Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death

Beneficial Effects of Estrogen in a Mouse Model of Cerebrovascular Insufficiency

BACKGROUND: The M(5) muscarinic acetylcholine receptor is known to play a crucial role in mediating acetylcholine dependent dilation of cerebral blood vessels. Previously, we reported that male M(5) muscarinic acetylcholine knockout mice (M5R(-/-) mice) suffer from a constitutive constriction of cerebral arteries, reduced cerebral blood flow, dendritic atrophy, and short-term memory loss, without necrosis and/or inflammation in the brain. METHODOLOGY/PRINCIPAL FINDINGS: We employed the Magnetic Resonance Angiography to study the area of the basilar artery in male and female M5R(-/-) mice. Here we show that female M5R(-/-) mice did not show the reduction in vascular area observed in male M5R(-/-) mice. However, ovariectomized female M5R(-/-) mice displayed phenotypic changes similar to male M5R(-/-) mice, strongly suggesting that estrogen plays a key role in the observed gender differences. We found that 17beta-estradiol (E2) induced nitric oxide release and ERK activation in a conditional immortalized mouse brain cerebrovascular endothelial cell line. Agonists of ERalpha, ERbeta, and GPR30 promoted ERK activation in this cell line. Moreover, in vivo magnetic resonance imaging studies showed that the cross section of the basilar artery was restored to normal in male M5R(-/-) mice treated with E2. Treatment with E2 also improved the performance of male M5R(-/-) mice in a cognitive test and reduced the atrophy of neural dendrites in the cerebral cortex and hippocampus. M5R(-/-) mice also showed astrocyte swelling in cortex and hippocampus using the three-dimensional reconstruction of electron microscope images. This phenotype was reversed by E2 treatment, similar to the observed deficits in dendrite morphology and the number of synapses. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that M5R(-/-) mice represent an excellent novel model system to study the beneficial effects of estrogen on cerebrovascular function and cognition. E2 may offer new therapeutic perspectives for the treatment of cerebrovascular insufficiency related memory dysfunction

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd

No association between circulating concentrations of vitamin D and risk of lung cancer: An analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in pre-diagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5,313 lung cancer cases and 5,313 controls selected from. Blood samples for the cases were collected, on average, 5 years prior to lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in 5 categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for 25(OH)D as both a continuous and categorical variable. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% confidence interval: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer ris

Ajuste social em pacientes com transtorno afetivo bipolar, unipolar, distimia e depressão dupla Social disability in patients with bipolar and unipolar affective disorders, dysthymia and double depression

OBJETIVOS: Dados internacionais mostram que os transtornos afetivos têm uma prevalência de, aproximadamente, 11,3% da população. Além disso, são uma das doenças que mais geram perdas sociais e nos relacionamentos familiares. O objetivo deste trabalho foi avaliar o ajuste social e familiar de pacientes com transtornos afetivos (bipolar, unipolar, distimia e com depressão dupla), comparando o resultado entre as categorias diagnósticas, além de verificar quais variáveis estão associadas e conduzem ao pior ajuste. MÉTODOS: Foram feitos a caracterização socioeconômica e demográfica e um levantamento dos dados de evolução e de história da doença por meio de um questionário elaborado para essa finalidade. Para a avaliação de ajuste social, utilizou-se a Escala de Avaliação da Incapacitação Psiquiátrica (DAS/OMS, 1998). O relacionamento familiar foi avaliado pelo Global Assessment of Relational Functioning Scale (GARF/APA, 1994). Foram estudados 100 pacientes em tratamento, por pelo menos seis meses, no Ambulatório de Psiquiatria da Faculdade de Medicina Unesp, Botucatu, SP. RESULTADOS/CONCLUSÕES: Com predomínio de mulheres, a maioria dos pacientes tinha no mínimo dois anos de seguimento, idade acima de 50 anos, baixa escolaridade e nível socioeconômico baixo. Não houve diferença estatística significativa quanto aos dados socioeconômicos e demográficos. Na análise de regressão logística, o diagnóstico e o relacionamento familiar tiveram papel significativo no resultado de ajustamento social. Os pacientes unipolares e os distímicos tiveram melhores resultados no ajustamento social e no relacionamento familiar do que os bipolares e aqueles com depressão dupla.<br>OBJECTIVES: International data show that affective disorders have a prevalence of 11.3% in the general population. Besides that, they are responsible for social dysfunctioning and family relationship distress. The aim of this study was to assess social and family disability in affective disorder patients (bipolar and unipolar disorders, dysthymia, and double depression); and then compare the results among diagnostic groups to identify variables associated with an increased level of disability. METHODS: Socioeconomic and demographic data as well as evolution, outcome and disease history data were collected using a specific questionnaire. To assess social disability, the Disability Assessment Scale (DAS-WHO, 1988) was used. Family relationship distress was assessed through the Global Assessment of Relational Functioning Scale (GARF-APA, 1994). A hundred patients who were under treatment for at least 6 months at the university outpatient clinic were studied. RESULTS/CONCLUSIONS: Most of the patients were females, 50 years old or more, had at least 2 years of follow-up, and low educational and socioeconomic level. There was no statistical significant differences among demographic and socioeconomic levels and different diagnostic categories. Logistic regression analysis showed an important impact in social functioning due to the diagnosis and family relationship. Unipolar and dysthymic patients had better outcome in social and family functioning than bipolar and double depression ones