CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.     

A fatal doxepin poisoning associated with a defective CYP2D6 genotype

It has been suggested that the polymorphism of the CYP2D6 gene can contribute to occurrence of fatal adverse effects. We therefore investigated postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates, with the manner of death denoted as accidental or undetermined. CYP2D6 genotypes were determined in 11 consecutive cases with samples available for DNA analysis. A case of fatal doxepin poisoning with an undetermined manner of death was found to coincide with a completely nonfunctional CYP2D6 genotype (*3/*4), indicating a total absence of CYP2D6 enzyme and suggesting a poor metabolizer phenotype. The doxepin concentration was 2.4 mg/L, the concentration of nordoxepin 2.9 mg/L, and the doxepin/nordoxepin ratio 0.83, the lowest found among the 35 nordoxepin-positive postmortem cases analyzed during the same year. No alcohols or other drugs were detected in the case. The CYP2C19 genotype was determined as that of an extensive metabolizer. The high N-desmethylmetabolite concentration is not consistent with acute intoxication. It is therefore probable that the defective genotype has contributed to the death, possibly involving repeated high dosage of doxepin. Our case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death.     

Explaining collaboration in consensual and conflictual governance networks

The conditions under which policy beliefs and influential actors shape collaborative behaviour in governance networks are not well understood. This article applies exponential random graph models to network data from Finland and Sweden to investigate how beliefs, reputational power and the role of public authorities structure collaboration ties in the two countries’ climate change governance networks. Results show that only in Finland's conflictual climate policy domain do actors collaborate with those with similar beliefs and with reputational power, while only in Sweden's consensual climate policy domain do public authorities play central impartial coordinating roles. These results indicate that conflict is present in a governance network when beliefs and reputational power determine collaboration and that it is absent when public authorities occupy central roles. They also suggest that relative success in climate policy action is likely to occur when public authorities take on network manager roles.     

Reliability and validity of eight dental age estimation methods for adults

This paper evaluates the reliability and validity of eight published dental age estimation methods for adults that may aid in victim identification. Age was calculated on 20 Caucasian teeth of known age according to the methods of Kvaal (for in situ and extracted teeth), Solheim (for in situ and sectioned teeth), Lamendin (for extracted teeth), Johanson (for sectioned teeth) and Bang (for extracted and sectioned teeth) by one independent observer. For each method, mean age error and standard error were assessed as the measures of accuracy and precision. In addition, method simplicity, requirements for tooth preparation and the equipment necessary were assessed and recommendations given for forensic use in various situations. Methods for sectioned teeth gave more reliable results when compared to methods for intact teeth.     

From path dependence to policy mixes for Nordic electric mobility: Lessons for accelerating future transport transitions

We examine the problem of how to accelerate policies related to electric vehicles (EVs) in the Nordic countries Denmark, Finland, Norway and Sweden. These four Nordic countries represent an interesting collection of cases by virtue of having common decarbonization targets extending to the transport sector, interlinked electric energy systems and a joint electricity market largely based on low-carbon energy while they are open societies bent on innovation, making them well adaptable to a transition toward electric mobility. Our analytical framework drawing from transition research, lock-in and path dependency and institutionalism enables us to discern technological, institutional and behavioral mechanisms which can have both constraining and enabling effects vis-à-vis this transition by means of shaping national socio-technical systems and regimes. On this basis, we also discuss how to develop policies accelerating the transition. We find that the incumbent industries can shape policy choice through the lock-in into institutional inter-dependencies. The accumulation of social and material features, and vested interests of actors, for its part can maintain regime level inertia, impeding the transition. Yet, technological lock-in can also enable EVs, by means of learning effects from technologically interrelated wind energy projects and available infrastructure in buildings that support the EV charging needs. Overall, the complexity of path-dependent mechanisms embedded in the dominant regimes, together with the diversity of emerging policy mixes, demands attention both on the technologies and broader socio-technical systems in order to properly assess the prospects of transition toward electric mobility.

     

Typing of XY (male) genotype from malignant neoplastic tissue by the amelogenin-based sex test

DNA profiling of a cancer tissue can be problematic because of genomic instability. Here we have analyzed gastrointestinal cancer specimens from 46 males, of which seven (15%) showed aberrations in determination of gender by the widely used amelogenin test. The X-type amelogenin allele in all cases remained intact. All male tumor samples showing frequent autosomal loss of heterozygosity had a decreased signal of the Y allele from the amelogenin marker. When tested with an alternate set of primers for the amelogenin locus, the Y-type allele showed loss of heterozygosity in the same seven cases. However, when amplified with 15 Y-specific STR primers, all the cancerous tissue Y chromosomes seemed to be intact. These results indicate when malignant neoplastic tissue specimens are used, that amelogenin-based gender determination should be carefully interpreted.     

Suicide by intracerebellar ballpoint pen

Self-inflicted eye injuries among psychiatric patients are relatively common. Transorbital penetrating traumas are more rare but if undiagnosed may cause lethal intracranial lesions. We report a fatal case of a 25-year-old schizophrenic man who introduced a plastic ballpoint pen through his right orbit up to the cerebellum. The computed tomography findings were misinterpreted as a penetrating track from a bullet. The patient died 4 days after the trauma, and the causative object was identified only at autopsy. When no precise information about an apparently trivial ocular trauma is available, clinicians and investigators must adequately consider, especially in psychiatric patients, the possibility of an intracranial penetrating lesion.     

Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood

Tramadol is an opioid drug metabolised in phase I by cytochrome P450 (CYP) enzymes, of which CYP2D6 is mainly responsible for the O-demethylation of tramadol, but is not involved in N-demethylation. Defects in the genes encoding drug metabolising enzymes (DMEs) may lead to adverse drug effects, even to death. To aid interpretation of the forensic toxicology results, we studied how the genetic variation of the CYP2D6 gene is reflected in tramadol metabolite ratios found in post-mortem samples. In 33 Finnish autopsy cases where tramadol was found, we analysed both the CYP2D6 genotype and the concentrations of tramadol and its metabolites O- and N-demethyltramadol. As expected, we found a correlation between the number of functional CYP2D6 alleles and the ratio of tramadol to O-demethyltramadol. We also found a correlation between the number of functional alleles and the ratio of tramadol to N-demethyltramadol. This can be explained by the complementary nature of the two main tramadol demethylation pathways. No known CYP2D6 inhibitors were associated with exceptional metabolic ratios. Furthermore, no accidental tramadol poisonings were associated with a defective CYP2D6 gene. Our results on the tramadol are among the first to demonstrate that genetic variation in drug metabolising enzymes can be analysed in post-mortem blood, and that it correlates well with the parent drug to metabolite ratios. The results also suggest that genetic factors play, in general, a dominant role over other factors in the metabolism of individual drugs.     

Who are the most highly cited forensic scientists in the United States?

The most highly cited forensic practitioners in the United States were identified using a publicly available citation database that used six different citation metrics to calculate each person's composite citation score. The publication and citation data were gleaned from Elsevier's SCOPUS database, which contained information about ~7 million scientist each of whom had at least five entries in the database. Each individual was categorized into 22 scientific fields and 176 subfields, one of which was legal and forensic medicine (LFM). The database contained citation records for 13,388 individuals having LFM as their primary research discipline and 282 of these (2%) were classified as being highly cited. Another 99 individuals in the database had LFM as their secondary discipline, making a total of 381 highly cited forensic practitioners from 35 different countries. The career-long publication records of each individual were compared using their composite citation scores. Of the 381 highly cited scientists, 93 (24%) had an address somewhere in the United States. The various branches of forensics they specialized in were anthropology, criminalistics, DNA/genetics, odontology, pathology, statistics/epidemiology, and toxicology. The two most highly cited scientists, according to their composite citation score, were both specialists in DNA/genetics. Bibliometric methods are widely used for evaluating research performance in academia and a similar approach might be useful in jurisprudence, such as when an expert witness is instructed to testify in court and explain the meaning of scientific evidence.