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Background As opposed to the decreasing overall rates of coronary heart disease (CHD) incidence and overall cardiovascular disease (CVD) mortality, heart failure (HF) and stroke incidence are increasing in young people, potentially due to rising rates of obesity and reduced cardiorespiratory fitness (CRF). Objectives We investigated trends in early major CVD outcomes in a large cohort of young men. Methods Successive cohorts of Swedish military conscripts from 1971 to 1995 (N = 1,258,432; mean age, 18.3 years) were followed, using data from the National Inpatient and Cause of Death registries. Cox proportional hazard models were used to analyse changes in 21-year CVD event rates. Results 21-year CVD and all-cause mortality and incidence of acute myocardial infarction (AMI) decreased progressively. Compared with the cohort conscripted in 1971-1975 (reference), the hazard ratios (HRs) for the last 1991-1995 cohort were 0.50 [95% confidence interval (CI) 0.42-0.59] for CVD mortality; 0.57 (95% CI 0.54-0.60) for all-cause mortality; and 0.63 (95% CI 0.53-0.75) for AMI. In contrast, the incidence of ischaemic stroke, intracerebral haemorrhage and HF increased with HRs of 1.43 (95% CI 1.17-1.75), 1.30 (95% CI 1.01-1.68) and 1.84 (95% CI 1.47-2.30), respectively. During the period, rates of obesity increased from 1.04% to 2.61%, whilst CRF scores decreased slightly. Adjustment for these factors influenced these secular trends only moderately. Conclusion Secular trends of young-onset CVD events demonstrated a marked shift from AMI and CVD mortality to HF and stroke incidence. Trends were significantly, though moderately, influenced by changing baseline BMI and CRF.

Systemic inflammation may be implicated in the pathophysiology of Parkinson’s disease (PD). Since PD occurs usually in later life, most studies of causal factors are conducted in older populations, so potentially important influences from early life cannot be adequately captured. We investigated whether the erythrocyte sedimentation rate (ESR) in early adulthood is associated with the subsequent development of PD in men. As part of Swedish national conscription testing conducted from 1968 through 1983 (N = 716,550), the erythrocyte sedimentation rate, as a measure of inflammation, was measured in 659,278 young men. The cohort was observed for subsequent PD events (N = 1513) through December 2016. Cox proportional hazards models were used to estimate the hazard ratios (HR) with 95% CI with adjustment for potential confounders. Individuals with higher ESRs were significantly less likely to be diagnosed with PD, as ESR was linearly and inversely associated with PD risk. The magnitude of the association between ESR and PD risk was similar for increases up to 15 mm/h, leveled off thereafter, and was non-significant for ESR values > 20 mm/h. The HR for PD with basic adjustments (age at conscription, year of conscription, test center and erythrocyte volume fraction) was 0.94 (95% CI 0.89–0.99, P = 0.02) per log2 increase in ESR, corresponding to a two-fold increase in ESR. Further adjustments for potential confounders (parental education, systolic and diastolic blood pressures, and IQ) scarcely altered the HR. The results suggest a prospective association between high ESR and reduced risk for PD.

Aims This study aims to investigate the association of resting heart rate (RHR) measured in late adolescence with long‐term risk of cause‐specific heart failure (HF) and subtypes of cardiomyopathy (CM), with special attention to cardiorespiratory fitness. Methods and results We performed a nation‐wide, register‐based cohort study of all Swedish men enrolled for conscription in 1968–2005 (n = 1 008 363; mean age = 18.3 years). RHR and arterial blood pressure were measured together with anthropometrics as part of the enlistment protocol. HF and its concomitant diagnoses, as well as all CM diagnoses, were collected from the national inpatient, outpatient, and cause of death registries. Risk estimates were calculated by Cox‐proportional hazards models while adjusting for potential confounders. During follow‐up, there were 8400 cases of first hospitalization for HF and 3377 for CM. Comparing the first and fifth quintiles of the RHR distribution, the hazard ratio (HR) for HF associated with coronary heart disease, diabetes, or hypertension was 1.25 [95% confidence interval (CI) = 1.13–1.38] after adjustment for body mass index, blood pressure, and cardiorespiratory fitness. The corresponding HR was 1.43 (CI = 1.08–1.90) for HF associated with CM and 1.34 (CI = 1.16–1.54) for HF without concomitant diagnosis. There was an association between RHR and dilated CM [HR = 1.47 (CI = 1.27–1.71)] but not hypertrophic, alcohol/drug‐induced, or other cardiomyopathies. Conclusions Adolescent RHR is associated with future risk of HF, regardless of associated aetiological condition. The association was strongest for HF associated with CM, driven by the association with dilated CM. These findings indicate a causal pathway between elevated RHR and myocardial dysfunction that warrants further investigation.

BACKGROUND As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long-term risks associated with adolescent obesity. OBJECTIVES This study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE). METHODS Nationwide register-based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to

Aim Wesought to study the association of alcohol consumption with the long-term risk of heart failure and all-cause mortality among adolescent men. Method We included 50 460 men (mean age 18.4 years; SD 0.72) that underwent enlistment for military service during 1968–1969. During this period, alcohol consumption was assessed with questionnaires as part of the enlistment protocol. Questionnaire data was transformed to grams of 100% ethanol/week and categorized as light (1–100 g/week), moderate (101–250 g/week), and high (>250 g/week). Follow-up was done through linkage to the nationwide Swedish patient- and cause of death registries. Risk of heart failure and all-cause mortality during follow-up was calculated with cox proportional hazard models, adjusted for age, conscription year, test centre, body mass index, systolic and diastolic blood pressure, parental education, intelligence quotient, cardiorespiratory fitness and muscle strength, and baseline comorbidities (diabetes mellitus and hypertension). Results During a median follow-up of 51 years, there were 803 incidentheart failure events (mean age at diagnosis, 61 years) and 6254 deaths (mean age: 55 years). Compared with non-drinkers (0 g/week), the adjusted hazard ratios (HR) for light, moderate and high alcohol consumption were 2.34 (1.24–4.40), 2.38 (1.22–4.68), 5.60 (2.68–11.69) for incident heart failure (Figure 1, model 4)and 1.27 (1.04–1.54), 1.66 (1.35–2.05), 2.25 (1.74–2.91) for all-cause mortality,respectively. Conclusion Alcohol consumption in adolescence is strongly associated with heart failure and all-cause mortality in adulthood. Our results suggests that even light alcohol consumption in adolescence is associated with higher long-term risk of heart failure and mortality. Funding Acknowledgement Type of funding sources: None. Figure 1. *Model 1 adjusted for age at conscription, conscription year, test center, body mass index and baseline comorbidities (diabetes mellitus and hypertension). †Model 2 as model 1 but additionally adjusted for systolic and diastolic blood pressure at baseline. ‡Model 3 as model 2 but additionally adjusted for parental education. #Model 4 as model 3 but additionally adjusted for intelligence quotient, cardiorespiratory fitness and muscle strength.

Background There is a need for high-quality research regarding exercise interventions for persons with anxiety disorders. We investigate whether a 12-week exercise intervention, with different intensities, could reduce anxiety symptoms in patients with anxiety disorders. Methods 286 patients were recruited from primary care in Sweden. Severity of symptoms was self-assessed using the Beck Anxiety Inventory (BAI) and the Montgomery Asberg Depression Rating Scale (MADRS-S). Participants were randomly assigned to one of two group exercise programs with cardiorespiratory and resistance training and one control/standard treatment non-exercise group, with 1:1:1 allocation. Results Patients in both exercise groups showed larger improvements in both anxiety and depressive symptoms compared to the control group. No differences in effect sizes were found between the two groups. To study a clinically relevant improvement, BAI and MADRS-S were dichotomized with the mean change in the control group as reference. In adjusted models the odds ratio for improved symptoms of anxiety after low-intensity training was 3.62 (CI 1.34–9.76) and after moderate/high intensity 4.88 (CI 1.66–14.39), for depressive symptoms 4.96 (CI 1.81–13.6) and 4.36 (CI 1.57–12.08) respectively. There was a significant intensity trend for improvement in anxiety symptoms. Limitations The use of self-rating measures which bears the risk of an under- or overestimation of symptoms. Conclusions A 12-week group exercise program proved effective for patients with anxiety syndromes in primary care. These findings strengthen the view of physical exercise as an effective treatment and could be more frequently made available in clinical practice for persons with anxiety issues.

BackgroundRecent reports show alarmingly high rates of suicide in middle-aged men, yet there are few long-term prospective studies that focus on suicidal behaviour in men in this age group.AimsTo prospectively explore associations of potential risk factors at age 18 with suicide and self-harm in middle-aged men.MethodA population-based Swedish longitudinal cohort study of male conscripts with no history of self-harm at enlistment in 1968–1989 (n= 987 583). Conscription examinations included measures of cognitive performance, stress resilience, psychiatric diagnoses, body mass index (BMI), cardiovascular fitness and muscle strength. Suicides and self-harm at age 45–65 years were identified in the National Hospital Register and Swedish Cause of Death Register. Risks were calculated using Cox proportional hazards models.ResultsLow stress resilience (cause-specific hazard ratio CHR = 2.31, 95% CI 1.95–2.74), low cognitive ability (CHR = 2.01, 95% CI 1.71–2.37) as well as psychiatric disorders and low cardiovascular fitness in late adolescence were associated with increased risk for suicide in middle-aged men. Similar risk estimates were obtained for self-harm. In addition, high and low BMI as well as low muscle strength were associated with increased risk of self-harm. Associations also remained significant after exclusion of men with self-harm before age 45.ConclusionsThis prospective study provides life-course perspective support that psychological and physical characteristics in late adolescence may have long-lasting consequences for suicidal behaviour in middle-aged men, a very large population at heightened risk of suicide.

Background Anxiety disorders are common and associated with reduced quality of life, impaired physical and mental health and an increased economic burden for society. While evidence exists for the effectiveness of exercise treatment for depression, there is a need for high-quality randomized clinical trials (RCT) with a focus on anxiety disorders. Further research is also warranted regarding outcomes of cognitive function, other health-related variables, dose-response effects, work ability and potential mechanisms. Method/design Using a parallel, RCT design with three assessment points (baseline, post-intervention and one-year follow-up), we aim to assess the effect of a 12-week exercise intervention in primary care patients with anxiety disorders (n = 180), diagnosed using the Mini International Neuropsychiatric Interview (M.I.N.I; Swedish version 6.0.0d DSM-IV). Participants are randomly assigned to three physical exercise groups: one low-intensity training group, one moderate- to high intensity training group and one control non-exercise group. Assessments include measures of anxiety symptoms, cognitive function, physical health variables such as cardiovascular fitness, sick-leave and levels of hormones/cytokines in blood samples. Discussion Findings from this study will provide novel insights regarding the effects of exercise treatment on not only anxiety symptoms but also other outcomes including mental and physical health, cognitive function, dose-response effects, work ability/sick leave and on biomarkers that may help explain underlying mechanisms. Trial registration The trial was registered at ClinicalTrial.gov NCT03247270 August 8, 2017. Electronic supplementary material The online version of this article (10.1186/s12888-019-2169-5) contains supplementary material, which is available to authorized users.

In recent years, evidence for hemoglobin (Hb) synthesis in both animal and human brains has been accumulating. While circulating Hb originating from cerebral hemorrhage or other conditions is toxic, there is also substantial production of neuronal Hb, which is influenced by conditions such as ischemia and regulated by growth hormone (GH), insulin-like growth factor-I (IGF-I), and other growth factors. In this review, we discuss the possible functions of circulating and brain Hb, mainly the neuronal form, with respect to the neuroprotective activities of GH and IGF-I against ischemia and neurodegenerative diseases. The molecular pathways that link Hb to the GH/IGF-I system are also reviewed, although the limited number of reports on this topic suggests a need for further studies. In summary, GH and/or IGF-I appear to be significant determinants of systemic and local brain Hb concentrations through mediating responses to oxygen and metabolic demand, as part of the neuroprotective effects exerted by GH and IGF-I. The nature and quantity of the latter deserve further exploration in specific experiments.

Supplemental Digital Content is available in the text., Background: Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy. Methods: This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18–45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers. Results: In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m2, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81–7.89) was found for severely obese subjects (BMI ≥35 kg/m2), as compared with BMI 20 to

ObjectiveTo investigate the possible connection between cardiorespiratory fitness (CRF) and muscle strength in early adulthood and severity of COVID-19 later in life.DesignProspective registry-based cohort study.Participants1 559 187 Swedish men, undergoing military conscription between 1968 and 2005 at a mean age of 18.3 (SD 0.73) years.Main outcome measuresHospitalisation, intensive care or death due to COVID-19 from March to September 2020, in relation to CRF and muscle strength.ResultsHigh CRF in late adolescence and early adulthood had a protective association with severe COVID-19 later in life with OR (95% CI) 0.76 (0.67 to 0.85) for hospitalisation (n=2 006), 0.61 (0.48 to 0.78) for intensive care (n=445) and 0.56 (0.37 to 0.85) for mortality (n=149), compared with the lowest category of CRF. The association remains unchanged when controlled for body mass index (BMI), blood pressure, chronic diseases and parental education level at baseline, and incident cardiovascular disease before 2020. Moreover, lower muscle strength in late adolescence showed a linear association with a higher risk of all three outcomes when controlled for BMI and height.ConclusionsPhysical fitness at a young age is associated with severity of COVID-19 many years later. This underscores the necessity to increase the general physical fitness of the population to offer protection against future viral pandemics.

The endogenous secretion of growth hormone (GH) is sexually dimorphic in rats with females having a more even and males a more pulsatile secretion and low trough levels. The mode of GH administration, mimicking the sexually dimorphic secretion, has different systemic effects. In the brains of male rats, we have previously found that the mode of GH administration differently affects neuron–haemoglobin beta (Hbb) expression whereas effects on other transcripts were moderate. The different modes of GH administration could have different effects on brain transcripts in female rats. Hypophysectomised female rats were given GH either as injections twice daily or as continuous infusion and GH-responsive transcripts were assessed by quantitative reverse transcription polymerase chain reaction in the hippocampus and parietal cortex (cortex). The different modes of GH-administration markedly increasedHbband 5′-aminolevulinate synthase 2 (Alas2) in both brain regions. As other effects were relatively moderate, a mixed model analysis (MMA) was used to investigate general effects of the treatments. In the hippocampus, MMA showed that GH-infusion suppressed glia- and neuron-related transcript expression levels, whereas GH-injections increased expression levels. In the cortex, GH-infusion instead increased neuron-related transcripts, whereas GH-injections had no significant effect. Interestingly, this contrasts to previous results obtained from male rat cortex where GH-infusion generally decreased expression levels. In conclusion, the results indicate that there is a small but significant difference in response to mode of GH administration in the hippocampus as compared to the cortex. For both modes of GH administration, there was a robust effect onHbbandAlas2.

Background/Introduction Elevated resting heart rate (RHR) is a known risk factor for HF. Whether elevated RHR is also associated with cardiomyopathy (CM), a common cause of heart failure in the young, is unknown. Purpose To investigate the association of resting heart rate (RHR) measured in late adolescence with long term risk of various subtypes of CM with special attention to cardiorespiratory fitness (CRF), an important predictor of RHR and myocardial dysfunction. Methods We followed a cohort of Swedish men enrolled for conscription in 1968–2005 (n=1,008,485; mean age=18.3 years) until December 2014. Outcomes of CM were collected from the national inpatient- (IPR), outpatient- (OPR) and cause of death registries and were divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Cox proportional hazard models were used to analyze the longitudinal association between RHR and outcomes while adjusting for potential confounders, including body mass index (BMI), arterial blood pressure and cardiorespiratory fitness (CRF). CRF was measured by maximum capacity ergometer testing as part of the enlistment protocol. Results During a mean follow up of 34 years, there were 3500 cases of a first hospitalization for CM (mean age at diagnosis, 50.1 years). Comparing the highest with the lowest quintile of the RHR distribution, we found a positive association between RHR and dilated CM (hazard ratio (HR) = 1.58 [confidence interval (CI) = 1.37–1.82]) after adjustment for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). There no significant association with alcohol/drug-induced (HR=1.32 [CI=0.94–1.85]) or other categories of CM. Conclusion Adolescent RHR is associated with future risk CM, independently of blood pressure, BMI and CRF. The association was driven by dilated CM. These findings are suggestive of a causal pathway between elevated heart rate and adverse cardiac remodeling that warrants further investigation. Acknowledgement/Funding The Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare

Background Increasing numbers of stroke cases in the young are reported in many countries, potentially at least partly due to rising rates of overweight and obesity. Most data on the effect of obesity on stroke is derived from middle aged populations; there is a comparative lack of information on the effect of excessive body weight in young people. Purpose We aimed to determine whether body mass index (BMI) at age 18 predicted early stroke events among men in Sweden. Methods Population-based Swedish cohort study of conscripts (n=1,668,921; mean age at baseline, 18.3 years) who enlisted during 1968–2005. Follow-up was done through linkage to the nationwide Swedish patient and death registries. Risk of a first hospitalization for stroke (any type) during follow-up (5–46 years) was calculated with Cox proportional hazards models. Objective baseline measures of fitness and cognition were included in the models in a second set of analyses. Results During follow-up there were 12,512 first hospitalizations for stroke (mean age at diagnosis, 48.5 (SD 9.4) years, maximum 64 years). Compared with men with BMI of 18.5 to 20.0 kg/m2, men with BMI 20 to Conclusion We found a rise in risk of early hospitalisation for stroke detectable already at normal levels of body weight at age 18, and rising to more than 3-fold in the highest weight category. Given increasing levels of body weight, and prevalence of overweight, obesity, and severe obesity in young adults, the increased incidence of stroke in the young may potentially partly be explained by rising body weight, with an obvious potential for prevention.

Background Cardiovascular disease (CVD) mortality is decreasing in Western countries, including Sweden. However, there are reports of increases in incidence in young people with respect to heart failure (HF) and atrial fibrillation (AF). The magnitude and causes of these changes are only partly known. Aims We investigated secular trends in incidence in CVD outcomes and their attenuation by changes in body mass index (BMI). The outcomes were risk of acute myocardial infarction (AMI), heart failure (HF) and atrial fibrillation (AF) as well as cardiovascular and all-cause death in a population of Swedish adolescents. Methods We followed a cohort of Swedish men enrolled for military service conscription in 1969–1996 (n=1,326,082; mean age=18.3) until December 2016, collected from the national inpatient (IPR) and outpatient registries (OPR). Cox-proportional hazard models were used to analyse the longitudinal change in incidence by with respect to early (0–21 years) of follow-up for subgroups with conscription 1968–1971, 1971–1976, 1976–1981, 1981–1986, 1986–1991, 1991–1996 (with the group born 1971–1976 as reference). Adjustments for potential confounders including BMI were performed. Results We found that CVD and all-cause mortality and MI decreased progressively during the follow-up with hazard ratios (HR) of 0.51, 95% confidence interval (CI) 0.43–0.62, HR 0.51 CI 0.57–0.62, and 0.60 CI 0.50–0.72, respectively. In contrast, we found increases in the incidence of HF (HR 1.86, CI 1.48–2.33], and AF (HR 8.26, CI 6.87–9.92). Adjustments for changes in BMI partly attenuated the changes in secular trends. Cubic spline models showed where the changes in secular trends were most prominent. Conclusion The incidences of cardiovascular outcomes show diverging secular changes. While MI and cardiovascular mortality are continually decreasing, there is an increase in HF and AF. The associations appear to be partly explained by changes in index BMI over time. Acknowledgement/Funding grants from the Swedish Government and the county councils, the ALF–GBG-719761, ALFGBG-751111, Swedish Stroke Association, Göteborg Medical Society

Background Cardiorespiratory fitness and physical activity have well–known cardio–protective effects. Along with reports on declining levels of physical activity globally, heart failure caused by cardiomyopathy is increasing among young people. Still, it is unknown whether poor fitness in adolescence can be associated with cardiomyopathy in adulthood. Purpose To study a possible link between cardiorespiratory fitness in adolescence and being diagnosed with cardiomyopathy in adulthood. Methods A nationwide register-based prospective cohort study of 1,668,893 young men (mean age 18.3 years, SD 0.7), enlisting for compulsory military service 1969–2005. Body mass index (BMI) and blood pressure were registered at baseline, along with test results for fitness. Values were trichotomized and about 13.5% were classified as having poor cardiorespiratory fitness. Cardiomyopathy diagnoses were identified from the National Hospital Register and Cause of Death Register, during an up to 46-year follow-up, and divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Hazard ratios (HR) were calculated with Cox proportional hazards models. Results During follow-up (median 27 years; interquartile interval 19–35 years), 4,477 cases of cardiomyopathy were registered, of which 2,631 (59%) were dilated, 673 (15%) were hypertrophic, and 480 (11%) were alcohol/drug-induced. Poor cardiorespiratory fitness was strongly associated with elevated risk of both dilated (HR 1.59, 95% confidence interval (CI) 1.38–1.83) and alcohol/drug–induced cardiomyopathy (HR 2.32, 95% CI 1.68–3.20), adjusted for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). Conclusion The present study shows that poor cardiorespiratory fitness in adolescence may be associated with both dilated and alcohol/drug–induced cardiomyopathy in adulthood. This strengthens the evidence of fitness as a cardio–protective factor, and brings further support to the importance of interventions promoting physical activity already in childhood. Acknowledgement/Funding The Swedish Research Council, The Swedish Heart and Lung Foundation

Background To improve cardiovascular disease (CVD) prevention, knowledge of early key risk factors, especially those that are modifiable such as overweight and obesity, is essential. Purpose We aimed to determine whether body mass index (BMI) at age 18 predicted early acute coronary events among men in Sweden. Methods Population-based Swedish cohort study of conscripts (n=1,668,921; mean age at baseline, 18.3 years) who enlisted during 1968–2005. Follow-up was done through linkage to the nationwide Swedish patient- and death registries. Risk of an acute coronary event (hospitalization for acute myocardial infarction or coronary death) during follow-up (5–46 years) was calculated with Cox proportional hazards models. Objective baseline measures of fitness and cognition were included in the models in a second set of analyses. Results During follow-up there were 22,412 acute coronary events (mean age at diagnosis, 50.2 (SD 7.4) years, maximum 64 years). Compared with men with BMI of 18.5 to 20.0 kg/m2, men with BMI 20 to Conclusion We found a rise in risk of an early acute coronary event detectable already at normal levels of body weight at age 18, and rising to more than 3-fold in the highest weight category. Given increasing levels of body weight, and prevalence of overweight and obesity in young adults, the current decrease in coronary heart disease incidence in Sweden may flatten or even reverse in the near future. Acknowledgement/Funding The Swedish Heart and Lung Foundation [2015-0438]; the Swedish Research Council [2013-5187,2013-4236]

Objectives: To examine the longitudinal relationship between cardiovascular fitness in young adult men and future risk of migraine and to estimate eventual differential effects among categories of body mass index (BMI) and blood pressure. Design: National, prospective, population-based cohort study. Setting: Sweden 1968–2014. Participants: 18-year-old Swedish men (n=1 819 828) who underwent mandatory military conscription examinations during the years 1968–2005. Primary and secondary outcomes: The primary outcome was the first dispensation of prescribed migraine-specific medication, identified using the Swedish Prescribed Drug Register. The secondary outcome was documented migraine diagnosis from the Swedish National Hospital Register. Results: During follow-up, 22 533 men filled a prescription for migraine-specific medication. After confounding adjustment, compared with high cardiovascular fitness, low and medium fitness increased the risk of migraine-specific medication (risk ratio (RR)low: 1.29, 95% CI 1.24 to 1.35; population attributable fraction: 3.6%, 95% CI 1.7% to 5.3% and RRmedium: 1.15, 95% CI 1.12 to 1.19; population attributable fraction: 8.0%, 95% CI 4.0% to 11.7%). To assess potential effect measure modification, stratified analyses of these association by levels of BMI and blood pressure showed that lower fitness levels increased risk of migraine across all groups except among underweight men or men with high diastolic blood pressure. Conclusions: Young men with a lower cardiovascular fitness had a higher long-term risk of developing pharmacological prescription-requiring migraine. This study contributes with information regarding risk factors for migraine in men, an understudied population in migraine research. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Background The association of serum insulin-like growth factor I (s-IGF-I) with favorable outcome after ischemic stroke (IS) beyond 2 years is unknown. We investigated whether the levels of s-IGF-I 3 months post-stroke were associated with functional recovery up to 7 years after IS, considering also mortality and recurrent strokes. Methods Patients (N=324; 65% males; mean age, 55 years) with s-IGF-I levels assessed 3 months after the index IS were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The modified Rankin Scale (mRS) was used to evaluate outcomes at 3 months, 2 and 7 years after IS, and recovery was defined as an improvement, no change, or deterioration in the shifts of mRS score. Baseline stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS). Results The mRS score distributions were better in the above-median s-IGF-I group (>146.7 ng/ml). The s-IGF-I level was not associated with recurrent stroke (N=79) or death (N=44), although it correlated with recovery (r=0.12, P=0.035). In the regression analysis, s-IGF-I associated with recovery between 3 months and 7 years (but not between 2 and 7 years). The associations did not withstand adjustment for age and sex. For comparison, the corresponding associations between 3 months and 2 years withstood all adjustments. Conclusion The association for s-IGF-I with long-term post-stroke recovery persists after 7 years, which is also reflected in the mRS score distributions at all time-points. The effects are however modest, and not driven by mortality or recurrent stroke.

Background and Purpose— Although the incidence of stroke is on the decline worldwide, this is not the case for early stroke. We aimed to determine whether nonpsychotic mental disorder at the age of 18 years is a risk factor for early stroke, and if adolescent cardiovascular fitness and intelligence quotient might attenuate the risk. Method— Population-based Swedish cohort study of conscripts (n=1 163 845) who enlisted during 1968 to 2005. At conscription, 45 064 males were diagnosed with nonpsychotic mental disorder. Risk of stroke during follow-up (5–42 years) was calculated with Cox proportional hazards models. Objective baseline measures of fitness and cognition were included in the models in a second set of analyses. Results— There were 7770 first-time stroke events. In adjusted models, increased risk for stroke was observed in men diagnosed with depressive/neurotic disorders (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11–1.37), personality disorders (HR, 1.52; 95% CI, 1.29–1.78), and alcohol/substance use disorders (HR, 1.61; 95% CI, 1.41–1.83) at conscription. Corresponding figures for fatal stroke were HR, 1.38; 95% CI, 1.06 to 1.79; HR, 2.26; 95% CI, 1.60 to 3.19; and HR, 2.20; 95% CI, 1.63 to 2.96. HRs for stroke were attenuated when fitness level and intelligence quotient were introduced. Associations remained significant for personality disorders and alcohol/substance use in the fully adjusted models. The interaction term was statistically significant for fitness but not for intelligence quotient. Conclusions— Our findings suggest that fitness may modify associations between nonpsychotic disorders and stroke. It remains to be clarified whether interventions designed to improve fitness in mentally ill youth can influence future risk of early stroke.

Growth hormone (GH) increases insulin-like growth factor I (IGF-I) production and both hormones affect hippocampal plasticity. We have previously shown that Hbb and Alas2 in the rat hippocampus were robustly regulated by GH-infusions for six days, whereas other transcripts were weakly affected. Here, we explored the effects of prolonged GH administration on transcripts linked to neuroprotection and investigated whether serum IGF-I administration may exert similar effects.Hypophysectomised female rats were infused with GH or IGF-I for 19 days. Hbb, Alas2 and seven additional GH- and IGF-I-related transcripts were quantified by Q-RT-PCR in rat hippocampus.Three transcripts, Hbb, Alas2, and Alox15 were increased by both GH and IGF-I administration. The other transcripts were marginally affected.The 19-day GH-infusion induced similar effects as those reported after 6-day GH treatment, with the addition of the regulation of transcript Alox15. IGF-I induced altered gene expression in relation to its effect on weight gain. This study underlines that there is an entity of transcripts involved in neuroprotection and vascular tone that is regulated by both systemic GH and IGF-I. For other transcripts, the longer duration of this study did not significantly enhance the marginal effects of GH administration seen previously.

BackgroundWhile risk of premature death is most pronounced among persons with severe mental illness, also milder conditions are associated with increased all-cause mortality. We examined non-psychotic mental (NPM) disorders and specific causes of natural death in a cohort of late adolescent men followed for up to 46 years.MethodsProspective cohort study of Swedish males (n=1 784 626) who took part in structured conscription interviews 1968–2005. 74 525 men were diagnosed with NPM disorders at or prior to conscription. Median follow-up time was 26 years. HRs for cause-specific mortality were calculated using Cox proportional hazards models.ResultsRisks in fully adjusted models were particularly elevated for death by infectious diseases (depressive and neurotic/adjustment disorders (HR 2.07; 95% CI 1.60 to 2.67), personality disorders (HR 2.90; 95% CI 1.96 to 4.28) and alcohol-related and other substance use disorders (HR 9.02; 95% CI 6.63 to 12.27)) as well as by gastrointestinal causes (depressive and neurotic/adjustment disorders (HR 1.64; 95% CI 1.42 to 1.89), personality disorders (HR 2.77; 95% CI 2.27 to 3.38) and alcohol-related/substance use disorders (HR 4.41; 95% CI 3.59 to 5.42)).ConclusionYoung men diagnosed with NPM disorders had a long-term increased mortality risk, in particular due to infectious and gastrointestinal conditions. These findings highlight the importance of early preventive actions for adolescents with mental illness.

Recurrent headache, abdominal and musculoskeletal pain are common in adolescents and it is therefore important to understand their impact on the transitional period from childhood to adulthood. However, studies of the prevalence over time and implications on educational outcomes are still limited, especially regarding multiple pain symptoms. The present study material consists of questionnaire surveys, completed in 2000 and 2008, including two study populations of 9th grade adolescents aged 15 living in West Sweden (n = 20 877). Pain symptoms and demographic variables were based on self-reports from the questionnaires, and school grades were obtained from Statistics Sweden after the student had finished their 9th grade. Between 2000 and 2008, the prevalence of abdominal pain increased among Swedish adolescents (largest increase in girls); the prevalence of headache increased only in girls; the prevalence of pain in upper body decreased only in boys. School grades were significantly lower among those with headache or abdominal pain. Among students with low school grades (10th percentile) the estimated difference between those having any of the symptoms or none were -27 school grade units (95% confidence interval for girls (-27.8; -26.0), for boys (-27.6; -25.5). Both symptoms being present pronounced the association. Low parental education increased the negative effect of symptoms on school grades, most pronounced in the group with the lowest grades. In conclusion, identification of pain symptoms may improve academic achievements, especially in students with multiple symptoms and with parents having low education. Further intervention studies are need.

Background and Purpose— Low cardiovascular fitness (fitness) in mid- and late life is a risk factor for stroke. However, the respective effects on long-term stroke risk of fitness and muscle strength in early adulthood are unknown. Therefore, we analyzed these in a large cohort of young men. Method— We performed a population-based longitudinal cohort study of Swedish male conscripts registered in 1968 to 2005. Data on fitness (by the cycle ergometric test; n=1 166 035) and muscle strength (n=1 563 750) were trichotomized (low, medium, and high). During a 42-year follow-up, risk of stroke (subarachnoidal hemorrhage, intracerebral hemorrhage, and ischemic stroke) and fatality were calculated with Cox proportional hazards models. To identify cases, we used the International Classification of Diseases - Eighth to Tenth Revision in the Hospital Discharge Register and the Cause of Death Register. Results— First-time stroke events were identified (subarachnoidal hemorrhage, n=895; intracerebral hemorrhage, n=2904; ischemic stroke, n=7767). For all stroke and fatality analysis any type of first-time stroke was recorded (n=10 917). There were inverse relationships in a dose–response fashion between fitness and muscle strength with any stroke (adjusted hazard ratios for the lowest, compared with the highest, tertile of each 1.70 [1.50–1.93] and 1.39 [1.27–1.53], respectively). There were stronger associations for fatal stroke. All 3 stroke types displayed similar associations. Associations between fitness and stroke remained when adjusted for muscle strength, whereas associations between muscle strength and stroke weakened/disappeared when adjusted for fitness. Conclusions— At the age of 18 years, low fitness and to a lesser degree low muscle strength were independently associated with an increased future stroke risk.

BackgroundCardiovascular fitness in late adolescence is associated with future risk of depression. Relationships with other mental disorders need elucidation. This study investigated whether fitness in late adolescence is associated with future risk of serious non-affective mental disorders. Further, we examined how having an affected brother might impact the relationship.MethodProspective, population-based cohort study of 1 109 786 Swedish male conscripts with no history of mental illness, who underwent conscription examinations at age 18 between 1968 and 2005. Cardiovascular fitness was objectively measured at conscription using a bicycle ergometer test. During the follow-up (3–42 years), incident cases of serious non-affective mental disorders (schizophrenia and schizophrenia-like disorders, other psychotic disorders and neurotic, stress-related and somatoform disorders) were identified through the Swedish National Hospital Discharge Register. Cox proportional hazards models were used to assess the influence of cardiovascular fitness at conscription and risk of serious non-affective mental disorders later in life.ResultsLow fitness was associated with increased risk for schizophrenia and schizophrenia-like disorders [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.29–1.61], other psychotic disorders (HR 1.41, 95% CI 1.27–1.56), and neurotic or stress-related and somatoform disorders (HR 1.45, 95% CI 1.37–1.54). Relationships persisted in models that included illness in brothers.ConclusionsLower fitness in late adolescent males is associated with increased risk of serious non-affective mental disorders in adulthood.

Recent research suggests that the incidence of amyotrophic lateral sclerosis (ALS) may be on the rise. Since ALS becomes predominant in later life, most studies on causal factors are conducted in middle-aged or older populations where potentially important influences from early life can usually not be adequately captured. We aimed to investigate predictors in young Swedish men for ALS in adulthood. Therefore, we performed a prospective cohort study of young men (aged 16–25, n = 1,819,817) who enlisted 1968–2005 and took part in comprehensive conscription examinations. Incident cases of ALS (n = 526) during up to 46 years of follow-up were identified in the National Hospital Register and Swedish Cause of Death Register. Those who developed ALS had lower BMI (body mass index) at conscription than their peers (p = 0.03). The risk of ALS during follow-up was calculated with Cox proportional hazards models. No associations were found with physical fitness, erythrocyte sedimentation rate, or non-psychotic mental disorders. Low overall muscle strength compared to high overall muscle strength [hazard ratio (HR) 1.36; 95% confidence interval (CI) 1.01–1.83] and low BMI (a one-unit increase HR 0.96; 95% CI 0.93–0.99) and lower erythrocyte volume fraction (a one-unit increase HR 0.96; 95% CI 0.92–0.998) were the statistically significant predictors for ALS in adjusted models. These findings provide novel epidemiologic evidence of a prospective association between low overall muscle strength and erythrocyte volume fraction in young men and ALS risk.

Aims To investigate the association between cardiorespiratory fitness (CRF) and muscle strength in late adolescence and the long-term risk of heart failure (HF). Methods A cohort was created of Swedish men enrolled in compulsory military service between 1968 and 2005 with measurements for CRF and muscle strength ( n = 1,226,623; mean age 18.3 years). They were followed until 31 December 2014 for HF hospitalization as recorded in the Swedish national inpatient registry. Results During the follow-up period (median (interquartile range) 28.4 (22.0-37.0) years), 7656 cases of first HF hospitalization were observed (mean ± SD age at diagnosis 50.1 ± 7.9 years). CRF and muscle strength were estimated by maximum capacity cycle ergometer testing and strength exercises (knee extension, elbow flexion and hand grip). Inverse dose-response relationships were found between CRF and muscle strength with HF as a primary or contributory diagnosis with an adjusted hazards ratio (95% confidence interval) of 1.60 (1.44-1.77) for low CRF and 1.45 (1.32-1.58) for low muscle strength categories. The associations of incident HF with CRF and muscle strength persisted, regardless of adjustments for the other potential confounders. The highest risk was observed for HF associated with coronary heart disease, diabetes or hypertension. Conclusions In this longitudinal study of young men, we found inverse and mutually independent associations between CRF and muscle strength with risk of hospitalization for HF. If causal, these results may emphasize the importance of the promotion of CRF and muscle strength in younger populations.

The endogenous secretion pattern in males of GH is episodic in rats and in humans, whereas GH administration is usually even. Different types of GH administration have different effects on body mass, longitudinal bone growth, and liver metabolism in rodents, whereas possible effects on brain plasticity have not been investigated. In this study, GH was administered as a continuous infusion or as two daily injections in hypophysectomized male rats. Thirteen transcripts previously known to respond to GH in the hippocampus and parietal cortex (cortex) were assessed by RT-PCR. To investigate the effects of type of GH administration on several transcripts with different variations, and categories of transcripts (neuron-, glia-, and GH-related), a mixed model analysis was applied. Accordingly, GH injections increased overall transcript abundance more than GH infusions (21% in the hippocampus,PP=0.09). Specifically, GH infusions and injections robustly increased neuronal hemoglobin beta (Hbb) expression significantly (1.8- to 3.6-fold), and GH injections were more effective than GH infusions in increasingHbbin the cortex (41%,P=0.02), whereas a 23% difference in the hippocampus was not significant. Also cortical connexin 43 was higher in the group with GH injections than in those with GH infusions (26%,PP=0.04) and glia-related transcripts of the hippocampus (15%,P=0.02). Thus, with the exception ofHbbthere is a moderate difference in responsiveness to different modes of GH administration.

While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. Material and methods During 1950–1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. Results Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.

Patients with early-onset dementia are a significantly under-recognized subgroup of patients with an increasing prevalence. Epidemiological studies are limited and studies of modifiable risk factors, such as physical fitness, are lacking. We aimed to investigate the associations between cardiovascular fitness individually and in combination with cognitive performance at age 18 and risk of early-onset dementia and mild cognitive impairment later in life. We performed a population-based cohort study of over 1.1 million Swedish, 18-year-old, male conscripts, who underwent conscription exams between 1968 and 2005. These males were then followed for up to 42 years. Objective data on cardiovascular fitness and cognitive performance were collected during conscription exams and were subsequently linked with hospital registries to calculate later risk of early-onset dementia and mild cognitive impairment using Cox proportional hazards models controlling for several confounders. The scores from the exams were divided into tertiles (low, medium, high) for the analyses. The mean follow-up time for the analyses was 25.7 years (standard deviation: 9.3) and the median was 27 years. In total, 30 195 315 person-years of follow-up were included in the study. In fully adjusted models, both low cardiovascular fitness and cognitive performance (compared to high) at age 18 were associated with increased risk for future early-onset dementia (cardiovascular fitness, n = 662 events: hazard ratio 2.49, 95%, confidence interval 1.87-3.32; cognitive performance, n = 657 events: hazard ratio 4.11, 95%, confidence interval 3.19-5.29) and mild cognitive impairment (cardiovascular fitness, n = 213 events: hazard ratio 3.57, 95%, confidence interval 2.23-5.74; cognitive performance, n = 212 events: hazard ratio 3.23, 95%, confidence interval 2.12-4.95). Poor performance on both cardiovascular fitness and cognitive tests was associated with a >7-fold (hazard ratio 7.34, 95%, confidence interval 5.08-10.58) and a >8-fold (hazard ratio 8.44, 95%, confidence interval 4.64-15.37) increased risk of early-onset dementia and early-onset mild cognitive impairment, respectively. In conclusion, lower cardiovascular fitness and cognitive performance in early adulthood were associated with an increased risk of early-onset dementia and mild cognitive impairment later in life, and the greatest risks were observed for individuals with a combination of low cardiovascular fitness and low cognitive performance.

Objective: To analyze the associations between cardiovascular fitness at age 18 years and future risk of epilepsy. Methods: Population-based cohort study of Swedish male conscripts (n = 1,173,079) born in 1950–1987, who were followed for up to 40 years. Data on cardiovascular fitness were collected during conscription exams and linked with hospital registers to calculate later risk of epilepsy using Cox proportional hazard models controlling for several confounders, including familial factors. Results: Epilepsy was recorded in 6,796 individuals during the follow-up time. In fully adjusted models, low and medium cardiovascular fitness (compared with high) at age 18 years was associated with increased risk of future epilepsy (hazard ratio 1.79, 95% confidence interval 1.57–2.03; and hazard ratio 1.36, 95% confidence interval 1.27–1.45, respectively). The associations changed only marginally after adjustment for familial influences and prior severe traumatic brain injury, cerebrovascular disease, or diabetes. Conclusions: Low cardiovascular fitness early in life is associated with an increased risk of epilepsy later in adulthood. These results agree with previous results from animal models. We propose that behaviors that increase cardiovascular fitness may act as positive disease-modifiers for the development of epilepsy.

BackgroundCardiovascular fitness influences many aspects of brain function. However, the relationship between cardiovascular fitness and suicidal behaviour is unknown. Therefore, we aimed to determine whether cardiovascular fitness at age 18 years is associated with future risk of suicide attempt/death.MethodWe performed a population-based Swedish longitudinal cohort study of male conscripts with no previous or ongoing mental illness (n = 1 136 527). The conscription examination, which took place during 1968–2005, included the cycle ergonometric test and tests of cognitive performance. Future risk of suicide attempt/death over a 5- to 42-year follow-up period was calculated with Cox proportional hazards models controlling for several confounders including familial factors.ResultsAt least one suicide attempt was recorded for 12 563 men. Death by suicide without a prior attempt was recorded in 4814 additional individuals. In fully adjusted models low cardiovascular fitness was associated with increased risk for future attempt/death by suicide [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.64–1.94]. The HR changed only marginally after exclusion of persons who received in-patient care for depression (HR 1.76, 95% CI 1.61–1.94). Poor performance on both the cardiovascular fitness and cognitive tests was associated with a fivefold increased risk of suicide attempt or suicide death (HR 5.46, 95% CI 4.78–6.24).ConclusionsLower cardiovascular fitness at age 18 years was, after adjustment for a number of potential confounders, associated with an increased risk of attempt/death by suicide in adulthood. It remains to be clarified whether interventions designed to improve fitness in teens can influence the risk of suicidal behaviour later in life.

Background Recent research suggests that the prevalence of early heart failure may be on the rise. Compromised mental health in adolescence may help to explain this phenomenon. We aimed to investigate whether nonpsychotic mental disorder and low stress resilience in late adolescence were associated with increased risk of early heart failure. Methods A prospective cohort study of 18-year-old men (n=1,784,450) who enlisted 1968–2005. At the conscription examination, 74,522 individuals were diagnosed with nonpsychotic mental disorders. Stress resilience was rated by psychologists; values were trichotomized. The risk of heart failure during the 46-year follow-up was calculated with Cox proportional hazards models. Baseline comorbidities, BMI, blood pressure, fitness, IQ, and parental education were included in the models. Results Incident cases of heart failure (n=9962) were identified in the National Hospital Register. In fully adjusted models, increased risk of early heart failure was observed in males diagnosed with nonpsychotic mental disorders at conscription (hazard ratio (HR), 1.36; 95% confidence interval (CI), 1.25–1.47). The highest risk was seen among men with the risk factor alcohol/substance use (HR 1.90; 95% CI 1.59–2.28). Conscripts with the risk factor low stress resilience showed increased risk of heart failure compared to those with high scores (HR 1.41; 95% CI 1.30–1.53). Conclusion Nonpsychotic mental disorder, as well as low stress resilience in late adolescence may be associated with increased risk of early heart failure. Adolescence is potentially an important time for mental health interventions that may reduce both short and long-term consequences.

BackgroundStudies suggest a role for cardiovascular fitness in the prevention of affective disorders.AimsTo determine whether cardiovascular fitness at age 18 is associated with future risk of serious affective illness.MethodPopulation-based Swedish cohort study of male conscripts (n= 1 117 292) born in 1950–1987 with no history of mental illness who were followed for 3–40 years. Data on cardiovascular fitness at conscription were linked with national hospital registers to calculate future risk of depression (requiring in-patient care) and bipolar disorder.ResultsIn fully adjusted models low cardiovascular fitness was associated with increased risk for serious depression (hazard ratios (HR)=1.96, 95%, CI 1.71–2.23). No such association could be shown for bipolar disorder (HR=1.11, 95% CI 0.84–1.47).ConclusionsLower cardiovascular fitness at age 18 was associated with increased risk of serious depression in adulthood. These results strengthen the theory of a cardiovascular contribution to the aetiology of depression.

During early adulthood, a phase in which the central nervous system displays considerable plasticity and in which important cognitive traits are shaped, the effects of exercise on cognition remain poorly understood. We performed a cohort study of all Swedish men born in 1950 through 1976 who were enlisted for military service at age 18 ( N = 1,221,727). Of these, 268,496 were full-sibling pairs, 3,147 twin pairs, and 1,432 monozygotic twin pairs. Physical fitness and intelligence performance data were collected during conscription examinations and linked with other national databases for information on school achievement, socioeconomic status, and sibship. Relationships between cardiovascular fitness and intelligence at age 18 were evaluated by linear models in the total cohort and in subgroups of full-sibling pairs and twin pairs. Cardiovascular fitness, as measured by ergometer cycling, positively associated with intelligence after adjusting for relevant confounders (regression coefficient b = 0.172; 95% CI, 0.168–0.176). Similar results were obtained within monozygotic twin pairs. In contrast, muscle strength was not associated with cognitive performance. Cross-twin cross-trait analyses showed that the associations were primarily explained by individual specific, non-shared environmental influences (≥80%), whereas heritability explained

IGF-I treatment has been shown to enhance cell genesis in the brains of adult GH- and IGF-I-deficient rodents; however, the influence of GH therapy remains poorly understood. The present study investigated the effects of peripheral recombinant bovine GH (bGH) on cellular proliferation and survival in the neurogenic regions (subventricular zone (SVZ), and dentate gyrus of the hippocampus), as well as the corpus callosum, striatum, parietal cortex, and piriform cortex. Hypopituitarism was induced in female rats by hypophysectomy, and the rats were supplemented with thyroxine and cortisone acetate. Subsequently, the rats received daily s.c. injections of bGH for either 6 or 28 days respectively. Following 5 days of peripheral bGH administration, the number of bromodeoxyuridine (BrdU)-positive cells was increased in the hippocampus, striatum, parietal cortex, and piriform cortex after 6 and 28 days. In the SVZ, however, BrdU-positive cells increased only after 28 days of bGH treatment. No significant change was observed in the corpus callosum. In the hippocampus, after 28 days of bGH treatment, the number of BrdU/NeuN-positive cells was increased proportionally to increase the number of BrdU-positive cells. 3H-thymidine incorporation in vitro revealed that 24 h of bGH exposure was sufficient to increase cell proliferation in adult hippocampal progenitor cells. This study shows for the first time that 1) peripheral bGH treatment increased the number of newborn cells in the adult brain and 2) bGH exerted a direct proliferative effect on neuronal progenitor cells in vitro.

Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I—at which stimulation of proliferation occurred—did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism. © 2003 Wiley-Liss, Inc.

In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D28K, microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 ± 17% (p< 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.

Objective Large-scale studies examining future trajectories of marginalisation and health in adolescents with mental illness are scarce. The aim of this study was to examine if non-psychotic psychiatric disorders (NPDs) were associated with future indicators of marginalisation and mortality. We also aimed to determine whether these associations might be mediated by education level and attenuated by high cognitive ability. Design This is a prospective cohort study with baseline data from the Swedish Conscription register. Setting The study was carried out in Sweden from 1969 to 2005. Participants All of the participants were 18-year-old men at mandatory conscription in Sweden between 1969 and 2005 (n=1 609 690). Measures NPDs were clinically diagnosed at conscription. Cognitive ability was measured by a standardised IQ test at conscription. National register data covered information on welfare support, long-term unemployment, disability pension (DP) and mortality over a period of 1–36 years. Results NPD at the age of 18 years was a predictor of future welfare support, OR 3.73 (95% CI 3.65 to 3.80); long-term unemployment, OR 1.97 (95% CI 1.94 to 2.01); DP, HR 2.95 (95% CI 2.89 to 3.02); and mortality, HR 2.45 (2.33–2.52). The adjusted models suggested that these associations were not confounded by fathers’ educational level, cognitive ability had only a minor attenuating effect on most associations and the mediating effect of own educational level was small. Conclusions The present study underlines a higher prevalence of future adversities in young men experiencing NPDs at the age of 18 years. It also indicates that higher cognitive ability may work as a potential resilience factor against future marginalisation and mortality.

GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2′-deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increasedIgf1andGfapmRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a(Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2(Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs(Glul)). However, IGF1R was correlated with the expression ofDor,Nr2a,Sapap2,GsandGfap. In summary, although localbGHexpression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose–response curve and cell-specific expression ofbGH.

Progenitor cells in the subgranular zone of the hippocampus may be of significance for functional recovery after various injuries because they have a regenerative potential to form new neuronal cells. The hippocampus has been shown to express the GH secretagogue (GHS) receptor 1a, and recent studies suggest GHS to both promote neurogenesis and have neuroprotective effects. The aim of the present study was to investigate whether GHS could stimulate cellular proliferation and exert cell protective effects in adult rat hippocampal progenitor (AHP) cells. Both hexarelin and ghrelin stimulated increased incorporation of 3H-thymidine, indicating an increased cell proliferation. Furthermore, hexarelin, but not ghrelin, showed protection against growth factor deprivation-induced apoptosis, as measured by annexin V binding and caspase-3 activity and also against necrosis, as measured by lactate dehydrogenase release. Hexarelin activated the MAPK and the phosphatidylinositol 3-kinase/Akt pathways, whereas ghrelin activated only the MAPK pathway. AHP cells did not express the GHS receptor 1a, but binding studies could show specific binding of both hexarelin and ghrelin, suggesting effects to be mediated by an alternative GHS receptor subtype. In conclusion, our results suggest a differential effect of hexarelin and ghrelin in AHP cells. We have demonstrated stimulation of 3H-thymidine incorporation with both hexarelin and ghrelin. Hexarelin, but not ghrelin, also showed a significant inhibition of apoptosis and necrosis. These results suggest a novel cell protective and proliferative role for GHS in the central nervous system.

We have previously shown that recombinant human (rh) IGF-I induces cell proliferation and neurogenesis in the hippocampus of hypophysectomized rats. In the current investigation, we determined the effects of rhIGF-I on proliferation and differentiation in the cerebral cortex. Adult hypophysectomized rats were injected with bromodeoxyuridine (BrdU) to label newborn cells (once a day for the first 5 d), and rhIGF-I was administered peripherally for 6 or 20 d. In the cerebral cortex, the number of BrdU-labeled cells increased after 20 d but not after 6 d of rhIGF-I infusion. This suggests that rhIGF-I enhances the survival of newborn cells in the cerebral cortex. Using BrdU labeling combined with the oligodendrocyte-specific markers myelin basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase, we demonstrated an increase in oligodendrogenesis in the cerebral cortex. The total amount of myelin basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase was also increased on Western blots of homogenates of the cerebral cortex, confirming the immunohistochemical findings. Also, we observed an increase in the number of capillary-associated BrdU-positive cells, although total capillary area was not increased. rhIGF-I treatment did not affect cortical astrogliogenesis and neurogenesis was not observed. The ability of rhIGF-I to induce cortical oligodendrogenesis may have implications for the regenerative potential of the cortex.

Publisher Summary This chapter illustrates the significance of Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in adult CNS progenitor cell regulation and cellular regeneration and possible clinical and functional aspects. Neurogenesis in the adult brain occurs in the hippocampal dentate gyrus and the subventricular zone. In addition, astrocytes and oligodendrocytes are also formed from these brain regions. Apart from the neuroprotective effects of IGF-I, peripheral infusion of and circulating IGF-I increase progenitor cell proliferation and neurogenesis in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-l-stimulated proliferation in vitro. Furthermore, the functional consequences of newborn cells of different lineages in the adult brain are reviewed especially with reference to exercise, enriched environment, learning, aging, and disease. The chapter also focuses on the role of IGF-I as being a putative regenerative agent in the adult CNS. Their use in clinical trial as treatment for human brain insults is yet to be established.

Scavenger receptor class B type I (SR-BI) is an HDL receptor that mediates selective HDL lipid uptake. Peroxisomes play an important role in lipid metabolism and peroxisomal targeting signal type 1 (PTS1)-containing proteins are translocated to peroxisomes by the peroxisomal targeting import receptor, Pex5p. We have previously identified a PTS1 motif in the intracellular domain of rat SR-BI. Here, we examine the possible interaction between Pex5p and SR-BI. Expression of a Flag-tagged intracellular domain of SR-BI resulted in translocation to the peroxisome as demonstrated by double labeling with anti-Flag IgG and anti-catalase IgG analyzed by confocal microscopy. Immunoprecipitation experiments with anti-SR-BI antibody showed that Pex5p co-precipitated with SR-BI. However, when an antibody against Pex5p was used for immunoprecipitation, only the 57kDa, non-glycosylated form, of SR-BI co-precipitated. We conclude that the PTS1 domain of SR-BI is functional and can mediate peroxisomal interaction via Pex5p, in vitro.

The aim of the present study was to investigate the potential direct effects of insulin-like growth factor-I (IGF-I) on adult rat hippocampal stem/progenitor cells (AHPs). IGF-I-treated cultures showed a dose-dependent increase in thymidine incorporation, total number of cells, and number of cells entering the mitosis phase. Pretreatment with fibroblast growth factor-2 (FGF-2) increased the IGF-I receptor (IGF-IR) expression, and both FGF-2 and IGF-I were required for maximal proliferation. Time-lapse recordings showed that IGF-I at 100 ng/ml decreased differentiation and increased proliferation of single AHPs. Specific inhibition of mitogen-activated protein kinase kinase (MAPKK), phosphatidylinositol 3-kinase (PI3-K), or the downstream effector of the PI3-K pathway, serine/threonine p70 S6 kinase (p70(S6K)), showed that both the MAPK and the PI3-K pathways participate in IGF-I-induced proliferation but that the MAPK activation is obligatory. These results were confirmed with dominant-negative constructs for these pathways. Stimulation of differentiation was found at a low dose (1 ng/ml) of IGF-I, clonal analysis indicating an instructive component of IGF-I signaling.

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.

An association of higher body mass index (BMI) with lower risk of attempted and completed suicide has been reported. In contrast, increasing BMI has been found to be associated with depression and other risk factors for suicidal behavior. We aimed to investigate this possible paradox in a cohort comprising 49 000 Swedish men. BMI, mental health, lifestyle and socioeconomic measures were recorded at conscription in 1969–70, at ages 18–20. Information on attempted suicide 1973–2008 and completed suicide 1971–2008 was obtained from national records. Hazard ratios (HR) were estimated by Cox proportional hazard models. We found that each standard deviation (SD) increase in BMI was associated with a 12% lower risk of later suicide attempt (HR 0.88, 95% CI 0.83–0.94). Associations were somewhat weaker for completed suicide and did not reach conventional levels of statistical significance (HR 0.93, 95% CI 0.85–1.01). Adjustment for a wide range of possible confounding factors had little effect on the associations. Lower BMI at conscription was also associated with higher prevalence of psychiatric diagnoses, low emotional control and depressed mood. Our results confirm previous findings regarding the association of higher BMI with a reduced risk of suicide, extending them to show similar findings in relation to suicide attempts. The associations were little affected by adjustment for a range of possible confounding factors. However, we found no evidence that high BMI was associated with an increased risk of depression cross-sectionally or longitudinally.

We have developed a novel method in which antisense DNA is selectively electroporated into individual adult neural progenitor cells. By electroporation of antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) we demonstrate that ciliary neurotrophic factor (CNTF) is an instructive signal for astroglial type 2 cell fate specifically mediated via activation of STAT3. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway induced only a transient increase in glial fibrillary acidic protein (GFAP) expression, and inhibition of this signaling pathway did not block the induction by CNTF of glial differentiation in progenitor cells. In addition we show that microelectroporation is a new powerful method for introducing antisense agents into single cells in complex cellular networks.

SummaryBackgroundTrends in prevalence of asthma and allergic diseases are still controversial, and rarely studied among adolescents at midpoint of puberty.MethodsIn 2000, a questionnaire was mailed to adolescents (n = 18,158) attending 9th grade at school and living in Västra Götaland County, Sweden. Eight years later, the same questionnaire was mailed to adolescents (n = 21,651), using identical inclusion criteria as previously. Altogether, 10,837 adolescents completed the questionnaire in 2000 and 11,754 in 2008. Differences in prevalence of physician diagnosed asthma, asthma symptoms, rhinitis, and eczema between the periods were analyzed by Chi-square test. Multiple logistic regression models were performed to test for trends in prevalence of these diseases, adjusting for potential confounders.ResultsPhysician diagnosed asthma and lifetime and current rhinitis were increased in 2008, while wheeze decreased (p