Die Bestimmung der Organgewichte ist ein entscheidender Bestandteil jeder Autopsie, da abnorme Organgewichte auf zugrunde liegende Erkrankungen oder pathologische Prozesse hinweisen können. Bei Kindern werden Körper- und Organmaße üblicherweise mit bestehenden Referenzdaten verglichen. Leider sind viele Studien veraltet, teilweise Jahrzehnte alt. Die vorliegende Studie wurde konzipiert, um aktuelle Organgewichte bei Kindern zu ermitteln und somit den Bedarf an aktualisierten Referenzwerten aufzuzeigen. Es wurden 227 natürliche und nichtnatürliche Todesfälle von Kindern im Alter von 0 bis 14 Jahren untersucht, die zwischen 2009 und 2023 im Institut für Rechtsmedizin der Medizinischen Hochschule Hannover am Standort Oldenburg obduziert wurden. Auf Basis der Sektionsprotokolle wurde eine anonymisierte retrospektive Analyse durchgeführt. Die Mittelwerte der Körpermaße und Organgewichte wurden nach Altersgruppen berechnet und mit den Angaben aus der Literatur verglichen. Wie in früheren Studien nahmen die Organgewichte mit dem Alter zu, jedoch wiesen die Kinder in unserer Studie eine höhere durchschnittliche Körperlänge auf und die Organgewichte lagen tendenziell höher als in früheren (älteren) Studien. Die Daten deuten auf eine langfristige Veränderung („säkularer Trend“) hin. Um Fehlinterpretationen vermeintlich erhöhter Organgewichte zu vermeiden, sollte die veraltete Literatur nicht mehr verwendet werden; neue Referenzwerte sind erforderlich.

Background: Organ weight assessment is a critical part of every autopsy because abnormal organ weights can serve as an indicator of underlying diseases or pathological processes. In children it is common practice to compare body and organ measurements with existing reference data. Unfortunately, many studies are outdated, partially decades old. Aims: The present study was designed to determine current organ weights in children and thus demonstrate the need for updated referential weights. Methods: A total of 227 natural and unnatural deaths of children aged 0-14 years, examined between 2009 and 2023 at the Institute of Forensic Medicine of the Hannover Medical School, Oldenburg site, were reviewed. Based on the autopsy reports, an anonymized retrospective analysis was conducted. The mean body measurements and organ weights were calculated by age group and compared with the values reported in the literature. Results: Organ weights increased with age as in previous studies but in our study the children were generally larger in height and the organ weights tended to be higher than in previous (older) studies. Discussion: The data point to a long-term change ("secular trend"). To avoid drawing incorrect conclusions from supposedly increased organ weights, the outdated literature should no longer be used and new reference values are necessary.

Hintergrund. Plötzliche und unerwartete Säuglingstode, bei denen auch nach Ausschöpfung der routinemäßig zur Verfügung stehenden Methodik keine plausible Todesursache gefunden wird, werden nach internationaler Konvention als Sudden Infant Death Syndrome, SIDS, klassifiziert. Fragestellung. In dieser Arbeit soll die Definition des SIDS im Wandel der Zeit beleuchtet werden und der Frage nachgegangen werden, ob dieser Begriff überhaupt noch zeitgemäß ist. Material und Methode. Es handelt sich um eine Übersichtsarbeit, basierend auf historischer und aktueller Literatur zu diesem Thema, Expertenempfehlungen und einer Auswertung amtlicher Statistiken. Ergebnisse. Die Definition des Begriffs „SIDS“ hat sich über mehr als 50 Jahren nur in wenigen Details geändert. Es handelt sich im Wesentlichen um eine Ausschlussdiagnose und nicht um eine Definition aufgrund des Vorhandenseins geteilter Merkmale. Die aktuelle „San Diego Definition“ beinhaltet allerdings Untergruppen, die in den älteren Fassungen noch nicht berücksichtigt wurden. In neuester Zeit wurde in den USA eine neue Nomenklatur eingeführt, die auf den Begriff SIDS verzichtet. Stattdessen wird die Bezeichnung „Unerklärter plötzlicher Tod“ („unexplained sudden death“) verwendet. Diese Arbeit diskutiert, ob dieser Paradigmenwechsel auch in Deutschland vollzogen werden sollte.

An analytical strategy for identification by an LC-MS/MS multitarget screening method and a suitable LC-MS/MS based quantification were developed for the psychotropic drug phenibut. The samples analyzed were collected during traffic control and were associated with driving under the influence of drugs. A positive sample for phenibut was identified in a single case of driving under the influence. The quantification revealed a drug concentration of 1.9 mu g/mL. An interaction with blood alcohol (BAC = 0.10%) was discussed as the explanation of the way of driving and deficit manifestations observed (swaying, nystagmus, quivering of the eyelid, and reddened eyes). According to the available information, the quantified phenibut concentration could be explained by an intake of four tablets (self-reported) during the day containing 250 mg of the drug. Chromatography was performed with a Luna 5 mu m C18 (2) 100 A, 150 mm x 2 mm analytical column, and a buffer system consisted of 10 mM ammonium acetate and 0.1% acetic acid (v/v) included in mobile phases marked as A (H2O/methanol = 95/5, v/v) and B (H2O/methanol = 3/97, v/v). An effective limit of detection (LOD = 0.002 mu g/mL) could be achieved for the multitarget screening method. The quantification of phenibut was performed on a second LC-MS/MS system with LOD/LOQ values of 0.22/0.40 mu g/mL. Since phenibut quantification data are rare, the presented information can be used with caution for evaluation of positive cases in the future.

Background: Sudden infant death syndrome (SIDS) is the leading cause of death among infants aged between one month and one year. Altered enzyme activities or expression of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have been observed in SIDS patients that might lead to disturbed autonomic function and, together with other risk factors, might trigger SIDS. To explore the contribution of AChE and BChE from a genomic viewpoint, we sought to investigate the association between SIDS and selected single nucleotide polymorphisms (SNPs) in the ACHE and BCHE genes. Methods: In this case-control study, 13 potentially regulatory SNPs were selected from ACHE and BCHE and were genotyped in 201 SIDS cases and 338 controls. The association of SIDS with the 11 successfully genotyped candidate variants was examined using statistical analyses of overall or stratified cases and haplotype analyses. Results: No significant overall associations were observed between SIDS and ACHE and BCHE variants in allele, genotype, and haplotype analyses. In subgroup analyses, eight variants were found to be nominally associated with SIDS, though these associations did not remain statistically significant after correction for multiple comparisons. One haplotype (T-C-G-C-C in rs3495-rs1803274-rs1355538-rs2048493-rs1126680) of BCHE was associated with the female SIDS subgroup (57.3% in controls vs. 46.3% in female SIDS cases, p = 0.010). Conclusions: The selected variants in ACHE and BCHE were not overall associated with SIDS in this study, and thus cannot generally explain the previously reported dysregulation of enzyme activities in SIDS. However, some evidence of association in subgroups and a possible contribution of variants other than those tested here would need to be explored in larger studies.

Background Sudden infant death syndrome (SIDS) has been considered to be triggered by a combination of underlying immune dysregulation and infections. The thymus is a crucial lymphatic organ responsible for T cell development in infancy. We hypothesized that an altered thymic immune status may be detectable by intrathymic cytokine profiling in SIDS. Methods 27 cytokines in protein lysates of thymus tissue and thymus weights were assessed in 26 SIDS cases and 16 infants who died of other reasons. Results Seventeen out of 27 cytokines were increased in thymic tissue of SIDS compared to controls without infections, and the most significant discrepancy was in infants younger than 20 weeks. The thymic cytokine profiles in SIDS cases were similar to those in controls with severe infection; however, the magnitude of the cytokine concentration elevation in SIDS was less pronounced, indicating sub-clinical infections in SIDS. In contrast to SIDS, intrathymic cytokine concentrations and thymus weight were increased with age in control children. Conclusions Elevated thymic cytokine expression and thymus weight, as well as impaired age-related alterations in SIDS, may be influenced by subclinical infection, which may play a role in initiating SIDS in infants with a compromised immune response. Impact Statement Increased thymic weight and cytokine concentration may suggest possible subclinical infection in SIDS. Elevated thymic weight and cytokine concentration mainly in SIDS cases aged <20 weeks. Age-related impairment in the thymic weight and cytokine expression may be impaired by subclinical infection in SIDS.

Objectives Disturbances of the central nervous system and immune system are thought to play a role in sudden infant death syndrome (SIDS). Dysregulated expression of sodium (Na + )/hydrogen (H + ) exchanger 3 (NHE3) in the brainstem and of interleukin 13 (IL13) in the lungs has been observed in SIDS. An association of single-nucleotide polymorphisms (SNPs) in NHE3 and IL13 with SIDS has been proposed, but controversial results were reported. Therefore, there is a need to revisit the association of SNPs in NHE3 and IL13 with SIDS. Methods Genotyping of rs71597645 (G1131A) and rs2247114 (C2405T) in NHE3 and rs20541 (+ 4464A/G) in IL13 was performed in 201 SIDS cases and 338 controls. A meta-analysis was performed after merging our data with previously published data (all from European populations). Results Polymorphisms rs2247114 ( NHE3 ) and rs20541 ( IL13 ) were significantly associated with SIDS overall and in multiple subgroups, but no association was found for rs71597645 ( NHE3 ). After combining our data with previously published data, a fixed-effect meta-analysis showed that rs2247114 in NHE3 retained a significant association with SIDS under a recessive model (OR 2.78, 95%CI 1.53 to 5.06; p = 0.0008). Conclusion Our findings suggest an association of NHE3 variant rs2247114 (C2405T), though not rs71597645 ( NHE3 ), with SIDS. A potential role of rs20541 ( IL13 ) still has to be elucidated. Especially NHE3 seems to be an interesting topic for future SIDS research.

Aim Impaired resilience to stress may be a factor in sudden infant death syndrome (SIDS). However, no comprehensive studies have been performed on polymorphisms that are relevant to the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress hormone cortisol.Methods We analysed 22 relevant single nucleotide polymorphisms (SNPs) in 206 anonymised SIDS cases who died at a mean of 131 days (range: 5-343) and 256 adult controls who were recruited from paternity testing cases. Additional stratified analyses were performed for sex, age and season of death. Both the cases and the controls were Caucasian.Results Variants for rs2235543 (HSD11B1) and rs3779250 (CRHR2) were associated with SIDS in the overall analysis, and borderline for rs2446432 (CRH), at least before corrections for multiple testing. A combination of these three variants was observed in 52.9% of SIDS cases but only 43.0% of controls (p = 0.039). Five or more variants showed an association in the subgroups.Conclusion Our findings suggest that the HPA axis influences SIDS and supports the hypothesis that an inadequate stress response may add to the risk. The associated variants for rs2235543, rs3779250 and rs2446432 appeared to decrease the cortisol concentration and impair an appropriate stress response.

AIMS:Alcohol use alters the reward signaling processes contributing to the development of addiction. We studied the effects of alcohol use disorder (AUD) on brain regions and blood of deceased women and men to examine sex-dependent differences in epigenetic changes associated with AUD. We investigated the effects of alcohol use on the gene promoter methylation of GABBR1 coding for GABAB receptor subunit 1 in blood and brain.METHODS:We chose six brain regions associated with addiction and the reward pathway (nucleus arcuatus, nucleus accumbens, the mamillary bodies, amygdala, hippocampus and anterior temporal cortex) and performed epigenetic profiling of the proximal promoter of the GABBR1 gene of post-mortem brain and blood samples of 17 individuals with AUD pathology (4 female, 13 male) and 31 healthy controls (10 female, 21 male).RESULTS:Our results show sex-specific effects of AUD on GABBR1 promoter methylation. Especially, CpG -4 showed significant tissue-independent changes and significantly decreased methylation levels for the AUD group in the amygdala and the mammillary bodies of men. We saw prominent and consistent change in CpG-4 across all investigated tissues. For women, no significant loci were observed.CONCLUSION:We found sex-dependent differences in GABBR1 promoter methylation in relation to AUD. CpG-4 hypomethylation in male individuals with AUD is consistent for most brain regions. Blood shows similar results without reaching significance, potentially serving as a peripheral marker for addiction-associated neuronal adaptations. Further research is needed to discover more contributing factors in the pathological alterations of alcohol addiction to offer sex-specific biomarkers and treatment.

Ramipril is a popular angiotensin-converting enzyme inhibitor applied in the treatment of hypertension. Its therapeutic effect is oriented on the concentration of the active metabolite ramiprilat. The information about toxic drug levels is missing in the literature. Therefore, the aim of this work was an indication of possible toxic ranges based on the analysis of real samples with high ramiprilat concentrations. For these purposes, an appropriate analytical LC–MS/MS method was developed and validated according to forensic guidelines and applied in the routine. Most real samples targeted for ramipril/ramiprilat were associated with the typical therapeutic drug range of 1–40 ng/mL described in the literature. However, higher drug levels with ramiprilat concentrations above 100 ng/mL could also be observed infrequently in cases of driving under the influence of drugs or attempted suicides. To the best of the author’s knowledge, this is the first time antemortem ramipril and ramiprilat concentrations associated with driving under the influence of drugs and suicide attempts were discussed from a forensic point of view. The collected data enabled an indication of the ramiprilat toxic concentration range from about 600 ng/mL to at least 3500 ng/mL. The toxic concentration range discussed can be applied in the forensic practice as a reference for future cases.

Background The detection of alterations in DNA methylation (DNAm) in normal human tissues may provide molecular insights for cancer development, the estimation of personal cancer risk, and a basis for early diagnosis of malignancies to reduce cancer lethality. Thus, whether DNAm allows discrimination between healthy normal and normal tumor-adjacent renal tissues is an important question. Methods DNAm of loci in the LINE1 repetitive sequence and ANKRD34B, NHLH2, TBR1 , and ZIC1 was measured in a total of 493 tissue samples representing 342 normal autopsy and 151 histopathological normal tumor-adjacent renal tissues by pyro-sequencing a total of 22 CpG sites. Results Unsupervised k-means clustering demonstrated a significant imbalance of tissue samples in three stable tissue clusters. Random forest classification demonstrated discrimination of normal and normal tumor-adjacent renal tissues with a median area under the ROC curve of 0.81 (p=2.7×10 −9 , diagnostic odds ratio 10.4). Variable importance analysis revealed CpG sites in LINE1 and ANKRD34B as the most important model contributors. Conclusions DNAm alterations in normal tissues allow detection of renal cancer with high diagnostic efficiency, defining a DNAm field effect in the kidney. The methylation signature may serve as a basis for an epigenetic DNAm clock permitting estimation of individual renal cancer risk.

Impaired resilience to stress may be a factor in sudden infant death syndrome (SIDS). However, no comprehensive studies have been performed on polymorphisms that are relevant to the hypothalamic–pituitary–adrenal (HPA) axis, which regulates the stress hormone cortisol. We analysed 22 relevant single nucleotide polymorphisms (SNPs) in 206 anonymised SIDS cases who died at a mean of 131 days (range: 5–343) and 256 adult controls who were recruited from paternity testing cases. Additional stratified analyses were performed for sex, age and season of death. Both the cases and the controls were Caucasian. Variants for rs2235543 ( HSD11B1 ) and rs3779250 ( CRHR2 ) were associated with SIDS in the overall analysis, and borderline for rs2446432 ( CRH ), at least before corrections for multiple testing. A combination of these three variants was observed in 52.9% of SIDS cases but only 43.0% of controls ( p  = 0.039). Five or more variants showed an association in the subgroups. Our findings suggest that the HPA axis influences SIDS and supports the hypothesis that an inadequate stress response may add to the risk. The associated variants for rs2235543, rs3779250 and rs2446432 appeared to decrease the cortisol concentration and impair an appropriate stress response.

328 autopsy cases of fatal pulmonary thromboembolism (PE) were compared to 984 age- and sex-matched controls to evaluate the association between obesity and PE in a forensic context. Both PE and control cases had a mean age of 67,8 years (male 62,9 years, females 71,7 years). The percentage of morbidly obese persons with a body mass index (BMI) of above 40 or abdominal subcutaneous adipose tissue of above 4 cm was higher in the PE group (8,39% vs. 4,67% and 29.45% vs. 23.40%, respectively). On the other side, that of very slim persons (BMI below 18.5 or adipose tissue below 3 cm) was significantly smaller (4,27% vs. 7,52% and 47.55% vs. 56,60%). We thus found a strong association between being overweight and death from PE, while slim persons seem to be at an advantage. As the group of underweight persons includes those suffering from chronic diseases with reduced mobility or hypercoagulability (e.g. tumor kachexia or sarkopenia due to immobilisation), this finding is to some extent unexpected.

Aims Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. Methods and results MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 & mu;g/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. Conclusion We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

AIMS:The dopamine receptor D2 (DRD2) is substantially involved in several forms of addiction. In addition to genetic polymorphisms, epigenetic mechanisms have emerged as an important means of regulation. Previously, DRD2 hypo- and hyper-methylation have been observed in alcohol use disorder (AUD). Blood samples are commonly used as a surrogate marker of epigenetic alterations in epigenetic research, but few specific comparisons between blood and brain tissue samples in AUD exist.METHODS:We used post-mortem brain tissue samples of 17 deceased patients with AUD and 31 deceased controls to investigate the relationship between blood and brain methylation of the DRD2 promoter.RESULTS:When investigating individual cytosine methylation sites (CpG), several significant differences were found in the nucleus accumbens and hippocampus in the study population. Investigating binding sites with significant differences in methylation levels revealed hypomethylated CpGs targeting mainly activating transcription factors.CONCLUSION:These findings support an altered transcription of the DRD2 gene in AUD specimens with a consecutively changed reward response in the brain. While methylation between specific brain regions and blood is comparable, our study further suggests that blood methylation cannot provide meaningful perspectives on DRD2 promoter methylation in the brain.