The Genetics of Obesity: What Have Genetic Studies Told Us About the Environment

Genetic studies have shown that both childhood and adult body mass index are substantially heritable. The evidence for shared family environmental influences is largely absent, even though there are clear indications that secular changes in energy expenditure have brought about a significant increase in the prevalence of obesity. This apparent inconsistency may be explained by the dual phenomena of the near-universality of access to environments that facilitate reductions in energy expenditure (e.g., TV as a recreational pastime), together with heritable individual differences in the response to or utilization of these environments. The impact of changes in nonshared environments on body weight can be estimated from biometrical genetical studies and is found to be both small and relatively short-lived. Genetic and environmental results from longitudinal studies are consistent with what is known about the changing distribution of adiposity during adulthood and clinical experience of the difficulty of maintaining behavioral-induced weight loss.     

The lifetime of automatic semantic priming effects may exceed two seconds

The N400 component of event-related potentials (ERPs) was obtained in a modified version of the Neely [J.H. Neely, Semantic priming and retrieval from lexical memory: Roles of inhibitionless spreading activation and limited-capacity attention, Journal of Experimental Psychology: General, Vol. 106 (1977), pp. 226-254.] paradigm which permits unconfounding of semantic priming effects due to automatic and attentional processes. It was found that a short stimulus onset asynchrony (SOA) of 250 ms between the prime and the target was associated with automatic but not expectancy effects on the amplitude of N400. At a long SOA of 2000 ms between prime and target, semantic priming effects on N400 were obtained associated with both automatic and expectancy processes. Moreover, there was no significance difference in the magnitude of the automatic effects at the two SOAs, suggesting that automatic processing had not decayed within the 2000 ms interval between the prime and target. The results support the two-processing interpretation of semantic priming advanced by Posner and Synder [M.I. Posner, C.R.R. Snyder, Attention and cognitive control, in: R.L. Solso (Ed.), Information Processing and Cognition: The Loyola Symposium, Erlbaum, Hillsdale, NJ (1975).] and concur with the results of Neely [J.H. Neely, Semantic priming and retrieval from lexical memory: Roles of inhibitionless spreading activation and limited-capacity attention, Journal of Experimental Psychology: General, Vol. 106 (1977), pp. 226-254], with the exception of indicating a longer persistence of automatic processes.     

Tobacco, alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development.

OBJECTIVE: This study reports prevalences of lifetime and current alcohol, tobacco and drug use in adolescents; examines associations between substance use and a number of putative risk factors; and estimates the contribution of genetic, shared and unique environmental influences on substance use. METHOD: Substance use data were collected using the Child and Adolescent Psychiatric Assessment on a population sample of 1,412 male and female monozygotic and dizygotic twin pairs, aged 8 through 16, from the Virginia Twin Study of Adolescent Behavioral Development. RESULTS: Heritabilities were estimated to be 84% and 82% for liability to lifetime and current tobacco use, respectively. For alcohol use the role of genes and environment varied according to the context of reporting. Liability to lifetime alcohol use was estimated to be under environmental control, with 71% of the variation shared by members of a twin pair and 29% unique to individual twins. Lifetime alcohol use without the permission of a parent or guardian and current use of alcohol were predominantly explained by genetic factors (h2 = 72% and 74%). The role of genetic factors increased and that of unique environmental factors decreased with increasing severity of alcohol use. Lifetime use of any drug showed a heritability of 45%, with the shared environment accounting for 47% of the variation. Shared environmental factors explained most of the variation in marijuana use. CONCLUSIONS: Genetic factors explained a significant proportion of the variation in the use of tobacco, alcohol and other drugs. Shared environmental factors contributed significantly to lifetime alcohol use and other drug use.     

Neuropsychological functioning and sleep patterns in the elderly.

OBJECTIVE: To discover whether reported sleep-wake disturbances in the elderly (more frequent nocturnal awakenings, earlier waking and more day time naps) are associated with neuropsychological dysfunction. DESIGN AND SETTING: A sample of 124 residents of a retirement village complex were interviewed about their sleep patterns and given neuropsychological assessments. Reported sleep-wake difficulties were combined to form two variables, "night sleep" and "day sleep". Additional sleep variables analysed were reported sleep duration and time of wakening. Principal components analysis of the neuropsychological test scores yielded four factors: "general ability", "memory", "motor", and "cerebral efficiency". MAIN OUTCOME MEASURES: A correlation analysis was performed for sleep variables, neuropsychological factors and age, mood scale and scores on indices of participation in physical and passive activities. RESULTS: There was no correlation between "night sleep" and the factor scores derived from the neuropsychological tests. "Day sleep" was correlated with "cerebral efficiency" only. Age was correlated with the "memory" and "motor" factors, the latter also being associated with participation in physical activities. CONCLUSION: Night sleep problems are not associated with neuropsychological deficits in a non-clinic population.     

The structure of schizotypy: a pilot multitrait twin study

This report of a pilot study examines 29 pairs of twins from a population-based registry on whom four domains of schizotypy have been measured: personal interview using the Structured Interview for Schizotypy, self-report questionnaire formed from eight published self-report scales, attentional battery of eight individual tests, and root mean square error on smooth pursuit eye tracking. Analyzing the twins as individuals revealed two independent dimensions of clinically rated schizotypy (positive symptom schizotypy and negative symptom schizotypy) and two independent dimensions of self-rated schizotypy (positive trait schizotypy and trait anhedonia). Positive symptom schizotypy was highly correlated with positive trait schizotypy, but not with attentional dysfunction or eye-tracking error. By contrast, negative symptom schizotypy was significantly related to trait anhedonia, attentional dysfunction, and eye-tracking error. Correlations in monozygotic and dizygotic twins suggested that genetic factors were important in all four domains of schizotypy. Except for eye-tracking error, the results are more consistent with a dimensional than a "disease" model of schizotypy. Replication of these results with a larger group of subjects is needed.     

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.     

Past, present, and future research in the field of composite tissue allotransplantation

In September 1998, a surgical team in Lyon, France, performed the first successful hand transplant. After this historic event, in January 1999, the University of Louisville performed the first hand transplant in the United States. These events sparked interest and debate concerning the justification of performing limb allotransplantation. The field of composite tissue allotransplantation (CTA) has made significant advances in the past two decades, yet advancement of the applications of CTA into the clinical arena had been fairly limited to this point. The most inherent controversy in CTA involves the fact that the clinical applications for the most part involve restoration of function and/or structural integrity. These procedures are done essentially for quality-of-life concerns, not life-saving issues. Present concern involves subjecting CTA recipients to a lifetime of postoperative immunosuppressive therapy. We cannot fully understand where we stand at present and in what future directions the field is heading unless we have an understanding of where we have been in composite tissue transplantation. This article reviews the historical aspects of CTA, discusses the present state of CTA, and speculates on potential future applications of CTA.     

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.