Geographic proximity is associated with transmission of suicidal behaviour among siblings.

OBJECTIVE: The aim of this study was to clarify the role of 'contagion', or social transmission, in risk of suicidal behaviour (SB) among siblings. METHODS: We followed Swedish sibling pairs until one of them (S1; N = 111,848) was registered for a suicide attempt or completion. We tested the effect of geographic proximity between siblings on risk of a first SB registration of S1's sibling (S2). To control for familial confounding, we conducted complementary analyses of sibling trios (N = 701), comparing risk in different siblings as a function of their respective proximity to S1. RESULTS: The best-fitting model across sibling pairs included an effect of distance between siblings (HR = 0.96, 95% CI = 0.93-0.99). Hazard ratios declined quickly up to 25 km and largely stabilized beyond 150 km. Across all pairs, a larger age difference between siblings was associated with reduced SB risk (HR = 0.96 95% CI = 0.93-0.98). Findings were consistent within the sibling trios. CONCLUSIONS: Consistent with the concept of suicide contagion, risk of suicidal behaviour subsequent to a sibling's suicide completion or attempt is higher as a function of sibling closeness. These findings are robust to potentially confounding familial factors.

Polygenic risk for severe psychopathology among Europeans is associated with major depressive disorder in Han Chinese women.

BACKGROUND: Previous studies have demonstrated that several major psychiatric disorders are influenced by shared genetic factors. This shared liability may influence clinical features of a given disorder (e.g. severity, age at onset). However, findings have largely been limited to European samples; little is known about the consistency of shared genetic liability across ethnicities. METHOD: The relationship between polygenic risk for several major psychiatric diagnoses and major depressive disorder (MDD) was examined in a sample of unrelated Han Chinese women. Polygenic risk scores (PRSs) were generated using European discovery samples and tested in the China, Oxford, and VCU Experimental Research on Genetic Epidemiology [CONVERGE (maximum N = 10 502)], a sample ascertained for recurrent MDD. Genetic correlations between discovery phenotypes and MDD were also assessed. In addition, within-case characteristics were examined. RESULTS: European-based polygenic risk for several major psychiatric disorder phenotypes was significantly associated with the MDD case status in CONVERGE. Risk for clinically significant indicators (neuroticism and subjective well-being) was also associated with case-control status. The variance accounted for by PRS for both psychopathology and for well-being was similar to estimates reported for within-ethnicity comparisons in European samples. However, European-based PRS were largely unassociated with CONVERGE family history, clinical characteristics, or comorbidity. CONCLUSIONS: The shared genetic liability across severe forms of psychopathology is largely consistent across European and Han Chinese ethnicities, with little attenuation of genetic signal relative to within-ethnicity analyses. The overall absence of associations between PRS for other disorders and within-MDD variation suggests that clinical characteristics of MDD may arise due to contributions from ethnicity-specific factors and/or pathoplasticity.

A developmental model for alcohol use disorders in Swedish men.

BACKGROUND: Alcohol use disorder (AUD) is a classic multifactorial syndrome and it is critical to understand the diversity of the relevant risk factors and how they inter-relate over development. METHOD: We examined 21 risk factors for AUD in four developmental tiers reflecting (i) birth, (ii) childhood and early adolescence, (iii) late adolescence, and (iv) early adulthood in 47 414 Swedish men of whom 3907 (8.2%) were registered for AUD at or after age 25 with a mean length of follow-up of 33.9 (6.6) years. Structural equational model fitting was performed using Mplus. RESULTS: The best-fitting model provided a good fit to the data and explained 23.4% of the variance in AUD. The five strongest predictors were: externalizing behaviors, criminal behavior, father's alcohol consumption, genetic risk, and low educational attainment. Two developmentally early familial/genetic risk factors had substantial direct paths to AUD: father's alcohol consumption and genetic liability. Other broad developmental pathways to risk for AUD were evident: externalizing, psychosocial and internalizing. Overall, the externalizing pathway to AUD was the strongest. However, these pathways were substantially interwoven over time such that risk factors from one domain were commonly predicted by and/or predicted risk factors from the other broad domains of risk. CONCLUSION: AUD in men is an etiologically complex syndrome influenced by familial-genetic, psychosocial, internalizing, and especially externalizing risk factors that act and interact over development and have complicated mediational pathways.

A prospective longitudinal model predicting early adult alcohol problems: evidence for a robust externalizing pathway.

BACKGROUND: Risk factors for alcohol problems (AP) include biological and environmental factors that are relevant across development. The pathways through which these factors are related, and how they lead to AP, are optimally considered in the context of a comprehensive developmental model. METHOD: Using data from a prospectively assessed, population-based UK cohort, we constructed a structural equation model that integrated risk factors reflecting individual, family and peer/community-level constructs across childhood, adolescence and young adulthood. These variables were used to predict AP at the age of 20 years. RESULTS: The final model explained over 30% of the variance in liability to age 20 years AP. Most prominent in the model was an externalizing pathway to AP, with conduct problems, sensation seeking, AP at age 17.5 years and illicit substance use acting as robust predictors. In conjunction with these individual-level risk factors, familial AP, peer relationships and low parental monitoring also predicted AP. Internalizing problems were less consistently associated with AP. Some risk factors previously identified were not associated with AP in the context of this comprehensive model. CONCLUSIONS: The etiology of young adult AP is complex, influenced by risk factors that manifest across development. The most prominent pathway to AP is via externalizing and related behaviors. These findings underscore the importance of jointly assessing both biologically influenced and environmental risk factors for AP in a developmental context.

A novel sibling-based design to quantify genetic and shared environmental effects: application to drug abuse, alcohol use disorder and criminal behavior.

BACKGROUND: Twin studies have been criticized for upwardly biased estimates that might contribute to the missing heritability problem. METHOD: We identified, from the general Swedish population born 1960-1990, informative sibships containing a proband, one reared-together full- or half-sibling and a full-, step- or half-sibling with varying degrees of childhood cohabitation with the proband. Estimates of genetic, shared and individual specific environment for drug abuse (DA), alcohol use disorder (AUD) and criminal behavior (CB), assessed from medical, legal or pharmacy registries, were obtained using Mplus. RESULTS: Aggregate estimates of additive genetic effects for DA, AUD and CB obtained separately in males and females varied from 0.46 to 0.73 and agreed with those obtained from monozygotic and dizygotic twins from the same population. Of 54 heritability estimates from individual classes of informative sibling trios (3 syndromes × 9 classes of trios × 2 sexes), heritability estimates from the siblings were lower, tied and higher than those from obtained from twins in 26, one and 27 comparisons, respectively. By contrast, of 54 shared environmental estimates, 33 were lower than those found in twins, one tied and 20 were higher. CONCLUSIONS: With adequate information, human populations can provide many methods for estimating genetic and shared environmental effects. For the three externalizing syndromes examined, concerns that heritability estimates from twin studies are upwardly biased or were not generalizable to more typical kinds of siblings were not supported. Overestimation of heritability from twin studies is not a likely explanation for the missing heritability problem.

Alcohol consumption in men is influenced by qualitatively different genetic factors in adolescence and adulthood.

BACKGROUND: Alcohol consumption is influenced by genetic factors. Previous studies have examined the heritability of alcohol consumption, or related phenotypes, from adolescence into adulthood, frequently finding that total heritability changes over time. However, it remains unclear whether the same genes underlie liability to alcohol consumption across development versus whether novel risk genes become important over time. Method A population-based study of adult male twins (n=1790) born in Virginia, USA, retrospectively reported on their average monthly alcohol consumption from early adolescence through adulthood. We used twin modeling methods to explore genetic and environmental influences on alcohol consumption over time. RESULTS: One latent genetic factor accounted for the majority of the heritability in alcohol consumption during mid- to late adolescence, but its influence declined thereafter; from young adulthood forward, heritability was largely attributable to a second genetic factor. The total heritability of alcohol consumption increased from 0 at ages 12-14 years to 0.40 by ages 18-21 years. Shared environmental factors declined in influence over time. CONCLUSIONS: The heritability of alcohol consumption over time is dynamic both quantitatively and qualitatively. These results have important implications for gene identification endeavors. Furthermore, these findings could inform efforts to elucidate developmentally dynamic behaviors, such as antisocial behavior.

A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence.

BACKGROUND: Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. METHOD: We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. RESULTS: The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. CONCLUSIONS: The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.

The distribution of automobile catalysts-cast platinum, palladium and rhodium in soils adjacent to roads and their uptake by grass.

The introduction of automobile catalysts has raised environmental concern, as this pollution control technology is also an emission source for the platinum group elements (PGE). The main aim of this study was to assess the concentrations of Pt, Pd, Rh and Au in soil and grass herbage collected adjacent to 5 roads. Soil and grass samples were collected from 4 fixed distances (0, 1, 2 and 5 m) from the road edge at each site. PGE and Au were determined by ICP-MS in all samples after acid digestion. The maximum soil Pt, Rh and Pd concentrations were measured at the road perimeters. Averaged across the sites, the Pt and Rh concentrations of 15.9+/-7.5 microg Pt kg(-1) and 22.40+/-4.73 microg Rh kg(-1) at 0-m distance decreased to 2.04+/-1.7 microg Pt kg(-1) and 3.51+/-1.96 microg Rh kg(-1), respectively at 5-m away from the roads. Pd concentrations were much higher than Pt or Rh, ranging from 120.8+/-12.0 microg Pd kg(-1) (0-m) to 84.2+/-10.9 microg Pd kg(-1) (5-m), possibly due to differences in its use, emission and/or soil chemistry. Au showed little or no change with distance from the roads. However, the average Au concentration of 18.98+/-0.98 microg Au kg(-1) provides clear evidence of some input possibly due to attrition of automobile electronics. No straightforward influence of traffic flow rates on PGE distribution was found. A combination of dispersal impeding local features and slow moving and stop-and-start traffic conditions or fast moving traffic with flat open spaces may have offset the expected impacts. Rh and Pt soil concentration accounted for 66% and 34% (P<0.01) of the variability observed, respectively in their plant concentrations. Grass Pd and Au concentrations had no relationship with their respective soil concentrations.

Reducing fluxes of faecal indicator compliance parameters to bathing waters from diffuse agricultural sources: the Brighouse Bay study, Scotland.

The European Water Framework Directive requires the integrated management of point and diffuse pollution to achieve 'good' water quality in 'protected areas'. These include bathing waters, which are regulated using faecal indicator organisms as compliance parameters. Thus, for the first time, European regulators are faced with the control of faecal indicator fluxes from agricultural sources where these impact on bathing water compliance locations. Concurrently, reforms to the European Union (EU) Common Agricultural Policy offer scope for supporting on-farm measures producing environmental benefits through the new 'single farm payments' and the concept of 'cross-compliance'. This paper reports the first UK study involving remedial measures, principally stream bank fencing, designed to reduce faecal indicator fluxes at the catchment scale. Considerable reduction in faecal indicator flux was observed, but this was insufficient to ensure bathing water compliance with either Directive 76/160/EEC standards or new health-evidence-based criteria proposed by WHO and the European Commission.

Genetic effects influencing risk for major depressive disorder in China and Europe.

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

SNP-based heritability estimates of the personality dimensions and polygenic prediction of both neuroticism and major depression: findings from CONVERGE.

Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case-control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 × 10-6). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism can be significantly predicted across ancestry, and highlight the importance of studying polygenic contributions to personality in non-European populations.

Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior.

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.

Early occlusion and late stricture of normal coronary arteries following blunt chest trauma.

A 27-year-old man had inferior myocardial infarction following superficial chest trauma. Coronary arteriography documented an isolated total occlusion of the right coronary artery, probably caused by localized extra-coronary compression, and no other evidence of intrinsic coronary disease. The left anterior descending artery later developed a localized proximal stenosis, most likely due to mural thrombus, which progressed rapidly to cause anterior myocardial infarction despite coronary artery surgery. The etiology of this lesion is discussed and support given to the "encrustation" hypothesis of human atherosclerosis. Exercise thallium scintigraphy proved helpful in the management of this case.

Health status and health practices--Alameda and beyond.

Using the population of St John's, Newfoundland, we did a constructive replication of previous studies testing the association between health practices and health status. A telephone questionnaire was applied to all adults in a probabilistic sample of households (3300 subjects, 85% response rate). Several health practices and preventive behaviours indexes were developed and tested. An additive index of six practices (breakfast, sleeping, drinking, smoking, weight and exercise) using the Alameda County definitions, and an additive score of five practices (excluding breakfast and with revised definitions for smoking, drinking and exercise) were analysed using log-linear models; there was association between the indexes and self-assessed health status when controlling for sex, age and education, with the exception of the six-practice index in males. The association between these two indexes and several variables and constructs of health status showed that the best relationships were with self-assessed health status and with a construct including variables measuring subjective health.

Atypical presentation of spontaneous pneumomediastinum.

Spontaneous pneumomediastinum is a rare clinical entity; when diagnosis is certain, no treatment is required and symptoms rarely recur. The clinical presentation is usually diagnostic; however, atypical symptoms may mandate further investigation before diagnosis can be established. We describe 2 patients with spontaneous pneumomediastinum who presented with dominant esophageal symptoms (odynophagia and dysphagia) suggestive of esophageal perforation. Investigation and management are discussed.

Successful treatment of massive pulmonary embolism after coronary artery bypass grafting due to heparin-induced thrombocytopenia.

Massive pulmonary embolism is a rare complication in patients undergoing coronary artery bypass grafting. Frequently patients have had exposure to heparin before the operation. In this article we report a patient who 6 days after a cardiac operation suffered a massive pulmonary embolism. The patient was later discovered to have heparin-associated thrombocytopenia with serum heparin antibody. We recommend patients receiving heparin have frequent platelet counts and those with induced thrombocytopenia undergo sensitivity testing.

Reoperation for recurrent aortic coarctation.

BACKGROUND: Recurrence of stenosis is a complication of coarctation repair associated with major long-term morbidity. Persistent or exercise-provoked hypertension may indicate recurrent coarctation. Patients failing or not amenable to balloon dilation should be managed surgically. METHODS: A retrospective chart review was performed. RESULTS: Forty-three patients were identified as having undergone repeat surgical intervention for recurrent aortic coarctation between the years 1976 and 1993 at The Hospital for Sick Children in Toronto. Seventy percent of the children had other congenital cardiac anomalies. Eighty-six percent of patients initially treated by subclavian flap aortoplasty or end-to-end anastomosis were managed at reoperation by patch aortoplasty, and 26% of patients also required augmentation of the transverse arch (under hypothermic circulatory arrest) for accompanying hypoplasia. Three patients underwent a second reoperation; all were treated at this reoperation with tube graft interposition. CONCLUSIONS: No ischemic spinal injury occurred in patients managed with either simple proximal aortic cross-clamping or cardiopulmonary bypass. No patient treated with transverse arch augmentation required further surgical intervention. Mortality at reoperation was 7% (3 patients), similar to that of first-time coarctation repair. At follow-up (mean duration, 4.5 years), 57% of patients are normotensive, with no measurable arm-leg gradient.

An empirical analysis of the dimensions of health status measures.

The objective of this study is to verify empirically the existence of separate dimensions in the overall concept of health status by analyzing 10 variables included in a questionnaire that was applied to all adults in a simple random sample of households in St John's, Newfoundland. The response rate was 85% for a total of 3300 subjects. These data were analyzed by frequencies and by associations with sex, age and education. Nonparametric correlation, factor and cluster analyses on variables were used to verify if health status had identifiable dimensions. All these methods produced similar results showing five distinct factors. The first factor is composed of variables related to disease (disability/chronic conditions/worry about health); the second, to happiness (happiness/emotional); the third, to subjective appraisal of health (physical condition/comparative level of energy/self-rated health status). Finally, the fourth and fifth factors were single variables; restriction of normal activities and social contacts. An interesting finding was that self-rated health status was distributed with almost equal weight in both the first and third factors. A validation of the 10 variables and the 5 factors was undertaken by studying their association with health care utilization. Two measures of utilization were used; number of physicians' visits in a year and number of hospital days in a 4-year period. Number of chronic conditions, disability and self-rated health status were associated with both measures of utilization; factor 1 was the only summary construct showing association with utilization. This paper demonstrates that self-rated health status is valid as a single measure of overall health status in this sample, being associated with both disease and subjective assessment components.

Gender differences in marital support following a shared life event.

Previous work has established that women with good marriages are less at risk of depression of clinical severity following a crisis than women in poor quality relationships. Evidence for such protectiveness is less clear for men. The paper examines the relationship between marital quality, onset of depression, and gender following a severely threatening life event. The results show that good quality of marriage related to lower rates of depression for both men and women, although the overall rate for women was higher. For women with a good marital relationship, but for whom support from partner was not forthcoming at the time of the crisis (i.e. the person was "let down"), risk was increased, confirming a result from a study in Islington. The current study shows that the same set of findings holds for men. Gender differences did emerge when the subjective need for support within the marital relationship is taken into account, with women expressing greater need. However, such a desire for support was not necessarily translated into support-seeking behaviour as in a poor relationship turning to a partner was frequently inopportune. Women were also more likely to seek support outside the marriage; as in the earlier Islington research this was related to a lower risk of depression for those in a poor relationship. An unexpected finding was that men who received support outside marriage had an increased risk of depression.

Valve surgery in octogenarians.

OBJECTIVE: To review the outcomes of octogenarians undergoing valve operations. PATIENTS AND METHODS: One hundred and twenty-five consecutive patients aged 80 years and over received valve operations between 1990 and 1996 at the Toronto General Hospital, Toronto, Ontario. All hospital survivors were prospectively followed for a mean of 36.6 months (range 0.1 to 89.9). RESULTS: One hundred and two patients received aortic valve operations, 18 patients received mitral procedures and five patients underwent double valve operations. Significant aortic stenosis was present in 95 of 102 patients (93%) receiving isolated aortic valve surgery, and mitral regurgitation was present in 16 of 18 patients (89%) undergoing mitral valve operations. Overall in-hospital mortality was 6.4% (n=8) and the perioperative infarction rate was 1.6% (n=2). In-hospital mortality was higher for mitral valve patients at 17% (n=3) than for aortic valve patients at 4% (n=4) (P=0.06). For the group overall, the six-year actuarial survival rate was 71.6+/-6%. The actuarial freedom from valve-related death was 97.1+/-2% at three years. Concomitant coronary artery disease was not significantly associated with perioperative mortality. Survivors had significantly improved New York Heart Association functional class status. CONCLUSION: In carefully selected patients aged 80 years and over, aortic valve surgery carries a low perioperative mortality with good intermediate term survival and benefits. Octogenarians undergoing mitral valve procedures experience higher perioperative mortality. Although the number of participants was small for this study, it does appear that coexistent coronary artery disease should not be the sole reason for denial of surgery because it has less of an impact on short and intermediate term survival than other factors.