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。     

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.      

Cost-effectiveness comparison of five interventions to increase mammography screening

BACKGROUND: Mammography is the primary method used for breast cancer screening. However, compliance with recommended screening practices is still below acceptable levels. This study examined the cost-effectiveness of five combinations of physician recommendation and telephone or in-person individualized counseling strategies for increasing compliance with mammography. METHODS: There were 808 participants who were randomly assigned to one of six groups. A logistic regression model with compliance as the dependent variable and group as the independent variable was used to test for significant differences and a ratio of cost to improvement in mammogram compliance evaluated the cost-effectiveness. RESULTS: Three of the interventions (in-person, telephone plus letter, and in-person plus letter) had significantly better compliance rates compared with the control, physician letter, or telephone alone. However, when considering costs, only one emerged as the superior strategy. The cost-effectiveness ratios for the five interventions show that telephone-plus-letter is the most cost-effective strategy, achieving a 35.6% mammography compliance at a marginal cost of $0.78 per 1% increase in women screened. CONCLUSIONS: A tailored phone prompt and physician reminder is an effective and economical intervention to increase mammography. Future research should confirm this finding and address its applicability to practice.     

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.     

Colony-stimulating factor 1 receptor signaling in the central nervous system and the potential of its pharmacological inhibitors to halt the progression of neurological disorders

Inflammopharmacology - Colony Stimulating Factor-1 (CSF-1)/Colony Stimulating Factor-1 Receptor (CSF-1R) signaling axis plays an essential role in the development, maintenance, and proliferation of...     

Enhancing memory of stair height by the motor experience of stepping

A concept emerging from recent studies on obstacle avoidance in quadrupeds is that working memory of the height of an obstacle established by visual information is enhanced by motor interactions with the obstacle. In this investigation, we found that this concept is valid in adult humans when viewing and walking up stairs. The main finding was that the memory of the height of stairs was enhanced when information about stair height was gained by walking up a short flight of stairs compared to when information about stair height was gained by vision alone. By measuring the maximum toe clearance when subjects step onto a stair, we observed that maximum toe clearance increased after diverting vision from the stair for a few seconds prior to stepping. Most of this increase occurred within a 2-s period between diverting vision from the stair and initiating the step. By contrast, this increase in maximum toe clearance after diverting vision from a stair was significantly reduced after subjects walked up two stairs prior to stepping onto a stair without vision. This reduction persisted for delays as long as 10?s between diverting vision from the stair and initiating the step. In four of twelve subjects, the maximum toe clearance after these long periods without vision of the stair was close to the value when steps were made with full vision of the stairs.     

The distribution of erythrocyte phospholipids in hereditary spherocytosis demonstrates a minimal role for erythrocyte spectrin on phospholipid diffusion and asymmetry

In the human erythrocyte membrane phosphatidylcholine and sphingomyelin reside mainly in the outer leaflet, whereas the aminophospholipids, phosphatidylethanolamine and phosphatidylserine, are mainly found in the inner leaflet. Maintenance of phospholipid asymmetry has been assumed to involve interactions between the aminophospholipids and the membrane skeleton, in particular spectrin. To investigate whether spectrin contributes to maintaining the phospholipid transbilayer distribution and kinetics of redistribution, we studied erythrocytes from hereditary spherocytosis patients whose spectrin levels ranged from 34% to 82% of normal. The phospholipid composition and the accessibility of membrane phospholipids to hydrolysis by phospholipases were in the normal range. Spin-labeled phosphatidylserine and phosphatidylethanolamine analogues that had been introduced into the outer leaflet were rapidly transported at 37 degrees C to the inner leaflet, whereas the redistribution of spin-labeled phosphatidylcholine was slower. The kinetics of transbilayer movement of these spin-labeled phospholipid in all samples was in the normal range and was not affected by the level of spectrin. Although these erythrocyte membranes contained as little as 34% of the normal level of spectrin and were characterized by several physical abnormalities, the composition, distribution, and transbilayer kinetics of the phospholipids were found to be normal. We therefore conclude that spectrin plays, at best, only a minor role in maintaining the distribution of erythrocyte membrane phospholipid.     

Phospholipase A2 levels in acute chest syndrome of sickle cell disease

Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non- SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100- fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS.     

Heterogeneity of B cell involvement in acute nonlymphocytic leukemia

In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.