Sex Differences in Outcomes after Stroke in Patients with Diabetes in Ontario, Canada.

BACKGROUND: Outcomes after stroke in those with diabetes are not well characterized, especially by sex and age. We sought to calculate the sex- and age-specific risk of cardiovascular outcomes after ischemic stroke among those with diabetes. METHODS: Using population-based demographic and administrative health-care databases in Ontario, Canada, all patients with diabetes hospitalized with index ischemic stroke between April 1, 2002, and March 31, 2012, were followed for death, stroke, and myocardial infarction (MI). The Kaplan-Meier survival analysis and Fine-Gray competing risk models estimated hazards of outcomes by sex and age, unadjusted and adjusted for demographics and vascular risk factors. RESULTS: Among 25,495 diabetic patients with index ischemic stroke, the incidence of death was higher in women than in men (14.08 per 100 person-years [95% confidence interval [CI], 13.73-14.44] versus 11.89 [11.60-12.19]) but was lower after adjustment for age and other risk factors (adjusted hazard ratio [HR], .95 [.92-.99]). Recurrent stroke incidence was similar by sex, but men were more likely to be readmitted for MI (1.99 per 100 person-years [1.89-2.10] versus 1.58 [1.49-1.68] among females). In multivariable models, females had a lower risk of readmission for any event (HR, .96 [95% CI, .93-.99]). CONCLUSIONS: In this large, population-based, retrospective study among diabetic patients with index stroke, women had a higher unadjusted death rate but lower unadjusted incidence of MI. In adjusted models, females had a lower death rate compared with males, although the increased risk of MI among males persisted. These findings confirm and quantify sex differences in outcomes after stroke in patients with diabetes

Sex Differences in Outcomes after Stroke in Patients with Diabetes in Ontario, Canada.

BACKGROUND: Outcomes after stroke in those with diabetes are not well characterized, especially by sex and age. We sought to calculate the sex- and age-specific risk of cardiovascular outcomes after ischemic stroke among those with diabetes. METHODS: Using population-based demographic and administrative health-care databases in Ontario, Canada, all patients with diabetes hospitalized with index ischemic stroke between April 1, 2002, and March 31, 2012, were followed for death, stroke, and myocardial infarction (MI). The Kaplan-Meier survival analysis and Fine-Gray competing risk models estimated hazards of outcomes by sex and age, unadjusted and adjusted for demographics and vascular risk factors. RESULTS: Among 25,495 diabetic patients with index ischemic stroke, the incidence of death was higher in women than in men (14.08 per 100 person-years [95% confidence interval [CI], 13.73-14.44] versus 11.89 [11.60-12.19]) but was lower after adjustment for age and other risk factors (adjusted hazard ratio [HR], .95 [.92-.99]). Recurrent stroke incidence was similar by sex, but men were more likely to be readmitted for MI (1.99 per 100 person-years [1.89-2.10] versus 1.58 [1.49-1.68] among females). In multivariable models, females had a lower risk of readmission for any event (HR, .96 [95% CI, .93-.99]). CONCLUSIONS: In this large, population-based, retrospective study among diabetic patients with index stroke, women had a higher unadjusted death rate but lower unadjusted incidence of MI. In adjusted models, females had a lower death rate compared with males, although the increased risk of MI among males persisted. These findings confirm and quantify sex differences in outcomes after stroke in patients with diabetes

Functional consequences of Kir2.1/Kir2.2 subunit heteromerization

Kir2 subunits form channels that underlie classical strongly inwardly rectifying potassium currents. While homomeric Kir2 channels display a number of distinct and physiologically important properties, the functional properties of heteromeric Kir2 assemblies, as well as the stoichiometries and the arrangements of Kir2 subunits in native channels, remain largely unknown. Therefore, we have implemented a concatemeric approach, whereby all four cloned Kir2 subunits were linked in tandem, in order to study the effects of Kir2.1 and Kir2.2 heteromerization on properties of the resulting channels. Kir2.2 subunits contributed stronger to single-channel conductance than Kir2.1 subunits, and channels containing two or more Kir2.2 subunits displayed conductances indistinguishable from that of a Kir2.2 homomeric channel. In contrast, single-channel kinetics was a more discriminating property. The open times were significantly shorter in Kir2.2 channels compared with Kir2.1 channels and decreased nearly proportionally to the number of Kir2.2 subunits in the heteromeric channel. Similarly, the sensitivity to block by barium also depended on the proportions of Kir2.1 to Kir2.2 subunits. Overall, the results showed that Kir2.1 and Kir2.2 subunits exert neither a dominant nor an anomalous effect on any of the properties of heteromeric channels. The data highlight opportunities and challenges of using differential properties of Kir2 channels in deciphering the subunit composition of native inwardly rectifying potassium currents

Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF

Children’s Stories Supporting the Development of Critical Literacy and Intercultural Understanding

This chapter examines the possibilities of applying children’s storybooks in supporting the development of critical literacy as well as intercultural understanding. Valuing and supporting children’s reading is known to provide understanding and empathy towards other human beings. The chapter focuses on theoretical notions related to promoting critical literacies through children’s storybooks, but also includes practical examples of utilizing multicultural children’s stories. The chapter introduces different strategies that parents and teachers can use to support the development of critical literacy, including critical thinking and understanding multiple perspectives. Focus is especially on young children, because they already are capable of moving beyond what is in front of them on the page. Since children’s storybooks offer possibilities for readers to question implicit assumptions about self and others, books can support readers in becoming more culturally aware and sensitive. Consequently, reading storybooks can affect children’s intercultural understanding, and the role of storybooks in children’s moral development – both shaping and changing attitudes – should be seen as transformative.Peer reviewe

Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register

Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke

Insulin and IGF1 signalling pathways in human astrocytes <i>in vitro</i> and <i>in vivo</i>; characterisation, subcellular localisation and modulation of the receptors.

Background The insulin/IGF1 signalling (IIS) pathways are involved in longevity regulation and are dysregulated in neurons in Alzheimer’s disease (AD). We previously showed downregulation in IIS gene expression in astrocytes with AD-neuropathology progression, but IIS in astrocytes remains poorly understood. We therefore examined the IIS pathway in human astrocytes and developed models to reduce IIS at the level of the insulin or the IGF1 receptor (IGF1R). Results We determined IIS was present and functional in human astrocytes by immunoblotting and showed astrocytes express the insulin receptor (IR)-B isoform of Ir. Immunocytochemistry and cell fractionation followed by western blotting revealed the phosphorylation status of insulin receptor substrate (IRS1) affects its subcellular localisation. To validate IRS1 expression patterns observed in culture, expression of key pathway components was assessed on post-mortem AD and control tissue using immunohistochemistry. Insulin signalling was impaired in cultured astrocytes by treatment with insulin + fructose and resulted in decreased IR and Akt phosphorylation (pAkt S473). A monoclonal antibody against IGF1R (MAB391) induced degradation of IGF1R receptor with an associated decrease in downstream pAkt S473. Neither treatment affected cell growth or viability as measured by MTT and Cyquant® assays or GFAP immunoreactivity. Discussion IIS is functional in astrocytes. IR-B is expressed in astrocytes which differs from the pattern in neurons, and may be important in differential susceptibility of astrocytes and neurons to insulin resistance. The variable presence of IRS1 in the nucleus, dependent on phosphorylation pattern, suggests the function of signalling molecules is not confined to cytoplasmic cascades. Down-regulation of IR and IGF1R, achieved by insulin + fructose and monoclonal antibody treatments, results in decreased downstream signalling, though the lack of effect on viability suggests that astrocytes can compensate for changes in single pathways. Changes in signalling in astrocytes, as well as in neurons, may be important in ageing and neurodegeneration

Understanding the influence of race/Ethnicity, gender, and class on inequalities in academic and non-academic outcomes among eighth-grade students: findings from an intersectionality approach

Socioeconomic, racial/ethnic, and gender inequalities in academic achievement have been widely reported in the US, but how these three axes of inequality intersect to determine academic and non-academic outcomes among school-aged children is not well understood. Using data from the US Early Childhood Longitudinal Study—Kindergarten (ECLS-K; N = 10,115), we apply an intersectionality approach to examine inequalities across eighth-grade outcomes at the intersection of six racial/ethnic and gender groups (Latino girls and boys, Black girls and boys, and White girls and boys) and four classes of socioeconomic advantage/disadvantage. Results of mixture models show large inequalities in socioemotional outcomes (internalizing behavior, locus of control, and self-concept) across classes of advantage/disadvantage. Within classes of advantage/disadvantage, racial/ethnic and gender inequalities are predominantly found in the most advantaged class, where Black boys and girls, and Latina girls, underperform White boys in academic assessments, but not in socioemotional outcomes. In these latter outcomes, Black boys and girls perform better than White boys. Latino boys show small differences as compared to White boys, mainly in science assessments. The contrasting outcomes between racial/ethnic and gender minorities in self-assessment and socioemotional outcomes, as compared to standardized assessments, highlight the detrimental effect that intersecting racial/ethnic and gender discrimination have in patterning academic outcomes that predict success in adult life. Interventions to eliminate achievement gaps cannot fully succeed as long as social stratification caused by gender and racial discrimination is not addressed