Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells

BACKGROUND: Astrocytomas are the most common type of primary central nervous system tumors. They are frequently associated with genetic mutations that deregulate cell cycle and render these tumors resistant to apoptosis. STAT3, signal transducer and activator of transcription 3, participates in several human cancers by inducing cell proliferation and inhibiting apoptosis and is frequently activated in astrocytomas. METHODS: RNA interference was used to knockdown STAT3 expression in human astrocytes and astrocytoma cell lines. The effect of STAT3 knockdown on apoptosis, cell proliferation, and gene expression was then assessed by standard methods. RESULTS: We have found that STAT3 is constitutively activated in several human astrocytoma cell lines. Knockdown of STAT3 expression by siRNA induces morphologic and biochemical changes consistent with apoptosis in several astrocytoma cell lines, but not in primary human astrocytes. Moreover, STAT3 is required for the expression of the antiapoptotic genes survivin and Bcl-xL in the A172 glioblastoma cell line. CONCLUSION: These results show that STAT3 is required for the survival of some astrocytomas. These studies suggest STAT3 siRNA could be a useful therapeutic agent for the treatment of astrocytomas

Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure

Effect of esophagogastric devascularization with splenectomy on schistossomal portal hypertension patients' immunity Efeito da cirurgia de desconexão ázigo-portal com esplenectomia na imunidade de doentes com hipertensão portal esquistossomótica

BACKGROUND: Surgical treatment of hemorrhagic complication in schistosomal portal hypertension in our hospital is an esophagogastric devascularization procedure with splenectomy. Infectious risks and immunological alterations imputed to splenectomy may have significant importance. To minimize the consequences of spleen absence, the use of subtotal splenectomy and spleen auto-transplantation were stimulated. AIM: To verify the immunologic alterations imposed by this procedure in our patients. METHOD: Twenty-eight patients with schistosomal portal hypertension and previous history of upper digestive bleeding due to esophagogastric varices rupture underwent elective esophagogastric devascularization and splenectomy. They were prospectively studied before esophagogastric devascularization procedure with splenectomy, 15 and 30 days, 3 and 6 months after the procedure. T and B-lymphocytes, CD4 and CD8 subpopulations were determinated by monoclonal antibodies. Immunoglobulins A, M, G and C3, C4 components of the complement were determinated by radial immunodiffusion. RESULTS: We observed important reduction of all immune cells, increase of IgG and normal levels of IgM, IgA, C3 and C4 at preoperative. CD4/CD8 relation was normal. Six months after esophagogastric devascularization procedure with splenectomy, significant increase in T-lymphocytes, CD4, CD8 and B-lymphocytes were observed. CD4/CD8 relation remained normal. We noted significant increase in C3. IgA, IgM, IgG and C4 had increased, but without significant difference. CONCLUSION: Esophagogastric devascularization procedure with splenectomy determines an increase in T and B-lymphocytes, CD4 and CD8 subpopulations without compromising immunoglobulins and components of complement levels.<br>RACIONAL: A cirurgia de desconexão ázigo-portal com esplenectomia é utilizada no tratamento da complicação hemorrágica varicosa dos esquistossomóticos hepatoesplênicos com hipertensão do sistema portal, no Serviço de Fígado e Hipertensão Portal da Santa Casa de São Paulo. Envolvendo a esplenectomia, os riscos infecciosos e alterações imunológicas imputados a ela têm importância significativa. A esplenectomia subtotal e o auto-implante esplênico foram alternativas descritas para minimizar as conseqüências da esplenectomia nesses doentes. OBJETIVO: Avaliar o estado imunológico dos esquistossomóticos hepatoesplênicos e qual a alteração imunológica imposta pelo procedimento nesses doentes. MÉTODO: Vinte e oito esquistossomóticos com hipertensão portal e episódio hemorrágico varicoso foram estudados prospectivamente antes, 15 e 30 dias e 3 e 6 meses após a desconexão ázigo-portal com esplenectomia. Realizou-se contagem de linfócitos T, B, células CD4+ e CD8+ através de anticorpos monoclonais e dosagem das imunoglobulinas A, M, G e frações C3 e C4 do sistema complemento por imunodifusão radial. RESULTADOS: Obteve-se diminuição importante de todas as células, aumento de IgG e níveis normais de IgM, IgA, C3 e C4 no pré-operatório. A relação CD4+/CD8+ foi normal. Seis meses após a cirurgia, houve aumento significativo do número de linfócitos T, CD4+, CD8+ e linfócitos B. A relação CD4+/CD8+ manteve-se normal, sem variação. Houve aumento significativo nos níveis de C3. IgA, IgM, IgG e C4 também aumentaram, mas sem diferença significativa. CONCLUSÃO: Os linfócitos T, suas subpopulações CD4+ e CD8+, e os linfócitos B estão diminuídos no pré-operatório. Decorridos 6 meses da desconexão ázigo-portal com esplenectomia houve aumento do número de linfócitos T, das subpopulações CD4+ e CD8+, e dos linfócitos B. Após a desconexão ázigo-portal com esplenectomia não houve alteração das dosagens de imunoglobulinas nem diminuição do sistema complemento

Global adaptation patterns of Australian and CIMMYT spring bread wheat

The International Adaptation Trial (IAT) is a special purpose nursery designed to investigate the genotype-by-environment interactions and worldwide adaptation for grain yield of Australian and CIMMYT spring bread wheat (Triticum aestivum L.) and durum wheat (T. turgidum L. var. durum). The IAT contains lines representing Australian and CIMMYT wheat breeding programs and was distributed to 91 countries between 2000 and 2004. Yield data of 41 reference lines from 106 trials were analysed. A multiplicative mixed model accounted for trial variance heterogeneity and inter-trial correlations characteristic of multi-environment trials. A factor analytic model explained 48% of the genetic variance for the reference lines. Pedigree information was then incorporated to partition the genetic line effects into additive and non-additive components. This model explained 67 and 56% of the additive by environment and non-additive by environment genetic variances, respectively. Australian and CIMMYT germplasm showed good adaptation to their respective target production environments. In general, Australian lines performed well in south and west Australia, South America, southern Africa, Iran and high latitude European and Canadian locations. CIMMYT lines performed well at CIMMYT's key yield testing location in Mexico (CIANO), north-eastern Australia, the Indo-Gangetic plains, West Asia North Africa and locations in Europe and Canada. Maturity explained some of the global adaptation patterns. In general, southern Australian germplasm were later maturing than CIMMYT material. While CIANO continues to provide adapted lines to northern Australia, selecting for yield among later maturing CIMMYT material in CIANO may identify lines adapted to southern and western Australian environments

Multimodal Voxel-Based Meta-Analysis of White Matter Abnormalities in Obsessive-Compulsive Disorder

White matter (WM) abnormalities have long been suspected in obsessive–compulsive disorder (OCD) but the available evidence has been inconsistent. We conducted the first multimodal meta-analysis of WM volume (WMV) and fractional anisotropy (FA) studies in OCD. All voxel-wise studies comparing WMV or FA between patients with OCD and healthy controls in the PubMed, ScienceDirect, Google Scholar, Web of Knowledge and Scopus databases were retrieved. Manual searches were also conducted and authors were contacted soliciting additional data. Thirty-four data sets were identified, of which 22 met inclusion criteria (five of them unpublished; comprising 537 adult and pediatric patients with OCD and 575 matched healthy controls). Whenever possible, raw statistical parametric maps were also obtained from the authors. Peak and raw WMV and FA data were combined using novel multimodal meta-analytic methods implemented in effect-size signed differential mapping. Patients with OCD showed widespread WM abnormalities, but findings were particularly robust in the anterior midline tracts (crossing between anterior parts of cingulum bundle and body of corpus callosum), which showed both increased WMV and decreased FA, possibly suggesting an increase of fiber crossing in these regions. This finding was also observed when the analysis was limited to adult participants, and especially pronounced in samples with a higher proportion of medicated patients. Therefore, patients with OCD may have widespread WM abnormalities, particularly evident in anterior midline tracts, although these changes might be, at least in part, attributable to the effects of therapeutic drugs