可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

Tradition and culture in Heidegger's Being and Time

In nursing literature, Heideggerian hermeneutics, as expounded in Being and Time , is taken well near unanimously to be an invitation to explore tradition and culture. Understanding, we are told in the name of Heidegger, is to be found in the realm of common meanings and shared practices. This interpretation of what Heidegger is about in Being and Time is neither unchallengeable nor unchallenged. While a number of scholars can be found to agree with it, there are many others who see it as an utter misreading of Heidegger. In their judgement, it is an interpretation diametrically opposed to what Heidegger sets forth in his treatise. For researchers interested in invoking Heidegger or following a Heideggerian approach, this is a frustrating impasse. The only valid starting point for resolving it, this article suggests, is a close reading of what Heidegger actually says in the pages of Being and Time .     

Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation.

Inhibitors of programmed cell death (apoptosis) may regulate tissue differentiation and aberrantly promote cell survival in neoplasia. A novel apoptosis inhibitor of the IAP gene family, designated survivin, was recently found in all of the most common human cancers but not in normal, terminally differentiated adult tissues. The expression of survivin in embryonic and fetal development was investigated. Immunohistochemistry and in situ hybridization studies demonstrated strong expression of survivin in several apoptosis-regulated fetal tissues, including the stem cell layer of stratified epithelia, endocrine pancreas, and thymic medulla, with a pattern that did not overlap with that of another apoptosis inhibitor, bcl-2. A sequence-specific antibody to survivin immunoblotted a single approximately 16.5-kd survivin band in human fetal lung, liver, heart, kidney, and gastrointestinal tract. In mouse embryo, prominent and nearly ubiquitous distribution of survivin was found at embryonic day (E)11.5, whereas at E15 to -21, survivin expression was restricted to the distal bronchiolar epithelium of the lung and neural-crest-derived cells, including dorsal root ganglion neurons, hypophysis, and the choroid plexus. These data suggest that expression of survivin in embryonic and fetal development may contribute to tissue homeostasis and differentiation independently of bcl-2. Aberrations of this developmental pathway may result in prominent re-expression of survivin in neoplasia and abnormally prolonged cell viability.     

A somatostatin analogue decreases embryonic loss following superovulation in rats by normalizing insulin-like growth factor-I action in the uterus

This study was designed to determine whether the somatostatin analogue, octreotide, could prevent embryonic loss by normalizing increased uterine insulin-like growth factor-I (IGF-I) action related to hyperoestrogenaemia following superovulation. Superovulated immature and oestradiol-17beta-treated adult rats were infused with 100 or 300 microg/ml of octreotide respectively, or injected daily with 1 or 10 microg of octreotide from day 1 to day 3 of pregnancy. On day 3, embryos were collected from the oviducts and uteri. Uterine luminal fluid was subjected to embryo culture. The amounts of uterine IGF-I and IGF binding proteins (IGFBP) were determined by radioimmunoassay and ligand binding assay respectively. Octreotide infusion normalized uterine IGF-I action following superovulatory and oestradiol-17beta treatment, by reducing IGF-I concentrations and increasing IGFBP concentrations. Octreotide infusion increased the number of normal embryos by 2.7-fold and 1.7-fold in superovulated and oestradiol-17beta- treated rats respectively, and reversed the detrimental effects of uterine luminal fluid on embryonic development caused by superovulatory and oestradiol-17beta treatment. Daily injections with octreotide had similar but reduced effects in all parameters examined in both treatment groups. In conclusion, octreotide may reduce embryonic loss, at least in part, by normalizing IGF-I action following superovulation.      

Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens

Spontaneous histopathological regression of cancer has been reported. The involvement of the immune system in such regression has been advocated, leading to the theory of immunological surveillance against cancer. A prediction of this theory is that common tumour antigens can be recognized upon repeated exposure by cell-mediated immunity, which leads to tumour regression and the subsequent appearance of tumour antigen-loss variants. However, no direct evidence has been provided in non-viral-induced experimental animal models of primary malignancy or in human primary cancer. This study examined two groups of melanoma patients where histopathological regression of the primary tumour was observed. Many of the 23 patients with multiple (> or =3) primary melanomas showed significant regression of their last melanoma (median 33%, mean 40) compared with matched melanomas from patients with a single primary melanoma (median 0%, mean 12) (p=0.0080), or compared with their first primary melanoma (p=0.0013). Regression was consistent with an 'immunization effect' seen in murine tumour transplantation studies, where inoculation with > or =3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in the expression of the melanoma common tumour antigen MART-1 in the last primary tumour from multiple melanoma patients (median 8%, mean 24) versus matched single melanoma patients (median 79%, mean 68) (p=0.0041) and in the last versus first tumour in multiple primary patients was found (p=0.0083). Metastases from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART-1 loss (median 0%, mean 11) compared with matched metastases from patients with non-regressing primary melanoma (median 51%, mean 50) (p=0.0013). MART-1 antigen-loss variants observed in the multiple primary and occult primary patients correlated with the presence of peripheral blood MART-1-specific cytotoxic T lymphocytes (CTLs) (p=0.03). No similar effects were observed with two other melanoma antigens, gp100 and CD63. Thus, in two groups of human melanoma patients, evidence is provided for histopathological tumour regression associated with cancer immune surveillance.     

A prospective trial of short‐fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation.     

Advancing aged care: a systematic review of economic evaluations of workforce structures and care processes in a residential care setting

Long-term care for older people is provided in both residential and non-residential settings, with residential settings tending to cater for individuals with higher care needs. Evidence relating to the costs and effectiveness of different workforce structures and care processes is important to facilitate the future planning of residential aged care services to promote high quality care and to enhance the quality of life of individuals living in residential care. A systematic review conducted up to December 2015 identified 19 studies containing an economic component; seven included a complete economic evaluation and 12 contained a cost analysis only. Key findings include the potential to create cost savings from a societal perspective through enhanced staffing levels and quality improvement interventions within residential aged care facilities, while integrated care models, including the integration of health disciplines and the integration between residents and care staff, were shown to have limited cost-saving potential. Six of the 19 identified studies examined dementia-specific structures and processes, in which person-centred interventions demonstrated the potential to reduce agitation and improve residents’ quality of life. Importantly, this review highlights methodological limitations in the existing evidence and an urgent need for future research to identify appropriate and meaningful outcome measures that can be used at a service planning level.     

Cognitive Overload? An Exploration of the Potential Impact of Cognitive Functioning in Discrete Choice Experiments with Older People in Health Care

ObjectivesThis exploratory study sought to investigate the effect of cognitive functioning on the consistency of individual responses to a discrete choice experiment (DCE) study conducted exclusively with older people.MethodsA DCE to investigate preferences for multidisciplinary rehabilitation was administered to a consenting sample of older patients (aged 65 years and older) after surgery to repair a fractured hip (N = 84). Conditional logit, mixed logit, heteroscedastic conditional logit, and generalized multinomial logit regression models were used to analyze the DCE data and to explore the relationship between the level of cognitive functioning (specifically the absence or presence of mild cognitive impairment as assessed by the Mini-Mental State Examination) and preference and scale heterogeneity.ResultsBoth the heteroscedastic conditional logit and generalized multinomial logit models indicated that the presence of mild cognitive impairment did not have a significant effect on the consistency of responses to the DCE.ConclusionsThis study provides important preliminary evidence relating to the effect of mild cognitive impairment on DCE responses for older people. It is important that further research be conducted in larger samples and more diverse populations to further substantiate the findings from this exploratory study and to assess the practicality and validity of the DCE approach with populations of older people.