounced in grafts with spasm versus no spasm (−1.97±0.61mm−1 vs. −0.81±0.57mm−1, p<0.0001). Histology confirmed lipid deposits in areas of RA with strong attenuation.

Conclusions

RA conduits otherwise considered acceptable for bypass grafting were often found by OCT imaging to have a substantial amount of lipid, which in turn strongly relates to the risk of postoperative spasm. Screening conduits based on characteristics of intimal quality may improve results following RA grafting.