硫酸镁治疗妊娠高血压综合征的群体药动学—药效学

用 NONMEM 程序分析硫酸镁治疗妊娠高血压综合征患者的群体药动学-药效学,以快—慢速率相继静脉输注二室开放模型拟合60例患者的群体药动学参数,以效应室与中央室连接的三室模型,用参数法拟合26例患者的Sigmoid E_max药效学模型的群体参数。采用分光光度法测定血镁浓度(以给药前的基础值作调整),选择舒张压降低的百分率为药效指标。硫酸镁的群体药动学参数为:群体典型值K₁₀(h^-1),K₁₂(h^-1),K₂₁(h^-1)和Vc(L)分别等于1.62,20.8,2.70,27.0,其个体间变异σ_K10(%),σ_K12(%),σ_K21(%),σ_Vc(%)分别等于25.70,14.13,24.33,34.04,浓度的残差变异σ_E(%)等于15.03。硫酸镁的群体药效学参数为:群体典型值E_max(%),C_e(50)(μg·ml^-1),υ,K_eo(h^-1)分别等于28.73,28.39,4.22,0.43。其个体间变异σ_Emax(%),σ_Ce(50)(%),σ_υ(%),σ_Keo(%)分别等于56.32,62.24,33.47,42.76。效应的残差变异σ'_E(%)等于28.54。     

云谷霉素的抗肿瘤作用

来自云南省关坪自然保护区土壤的一株链霉菌产生的抗生素云谷霉素经鉴别确定为谷氏菌素。本研究通过口服给药,证明云谷霉素对小鼠结肠癌26和肉瘤180(实体型)有显著疗效;用小鼠可耐受剂量,对小鼠结肠癌26和肉瘤180的抑瘤率分别达85%和83%。提示云谷霉素用于治疗肿瘤的可能性。     

Caffeine inhibits the viability and osteogenic differentiation of rat bone marrow-derived mesenchymal stromal cells

Background and purpose:

Soluble guanylate cyclase (sGC) is the signal transduction enzyme most responsible for mediating the effects of nitric oxide (NO). Recently, NO-independent small molecule activators of sGC have been developed that have promising clinical activities. We have shown that the secreted matrix protein thrombospondin-1 (TSP-1) binds to CD47 and potently inhibits NO stimulation of sGC in endothelial and vascular smooth muscle cells (VSMCs) and platelets. Here we show that TSP-1 signalling via CD47 inhibits sGC activation by NO-independent sGC activating small molecules.

Experimental approach:

Vascular smooth muscle cells and washed human platelets were pretreated with TSP-1 (2.2 nM) in the presence of haeme-dependent sGC activators (YC-1, BAY 41-2272), and a haeme-independent activator (meso-porphyrin IX), and cGMP levels were measured. The effect of sGC activators on platelet aggregation and contraction of VSMC embedded in collagen gels was also assayed in the presence and absence of TSP-1.

Key results:

Thrombospondin-1 inhibited sGC activator-dependent increase in cGMP in VSMC and platelets. TSP-1 pretreatment also inhibited the ability of these agents to delay thrombin-induced platelet aggregation. TSP-1 pretreatment reduced the ability of sGC activating agents to abrogate VSMC contraction in vitro.

Conclusions and implications:

This work demonstrates that TSP-1 is a universal inhibitor of sGC, blocking both haeme-dependent and haeme-independent activation. These data coupled with the reported increases in TSP-1 with age, diabetes, ischaemia/reperfusion, and atherosclerosis implies that the therapeutic potential of all drugs that activate sGC could be compromised in disease states where TSP-1/CD47 signalling is elevated.     

Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus

Mice naturally infected by Helicobacter hepaticus develop a chronic active hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer was used to examine the impact of bacterial infection on the hepatic expression and activity of enzymes involved in carcinogen bioactivation (phase I enzymes) and detoxification (phase II enzymes). No major differences in total cytochrome P450 (CYP) content were found between control and infected mice during the course of the study. The most striking modulations of individual isoenzymes were the increases in immunohistochemical staining observed for CYP1A and CYP2A5 in relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged over 12 months was confirmed by the observed increases in coumarin 7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an indicator for superoxide formation, demonstrated that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase II enzymes, an enhancement of glutathione S-transferase (GST) activities, related to the disease process, was observed in infected mice. An age- specific increase of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression was also demonstrated by immunohistochemical staining. In contrast, catalase and glutathione- peroxidase activities, as well as reduced glutathione content were decreased in the early stages of disease (3-9 months) in infected mice compared to age-matched control mice. Overall, these results suggest that alterations in CYP and GST expression may contribute to the aetiology of tumour incidence due to H. hepaticus infection via production of reactive oxygen species.      

Extensive Mongolian Spots with Autosomal Dominant Inheritance

Background

Mongolian spots are benign skin markings at birth which fade and disappear as the child grows. Often persistent extensive Mongolian spots are associated with inborn error of metabolism. We report thirteen people of the single family manifested with extensive Mongolian spots showing autosomal dominant inheritance.

Case Presentation

A one day old female child, product of second degree consanguineous marriage, born by normal vaginal delivery with history of meconium stained amniotic fluid and birth asphyxia. On examination the child showed extensive bluish discoloration of the body involving trunk and extremities in both anterior and posterior aspects associated with bluish discoloration of the tongue. A detailed family history revealed most of the family members manifested with extensive bluish discoloration of the body soon after birth which faded in the first few years of life and completely disappeared by puberty. Thus it was diagnosed to be extensive Mongolian spots with an autosomal dominant inheritance.

Conclusion

Knowledge about the natural history of extensive Mongolian spots, their inheritance and association with certain metabolic diseases mainly IEM and Mucopolysaccharidosis aids in the diagnosis and in order to improve the patient''s prognosis.     

Presence of Porphyromonas gingivalis and plasma cell dominance in gingival tissues with periodontitis

Oral Diseases (2010) 16 , 375–381 Objective: Porphyromonas gingivalis can invade and survive within its host epithelial cells. The aim of this study was to test our hypothesis that persistent presence of intracellular periodontal pathogens in gingival tissue causes the chronic inflammation and that an inappropriate immune response is a risk factor for periodontitis. Methods: Together with the presence of P. gingivalis, the distribution of B cells, plasma cells, and CD4⁺, CD8⁺, and FOXP3⁺ regulatory T cells was evaluated in gingival tissues from healthy (n = 7) and periodontitis (n = 8) sites by in situ hybridization and immunohistochemistry, respectively. Results: Porphyromonas gingivalis was detected in proximity to inflammatory infiltrates in three and seven biopsies from the healthy and periodontitis sites, respectively. Compared with healthy sites, periodontal lesions contained a significantly increased number of each immune cell studied with a relative dominance of plasma cells over T cells. Conclusions: Persistent bacterial invasion of gingival tissues in combination with a plasma cell‐dominant immune response may be involved in the pathogenesis of periodontitis.     

免疫抑制成分异雷公藤春碱的分离与结构

从雷公藤(Tripterygium wilfordii Hook.f.)根皮中分离到一种倍半萜生物碱，根据理化性质和光谱(UV，TR，Ms，HRMs，¹HNMR，¹³CNMR．¹H-¹H COSY，¹H-¹³C COSY．2D-NOESY，¹H-¹³C COLOC)数据解析，鉴定为一种新的生物碱，命名为异雷公藤春碱嘛(isowilfortrine)。药理实验证明该生物碱有免疫抑制活性．并发现对白血病细响有抑制作用。