Etiology Of Sudden Infant Death Syndrome Research Articles

Butyrylcholinesterase Is Not Required for the Neonatal Autoresuscitation Reflex

Sudden Infant Death Syndrome (SIDS) is the leading cause of infant death under the age of one year of age, taking the lives of more than 1,400 infants annually, and comprising approximately 41% of all Sudden Unexpected Infant Death (SUID) cases. SIDS etiology remains vastly unknown but is best explained via a triple risk model that proposes SIDS occurs in a vulnerable infant during a critical developmental period when triggered by an external stressor. In SIDS it is hypothesized that there is first a failure in arousal followed by failure in the protective autoresuscitation reflex; a defense mechanism for an infant that is in a hypoxic coma, that promotes deep gasping to attempt to restart cardiovascular function. Many SIDS case studies reveal associations with genetic variants and abnormal biomarkers; however, it is unclear whether these variants are causal. Recently a case study identified a broad association between reduced blood BChE activity and SIDS cases, yet the functional relationship between BChE and respiratory regulation remains to be investigated. We aimed to functionally test the relationship between BChE and the neonatal autoresuscitation reflex utilizing a rapid pipeline for precision genetic modeling and high-throughput functional testing developed by the Ray Lab. BChE loss of function mice, generated through targeted genetic editing, were tested for neonatal autoresuscitation on our automated closed loop phenotyping platform, Looper. Postnatal day 7-8 mice were exposed to 3% CO2 and 97% N2 stimuli to induce a state of hypoxia resulting in detection of bradycardia, initial hyperventilation, hypoventilation, and apnea followed by restoration of room air conditions to facilitate the autoresuscitation reflex and cardio-respiratory recovery. Male and female mice were exposed to repeated anoxic gas challenges and allowed to autoresuscitate until death occurred. Data suggest that loss of BChE function does not affect neonatal autoresuscitation. BChE knockout mice and heterozygous mice survived similar amounts of anoxic challenges as wild type controls. No sex differences were observed between the number of anoxic challenges survived in males and females for all genotypes. Our data demonstrate the first functional assessment of BChE in neonatal cardio-respiratory regulation and the autoresuscitation response and highlight that BChE is not required for successful neonatal autoresuscitation. Additional analyses of respiratory parameters from respiratory trace data for BChE loss of function mice will aid in a further understanding if BChE loss of function is implicated in other aspects respiratory regulation. Funding: Precision Core funding U54 OD030165. NIH/NHLBI R01HLN161142-01 and R01HL130249-07. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Correlation of gestational age and age at death in sudden infant death syndrome: another pointer to the role of critical developmental period?

Filiano and Kinney proposed a triple-risk model for the sudden infant death syndrome (SIDS) that involves the intersection of three risks: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). The primary evidence for the role of a critical developmental period in SIDS etiology is the peak of cases around the third month of life. Independently, several studies pointed to correlation between gestational age and age at death in SIDS, but used that to assess the SIDS risk for preterm infants, ignoring further ramifications. We did a detailed analysis of CDC data spanning over two decades (1983-2011). We focused not only on the correlation between two age variables (gestational and age at death), but also on the possibility of misdiagnosis. Also, we attempted to account for potential biases in the data induced by the ICD-9/ICD-190 transition or the "Back to Sleep" campaign. The peak of deaths in the third month of life, that was the main argument for the role of the critical development period, wasn't unique to SIDS. However, we confirmed an almost linear and negative correlation between gestational age and the week of death due to SIDS. This pattern (slope of correlation < 0 and significance of correlation p < 0.05) is characteristic of SIDS among all diseases analyzed in the study. We interpret the results as the evidence of the role of the critical development period in SIDS etiology. Possibly more attention in the future research should be put to theories that are based on homeostatic control.

Variants in genes encoding the SUR1-TRPM4 non-selective cation channel and sudden infant death syndrome (SIDS): potentially increased risk for cerebral edema

Increasing evidence suggests that brain edema might play an important role in the pathogenesis of sudden infant death syndrome (SIDS) and that variants of genes for cerebral water channels might be associated with SIDS. The role of the sulfonylurea receptor 1 (SUR1)–transient receptor potential melastatin 4 (TRPM4) non-selective cation channel in cerebral edema was demonstrated by extensive studies. Therefore, we hypothesized that variants at genes of the SUR1-TRPM4 channel complex might be linked to SIDS. Twenty-four polymorphisms in candidate genes involved in the SUR1-TRPM4 non-selective cation channel were investigated in 185 SIDS cases and 339 controls. One (rs11667393 in TRPM4) of these analyzed SNPs reached nominal significance regarding an association with SIDS in the overall analysis (additive model: p = 0.015, OR = 1.438, 95% CI = 1.074–1.925; dominant model: p = 0.036; OR = 1.468, 95% CI = 1.024–2.106). In the stratified analysis, further 8 variants in ABCC8 (encoding SUR1) or TRPM4 showed pronounced associations. However, none of the results remained significant after correction for multiple testing. This preliminary study has provided the first evidence for a genetic role of the SUR1-TRPM4 complex in the etiology of SIDS, and we suggest that our initial results should be evaluated by further studies.

Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.

Sudden Infant Death Syndrome (SIDS) occurs in apparently healthy infants and is unpredictable and unexplained despite thorough investigations and enormous research efforts. The hypothesis tested in this case-control study concerns mitochondrial involvement in SIDS occurrence. Mitochondrial DNA content (MtDNAcn) was measured in 24 SIDS cerebral cortex samples and 18 controls using real-time PCR. The median (interquartile range) mtDNAcn in SIDS and controls was 2578 (2224-3838) and 1452 (724-2517) copies per nuclear DNA, respectively (P = 0.0001). MtDNAcn values were higher in SIDS victims born to non-smoking parents (n = 7) 4984 (2832-6908) compared to the controls (n = 5) 2020 (478-2386) (P = 0.006). Increased levels of mtDNAcn have been observed in the SIDS cases with mild defects in nuclei not essential for life compared to those found in SIDS cases with severe alterations of respiratory function (P = 0.034) 3571 (2568-5053) (n = 14) 2356 (1909-3132) (n = 8), respectively. Our study revealed for the first time higher mtDNAcn in the cerebral cortex of the SIDS cases than the controls, indicating metabolic alterations. MtDNAcn plays an important role in compensatory mechanisms against environmental factors affecting human health. Despite the small sample size, mtDNA may prove to be a potential forensic biomarker for autopsied SIDS victims for gaining new insights into the etiology of SIDS. Mitochondrial DNA content evaluated in cerebral cortex samples is higher in SIDS victims than controls. These results represent a novel line of investigation for the etiology of SIDS and could have a significant role in the compensatory mechanism due to environmental factors affecting human health. These findings suggest that the mitochondria are involved in SIDS: mtDNA content may represent a biomarker of this syndrome.

Infection, Celestial Influences, and Sudden Infant Death Syndrome: A New Paradigm.

The etiology of sudden infant death syndrome (SIDS) still remains unclear. This situation would seem unprecedented for 21st-century medical science. This article explores scientific fields that have not been largely considered in investigating the etiology of SIDS so far. In this study, we examined previously ignored studies on heliobiology, celestial influences, and SIDS in the non-medical literature in an attempt to answer the following questions: is there a relationship between sunspot/solar activity and the occurrence of SIDS? Could there be alternative reasons for the decline in SIDS incidences in the 1990s that were originally attributed to the “Back-to-Sleep” campaign? We note that the decline coincided with the ~11-year cyclical diminution in sunspot numbers (SSNs). The SSN/SIDS relationship does not necessarily imply causality; however, it supports published data regarding sunspots, Schumann resonance, and geomagnetic effects. How solar energy could adversely influence a baby’s existence remains conjectural. Observations in this respect suggest pathways involving melatonin and/or infection/inflammation.

Evidence for an association of interferon gene variants with sudden infant death syndrome.

There is evidence that inflammation plays a role in the etiology of sudden infant death syndrome (SIDS). Immune system dysregulation seems to be the background of higher infection susceptibility in SIDS infants. This phenotype is possibly determined by genetic factors. Twenty-three single nucleotide polymorphisms (SNPs) in the following 13 candidate genes governing the immune system were successfully genotyped in 251 Caucasian SIDS cases and 336 controls from Germany: ADAR1, CSF2RB, DDX58, IFNA1, IFNA21, IFNA8, IFNAR2, IFNG, IL6, MX2, OAS1, OAS3, and TNFA. Associations between genotypes and SIDS were then statistically evaluated using logistic regression analyses. Overall analysis revealed statistically significant results for two variants in interferon gamma (IFNG) (rs2069705: OR 1.40 (1.07; 1.83), p = 0.01; and rs2069727: OR 0.75 (0.59; 0.96), p = 0.02) and for one variant in interferon alpha 8 (IFNA8) (rs1330321: OR 1.85 (1.06; 3.21), p = 0.03). Haplotype analyses identified a three-marker risk IFNG haplotype rs2069727-rs2069718-rs2069705 associated with SIDS (OR = 1.62, 95% CI 1.23-2.13; p = 0.0003). Subgroup associations were found for variants in adenosine deaminase acting on RNA1 (ADAR1), 2',5'-oligoadenylate synthetase-1 (OAS1) and colony stimulating factor 2 receptor beta common subunit (CSF2RB). In summary, this large study of 251 SIDS cases for common variants in 13 candidate genes governing the immune system has provided first evidence for a role of IFNG in the etiology of SIDS and should stimulate further research into the clinicopathological relevance of immunomodulatory genes for this fatal syndrome.

Turning a negative into a positive

In this volume of The Journal, Tester et al described the results of a large study employing whole exome sequencing for rare variants in sudden infant death syndrome (SIDS). These investigators carried out whole exome sequencing on 278 cases of SIDS and compared the results to 973 ethnic-matched controls. One Reviewer remarked, “Many of us have been waiting for this paper after its initial presentation in oral form. There was a sharp intake of breath around the room as an essentially negative report came out.” Indeed, while no exome-wide significant differences (P < 2.5 × 10−6) in burden of ultra-rare variants was detected for any genes this is still a notable effort. This was a substantial undertaking and represents important results for the research community, the clinical community, and the families of patients with sudden infant death syndrome. Although this negative result suggests that there is not a readily discernible monogenic cause of SIDS, it does not rule out genetics per se. Many complex disorders are due to alterations in multiple genes in networks and pathways. That remains to be explored in SIDS. The authors also note that there are some rare “monogenic causes of SIDS including mutations in ion-channel genes, SCN5A and SCN4A.” Thus ultra-rare genetic variations in the exome do not represent an abundant explanation underlying the etiology of SIDS. It is possible that additional studies may identify SIDS susceptibility genes with varying penetrance but it remains likely from these data that monogenic disorders stemming from cardiac channelopathies and other established sudden death pathways will comprise less than 10% of all SIDS. This very substantial effort, albeit negative, has contributed important work in this field. Negative findings have garnered great controversy and publicity in science. The longstanding bias against publication of negative findings is beginning to be reversed by recognition of the importance of such results. A recent Editorial describing negative studies in cancer research has pointed out the importance of recognition of negative trials (JAMA Oncol 2016;2:865-6). Obvious benefits include dissuading individuals from unnecessary duplication. Negative trials may identify treatments with less morbidity and less cost compared to newer, more intensive therapies that turn out to lack benefit. Negative trials in intensive therapy for breast cancer have led to improvements and recognition that, in some patients, more radical treatments are unnecessary. The authors of the Editorial recommend that, for negative trials, it is important to include their impact on patient care. In the case of this negative result for SIDS, family appreciation of, in this case lack of, genetic etiologies for the great majority of SIDS cases may provide some comfort or at least enhanced understanding. Article page 423 ▶ Exome-Wide Rare Variant Analyses in Sudden Infant Death SyndromeThe Journal of PediatricsVol. 203PreviewTo determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Full-Text PDF

Microbiome-Gut-Brain Axis: A Pathway for Improving Brainstem Serotonin Homeostasis and Successful Autoresuscitation in SIDS-A Novel Hypothesis.

Sudden infant death syndrome (SIDS) continues to be a major public health issue. Following its major decline since the “Back to Sleep” campaign, the incidence of SIDS has plateaued, with an annual incidence of about 1,500 SIDS-related deaths in the United States and thousands more throughout the world. The etiology of SIDS, the major cause of postneonatal mortality in the western world, is still poorly understood. Although sleeping in prone position is a major risk factor, SIDS continues to occur even in the supine sleeping position. The triple-risk model of Filiano and Kinney emphasizes the interaction between a susceptible infant during a critical developmental period and stressor/s in the pathogenesis of SIDS. Recent evidence ranges from dysregulated autonomic control to findings of altered neurochemistry, especially the serotonergic system that plays an important role in brainstem cardiorespiratory/thermoregulatory centers. Brainstem serotonin (5-HT) and tryptophan hydroxylase-2 (TPH-2) levels have been shown to be lower in SIDS, supporting the evidence that defects in the medullary serotonergic system play a significant role in SIDS. Pathogenic bacteria and their enterotoxins have been associated with SIDS, although no direct evidence has been established. We present a new hypothesis that the infant’s gut microbiome, and/or its metabolites, by its direct effects on the gut enterochromaffin cells, stimulates the afferent gut vagal endings by releasing serotonin (paracrine effect), optimizing autoresuscitation by modulating brainstem 5-HT levels through the microbiome–gut–brain axis, thus playing a significant role in SIDS during the critical period of gut flora development and vulnerability to SIDS. The shared similarities between various risk factors for SIDS and their relationship with the infant gut microbiome support our hypothesis. Comprehensive gut-microbiome studies are required to test our hypothesis.

Candidate gene variants of the immune system and sudden infant death syndrome.

Sudden infant death syndrome (SIDS) causes early infant death with an incidence between 0.5 and 2.5 cases among 1000 live births. Besides central sleep apnea and thermal dysregulation, infections have been repeatedly suggested to be implicated in SIDS etiology. To test the risk contribution of common genetic variants related to infection, we genotyped 40 single-nucleotide polymorphisms (SNPs) from 15 candidate genes for association with SIDS in a total of 579 cases and 1124 controls from Germany and the UK in a two-stage case control design. The discovery-stage series (267 SIDS cases and 303 controls) revealed nominally significant associations for variants in interleukin 6 (IL6) (rs1880243), interleukin 10 (IL10) (rs1800871, rs1800872), and mannose-binding lectin 2 (MBL2) (rs930506), and for several other variants in subgroups. Meta-analyses were then performed in adding genotype information from a genome-wide association study of another 312 European SIDS cases and 821 controls. Overall associations were observed for two independent variants in MBL2: rs930506 in a co-dominant model (odds ratio (OR) = 0.82, p = 0.04) and rs1838065 in a dominant model (OR = 1.27, p = 0.03). Our study did not replicate published associations of IL10 variants with SIDS. However, the evidence for two independent MBL2 variants in the combined analysis of two large series seems consistent with the hypothesis that infection may play a role in SIDS pathogenesis.

Sudden infant death syndrome: Postulated role of impaired vasoactive neuropeptide-related inflammatory modulation

Sudden infant death syndrome (SIDS) has been extensively investigated in the context of infection as a contributing factor in the death of otherwise apparently healthy infants. A number of infectious agents have been implicated suggesting the causal pathomechanism is related to infection, but not necessarily solely attributable to any one type of infection. An alternative provocative hypothesis is that of post-infection autoimmunity affecting critical novel neurotransmitters of the vasoactive neuropeptide family. Their role in respiratory and cardiac functioning together with novel hypotheses postulating their autoimmune compromise may suggest a role in SIDS etiology following infection. Animal models demonstrate their vital role in neonatal survival and the neuronal control of breathing. Autoimmune compromise of vasoactive neuropeptide receptors through molecular mimicry following infection or idiopathic autoimmunity is postulated as a cause of SIDS.

Brain weight in sudden unexpected death in infancy: experience from a large single-centre cohort.

Published reports of brain weight in sudden infant death syndrome (SIDS) are contradictory, although several have concluded that brain weight is increased in SIDS compared with controls or reference data. This is important as, if brain weight is significantly different, it may be of diagnostic use or provide insights into the aetiology of SIDS. The aim of this study was to use a large series of well-characterized sudden unexpected infant deaths from a single centre to provide definitive data regarding this issue. A retrospective review identified 1100 infants who had died suddenly and undergone a comprehensive autopsy at Great Ormond Street Hospital between 1996 and 2011. They were split into two groups: those in whom death could be explained and those whose deaths remained unexplained despite full investigation (SIDS/unexplained sudden unexpected death in infancy). There were 1100 cases of whom 573 (52%) were unexplained and 527 (48%) explained. Multiple regression analysis, which adjusted for sex, age and post-mortem interval, showed no difference in the ratio of brain weight : body weight between those infants dying of explained causes and those in whom no cause could be found. This finding remained true when restricting analysis to those with macroscopically normal brains. In this large series of infants dying of both explained and unexplained causes, brain weight, once corrected for body weight, did not vary consistently with the cause of death. Brain weight cannot be used as a diagnostic indicator of the cause of death or to inform hypothetical models of the pathogenesis of SIDS.

Animal models for assessment of infection and inflammation: contributions to elucidating the pathophysiology of sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is still not well understood. It is defined as the sudden and unexpected death of an infant without a definitive cause. There are numerous hypotheses about the etiology of SIDS but the exact cause or causes have never been pinpointed. Examination of theoretical pathologies might only be possible in animal models. Development of these models requires consideration of the environmental and/or developmental risk factors often associated with SIDS, as they need to explain how the risk factors could contribute to the cause of death. These models were initially developed in common laboratory animals to test various hypotheses to explain these infant deaths – guinea pig, piglet, mouse, neonatal rabbit, and neonatal rat. Currently, there are growing numbers of researchers using genetically altered animals to examine specific areas of interest. This review describes the different systems and models developed to examine the diverse hypotheses for the cause of SIDS and their potential for defining a causal mechanism or mechanisms.

The mesencephalic nucleus of the trigeminal nerve and the SIDS

Sudden infant death syndrome (SIDS) is a major cause of infant mortality throughout the world, yet its cause and mechanism of action remain poorly understood. Here, we discuss a novel model of the etiology of SIDS which ties together what is known about the brain regions thought to be affected in SIDS infants with a defined neuroanatomical circuit and a documented preventative factor in young children. We propose that SIDS occurs due to a lack of sufficient development and plasticity of glutamatergic synapses in the mesencephalic nucleus of the trigeminal nerve (Me5) and reticular formation (RF) of the brainstem. This model is supported by evidence of brainstem dysfunction in SIDS as well as evidence of signaling through the Me5 and RF in another means of regulating cortical arousal. Furthermore, long-term plasticity of glutamatergic synapses is well known to play a critical role in learning and memory in other regions of the brain, implying that those mechanisms may also be relevant in the development of brainstem circuitry. This model clearly explains why SIDS deaths appear so suddenly with little pathological explanation and suggests a potentially novel way to prevent these deaths from occurring.

Association between polymorphisms in the P2RY1 and SSTR2 genes and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is a multifactorial syndrome and we believe that an inefficient respiratory response to certain homeostatic stressors, such as hypoxia and hypercapnia, is a key factor in the etiology of SIDS. Hence, we genotyped two single nucleotide polymorphisms (SNPs) in genes of importance for respiratory control: P2RY1 (adenosine diphosphate/adenosine triphosphate receptor) and SSTR2 (somatostatin receptor). Two SNPs, Rs1466113 (C > G dimorphism in SSTR2) and rs701265 (A > G dimorphism in P2RY1), were typed in 175 SIDS cases and 195 controls and 275 SIDS cases and 338 controls, respectively. Genotyping was performed using TaqMan technology. The determined genotype frequencies were SSTR2: CC (14.4%), CG (49.7%), GG (35.9%) in controls and CC (17.1%), CG (49.1%), and GG (33.8%) in SIDS; P2RY1: AA (70.6%), AG (28.7%), GG (0.7%) in SIDS and AA (68.3%), AG (27.9%), and GG (3.8%) in the control group. For rs701265 in P2RY1, homozygous G carriers were significantly more frequent in the control group (p = 0.02). We think that allele G provides a protective effect in events of ventilatory stress. Moreover, the significant lack of P2Y1 G allele homozygotes in the SIDS group shows that respiratory response plays an important role in the etiology of SIDS. Thus, we believe it is worthwhile to further investigate functional polymorphisms within genes that are involved in respiratory control in the future.

Monoamine Oxidase A Gene Polymorphism and the Pathogenesis of Sudden Infant Death Syndrome

To test the hypothesis that there is a significant association between functionally relevant allelic variants of the monoamine oxidase A (MAO-A) polymorphism and sudden infant death syndrome (SIDS). In a case-control study of 142 cases of SIDS and 280 sex-matched control cases, the distribution of allelic and genotype variants of a promoter polymorphism of the MAO-A gene was examined using polymerase chain reaction locus amplification and fluorescence based fragment length analysis. There was a significantly differential distribution of allelic and genotype variants between females with SIDS and controls. Moreover, there was a significant association between SIDS in females and allelic and genotype variants, each related to a higher transcriptional activity at the MAO-A locus. Our results suggest a role of MAO-A in female SIDS pathogenesis exerted by functionally relevant allelic and genotype variants of the MAO-A polymorphism. However, with the complex and inconsistent evidence available to date, the impact of the MAO-A promoter polymorphism on SIDS etiology remains unclear.

Brain weight–body weight ratio in sudden infant death syndrome revisited

To determine whether the brain-body weight ratio is increased in sudden infant death syndrome (SIDS). Review of autopsy files from Forensic Science SA, South Australia was undertaken over an eight-year period from 1999 to 2006, with classification of cases according to the San Diego definition. Sudden and/or unexpected deaths in previously healthy infants due to asphyxia or infection were selected as controls. There were 42 SIDS cases and 25 controls. The SIDS cases were aged from 1 to 42 weeks (mean: 16.26 ± 1.5 weeks) with a male to female ratio of 26:16. The control infants were aged from 3 to 48 weeks (mean: 19.24 ± 2.9 weeks) (P > 0.05) (M:F = 16:9) and included 13 cases of asphyxia and 12 cases of sepsis. Comparison of the brain-body weight ratios failed to demonstrate a significant difference: SIDS mean = 0.121 ± 0.003; control mean = 0.115 ± 0.003 (P > 0.05). Although, there was a trend towards higher brain-body weight ratios in SIDS infants, this did not reach significance. The role of brain weight in the aetiology of SIDS remains controversial.

Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia

Pet-1(-/-) mice with a prenatal, genetically induced loss of 5-hydroxytryptamine (5-HT, serotonin) neurones are compromised in their ability to withstand episodic environmental anoxia via autoresuscitation. Given the prenatal role of 5-HT neurones in the development of neural networks, here we ask if a postnatal loss of 5-HT neurones also compromises autoresuscitation. We treated neonatal rat pups at postnatal day (P)2-3 with an intra-cisternal injection of 5,7-dihydroxytryptamine (5,7-DHT; ~40 μg; n = 8) to pharmacologically lesion the 5-HT system, or vehicle (control; n = 14). At P7-10 we exposed unanaesthetized treated and control pups to 15 episodes of environmental anoxia (97% N(2), 3% CO(2)). Medullary 5-HT content was reduced 80% by 5,7-DHT treatment (P < 0.001). Baseline ventilation (V(E)), metabolic rate (V(O(2))), ventilatory equivalent (V(E)/V(O(2))), heart rate (HR), heart rate variability (HRV) and arterial haemoglobin saturation (S(aO(2))) were no different in 5-HT-deficient pups compared to controls. However, only 25% of 5-HT-deficient pups survived all 15 episodes of environmental anoxia, compared to 79% of control littermates (P = 0.007). High mortality of 5,7-DHT-treated pups was associated with delayed onset of gasping (P < 0.001), delayed recovery of HR from hypoxic-induced bradycardia (P < 0.001), and delayed recovery of eupnoea from hypoxic-induced apnoea (P < 0.001). Treatment with 5,7-DHT affected neither the gasping pattern once initiated, nor HR, V(E)/V(O(2)) or S(aO(2)) during the intervening episodes of room air. A significant increase in HRV occurred in all animals with repeated exposure, and in 5-HT-deficient pups this increase occurred immediately prior to death. We conclude that a postnatal loss of brainstem 5-HT content compromises autoresuscitation in response to environmental anoxia. This report provides new evidence in rat pups that 5-HT neurones serve a physiological role in autoresuscitation. Our data may be relevant to understanding the aetiology of the sudden infant death syndrome (SIDS), in which there is medullary 5-HT deficiency and in some cases evidence of severe hypoxia and failed autoresuscitation.

Activation of GABAA or 5HT1A receptors in the raphé pallidus abolish the cardiovascular responses to exogenous stress in conscious rats

Dysfunction in serotonin (5HT) neurotransmission in the brainstem of infants may disrupt protective responses to stress and increase the risk for Sudden Infant Death Syndrome (SIDS). The raphé pallidus (NRP) and other brainstem nuclei are rich in 5HT and are thought to mediate stress responses, including increases in blood pressure (BP) and heart rate (HR). Determining how 5HT neurotransmission in the brainstem mediates responses to stress will help to explain how dysfunction in neurotransmission could increase the risk of SIDS. It was hypothesized that alterations in neurotransmission in the NRP, specifically activation of the 5HT(1A) receptor subtype, would block cardiovascular responses to various types of exogenous stress. Using aseptic techniques, male Sprague-Dawley rats were instrumented with radiotelemetry probes which enabled non-invasive measurement of BP and HR. An indwelling microinjection cannula was also stereotaxically implanted into the NRP for injection of drugs that altered local 5HT neurotransmission. Following a one week recovery period, rats were microinjected with either muscimol (GABA(A) receptor agonist), 8-OH-DPAT (agonist to the inhibitory 5HT(1A) receptor), or a vehicle control (artificial cerebral spinal fluid; ACSF) immediately prior to exposure to one of three stressors: handling, air jet, or restraint. Physical handling and restraint of the animal were designed to elicit a mild and a maximal stress response respectively; while an air jet directed at the rat's face was used to provoke a psychological stress that did not require physical contact. All three stressors elicited similar and significant elevations in HR and BP following ACSF that persisted for at least 15 min with BP and HR elevated by ∼14.0 mmHg and ∼56.3 bpm respectively. The similarity in the stress responses suggest even mild handling of a rat elicits a maximal sympathoexcitatory response. The stress response was abolished following 8-OH-DPAT or muscimol microinjection suggesting the cardiovascular responses to stress are mediated by the NRP and likely involve the 5HT(1A) receptor. Impairment in 5HT(1A) receptor function in the NRP likely impairs the normal cardioprotective responses to stress and may contribute to the etiology of SIDS.

Genetics of the sudden infant death syndrome

The sudden infant death syndrome (SIDS) is currently defined as “the sudden unexpected death of an infant less than 1 year of age with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation”. SIDS, whose etiology remains rather vague, is still the major cause of death among infants between 1 month and 1 year of age in industrialized countries with varying incidences in different populations. Herein, after touching on definitory approaches and several current hypotheses concerning SIDS etiology, we focus on the triple risk model of SIDS and discuss two large classes of genetic factors potentially contributing to or predisposing for the generation of a vulnerable infant that, when encountering an environmental trigger, may succumb to SIDS. We conclude by acknowledging that for the integration of the vast and complex genetic evidence concerning SIDS, a lot more research will be required and we briefly discuss the potential use of recently presented animal models for functional studies of SIDS pathology.

Sudden infant death syndrome, population mixing and oil-related development in western Norway

ABSTRACTA number of features of sudden infant death syndrome (SIDS) point to an aetiological role for apparentlyminor infections. The spread of infections is influenced by the rate of contact between infectiouscases and susceptibles in the population. This is likely to differ geographically depending on patternsof social contacts, with epidemics being particularly likely where an influx of migrants leads to highrates of mixing of populations lacking herd immunity. It has been shown that geographical variationsin SIDS deaths in England and Wales are strongly associated with rates of long distance in-migrationinto districts. The large influx of population into parts of western Norway as a result of oil-related developmentprovides an opportunity to examine this issue further. The most intensive development hasbeen in the Stavanger area in the county of Rogaland. Published migration statistics show that therewas a rapid build-up of long distance migration into this area reaching a peak in the late 1970s. Furthernorth, the Bergen area in the county of Hordaland was little affected by oil-related activities in the1970s. However, the more recent development of oil provinces further north has led to more activity inthe Bergen area and an increase in in-migration from the mid 1980s onwards. Annual data from 1969onwards on SIDS deaths in Rogaland and Hordaland counties and for Norway were used to assesswhether trends in SIDS mortality and migration showed any associations. Before the main populationinflux Rogaland had a SIDS rate that was below the Norwegian average. However, since the mid1970s SIDS rates have been significantly in excess of the national average. In Hordaland SIDS rateswere low throughout the 1970s but increased substantially to be significantly in excess of the Norwegianaverage in the late 1980s. In both areas population influxes resulting from oil-related developmentwere therefore followed by a significant increase in mortality rates from SIDS. There is no evidencethat these trends can be accounted for by changing patterns of known risk factors for SIDS in theseareas nor of artefacts in the registration of SIDS cases. The results of this study therefore support theBritish evidence that population mixing may be a significant factor in the aetiology of SIDS.