Modification of low density lipoprotein potentiates its inhibitory effect on catecholamine secretion in cultured bovine adrenal medullary cells

Low density lipoprotein (LDL) and lipoprotein(a) suppress catecholamine secretion in cultured adrenal medullary cells. Modification of LDL by oxidation or acetylation potentiates various atherogenic actions of LDL. In the present study, we investigated whether the modification of LDL influences catecholamine secretion in cultured bovine adrenal medullary cells. The exposure of LDL to CuSO₄ caused a time-dependent oxidation of LDL. Maximal oxidation of LDL was observed after exposure to CuSO₄ for 24 h. Native LDL inhibited catecholamine secretion induced by carbachol to 68.5% of control. Oxidized LDL caused further inhibition of carbachol-evoked secretion to 37.6% of control. Acetylated LDL inhibited it to 41.0% of control. There was a good correlation between the extent of LDL oxidation and the inhibition of catecholamine secretion. These results suggest that oxidation or acetylation of LDL augments its inhibitory effect on the secretion of catecholamines. Since catecholamines are a risk factor of atherosclerosis, the inhibitory effect by such modified LDL may be a mechanism inhibiting atherosclerotic progression. Received: 29 January 1999 / Accepted: 19 April 1999 / Published online: 22 June 1999     

The effects of clofibrate on plasma glucose,lipoproteins, fibrinogen,and other biochemical and haematological variables in patients with mature onset diabetes mellitus

Summary We have studied the effects of clofibrate treatment on glucose tolerance and plasma insulin, plasma triglyceride, cholesterol and non-esterified fatty acid (NEFA) levels, and on various haematological variables (including plasma fibrinogen level, red cell flexibility, whole blood viscosity, and plasma -thromboglobulin level) in patients with mature-onset diabetes. Twenty-two patients (11 men and 11 women) were randomly allotted to treatment with clofibrate, 1 g twice daily, or a corn-oil placebo for 12 weeks, and then changed to the alternate medication for another 12 weeks. Half the patients took clofibrate in the first 12 weeks of the study, and half took the placebo. The patients stayed on their usual diet, and 13 also took tolbutamide before and during the trial. The trial was double-blind. At the beginning, middle and end of the trial fasting measurements were made, and plasma glucose, insulin, triglyceride, and NEFA concentrations were then measured repeatedly during the next 8 h (from 8.00 a. m. to 4 p. m.), to allow calculation of the mean 8-h concentration of these substances. In general, plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen were lower when the patients were taking clofibrate then when they were taking the corn-oil placebo, but higher when taking the placebo than at entry to the trial. We favour the explanation that clofibrate has lowered these concentrations, when compared with the placebo. The alternative interpretation, that 2 g per day of the placebo increases plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen, and that clofibrate has little effect, seems unlikely. The first interpretation, that clofibrate has a positive effect when compared with an inert placebo, has been adopted when interpreting the results. Clofibrate treatment led to a 15% lower fasting blood glucose level, and 11% lower mean 8-h glucose concentration than did placebo (p<0.01) but it did not significantly change plasma insulin concentration. The fasting and mean 8-hour concentrations of plasma triglyceride and fasting plasma cholesterol concentrations were reduced by clofibrate (by 44%, 33% and 10% respectively, p<0.05). Clofibrate decreased the fasting plasma NEFA level by 27% (p<0.01), and the mean 8-h plasma NEFA concentration by 23% (p<0.05). A weak relationship between the mean 8-h levels of plasma NEFA and plasma glucose (r=0.49, p<0.05) was consistent with the suggestion that the change in plasma glucose could, in part, be due to a change in NEFA concentration. The mean plasma fibrinogen concentration was decreased 23% by clofibrate (p<0.01). There was a positive correlation between the observed decrease during treatment and the baseline fibrinogen concentration (r=0.80, p<0.001), i. e. the greatest decrease occurred in those subjects with the highest plasma fibrinogen concentrations. Whole blood viscosity fell slightly, but erythrocyte flexibility was not significantly changed by clofibrate. The mean haemoglobin concentration and leucocyte count fell slightly during clofibrate treatment and the platelet count rose. -thromboglobulin was not affected. Clofibrate treatment was associated with rises in plasma albumin, urea, creatine kinase and aspartate aminotransferase, and falls in plasma bilirubin, -glutamyl-transpeptidase and alkaline phosphatase. Most of these changes occurred within the reference range.     

The Effect of Parenterally Administered Cyclodextrins on Cholesterol Levels in the Rat

The inclusion complex formation of intravenously administered hydroxypropyl--cyclodextrin and -cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol--cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered -cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl--cyclodextrin after intravenous administration.     

Effect of oxidized derivatives of cholesterol on uptake and degradation of very low-density β-lipoproteins by human and rabbit hepatocytes

Research Institute of Cardiology, Tomsk Scientific Center, Academy of Medical Sciences of the USSR. Research Institute of Experimental Cardiology, All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 3, pp. 254–256, March, 1991.     

Retropublic colpourethropexy with transabdominal anterior and/or posterior repair for the treatment of genuine stress urinary incontinence and genital prolapse

A new operative technique combining retropublic colpourethropexy with transabdominal internal anterior and/or internal posterior repair for the treatment of genuine stress incontinence (GSI) and genital prolapse is described in 75 cases. The overall success rate in correcting GSI was 92.0%, with a 94.8% success rate in the primary surgical group (n=58) and an 82.4% in the secondary group (n=17). Average follow-up has been 1.31 years (range 6 weeks–6 years). There was a 3.4% incidence of residual prolapse. Nine patients also underwent concomitant colpourethropexy. Overall surgical complications include febrile morbidity 4/75 (5.3%), wound infection 1/75 (1.3%), deep vein thrombosis 1/75 (1.3%) and partial ureteric obstruction 1/75 (1.3%). There were no statistically significant changes in multichannel urodynamic studies preoperatively and at 1 year following surgery. Onethird (2/6) of the GSI failures had low MUCP (<20 cm H₂O) prior to surgery and continued so at 1 year follow-up.EDITORIAL COMMENT: Genital prolapse is often present in patients who have GSI. If an operation is performed to correct the GSI, and those areas of weakness in the pelvic support system that are contributing to the genital prolapse are not treated, the genital prolapse will become more severe. In the operation which has been described, the colpopexy sutures will correct any cystourethrocele, and the removal of the wedge of tissue from the anterior superior vaginal wall will correct the cystocele. The removal of the wedge of tissue from the posterior superior vaginal wall will reduce the redundancy of the posterior vaginal fornix, but a culdeplasty of the Moschcowitz or Halban type is recommended to treat or prevent an enterocele and to place the vaginal apex in the hollow of the sacrum. Any coexistent rectocele must always be treated vaginally. If it is not treated, it will appear to be more advanced following elevation of the anterior vaginal wall by retropubic urethropexy and the anterior repair which has been recommended.Genital prolapse is best treated by a vaginal approach. When one must une an abdominal approach, ancillary procedures such as the authors have described should be considered. A bulbous upper vagina is ideal for childbearing but if the apical support system and vaginal wall is weakened it is predisposed to prolapse. If the surgeon, in operating for genital prolapse, which involves the upper vagina, will taper the vaginal apex and support it by obliteration of the cul-desac and shortening and reattachment of the uterosacralcardinal complex, postoperative prolapse will be less likely to recur.     

Influence of age and of desmotropic drugs on the step phenomenon observed in rat skin

Summary Comprehensive analysis of the mechanical properties of rat skin revealed the step phenomenon. This particular observation was made after constant strain rate (analysis of stress strain curves) as well as after constant load (creep experiments). Relative low extensions or low loads were necessary to provoke the steps. In most cases two, sometimes three steps were observed. The step phenomenon was found mainly in skin strips punched out perpendicularly to the body axis. Probably some bonds in the fibrous network are broken giving way to additional elongation whereafter stronger links take over the stress. Since earlier studies demonstrated a pronounced influence of age and of desmotropic drugs on mechanical properties at ultimate load, e.g., tensile strength, ultimate modulus of elasticity, and ultimate strain, also the step phenomenon was studied under these conditions. In stress-strain experiments most of the steps were found at the ages of 2 and 4 months. Total stress loss and total work loss due to the steps were the highest at the age of 4 months. If, however, these values were calculated as percentage of ultimate values, the highest figures were found in young animals. Elongation gain due to the steps also showed a maximum at time of maturation, e.g., 4 months. Similar findings were achieved in creep experiments at medium load (200 g). After treatment with prednisolone acetate more steps and after treatment with d-penicillamine fewer steps were observed. In stress-strain experiments total stress loss and total work loss due to steps were more than twice as high than controls after prednisolone treatment and only one half after d-penicillamine. If calculated as percentage of ultimate stress or percentage of work input, these changes disappeared because of similar changes at ultimate load. However, elongation gain due to steps, which was not significantly influenced by prednisolone acetate but significantly decreased by d-penicillamine, showed the same changes when calculated as percentage of ultimate strain. Under all conditions the step phenomenon mainly influenced the extension parameters. The data presented here confirm earlier observations that mechanical properties at low loads or low and medium extensions show at least to some extent a different pattern under the influence of maturation and age and after treatment with desmotropic drugs compared to the mechanical parameters at ultimate load.     

A contribution to a new test method for dandruff-inhibiting and “keratolytic” action of drugs

Summary Free cholesterol in lipids from the scalp and hair is predominantly a constituent of epidermal lipids. Therefore, a reduction in cholesterol content induced by a drug indicates a reduction in cell turnover in the epidermis. As, according to the literature, increased cell turnover in the epidermis results in formation of dandruff, a reduction in the proportion of cholesterol should indicate inhibition of the formation of dandruff. Conversely, an increase in free cholesterol should generally indicate a keratolytic effect. So unequivocal an interpretation has not so far been possible in persons with dandruff, as it was not known whether free cholesterol was increased or decreased. In addition, this interpretation was not possible after use of antimicrobial substances, as in vitro investigations had failed to exclude microbial esterification of cholesterol on the scalp. The present investigation has shown that correlation of free cholesterol level with cell turnover is permissible in patients with dandruff, even if antimicrobial drugs are being tested.     

小剂量尿激酶联合低分子肝素治疗不稳定心绞痛的疗效观察

目的针对不稳定型心绞痛(UA)的发病机理,比较小剂量尿激酶(UK)联合低分子肝素(LMWH)与常规方法联合LMWH治疗UA的疗效,以探讨治疗UA的合理方案。方法采用随机分组,对照小剂量UK联合LMWH组及常规治疗联合LMWH组的疗效。结果采用小剂量UK联合LM-WH组比常规治疗联合LMWH组能更快控制症状(P<0.05),无明显副作用,近期疗效确切,但两组的有效率差异无显著意义(P>0.05),故仍是一种价-效比适合的方案。结论在目前介入疗法普及率有限的情况下,在基层医院尤其适用,并为有条件的患者赢得时间。     

低频超声波透皮给药的强度对皮肤组织的影响

目的　探讨不同强度下低频超声波介导透皮给药对人体皮肤组织的影响。方法　以 2 4例健康青年志愿者的双上臂作为试验区域 ,每个试验者两上臂同时涂抹 1geutecticmixtureoflocalanesthetics,10min后分别采用 0 .5、1W·cm-2 的能量进行低频超声 (2 0kHz )介导 ,介导时间 10min。每 5min测量两组镇痛起始时间 ,试验结束后观察皮肤组织的变化。结果　能量为 1W·cm-2 的低频超声组平均镇痛起始时间为 32 .75± 3.73min ,0 .5W·cm-2 组为 37.6 5± 3.2 4min。低频超声可使角质层间质增宽和疏松 ,0 .5W·cm-2 组未见组织学病理损害 ,1W·cm-2 组可见点状红疹 ,类似二度烫伤。结论　能量高可更快促进药物透过皮肤 ,但高能量可引起皮肤组织病理性损害 ,0 .5W·cm-2 组能量是比较安全的低频给药方式。     

小分割分次立体定向放射治疗脑转移瘤近期疗效观察

目的观察小分割分次立体定向放射治疗(fractionated stereotatic radiation therapy,FSRT)脑转移瘤的近期疗效.方法15例病人单纯全脑外照射(WBRT组),中间平面剂量20～40Gy/10～20次/2～4周.17例病人接受FSRT(FSRT组),每次分次剂量为2.5～3.0Gy.其中11病人行单纯FSRT,中心总剂量为30～60Gy/1 0～20次/2～4周;6例病人先行WBRT,然后行FSRT,中心总剂量为46～60Gy/5～6周.结果KSP评分增加10分以上者,WBRT组为5 3.3%,FSRT组为82.4%.(P＜0.05).WBRT组有效率(CR PR)为50.0%;FSRT组有效率(CR PR)为80.0%.中位生存率:WBRT组为3.5月,FSRT组为10.0月.结论FSRT能有效地控制脑转移瘤,减轻神经系统症状,提高生存质量,延长病人生存期,而没有增加副作用,值得临床推广应用.