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1.  Digested wheat gluten inhibits binding between leptin and its receptor 
BMC Biochemistry  2015;16:3.
Background
Leptin resistance is considered a primary risk factor for obesity. It has been hypothesized that dietary cereal grain protein could cause leptin resistance by preventing leptin from binding to its receptor. Non-degraded dietary wheat protein has been found in human serum at a mean level of 41 ng/mL. Here, we report our findings from testing whether enzymatically digested gluten from wheat prevents leptin from binding to the leptin receptor in vitro.
Gluten from wheat was digested with pepsin and trypsin under physiological conditions. Pepsin and trypsin activity was removed from the gluten digest with a 10 kDa spin-filter or by heat treatment at 100°C for 30 min. Binding to the leptin receptor of leptin mixed with gluten digest at a series of concentrations was measured using surface plasmon resonance technology.
Results
Binding of the gluten digest to the leptin receptor was not detected. Spin-filtered gluten digest inhibited binding of leptin to the leptin receptor, with 50% inhibition at a gluten digest concentration of ~10 ng/mL. Heat-treated gluten digest did not inhibit leptin binding.
Conclusions
Digested wheat gluten inhibits binding of leptin to the leptin receptor, with half-maximal inhibition at 10 ng/mL. The inhibition is significant at clinically relevant concentrations and could therefore serve as a novel pathway to investigate to understand the molecular basis of leptin resistance, obesity and associated disorders.
doi:10.1186/s12858-015-0032-y
PMCID: PMC4308898  PMID: 25600821
Gluten; Leptin; Leptin resistance; Obesity
2.  Age, period and cohort trends in drug abuse hospitalizations within the total Swedish population (1975-2010)* 
Drug and alcohol dependence  2013;134:355-361.
Background:
The societal consequences of drug abuse (DA) are severe and well documented, the World Health Organization recommending tracking of population trends for effective policy responses in treatment of DA and delivery of health care services. However, to correctly identify possible sources of DA change, one must first disentangle three different time-related influences on the need for treatment due to DA: age effects, period effects and cohort effects.
Methods:
We constructed our main Swedish national DA database (spanning four decades) by linking healthcare data from the Swedish Hospital Discharge Register to individuals, which included hospitalisations in Sweden for 1975-2010. All hospitalized DA cases were identified by ICD codes. Our Swedish national sample consisted of 3,078,129 men and 2,921,816 women. We employed a cross-classified multilevel logistic regression model to disentangle any net age, period and cohort effects on DA hospitalization rates.
Results:
We found distinct net age, period and cohort effects, each influencing the predicted probability ofhospitalisation for DA in men and women. Peak age for DA in both sexes was 33-35 years; net period effects showed an increase in hospitalisation for DA from 1996 to 2001; and in birth cohorts 1968-74, we saw a considerable reduction (around 75%) in predicted probability of hospitalisation for DA.
Conclusions:
The use of hospital admissions could be regarded as a proxy of the population's health service use for DA. Our results may thus constitute a basis for effective prevention planning, treatment and other appropriate policy responses.
doi:10.1016/j.drugalcdep.2013.11.011
PMCID: PMC3909834  PMID: 24300899
Sweden; drug abuse; age-period-cohort effects; longitudinal; trends
3.  Statin use and risk of depression: a Swedish national cohort study 
BMC Psychiatry  2014;14(1):348.
Background
Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990).
Methods
National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.
Results
Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81).
Conclusions
The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.
doi:10.1186/s12888-014-0348-y
PMCID: PMC4266881  PMID: 25471121
Statins; Atorvastatin; Simvastatin; Depression; Aetiology; Inflammation; Oxidative stress
4.  Familial Risks of Kidney Failure in Sweden: A Nationwide Family Study 
PLoS ONE  2014;9(11):e113353.
Background
The value of family history as a risk factor for kidney failure has not been determined in a nationwide setting.
Aim
This nationwide family study aimed to determine familial risks for kidney failure in Sweden.
Methods
The Swedish multi-generation register on 0–78-year-old subjects were linked to the Swedish patient register and the Cause of death register for 1987–2010. Individuals diagnosed with acute kidney failure (n = 10063), chronic kidney failure (n = 18668), or unspecified kidney failure (n = 3731) were included. Kidney failure patients with cystic kidney disease, congenital kidney and urinary tract malformations, urolithiasis, and rare inherited kidney syndromes, and hyperoxaluria were excluded. Standardized incidence ratios (SIRs) were calculated for individuals whose parents/siblings were diagnosed with kidney failure compared to those whose parents or siblings were not.
Results
The concordant (same disease) familial risks (sibling/parent history) were increased for chronic kidney failure SIR = 2.02 (95% confidence interval, CI 1.90–2.14) but not for acute kidney failure SIR = 1.08 (95% CI 0.94–1.22) and for unspecified kidney failure SIR = 1.25 (95% CI 0.94–1.63). However, the discordant (different disease) familial risk for acute kidney failure SIR = 1.19 (95% CI 1.06–1.32) and unspecified kidney failure SIR = 1.63 (95% CI 1.40–1.90) was significantly increased in individuals with a family history of chronic kidney failure. The familial risk for chronic kidney failure was similar for males SIR = 2.04 (95% CI 1.90–2.20) and females SIR = 1.97 (95% CI 1.78–2.17). Familial risks for chronic kidney failure were highest at age of 10–19 years SIR = 6.33 (95% CI 4.16–9.22).
Conclusions
The present study shows that family history is an important risk factor for chronic kidney failure but to a lower degree for acute kidney failure and unspecified kidney failure.
doi:10.1371/journal.pone.0113353
PMCID: PMC4244139  PMID: 25423475
5.  Immigrant enclaves and risk of diabetes: a prospective study 
BMC Public Health  2014;14(1):1093.
Background
The diversity of the Swedish population has increased substantially over the past three decades. The aim of this study was to assess whether living in an ethnic enclave is associated with risk of diabetes mellitus (DM) among first and second-generation immigrants and native Swedes.
Methods
Cumulative incidence of DM in three urban municipalities was assessed from 2006–2010 by linking records from the national census, multi-generational family register, and prescription drug register. Immigrant enclaves were identified using Moran’s Index. Multi-level logistic regression was used to assess the relationship between enclave residence and risk of DM for three groups: Iraqi immigrants, non-Iraqi immigrants, and native Swedes (N = 887,603).
Results
The cumulative incidence of DM was greater in Iraqi enclaves compared to other neighborhoods (4.7% vs. 2.3%). Among Iraqi immigrants, enclave residence was not associated with odds of DM (Odds ratio (OR): 1.03, 95% Confidence Interval (CI): 0.86 – 1.24). Among other immigrants, enclave residence was not associated with DM after accounting for neighborhood deprivation. Among native Swedes, enclave residence was associated with elevated risk of DM even after accounting for neighborhood deprivation and individual-level characteristics (OR: 1.23, 95% CI: 1.11 – 1.36).
Conclusions
Residential ethnic composition is associated with DM but this relationship differs across ethnic group. Enclave residence is not associated with increased odds of DM for immigrants, regardless of their nation of origin, but it is associated with increased likelihood of DM for native Swedes.
doi:10.1186/1471-2458-14-1093
PMCID: PMC4221671  PMID: 25335856
6.  MORTALITY IN PERSONS WITH MENTAL DISORDERS IS SUBSTANTIALLY OVERESTIMATED USING INPATIENT PSYCHIATRIC DIAGNOSES 
Journal of psychiatric research  2013;47(10):1298-1303.
Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N=7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001–2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85–5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08–5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (~20–30%) or excluded (~25–40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies.
doi:10.1016/j.jpsychires.2013.05.034
PMCID: PMC3746500  PMID: 23806577
mental disorders; mortality; suicide
7.  Subsequent brain tumors in patients with autoimmune disease 
Neuro-Oncology  2013;15(9):1142-1150.
Background
Previous studies have reported increased risk of brain tumors after allergic conditions, but no systematic analyses of these tumors in patients with autoimmune disease (AId) have been performed. No data are available on survival among patients with AId from brain tumors. We analyzed systematically risks and survival in histological types of brain tumors among patients who received a diagnosis of 33 different AIds.
Patients and Methods
Standardized incidence ratios (SIRs) for brain tumors or hazard ratios (HRs) of deaths after brain tumors were calculated up to 2008 in 402 462 patients hospitalized for AId after 1964 and were compared with data on the population not hospitalized for AIds.
Results
Brain tumors were diagnosed in 880 patients with AId. No increased or decreased risks (SIRs) were noted for glioma, whereas the increased SIRs for meningioma after many AIds were likely to be attributable to surveillance bias. The data on survival showed overall decreases for glioma (HR, 1.15) and meningioma (HR, 1.26). The survival in both was decreased in patients with chronic rheumatic heart disease, multiple sclerosis, and rheumatoid arthritis. Overall, HRs were increased for glioma after 6 AIds and for meningioma after 7 AIds.
Conclusions
The present data showed that none of the 33 AIds influenced the risk of glioma. However, many AIds negatively influence survival in glioma and meningioma, probably through added physical burden or therapeutic limitations. Information of an existing AId in patients with newly diagnosed brain tumors should help the prognostic assessment and the design of treatment.
doi:10.1093/neuonc/not070
PMCID: PMC3748918  PMID: 23757294
comorbidity; glioma; hazard ratio; meningioma; standardized incidence ratio
8.  Depression, neighborhood deprivation and risk of type 2 diabetes 
Health & place  2013;23:63-69.
Neighborhood characteristics have been associated with both depression and diabetes, but to date little attention has been paid to whether the association between depression and diabetes varies across different types of neighborhoods. This prospective study examined the relationship between depression, neighborhood deprivation, and risk of type 2 diabetes among 336,340 adults from a national-representative sample of primary care centers in Sweden (2001–2007). Multi-level logistic regression models were used to assess associations between depression and risk of type 2 diabetes across affluent and deprived neighborhoods. After accounting for demographic, individual-level socioeconomic, and health characteristics, depression was significantly associated with risk of diabetes (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.06–1.14), as was neighborhood deprivation (OR for high vs. low deprivation: 1.66, 95% CI: 1.22–1.34). The interaction term between depression and neighborhood deprivation was non-significant, indicating that the relationship between depression and diabetes risk is similar across levels of neighborhood socioeconomic deprivation.
doi:10.1016/j.healthplace.2013.05.004
PMCID: PMC3773725  PMID: 23771166
Depression; Type 2 diabetes mellitus; Residence characteristics; Multi-level analysis; Socioeconomic factors
9.  Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders 
eLife  2014;3:e02917.
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.
DOI: http://dx.doi.org/10.7554/eLife.02917.001
eLife digest
Children learn to talk, manage their emotions, and control their behavior in a period when the brain is developing rapidly. The first signs of several developmental disorders, such as autism and attention-deficit/hyperactivity disorder (ADHD), may also emerge during this period. Children with autism may have difficulties with social interactions and communication, while those with attention-deficit/hyperactivity disorder may struggle to pay attention to a task and may be more active than other children.
Autism or ADHD are diagnosed based on the child's behavior because the underlying causes of the disorders are not well understood. Both genes and the environment have been linked to the conditions; and it was recently suggested that certain common genetic mutations are more common in children with ADHD or autism. However, as some of the mutations linked to autism are not found in the genes of the affected children's parents, it is likely that they occurred in either of the sperm or the egg cell from the parents.
Exposure to harmful substances in the environment can cause mutations in egg or sperm cells, or alter the expression of genes without changing the gene sequence. Excessive alcohol consumption is one environmental factor that can mutate genes or alter gene expression. Here, Sundquist et al. have looked to see if there is a relationship between a child having a parent with an alcohol use problem and the child's risk of developing autism or ADHD.
Examining national medical registries identified 24,157 people with autism and 49,348 with ADHD in Sweden between 1987 and 2010. Sundquist et al. discovered that autism and ADHD were more common in individuals who had a parent with a history of an alcohol use disorder than in those whose parents had no history of an alcohol use disorder. There was also an even greater risk of either condition if the parent had been diagnosed with an alcohol use problem before the birth of the child.
Adopted children who had a biological parent with an alcohol use disorder were at a greater risk of autism and ADHD than those whose adoptive parent had an alcohol use disorder. However, as very few adopted parents were diagnosed with an alcohol use problem, it is important to be cautious about drawing firm conclusions from this observation.
Sundquist et al. estimate that around 4% of autism cases and 11% of ADHD cases could be avoided if parents abstained from heavy alcohol consumption. Though these findings are consistent with parents with an alcohol use disorder being more likely to pass on mutations to their children, there are also other possible explanations. As such, further research examining the underlying cause is still needed.
DOI: http://dx.doi.org/10.7554/eLife.02917.002
doi:10.7554/eLife.02917
PMCID: PMC4135348  PMID: 25139954
autism; ADHD; alcohol use disorders; human
10.  Venous Thromboembolism and Varicose Veins Share Familial Susceptibility: A Nationwide Family Study in Sweden 
Background
Varicose veins (VVs) have been associated with venous thromboembolism (VTE), but whether these diseases share familial susceptibility has not been determined. This nationwide study aimed to determine whether VTE shares familial susceptibility with VVs.
Methods and Results
Swedish Multigeneration Register data for persons aged 0 to 76 years during the period 1964–2008 were linked to the Swedish Inpatient and Outpatient Registers. Familial risks (standardized incidence ratios [SIRs]) of VTE and VVs were examined in 2 ways (ie, bidirectionally): risk of VTE in subjects whose siblings had been diagnosed with VVs and risk of VVs in persons whose siblings had been diagnosed with VTE. The analyses were repeated for spouses to determine the importance of shared adult family environment. In total, 96 810 siblings had VVs and 87 564 had VTE. An increased risk of VTE was observed in persons whose siblings had VVs (SIR 1.30, 95% CI 1.26 to 1.33), whereas persons whose siblings had VTE had an increased risk of VVs (SIR 1.30, 95% CI 1.27 to 1.34). If 2 or more siblings were affected by VTE, the risk for VVs was 1.70 (95% CI 1.53 to 1.88). Conversely, if 2 or more siblings were affected by VVs, the risk for VTE was 1.52 (95% CI 1.38 to 1.67). In spouses of VTE patients, a minor increased risk of VVs was observed (SIR 1.05 for husbands, SIR 1.06 for wives). The risk of VTE in spouses of VV patients was similarly small (SIR 1.01 for husbands, SIR 1.05 for wives).
Conclusions
VVs and VTE share familial susceptibility. This novel finding suggests the existence of shared familial and possibly genetic factors.
doi:10.1161/JAHA.114.000850
PMCID: PMC4310366  PMID: 25158864
embolism; epidemiology; genetics; thrombosis; veins
11.  Causes of death in patients with extranodal cancer of unknown primary: searching for the primary site 
BMC Cancer  2014;14:439.
Background
Cancer of unknown primary (CUP) is a fatal cancer, accounting for 3–5% of all diagnosed cancers. Finding the primary site is important for therapeutic choices and we believe that the organ which is designated as the cause of death may give clues about the primary site.
Methods
A total of 20,570 patients with CUP were identified from the Swedish Family-Cancer Database. Causes of death – as reported in the death certificate - were investigated, analyzing reported metastatic sites and histological subtypes separately. Survival was compared with metastatic cancer with a known primary tumor.
Results
An organ-specific cancer could be identified as a cause of death in approximately 60% of all CUP patients with adenocarcinoma or undifferentiated histology. In adenocarcinoma, lung cancer was the most frequent cause of death (20%), followed by pancreatic cancer (14%), and ovarian cancer (11%). Lung cancer was the most common cause of death in patients with CUP metastases diagnosed in the nervous system (69%), respiratory system (53%), and bone (47%), whereas ovarian cancer was the most common cause of death when CUP was diagnosed in the pelvis (47%) or the peritoneum (32%). In CUP diagnosed in the liver, liver and pancreatic cancers accounted for 26% and 22% of deaths, respectively. Also in squamous cell CUP, lung cancer was the most common cause of death (45%).
Conclusions
According to the causes of death, the primary site appeared frequently to be either the organ where CUP metastases were diagnosed or an organ which may be traced through the known metastatic patterns of different cancer types.
doi:10.1186/1471-2407-14-439
PMCID: PMC4077560  PMID: 24929562
Cancer of unknown primary; CUP; Cause of death
12.  Alcohol Consumption Has a Protective Effect against Hematological Malignancies: a Population-Based Study in Sweden Including 420,489 Individuals with Alcohol Use Disorders12345 
Neoplasia (New York, N.Y.)  2014;16(3):229-234.e1.
BACKGROUND: It has been suggested that alcohol consumption is associated with increased risk of a few solid cancers, although studies that examined the association with hematological malignancies have shown inconsistent results. In this study, we examined the risk of hematological malignancies among individuals who had alcohol use disorders (AUDs) in Sweden. METHODS: Individuals with AUDs were identified from the nationwide Swedish Hospital Discharge Register and Outpatient Register, the Crime Register, and the Prescription Drug Register, and they were linked to the Swedish Cancer Registry to calculate standardized incidence ratios (SIRs) of hematological malignancies, using those Swedes without AUDs as a reference. In addition, we used a quasi-experimental sibling design to investigate the odds ratios among sibling pairs who were discordant with AUDs. RESULTS: A total of 420,489 individuals were identified with AUDs. After more than 15 million person-years of follow-up, a total of 1755 individuals developed hematological malignancies demonstrating a low risk, i.e., SIR = 0.60 (95% confidence interval = 0.57-0.63). People with AUDs had low risks for developing specific types of malignancies. The lowest risk (0.51) was for leukemia, followed by myeloma (0.52), non-Hodgkin lymphoma (0.65), and Hodgkin disease (0.71). The risk was lower among AUDs identified at an older age. The low risks of hematological malignancies were also noted using sibling analysis. CONCLUSIONS: Our data suggest that alcohol consumption has a protective effect against hematological malignancies. However, further studies are needed to identity the underlying mechanisms of the protective effect of alcohol consumption against hematological malignancies.
doi:10.1016/j.neo.2014.03.003
PMCID: PMC4094792  PMID: 24783999
13.  Incidence of Cancer in Patients With Schizophrenia and Their First-Degree Relatives: A Population-Based Study in Sweden 
Schizophrenia Bulletin  2012;39(3):527-536.
Context
Previous studies of the association between schizophrenia and cancer have produced conflicting results, probably because of the failure to control for confounding factors.
Objective
To test if the possible association between schizophrenia and cancer is genetic by investigating the incidence of cancer in patients with schizophrenia and their relatives.
Design
Retrospective cohort study with follow-up between 1965 and 2008. Estimated smoking rates were used to adjust the incidence rates of smoking-related cancers.
Participants
The entire Swedish population.
Main outcome measures
Risk of overall cancer and 34 site-/type-specific cancers.
Results
A total of 59 233 patients in Sweden with schizophrenia were identified, of whom 6137 developed cancer during the study period, giving a decreased standardized incidence ratio (SIR) of 0.79 (95% CI 0.77–0.81). The decrease was more pronounced (SIR 0.40, 95% CI 0.38–0.43) before the first diagnosis of schizophrenia. The overall risk was significantly reduced among their unaffected parents (SIR 0.96, 95% CI 0.94–0.98) and siblings (SIR 0.92, 95% CI 0.89–0.96). Sex-stratified analyses indicated different incidence rates between males and females, with female patients having higher cancer risks than the general population.
Conclusions
The significantly decreased incidences of cancers in patients diagnosed with schizophrenia and their unaffected relatives suggest that familiar/genetic factors contributing to schizophrenia may protect against the development of cancer, especially for those cancer sites observed in both settings. The increased risk of breast, cervical, and endometrial cancers after the first diagnosis of schizophrenia could be attributed to nongenetic factors such as antipsychotics administration, which may justify preventive medical screening.
doi:10.1093/schbul/sbs065
PMCID: PMC3627760  PMID: 22522642
cancer; schizophrenia; national databases
15.  Peer Deviance, Parental Divorce, and Genetic Risk in the Prediction of Drug Abuse in a Nationwide Swedish Sample 
JAMA psychiatry  2014;71(4):439-445.
IMPORTANCE
Peer deviance (PD) strongly predicts externalizing psychopathologic conditions but has not been previously assessable in population cohorts. We sought to develop such an index of PD and to clarify its effects on risk of drug abuse (DA).
OBJECTIVES
To examine how strongly PD increases the risk of DA and whether this community-level liability indicator interacts with key DA risk factors at the individual and family levels.
DESIGN, SETTING, AND PARTICIPANTS
Studies of future DA registration in 1 401 698 Swedish probands born from January 1, 1970, through December 31, 1985, and their adolescent peers in approximately 9200 small community areas. Peer deviance was defined as the proportion of individuals born within 5 years of the proband living in the same small community when the proband was 15 years old who eventually were registered for DA.
MAIN OUTCOMES AND MEASURES
Drug abuse recorded in medical, legal, or pharmacy registry records.
RESULTS
Peer deviance was associated with future DA in the proband, with rates of DA in older and male peers more strongly predictive than in younger or female peers. The predictive power of PD was only slightly attenuated by adding measures of community deprivation, collective efficacy, or family socioeconomic status. Probands whose parents were divorced were more sensitive to the pathogenic effects of high PD environments. A robust positive interaction was also seen between genetic risk of DA (indexed by rates of DA in first-, second-, and third-degree relatives) and PD exposure.
CONCLUSIONS AND RELEVANCE
With sufficient data, PD can be measured in populations and strongly predicts DA. In a nationwide sample, risk factors at the level of the individual (genetic vulnerability), family (parental loss), and community (PD) contribute substantially to risk of DA. Individuals at elevated DA risk because of parental divorce or high genetic liability are more sensitive to the pathogenic effects of PD. Although the effect of our PD measure on DA liability cannot be explained by standard measures of community or family risk, we cannot, with available data, discriminate definitively between the effect of true peer effects and other unmeasured risk factors.
doi:10.1001/jamapsychiatry.2013.4166
PMCID: PMC4002385  PMID: 24576925
16.  Association of Overweight and Elevation with Chronic Knee and Low Back Pain: A Cross-Sectional Study 
It is known that overweight is associated with chronic knee pain (CKP) and chronic low back pain (CLBP). Several risk factors for these conditions have been postulated, including age, sex, overweight, occupation, and socioeconomic factors. In addition, physical environment has been studied as a potential risk factor in recent years. However, the associations of overweight and physical environment with CKP and CLBP remains unclear. The aim of this study conducted in a rural mountainous region was to examine whether overweight individuals living at higher elevations have an increased probability of experiencing CKP and CLBP. In 2009, we conducted a mail survey with a random sample aged between 40 to 79 years. Questionnaires were sent to 6,000 individuals and a total of 4,559 individuals responded to this survey. After excluding the respondents with missing data, we conducted a logistic regression analysis of the data for 3,109 individuals. There was statistically significantly higher adjusted odds ratio (aOR) of CKP for those who were overweight living at low elevation (aOR = 1.90, 95% CI = 1.21–2.98), moderate elevation (aOR = 1.73, 95% CI = 1.05–2.87), and high elevation (aOR = 2.13, 95% CI = 1.31–3.46) than those who were not overweight living at low elevation. However, similar patterns were not observed for CLBP. Our results show that specific overweight–elevation associations were observed for CKP in a rural mountainous region.
doi:10.3390/ijerph110404417
PMCID: PMC4025028  PMID: 24758895
physical environment; overweight; chronic knee pain; chronic low back pain
17.  Preterm birth and unintentional injuries: risks to children, adolescents and young adults show no consistent pattern 
Aim
Preterm birth is associated with a number of physical and mental health issues. The aim of this study was to find out if there was also any association between individuals born preterm in Sweden between 1984 and 2006 and the risk of unintentional injuries during childhood, adolescence and young adulthood.
Methods
The study followed 2,297,134 individuals, including 5.9% born preterm, from 1985 to 2007 for unintentional injuries leading to hospitalisation or death (n=244,021). The males and females were divided into four age groups: 1–5 years, 6–12 years, 13–18 years and 19–23 years. Hazard ratios were calculated for falls, transport injuries and other injuries.
Results
After adjusting for a comprehensive set of covariates, some of the preterm subgroups demonstrated slightly increased risks of unintentional injuries, while others showed slightly decreased risks. However, most of the estimates were borderline or non-significant in both males and females. In addition, the absolute risk differences between individuals born preterm and full term were small.
Conclusion
Despite the association between preterm birth and a variety of physical and mental health consequences, this study shows that there is no consistent risk pattern between preterm birth and unintentional injuries in childhood, adolescence and young adulthood.
doi:10.1111/apa.12106
PMCID: PMC3566316  PMID: 23181809
accidents; adolescence; childhood; preterm birth; injuries
18.  Determination of 14 Circulating microRNAs in Swedes and Iraqis with and without Diabetes Mellitus Type 2 
PLoS ONE  2014;9(1):e86792.
Background
Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D.
Methods
A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR.
Results
In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017).
Conclusion
This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.
doi:10.1371/journal.pone.0086792
PMCID: PMC3907562  PMID: 24497980
19.  Effects of prescribed antithrombotics and other cardiovascular pharmacotherapies on all-cause mortality in patients with diabetes and atrial fibrillation – a cohort study from Sweden using propensity score analyses 
Aims
To study mortality rates among patients with diabetes and concomitant atrial fibrillation (AF), prescribed different cardiovascular drugs in primary health care.
Methods
Study population consisted of men (n = 1319) and women (n = 1094) aged ≥45 years from a database including 75 primary care centres in Sweden. Cox regression analysis, with hazard ratios (HRs), 95% confidence interval (95% CIs) and mortality (years to death) as outcome, and Laplace regression, with difference in time to first 10% mortality (with 95% CI), were performed. Independent variables were prescribed cardiovascular drugs. Regression models were adjusted for a propensity score calculated separately for each prescribed drug class (comprising age, cardiovascular co-morbidities, education, marital status and pharmacotherapy).
Results
Overall mortality was lower in the whole sample for anticoagulants vs no treatment (HR 0.45; 95% CI 0.26-0.77); and among patients < 80 years for anticoagulants vs. antiplatelets (HR 0.44; 95% CI 0.25-0.78); while among individuals aged ≥80 years, antiplatelets (HR 0.47; 95% CI 0.26-0.87) and anticoagulants (HR 0.49; 95% CI 0.24-1.00) vs. no treatment were equally effective. Statins were associated with lower mortality among those <80 years (HR 0.45; 95% CI 0.29-0.71). Laplace regression models in the whole sample, with years to first 10% of total mortality as outcome, were significant for: among patients < 80 years anticoagulants vs. no treatment 2.70 years (95% CI 0.04-5.37), anticoagulants vs. antiplatelets 2.31 years (95% CI 0.84-3.79), and those ≥80 antiplatelets vs. no treatment 1.78 years (95% CI 1.04-2.52).
Conclusions
Our findings suggest that antiplatelets could exert a beneficial effect among those above 80 years.
doi:10.1186/1758-5996-6-2
PMCID: PMC3892066  PMID: 24397919
Antithrombotic drugs; Statins; Pharmacotherapy; Mortality; Follow-up
20.  A healthy diet with and without cereal grains and dairy products in patients with type 2 diabetes: study protocol for a random-order cross-over pilot study - Alimentation and Diabetes in Lanzarote -ADILAN 
Trials  2014;15:2.
Background
Research on the role of nutrition in type 2 diabetes has largely focused on macro/micronutrient composition and dietary fiber intake, while fewer studies have tested the effects of differing food choice. Some observational studies and short-term intervention studies suggest that a food pattern mimicking the diet with which humans evolved positively influences glucose control and associated endocrine systems. Such a food pattern mainly differs from other common healthy food patterns in its absence of cereal grains and dairy products. The primary aim of this pilot study is to determine the effect of two healthy diets with or without cereal grains and dairy products on glucose control, while keeping participants’ weight stable and other food parameters, such as macro/micronutrient composition, dietary fiber and glycemic load, the same in both diets.
Methods/Design
We intend to include 15 adult patients with a medical diagnosis of type 2 diabetes mellitus with or without medication and with an increased waist circumference (≥ 80 cm for women and ≥ 94 cm for men) in a random-order cross-over diet intervention study during two periods of four-weeks separated by a six-week washout period. Patients will be instructed to eat two healthy diets according to official dietary guidelines with respect to macro/micronutrient composition and fiber content, but differing in the type of food included, with one diet being without cereal grains and dairy products. Lunch will be served in a hospital kitchen for control of nutrient intake, while the rest of the meals will be eaten at home according to specific directions. The energy content of the diets will be individually adjusted to maintain a stable body weight during the two four-week intervention periods. Primary outcomes will be change in fasting plasma glucagon and fructosamine, while secondary outcomes include change in fasting glucose and glycated hemoglobin, glucose and glucagon response during oral glucose tolerance test, blood lipids, blood pressure, C-reactive protein, body composition, quality of life, subjective experience with the two diets, satiety scores and changes in medication.
Discussion
Using these results, we will assess the need to conduct larger and longer studies with similar design.
Trial registration
This trial was registered at clinicaltrials.gov as NCT01891955 and Spanish Agency of Medication and Sanitary Products (AEMPS) registration code: MFV-ADI-2013-01.
doi:10.1186/1745-6215-15-2
PMCID: PMC3884016  PMID: 24383431
Protocol; Random-order cross-over trial; Type 2 diabetes mellitus; Metabolic diseases; Dietary intervention; Grain-free diet; Dairy-free diet; Glucagon; Fructosamine
21.  Perinatal and Family Risk Factors for Hodgkin Lymphoma in Childhood Through Young Adulthood 
American Journal of Epidemiology  2012;176(12):1147-1158.
The incidence of Hodgkin lymphoma has increased among adolescents and young adults in recent decades, but the relevant risk factors in early life are still unknown. A national cohort study was conducted of 3,571,574 individuals born in Sweden in 1973–2008 and followed up for Hodgkin lymphoma incidence through 2009, to examine perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood (ages 0–37 years). There were 943 Hodgkin lymphoma cases identified in 66.3 million person-years of follow-up. High fetal growth was associated with an increased risk of Hodgkin lymphoma after adjustment for gestational age at birth and other potential confounders (Ptrend = 0.005). Family history of Hodgkin lymphoma in a sibling or parent also was strongly associated with an increased risk, with adjusted hazard ratios = 8.83 (95% confidence interval: 3.67, 21.30) and 7.19 (95% confidence interval: 3.58, 14.44), respectively. No association was found between gestational age at birth, birth order, twinning, parental age, or parental education and Hodgkin lymphoma. These findings did not vary by age at Hodgkin lymphoma diagnosis. Similar associations were found for nodular sclerosis and mixed cellularity subtypes. These findings suggest that perinatal factors including possible growth factor pathways may contribute to the risk of Hodgkin lymphoma in childhood through young adulthood.
doi:10.1093/aje/kws212
PMCID: PMC3571233  PMID: 23171883
birth order; family; fetal development; gestational age; Hodgkin disease; lymphoma; maternal age
22.  Impact of yoga on blood pressure and quality of life in patients with hypertension – a controlled trial in primary care, matched for systolic blood pressure 
Background
Medical treatment of hypertension is not always sufficient to achieve blood pressure control. Despite this, previous studies on supplementary therapies, such as yoga, are relatively few. We investigated the effects of two yoga interventions on blood pressure and quality of life in patients in primary health care diagnosed with hypertension.
Methods
Adult patients (age 20–80 years) with diagnosed hypertension were identified by an electronic chart search at a primary health care center in southern Sweden. In total, 83 subjects with blood pressure values of 120–179/≤109 mmHg at baseline were enrolled. At baseline, the patients underwent standardized blood pressure measurement at the health care center and they completed a questionnaire on self-rated quality of life (WHOQOL-BREF). There were three groups: 1) yoga class with yoga instructor (n = 28); 2) yoga at home (n = 28); and 3) a control group (n = 27). The participants were matched at the group level for systolic blood pressure. After 12 weeks of intervention, the assessments were performed again. At baseline a majority of the patients (92%) were on antihypertensive medication, and the patients were requested not to change their medication during the study.
Results
The yoga class group showed no improvement in blood pressure or self-rated quality of life, while in the yoga at home group there was a decline in diastolic blood pressure of 4.4 mmHg (p < 0.05) compared to the control group. Moreover, the yoga at home group showed significant improvement in self-rated quality of life compared to the control group (p < 0.05).
Conclusions
A short yoga program for the patient to practice at home seems to have an antihypertensive effect, as well as a positive effect on self-rated quality of life compared to controls. This implies that simple yoga exercises may be useful as a supplementary blood pressure therapy in addition to medical treatment when prescribed by primary care physicians.
Trial registration
ClinicalTrials.gov (NCT01302535)
doi:10.1186/1471-2261-13-111
PMCID: PMC4029555  PMID: 24314119
Hypertension; Yoga; Quality of life; Primary health care; Complementary therapies
23.  The association between cytokines and insulin sensitivity in Iraqi immigrants and native Swedes 
BMJ Open  2013;3(11):e003473.
Objectives
To investigate the associations between cytokines and insulin sensitivity in Swedish residents born in Iraq and Swedish residents born in Sweden.
Design
Cross-sectional study.
Settings
Iraqi and Swedish origin residents of Rosengård area of Malmö, aged 45–65 years, were randomly selected from the census register.
Participants/methods
194 (Iraqi, n=107; Swedish, n=87) participants agreed to participate in the study. Nineteen participants dropped out (Iraqi, n=11; Swedish, n=8). Participants who had already been diagnosed with type 2 diabetes mellitus (T2DM), those who could not participate in an oral glucose tolerance test and those who had a cold/fever at the time of blood sampling were excluded. In total, serum samples from 135 individuals of Swedish (n=62) and Iraqi (n=73) origin were included. Serum concentrations of a panel of 10 cytokines, comprising interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, interferon-γ and tumour necrosis factor-α were analysed by Luminex multiplex assay.
Results
In the whole study population, levels of all tested cytokines were inversely associated with insulin sensitivity index (ISI), independent of age, sex, body mass index (BMI), sedentary lifestyle and family history of T2DM (p ≤ 0.05). Interestingly, stratification of the study population according to country of birth showed a significant inverse association between all tested cytokines and ISI in the Iraqi-born population (p ≤ 0.01). The association was independent of age, sex, BMI, sedentary lifestyle and family history of T2DM. In contrast, with the exception for IL-6 (p=0.05), no other tested cytokine was found to be significantly associated with ISI in the Swedish-born population (p≥0.05).
Conclusions
Our results show an association between cytokines and ISI in the Iraqi-born population but not in the Swedish-born population.
doi:10.1136/bmjopen-2013-003473
PMCID: PMC3845052  PMID: 24293202
Diabetes & Endocrinology; Molecular Biology
24.  Longitudinal age-and cohort trends in body mass index in Sweden – a 24-year follow-up study 
BMC Public Health  2013;13:893.
Background
The aim of this longitudinal study was to analyze whether mean Body Mass Index (BMI), assessed at four occasions, changed within different age groups and birth cohorts over time, i.e., between 1980/81 and 2004/05, after adjustment for possible confounders.
Methods
A sample of 2728 men and 2770 women aged 16–71 years at study start were randomly drawn from the Swedish Total Population Register and followed from 1980/81 to 2004/05. The same sample was assessed on four occasions during the 24-year study period (i.e., every eighth year). The outcome variable, BMI, was based on self-reported height and weight. A mixed model, with random intercept and random slope, was used to estimate annual changes in BMI within the different age groups and birth cohorts.
Results
Mean BMI increased from 24.1 to 25.5 for men and from 23.1 to 24.3 for women during the 24-year study period. The annual change by age group was highest in the ages of 32–39, 40–47 and 48–55 years among men, and in the ages of 24–31, 32–39, and 40–47 years among women. The highest annual changes were found in the youngest birth cohorts for both men and women, i.e., those born 1958–65, 1966–73, and 1974–81. For each birth cohort, the annual change in BMI increased compared to the previous, i.e., older, birth cohort. In addition, age-by-cohort interaction tests revealed that the increase in BMI by increasing age was higher in the younger birth cohorts (1966–1989) than in the older ones.
Conclusions
Public health policies should target those age groups and birth cohorts with the highest increases in BMI. For example, younger birth cohorts had higher annual increases in BMI than older birth cohorts, which means that younger cohorts increased their BMI more than older ones during the study period.
doi:10.1186/1471-2458-13-893
PMCID: PMC3849274  PMID: 24074433
Age; Birth cohort; Body mass index; Longitudinal data; Mixed models
25.  Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases 
BMC Medical Genetics  2013;14:88.
Background
Amyloidoses are a heterogeneous group of progressive diseases caused by tissue deposition of misfolded proteins. According to the International Classification of Diseases, hereditary amyloidosis is divided into neuropathic and non-neuropathic forms. In Sweden, neuropathic heredofamilial amyloidosis has been identified as familial amyloidotic polyneuropathy (FAP), a fatal disease that is treated by liver transplantation. The non-neuropathic form includes familial autoinflammatory diseases. As no incidence data on these hereditary diseases are available and as even diagnostic data on non-neuropathic forms are lacking we determined the incidence of these diseases and characterized non-neuropathic conditions.
Methods
Patients were identified using data from the Swedish Hospital Discharge Register and from the Outpatient Register for 2001 through 2008. All patients discharged with hereditary amyloidosis diagnoses were included and standardized incidence rates were calculated.
Results
Non-neuropathic disease was diagnosed in 210 patients, with an incidence of 2.83 per million. FAP was diagnosed in 221 patients, with an incidence of 2.02 per million. Two northern provinces that are home to 5% of the Swedish population accounted for 77% of FAP cases; the incidence in one of them, West Bothnia, was 100 times that in the rest of Sweden. Approximately 98% of non-neuropathic disease patients were immigrants, most of whom were from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500-fold higher than that in individuals with Swedish parents. Even the early onset of these conditions identified them as familial autoinflammatory diseases.
Conclusions
FAP cases were highly concentrated in the two northernmost provinces. Non-neuropathic familial autoinflammatory diseases were of early-onset and immigrant origin most likely related to periodic fever syndromes. Paradoxically, FAP has remained endemic, in spite of population movements within the country, while familial autoinflammatory diseases, with an incidence exceeding that of FAP, were brought into the country as a result of immigration mainly from the Eastern Mediterranean area.
doi:10.1186/1471-2350-14-88
PMCID: PMC3766062  PMID: 24138840
Hospitalization; Heritable amyloidosis; Periodic fever syndrome; Mutation

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