Brain water content in sudden unexpected infant death.

The extensive and rapid development of the human brain during the first years of life complicates the postmortem diagnosis of brain edema in infancy. The aim of this study was to describe brain water content, the brain weight/body weight ratio, and the brain weight/head circumference ratio throughout the first years of life. Furthermore, we examined the relationship between these parameters and rs2075575 in the AQP4 gene. Our hypothesis was that dysregulated water homeostasis might be a risk factor for sudden infant death syndrome (SIDS), which may be reflected by increased water content in the brain. The study included 90 subjects with sudden unexpected death < 4 years of age: 22 cases of sudden infant death syndrome, 11 cases of sudden unexplained death in childhood, 47 cases of death due to disease, and 10 cases of accident/violent death. Brain water content, brain weight/body weight ratio, and brain weight/head circumference ratio were investigated according to corrected age, diagnosis group, attempt to resuscitate, and presence of brain edema. We found that brain water content and brain weight/body weight ratio were significantly reduced with increasing age, while brain weight/head circumference were increased. Brain weight/head circumference was correlated with brain water content. Cases with brain edema had a significantly higher brain weight/head circumference than the non-edematous cases. No differences were found between the diagnosis groups for any of the investigated parameters. In summary, the findings contribute to the current body of knowledge regarding brain growth during the first months of life.

Aquaporin-1 and aquaporin-9 gene variations in sudden infant death syndrome.

Several studies have indicated that a vulnerability in the development and regulation of brain function is involved in sudden infant death syndrome (SIDS). The aim of this study was to investigate the genes encoding the brain aquaporins (AQPs) AQP1 and AQP9 in SIDS. The hypothesis was that specific variants of these genes are part of the genetic vulnerability predisposing infants to sudden unexpected death. The study included 168 SIDS cases with a median age of 15.5 (range 2-52) weeks and 372 adolescent/adult deceased controls with a median age of 44 (range 11-91) years. In the AQP1 gene, the rs17159702 CC/CT genotypes were found to be associated with SIDS (p = 0.02). In the AQP9 gene, the combination of a TT genotype of rs8042354, rs2292711 and rs13329178 was more frequent in SIDS cases than in controls (p = 0.03). In the SIDS group, an association was found between genetic variations in the AQP1 gene and maternal smoking and between the 3xTT combination in the AQP9 gene and being found lifeless in a prone position. In conclusion, this study adds further evidence to the involvement of brain aquaporins in SIDS, suggesting that specific variants of AQP genes constitute a genetic predisposition, making the infant vulnerable to sudden death together with external risk factors and probably other genetic factors.

Long QT syndrome KCNH2 mutation with sequential fetal and maternal sudden death.

We report a case of a woman who experienced intrauterine fetal death at full term pregnancy, and then died suddenly soon after learning about the death of her fetus. At autopsy, previously undiagnosed neurofibromatosis and an adrenal gland pheochromocytoma were discovered in the mother. Genetic screening also revealed a novel KCNH2mutation in both fetus and mother indicating type 2 congenital long-QT syndrome (LQTS). A catecholamine surge was suspected as the precipitating event of fetal cardiac arrhythmia and sudden fetal death, while the addition of emotional stress provoked a lethal cardiac event in the mother. This case illustrates the potential for lethal interactions between two occult diseases (pheochromocytoma, LQTS).

A global metabolomics minefield: Confounding effects of preanalytical factors when studying rare disorders.

A common challenge when studying rare diseases or medical conditions is the limited number of patients, usually resulting in long inclusion periods as well as unequal sampling and storage conditions. The main purpose of this study was to demonstrate the challenges when comparing samples subject to different preanalytical conditions. We performed a global (commonly referred to as "untargeted") liquid chromatography-high resolution mass spectrometry metabolomics analysis of blood samples from cases of sudden infant death syndrome and controls stored as dried blood spots on a chemical-free filter card for 15 years at room temperature compared with the same blood samples stored as whole blood at -80°C before preparing new dried blood spots using a chemically treated filter card. Principal component analysis plots distinctly separated the samples based on the type of filter card and storage, but not sudden infant death syndrome versus controls. Note that, 1263 out of 5161 and 642 out of 1587 metabolite features detected in positive and negative ionization mode, respectively, were found to have significant 2-fold changes in amounts corresponding to different preanalytical conditions. The study demonstrates that the dried blood spot metabolome is largely affected by preanalytical factors. This emphasizes the importance of thoroughly addressing preanalytical factors during study design and interpretation, enabling identification of real, biological differences between sample groups whilst preventing other factors or random variation to be falsely interpreted as positive results.

An infant with subdural hematoma and retinal hemorrhages: does von Willebrand disease explain the findings?

An 11-month-old girl presented to hospital with a massive subdural haematoma and bilateral retinal haemorrhages following an allegedly minor fall. There were no external signs of bruising and no prior bleeding tendency was reported. Although initial analyses were normal, repeated testing of the coagulation-fibrinolysis system led to a diagnosis of mild von Willebrand disease (vWD) Type 1. It was concluded that minor head trauma as described by the parents, in the presence of such a coagulation disorder, could explain the findings. Police charges against the parents, initially accused of child abuse, were withdrawn. Retinal haemorrhages in infants with vWD have not been previously reported. This case highlights the importance of considering vWD as a possible contributory factor in cases of infant head injury.

Violent Infant Surrogate Shaking: Continuous High-Magnitude Centripetal Force and Abrupt Shift in Tangential Acceleration May Explain High Risk of Subdural Hemorrhage.

Violent shaking is believed to be a common mechanism of injury in pediatric abusive head trauma. Typical intracranial injuries include subdural and retinal hemorrhages. Using a laboratory surrogate model we conducted experiments evaluating the head motion patterns that may occur in violent shaking. An anthropomorphic test device (ATD; Q0 dummy) matching an infant of 3.5 kg was assembled. The head interior was equipped with accelerometers enabling assessment of three-axial accelerations. Fifteen volunteers were asked to shake the surrogate vigorously holding a firm grip around the torso. We observed the volunteers performing manual shaking of the surrogate at a median duration of 15.5 sec (range 5-54 sec). Typical acceleration/deceleration patterns were produced after 2-3 shakes with a steady-state shaking motion at a pace of 4-6 cycles (back and forth) per second. Mean peak sagittal tangential accelerations at the vertex were 45.7g (range 14.2-105.1g). The acceleration component in the orthogonal direction, the radial acceleration, fluctuated around a negative mean of more than 4g showing that the surrogate head was continuously subjected to centripetal forces caused by rotations. This surrogate experiment showed that violent shaking may induce high peak tangential accelerations and concomitantly a continuous high-magnitude centripetal force. We hypothesize that the latter component may cause increased pressure in the subdural compartment in the cranial roof and may cause constant compression of the brain and possibly increased stretching or shearing of the bridging veins. This may contribute to the mechanism accountable for subdural hematoma in abusive head trauma.

Aquaporin 4 expression in the hippocampus in sudden infant death syndrome and sudden unexplained death in childhood.

Aquaporin 4 (AQP4) is the main membrane water channel in the brain involved in regulating water homeostasis. The water distribution in neural tissue is often dysregulated after hypoxic neural injury. Previous research has indicated that victims of sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC) have an underlying brain dysfunction that impairs their critical arousal response to hypoxic stress during sleep. The aim of this study was to determine the expression levels of AQP4 in the hippocampus in SIDS/SUDC cases and controls, and compare the findings with AQP4 genotypes that previously have been shown to be associated with SIDS. Immunochemical staining and morphometry were used to evaluate the density of AQP4-positive astrocytes in 30 SIDS/SUDC cases and 26 controls. AQP4-positive cells were counted in grids covering three layers in the hippocampus, which revealed that their count in any of the layers did not differ significantly between cases and controls. A decline in AQP4 expression was observed for infants older than 12 weeks. The AQP4 expression was lower in infants and children with the rs2075575 CT/TT genotype than in those with the CC genotype. This study indicates that AQP4 expression may be influenced by both age and genotype in infants. The role of AQP4 in the pathogenesis of SIDS remains to be elucidated.

Surfactant protein A and D gene polymorphisms and protein expression in victims of sudden infant death.

AIM: To investigate the innate immune components surfactant protein A (SP-A) and D (SP-D) in victims of sudden infant death syndrome (SIDS). METHODS: Ten common single nucleotide polymorphisms (SNPs) in the exons of SP-A1, SP-A2 and SP-D genes were analysed in 42 cases of SIDS and 46 explained sudden infant deaths. SP-A and SP-D protein expression in tissue from the aerodigestive tract was semi-quantitatively evaluated by immunohistochemistry. RESULTS: SP-D immunoreactivity was found in lungs and tissue from submandibular gland, palatine tonsils and duodenum. Positive SP-A immune staining was found exclusively in lung tissue. Neither the allele nor the haplotype distribution of the SP-A and SP-D genes was significantly different in SIDS compared to explained deaths. The most common SP-A haplotype, 6A2/1A0, tended to be overrepresented in the cases with low immunohistochemical SP-A expression (61%) compared to cases with high expression (49%), p = 0.08. The SP-D expression was not influenced by the 11 C/T or 160 A/G polymorphisms. CONCLUSION: No significant association between the common genetic variants of SP-A and SP-D and SIDS is disclosed by the present study. However, low SP-A protein expression may possibly be determined by the 6A2/1A0 SP-A haplotype, this should be subject for further investigation.

Postmortem evaluation of brain edema: An attempt with measurements of water content and brain-weight-to-inner-skull-circumference ratio.

INTRODUCTION: Postmortem evaluations of cerebral edema typically involve examinations of macroscopic features such as the presence of pressure signs and compression of the ventricles. Global massive edema is easily detectable in an autopsy, but less-extensive edema may be difficult to diagnose. AIM: The aim of this study was to compare measurements of brain water contents, postmortem CT radiodensity and brain weight to skull size in edematous and nonedematous brains in order to develop an objective method for postmortem evaluations of brain edema. METHOD: Fifty-four subjects autopsied at Oslo University Hospital underwent a standard forensic postmortem examination, including a computed axial tomography (CT) scan, measurement of brain weight, and macroscopic evaluation of the brain. CT images were used to roughly measure the inner skull circumference. The water content of the brain was determined by excising samples of approximately 1 g of brain tissue from eight different areas of the brain surface, drying them, and measuring their percentage water content. RESULTS: The main finding was a significant relationship between brain weight and inner skull circumference, with the ratio between these two parameters being significantly higher in cases with severe postmortem brain edema than in cases with very little or no brain edema. The water content did not differ significantly between the edema and nonedema cases. There were no significant changes in radiodensity. CONCLUSION: This indicates that the brain-weight-to-inner-skull-circumference ratio may serve as a good marker for severe brain edema in postmortem diagnostics, whereas measurements of water content can be misleading.

Telomere instability detected in sporadic colon cancers, some showing mutations in a mismatch repair gene.

Human telomeres are essential for genome stability and are composed of long simple tandem repeat arrays (STRs), comprising the consensus TTAGGG repeat interspersed, at the proximal end, with sequence-variant repeats. While the dynamics of telomere attrition through incomplete replication has been studied extensively, the effects on telomeres of error-prone DNA repair processes, known to affect other STRs, are poorly understood. We have compared the TTAGGG and sequence-variant interspersion patterns in the proximal 720 bp of telomeres in colon cancer and normal DNA samples. The frequency of telomere mutations was 5.8% per allele in a randomly collected panel of sporadic colon cancers, showing that telomere mutations occur in vivo. The mutation frequency rose to 18.6% per allele in sporadic tumours that exhibit instability at the polyA tract in the TGFbetaRII gene and to 35% per allele in tumours with somatic mutations in the hMSH2 gene. The majority of the characterized mutations resulted in the loss of one or a few repeats. If the mutation spectrum and frequency described here is reiterated in the rest of the array, there is the potential for extensive telomere destabilization especially in mismatch repair-defective cells. This may in turn lead to a greater requirement for telomere length maintenance earlier in tumourigenesis.

Mitochondrial microsatellite instability in colorectal carcinomas--frequency and association with nuclear microsatellite instability.

The D310 mononucleotide repeat in the D-loop region in mitochondrial DNA has been identified as a hotspot for alterations in primary tumours. We examined D310 alterations as well as repeats in the ND1 and ND5 genes, in 95 colorectal carcinomas and in 95 controls without known gastrointestinal malignancy. D310 alterations were found in 32 (34%) of the carcinomas, in contrast to two persons (2%) in the control group. Thus, when frequency is concerned, D310 seems to be a hotspot for alterations in colorectal cancer. No mutations were found in the ND1 and ND5 genes. D310 instability was not associated with nuclear microsatellite instability, indicating different mechanisms of occurrence.

[Bed sharing and sudden infant death]. / Samsoving og krybbedød.

BACKGROUND: The aim of the study was to investigate bed sharing as a risk factor for sudden infant death syndrome (SIDS). MATERIAL AND METHODS: Firstly, SIDS cases examined at our institute in two six-year periods before and after the back-to-sleep campaign (1984-89 and 1998-2003) were investigated. Secondly, a case-control study was performed, an investigation of variables such as bed sharing, parental smoking and breast-feeding in the SIDS group from the latter period versus 244 live control infants. RESULTS: The age distribution of the SIDS victims in the two periods with high and low SIDS rates differed significantly (p = 0.004). In the latter period, fewer SIDS cases were seen in the classical distributional peak between the third and the fourth month of life, and a larger proportion of SIDS cases were seen within the first month of life. Furthermore, a smaller proportion of SIDS victims were found dead in the prone position (decrease from 89% to 49%, p < 0.001); and bed sharing at time of death occurred more frequently (increase from 7% to 35%, p < 0.001). In the case-control study, bed sharing was a significant risk factor for SIDS in infants aged 0-2 months (multivariate OR 5.3; 95 % CI 1.3-22, p = 0.02). Bed sharing with a smoking mother was associated with a 16-fold increased risk of SIDS (OR 16; 95% CI 2.1 - 118, p = 0.007). No relationship between bed sharing and SIDS was evident for age >2 months. Only 12% of the bed sharing SIDS victims aged <2 months where found in the prone position. INTERPRETATION: Bed sharing is associated with an increased risk of SIDS for infants <2 months of age. Particularly hazardous is bed sharing with a smoking parent.

Evaluation of diagnostic tools applied in the examination of sudden unexpected deaths in infancy and early childhood.

During the period between 1984 and 1999, 309 cases of sudden unexpected death in infancy and early childhood (0-3 years) were investigated at the Institute of Forensic Medicine in Oslo. In 73 cases, an explainable cause of death was found. In this non-sudden infant death syndrome (SIDS) group, 42 cases were due to disease, 14 to accidents, 7 to neglect/abuse and 10 cases were due to homicide. In 43 cases, there were pathological findings at the autopsy or suspect features in the history and/or circumstances, which were, however, insufficient to explain death ("borderline" SIDS). In the remaining 193 cases, nothing of significance was detected ("pure" SIDS). The purpose of the present study was to evaluate the importance of the different diagnostic tools used in diagnosing non-SIDS and borderline SIDS cases. The definition of SIDS requires a negative history as well as a negative autopsy result. Thus, the following variables were analysed: circumstances, medical history and autopsy, which included a gross pathological investigation, histology, neuropathology, microbiology, radiology and toxicology. In diagnosing deaths due to disease, histology, neuropathology and microbiology were the most important diagnostic tools. In contrast, information about the circumstances of death and the gross pathological findings at autopsy most often revealed the cause of death in accidents and cases of neglect/abuse and homicide. Following the drop in SIDS rate in Norway after 1989, the share of pure SIDS in proportion to the total population of sudden unexpected deaths in infancy and early childhood has decreased. The increasing proportion of non-SIDS and borderline SIDS cases presents a challenge to improve the quality of the investigation in cases of sudden death in infancy and early childhood.

[Of what significance are diseases, intoxication and suicide in fatal traffic accidents?]. / Hvilken betydning har sykdom, ruspåvirkning og selvmord ved dødsfall blant bilførere?

BACKGROUND: A large proportion of fatal car accidents cannot be explained by traffic environment, technical defects or risk-taking behaviour. Driver impairment from disease, alcohol, drugs or suicidal impulses may be involved. MATERIAL AND METHOD: Autopsy protocols from 167 car drivers involved in traffic accidents in Southeast Norway 1994-99 were reviewed retrospectively. RESULTS: In 89 of 135 deaths caused by trauma, there were no apparent explanations for the accident prior to autopsy. No differences were found with regard to signs of disease between drivers involved in unexplained and explained accidents. Drivers dead from trauma compared to drivers dead from natural causes had less often ischemic heart disease (p < 0.01). Blood alcohol level was above the statutory limit in 20% of drivers in both unexplained and explained accidents, and drugs were found in the blood in 27% of such cases. Only 13% of drivers in explained accidents collided with large motor vehicles, compared to 44% of the unexplained accidents. INTERPRETATION: Drivers with fatal injuries sustained in unexplained accidents seldom show signs of cardiac disease that could have contributed to the accident. It seems that such unexplained accidents are more often due to driving under the influence of alcohol or drugs, or to possible suicidal impulses.

In-depth evaluation of real-world car collisions: fatal and severe injuries in children are predominantly caused by restraint errors and unstrapped cargo.

OBJECTIVE: Major improvements have taken place in the development of child restraint systems and in-car safety in general, but motor vehicle accidents remain the leading cause of death and disability in children. An interdisciplinary study was therefore performed to investigate the injury mechanisms in car collisions involving children. METHODS: Motor vehicle collisions (MVCs) resulting in death or serious injuries to the drivers or their passengers in the southeastern part of Norway in the period 2007-2009 were included in the study if children less than 16 years of age were passengers. An investigation team examined the crash scene within 24 h of the accident. The internal and external environment of the vehicle was investigated, with particular focus on safety equipment and registration of child occupant contact points. Information was collected from witnesses, crash victims, the police, road authority reports, and medical records. Clinical or postmortem examinations were performed on the child occupants. RESULTS: Fifteen high-impact car crashes involving 27 child occupants were investigated: 7 children died (median [range] age 8 (0-15) years), 8 were severely injured (8 [5-13] years), and 12 sustained minor or no injuries (3.5 [0-14] years). Fourteen out of 15 fatalities or severe injuries (MAIS ≥3) were found to be due to various safety errors: harness straps or seat belts incorrectly routed (5/15) or poorly adjusted (4/15), unstrapped luggage (4/15), or technical errors (1/15). All 7 of the fatally injured children died at the crash scene, and 6 died due to head/upper neck trauma. No safety errors were found among the 12 children with either minor or no injuries. No association was found between the instantaneous change in velocity (ΔV) and the injury severity. CONCLUSION: The risk of child passengers being severely or fatally injured in MVCs is significantly higher when they are incorrectly restrained or exposed to unsecured heavy luggage. Appropriate crash investigations may provide important information regarding the injury mechanisms, which will be necessary for the implementation of preventive measures to reduce future fatalities.