Stanniocalcin-1 in cell stress and differentiation

Stanniocalcin-1 (STC-1) is a 56 kD homodimeric protein which was originally identified in bony fish, where it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. STC-1 was considered unique to fish until the cloning of cDNA for human STC-1 in 1995 and mouse Stc-1 in 1996. STC-1 is conserved through evolution with human and salmon STC-1 sharing 60% identity and 80% similarity. The surprisingly high homology between mammalian and fish STC-1 and the protective actions of STC-1 in terminally differentiated neurons, originally reported by my colleagues, prompted me to further study the role of STC-1 in cell stress and differentiation. One purpose was to determine whether there is an inter-relationship between terminally differentiated cells and STC-1 expression. The study revealed an accumulation of STC-1 in mature megakaryocytes and adipocytes, i.e. postmitotic cells with limited or lost proliferative capacity. Still proliferating uninduced cells were negative for STC-1 mRNA and protein, whereas differentiating cells accumulated STC-1 in their cytoplasm. Interestingly, in liposarcomas the grade inversely correlated with STC-1 expression. Another aim was to study how STC-1 gene expression is regulated. Given that IL-6 is a cytokine with neuroprotective actions, by unknown mechanisms, we examined whether IL-6 regulates STC-1 gene expression. Treatment of human neural Paju cells with IL-6 induced a dose-dependent upregulation of STC-1 mRNA levels. This induction of STC-1 expression by IL-6 occurred mainly through the MAPK signaling pathway. Furthermore, I studied the role of IL-6-mediated STC-1 expression as a mechanism of cytoprotection conferred by hypoxic preconditioning (HOPC) in brain and heart. My findings show that Stc-1 was upregulated in brain after hypoxia treatment. In the brain of IL-6 deficient mice, however, no upregulation of Stc-1 expression was evident. After induced brain injury the STC-1 response in brains of IL-6 transgenic mice, with IL-6 overexpression in astroglial cells, was stronger than in brains of WT mice. These results indicate that IL-6-mediated expression of STC-1 is one molecular mechanism of HOPC-induced tolerance to brain ischemia. The protection conferred by HOPC in heart occurs during a bimodal time course comprising early and delayed preconditioning. Interestingly, my results showed that the expression of Stc-1 in heart was upregulated in a biphasic manner during HOPC. IL-6 deficient mice did not, however, show a similar biphasic manner of Stc-1 upregulation as did WT mice. Instead, only an early upregulation of Stc-1 expression was evident. The results suggest that the upregulation of Stc-1 during the delayed preconditioning is IL-6-dependent. The upregulated expression of Stc-1 during the early preconditioning, however, is only partly IL-6-dependent and possibly also directly mediated by HIF-1. These findings suggest that STC-1 is a pro-survival protein for terminally differentiated cells and that STC-1 expression may in fact be regulated by stress. In addition, I show that STC-1 gene upregulation, mediated in part by IL-6, is a new mechanism of protection conferred by HOPC in brain and heart. Because of its importance for fundamental biological processes, such as differentiation and cytoprotection, STC-1 may have therapeutic implications for management of stroke, neurodegenerative diseases, cancer, and obesity.Stanniocalcin 1 (STC-1) är ett homodimert glykoprotein som ansågs vara unikt för fiskar tills musens och människans STC-1 klonades 1995 respektive 1996. STC-1 är evolutivt tämligen oförändrat; homologin mellan fiskens och människans STC-1 är 80%. Hos fisken skyddar STC-1 mot toxiska kalciumhalter (hyperkalcemi). Funktionen hos STC-1 i däggdjur är emellertid okänd. Vår forskargrupp har tidigare påvisat att terminalt utmognade neuroner producerar STC-1 och att detta protein skyddar mot cellskada förosakad av hjärninfarkt. Mot bakgrund av dessa resultat har målsättningen med min avhandling varit att undersöka betydelsen av STC-1 vid cell stress och differentiering. Jag har funnit ett samband mellan STC-1 och terminal differentiering. Jag har visat att megakaryocyter och fettceller, båda postmitotiska, terminalt utmognade celler, producerar STC-1. Dessutom har jag påvisat, att på konstgjord väg framkallad terminal differentiering i två cellinjer, K562 och 3T3-L1, inducerar produktionen av STC-1. Jag har också påvisat att STC-1 induceras av interleukin 6 (IL-6), ett cytokin med neuroprotektiva egenskaper. Genom att utsätta vävnader för korta perioder av syrebrist (hypoxi), utvecklas ett skydd mot påföljande ischemisk skada (infarkt). Mekanismen bakom detta fenomen, även kallat hypoxic preconditioning (HOPC), är okänd. Jag har studerat HOPC - fenomenet hos möss och av mina resultat framgår det att IL-6 inducerat STC-1 är en bakomliggande mekanism till HOPC-skyddet i både hjärna och hjärta. Dessa resultat tyder på att STC-1 är en överlevnadsfaktor för terminalt utmognade celler. Stress, såsom hypoxi, utlöser sannolikt STC-1 som den skyddande faktorn. Eftersom STC-1 är involverat i så grundläggande biologiska processer som terminal differentiering och cellskydd, är dess tillämpningsområde brett och kan tänkas omfatta vården av stroke, neurodegenerativa sjukdomar, fetma och cancer

Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings

Background: To assess the risk of psychiatric disorders in Ehlers-Danlos syndrome (EDS) and hypermobility syndrome. Methods: Nationwide population-based matched cohort study. EDS, hypermobility syndrome and psychiatric disorders were identified through Swedish national registries. Individuals with EDS (n = 1,771) were matched with comparison individuals (n = 17,710). Further, siblings to individuals with EDS who did not have an EDS diagnosis themselves were compared with matched comparison siblings. Using conditional logistic regression, risk of autism spectrum disorder (ASD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), depression, attempted suicide, suicide and schizophrenia were estimated. The same analyses were conducted in individuals with hypermobility syndrome (n = 10,019) and their siblings. Results: EDS was associated with ASD: risk ratio (RR) 7.4, 95 % confidence interval (95 % CI) 5.2–10.7; bipolar disorder: RR 2.7, CI 1.5–4.7; ADHD: RR 5.6, CI 4.2–7.4; depression: RR 3.4, 95 % CI 2.9–4.1; and attempted suicide: RR 2.1, 95 % CI 1. 7–2.7, but not with suicide or schizophrenia. EDS siblings were at increased risk of ADHD: RR 2.1, 95 % CI 1.4–3.3; depression: RR 1.5, 95 % CI 1.1–1.8; and suicide attempt: RR 1.8, 95 % CI 1.4–2.3. Similar results were observed for individuals with hypermobility syndrome and their siblings. Conclusions: Individuals with EDS and hypermobility syndrome are at increased risks of being diagnosed with psychiatric disorders. These risk increases may have a genetic and/or early environmental background as suggested by evidence showing that siblings to patients have elevated risks of certain psychiatric disorders.NonePublishe

Developing digital mental health tools for youth with diabetes: an agenda for future research

Youth living with diabetes face a concurrent challenge: managing a chronic health condition and managing the psychosocial and developmental changes that are characteristic of adolescence and young adulthood. Despite these unique challenges, psychological support is often difficult for youth with diabetes to access due to a lack of trained mental health professionals and other resource constraints. Digital wellbeing tools offer the potential to improve access to psychological support for this population. However, very few digital wellbeing tools exist for youth with diabetes. Of those that do exist, very few are evidence-based therapies, undermining their contribution to the field. Given the increasing global prevalence of diabetes in young people, the support necessitated by the challenges experienced by this population is not always accessible in a face-to-face setting and cannot be effectively scaled to meet demand. To support the health and wellbeing of youth with diabetes, there is a clear need to develop digital interventions that are widely accessible to users, but, more saliently, grounded in empirical evidence that supports their efficacy. Thus, the purpose of this paper is to offer an agenda for future research, including insights into which psychological techniques and behavioral change theories may be a good conceptual fit for digital mental health interventions, and how these tools may be best developed and utilized by the individuals that need them. Scalable, evidence-based wellbeing tools for this population are urgently required to improve psychological outcomes, and potentially, improve the equity of service access

Childhood neurodevelopmental disorders and violent criminality : a sibling control study

Introduction: The longitudinal relationship between attention deficit hyperactivity disorder (ADHD) and violent criminality has been extensively documented, while long-term effects of autism spectrum disorders (ASDs), tic disorders (TDs), and obsessive compulsive disorder (OCD) on criminality have been scarcely studied.Methods: Using population-based registers of all child and adolescent mental health services in Stockholm, we identified 3,391 children, born 1984–1994, with neurodevelopmental disorders, and compared their risk for subsequent violent criminality with matched controls. Results: Individuals with ADHD or TDs were at elevated risk of committing violent crimes, no such association could be seen for ASDs or OCD. Conclusions: ADHD and TDs are risk factors for subsequent violent criminality, while ASDs and OCD are not associated with violent criminality.VetenskapsrådetFASAccepte

Does high optimism protect against the inter-generational transmission of high BMI? The Cardiovascular Risk in Young Finns Study

Objective: The transmission of overweight from one generation to the next is well established, however little is known about what psychosocial factors may protect against this familial risk. The aim of this study was to examine whether optimism plays a role in the intergenerational transmission of obesity. Methods: Our sample included 1043 participants from the prospective Cardiovascular Risk in Young FINNS Study. Optimism was measured in early adulthood (2001) when the cohort was aged 24-39 years. BMI was measured in 2001 (baseline) and 2012 when they were aged 35-50 years. Parental BMI was measured in 1980. Hierarchical linear regression and logistic regression were used to examine the association between optimism and future BMI/obesity, and whether an interaction existed between optimism and parental BMI when predicting BMI/obesity 11 years later. Results: High optimism in young adulthood demonstrated a negative relationship with high BMI in mid-adulthood, but only in women (beta = - 0.127, p = 0.001). The optimism x maternal BMI interaction term was a significant predictor of future BMI in women (beta = 0.588, p = 0.036). The logistic regression results confirmed that high optimism predicted reduced obesity in women (OR = 0.68, 95% CI, 0.55-0.86), however the optimism x maternal obesity interaction term was not a significant predictor (OR = 0.50, 95% CI, 0.10-2.48). Conclusions: Our findings supported our hypothesis that high optimism mitigated the intergenerational transmission of high BMI, but only in women. These findings also provided evidence that positive psychosocial factors such as optimism are associated with long-term protective effects on BMI in women.Peer reviewe

Latent Classes of Symptoms related to Clinically Depressed Mood in Adolescents

The diagnosis of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders, is based only on adult symptomatology of depression and not adapted for age and gender. This may contribute to the low diagnostic specificity and validity of adolescent MDD. In this study, we investigated whether latent classes based on symptoms associated with depressed mood could be identified in a sample of adolescents seeking psychiatric care, regardless of traditionally defined diagnostic categories.Self-reports of the Strengths and Difficulties Questionnaire and the Development and Well-Being Assessment were collected consecutively from all new patients between the ages of 13 and 17 years at two psychiatric outpatient clinics in Stockholm, Sweden. Those who reported depressed mood at intake yielded a sample of 21 boys and 156 girls. Latent class analyses were performed for all screening items and for the depression-specific items of the Development and Well-Being Assessment.The symptoms that were reported in association with depressed mood differentiated the adolescents into two classes. One class had moderate emotional severity scores on the Strengths and Difficulties Questionnaire and mainly symptoms that were congruent with the Diagnostic and Statistical Manual of Mental Disorders criteria for MDD. The other class had higher emotional severity scores and similar symptoms to those reported in the first class. However, in addition, this group demonstrated more diverse symptomatology, including vegetative symptoms, suicidal ideation, anxiety, conduct problems, body dysmorphic symptoms, and deliberate vomiting. The classes predicted functional impairment in that the members of the second class showed more functional impairment.The relatively small sample size limited the generalizability of the results of this study, and the amount of items included in the analysis was restricted by the rules of latent class analysis. No conclusions about gender differences between the classes could be could be drawn as a result of the low number of boys included in the study.Two distinct classes were identified among adolescents with depressed mood. The class with highest emotional symptom severity score and the most functional impairment had a more diverse symptomatology that included symptoms that were not congruent with the traditional diagnostic criteria of MDD. However, this additional symptomatology is clinically important to consider. As a result, the clinical usefulness of the Diagnostic and Statistical Manual of Mental Disorders during the diagnostic process of adolescent depression is questioned

Work participation and physicality of work in young adulthood and the development of unhealthy lifestyle habits and obesity later in life : a prospective cohort study

Objective To determine the effects of early entry into the labour market and physicality of work in young adulthood on the development of obesity and unhealthy lifestyle habits later in life. Methods This study is a part of the Young Finns Study. Entry into the labour market and physicality of work were measured at baseline, when participants were aged 18, 21, or 24 years in 1986 or 18 years in 1989. Follow-up of lifestyle habits were conducted in 2001, 2007 and 2011. The outcomes were obesity (n=5558 observations), abdominal obesity (n=4060 observations), daily smoking (n=5628) and leisure time physical activity (n=5946) and analysed with generalised estimating equation. Results Compared with sedentary work, physicality of work in young adulthood increased the odds of future obesity (adjusted OR=1.32, 95% CI 1.01 to 1.74 for light/moderate work and OR=1.44, 95% CI 0.99 to 2.08 for heavy manual work (particularly in women OR=2.03, 95% CI 1.07 to 3.84)) and future smoking (OR=1.79, 95% CI 1.39 to 2.30 for light/moderate work and OR=2.01, 95% CI 1.47 to 2.76 for heavy manual work (particularly in women OR=2.81, 95% CI 1.60 to 4.91)). For those who entered the labour market at ages 18-21 or younger, the odds of smoking was 1.85 times (95% CI 1.26 to 2.73) and that of obesity 1.45 times (95% CI 1.01 to 2.10) higher, and the rate of leisure time physical activity was 0.73 times (95% CI 0.58 to 0.93) lower compared with those who entered the labour market at ages 22-24 years. Conclusion Early entry into the labour market and physicality of work in young adulthood shape the development of obesity and unhealthy behaviours in later adulthood.Peer reviewe

Low Sense of Coherence (SOC) is a mirror of general anxiety and persistent depressive symptoms in adolescent girls - a cross-sectional study of a clinical and a non-clinical cohort

<p>Abstract</p> <p>Background</p> <p>The Sense of Coherence (SOC) scale is assumed to measure a distinct salutogenic construct separated from measures of anxiety and depression. Our aim was to challenge this concept.</p> <p>Methods</p> <p>The SOC-scale, Beck's Depression Inventory (BDI), Beck's Anxiety Inventory (BAI) , the emotional subscale of the Strengths and Difficulties Questionnaire (SDQ-em) and self-assessed health-related and physiological parameters were collected from a sample of non-clinical adolescent females (n = 66, mean age 16.5 years with a range of 15.9-17.7 years) and from female psychiatric patients (n = 73), mean age 16.8 years with a range of 14.5-18.4 years), with diagnoses of major depressive disorders (MDD) and anxiety disorders.</p> <p>Results</p> <p>The SOC scores showed high inverse correlations to BDI, BAI and SDQ-em. In the non-clinical sample the correlation coefficient was -0.86 to -0.73 and in the clinical samples -0.74 to -0.53 (p < 0.001). Multiple regression models showed that BDI was the strongest predictor of SOC in the non-clinical (beta coefficient -0.47) and clinical sample (beta coefficient -0.52). The total degree of explanation of self assessed anxiety and depression on the SOC variance estimated by multiple R²= 0.74, adjusted R²= 0.73 in the non-clinical sample and multiple R²= 0.66, adjusted R²= 0.65 in the clinical sample.</p> <p>Multivariate analyses failed to isolate SOC as a separate construct and the SOC-scale, BDI, BAI and SDQ-em showed similar patterns of correlations to self-reported and physiological health parameters in both samples. The SOC-scale was the most stable measure over six months.</p> <p>Conclusions</p> <p>The SOC-scale did not appear to be a measure of a distinct salutogenic construct, but an inverse measure of persistent depressive symptoms and generalized social anxiety similar to the diagnostic criteria for major depressive disorder (MDD), dysthymic disorder, generalized anxiety disorder (GAD) or generalized social anxiety disorder (SAD) according to DSM-IV. These symptoms were better captured with SOC than by the specialized scales for anxiety and depression. Self-assessment scales that adequately identify MDD, dysthymic disorder, GAD and SAD need to be implemented. Comorbidity of these disorders is common in adolescent females and corresponds to a more severe symptomatology and impaired global function.</p

The Association Between Social Support, Body Mass Index and Increased Risk of Prediabetes : the Cardiovascular Risk in Young Finns Study

The psychosocial determinants of prediabetes are poorly understood. The aims of our study were (1) to analyse the association between perceived social support in young adulthood and fasting glucose levels and prediabetes in mid-adulthood in a cohort of healthy Finns, (2) to explore whether body mass index (BMI), inflammation or depression mediate this relationship, (3) and to examine the association between social support trajectory groups and fasting glucose. A prospective design was used with an analytic sample of 1250 participants aged 3-18 years at baseline (1980) and aged 12-39 years when social support was measured. Fasting glucose and prediabetes were assessed 32 years after baseline. Linear and logistic regression was used to examine the association between social support and the outcome measures. A bootstrapping technique was used to examine mediation effects. Social support was associated with future glucose levels in women after adjusting for childhood socioeconomic status (SES) and youth depression (beta = -0.136, p = 0.001) and also predicted prediabetes in women after adjusting for childhood SES (beta = 1.31, 95 % CI 1.02 to 1.69, p = 0.031). Both associations were attenuated after adjusting for BMI in mid-adulthood. BMI was found to mediate the relationship between social support and prediabetes in women (beta for indirect effect beta = 0.09, SE = 0.03, CI = 0.03 to 0.16). Low perceived social support in young adulthood is associated with high fasting glucose and prediabetes in mid-adulthood in women but not men. The association between social support and prediabetes in women can be partly explained by BMI.Peer reviewe