Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers.

The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide.

Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.

CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.

Differences in DNA methylation patterns and expression of the CCRK gene in human and nonhuman primate cortices.

Changes in DNA methylation patterns during embryo development and differentiation processes are linked to the transcriptional plasticity of our genome. However, little is known about the evolutionary conservation of DNA methylation patterns and the evolutionary impact of epigenetic differences between closely related species. Here we compared the methylation patterns of CpG islands (CGIs) in the promoter regions of seven genes in humans and chimpanzees. We identified a block of CpGs in the cell cycle-related kinase (CCRK) gene that is more methylated in the adult human cortex than in the chimpanzee cortex and, in addition, it exhibits considerable intraspecific variation both in humans and chimpanzees. The species-specifically methylated region (SMR) lies between the almost completely methylated 5' region and the completely demethylated 3' region of the presumed CCRK CGI promoter. It is part of an Alu-Sg1 repeat that has been integrated into the promoter region in a common ancestor of humans and New World monkeys. This SMR is relatively hypomethylated in the rhesus monkey cortex and more or less completely methylated in the baboon cortex, indicating extraordinary methylation dynamics during primate evolution. The mRNA expression level of CCRK has also changed during the course of primate evolution. CCRK is expressed at much higher levels in human and baboon cortices, which display an average SMR methylation of 70% and 100%, respectively, than in chimpanzee and rhesus macaque cortices with an average SMR methylation of 35% and 40%, respectively. The observed evolutionary dynamics suggests a possibility that CCRK has been important for evolution of the primate brain.

Investigation of Sudan IV staining areas in aortas of infants and children: possible prelesional stages of atherogenesis.

OBJECTIVES/METHODS: Although atherosclerosis in infants and children is generally acknowledged, the temporal and spatial sequence of LDL insudation, modification and intimal monocyte accumulation has not been systematically studied. We have investigated herein very early stages of lesion formation in human aortas of individuals up to the age of 15 years. Aortic specimens from 61 cases (37 male, 24 female) were examined. 34 cases were <1 year old, 16 cases were between 1 and 5 years old, and 11 cases were between 6 and 15 years old. Areas preselected under a dissection microscope after Sudan IV staining were investigated in depth by immunohistochemical staining for apolipoprotein B, monocytes/macrophages, smooth muscle cells (SMCs), enzymatically and oxidatively modified lipoproteins, C-reactive protein and complement components. RESULTS: (i) Lipoprotein accumulation in the intima before macrophage infiltration, (ii) virtually no extracellular lipoprotein modification, either enzymatic or oxidative, within intimal lesions in infancy (<1 year), (iii) onset of extracellular enzymatic modification of low-density lipoprotein (LDL) in the age group between 6 and 15 years and (iv) no coincidence of lipoprotein accumulation in the intima with activation of the terminal complement cascade as known from early atherosclerotic lesions in adults. CONCLUSIONS: The present study indicates the existence of hitherto undescribed prelesional stages in atherogenesis characterized by 'inert' lipoprotein insudation in individuals <1 year of age without lipoprotein modification, monocyte/macrophage infiltration and/or inflammation on the one hand and the onset of extracellular enzymatic rather than oxidative lipoprotein modification in individuals between 6 and 15 years of age on the other hand. Further investigations of these stages should advance understanding of events underlying initiation, progression and regression of intimal lesions developing in early atherogenesis.

[Homicides by sharp force with nearly complete penetration of the weapon]. / Tötungsdelikte durch scharfe Gewalt mit nahezu vollständigem Eindringen des Tatwerkzeuges.

Despite a large number of publications on sharp force injuries, there are no specific reports on homicides with nearly complete penetration of the weapon into the body of the victim. We present three cases in which the crime was committed in this unusual way. The victims were males aged between 28 and 71 years. They were killed by multiple sharp force. The weapons used were knives with a total length of up to about 20 cm, which penetrated into the body (almost) completely including the handle. Involved body regions were the front and back of the chest and the neck. In one case, two different sharp weapons were found in the trunk. The injuries inflicted on the internal organs by the penetrating knives caused massive bleeding and were the leading cause of death. Additional remarkable features were complex patterns of injury by further sharp and blunt force and, in one case, tying. The victims were highly intoxicated (by alcohol and, in one case, illegal drugs), which made them nearly incapable of acting. All perpetrators were male, between 23 and 33 years of age, strongly influenced by alcohol and loosely acquainted with the victims. The kind of committing the offence seems to be explainable only against the background of an absolute will to annihilate ("overkill").

["Overkill" in a case of neonaticide]. / "Overkill" im Rahmen einer Neugeborenen-Tötung.

A 14-year-old girl was found unconscious in a pool of blood by her mother in the family bathroom. A gynecological emergency operation revealed a state after spontaneous delivery. A few days later the corpse of a newborn, smeared with blood, was found by the father of the girl in a laundry basket in the bathroom. The autopsy revealed signs of blunt force against the cranium as well as multiple lesions caused by sharp force in the area of the neck and the thorax. The newborn died of hemorrhagic shock due to severance of the left subclavian artery. The pattern of injuries is presented. In addition, the girl's statement with respect to the course of events is discussed. Finally, this rare manner of committing neonaticide is compared with former reports in the literature.