Sudden Infant Death Syndrome (SIDS) is the sudden and unexpected death of an otherwise healthy infant less than 1 year of age where the cause of death remains unexplained after a thorough post-mortem investigation and evaluation of the circumstances. Epidemiological, clinical, biochemical, immunological and pathological evidence indicates that three factors must coincide for SIDS to occur: a vulnerable developmental stage of the immune system and central nervous system in the infant, predisposing factors, and external trigger events. This model is referred to as the fatal triangle or triple risk hypothesis. The concept of a vicious spiral in SIDS, starting with the fatal triangle and ending in death, is proposed as a model to understand the death mechanism. The vicious spiral is initiated by a mucosal infection and immune activation in the upper respiratory and digestive tracts, increased production of cytokines, and an overstimulation of the immature and rapidly developing immune system. A second trigger is the prone sleeping position, which may lead to rebreathing and hypercapnia, in addition to intensify the immune stimulation. In susceptible infants, this induces an aberrant cytokine production that affects sleep regulation, induces hyperthermia, and disrupts arousal mechanisms. In turn, this initiates downregulation of respiration and hypoxemia, which is worsened by nicotine. Inefficient autoresuscitation results in severe hypoxia and accumulation of hypoxic markers which, if not prevented by a normally functioning serotonergic network, contribute to a self-amplifying vicious spiral that eventually leads to coma and death. The purpose of this review is to summarize the research that underpins the concept of the vicious spiral.

Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported (Barp et al. 2017a, 2017b). Rats were exposed to feed containing 0-4000 mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular masses < C25 (S-C25), ii) dewaxed, mainly molecular masses > C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanes > C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were related to accumulated n-alkanes (wax) above C25, presumably not relevant for humans, but also to MOSH from S-C25, mainly consisting of iso-alkanes and substituted cycloalkanes below C25 with a small proportion of n-alkanes. Induction of liver granuloma appeared to be related to n-alkanes > C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. Iso-alkanes and substituted cycloalkanes accumulating in rat liver and spleen were similar to those accumulating in humans.

AIM:This study reviewed cases of sudden unexpected child deaths in Norway to determine the significance of death-scene investigations (DSIs) in establishing cause and manner of death, and thereby it is relevance to legal protection. METHODS:Data from forensic autopsy reports and DSIs were collected and analysed for cases of unexpected deaths in children below 4 years of age in Norway during 2010-2016. RESULTS:Out of 141 cases, the death scene was investigated as a voluntary procedure in 75 cases and by the police in 41 cases. The cause of death remained unexplained in 81/141 (57%) of the cases, of which 46/141 (33%) met the criteria for sudden infant death syndrome (SIDS) or sudden unexplained death in early childhood (SUDC). The manner of death was determined in 102/141 (72%). Voluntary DSI increased the ability to rule out accidental suffocation, facilitated evaluations of environmental risk factors and enabled detection of possible neglect. CONCLUSION:Death-scene investigations illuminate uncertainty about the cause of death, especially in grey-area cases where accidental suffocation, neglect or abuse is suspected. Knowledge about the course of events and the cause of death enhances both the child's and the caregiver's legal protection. Death-scene investigations should therefore be mandatory.

This study reviewed cases of sudden unexpected child deaths in Norway to determine the significance of death-scene investigations (DSIs) in establishing cause and manner of death, and thereby it is relevance to legal protection. Data from forensic autopsy reports and DSIs were collected and analysed for cases of unexpected deaths in children below 4 years of age in Norway during 2010-2016. Out of 141 cases, the death scene was investigated as a voluntary procedure in 75 cases and by the police in 41 cases. The cause of death remained unexplained in 81/141 (57%) of the cases, of which 46/141 (33%) met the criteria for sudden infant death syndrome (SIDS) or sudden unexplained death in early childhood (SUDC). The manner of death was determined in 102/141 (72%). Voluntary DSI increased the ability to rule out accidental suffocation, facilitated evaluations of environmental risk factors and enabled detection of possible neglect. Death-scene investigations illuminate uncertainty about the cause of death, especially in grey-area cases where accidental suffocation, neglect or abuse is suspected. Knowledge about the course of events and the cause of death enhances both the child's and the caregiver's legal protection. Death-scene investigations should therefore be mandatory.

Background Genetic predispositions in cases suffering sudden unexpected infant death have been a research focus worldwide during the past decade. Despite large efforts, there is still uncertainty concerning the molecular pathogenesis of these deaths. With genetic technology in constant development, the possibility of an alternative approach into this research field has become available, like mRNA expression studies. Methods In this study, we investigated mRNA gene expression in 14 cases who died suddenly and unexpectedly from infection without a history of severe illness prior to death. The control group included eight accidents, two cases of natural death, one undetermined, one case of medical malpractice, and two homicides. The study included tissue from liver, heart, and brain using Illumina whole-genome gene expression assay. Results From the array, 19 genes showed altered expression in the infectious deaths compared to controls. Tissue from the heart showed 15 genes with altered mRNA expression compared to the control group. Conclusions Downregulation of KCNE5 in heart tissue from cases of infectious death was of particular interest. Variants of KCNE5 are associated with Brugada syndrome and sudden death and could be responsible for the fatal outcome in the group of infectious death. Impact KCNE5 is downregulated in tissue from the heart in cases of infectious death in infancy. This study provides knowledge about the gene expression profile in cases of infectious death. Variants of a gene known to give increased risk of cardiac arrhythmia is downregulated in cases of infectious death in infancy. The results could give us better knowledge as to why some infants do not survive an infection. This study provides a candidate gene for future studies.

Aim: Disturbances in brain function and development may play a role in sudden infant death syndrome (SIDS). This Norwegian study aimed to test the hypothesis that specific variants of genes involved in water transport and potassium homeostasis would be predisposing factors for SIDS.Methods: Genetic variation in the genes encoding aquaporin-4 (AQP4), Kir4.1 (KCNJ10) and a-syntrophin was analysed in 171 SIDS cases (62.6% male) with a median age of 15.5 (2-52) weeks and 398 adult controls (70.6% male) with a median age of 44 (1191) years. All the subjects were Caucasians who were autopsied from 1988 to 2013.Results: The CC genotype of rs72878794 in the AQP4 gene and a combination of the CC genotype in rs17375748, rs1130183, rs12133079 and rs1186688 in KCNJ10 (4xCC) were found to be associated with SIDS. The SIDS cases with the 4xCC SNP combination were younger than the SIDS cases with other genotype combinations (p = 0.006).Conclusion: This study indicates that genetic variations in KCNJ10 and AQP4 may be predisposing factors for SIDS. Alterations in the expression of the AQP4/Kir4.1 complex can disrupt water and ion homeostasis, which may influence brain development and facilitate brain oedema formation This may be especially unfavourable during the first weeks of life.

Disturbances in brain function and development may play a role in sudden infant death syndrome (SIDS). This Norwegian study aimed to test the hypothesis that specific variants of genes involved in water transport and potassium homeostasis would be predisposing factors for SIDS. Genetic variation in the genes encoding aquaporin-4 (AQP4), Kir4.1 (KCNJ10) and α -syntrophin was analysed in 171 SIDS cases (62.6% male) with a median age of 15.5 (2–52) weeks and 398 adult controls (70.6% male) with a median age of 44 (11–91) years. All the subjects were Caucasians who were autopsied from 1988 to 2013. The CC genotype of rs72878794 in the AQP4 gene and a combination of the CC genotype in rs17375748, rs1130183, rs12133079 and rs1186688 in KCNJ10 (4xCC) were found to be associated with SIDS. The SIDS cases with the 4xCC SNP combination were younger than the SIDS cases with other genotype combinations (p = 0.006). This study indicates that genetic variations in KCNJ10 and AQP4 may be predisposing factors for SIDS. Alterations in the expression of the AQP4/Kir4.1 complex can disrupt water and ion homeostasis, which may influence brain development and facilitate brain oedema formation This may be especially unfavourable during the first weeks of life.

The pathophysiology and outcome of meningococcal septic shock is closely associated with the plasma level of N. meningitidis lipopolysaccharides (LPS, endotoxin) and the circulating level of meningococcal DNA. The aim of the present study was to quantify the number of N. meningitidis in different formalin-fixed, paraffin-embedded (FFPE) tissue samples and fresh frozen (FF) tissue samples from patients with systemic meningococcal disease (SMD), to explore the distribution of N. meningitidis in the body.

Background: A large number of studies have tried to uncover a genetic predisposition for sudden infant death syndrome (SIDS), but there is still uncertainty concerning the pathogenesis of these deaths. The purpose of this study was to investigate mRNA gene expression in SIDS cases and controls, in order to uncover genes that are differentially expressed in the two groups. Methods: Tissue from brain, heart, and liver from 15 SIDS cases and 15 controls were included in the study, and mRNA expression was determined using the Illumina whole genome gene expression DASL HT assay. Results: Seventeen genes showed significantly altered expression compared to controls, after correction for multiple testing. Three genes involved in the immune system were of particular interest, including the downregulation of MyD88 in tissue from SIDS brains, as well as the downregulation of the genes encoding CCL3 and UNC13 in the liver. Conclusion: These findings indicate that there is an altered expression of genes involved in the inflammatory process in a proportion of SIDS cases, which further strengthen the hypothesis that impaired immune response play a role in this syndrome.

Fulminant meningococcal sepsis is characterized by a massive growth of bacteria in the circulation, regarded as the primary inflammatory site, with no specific solid organ focus. Here we aimed to study the local inflammatory response in organs using a porcine model of fulminant meningococcal septic shock challenged with exponentially increasing doses of heat inactivated Neisseria meningitidis. The results were compared with those obtained in organs post mortem from three patients with lethal meningococcal septic shock. Nine patients with lethal pneumococcal disease and 14 patients with sudden infant death syndrome served as controls. Frozen tissue were thawed, homogenized and prepared for quantification of bacterial DNA by real-time polymerase chain reaction, and key inflammatory mediators were measured by ELISA in the pig material and by multiplex in the human material. In addition, gene expression assayed by Affymetrix gene expression profiling was performed in the pig study. The porcine model revealed a major influx of N. meningitidis in lungs, liver, spleen, and kidneys accompanied with major production of cardinal inflammatory mediators including tumor necrosis factor, interleukin (IL)-1β, IL-6, and IL-8, far exceeding the amount detected in blood. Genes encoding for these mediators revealed a similar profile. By comparing the wild-type with a lipopolysaccharide (LPS) deficient meningococcal strain, we documented that LPS was the dominant group of molecules inducing organ inflammation and was required for IL-8 production. IL-10 production was predominantly stimulated by non-LPS molecules. The massive organ inflammation in the porcine model was present in the three patients dying of meningococcal shock and differed markedly from the patients with lethal pneumococcal infections and sudden infant death syndrome. In conclusion, in meningococcal sepsis, a massive local inflammatory response occurs in specific organs.

The purpose of this study was to investigate common polymorphisms in the genes encoding monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) in Norwegian cases of sudden infant death syndrome (SIDS). This was done to further elucidate the role of genetic variation in these genes and SIDS. A variable number of tandem repeat area in the promoter of the MAOA gene and rs25531 in the promoter region of the gene encoding 5-HTT were investigated in 193 SIDS cases and 335 controls. The methods used were polymerase chain reaction, restriction fragment analysis and gel electrophoresis. There were no differences between SIDS cases and controls for any of the investigated polymorphisms. This was also true when male and female SIDS cases were analysed separately. This article indicates that neither the VNTR in the promoter of the MAOA gene, nor rs25531 in the gene encoding 5-HTT, is involved in SIDS. However, as medullary serotonergic abnormalities most likely contribute to the death in at least some SIDS cases, it is important to investigate these genes, as well as other genes involved in the serotonergic network, in more detail.

AimThe purpose of this study was to investigate common polymorphisms in the genes encoding monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) in Norwegian cases of sudden infant death syndrome (SIDS). This was done to further elucidate the role of genetic variation in these genes and SIDS.MethodsA variable number of tandem repeat area in the promoter of the MAOA gene and rs25531 in the promoter region of the gene encoding 5-HTT were investigated in 193 SIDS cases and 335 controls. The methods used were polymerase chain reaction, restriction fragment analysis and gel electrophoresis.ResultsThere were no differences between SIDS cases and controls for any of the investigated polymorphisms. This was also true when male and female SIDS cases were analysed separately.ConclusionThis article indicates that neither the VNTR in the promoter of the MAOA gene, nor rs25531 in the gene encoding 5-HTT, is involved in SIDS. However, as medullary serotonergic abnormalities most likely contribute to the death in at least some SIDS cases, it is important to investigate these genes, as well as other genes involved in the serotonergic network, in more detail.

The mucosal immune system and cytokines are activated in a large proportion of cases of sudden infant death syndrome (SIDS). Our aim was to search for a possible association between cytokine polymorphisms and immune stimulation of the laryngeal mucosal in SIDS. HLA-DR expression in laryngeal mucosal glands and surface epithelium in 97 SIDS victims was evaluated applying a semi-quantitative scoring system. The findings were related to cytokine gene polymorphisms as well as to the level of various cytokines in the cerebrospinal fluid (CSF). A risk score was established: a score of 0 prepresenting negative HLA-DR, supine position and no fever prior to death. The IL-6 -176CG/CC genotype was found in 92.3% of the SIDS cases with positive score for all risk factors (p = 0.01). Infants with high HLA-DR score had high levels of IL-6 in the cerebrospinal fluid (>30 μg/L) (p = 0.005). Furthermore, the IL-8 SNPs -781 CT/TT genotypes and −251 AA/AT genotypes were observed in 93% of the SIDS cases with one or more of the risk factors present compared with SIDS cases no risk factors reported (p = 0.003 and p = 0.016, respectively). This study adds further evidence to the hypothesis that there are genetically associated disturbances of immunological homoeostasis in SIDS.

Aim The mucosal immune system and cytokines are activated in a large proportion of cases of sudden infant death syndrome (SIDS). Our aim was to search for a possible association between cytokine polymorphisms and immune stimulation of the laryngeal mucosal in SIDS. Methods HLA-DR expression in laryngeal mucosal glands and surface epithelium in 97 SIDS victims was evaluated applying a semi-quantitative scoring system. The findings were related to cytokine gene polymorphisms as well as to the level of various cytokines in the cerebrospinal fluid (CSF). A risk score was established: a score of 0 prepresenting negative HLA-DR, supine position and no fever prior to death. Results The IL-6 -176CG/CC genotype was found in 92.3% of the SIDS cases with positive score for all risk factors (p=0.01). Infants with high HLA-DR score had high levels of IL-6 in the cerebrospinal fluid (>30g/L) (p=0.005). Furthermore, the IL-8 SNPs -781 CT/TT genotypes and 251 AA/AT genotypes were observed in 93% of the SIDS cases with one or more of the risk factors present compared with SIDS cases no risk factors reported (p=0.003 and p=0.016, respectively). Conclusion This study adds further evidence to the hypothesis that there are genetically associated disturbances of immunological homoeostasis in SIDS.

Autopsies can give valuable information about the cause of death, and represent an important tool for obtaining valid cause of death statistics. In particular, they may shed light on the circumstances of death in ambiguous and criminal cases. To address the need for information on current autopsy practices, forensic autopsy rates in two counties in Central Norway over the period 2007-2009 were assessed. To investigate toxicological findings that could possibly remain undisclosed without the performance of an autopsy, the impact of alcohol and drugs in forensic autopsy cases from this material was evaluated. The total forensic autopsy rate in this material was 3%. The forensic autopsy rates were low for natural deaths (1%), accidental falls (12%) and the heterogeneous category "other accidents" (21%), relatively high for accidental poisonings (84%), and less than adequate for road traffic accidents (57%). For suicides the forensic autopsy rate was 63%, and for recognized homicides 100%. The total forensic autopsy rate was higher for men than for women (5% vs. 2%), and decreased with age, being 38% in the age group <30 years, 23% in the age group 30-59 years, and 1% in the age group >59 years. Despite that Norwegian legislation and regulations regarding forensic autopsy requests are national, the forensic autopsy rates were generally lower in the county of Nord-Trøndelag than in Sør-Trøndelag, with most striking differences in suicide deaths (11% vs. 91%) and road traffic accidents (46% vs. 67%). This illustrates how autopsy rates, and possibly cause of death registries, might be susceptible to the influence of regional variations in law enforcement, with possible consequences for the quality and validity of cause of death statistics. Of the forensic autopsy cases where toxicological analysis was performed (361 of 364 cases) a total of 71% had positive toxicology results; 12% were positive for alcohol only, 44% were positive for drugs only, and 15% were positive for both alcohol and drugs. The toxicology results suggest that alcohol and drugs are important factors in sudden unexpected deaths, and that a thorough and comprehensive toxicological analysis is called for when investigating these deaths. Mean BAC in alcohol positive forensic autopsy cases was 1.7‰ (median 1.6‰, range 0.29-4.1‰). The average number of substances detected in toxicology positive cases was 2.6 (median 2, range 1-10). The by far most frequently detected classes of substances were (1) benzodiazepines, (2) opioids and (3) alcohol.

Several studies indicate that interleukin gene polymorphisms are of importance to sudden infant death syndrome (SIDS), and so far it has been reported that associations between SIDS and polymorphism in the genes encoding tumor necrosis factor alpha, IL (interleukin)-6, and IL-10. IL-1 are important for the synthesis of acute phase proteins, and it is a pyrogen cytokine that may cause fever. The purpose of the present study was to investigate two polymorphisms in the IL-1α gene; a variable number of tandem repeat (VNTR) in intron 6 and a single nucleotide polymorphism in +4845G/T, as well as the −511C/T polymorphism in the gene encoding IL-1β, and a VNTR in intron 2 of the competitive antagonist IL-1Ra, in SIDS cases, cases of infectious death, and controls. Furthermore, the genotypes were correlated with known external risk factors for SIDS. When investigating each polymorphism separately, no differences in genotype distribution between the diagnosis groups and controls were found. However, when combining VNTR and single nucleotide polymorphism genotypes, an association between the gene combination IL-1α VNTR A1A1/IL-1β+ +4845TT and SIDS was disclosed (p < 0.01). In the SIDS group it was also found that the genotypes IL-1β −511CC/CT were significantly more frequent in the SIDS victims found dead in a prone sleeping position, compared with SIDS victims found dead in other sleeping positions (p = 0.004). The findings in the present study indicate that specific interleukin gene variants may be a predisposing factor for sudden unexpected infant death.

The purpose of this study was to investigate the aquaporin-4 (AQP4) gene in cases of sudden infant death syndrome (SIDS) and controls and to elucidate the hypothesis that a genetically determined disturbed water homeostasis in the brain is involved as a predisposing factor in SIDS. The single nucleotide polymorphisms (SNPs) rs2075575, rs4800773, rs162004, and rs3763043 in the AQP4 gene were investigated in 141 SIDS cases and 179 controls. For each SIDS case, a brain/body weight ratio was calculated. The study revealed an association between the T allele and the CT/TT genotypes of rs2075575 and SIDS (C versus T, p < 0.01; CC versus CT/TT, p = 0.03). For the other three investigated SNPs, there were no differences in genotype frequencies between SIDS cases and controls. For the SNP rs2075575, it was also found an association between brain/body weight ratio and genotype in the SIDS cases aged 0.3–12 wk (p = 0.014, median ratio CC 10.6, CT/TT 12.1). In conclusion, this study indicates that rs2075575 may be of significance as a predisposing factor for SIDS, and that the CT/TT genotypes are associated with an increased brain/body weight ratio in infants dying from SIDS during the vulnerable period from birth up to 3 mo of age.