2,4-二氨基-5-取代苄基嘧啶类化合物的合成及其抑酶活性

本文设计并合成了18个在苄基上带有不同体积取代基的2,4-二氨基-5-取代苄基嘧啶类化合物。测定了这些化合物对乳酪菌二氢叶酸还原酶及对鸡肝二氢叶酸还原酶的表观50%抑制作用。其中2,4-二氨基-5-(3′-羟基-4′-甲氧基)苄基、2,4-二氨基-5-(3′-甲氧基-4′-甲氧乙氧基)苄基嘧啶对上述二氢叶酸还原酶(DHFR)的选择性较好。     

Risk Profiles for Mild Cognitive Impairment Vary by Age and Sex: The Sydney Memory and Ageing Study

OBJECTIVES:: To examine age- and sex-related differences in risk and protective factors for mild cognitive impairment (MCI) in community-based elderly individuals. DESIGN:: Cross-sectional study. SETTING:: The population-based Sydney Memory and Ageing Study. PARTICIPANTS:: A total of 757 nondemented, community-dwelling elderly individuals from an English-speaking background categorized as younger (70-79 years) or older (80-90 years). MEASUREMENTS:: Risk of MCI was determined for sociodemographic, lifestyle, and cardiac, physical, mental, and general health factors using age- (and sex-) adjusted multiple regressions comprising initially significant univariate factors. RESULTS:: The point prevalence of MCI within our sample was 39.1% overall: it was lowest in younger women (32.3%) and similar across men and older women (41.9%-43.6%). The risk of MCI across all participants was increased by the APOE ?4 allele, high homocysteine, and heart disease; and decreased by better odor identification, visual acuity, and mental activity. Risk factors in all younger participants were slow 6-m walk, poor odor identification, and high homocysteine. Risk of MCI was associated in younger women with history of depression, less mental activity, slower 6-m walk, poorer visual acuity, and higher homocysteine; and in younger men with poorer odor identification and higher homocysteine. Older participants showed no significant risk factors for MCI, except for poorer visual acuity in men. Supporting these findings were statistically significant interactions that reflected the differences in risk factor profiles between age and/or sex groups. CONCLUSIONS:: Risk factors for MCI differ in men and women and vary with age. This has implications for preventing MCI and possibly dementia.     

Neuropsychiatric symptoms in older people with and without cognitive impairment

Neuropsychiatric symptoms (NPS) are non-cognitive disturbances such as depression. Rates of NPS have been shown to increase as cognitive ability declines and may be useful in predicting transition from mild cognitive impairment (MCI) to dementia. This community-based study reports the association between NPS and cognitive decline over two years. Participants included 873 community dwelling adults aged 70-90 years enrolled in the Sydney Memory and Ageing Study. NPS were assessed by the Neuropsychiatric Inventory (NPI). Cognitive impairment was defined by diagnosis (MCI or incident dementia) or neuropsychological test performance across five cognitive domains. Cognitive decline was defined by progression to dementia or worse neuropsychological performance. Total NPS at baseline did not differ between those without cognitive impairment (26.2%) and those with MCI (28.8%), but agitation and apathy were associated with MCI. Only baseline depression was associated with dementia at follow-up. Total NPS at baseline was cross-sectionally associated with cognitive impairment in executive function, attention, and global cognition, but did not predict cognitive decline. Depression, anxiety, agitation, anxiety, and apathy were all associated with impairment in at least one cognitive domain, but only anxiety and agitation were significantly associated with cognitive decline. Sensitivity analyses applied more stringent criteria for NPS and cognitive impairment in MCI but did not alter interpretation of results from the main analysis. Overall rates of NPS at baseline were not associated with MCI, dementia, or cognitive decline over two years. Additional follow-up is needed to further examine this association over a longer time course.     

Performance-Based Assessment of Instrumental Activities of Daily Living: Validation of the Sydney Test of Activities of Daily Living in Memory Disorders (STAM)

Objectives

The distinction between dementia and mild cognitive impairment (MCI) relies upon the evaluation of independence in instrumental activities of daily living (IADL). Self- and informant reports are prone to bias. Clinician-based performance tests are limited by long administration times, restricted access, or inadequate validation. To close this gap, we developed and validated a performance-based measure of IADL, the Sydney Test of Activities of Daily Living in Memory Disorders (STAM).

Risk Factors for Mild Cognitive Impairment,Dementia and Mortality: The Sydney Memory and Ageing Study

Background

The nature and commonality of late-life risk factors for mild cognitive impairment (MCI), dementia, and mortality remain unclear. Our aim was to investigate potential risk factors, simultaneously in a single cohort including many individuals initially with normal cognition and followed for 6 years.

p53 and MDM2 expression in odontogenic cysts and tumours

OBJECTIVE: The aim of this report was to assess p53 and MDM2 expression in odontogenic cysts and tumours, as they are known to play important roles in cell proliferation and tumorigenesis. MATERIALS AND METHODS: The expression of p53 and MDM2 proteins was determined immunohistochemically in 51 formalin-fixed, paraffin embedded specimens of odontogenic cysts and tumours.RESULTS: No positivity to p53 was found in the cases studied. MDM2 expression in ameloblastoma was higher than in radicular cysts, but lower than that observed in odontogenic keratocysts. No difference was observed between MDM2 expression in radicular cyst and adenomatoid odontogenic tumour. The clear-cell odontogenic ameloblastoma presented strong immunoreaction to this antigen.CONCLUSIONS: The results suggest that MDM2 overexpression may be involved in the pathogenesis of some odontogenic lesions.     

Immune responses to Aspergillus antigen in IL‐4‐/‐ mice and the effect of eosinophil ablation

BACKGROUND: Exposure to Aspergillus fumigatus allergens results in enhanced total serum IgE and peripheral blood eosinophils in mice. The associated pulmonary inflammation and immunologic responses are comparable to those detected in human allergic bronchopulmonary aspergillosis. Allergen-induced cytokines are thought to regulate the inflammatory and immune responses in these animals. METHODS: In the present study, we exposed C57BL/6 and BALB/c mice to A. fumigatus antigen. Both wild-type and IL-4 knockout phenotypes of animals of both strains were used. Some animals were also treated with anti-IL-5 or anti-IFN-gamma. Total serum IgE, Aspergillus species IgG subclass, peripheral blood eosinophils, and lung histology were studied. RESULTS: The results demonstrate similar lung inflammation in all wild-type and IL-4-/- animals exposed to A. fumigatus antigen. Similarly, in spite of the diverse immune response produced by the anticytokine treatment, no major differences were detected among any of the animal groups studied. CONCLUSIONS: It can be concluded that A. fumigatus exposure in an immunologically unaltered host is predominantly of a Th2 type, and that depletion of the Th2 cytokine leads to a similar lung inflammation but with a characteristic Th1 response, suggesting that the pathogenesis of allergic aspergillosis is the result of multiple induction pathways.