Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

A comparison of the effects of a macrobiotic diet and a western diet on drug metabolism and plasma lipids in man

Summary We have compared the effects of two dietary regimens with different macronutrient compositions — a macrobiotic diet and a Western diet — on drug metabolism and plasma lipids in seven healthy volunteers.The macrobiotic diet, high in carbohydrate, low in protein and fat, and devoid of animal food sources, was eaten for a ten day control period, as was the Western diet, high in calories, fat, and protein, as well as animal food sources. We determined the influences of these diets on the clearance of orally administered antipyrine, oxazepam, and methadone, as well as on plasma lipids.There was a statistically significant change in antipyrine clearance as well as in plasma LDL-cholesterol and HDL-cholesterol after the dietary periods. This suggests that the influence of dietary changes may have some effect on the clearance of therapeutic drugs. However, this is not universal and is probably important when the drug is highly dependent on the mixed-function oxidase system.     

Klinefelter's Syndrome: Hypogonadism,abnormal carbohydrate metabolism. Is it a result of biotin deficiency?

The aetiology of Klinefelter's Syndrome is not known. The causative factor(s) must explain the hypogonadism, low androgen levels, the disordered carbohydrate metabolism and the commonly associated psychiatric conditions. A biotin deficient/dependent state can account for the above. A biotin deficient Klinefelter's Syndrome patients with the above is described. The possible role of biotin in the primary, secondary and tertiary prevention of Klinefelter's Syndrome needs further research.     

Spermidine/Spermine N-Acetyltransferase, a New Biochemical Marker for Epithelial Proliferation in Rat Bladder

We examined the activity of spermidine/spermine N ¹-acetyltransferase (SAT), a rate-limiting enzyme of the biodegradation of polyamines, in N -butyl- N -(4–hydroxybutyI)nitrosamine-induced transitional cell carcinoma (TCC) and melamine-induced papillomatosis of rat bladder, and compared the activity to that of ornithine decarboxylase (ODC). Both activities were higher in both lesions than in control rats. The difference between SAT and ODC activities in cancerous tissue and papillomatosis was not significant. Cells stained for proliferating cell nuclear antigen (PCNA) were abundant in papillomatosis. TCC had areas with much PCNA. The results indicated that an elevation of SAT activity occurs in both reversible and irreversible proliferation of bladder epithelium and could be important in bladder carcinogenesis.     

Surgical metabolism

Summary. Trauma, operative interventions, infection and other disturbances of homeostasis lead to a uniform reaction of the body, namely release and activation of hormones and cytokines. Profound alterations of substrate flow result, with mobilization of energy stores and degradation of structural and functional proteins of vital organs like the gut mucosa. Due to these reactions the energy demands of the organs are met and energy-consuming synthesis of substrates is indicated. Clinically, hypermetabolism, hyperglycemia, lipolysis and increased urea production with negative nitrogen balance can be observed. The metabolic reactivity is reached by an increased substrate cycling. To avoid negative consequences such as organ dysfunction, a rational situation-adapted substrate supply is warranted as well as reduction of catabolic stimuli and stimulation of anabolic factors. The metabolic care of the surgical patient is still a basic and important task.      

胃肠道肿瘤病人围手术期细胞因子及蛋白质代谢的变化

目的 :探讨胃肠道肿瘤病人手术后肿瘤坏死因子 α (TNF α)、白介素 6 (IL 6 )、白介素 10 (IL 10 )的变化以及与蛋白质代谢的关系。　方法 :用酶联免疫法 (ELISA)检测 19例胃肠道肿瘤根治术病人术前和术后 1、3、5天血清TNF α、IL 6和IL 10水平 ,同时检测蛋白质分解代谢相关指标、2 4h尿中尿素和肌酐排泄量。　结果 :胃肠道肿瘤根治术后病人TNF α呈下降趋势 ,术后第 1天较术前明显下降 (P <0 .0 5 )。IL 6和IL 10术后升高 (P <0 .0 1) ,尤以术后第 1天升高明显。术后 2 4h尿中尿素和肌酐排泄量明显升高。　结论 :胃肠道肿瘤根治术后病人IL 6和IL 10的升高支持手术应激导致的细胞因子释放变化 ,但TNF α呈下降趋势 ,可能与胃肠道肿瘤病人术前TNF α的高表达有关。术后蛋白质分解代谢增加 ,可能与细胞因子IL 6和IL 10的升高有关。     

The problem of rickets in UK Asians

A large body of work relating to the occurrence of rickets in UK Asians is reviewed. Several theories of the aetiology of this condition are shown to be untenable: it is not exclusively a function of sunlight deprivation or of darker pigmentation; nor is it simply due to phytate-induced losses of calcium from the gut. Asian rickets, however, is associated with a high consumption of cereals, and experiments with rats have suggested a mechanism. In the absence of adequate vitamin D from sunlight, the low-calcium, high cereal intake of the UK Asian population may induce a state of mild secondary hyperparathyroidism which enhances the destruction of vitamin D and leads to a progressive reduction in vitamin D status and, ultimately, to the development of clinical rickets.     

Monitoring myocardial reperfusion injury with NADH fluorometry.

Using NADH fluorometry to monitor myocardial metabolism, the mechanism of reperfusion injury was investigated after the delivery of an experimental reperfusate. Using an isolated working heart preparation, rat hearts underwent 15 min of global ischemia at 37 degrees C. Following the ischemic insult, an oxygenated enriched reperfusion solution was given for 5 min. The hearts were then returned to a working state and aortic flow recorded to evaluate recovery. NADH levels were monitored throughout the experiment with a fluorometer and glycogen, AMP, ADP, and ATP were measured biochemically pre- and postischemia, after reperfusion and after recovery. In this study, reperfusion injury was best abated by an enriched reperfusate. Our results indicate the mechanism for this amelioration is not high-energy phosphate replenishment. Rather, as indicated by NADH fluorescence, the hearts attain an intermediate level of metabolism that permits glycogen to be restored and functional recovery to be improved.