St. Patrick's Hospital

Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr-abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells.

Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr- abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells.

Although the role of education in addressing the challenges of climate change is increasingly recognized, the education sector remains underutilized as a strategic resource to mitigate and adapt to climate change. Education stakeholders in many countries have yet to develop a coherent framework for climate change education (CCE). This article underscores the critical role that education can and should play in addressing and responding to climate change in all of its complexity. It provides rationales as to why CCE should be addressed in the context of Education for Sustainable Development (ESD). Advancing CCE in the context of ESD, or Climate Change Education for Sustainable Development (CCESD), requires enhancement of learners’ understanding of the causes and consequences of climate change and their readiness to take actions to address it. The article presents key organizing principles of CCESD and outlines key knowledge, skills, attitudes, dispositions and competences to be fostered through it.

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

This paper considers three potentially important modifications to the theory of reasoned action (Fishbein, 1980). It was hypothesized that behavioural norms, or beliefs about the behaviours of others, are important influences above and beyond subjective norms; the effects of attitudes and normative beliefs on intentions and behaviours are interdependent and interactive rather than additive; and the beliefs underlying subjective and behavioural norms are multidimensional rather than unidimensional. These hypotheses were tested in two surveys of smoking intentions and behaviour. The respondents in the first study were primary school children and those in the second study were college students. In both cases behavioural norms and the attitude-normative belief interactions led to significant increases in the prediction of smoking intentions and behaviour. Exploratory factor analyses also suggested that the beliefs underlying subjective norms may be multidimensional rather than unidimensional. These results thus support the hypotheses and suggest that the theory of reasoned action should be modified accordingly.

Cell death can occur by two possible mechanisms, necrosis or apoptosis. Necrosis is the classically recognised form of cell death and is characterised by high amplitude swelling of the mitochondria, nuclear flocculation and uncontrolled cell lysis. Tissue necrosis is normally seen following severe trauma to cells. The alternative form of cell death is via a programmed sequence of events and is termed apoptosis. Apoptosis occurs under a variety of physiological conditions and cells dying by this process undergo cytoplasmic and nuclear condensation, coupled with cleavage of the cell's DNA into nucleosome size fragments. DNA cleavage is due to the activation of a specific endogenous endonuclease. The cell finally fragments into apoptotic bodies which are engulfed by neighbouring cells and degraded. Apoptosis is an energy requiring process requiring intact energy generating systems, unlike that of necrosis. In relation to malignant disease, apoptosis is the mechanism by which cytotoxic T cells kill tumour target cells; it may also be the mechanism which accounts for the high loss of cells in growing tumour masses. Extensive apoptosis is seen in regressing tumours and also in those treated with chemotherapeutic agents. This form of death may require the activation of specific death genes, although in view of work carried out in this and other laboratories, demonstrating that inhibitors of both protein and RNA synthesis will readily induce apoptosis, this may not be universal. Finally, apoptosis has far reaching implications for the treatment of malignant disease, since only by understanding how cells die will be able to develop more effective means of killing them.

BACKGROUND: Patients with major depressive disorder (MDD) who attempt or complete suicide have elevated inflammation compared to nonsuicidal patients with MDD. However, greater severity of depression and the medical lethality of suicide attempts could account for such elevated inflammation in suicide attempters and suicide completers. METHODS: To clarify, we measured inflammatory markers in patients with MDD with and without high levels of suicidal ideation and in nondepressed controls (N = 124). Levels of suicidal ideation, depression severity, and recent suicide attempts were assessed by structured clinical interviews. A composite score including the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) was used as an inflammatory index. Analysis of covariance models were used to assess group differences with adjustments for age and gender. RESULTS: Patients with MDD and high suicidal ideation had significantly higher inflammatory index scores than both controls, F(1,53) = 18.08, partial η(2) = .25, P < .001, and patients with MDD and lower suicidal ideation F(1,44) = 7.59, partial η(2) = .15, P = .009. In contrast, patients with lower suicidal ideation were not significantly different from controls on the inflammatory index, F(1,63) = .52, partial η(2) = .01, P = .47. Follow-up analyses indicated that differences between patients with MDD and high versus lower suicidal ideation were independent of depression severity and recent suicide attempts. CONCLUSIONS: Suicidal ideation may be uniquely associated with inflammation in depressed patients.

Lack of physical activity is a global public health problem causing not only morbidity and premature mortality, but it is also a major economic burden worldwide. One of the cornerstones of a physically active lifestyle is Motor Competence (MC). MC is a complex biocultural attribute and therefore, its study requires a multi-sectoral, multi-, inter- and transdisciplinary approach. MC is a growing area of research, especially in children and adolescents due to its positive association with a plethora of health and developmental outcomes. Many questions, however, remain to be answered in this field of research, with regard to: (i) Health and Developmental-related Associations of MC; (ii) Assessment of MC; (iii) Prevalence and Trends of MC; (iv) Correlates and Determinants of MC; (v) MC Interventions, and (vi) Translating MC Research into Practice and Policy. This paper presents a narrative review of the literature, summarizing current knowledge, identifying key research gaps and presenting questions for future investigation on MC in children and adolescents. This is a collaborative effort from the International Motor Competence Network (IMCNetwork) a network of academics and researchers aiming to promote international collaborative research and knowledge translation in the expansive field of MC. The knowledge and deliverables generated by addressing and answering the aforementioned research questions on MC presented in this review have the potential to shape the ways in which researchers and practitioners promote MC and physical activity in children and adolescents across the world.

Social networks have been associated with a wide variety of health outcomes in older people. We examined the dimensions underlying the Wenger social support network type assessment to identify dimensions associated with mental and physical health. We interviewed 1334 community-dwelling participants aged 65+. The Geriatric Mental State automated geriatric examination for computer-assisted taxonomy interview was used to rate psychiatric symptoms and quality of life. Cognitive impairment was defined as a score of <24 on the mini mental state examination. Clustering around latent variables identified two uncorrelated social support network domains: family (distance from and contact with relatives) and social engagement. Social engagement was associated with a lower age- and sex-adjusted prevalence of depression (odds ratio for a one-tertile increase 0.48), generalised anxiety disorder (OR 0.60), cognitive impairment (OR 0.68) and physical disability (OR 0.62) all p < 0.001. Adjusted for age, sex, depression, cognitive impairment and disability, the social engagement domain was also associated with better quality of life (OR 1.5) self-rated happiness (OR 1.3) and rating life as worth living (OR 1.4). The family domain, on the other hand, was not significantly associated with any health outcome. The results suggest that elective relationships and social engagement are the 'active ingredients' of social networks which promote health in later life.

OBJECTIVES: Numerous long-term studies of depression in psychiatric settings have shown a poor clinical outcome but little emphasis has been placed on psychosocial or functional outcome in studies to date. This article reviews published data on long-term social functioning after depression and considers why psychosocial recovery appears delayed compared with clinical recovery. METHODS: Searches were carried out of the databases MEDLINE, PSYCHLIT and EMBASE for articles published from 1980 using keywords relating to social and functional outcomes of unipolar and bipolar depression. Review articles and relevant textbooks were also searched. RESULTS: The few outcome studies published have described long-term functional impairment in the majority of patients but have been limited by methodological shortcomings. Psychosocial impairment tends to persist even after clinical remission from depression. Residual symptomatology after remission from depression may lead to enduring psychosocial impairment, as may subtle neurocognitive deficits. Axis I and II comorbidities predict a poor psychosocial outcome, but episodes of depression do not appear to lead to personality 'scarring'. CONCLUSIONS: Future outcome studies need to focus on longitudinal social functioning. Full functional recovery after an episode of depression should be the goal of treatment as enduring residual symptoms lead to long-term psychosocial impairment.

OBJECTIVE: ECT is the most effective treatment for severe depression. Previous efficacy studies, using thrice-weekly brief-pulse ECT, reported that high-dose (6× seizure threshold) right unilateral ECT is similar to bitemporal ECT but may have fewer cognitive side effects. The authors aimed to assess the effectiveness and cognitive side effects of twice-weekly moderate-dose (1.5× seizure threshold) bitemporal ECT with high-dose unilateral ECT in real-world practice. METHOD: This was a pragmatic, patient- and rater-blinded, noninferiority trial of patients with major depression (N=138; 63% female; age=56.7 years [SD=14.8]) in a national ECT service with a 6-month follow-up. Participants were independently randomly assigned to bitemporal or high-dose unilateral ECT. The primary outcome was change in the 24-item Hamilton Depression Rating Scale (HAM-D) score after the ECT course; the prespecified noninferiority margin was 4.0 points. Secondary outcomes included response and remission rates, relapse status after 6 months, and cognition. RESULTS: Of the eligible patients, 69 were assigned to bitemporal ECT and 69 to unilateral ECT. High-dose unilateral ECT was noninferior to bitemporal ECT regarding the 24-item HAM-D scores after the ECT course (mean difference=1.08 points in favor of unilateral ECT [95% CI=-1.67 to 3.84]). There were no significant differences for response and remission or 6-month relapse status. Recovery of orientation was quicker following unilateral ECT (median=19.1 minutes versus 26.4 minutes). Bitemporal ECT was associated with a lower percent recall of autobiographical information (odds ratio=0.66) that persisted for 6 months. CONCLUSIONS: Twice-weekly high-dose unilateral ECT is not inferior to bitemporal ECT for depression and may be preferable because of its better cognitive side-effect profile.

Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

Gender differences in scholastic achievement as a function of method of measurement were examined by comparing the performance of 15‐year‐old boys (N = 739) and girls (N = 758) in Irish schools on multiple‐choice tests and free‐response tests (requiring short written answers) of mathematics, Irish, and English achievement. Males performed significantly better than females on multiple‐choice tests compared to their performance on free‐response examinations. An expectation that the gender difference would be larger for the languages and smaller for mathematics because of the superior verbal skills attributed to females was not fulfilled.

OBJECTIVES: To determine the prevalence of dementia in an Irish sample of people with Down's syndrome (DS) and to examine associated clinical characteristics of dementia in this group. METHOD: 285 people with DS (Age 35-74 years, mean age +/- SD 46.5 +/- 8.2 years) were included in this cross-sectional study. The diagnosis of dementia was made using modified DSMIV criteria. Cognitive tests used were the Down's syndrome Mental Status Examination (DSMSE), Test for Severe Impairment (TSI) and adaptive function was measured by the Daily Living Skills Questionnaire (DLSQ). RESULTS: The overall prevalence of dementia was 13.3%. The presence of dementia was associated with epilepsy, myoclonus, and head injury. The demented DS group were significantly older (n = 38, mean age 54.7 years SD +/- 7.5) than the non-demented (n = 246, mean age 45.6, SD +/- 7.3). The TSI and DLSQ had a satisfactory spread of scores without 'floor' or 'ceiling' effects in people with moderate and severe learning disability. Median scores in demented versus the non-demented groups were significantly different for each measure of function. CONCLUSIONS: Dementia had a prevalence of 13.3% and occurred at a mean age of 54.7 years. The combination of DLSQ score, age and presence of epilepsy were found to predict presence of dementia.

Lithium was first successfully used in the treatment of mania by Cade (1949), and its efficacy in reducing mania was confirmed in double-blind trials by Schou et al. (1954) and Maggs (1963).

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

The Program for International Student Assessment (PISA) is a global effort to assess reading literacy. The authors of this article focus on the variable of engagement—the student characteristic on PISA that had the largest correlation with achievement in reading. Next, salient findings related to engagement from three English‐speaking PISA countries (the United States, the United Kingdom, and Ireland) are presented. The authors conclude with a discussion of lessons about reading engagement derived from findings common to the authors' three nations with implications for policy and practice.

The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

A happy combination of lucid writing and careful analysis or worldwide research. For both educators and policy-makers, it will illuminate the educational roles of families and the potential of families and schools to work together.?Harold Howe II, senior lecturer in education at Harvard University and former U.S. Commissioner of Education

There is a growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of depression, particularly with respect to predicting response to specific therapeutic strategies. MicroRNAs are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level and emerging evidence from a range of studies has highlighted their biomarker potential. Here we compared healthy controls (n=20) with patients diagnosed with major depression (n=40) and who were treatment-resistant to identify peripheral microRNA biomarkers, which could be used for diagnosis and to predict response to electroconvulsive therapy (ECT) and ketamine (KET) infusions, treatments that have previously shown to be effective in treatment-resistant depression (TRD). At baseline and after treatment, blood samples were taken and symptom severity scores rated using the Hamilton Depression Rating Scale (HDRS). Samples were analyzed for microRNA expression using microarray and validated using quantitative PCR. As expected, both treatments reduced HDRS scores. Compared with controls, the baseline expression of the microRNA let-7b was less by ~40% in TRD patients compared with controls. The baseline expression of let-7c was also lower by ~50% in TRD patients who received ECT. Bioinformatic analysis revealed that let-7b and let-7c regulates the expression of 27 genes in the PI3k-Akt-mTOR signaling pathway, which has previously been reported to be dysfunctional in depression. The expression of miR-16, miR-182, miR-451 and miR-223 were similar to that in controls. Baseline microRNA expression could not predict treatment response and microRNAs were unaffected by treatment. Taken together, we have identified let-7b and let-7c as candidate biomarkers of major depression.