Discrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level

OBJECTIVE: To describe the death of a toddler after a therapeutic dose of dextromethorphan and its investigation. STUDY DESIGN: Case report, cytochrome P450 phenotype and genotype determination in the victim and post-mortem drug redistribution study performed in rats. RESULTS: A 20-month Asian male who received 3 mg of dextromethorphan once at 09:00 h and again at 22:00 h was found dead at 04:35 h. Post-mortem examination showed signs of early bronchopneumonia (bacterial cultures were negative); dextromethorphan and dextrorphan blood concentrations taken from the heart cavity were 500 ng/ml (1. 84 micromol/l) and 200 ng/ml (0.78 micromol/l), respectively. Despite the dextromethorphan level being almost 100-fold higher than expected after therapeutic doses, intentional or unintentional overdose was extremely unlikely; other potential causes were investigated. Post-mortem drug redistribution study performed in rats showed that dextromethorphan does not undergo extensive redistribution after death (6+/-5-fold increase) and could not explain the observed dextromethorphan level. The dextromethorphan/dextrorphan concentration ratio of 2.5 found in this toddler was compatible with a slow CYP2D6 metabolizer phenotype. However, the toddler exhibited a fast metabolizer genotype. Potential reasons for this discrepancy are discussed. CONCLUSION: CYP450 phenotypes derived from post-mortem blood levels should be interpreted with caution and preferably confirmed by a genotype analysis.     

Hair analysis by using radioimmunoassay, high-performance liquid chromatography and capillary electrophoresis to investigate chronic exposure to heroin, cocaine and/or ecstasy in applicants for driving licences

The present paper describes an integrated diagnostic strategy to check the physical fitness of subjects, formerly users of illicit drugs, to obtain a driving license, after having quit their addiction. According to the Italian law, applicants for a driving license with a history of drug abuse must give evidence to have quit this behaviour and to show no risk of relapse in the future. To prove this, at our institute, they undergo medical examination, hair analysis and a urinalysis program on eight seriate samples, collected over about 40 days. About 700 subjects per year are investigated with this strategy. The hair samples are screened for opiates (morphine), cocaine and ecstasy, the most abused illicit substances in our region, by using commercial radioimmunoassays adopting cut-off levels of 0.1 ng/mg. All positive samples and about 10% of negatives are confirmed by high-performance liquid chromatography. Further confirmation of results can be carried out by capillary electrophoresis (and/or GC/MS or MS/MS). In 1998, the prevalence of positives for morphine, cocaine and ecstasy was 4.8, 11.3 and 2.6%, respectively. In this year, for the first time, the percentage of hair samples positive for cocaine was greater than that for opiates. The results of this integrated diagnostic strategy are presented and discussed, with particular emphasis on the comparison between hair analysis on a single sample and seriate urinalyses (on eight samples).     

Determination of sex from femora

The determination of sex from bones or bone fragments considerably contributes to identifying unknown bodies or skeletal remains. Due to temporal change and regional differences anthropometric standards have to be constantly renewed. The present study provides measurements of femoral dimensions in a contemporary German population and analyses sexual dimorphism by discriminant analysis. Maximum length (male: 46.4+/-2.4 cm, female: 43.4+/-2.4 cm), maximum midshaft diameter (male: 3.1+/-0.2 cm, female: 2.8+/-0.2 cm), condylar width (male: 8.4+/-1.0 cm, female: 7.7+/-0.5 cm), vertical head diameter (male: 4.9+/-0.3 cm, female: 4.4+/-0.3 cm), head circumference (male: 15.7+/-0.8 cm, female: 13.8+/-1.0 cm) and transverse head diameter (male: 4.9+/-0.3 cm, female: 4.3+/-0.3 cm) were measured in 170 femora, 100 from male (age: 16-92 years, mean: 60.8 years; body height: 153-190 cm, mean: 171 cm) and 70 from female (age: 20-96 years, mean: 72 years; body height: 146-175 cm, mean: 161 cm) individuals. In the discriminant analysis (leave-one-out-method) 67.7% of cases could be grouped correctly with the maximum length alone, 72.4% with the maximum midshaft diameter, 81.4% with the condylar width, 86.8% with the vertical head diameter, 87.7% with the head circumference and 89.6% with the transverse head diameter. The stepwise procedure with all head measurements showed that the results for the transverse head diameter could not be improved. With all measurements subjected to stepwise procedure 91.7% of cases could be classified correctly combining midshaft diameter and head circumference (D=3.012xmidshaft diameter in cm+0.780xhead circumference in cm 20.569).     

Comparison of nonradioactive microtiter plate enzyme immunoassays for the sensitive detection of fentanyl

Fentanyl is a very strong opioid with analgesic properties that are approximately 80 times stronger than those of morphine and therefore is used in major surgery and treatment of pain in tumor patients. Cases of fentanyl abuse by intravenous injection, inhalation, oral or nasal application have been reported especially in the USA. Therapeutic levels of fentanyl are as low as 1 ng/ml of serum and therefore a screening test must have a detection limit below that concentration. Recently three non-radioactive enzyme immunoassays (EIAs) have become commercially available from COZART, STC and DIAGNOSTIX, all of them supplied by MAHSAN Diagnostika for evaluation with serum samples from forensic and clinical cases. A calibration curve is obtained with samples that contain 0, 0.1, 0.5, 1 and 5 ng fentanyl per ml of negative serum. The calibration curve of COZART is especially in the low range, steeper than those of STC and DIAGNOSTIX. The cut-off for all these EIAs, however, can be set at 0.5 ng/ml. After the administration of therapeutic doses, fentanyl concentrations were between 3 and more than 5 ng/ml as determined with the EIAs. The presence of the typical drugs of abuse, e.g. heroin, methadone, cocaine, cannabinoids and amphetamines including the derivatives of methylenedioxyamphetamine, don't generate false-positive results. No cross-reactivity was also observed at toxic levels of benzodiazepines and paracetamol and therapeutic levels of barbiturates, phenothiazines, antidepressants and analgesics. The EIAs tested so far appear to be suitable for the detection of fentanyl at therapeutic levels. False-positive results or cross-reactivity towards other compounds have not been observed.     

Teaching scientific integrity and research ethics

Cases of misconduct in scientific research have enforced a lively public and scientific discussion. The international scientific community has been engaged during the last years in the search for adequate responses to fraud and misconduct. Most of the new guidelines emphasize the responsibility of researchers and scientific institutions for preventive measures; the teaching of research ethics should be included in undergraduate and postgraduate academic education. At the Universities of Ulm and Marburg members of the 'Study group Ethics in Medicine' are developing a teaching program in Research Ethics. They now offer courses: teaching in small groups (7-15 participants) with structured case discussions. These courses are not mandatory. The first steps in the development of the teaching program for young scientists in medicine, biology, chemistry, and physics have been taken. The fields of conflicts in these different fields of science are very similar. We offered five case discussion sessions with mixed groups (postgraduate students, postdocs, head of departments) and the first results are very positive: high acceptance, high motivation, high demand for next courses.     

应用40Hz听觉相关电位与听性脑干反应评估听阈

对 42例 74耳（正常听力组 32耳,检案中主诉听力下降 42耳）分别进行纯音测定,声导抗测定,听性脑干反应 (Auditory Brainstem Response,ABR)及 0.5～ 2kHz范围的 40Hz听觉相关电位 (40Hertz Auditory Event－ related Potential,40Hz AERP)测定,对其中 20耳进行睡眠及清醒两种状态的 40Hz AERP测定。将纯音听阈、 40Hz AERP反应阈、 ABR反应阈三者之间进行比较分析。结果表明,正常听力耳 40Hz AERP反应阈值较纯音测听阈值高,在不同频率的校正值 (差值 )不同, 0.5 kHz为 12.7± 6.4(dBnHL); 1kHz为 14.7± 6.3(dBnHL); 2 kHz为 15± 5.6(dBnHL)。 ABR阈值比行为听阈高,校正值为 8.9± 5.3(dBnHL)。睡眠状态时 40Hz AERP阈值较清醒状态阈值高,校正值为 9.7± 2.45(dBnHL)。检案中主诉听力下降者主、客观语音频率均值之间明显不相符 ,误差率为 61％。本研究表明单纯使用 ABR、纯音测听中任何一种方法估计语音频率听阈均有一定的误差。     

病毒性心肌炎心肌碱性成纤维生长因子的实验研究

用 8只小鼠接种柯萨奇 B3病毒（ Coxsackie B3 viral CVB3）,形成病毒性心肌炎动物模型。用免疫组织化学方法对心肌碱性成纤维生长因子（ basic Fibroblast Growth Factor:bFGF）的变化进行了研究。目的是观察 CVB3对心肌的损害。结果发现小鼠感染病毒第 3天病变心肌中即有 bFGF阳性表达,并且随病程的延长其阳性程度随之增加。常规 HE染色通常在感染病毒 5天后才出现明显的镜下改变。本研究提示 bFGF可以为病毒性心肌炎早期轻微病变的判定提供帮助。     

美国对缅甸的政策

美国巩固在缅甸的政治地位的企图 由于缅甸处于有利的地理位置、它在东南亚国家中所起的政治影响以及蕴藏有富饶的自然资源(主要是战略资源),因此,它在美帝国主义的蓄谋侵略的计划中占据着重要的地位。 美国对缅甸感兴趣的首先在于军事战略和政治方面。关于这点,美国统治集团代表人物的演说以及美国的报刊屡屡谈及。美国国家计划协会委员哈