Synergistic actions of the vitamin D analogue MC 1288 and 15-deoxyspergualin in xenotransplantation

Abstract: The vitamin D analogue MC 1288 (20-epi-1α,25-dihydroxycholecalciferol) effectively postpones rejection of cardiac, intestinal, skin, and aortic allografts. MC 1288 binds to the vitamin D receptor and is thus assumed to exert its immunosuppressive effects via the same mechanisms as 1α,25-dihydroxycholecalciferol, the active form of vitamin D. 1α,25-Dihydroxycholecalciferol has been demonstrated to inhibit the production of various cytokines (interleukin-2, interferon-γ, granulocyte macrophage colony-stimulating factor, and interleukin-12) and to prevent B lymphocyte secretion of immunoglobulins. In the present study MC 1288 was evaluated for its ability to prevent rejection of mouse-to-rat cardiac xenografts, alone and in combination with 15-deoxyspergualin (DSG). Combined treatment with MC 1288 (given days -1 to 9) and DSG (given day -1 and onward) postponed rejection from day 3.0 (untreated recipients) until day 19.5. In rats treated with MC 1288 or DSG as monotherapy, rejection occurred after 3.0 and 7.5 days, respectively. Functioning grafts, obtained on day 9 from recipients treated with MC 1288 and DSG in combination, displayed an almost normal morphology without any obvious deposition of immunoglobulins in the vessels of the grafts and with just a few infiltrating cells. Thus, we have demonstrated synergistic actions of MC 1288 and DSG in delaying rejection of xenografts. Analysis of cellular infiltration, immunoglobulin deposition and graft survival times in the various treatment groups indicate a combined inhibitory effect of these two drugs on the level of macrophage effector function, direct or indirect via T lymphocytes, as well as on antibody production.     

Cytokine Production by Lymphocytes in Pregnancy

PROBLEM: In the presence of progesterone lymphocytes of pregnant women release a 34- kDa protein named the progesterone-induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti-abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF- and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated. METHOD OF STUDY: Interleukin (IL)-12 and IL-10 production and PIBF expression in peripheral lymphocytes of 111 healthy pregnant women and 120 women at risk for premature pregnancy termination were detected by immunocytochemistry. RESULTS: We found increased IL-12 and low PIBF and IL-10 expression on lymphocytes of “risk” patients, and a high rate of IL-10 and PIBF positivity on lymphocytes from healthy pregnant women. The cytokine production pattern of the lymphocytes was related to the presence or absence of previous abortions as well as to the outcome of pregnancy. CONCLUSION: These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.     

营养缺乏及补充维生素A对大鼠肺巨噬细胞功能的影响

采用Ｗｉｓｔａｒ大鼠，从怀孕１６天进行限食喂养直到生后４５天，干预组从生后第３６天及第４２天分别给予维生素Ａ灌胃，每次２０００ＩＵ。结果表明，补充维生素Ａ可明显增加大鼠的胸腺重量、肺巨噬细胞的数目、巨噬细胞的吞噬功能及ＮＯ－２的分泌。维生素Ａ可部分纠正营养缺乏导致的免疫缺陷、胸腺萎缩，活化肺巨噬细胞功能，其作用机制有待于进一步研究。     

Antiviral triterpenes fromPrunella vulgaris

Two triterpenes 1 and 2 with antiviral activity againstHerpes simplex virus type 1in vitro were isolated fromPrunella vulgaris. Each compound caused a significant reduction in viral cytopathic effect whenvero cells were exposed to them for 72 hours after viral challenge. They were identified asbetulinic acid(1) and 2α, 3α-dihydroxyurs-12-en-28-oic acid(2) on the basis of their spectroscopic properties. The antiviral activity of them was estimated as EC₅₀=30 μg/ml(1) and 8 μg/ml(2), respectively by plaque reduction assay.     

Suggestive linkage to chromosome 19 in a large Cuban family with late‐onset Parkinson's disease

The identification of disease genes using family‐based approaches has provided important insights into the pathogenesis of Parkinson's disease (PD) demonstrating the importance of genetic studies on monogenic forms of the disease. We studied a large Cuban family with typical, late‐onset PD and probable autosomal dominant inheritance. Mean age at onset was 61.2 years (±12.53, 45–76). Other phenotypes such as essential tremor and atypical parkinsonism were observed in this family. We carried out a genome‐wide scan and linkage analyses. The genetic data were analyzed using a conservative model in which only patients with clinically definite or likely PD were considered affected, other phenotypes were regarded as “unknown.” Multipoint analyses yielded a maximum LOD of 2.26 between markers D19S221 and D19S840. Haplotype analysis showed a region on chromosome 19 shared by six of seven PD patients. The essential tremor phenotype and the atypical parkinsonism do not segregate with this haplotype, suggesting a different etiology. Our findings suggest the presence of a novel locus for PD on chromosome 19p13.3–q12. We propose that an oligogenic model with moderate contribution of two or three genes rather than a “pure” monogenic model might explain better the wide range in age at onset, the reduced penetrance and the phenotypical variability observed in PD families. © 2003 Movement Disorder Society     

维生素E对烧伤小鼠免疫功能改善及其机制

本实验研究了维生素Ｅ（ＶＥ）改善烧伤后免疫功能的作用，并对其作用机制进行了探讨。结果显示，小鼠１１％～１２％总体表面积（ＴＢＳＡ）全层皮肤烧伤后血、肝、脾中过氧化脂质（ＬＰＯ）水平升高、谷胱甘肽（ＧＳＨ）含量下降，淋巴细胞增殖反应、白介素一２（ＩＬ一２）生成、空斑形成细胞（ＩＪＦＣ）形成及迟发型超敏反应（ＤＴＨ）均处于抑制状态。投予ＶＥ后可防止烧伤动物体内ＬＰＯ水平、ＧＳＨ含量明显变化，免疫功能受抑制的程度也明显小于未投予组。以超氧化物歧化酶（ＳＯＤ）处理的作用与ＶＥ相同。体外实验显示，过氧化亚油酸可抑制淋巴细胞增殖反应以及ＩＬ一２产生、诱发淋巴细胞脂质过氧化、降低淋巴细胞内ＧＳＨ含量。淋巴细胞上述功能的抑制与ＬＰＯ水平密切相关；加入ＶＥ可抑制过氧化亚油酸对淋巴细胞的上述作用。提示ＶＥ可改善烧伤后免疫功能，其机制可能是通过抗氧化作用而发挥的。     

林县冬贮菜中亚硝酸盐及维生素C的含量分析

对林县食管癌高发区两种冬贮菜中亚硝酸盐和维生素C的动态分析,表明亚硝酸盐含量随蔬菜冬贮时间延长而增加,维生素C含量则逐渐降低,两者成负相关。提示蔬菜冬贮过程中应尽量减少维生素C的破坏。     

Myoblast fusion in Drosophila melanogaster is mediated through a fusion-restricted myogenic-adhesive structure (FuRMAS).

During myogenesis in Drosophila embryos, a prominent adhesive structure is formed between precursor cells and fusion-competent myoblasts (fcms). Here, we show that Duf/Kirre and its interaction partners Rols7 (found in founder myoblasts and growing myotubes) and Sns (found in fcms) are organized in a ring-structure at the contact points of fcms with precursor cells, while cytoskeletal components like F-actin and Titin are centered in this ring in both cell types. The cytoplasmic protein Blow colocalizes with the actin plugs in fcms after cell adhesion. Furthermore, the requirement of additional as yet unidentified components was demonstrated by using mammalian C2C12 myoblasts. In this study, we propose that the fusion-restricted myogenic-adhesive structure (FuRMAS) is pivotal in linking cell adhesion as well as local F-actin assembly and dynamics to downstream events that ultimately lead to plasma membrane fusion. Moreover, we suggest that the FuRMAS may restrict the area of membrane breakdown.     

Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

高效液相法测定金樱子中三萜酸类成分的含量

定量测定不同产地金樱子中2α,3α,19α,23-四羟基乌苏-12-烯-28-羧酸的含量.采用高效液相法,色谱柱:Kromasil-C18(4.6 mm×250 mm,5 μm)柱,大连依利特公司;检测波长203 nm,柱温:35 ℃;流动相:乙腈-水(35:65),流速1 mL/min.结果表示所测成分与其他组分具有良好的分离度,线性范围为0.4～10 μg, 加样回收率为102.5%,RSD=2.66%.说明不同产地的三萜类有机酸的含量差别很大.本方法操作简单,结果准确,可用于含2α,3α,19α,23-四羟基乌苏-12-烯-28-羧酸的药物的含量测定.