Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.     

A Safer Method for Body Restoration Following Autopsy

Restoration of autopsy incisions can result in inadvertent needle stick injury to the prosector, which can be difficult to prevent even with the use of personal protective equipment such as Kevlar cut resistant gloves. We present a new technique for closure of autopsy incisions using a commonly available commercial hardware tool, a hole punch with a lever enhanced action, combined with blunt probe sewing, which results in an esthetic and leak‐proof means of restoring cadavers. This technique is especially useful in cases which may pose blood‐borne infection risks to the prosector.     

Personality Traits are Related to Intimate Partner Violence Among Securely Attached Individuals

The general assumption has been that male batterers from clinical samples were mostly insecurely attached as compared to non-batterers. Recently, a large group was found (39.4 % of batterers in a clinical sample) whose main attachment style was secure. No previous studies have examined specifically the securely attached batterer. The aim of the present study was to test whether antisocial personality disorder (ASPD) and narcissistic personality disorder (NPD), but not borderline personality disorder (BPD), traits may be related to battering among securely attached individuals. Twenty-seven securely attached batterers, 45 insecurely attached batterers, 40 securely attached controls, and 22 insecurely attached controls who lived in the Netherlands, filled in self-report measures of personality disorder traits (i.e., antisocial, narcissism, borderline) and attachment (i.e., avoidant and anxious). Results showed that ASPD traits explained 19 % of the variance of battering in securely attached individuals. NPD and BPD traits are related to battering among securely attached individuals when NPD and BPD traits were entered alone in the equation.     

Representative bureaucracy,international organizations and public service bargains

Academic interest in the administrative aspects of international organizations is on the rise. Yet, an issue that has received little attention is bureaucratic representation—the extent to which international bureaucracies are representative of the polity that they serve. The article theorizes the rationales for and forms of representative bureaucracy in international organizations by combining insights from the representative bureaucracy literature with the ‘public service bargains’ framework. It argues that bureaucratic representation is highly relevant in international organizations, given the diverse polity these organizations serve and their precarious legitimacy. It distinguishes three types of representational ‘bargains’ between international organizations and those they serve, centred on power, equal opportunities and diversity, and discusses under which conditions each type of bargain is likely to be struck. The argument contributes to discussions about representative bureaucracy in international organizations and to broader theoretical debates about international public administration.     

How Do Advocacy Think Tanks Relate to Academic Knowledge? The Case of Norway

Think tanks often present themselves as contributors to a more reflective and informed political debate and their policy advice as based on knowledge and research. Yet, they also claim to be alternatives to university research and research institutes and often use knowledge and expertise to pursue explicitly ideological agendas. How do think tanks handle this balancing act of knowledge provision and ideological commitment? How do they relate to academia and what characterizes their approach to academic knowledge? The paper explores these questions through an investigation of the three main advocacy think tanks in Norway, based on an analysis of their organization, activities, staff and publications, and through interviews with think tank staff. The paper describes the specific ways in which these think tanks gather and utilize knowledge, and how they position themselves relative to academia. It also reflects on possible explanations for this pattern and on its normative implications.     

Interracial marriages in twentieth-century Cape Town: evidence from Anglican marriage records

ABSTRACT

One of the most controversial laws promulgated by the National Party as part of South Africa’s mid-twentieth century apartheid policies was the 1949 Prohibition of Mixed Marriages Act. This Act stipulated that ‘a marriage between a European and non-European may not be solemnized, and any such marriage solemnized in contravention of the provisions of this section shall be void and of null effect’. We use more than 23,000 newly-transcribed Anglican marriage records of Cape Town for the period 1911 to 1964 to show that the Act had mostly followed, and not led, changing interracial marriage practices. In the years before the Act’s promulgation, interracial marriages were rare and on the decline, despite the fact that apartheid-era policies had not yet been institutionalized. Our results suggests that marriage behaviour in Cape Town, and probably in South Africa more generally, was shaped by racial stratification early in the twentieth century. The Prohibition of Mixed Marriages Act of 1949, although devastating to those affected, was a correlate to rather than the cause of changing marriage behaviour.     

Psychostimulant Use and Fatal Stroke in Young Adults

Psychostimulant use is associated with increased stroke risk. To determine the proportion of psychostimulant users among fatal strokes in young adults (15–44 years), all cases were retrieved from the National Coronial Information System (1/1/2009–31/12/2016). A total of 279 cases were identified: hemorrhagic (259), ischemic (8), thrombotic (8), and mycotic (4). Fifty (17.9%) were identified as psychostimulant users. Psychostimulants in blood were detected in 37/45 where toxicology was available, predominantly methamphetamine (32/45). Hemorrhagic strokes in the psychostimulant group were more likely to be intraparenchymal (OR 2.33). Psychostimulant users were less likely to be obese (OR 0.31), but more likely to have a history of tobacco use (OR 2.64). No psychostimulant user had a previous stroke history, was gravid/postpartum, or diagnosed with cerebral vasculitis or endocarditis. The work illustrates the substantial role of psychostimulant use in fatal strokes among young adults. In cases of hemorrhagic stroke among young adults, psychostimulant use should be considered.     

Spontaneous formation of γ-hydroxybutyric acid from γ-butyrolactone in tap water solutions

The spontaneous conversion of γ-butyrolactone (GBL) to γ-hydroxybutyric acid (GHB) in seven different Swedish tap waters was investigated. The waters used in the study were selected to represent the diversity among Swedish tap waters as well as possible, which was enabled by principal component analysis (PCA) of a number of water quality parameters. GBL solutions (5, 25 and 50% v/v) were prepared in each of the tap waters and in deionized water and the formation of GHB was followed over time. The GHB quantifications were made using a CZE method, employing a carrier electrolyte consisting of 25mM benzoic acid, 54mM tris(hydroxymethyl)aminomethane (Tris) and 1.7mM tetradecyltrimethylammonium bromide (TTAB), which was developed as a part of the current study. Data evaluation showed that the formation of GHB was largely dependent on the type of tap water. For example, there was a negative correlation between the kinetics of the GHB formation and the alkalinity of the tap waters (r(2)=0.990). This could be explained by a faster decrease in pH in the waters with low buffering capacity (i.e. low alkalinity), which catalysed the hydrolysis of GBL. Equilibrium was reached after 40-250 days depending on the initial GBL concentration and the type of tap water. The level of the equilibrium appeared to be dependent on the initial GBL concentration and ranged from 26 to 37%. Gained knowledge on the levels of the GHB/GBL equilibrium and the kinetics of the formation of GHB in tap water solutions of GBL, including the influence of the tap water quality, may be useful information for casework with the GHB/GBL problem in focus.     

Clinical Characteristics of Fatal Methamphetamine‐related Stroke: A National Study

The study aimed to determine the clinical characteristics of fatal methamphetamine‐related stroke in Australia, 2009–2015. There were 38 cases, 60.5% male, with a mean age of 40.3 years. In no case was there evidence that this was the first time methamphetamine had been used by the decedent, and 52.6% had known histories of injecting drug use. The stroke was hemorrhagic in 37 of 38 cases. In 21.1% of cases, the stroke was purely parenchymal and, in 18.4%, involved purely the subarachnoid space. A ruptured berry aneurysm was present in 31.6% and in 68.8% of initial subarachnoid hemorrhages. There was evidence of systemic hypertension in 8 of 25 cases in which full autopsy findings were available. With increased use of methamphetamine, there is a high probability of increased hemorrhagic stroke incidence among young people. In cases of fatal hemorrhagic stroke among young cases presenting to autopsy, the possibility of methamphetamine use should be borne in mind.