Mattias Kettner

A Common Human μ-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain

The single nucleotide polymorphism 118A>G of the human μ-opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the μ-opioid receptor-specific agonist DAMGO, we analyzed the μ-opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (SII) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D μ-opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the SII region of homo- and heterozygous carriers of the variant 118G allele (n = 18), DAMGO was only 62% as efficient (p = 0.002) as in homozygous carriers of the wild-type 118A allele (n = 15). In contrast, the number of [3H]DAMGO binding sites was unaffected. Hence, the μ-opioid receptor G-protein coupling efficacy in SII of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p < 0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of μ-opioid receptor variant N40D.

Digital forensic osteology: Morphological sexing of skeletal remains using volume-rendered cranial CT scans

Because of the increasing lack of recent bone collections, ethical issues concerning maceration procedures, and progress in radiological imaging techniques, computed tomography (CT) scans offer an alternative to traditional anthropological bone collection. The present study examined volume-rendered cranial CT (CCT) scans from 50 crania to morphologically evaluate sex characteristics. CCT scans were performed and scored by two teams (Teams A and B) of two examiners each (2x50=100 examinations) to evaluate the occurrence and/or absence of morphological traits. Altogether, 60 of 100 crania (31 Team A+29 Team B) crania were determined to be male, and 40 (19 Team A+21 Team B) were determined to be female when using the scoring system adapted from Knussmann. These results imply a sex determination accuracy rate of 96%. Only in one case was recalculation of weighting factors necessary to determine one additional correct classification. As a single parameter, arcus superciliaris evaluation permitted the most accurate sex determination (female, 84.2%; male, 85.5%). No significant difference in accuracy rates was observed between the two sexes (p<0.65, chi(2)=0.39, Fishers exact test). Interobserver bias rates for both teams were very low (kappa=0.83). The present study shows that volume-rendered CCT images are suitable for the collection of data concerning morphologic sex determination of skulls. Thus, this method may be helpful in both actual forensic casework and the systematic reevaluation and improvement of classical anthropological methods and their adaptation to changing populations.

Intranuclear aggregation of nonexpanded ataxin-3 in marinesco bodies of the nonhuman primate substantia nigra

Marinesco bodies (MB) are intranuclear inclusion bodies predominantly found in melanin-pigmented neurons of the substantia nigra. MB are demonstrable not only in humans but also in nonhuman primates. In the present study MB of aged rhesus monkeys (Macaca mulatta; n = 15; mean age 16 years) and aged baboons (Papio anubis; n = 13; mean age 25 years) were examined immunohistochemically. MB were found to be immunoreactive for ubiquitin, a protein involved in initiation of proteasome-mediated proteolysis. We also demonstrate that MB in monkeys are intensely immunoreactive for the protein ataxin-3 as detected by using two monoclonal anti-ataxin-3 antibodies (1H9 and 2B6). The abnormally expanded form of this polyglutamine protein is known to be causally involved in spinocerebellar ataxia type 3 or Machado-Joseph disease. The monoclonal antibody 1C2 was employed to examine whether ataxin-3 in MB in monkeys contains such an abnormally expanded polyglutamine stretch. MB were consistently 1C2-immunonegative, indicating that they are composed of normal wild-type ataxin-3. In conclusion MB in nonhuman primates permit experimental examination of mechanisms involved in transnuclear localization, intranuclear aggregation, and ubiquitination of nonexpanded polyglutamine proteins.

Reverse Engineering—Rapid Prototyping of the Skull in Forensic Trauma Analysis

Abstract:  Rapid prototyping (RP) comprises a variety of automated manufacturing techniques such as selective laser sintering (SLS), stereolithography, and three‐dimensional printing (3DP), which use virtual 3D data sets to fabricate solid forms in a layer‐by‐layer technique. Despite a growing demand for (virtual) reconstruction models in daily forensic casework, maceration of the skull is frequently assigned to ensure haptic evidence presentation in the courtroom. Owing to the progress in the field of forensic radiology, 3D data sets of relevant cases are usually available to the forensic expert. Here, we present a first application of RP in forensic medicine using computed tomography scans for the fabrication of an SLS skull model in a case of fatal hammer impacts to the head. The report is intended to show that this method fully respects the dignity of the deceased and is consistent with medical ethics but nevertheless provides an excellent 3D impression of anatomical structures and injuries.

Dual energy CT for the assessment of reperfused chronic infarction - a feasibility study in a porcine model.

Backround Detection of myocardial infarction has been the focus of considerable research over the past few decades. Recently developed dual source computed tomography (DSCT) scanners with dual energy mode have been used to detect myocardial infarction, but the studies on this topic are few. Purpose To evaluate the feasibility and performance of dual energy CT (DECT) during arterial phase in coronary CT angiography for the detection of chronic infarction compared with late enhancement MRI (LE-MRI) and histopathology in a porcine model of reperfused myocardial infarction. Material and Methods Myocardial infarctions were induced by 30 min occlusion of the proximal left anterior descending coronary artery in eight minipigs. DECT, post-contrast LE-MRI and histopathology were performed 60 days after infarct induction. The CT scan was performed in dual energy mode using a dedicated protocol. Myocardial iodine distribution was superimposed as color maps on grey scale multiplanar reformats of the heart. Two radiologists in consensus interpreted all imaging studies for presence of gadolinium uptake at LE-MRI reduced iodine content at DECT and hypoenhanced areas in the initial 100 kV coronary CT angiography images that were acquired during the DECT-acquisition. Results were compared with histopathology. Results Based on evaluable segments, DECT showed a sensitivity and specificity of 0.72 and 0.88; LE-MRI showed a sensitivity and specificity of 0.78 and 0.92; and the 100 kV data-set of the DECT scan showed a sensitivity and specificity of 0.60 and 0.93, respectively, for the detection of histological proved ischemia. Conclusion DECT during arterial phase coronary CT angiography, which is ordinarily used for coronary artery evaluation, is feasible for the detection of a chronic reperfused myocardial infarction.

Fatal outcome of a sand aspiration

Although extensive deep aspiration of sand, gravel, or dirt is a very rare incident, its consequences may be severe ranging from the necessity of immediate intensive care to death. Cases reported so far were due to external causes such as cave-ins, near drowning, or being buried under sand masses. We report a case of a 2 1/2-year-old boy who ingested sand while playing in a sandbox with his older brother. Despite early resuscitation and endotracheal intubation efforts, he died subsequently showing clinical signs of asphyxia due to airway obstruction. Autopsy revealed sand masses obstructing the trachea and lobar bronchi of both lungs as well as brain edema, while no signs of blunt trauma, forced sand ingestion, or preexisting medical conditions were found. This case demonstrates that fatal self-administered sand aspiration may occur in early childhood. The pathophysiology of the lethal outcome with regard to the physical properties of sand and implications for the clinical assessment of emergency situations are discussed.

Localization of an endocannabinoid system in the hypophysial pars tuberalis and pars distalis of man

The hypophysial pars tuberalis (PT) acts as an important interface between neuroendocrine brain centers (hypothalamus, pineal organ) and the pars distalis (PD) of the hypophysis. Recently, we have identified an endocannabinoid system in the PT of hamsters and provided evidence that 2-arachidonoylglycerol is a messenger molecule that appears to play an essential role in seasonal reproduction and prolactin release by acting on the cannabinoid receptors in the PD. We now demonstrate the enzymes involved in endocannabinoid synthesis and degradation, namely sn-1-selective diacylglycerol lipase α, N-acylphosphatidylethanolamine-specific phospholipase D, and monoacylglycerol lipase, in the PT of man by means of immunohistochemistry. High-performance liquid chromatography coupled with tandem mass spectrometry revealed 2-arachidonoylglycerol and other endocannabinoids in the human PT. Furthermore, we detected the expression of the cannabinoid receptor 1 (CB1), a primary receptor for endocannabinoids, in the PD. Double-immunofluorescence staining for CB1 and various hypophysial hormones or S-100, a marker for folliculostellate (FS) cells, revealed that CB1 immunoreactivity was mainly localized to corticotrophs and FS-cells. A limited number of lactotrophs and somatotrophs also showed CB1 immunoreactivity, which was however absent from gonadotrophs and thyrotrophs. Our data thus indicate that the human PT comprises an endocannabinoid system, and that corticotrophs and FS-cells are the main target cells for endocannabinoids. The functional significance of this newly discovered pathway remains to be elucidated in man; it might be related to the control of stress responses and/or reflect a remnant seasonal control of hypophysial hormonal secretion.

Analysis of laryngeal fractures in decomposed bodies using microfocus computed tomography (mfCT)

Postmortem computed tomography (CT) is now routinely performed in forensic autopsies. Microfocus computed tomography (mfCT) has attracted recent attention because it can provide more detailed information than routine postmortem CT can. This feasibility study evaluated the usefulness of mfCT for examination of the hyoid bone and thyroid cartilage in cases of suspected strangulation, where advanced decomposition precludes detection of petechial hemorrhages and hemorrhages adjacent to fractures. The results show that mfCT was useful for identification of thin fracture lines in the fragile laryngeal structures. We suggest that mfCT should be considered for forensic autopsies in cases of suspected strangulation with advanced decomposition.

A fatal case of CO(2) intoxication in a fermentation tank.

Carbon dioxide (CO2) is an odorless constituent of air. Higher concentrations can be detected in geothermal and automotive emissions, fermentation, and sublimation of dry ice. An unskilled worker entered a fermentation tank to clean it, which had not been done for about 5 months allowing for high concentrations of CO2 to build up. A second worker entered the tank to rescue the first one. Shortly after both were found the first worker was rescued directly whereas the tank had to be rotated to pull the second worker out. Cardiopulmonary resuscitation was successful only for the first worker. Medico‐legal autopsy showed bruises, hematoma, myocardial hemorrhage, and edema of the lungs. The right lung was vacuum degassed in an argon atmosphere and quadrupole‐mass‐spectrometry showed an elevated CO2 content in lung gases. Thus, CO2 intoxication/asphyxia in a vitiated atmosphere due to fermentation of wine mash was established as the cause of death.

Suicide in children and adolescents - a 13-year study with 78 cases

OBJECTIVE Updated and regional data about the circumstances of death and the psychosocial backgrounds of suicides can be helpful for improving suicide-preventive strategies in childhood and adolescence. METHOD All known cases of completed suicide in the period from 1996 to 2008 in persons ≤ 21 years of age from the Institute of Forensic Medicine, Frankfurt/Main were analysed in a retrospective study. We included 78 cases and matched them with a comparative sample of 1,797 adult suicides of persons > 21 years of age. RESULTS Within the chosen period there was a 44 % decrease in incidence of suicide in the group of ≤ 21-year-olds. The fraction of incarcerated persons in this group was 8.0 % compared to 2.56 % in the adult group. Differences from suicide in adulthood were also demonstrated in terms of suicide-related substance abuse (less detection of alcohol, more frequent detection of illicit drugs) and choice of methods (more deaths by being hit by a train). CONCLUSIONS Incarcerated adolescents are an important risk group for suicidal tendency and need increased, well-directed preventive measures. Clinical adolescent psychiatry should pay special attention to the indications in this study of an age-dependent association of drug use in suicide.