Methadone-related fatalities: review in the Ghent district between 1978-2008.

Previous research demonstrated that Methadone Maintenance Programs (MMP) and Methadone Maintenance Treatment/Therapy (MMT) could significantly reduce the mortality risk. However, in current forensic practice, methadone ingestion can still directly or indirectly be involved in fatalities. The objectives of this study were twofold. Firstly, referring to the wide range of blood levels reported in methadone-related fatalities, we aimed to provide insight into the interpretation of a quantitative post-mortem blood concentration. Secondly, to examine and discuss possible causes, mechanisms and manners of death. During a 30-year-period, all medico-legal files at the Department of Forensic Medicine (Ghent University) were searched through, to investigate whether methadone was involved in the fatal outcome. A significant increase in the methadone-related fatalities was found since 1995, which has also been noticed in other studies. In our study (n=48), the most frequent cause of death was intoxication: only one was due to a pure methadone intoxication, whereas in all other fatal intoxications, a poly-drug intoxication was found. In this study, cardiopulmonary failure, induced by depression of the vital centres in the brainstem, was--as expected--the most important mechanism of death. When we considered the post-mortem blood levels in our study group, we observed a wide range, namely between 0.10 and 4.13 microg/ml (median: 0.54 microg/ml, mean: 0.81 microg/ml, SD: 0.14). This was in line with previous reports, although the extreme values differed. We conclude that the interpretation of post-mortem methadone blood levels is still hazardous due to e.g. difficulties to assess the individual tolerance level, the variety of surviving periods after ingestion, interfering post-mortem redistribution and the combined ingestion of methadone with other drugs. Therefore, a close collaboration between the forensic pathologist and toxicologist is recommended in order to provide a well-grounded conclusion.

Transthyretin levels in the vitreous correlate with change in visual acuity after vitrectomy.

BACKGROUND/AIM: Little is known about biochemical markers related to change in visual acuity after vitrectomy. The potential use of transthyretin (TTR), a carrier of the retinol/retinol-binding protein, as a biochemical marker protein, was investigated. METHODS: TTR was measured using immunonephelometry in a group of patients (n = 77) in longstanding (>1 week) retinal detachment (n = 29), fresh (<1 week) retinal detachment (n = 17), macular holes (n = 20) or diabetic retinopathy (n = 11). Vitreous samples were taken at the start of every vitrectomy procedure. For reference values, cadaver specimens (n = 73) were used. RESULTS: Reference values for vitreous TTR (median 18 mg/l; IQR 4 to 24 mg/l) comprised 2.2% of reference values for vitreous protein levels (median 538 mg/l; IQR 269 to 987 mg/l). Vitreous TTR values of patients were comparable in all disorders. Vitreous TTR values were higher in phakic (median 22.5 mg/l; IQR 10 to 27 mg/l) than in pseudophakic patients (median 12 mg/l; IQR 8 to 19 mg/l; p = 0.06). Postoperative change in visual acuity correlated well with vitreous TTR values found peroperatively (r(s) = 0.408; p = 0.012). Both change in visual acuity and lens status were the only variables which proved to explain the variance of TTR (multiple correlation coefficient: 0.494; phakic status: t = 2.767; p = 0.0084; and change in visual acuity t = 2.924: p = 0.0056). CONCLUSION: Vitreous fluid concentrations of TTR can be regarded as a biochemical marker for retinal function.

Fatality due to combined use of the designer drugs MDMA and PMA: a distribution study.

We present a fatal case involving the combined ingestion of amphetamine, 3,4-methylenedioxymethylamphetamine, 3,4-methylenedioxyamphetamine, and paramethoxyamphetamine. Various postmortem specimens (e.g., several blood samples, urine, and tissue samples) were analyzed to study the distribution of the compounds and their metabolites in the human body. Quantitation took place using liquid chromatography-sonic spray ionization-mass spectrometry after pretreatment with a liquid-liquid extraction. The medico-legal findings were compatible with a disseminated intravascular coagulation induced by hyperthermia caused by the simultaneous intake of the amphetamine analogues.

Analysis of flecainide and two metabolites in biological specimens by HPLC: application to a fatal intoxication.

A few days after her admittance to a hospital for a suicide attempt with benzodiazepines, a 15-year-old girl was found dead in bed. At autopsy, no specific anatomo-pathologic cause of death was identified. Systematic toxicological analysis (HPLC-DAD, GC-NPD, and GC-MS) of postmortem blood and urine revealed the presence of high concentrations of flecainide and its two major metabolites. Flecainide is a class IC anti-arrhythmic drug causing a decreased intracardiac conduction velocity in all parts of the heart. To identify and quantitate flecainide together with its metabolites in blood, urine, and other toxicologically relevant matrices, a new method was developed using high-performance liquid chromatography with diode-array detection. All compounds were separated on a Hypersil BDS phenyl column using water, methanol, and 1.5M ammonium acetate in a gradient system. Chromatographic analysis was preceded by an optimized solid-phase extraction procedure on RP-C18 extraction columns. The flecainide concentrations in blood and urine were 18.73 and 28.3 mg/L, respectively, and the metabolites were detected only in urine at the following concentrations: 9.4 mg/L for meta-O-dealkylated flecainide and 8.59 mg/L for meta-O-dealkylated flecainide lactam. Based on these results, it was concluded that the suicide was consistent with an overdose of this anti-arrhythmic drug.

An unusual case of homicide by use of repeated administration of organophosphate insecticides.

We present an unusual murder case by use of repeated administration of organophosphate insecticides. A 49-year-old woman suffering from mental retardation, epileptic fits and acromegaly was poisoned by her husband. At first, her death was considered as a 'sudden and unexpected' natural death. Abdominal abscesses of pancreatic origin found at autopsy were compatible with repeated administration of pesticides with anticholinergic action. In her medical history at least one episode consistent with an organophosphate intoxication was retrieved. Thorough inquiry revealed that the victim had ingested phosphamidon and/or omethoate orally. Organophosphate intoxication should be considered when unexplained neurological symptoms are associated with pancreatic disturbances.

One fatal and seven non-fatal cases of 4-methylthioamphetamine (4-MTA) intoxication: clinico-pathological findings.

We present a case history involving one fatal and seven survived cases of intoxication with 4-methylthioamphetamine (4-MTA), also called para-methylthioamphetamine (p-MTA) or methylthioamphetamine (MTA), a relatively new amphetamine analogue. Two of the seven survivors required a 24-h-period of observation in hospital. This report proves once again that the new amphetamine designer drugs are not without danger, as is thought by many young people. In addition, individually different subjective reactions are described. Finally, the medico-legal implications of new, as yet unregistered drugs are discussed.

An unusual case of suicide by means of a pneumatic hammer.

We describe an extraordinary case of a 49-year-old man who committed suicide by using a pneumatic hammer. As an industrial accident was initially assumed, difficulties in determining the manner of death are discussed. In addition, the ability to perform activity and evidence of a protracted agony in a situation of extensive cerebral destruction are considered. To our knowledge, no such case of suicide has ever been reported.

Fatal 4-MTA intoxication: development of a liquid chromatographic-tandem mass spectrometric assay for multiple matrices.

The case history and toxicological findings of an overdose fatality involving 4-methylthioamphetamine (4-MTA) and 3,4-methylenedioxymethamphetamine (MDMA) are reported along with a description of the analytical method. Detection and quantitation of 4-MTA and MDMA were performed by liquid chromatography-tandem mass spectrometry using phentermine as internal standard. Application of this technique to a variety of matrices allowed an insight in the distribution of 4-MTA. Several blood samples including femoral vein blood (5.23 mg/L), urine (95.5 mg/L), vitreous humor (1.31 mg/L), bile (36.4 mg/L), and numerous tissue samples such as liver (30.8 mg/kg), spleen (4.10 mg/kg), and frontal lobe (31.7 mg/kg) were assayed. These values indicated that 4-MTA could be identified as the cause of this fatality, whereas the concentrations of MDMA, also described, are less important because the concentrations found are lower. This case reports, for the first time, an extensive toxicological analysis of 4-MTA, by which the data presented may shed some light on the distribution of 4-MTA.

Determination of the designer drugs 3, 4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, and 3,4-methylenedioxyamphetamine with HPLC and fluorescence detection in whole blood, serum, vitreous humor, and urine.

BACKGROUND: The popular designer drugs 3, 4-methylenedioxymethamphetamine (MDMA) and 3, 4-methylenedioxyethylamphetamine (MDEA) can be determined in serum, whole blood, and urine, but also in vitreous humor. The latter matrix is interesting when dealing with decomposed bodies in a toxicological setting. METHODS: After extraction, chromatographic separation was achieved on a narrow-bore C(18) column by gradient elution with fluorometric detection; results were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The method was linear over the range of 2-1000 microg/L for whole blood, serum, and vitreous humor, and 0.1-5 mg/L for urine. Extraction recoveries were >70%, imprecision (CV) was 2.5-19%, and analytical recoveries were 95.5-104.4%. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.8 and 2 microg/L, respectively, for whole blood, serum, and vitreous humor, and 2.5 microg/L and 0.1 mg/L, respectively, for urine. Excellent correlations between the quantitative LC-fluorescence and LC-MS/MS results were obtained. We found the following concentrations in a thanatochemical distribution study in rabbits: in serum, 5.3-685 microg/L for MDMA and from the LOQ to 14.5 microg/L for 3, 4-methylenedioxyamphetamine (MDA); in whole blood, 19.7-710 microg/L for MDMA and from the LOQ to 17.8 microg/L for MDA; in vitreous humor, 12.1-97.8 microg/L for MDMA and from the LOQ to 3.86 microg/L for MDA. In routine toxicological urine samples, concentrations ranged from LOQ to 14.62 mg/L for MDA, from LOQ to 157 mg/L for MDMA, and from LOQ to 32.54 mg/L for MDEA. CONCLUSIONS: The HPLC method described is sensitive, specific, and suitable for the determination of MDMA, MDEA, and MDA in whole blood, serum, vitreous humor, and urine.

Medico-legal implications of hidden thyroid dysfunction: a study of two cases.

In this paper we present two cases in which thyroid disorders were unexpectedly brought to view. The question we ponder is whether hidden thyroid dysfunction may be important in the cause, mechanism and manner of death, or just an incidental discovery during the post-mortem examination. A short literature review has been conducted in order to evaluate previously reported cases of thyroid pathology and sudden death. The significance of post-mortem evaluation of thyroid hormones (T3 and T4) will be considered briefly.

Is vitreous humour useful for the interpretation of 3,4-methylenedioxymethamphetamine (MDMA) blood levels? Experimental approach with rabbits.

As drug instability and redistribution are factors known to affect the interpretation of post-mortem blood levels, we questioned whether post-mortem vitreous humour concentrations could be useful as predictors for the MDMA load at the time of death. In a first series of in vivo experiments using rabbits, 3,4-methylenedioxymethamphetamine (MDMA) concentrations in plasma, blood and vitreous humour were studied as a function of time after intravenous (i.v.) administration of MDMA. Equilibration between the vascular compartment and vitreous humour was attained about 1 h after i.v. MDMA administration. In a second series of experiments, the post-mortem stability of MDMA in vitreous humour in relation to ambient temperature was investigated. Post-mortem MDMA concentrations in vitreous humour were closer to the ante-mortem blood levels when compared to cardiac blood samples. These preliminary investigations in the rabbit model indicate that measurements of vitreous humour concentrations could also be of interest for predicting the blood concentration at the time of death in humans.

Endocardial fibroelastosis as a cause of sudden unexpected death.

We present a case of primary endocardial fibroelastosis (EFE) which had been diagnosed in a 16-year-old girl who died suddenly and unexpectedly. This exceptional cause of death in adolescence led to a short literature review comparing our findings with previous medicolegal reports.

Can routinely combined analysis of glucose and lactate in vitreous humour be useful in current forensic practice?

To confirm and extend previous research concerning glucose and lactate in vitreous humour, we investigated a randomly selected study population of 271 forensic cases. On the whole, we find our results agree with those of previous studies, but we add certain observations. First, when we considered the sum value of glucose and lactate in the vitreous humour, we found that not only diabetes patients are included in the higher range group (values > or = 430 mg%): intensive reanimation or prolonged or intense agony should also be taken into account. Indeed, when we split our study group into acute agony and prolonged agony subgroups, we noticed a statistically significant difference; persons dying after protracted agony showed a higher sum value, which can be explained in terms of biophysical dynamics. Second, a positive correlation was found between the lactate and the sum values on one hand, and the postmortem interval on the other. However, the vitreous glucose, lactate, and sum values are so dispersed that a precise determination of the postmortem interval cannot be obtained on the basis of these parameters. Additionally, we compared several causes of death, but unfortunately, we did not manage to reveal that some causes of death were specifically limited to high or low concentrations. Indeed, the statistically significant differences in sum values could easily be explained by factors such as intensity of agony, reanimation attempts, or iatrogenic interventions (e.g., glucose infusions). Nonetheless, when the death scene as a whole is unclear or confusing, analysis of the vitreous humour can provide some insights, provided that the other autopsy findings are also taken into consideration.