Self-inflicted injury among adolescents and young adults - the role of ethnicity, socioeconomic conditions and school performance

Background: Over the past ten years, the number of hospitalisations due to self-inflicted injury has increased significantly among young people in Sweden. The underlying causes are often both psychological and social. Whilst the great deal of research into SII in youth has focused upon psychological factors, the influence of the social ones has been investigated to a lesser extent. The general picture is that females, ethnic minorities, and youth from less favorable socioeconomic background appear to be particularly at risk. Furthermore, increasing empirical evidence is emerging for the important role of school performance. Aim: The overall aim of this thesis is to investigate the role of ethnicity, socioeconomic conditions and school performance, both at an individual and school level, on the risk of hospitalization due to SII among youth in Sweden. Since these factors, most probably, do not operate in isolation from each other, we aimed to study how they are interrelated in their effects on risk of SII. Study I aimed to examine socioeconomic factors as confounders of the association between ethnicity and risk of hospital admission due to SII among youth Study II aimed to examine whether the grade point average when leaving compulsory school predict hospital admission because of SII among youth Study III aimed to investigate the impact of parental SES on youths‘ risk of hospital admission because of SII and whether this influence is mediated or/and moderated by a subjects` school performance Study IV aimed to examine how both individual-level factors and school composition are related to an individual-level risk of SII, as well as to assess interactions effects between individual-level and school composition-level factors (cross-level effects) Method: All four studies are based on data from the national registers of the Swedish National Board of Health and Welfare and Statistics Sweden comprising information about socioeconomic and health indicators of the entire Swedish population. The study population consisted of the entire Swedish population born between 1973 and 1982 (N=1 009 157) and between 1973 and 1977 (N=491 258) residing in Sweden according to the Swedish Population and Housing Census of 1985 or 1990. The outcome variable—hospital admission at least once due to SII was obtained through individual records linkage to the National Hospital Discharge Register. Information about country of birth of the individuals in the study population and their parents was obtained from the Register of the Total Population. Socioeconomic variables were created by linkage to: The Swedish Population and Housing Census 1985 and 1990. School performance indicator, grade point average at the time of leaving compulsory school was created by linkage to The National School Register. Results: Ethnic minorities in Sweden (except those from Southern Europe) had an increased risk of SII as compared with the native population (HRs ranged between 1.6 and 2.3). When socioeconomic conditions were also adjusted for, however, the risks decreased for all ethnic minorities, but remained significantly higher for immigrants from Finland, Western Europe/other Western countries and those in the mixed group. School performance in compulsory school clearly emerged as an important independent predictor of SII [HRs ranged between 1.4 (for GPA=M+1SD) and 6.2 for GPA=(<M-1SD)]. School performance appeared not only as an independent predictor of SII but also as a mediator between parental SES and SII and accounted for as much as 60% of the variance. The risk of SII varied significantly between schools. Individuals who attended schools characterized by a higher proportion of students with low parental SES and single-parent households had a small, but statistically significant excess risk of SII, above and beyond individual background. School-level factors, however, explained less than 1% of student‘s risk of SII. Conclusions: The increased risk for SII among youth in non-Western ethnic minorities in Sweden seems to be explained mainly by socioeconomic factors. School performance is an important mediator through which low parental SES translates into risk of SII and poor school performance should be considered as a warning sign for increased risk of SII among young people. School-level factors explain only a small percentage of student‘s risk of SII, indicating that the differences in SII mainly seem to be due to individual characteristics

A national cohort study of parental socioeconomic status and non-fatal suicidal behaviour-the mediating role of school performance

Background: A link between low parental socioeconomic status and mental health problems in offspring is well established in previous research. The mechanisms that explain this link are largely unknown. The present study investigated whether school performance was a mediating and/or moderating factor in the path between parental socioeconomic status and the risk of hospital admission for non-fatal suicidal behaviour. Methods: A national cohort of 447 929 children born during 1973-1977 was followed prospectively in the National Patient Discharge Register from the end of their ninth and final year of compulsory school until 2001. Multivariate Cox proportional hazards and linear regression analyses were performed to test whether the association between parental socioeconomic status and non-fatal suicidal behaviour was mediated or moderated by school performance. Results: The results of a series of multiple regression analyses, adjusted for demographic variables, revealed that school performance was as an important mediator in the relationship between parental socioeconomic status and risk of non-fatal suicidal behaviour, accounting for 60% of the variance. The hypothesized moderation of parental socioeconomic status-non-fatal suicidal behaviour relationship by school performance was not supported. Conclusions: School performance is an important mediator through which parental socioeconomic status translates into a risk for non-fatal suicidal behaviour. Prevention efforts aimed to reduce socioeconomic inequalities in non-fatal suicidal behaviour among young people will need to consider socioeconomic inequalities in school performance

Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone

We investigated the function of cyclin-dependent kinase 2 (Cdk2) in neural progenitor cells during postnatal development. Chondroitin sulfate proteoglycan (NG2)–expressing progenitor cells of the subventricular zone (SVZ) show no significant difference in density and proliferation between Cdk2−/− and wild-type mice at perinatal ages and are reduced only in adult Cdk2−/− mice. Adult Cdk2−/− SVZ cells in culture display decreased self-renewal capacity and enhanced differentiation. Compensatory mechanisms in perinatal Cdk2−/− SVZ cells, which persist until postnatal day 15, involve increased Cdk4 expression that results in retinoblastoma protein inactivation. A subsequent decline in Cdk4 activity to wild-type levels in postnatal day 28 Cdk2−/− cells coincides with lower NG2+ proliferation and self-renewal capacity similar to adult levels. Cdk4 silencing in perinatal Cdk2−/− SVZ cells abolishes Cdk4 up-regulation and reduces cell proliferation and self- renewal to adult levels. Conversely, Cdk4 overexpression in adult SVZ cells restores proliferative capacity to wild-type levels. Thus, although Cdk2 is functionally redundant in perinatal SVZ, it is important for adult progenitor cell proliferation and self-renewal through age-dependent regulation of Cdk4

Molecular analysis of three novel G6PD variants : G6PD Pedoplis-Ckaro, G6PD Piotrkow and G6PD Krakow

We present three novel mutations in the G6PD gene and discuss the changes they cause in the 3-dimensional structure of the enzyme: 573C→G substitution that predicts Phe to Leu at position 191 in the C-terminus of helix αe, 851T→C mutation which results in the substitution 284Val→→Ala in the β+α domain close to the C-terminal part of helix αj, and 1175T→C substitution that predicts Ile to Thr change at position 392

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.

Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI

Lipid peroxidation and glutathione peroxidase activity relationship in breast cancer depends on functional polymorphism of GPX1

Functional SNPs selected for the study. Table S2. Restriction fragment analysis for BRCA1 mutations. Table S3. Oxidative stress parameters in breast cancer cases according to treatment. (DOCX 31 kb

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials