Reliability and Validity of the Persian Version of the World Health Organization-Five Well-Being Index

Background: A multidimensional approach to health which addresses the psychological features of health justifies the necessity of designing or validation of brief instruments for screening in general population. This study aims to evaluate the reliability and validity of the Persian version of the WHO-5-P as a brief scale of well-being.Methods: In this study 451 individuals, i.e., over-15-year old subjects completed the WHO-5-P and GHQ-28 questionnaires. Crombach’s alpha and factor analysis were used for internal consistency evaluation. For predictive validity we compared WHO-5-P with GHQ-28 scores using receiver operating characteristic (ROC) analysis.Results: The mean age, score of WHO-5-P and GHQ-28 were 32.3±11.5, 13.4±6.5, and 25.4±13.4 respectively. The WHO-5-P had an acceptable internal consistency (α= 0.94), and it showed adequate convergent validity with the GHQ-28 (r= -0.66; P<0.001). The optimal cut-off score of the WHO-5-P was <13 (12.13) with a sensitivity of 0.68 and a specificity of 0.85. The area under curve in this study was 0.82. Confirmatory factor analysis revealed one factor structure.Conclusions: WHO-5-P is a valid and reliable instrument for screening psychological state

Reliability and Validity of the Persian Version of the World Health Organization-Five Well-Being Index

Background: A multidimensional approach to health which addresses the psychological features of health justifies the necessity of designing or validation of brief instruments for screening in general population. This study aims to evaluate the reliability and validity of the Persian version of the WHO-5-P as a brief scale of well-being.Methods: In this study 451 individuals, i.e., over-15-year old subjects completed the WHO-5-P and GHQ-28 questionnaires. Crombach’s alpha and factor analysis were used for internal consistency evaluation. For predictive validity we compared WHO-5-P with GHQ-28 scores using receiver operating characteristic (ROC) analysis.Results: The mean age, score of WHO-5-P and GHQ-28 were 32.3±11.5, 13.4±6.5, and 25.4±13.4 respectively. The WHO-5-P had an acceptable internal consistency (α= 0.94), and it showed adequate convergent validity with the GHQ-28 (r= -0.66; P<0.001). The optimal cut-off score of the WHO-5-P was <13 (12.13) with a sensitivity of 0.68 and a specificity of 0.85. The area under curve in this study was 0.82. Confirmatory factor analysis revealed one factor structure.Conclusions: WHO-5-P is a valid and reliable instrument for screening psychological state

β-Amyloid 1-42 Oligomers Impair Function of Human Embryonic Stem Cell-Derived Forebrain Cholinergic Neurons

Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the β-amyloid (Aβ) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Aβ1-40 and Aβ1-42 (nM-µM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Aβ1–40 increased the number of functional neurons, whereas oligomeric Aβ1–42 suppressed the number of functional neurons. Interestingly, oligomeric Aβ exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Aβ1–40 and Aβ1–42 induced gliogenesis. These findings indicate that Aβ1–42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Aβ

Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease

The accumulation of β-amyloid in the brain is an early event in Alzheimer’s disease. This study presents the first patient with Alzheimer’s disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer’s disease brain. The patient underwent positron emission tomography studies with 18F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of 3H-nicotine and 125I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes

Characterization and expression of subtypes of nicotinic receptors in brain and adrenal medulla : With focus on development, Alzheimer's disease and transgenic animal models

The cholinergic nicotinic receptors (nAChRs) seem to play an important role in numerous important physiological processes in brain as well as peripheral tissues of man. In first trimester human brain mRNA levels for the alpha3, alpha4, alpha5, alpha7, beta2, beta3, and beta4 nAChR subunits and binding sites were detected at 5 weeks of gestation. A significant decrease in both number of 3 Hcytisine binding sites (alpha4 ligand) and mRNA level for the alpha4 nAChR while no change in 3 Hepibatidine binding sites (alpha3 and alpha4 ligand) or level of alpha3 mRNA was seen in the aged brain compared to fetal brain. In contrast, a significantly decreased number of the 3 H-epibatidine binding sites was observed in the aged adrenal medulla compared to fetal adrenal medulla. The relative mRNA level of alpha3 nAChR subunit was found to be 1000% higher in adult mice adrenal medulla compared to brain while a corresponding -40% and -29% lower mRNA expression of alpha4 and alpha7 nAChR subunits was observed in mice adrenal medulla compared to brain. A significantly higher protein level for the alpha3 nAChR subunit was observed of the rat adrenal medulla while the alpha4 subunit protein was much lower. Saturation binding studies With 3 H-epibatidine in homogenates of rat adrenal medulla revealed the presence of solely one high affinity binding site suggesting a high abundance of the alpha3 nAChR subtype in comparison to the alpha4 and alpha7 nAChR subunits in rodent adrenal medulla. An age- related reduction in receptor protein levels were observed for the alpha3, alpha4, alpha7 and beta2 nAChR subunits in both brain and adrenal medulla of rat. Changes in nAChR subtypes were compared in the adrenal medulla and brain of two different transgenic mice models i.e. the APPSWETg, which overexpress human beta-amyloid and hAChE-Tg which over- express human acetylcholine- esterase. Both transgenic mice models show impairment in cognitive function although the underlying causative mechanisms are probably different. An increased relative mRNA level for the alpha7 subunit was observed in adrenal medulla of both APPSWETg (+53%) and hAChE-Tg (+56%) while no significant change in alpha7 mRNA was observed in the brain in the transgenic mice compared to non-transgenic mice. On the other hand, opposite changes were observed for the alpha3 mRNA in adrenal medulla where an increase (+18%) was observed in hAChE-Tg mice while a decrease (-28%) was observed in APPSWETg mice. Thus, different underlying pathological mechanisms can cause different changes in the expression levels of various niches in brain and adrenal medulla. Changes in nAChR subtypes were investigated in the autopsy brain tissues from Patients with Alzheimer's disease (AD). A significant decrease in protein levels of the nAChR subtypes and number of nAChR binding sites were observed while no significant change was observed in the corresponding subunit mRNA levels except for the alpha7 subunit where an increase in relative mRNA level was observed in the hippocampus. The findings suggest that the changes in nAChRs in AD seem mainly to occur at posttranscriptional level. Nicotine is well known to induce an upregulation of the nAChRs in brain. In rat sub-chronical treatement with nicotine caused no upregulation in the either 3 H-nicotine or 3 H-epibatidine binding sites in the adrenal medulla while a significant increase in number of binding sites of both ligands was measured in the brain. The findings suggest both receptor subtype and organ-specific effects of nicotine exposure. Investigation of post-mortem brain tissue from smoking AD patients and controls showed an upregulation of the alpha4 nAChR protein and binding sites compared to non-smoking subjects. No significant change was detected in the mRNA levels for the various nAChRs subunits either in smoking controls or in smoking AD patients. In addition significantly lower levels of both soluble and insoluble Abeta 1-40 and AP 1-42 were observed in frontal and temporal cortex of smoking AD subjects compared to non-smoking AD subjects. From the findings of this thesis it is evident that different nAChRs with different subtype specificity and density express in brain and adrenal medulla. Internal and external factors including development, ageing, pathological mechanism and drug exposure differently regulate the expression levels of the various nAChR subtypes in adrenal medulla compared to brain

Retinoic Acid And Nerve Growth Factor Induce Differential Regulation Of Nicotinic Acetylcholine Receptor Subunit Expression In Sn56 Cells

Retinoic acid (RA) and nerve growth factor (NGF) have multiple functions in the regulation of neuronal development. In the present study, we characterized the expression of different nicotinic acetylcholine receptor (nAChR) subtypes in the cholinergic SN56 cell line and investigated the roles of RA and NGF in the expression of choline acetyltransferase (ChAT) and different nAChR subtypes. The nAChR agonist [3H]epibatidine was bound to two sites, with apparent affinities of 13 and 380 pM. RT-PCR analysis revealed expression of α3, α4, α5, α7, β2, and β4 nAChR subunits. RA treatment induced morphological changes, and the mRNA level of ChAT was maximally elevated after 4 days of exposure. The density of [3H]epibatidine binding sites and the mRNA and protein level of the α3 and β2 nAChR subunits were also increased by RA-induced differentiation. RA down-regulated the mRNA and protein level of the α4 nAChR subunit, whereas no significant change was observed in the mRNA and protein level of the α7 nAChR subunit. NGF treatment increased the mRNA and protein level of the α3 and β2 nAChR subunits. No morphological effects of NGF were observed, and the mRNA level of ChAT and mRNA and protein level of the α4 and α7 nAChR subunits were not significantly altered. Validation was performed with real-time RT-PCR. The present results show that RA and NGF have different effects on the expression of ChAT and the morphology and the expression pattern of different nAChR subunits in cholinergic SN56 cells. © 2007 Wiley-Liss, Inc

Serum metabolomic biomarkers of dementia

Aims: This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis. Methods: Cognitively healthy participants were followed up for 5-20 years. Cognitive assessment, serum sampling, and diagnosis were completed every 5 years. Multivariate analyses were conducted on the metabolite profiles generated by gas chromatography/time-of-flight mass spectrometry. Results: A significant group separation was found between demented patients and controls, and between incident cases and controls. Metabolites that contributed in both analyses were 3,4-dihydroxybutanoic acid, docosapentaenoic acid, and uric acid. Conclusions: Serum metabolite profiles are altered in demented patients, and detectable up to 5 years preceding the diagnosis. Blood sampling can make an important contribution to the early prediction of conversion to dementia

Serum metabolomic biomarkers of dementia

Aims: This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis. Methods: Cognitively healthy participants were followed up for 5-20 years. Cognitive assessment, serum sampling, and diagnosis were completed every 5 years. Multivariate analyses were conducted on the metabolite profiles generated by gas chromatography/time-of-flight mass spectrometry. Results: A significant group separation was found between demented patients and controls, and between incident cases and controls. Metabolites that contributed in both analyses were 3,4-dihydroxybutanoic acid, docosapentaenoic acid, and uric acid. Conclusions: Serum metabolite profiles are altered in demented patients, and detectable up to 5 years preceding the diagnosis. Blood sampling can make an important contribution to the early prediction of conversion to dementia

eNanoMapper applications to support the risk assessment of nanomaterials

<p>The infrastructure developed within eNanoMapper project aims to support the data management in the area of nano safety research and to enable an integrated approach for the risk assessment of nanomaterials. To achieve these, eNanoMapper developed an ontology, a data infrastructure and modelling tools with applicability in risk assessment of nanomaterials. By merging the expertise of partners in statistical and data mining tools and in predictive toxicology, biology and nanotechnology research, eNanoMapper developed resources and tools for predicting toxicity of nanomaterials and worked towards improving the standards in risk assessment of nanomaterials. The ontology includes common vocabulary terms used in nanosafety research and aims to provide a clear explanation of nanostructures based on information relating to their characterization, relevant experimental paradigms, biological interactions, safety indications and the integration of data from existing nanotoxicology sources. To support a collaborative safety assessment approach an infrastructure for data management was developed, with a database which includes functionalities for data protection, data sharing, data quality assurance, search and interfaces for different needs and usages, comparability and cross-talk with other databases. Further, a collection of descriptors, computational toxicology models and modelling tools were developed, to enable the use and integration of nanosafety data from various sources. The project provides also a rich source of information and documentation (e.g. tutorials, webinars, publications) to support and guide the users. eNanoMapper is supported by European Commission 7^th Framework Programme for Research and Technological Development Grant (Grant agreement no: 604134).</p