Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography.After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement of infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 ± 1.9% in the control group, 72.4 ± 2.4% in the propranolol-treated dogs (p < 0.05 versus control group); 57.9 ± 4.4% in the timolol-treated dogs (p < 0.01 versus control group; p < 0.05 versus propranolol) and 54.4 ± 3.7% in the metoprolol-treated dogs (p < 0.01 versus control group; p < 0.05 versus propranolol).Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol

Aqp 9 and Brain Tumour Stem Cells

Several studies have implicated the aquaporins (aqp) 1, 4, and 9 in the pathogenesis of malignant brain tumours, suggesting that they contribute to motility, invasiveness, and oedema formation and facilitate metabolism in tumour cells under hypoxic conditions. We have studied the expression of aqp1, 4, and 9 in biopsies from glioblastomas, isolated tumour stem cells grown in a tumoursphere assay and analyzed the progenitor and differentiated cells from these cultures. We have compared these to the situation in normal rat brain, its stem cells, and differentiated cells derived thereof. In short, qPCR in tumour tissue showed presence of aqp1, 4, and 9. In the tumour progenitor population, aqp9 was markedly more highly expressed, whilst in tumour-derived differentiated cells, aqp4 was downregulated. However, immunostaining did not reveal increased protein expression of aqp9 in the tumourspheres containing progenitor cells; in contrast, its expression (both mRNA and protein) was high in differentiated cultures. We, therefore, propose that aquaporin 9 may have a central role in the tumorigenesis of glioblastoma

Functional temozolomide sensitivity testing of patient-specific glioblastoma stem cell cultures is predictive of clinical outcome

Serum-free culturing of patient-derived glioblastoma biopsies enrich for glioblastoma stem cells (GSCs) and is recognized as a disease-relevant model system in glioblastoma (GBM). We hypothesized that the temozolomide (TMZ) drug sensitivity of patient-derived GSC cultures correlates to clinical sensitivity patterns and has clinical predictive value in a cohort of GBM patients. To this aim, we established 51 individual GSC cultures from surgical biopsies from both treatment-naive primary and pretreated recurrent GBM patients. The cultures were evaluated for sensitivity to TMZ over a dosing range achievable in normal clinical practice. Drug efficacy was quantified by the drug sensitivity score. MGMT-methylation status was investigated by pyrosequencing. Correlative, contin-gency, and survival analyses were performed for associations between experimental and clinical data. We found a heterogeneous response to temozolomide in the GSC culture cohort. There were significant differences in the sensitivity to TMZ between the newly diagnosed and the TMZ-treated recurrent disease (pPeer reviewe

Gene expression profiles in rat brain disclose CNS signature genes and regional patterns of functional specialisation

Background: The mammalian brain is divided into distinct regions with structural and neurophysiological differences. As a result, gene expression is likely to vary between regions in relation to their cellular composition and neuronal function. In order to improve our knowledge and understanding of regional patterns of gene expression in the CNS, we have generated a global map of gene expression in selected regions of the adult rat brain (frontomedial-, temporal- and occipital cortex, hippocampus, striatum and cerebellum; both right and left sides) as well as in three major non-neural tissues (spleen, liver and kidney) using the Applied Biosystems Rat Genome Survey Microarray. Results: By unsupervised hierarchical clustering, we found that the transcriptome within a region was highly conserved among individual rats and that there were no systematic differences between the two hemispheres (right versus left side). Further, we identified distinct sets of genes showing significant regional enrichment. Functional annotation of each of these gene sets clearly reflected several important physiological features of the region in question, including synaptic transmission within the cortex, neurogenesis in hippocampus and G-protein-mediated signalling in striatum. In addition, we were able to reveal potentially new regional features, such as mRNA transcription- and neurogenesis-annotated activities in cerebellum and differential use of glutamate signalling between regions. Finally, we determined a set of 'CNSsignature' genes that uncover characteristics of several common neuronal processes in the CNS, with marked overrepresentation of specific features of synaptic transmission, ion transport and cell communication, as well as numerous novel unclassified genes. Conclusion: We have generated a global map of gene expression in the rat brain and used this to determine functional processes and pathways that have a regional preference or ubiquitous distribution within the CNS, respectively. The existence of shared specialised neuronal activities in CNS is interesting in a context of potential functional redundancy, and future studies should further explore the overall characteristics of CNS-specific versus region-specific gene profiles in the brain

Benzodiazepines and antidepressants: Effects on cognitive and functional decline in Alzheimer's disease and Lewy body dementia

Objectives We aim to study the effects of the prescription of benzodiazepines and antidepressants on cognitive and functional decline in older adults living with Alzheimer's disease (AD) and Lewy body dementia (LBD) over a 5-year follow-up. Methods This is a longitudinal analysis of a Norwegian cohort study entitled “The Dementia Study of Western Norway” (DemVest). We included 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed annually for 5 years. Three prescription groups were defined: only benzodiazepines (BZD), only antidepressants (ADep), and the combination of benzodiazepines and antidepressants (BZD-ADep). Linear mixed-effects models were conducted to analyze the effect of the defined groups on the outcomes. The outcomes were functional decline, measured by the Rapid Disability Rating Scale—2, and cognition measured with the Mini-Mental State Examination. Results Prescription of the combination of benzodiazepines and antidepressants in LBD was associated with faster functional decline. In AD, the prescription of BZD and BZD-ADep was associated with greater functional deterioration. ADep alone did not show positive or negative significant associations with the studied outcomes. Conclusions BZD and especially the combination of BZD and ADep are associated with functional decline in AD and LBD and should be used cautiously.publishedVersio

Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome

AbstractGlioblastoma is the most common brain tumor. Median survival in unselected patients is <10 months. The tumor harbors stem-like cells that self-renew and propagate upon serial transplantation in mice, although the clinical relevance of these cells has not been well documented. We have performed the first genome-wide analysis that directly relates the gene expression profile of nine enriched populations of glioblastoma stem cells (GSCs) to five identically isolated and cultivated populations of stem cells from the normal adult human brain. Although the two cell types share common stem- and lineage-related markers, GSCs show a more heterogeneous gene expression. We identified a number of pathways that are dysregulated in GSCs. A subset of these pathways has previously been identified in leukemic stem cells, suggesting that cancer stem cells of different origin may have common features. Genes upregulated in GSCs were also highly expressed in embryonic and induced pluripotent stem cells. We found that canonical Wnt-signaling plays an important role in GSCs, but not in adult human neural stem cells. As well we identified a 30-gene signature highly overexpressed in GSCs. The expression of these signature genes correlates with clinical outcome and demonstrates the clinical relevance of GSCs

Mapping trends in the care workforce using SOC 1990 and SOC 2000

NAT12/NAA30 knockdown resulted in dysregulation of the hypoxia response pathway as shown by microarray analysis. Asterisks signify p values and indicate level of significance. *=(p≈0.01-0.05), **=(p≈0.001-0.01)

Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder

<p>Abstract</p> <p>Background</p> <p>Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.</p> <p>Methods</p> <p>Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.</p> <p>Results</p> <p>The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively.</p> <p>Conclusions</p> <p>A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials.</p> <p>Trial Registration</p> <p>The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).</p