Long-term survival after endovascular and open repair of unruptured abdominal aortic aneurysm.

BACKGROUND: The aim of this study was to examine patterns of 10-year survival after elective repair of unruptured abdominal aortic aneurysms (AAAs) in different patient groups. METHODS: Patients having open repair or endovascular aneurysm repair (EVAR) in the English National Health Service between January 2006 and December 2015 were identified from Hospital Episode Statistics data. Postoperative survival among patients of different age and Royal College of Surgeons of England (RCS) modified Charlson co-morbidity score profiles were analysed using flexible parametric survival models. The relationship between patient characteristics and risk of rupture after repair was also analysed. RESULTS: Some 37 138 patients underwent elective AAA repair, of which 15 523 were open and 21 615 were endovascular. The 10-year mortality rate was 38·1 per cent for patients aged under 70 years, and the survival trajectories for open repair and EVAR were similar when patients had no RCS-modified Charlson co-morbidity. Among older patients or those with co-morbidity, the 10-year mortality rate rose, exceeding 70 per cent for patients aged 80 years. Mean survival times over 10 years for open repair and EVAR were often similar in subgroups of older and more co-morbid patients, but their survival trajectories became increasingly dissimilar, with open repair showing greater short-term risk within 6 months but lower 10-year mortality rates. The risk of rupture over 9 years was 3·4 per cent for EVAR and 0·9 per cent for open repair, and was weakly associated with patient factors. CONCLUSION: Long-term survival patterns after elective open repair and EVAR for unruptured AAA vary markedly across patients with different age and co-morbidity profiles.

ANTECEDENTES: El objetivo de este artículo fue examinar los patrones de supervivencia a 10 aáos tras reparación electiva de aneurismas de la aorta abdominal sin rotura (abdominal aortic aneurysms, AAA) en diferentes grupos de pacientes. MÉTODOS: Se identificaron pacientes sometidos a reparación abierta (open repair, OR) o reparación endovascular (endovascular aneurysm repair, EVAR) del aneurisma en el Sistema Nacional de Salud Inglés entre enero de 2006 y diciembre de 2015, a partir de los datos del Hospital Episode Statistics. Se analizaron la supervivencia postoperatoria entre los pacientes de diferentes edades y los perfiles de comorbilidad con la puntuación de Charlson modificada del Royal College of Surgeons of England (RCS) utilizando modelos de supervivencia paramétricos flexibles. También se analizó la relación entre las características de los pacientes y el riesgo de rotura tras la reparación. RESULTADOS: Un total de 37.138 pacientes fueron sometidos a reparaciones electivas de AAA, de las cuales 15.523 fueron reparaciones abiertas y 21.615 endovasculares. La mortalidad a los 10 aáos fue del 38% para los pacientes de edad inferior a los 70 aáos, y las curvas de supervivencia de la OR y EVAR fueron similares cuando los pacientes no tenían comorbilidad con el Charlson modificado del RCS. Entre los pacientes de edad avanzada y aquellos pacientes con comorbilidad, la mortalidad a los 10 aáos aumentó, excediendo el 70% para los pacientes de más de 80 aáos de edad. La media de los tiempos de supervivencia superior a 10 aáos para OR y EVAR fueron similares dentro de los subgrupos de pacientes de edad avanzada y más comorbilidad, pero las curvas de supervivencia se hicieron cada vez más diferentes, con la OR mostrando un mayor riesgo a corto plazo en los primeros 6 meses pero tasas de mortalidad a los 10 aáos más bajas. El riesgo de rotura mas allá de los 9 aáos fue 3,4% para EVAR y 0,9% para la reparación abierta, con una débil asociación con los factores inherentes a los pacientes. CONCLUSIÓN: Los patrones de supervivencia a largo plazo tras OR y EVAR electivas para AAA sin rotura varían notablemente entre pacientes con perfiles de edad y comorbilidad diferentes.

Population-based study of mortality and major amputation following lower limb revascularization.

BACKGROUND: The aim of this study was to estimate separate risks of major lower limb amputation and death following revascularization for peripheral artery disease (PAD) using competing risks analysis. METHODS: Routinely collected data from Hospital Episode Statistics (HES) were used to identify patients who underwent endovascular or open lower limb revascularization for PAD in England from 2005 to 2015. The primary outcomes were major lower limb amputation and death within 5 years of revascularization. Cox proportional hazards and Fine-Gray competing risks regression were used to examine the competing risks of these outcomes. RESULTS: Some 164 845 patients underwent their first lower limb revascularization for PAD during the study interval. Most were men (64·6 per cent) and the median age was 71 (i.q.r. 62-78) years. Following endovascular revascularization, the 5-year cumulative incidence of amputation was 4·2 per cent in patients with intermittent claudication and 18·0 per cent in those with a record of tissue loss. The corresponding rates were 10·8 and 25·3 per cent respectively after open revascularization, and 8·1 and 25·0 per cent after combined procedures. The 5-year cumulative incidence of death varied from 24·5 to 39·8 per cent, depending on procedure type. Competing risks methods consistently produced lower estimates than standard methods. CONCLUSION: The 5-year risk of major amputation following lower limb revascularization for PAD appears lower than estimated previously. Patients undergoing revascularization for tissue loss and those who require an open procedure are at highest risk of limb loss.

Associations of tissue transglutaminase antibody seropositivity with coronary heart disease: Findings from a prospective cohort study.

BACKGROUND AND AIMS: Clinical experience and observational studies suggest that individuals with coeliac disease are at increased risk of coronary heart disease (CHD), but the precise mechanism for this is unclear. Laboratory studies suggest that it may relate to tissue transglutaminase antibodies (tTGAs). Our aim was to examine whether seropositivity for tTGA and endomysial antibodies (EMAs) are associated with incident CHD in humans. METHODS AND RESULTS: We used data from Mini-Finland Health Survey, a prospective cohort study of Finnish men and women aged 35-80 at study baseline 1978-80. TTGA and EMA seropositivities were ascertained from baseline blood samples and incident CHD events were identified from national hospitalisation and death registers. Cox regression was used to examine the associations between antibody seropositivity and incident CHD. Of 6887 men and women, 562 were seropositive for tTGAs and 72 for EMAs. During a median follow-up of 26 years, 2367 individuals experienced a CHD event. We found no clear evidence for an association between tTGA positivity (hazard ratio, HR: 1.04, 95% confidence interval, CI: 0.83, 1.30) or EMA positivity (HR: 1.16, 95% CI: 0.77, 1.74) and incident CHD, once pre-existing CVD and known CHD risk factors had been adjusted for. CONCLUSION: We found no clear evidence for an association of tTGA or EMA seropositivity with incident CHD outcomes, suggesting that tTG autoimmunity is unlikely to be the biological link between coeliac disease and CHD.

Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.

BACKGROUND: Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. METHOD: We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. RESULTS: We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). CONCLUSIONS: Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.

Editor's Choice - Delays to Surgery and Procedural Risks Following Carotid Endarterectomy in the UK National Vascular Registry.

OBJECTIVE: Guidelines recommend that patients suffering an ischaemic transient ischaemic attack (TIA) or stroke caused by carotid artery stenosis should undergo carotid endarterectomy (CEA) within 14 days. METHOD: The degree to which UK vascular units met this standard was examined and whether rapid interventions were associated with procedural risks. The study analysed patients undergoing CEA between January 2009 and December 2014 from 100 UK NHS hospitals. Data were collected on patient characteristics, intervals of time from symptoms to surgery, and 30-day postoperative outcomes. The relationship between outcomes and time from symptom to surgery was evaluated using multilevel multivariable logistic regression. RESULTS: In 23,235 patients, the median time from TIA/stroke to CEA decreased over time, from 22 days (IQR 10-56) in 2009 to 12 days (IQR 7-26) in 2014. The proportion of patients treated within 14 days increased from 37% to 58%. This improvement was produced by shorter times across the care pathway: symptoms to referral, from medical review to being seen by a vascular surgeon, and then to surgery. The spread of the median time from symptom to surgery among NHS hospitals shrank between 2009 and 2013 but then grew slightly. Low-, medium-, and high-volume NHS hospitals all improved their performance similarly. Performing CEA within 48 h of symptom onset was associated with a small increase in the 30-day stroke and death rate: 3.1% (0-2 days) compared with 2.0% (3-7 days); adjusted odds ratio 1.64 (95% CI 1.04-2.59) but not with longer delays. CONCLUSIONS: The delay from symptom to CEA in symptomatic patients with ipsilateral 50-99% carotid stenoses has reduced substantially, although 42% of patients underwent CEA after the recommended 14 days. The risk of stroke after CEA was low, but there may be a small increase in risk during the first 48 h after symptoms.

Associations of coeliac disease with coronary heart disease and cerebrovascular disease: A systematic review and meta-analysis.

AIMS: Clinical experience suggests that atherosclerotic disease is common in individuals with coeliac disease, but epidemiological studies have had contradicting findings. To summarise the currently available evidence, we systematically reviewed and analysed observational studies of the association of coeliac disease or dermatitis herpetiformis with coronary heart disease (CHD) or stroke. DATA SYNTHESIS: We searched for studies comparing CHD or stroke outcomes with individuals with and without coeliac disease or dermatitis herpetiformis. Three investigators independently searched electronic databases, identified relevant studies and extracted data. Study-specific results were combined in random-effects meta-analyses, and heterogeneity was quantified using the I(2) statistic and meta-regression. Twenty-one studies were included in our systematic review and 18 in the meta-analyses. For CHD, the pooled hazard ratio for incident disease was 1.05 (95% confidence interval (CI): 0.93, 1.19) and the overall standardised mortality ratio was 1.21 (0.99, 1.49). For stroke and brain haemorrhage, the corresponding estimates were 1.10 (95% CI: 1.00, 1.21) and 1.43 (0.97, 2.10), respectively. There was moderate to considerable heterogeneity among the study-specific estimates. In addition, many estimates were based on small numbers of outcomes and they had limitations in terms of adjustment for potential confounders. CONCLUSION: Our meta-analyses lend some support to an association between coeliac disease and CHD or cerebrovascular disease, but the evidence base was heterogeneous and had limitations. Our systematic review highlighted a need in this area for adequately powered prospective studies with appropriate adjustment for potentially confounding factors.

Job strain and the risk of severe asthma exacerbations: a meta-analysis of individual-participant data from 100 000 European men and women.

BACKGROUND: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. METHODS: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. RESULTS: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). CONCLUSIONS: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Self-reported life satisfaction and alcohol use: a 15-year follow-up of healthy adult twins.

AIMS: To study the bidirectional relationships between life satisfaction (LS) and alcohol use. METHODS: Health questionnaires were administered in 1975, 1981 and 1990 to a population-based sample of healthy Finnish twins aged 18-45 at baseline (n = 14,083). These included a LS scale and three indicators for adverse alcohol use: binge drinking, passing out and high consumption (women/men ≥400/800 g/month). In longitudinal analyses, logistic regression, pair-wise case-control analyses and growth models were applied. RESULTS: All alcohol indicators increased the age-adjusted risk of becoming dissatisfied regardless of study period [binge drinking odds ratio (OR)(1975-1990 )= 1.29; 95% confidence interval (CI) 1.12-1.50; high consumption OR(1975-1990 )= 1.60; 1.29-1.99 and passing out OR(1981-1990 )= 2.01; 1.57-2.57]. Also, the dissatisfied had an increased subsequent risk for adverse alcohol use. The risk for passing out due to drinking (OR(1975-1990 )= 1.50; 1.22-1.86) was increased regardless of study period, while high consumption (OR(1975-1981 )= 1.97; 1.40-2.77; OR(1981-1990 )= 2.48; 1.50-4.12) and binge drinking (OR(1975-1981 )= 1.37; 1.12-1.67) showed some variation by the study period. Predictions remained after multiple adjustments. Longitudinally, high consumption predicted dissatisfaction somewhat more strongly than vice versa. The change/levels within the whole range of LS and alcohol consumption were only slightly associated in the entire study population. CONCLUSION: Life dissatisfaction and adverse alcohol use reciprocally predict each other prospectively. The heavier the alcohol use the stronger the relationship.

Job strain in relation to body mass index: pooled analysis of 160 000 adults from 13 cohort studies.

BACKGROUND: Evidence of an association between job strain and obesity is inconsistent, mostly limited to small-scale studies, and does not distinguish between categories of underweight or obesity subclasses. OBJECTIVES: To examine the association between job strain and body mass index (BMI) in a large adult population. METHODS: We performed a pooled cross-sectional analysis based on individual-level data from 13 European studies resulting in a total of 161 746 participants (49% men, mean age, 43.7 years). Longitudinal analysis with a median follow-up of 4 years was possible for four cohort studies (n = 42 222). RESULTS: A total of 86 429 participants were of normal weight (BMI 18.5-24.9 kg m(-2) ), 2149 were underweight (BMI < 18.5 kg m(-2) ), 56 572 overweight (BMI 25.0-29.9 kg m(-2) ) and 13 523 class I (BMI 30-34.9 kg m(-2) ) and 3073 classes II/III (BMI ≥ 35 kg m(-2) ) obese. In addition, 27 010 (17%) participants reported job strain. In cross-sectional analyses, we found increased odds of job strain amongst underweight [odds ratio 1.12, 95% confidence interval (CI) 1.00-1.25], obese class I (odds ratio 1.07, 95% CI 1.02-1.12) and obese classes II/III participants (odds ratio 1.14, 95% CI 1.01-1.28) as compared with participants of normal weight. In longitudinal analysis, both weight gain and weight loss were related to the onset of job strain during follow-up. CONCLUSIONS: In an analysis of European data, we found both weight gain and weight loss to be associated with the onset of job strain, consistent with a 'U'-shaped cross-sectional association between job strain and BMI. These associations were relatively modest; therefore, it is unlikely that intervention to reduce job strain would be effective in combating obesity at a population level.

Handedness in the helsinki ultrasound trial.

OBJECTIVES: To determine whether exposure to prenatal ultrasound increases non-right-handedness in boys. METHODS: The association between exposure to prenatal ultrasound and handedness was tested, using logistic regression analysis, in the Helsinki Ultrasound Trial data. We applied an intention-to-treat approach in this analysis of a subset of 4150 subjects whose parents answered a follow-up questionnaire on handedness when the children were aged 13-15 years. RESULTS: The odds ratio for non-right-handedness of children who had been exposed to prenatal ultrasound was 1.16 (0.98-1.37) for all subjects, 1.12 (0.89-1.41) for boys and 1.24 (0.97-1.58) for girls. CONCLUSIONS: We could not confirm the hypothesis that prenatal ultrasound exposure and handedness are associated. Our findings were independent of the particular definition of handedness used, whether it was considered according to the writing hand alone or defined using a laterality quotient.

Life experiences after stroke among Iranian stroke survivors.

BACKGROUND: Stroke is a major cause of disability worldwide. It is a life-threatening and life-altering event, which leaves many physical and mental disabilities, thus creating major social and economic burdens. Experiencing a stroke and its aftermath can be devastating for patients and their families. In Iran, many services are not available for those who lack property; this may result in many difficulties and long-term problems for stroke survivors and their family members who are usually the main caregivers in Iranian cultural. Despite its effect on their lives, little is known about how the survivors perceive stroke in the Iranian context, therefore, knowing more about this process may enhance problem identification and problem solving. AIM: To illuminate how stroke survivors experience and perceive life after stroke. METHOD: A grounded theory approach was recruited using semi-structured interviews with 10 stroke survivors. FINDINGS: The survivors perceived that inadequate social and financial support, lack of an educational plan, lack of access to rehabilitative services, physical and psychological problems led them to functional disturbances, poor socio-economical situation and life disintegration. The core concept of life after stroke was functional disturbances. CONCLUSIONS: The study shows the need to support the stroke survivors in their coping process with their new situation by providing appropriate discharge plans, social and financial support, social insurances and training programmes for the stroke survivors and their families.

Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study.

AIMS/HYPOTHESIS: We investigated whether BMI predicts type 2 diabetes in twins and to what extent that is explained by common genetic factors. METHODS: This was a population-based twin cohort study. Monozygotic (n = 4,076) and dizygotic (n = 9,109) non-diabetic twin pairs born before 1958 answered a questionnaire in 1975, from which BMI was obtained. Information on incident cases of diabetes was obtained by linkage to nationwide registers until 2005. RESULTS: Altogether, 1,332 twins (6.3% of men, 5.1% of women) developed type 2 diabetes. The HR for type 2 diabetes increased monotonically with a mean of 1.22 (95% CI 1.20-1.24) per BMI unit and of 1.97 (95% CI 1.87-2.08) per SD of BMI. The HRs for lean, overweight, obese and morbidly obese participants were 0.59, 2.96, 6.80 and 13.64 as compared with normal weight participants. Model heritability estimates for bivariate variance due to an additive genetic component and non-shared environmental component were 75% (men) and 71% (women) for BMI, and 73% and 64%, respectively for type 2 diabetes. The correlations between genetic variance components (r (g)) indicated that one fifth of the covariance of BMI and type 2 diabetes was due to shared genetic influences. Although the mean monozygotic concordance for type 2 diabetes was approximately twice the dizygotic one, age of onset of diabetes within twin pair members varied greatly, irrespective of zygosity. CONCLUSIONS/INTERPRETATION: A 28-year follow-up of adult Finnish twins showed that despite high trait heritability estimates, only a fraction of covariation in BMI and incident type 2 diabetes was of genetic origin.

Migrants' perceptions of using interpreters in health care.

BACKGROUND: The number of foreign-born people who do not share a common language has increased due to extensive international migration, which will increase in the future. There is limited knowledge about the users' perceptions of interpreters in health care. AIM: To describe how individuals from former Yugoslavia, living in Sweden, perceived the use of interpreters in Swedish healthcare services. METHOD: A phenomenographic approach was employed. Data were collected by semi-structured interviews during 2006-2007 with 17 people, aged 29-75 years, from former Yugoslavia, living in Sweden. FINDINGS: Three descriptive categories were identified: (1) prerequisites for good interpretation situations; (2) the interpretation situation - aspects of satisfaction or dissatisfaction; and (3) measures to facilitate and improve the interpreter situation. The interpreter's competence, attitude, appearance and an appropriate environment are important prerequisites for interpretation. The interpreter was perceived as being a communication aid and a guide in the healthcare system in terms of information and practical issues, but also as a hindrance. A desirable professional interpreter was perceived as highly skilled in medical terminology and language, working in face-to-face interaction. CONCLUSION: Using an interpreter was perceived as a hindrance, though also needed in communication with healthcare staff and as a guide in the healthcare system. Face-to-face interaction was preferred, with the interpreter as an aid to communication. As part of individual care planning it is important to use interpreters according to the patients' desires. Healthcare organizations and guidelines for interpreters need to be developed in order for patients to have easy access to highly skilled professional interpreters.

Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genome-wide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q.

Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families.

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.

Mesoporous silicon microparticles for oral drug delivery: loading and release of five model drugs.

Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

Life dissatisfaction and subsequent work disability in an 11-year follow-up.

BACKGROUND: Mental disorders are associated with disability, but the long-term effects of low subjective well-being on work ability in general population are not known. In this study we investigated whether self-reported life dissatisfaction predicts work disability. METHOD: A nationwide sample of Finnish twins aged 18-54 years (N = 22,136), unselected for health status responded to a health questionnaire with a four-item life satisfaction scale (range 4-20) covering interest, happiness, easiness and loneliness of life in 1975 and 1981. Cox regression for all subjects and conditional logistic regression for discordant twin pairs were used to compare the risk of subsequent work disability (N = 1200) (Nationwide Disability Register) between the dissatisfied and satisfied. RESULTS: Life dissatisfaction predicted subsequent (1977-87) work disability pension due to psychiatric and non-psychiatric causes among the healthy at baseline, and that due to psychiatric causes among the ill. After controlling for age, marital status, social class and health behaviour, these risks remained significant. Repeatedly reported (1975 and 1981) life dissatisfaction was strongly associated with increased (age-adjusted) risk of subsequent (1982-87) work disability due to psychiatric and also that due to non-psychiatric causes among the healthy. When twin pairs discordant for end-point disability status were analysed, risk differences related to life satisfaction were only slightly decreased, but they did not differ significantly between monozygotic and dizygotic pairs. CONCLUSION: Life dissatisfaction predicts subsequent work disability especially among the healthy.

Life satisfaction and suicide: a 20-year follow-up study.

OBJECTIVE: The authors investigated whether self-reported life satisfaction predicted suicide over a period of 20 years (1976-1995) in adults unselected for mental health status. METHOD: A nationwide sample of adults aged 18-64 years (N=29,173) from the Finnish Twin Cohort responded to a health questionnaire that included a life satisfaction scale (score range=4-20, with higher scores indicating greater dissatisfaction) that covered four items: interest in life, happiness, general ease of living, and feeling of loneliness. "Dissatisfied" subjects (life satisfaction score=12-20) were compared to "satisfied" subjects (score=4-6). Mortality data were derived from the national registry and analyzed with Cox regression. RESULTS: Dissatisfaction at baseline (life satisfaction score=12-20) was associated with a higher risk of suicide throughout the 20-year follow-up period (age-adjusted hazard ratio=3.02, 95% confidence interval [CI]=1.83-4.98). The association was somewhat stronger in the first decade (hazard ratio=4.46, 95% CI=1.95-10.20) than in the second (hazard ratio=2.34, 95% CI=1.24-4.45). A dose-response relationship was also found. Men with the highest degrees of dissatisfaction (life satisfaction score=19-20) were 24.85 times as prone to commit suicide as satisfied men during the first 10 years of the follow-up period. Throughout the entire follow-up, life dissatisfaction still predicted suicide after adjusting for age, sex, baseline health status, alcohol consumption, smoking status, and physical activity (hazard ratio=1.74, 95% CI=1.02-2.97). Subjects who reported dissatisfaction at baseline and again 6 years later showed a high suicide risk (hazard ratio=6.84, 95% CI=1.99-23.50) compared to those who repeatedly reported satisfaction. CONCLUSIONS: Life dissatisfaction has a long-term effect on the risk of suicide, and this seems to be partly mediated through poor health behavior. Life satisfaction seems to be a composite health indicator.

Self-reported life satisfaction and 20-year mortality in healthy Finnish adults.

The authors investigated the role of self-reported life satisfaction in mortality with a prospective cohort study (1976-1995). A nationwide sample of healthy adults (18-64 years, n = 22,461) from the Finnish Twin Cohort responded to a questionnaire about life satisfaction and known predictors of mortality in 1975. A summary score for life satisfaction (LS), defined as interest in life, happiness, loneliness, and general ease of living (scale range, 4-20), was determined and used as a three-category variable: the satisfied (LS, 4-6) (21%), the intermediate group (LS, 7-11) (65%), and the dissatisfied (LS, 12-20) (14%). Mortality data were analyzed with Cox regression. Dissatisfaction was linearly associated with increased mortality. The age-adjusted hazard ratios of all-cause, disease, or injury mortality among dissatisfied versus satisfied men were 2.11 (95% confidence interval (CI): 1.68, 2.64), 1.83 (95% CI: 1.40, 2.39), and 3.01 (95% CI: 1.94, 4.69), respectively. Adjusting for marital status, social class, smoking, alcohol use, and physical activity diminished these risks to 1.49 (95% CI: 1.16, 1.92), 1.35 (95% CI: 1.01, 1.82), and 1.93 (95% CI: 1.19, 3.12), respectively. Dissatisfaction was associated with increased disease mortality, particularly in men with heavy alcohol use (hazard ratio = 3.76, 95% CI: 1.61, 8.80). Women did not show similar associations between life satisfaction and mortality. Life dissatisfaction may predict mortality and serve as a general health risk indicator. This effect seems to be partially mediated through adverse health behavior.