Hypoglycemic and anti-lipemic effects of the aqueous extract from Cissus sicyoides

Background

Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.

Results

DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.

Conclusion

Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.     

出血热误诊为上呼吸道感染1例

1病例报告患者,男,22岁,因间歇性全身乏力、肌肉酸痛2 wk,发冷1 wk,发热4 d入院.曾在我院查WBC 4.5×109/L,N 0.60,L 0.4,体温波动在38～40℃.初步诊断"上呼吸道感染",用阿莫西林、VC银翘片、清热解毒冲剂等治疗无效.查体:T 38.9℃,BP面性12/8 kPa.全身皮肤无出血点,双眼球结膜轻度充血,咽部充血,软腭未见充血点,心肺腹部未见阳性体征.实验室检查:WBC 7.85 × 109/L,N 0.79,L 0.21,HGB 150g/L,PCL30×109/L,尿蛋白3.2g/L,流行性出血热抗体( ).诊断:流行性出血热.入院后立即按照流行性出血热的治疗原则给予抗病毒、抗渗出、抗出血治疗.具体包括卧床休息,给予高热量,多维生素,易消化饮食;维持水、电解质、酸碱及血浆渗透压平衡;给予大剂量(5 g)Vit.C和Vit.E.同时给予氢化可地松100 mg/d,稀释后缓慢静脉滴注.入院后3 d患者的尿量由450 mL/d增至750 mL/d,肌酐204.6μmol/L,BUN 13.3 mmol/L.5 d尿量增加至4000 mL/d.经综合治疗10 d,肌酐和BUN检查等正常,痊愈出院,随访1 mo未见异常.     

The mutagenic response at the ouabain resistance locus in T cells of mice exposed to N-ethyl-N-nitrosourea parallels the response at the Hprt locus and correlates with mutation target size

The lymphocyte Hprt gene has been used extensively as a reporter locus to monitor the mutational effects of the exposure of animals to genotoxicants. Implicit in this view of the function of a reporter gene is the assumption that its mutagenic response is representative of that of other genes in the organism. As a test of this hypothesis we compared the frequency of 6-thioguanine-resistant (TGr) mutants at the Hprt locus with the mutant frequency (MF) induced at another locus, the ouabain resistance (Oua) locus. The frequency of spontaneous OUA(R) mutants was estimated to be 1.1x10(-7) (MF between <0.3 and 1.1x10(- 7)), which was approximately 30-fold less than the spontaneous TGr MF. Following treatment with N-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two dose levels (50 and 150 mg/kg ENU) and two time points (3 and 6 weeks post-exposure) was consistently 8- to 9-fold lower than the corresponding TGr MF. Thus the mutagenic response of the Oua locus closely paralleled that of the Hprt locus, indicating a similarity in their response to ENU. In addition, the Oua locus was 3-4 times more sensitive than the Hprt locus to the mutagenic effect of ENU, as measured by the fold increase in MF over the background level. The number of ENU-mutable sites capable of resulting in a TGr or OUA(R) phenotype, otherwise known as the mutation target size, was estimated to differ by an order of magnitude between the two loci. This difference in target size correlates with, and therefore may largely account for, the difference in induced MF between both loci.      

Specificity of mutagenesis by 4-aminobiphenyl: mutations at G residues in bacteriophage M13 DNA and G-->C transversions at a unique dG(8-ABP) lesion in single-stranded DNA

Mutagenesis by the human bladder carcinogen 4-aminobiphenyl (ABP) was studied in single-stranded DNA from a bacteriophage M13 cloning vector. In comparison to ABP lesions in double-stranded DNA, lesions in single- stranded DNA were approximately 70-fold more mutagenic and 50-fold more genotoxic. Sequencing analysis of ABP-induced mutations in the lacZ gene revealed exclusively base-pair substitutions, with over 80% of the mutations occurring at G sites; the G at position 6310 accounted for 25% of the observed mutations. Among the sequence changes at G sites, G- ->T transversions predominated, followed by G-->C transversions and G-- >A transitions. In order to further elucidate the mutagenic mechanism of ABP, an oligonucleotide containing the major DNA adduct, N- (deoxyguanosin-8-yl)-4-aminobiphenyl (dG(8-ABP)), was situated within the PstI site of a single-stranded M13 genome. After in vivo replication of the adduct containing ABP-modified and control (unadducted) genomes, the mutational frequency and mutational specificity of the dG(8-ABP) lesion were determined. The targeted mutational efficiency was approximately 0.01%, and the primary mutation observed was the G-->C transversion. Thus dG(8-ABP), albeit weakly mutagenic at the PstI site, can contribute to the mutational spectrum of ABP lesions.      

The predictive value of the zona-free hamster egg penetration test in relation to in-vitro fertilization at various insemination concentrations

The aim of the study was to evaluate the predictive value of the zona- free hamster egg penetration test (ZHEPT) for success in in-vitro fertilization (IVF) at various insemination concentrations ranging between 0.1 and >0.6 x 10(6)/ml. The ZHEPT was assessed using sperm samples from 87 couples undergoing IVF treatment. A similar test was simultaneously performed on the same semen sample following ionophore induction of the acrosome reaction (ZHEPTii test). Both the tests were poorly correlated with the fertilization rate of IVF at all the insemination concentrations except at >0.6 x 10(6)/ml, when there was good correlation between the ZHEPTii test and the fertilization rate. Following exclusion of two cases with an oocyte problem, further statistical analysis revealed that both the ZHEPT and ZHEPTii tests were poorly correlated with fertilization rate in IVF in this treatment group. This study suggests that the ZHEPT (with and without ionophore induction of the acrosome reaction) has a poor predictive value for the success of fertilization in IVF treatment at any insemination concentration.      

p14ARF expression in invasive breast cancers and ductal carcinoma in situ – relationships to p53 and Hdm2

Introduction  

p14^ARF stabilises nuclear p53, with a variable expression of p14^ARF mRNA in breast cancers. In vitro, nuclear p14^ARF binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53. p14^ARF is negatively regulated by p53 and through p53-independent pathways. No studies have yet examined levels of p14^ARF protein expression in breast cancer and their relationship to Hdm2/p53 immunoreactivity or subcellular localisation. Previously, immunohistochemical expression of cytoplasmic p14^ARF, p53 and Hdm2 has been described. HER-2 (c-erbB2/neu) predicts prognosis and interacts with the p14^ARF/Hdm2 pathway to inactivate p14^ARF and to influence Hdm2 activity and localisation. This study examined p14^ARF and p53/Hdm2 expression and subcellular localisation by using immunohistochemistry in a series of invasive ductal breast cancers (IDCs) with concomitant ductal carcinoma in situ (DCIS), to evaluate whether findings in vitro were related to clinicopathological parameters such as HER-2 and their effect on patient outcome.     

Differential depression at excitatory and inhibitory synapses in visual cortex

The function of cortical circuits depends critically on the balance between excitation and inhibition. This balance reflects not only the relative numbers of excitatory and inhibitory synapses but also their relative strengths. Recent studies of excitatory synapses in visual and somatosensory cortices have emphasized that synaptic strength is not a fixed quantity but is a dynamic variable that reflects recent presynaptic activity. Here, we compare the dynamics of synaptic transmission at excitatory and inhibitory synapses onto visual cortical pyramidal neurons. We find that inhibitory synapses show less overall depression than excitatory synapses and that the kinetics of recovery from depression also differ between the two classes of synapse. When excitatory and inhibitory synapses are stimulated concurrently, this differential depression produces a time- and frequency-dependent shift in the reversal potential of the composite postsynaptic current. These results indicate that the balance between excitation and inhibition can change dynamically as a function of activity.     

Blockade of clearance of immune complexes by an anti-F(cγ) receptor monoclonal antibody

Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune- mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4). Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood. The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcγR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.     

体表高频超声技术评价家兔血管成形术后再狭窄模型与病理学结果的相关性

目的:分析体表高频超声检测家兔血管内球囊成形术后再狭窄程度与组织病理学分析的相关性。评估体表超声检测的可行性、可靠性及应用价值。方法:实验于2002-03/2003-12在北京中医药大学中医内科学重点学科实验室完成。①日本大耳白兔26只,随机分为正常组10只、假手术组6只、模型组10只。②模型组电刺激兔颈总动脉,电流1.2mA,刺激12～15min,术后第2天喂饲高脂饲料共8周,假手术组仅剥离颈总动脉,不做电刺激,喂高脂饲料,正常组不施加任何干预因素。③模型组和假手术组根据B超选择颈总动脉有斑块或血流明显改变者行球囊血管内成形术。分别于电刺激后8周、血管成形术后4周行超声检查动脉内径和动脉内膜厚度。④所有动物于血管成形术后4周处死取材,进行病理学半定量分析,并与超声测量结果进行相关分析。结果:进入结果分析数量24只,正常组中途死亡1只,原因为牙齿畸型影响进食。模型组1只因电刺激8周时超声评价颈动脉未形成斑块及血流无明显改变而剔出实验。①超声检测电刺激8周时正常组内膜厚为(0.028±0.004)cm,模型组管壁明显增厚(0.043±0.014)cm,差异有显著性(P<0.05),至血管成形术后膜厚增加更明显(0.064±0.002)cm,内径稍有扩大,但差异不显著。②超声检测模型组颈动脉内径与膜厚的测量结果与病理学测量结果呈正相关关系(OR=0.361,P<0.05;OR=0.526,P<0.01),病理狭窄率与超声是否检测到斑块呈正相关关系(OR=0.796,P<0.01)。结论:体表高频超声在评价家兔颈动脉狭窄诊断中有一定应用价值,与病理学半定量分析结果相关性良好。     

Prevalence of asymptomatic left ventricular systolic dysfunction in hypertensive Nigerians: echocardiographic study of 832 subjects

Background

We sought to determine the prevalence of echocardiographically determined left ventricular systolic dysfunction in asymptomatic hypertensive subjects seen in Abeokuta, Nigeria.

Methods

Echocardiography was performed in 832 consecutive hypertensive subjects referred for cardiac evaluation over a three-year period.

Results

Data were obtained in 832 subjects (50.1% women) aged 56.0 ± 12.7 years (men 56.9 ± 13.3 years, women 55.0 ± 12.0 years, range 15–88). The prevalence of left ventricular systolic dysfunction (LVSD) was 18.1% in the study population (mild LVSD = 9.6%, moderate LVSD = 3.7% and severe LVSD = 4.8%). In a multivariate analysis, male gender, body mass index and LV mass were the predictors of LVSD.

Conclusion

Significant numbers of hypertensive subjects in this study had varying degrees of left ventricular systolic dysfunction. Early introduction of disease-modifying drugs in these patients, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers may retard or prevent the progression to overt heart failure.