Sudden Infant Death Syndrome Infants Research Articles

Dysregulation of platelet serotonin, 14–3–3, and GPIX in sudden infant death syndrome

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14–3–3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14–3–3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14–3–3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14–3–3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14–3–3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14–3–3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1A and 5-HT2A/C binding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/C binding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/C binding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.

Choline-acetyltransferase (ChAT) and acetylcholinesterase (AChE) in the human infant dorsal motor nucleus of the Vagus (DMNV), and alterations according to sudden infant death syndrome (SIDS) category

Amongst other molecules, the cholinergic system consists of choline-acetyltransferase (ChAT, − synthesis enzyme), acetylcholinesterase (AChE – primary hydrolysis enzyme), and butyrylcholinesterase (BuChE – secondary hydrolysis enzyme). In the brainstem, the Dorsal Motor Nucleus of The Vagus (DMNV) has high cholinergic expression and is a region of interest in the neuropathology of sudden infant death syndrome (SIDS). SIDS is the unexpected death of a seemingly healthy infant, but postmortem brainstem abnormalities suggesting altered cholinergic regulation have been found.This study aimed to determine the percentage of positive ChAT and AChE neurons within the infant DMNV through immunohistochemistry at the three levels of the brainstem medulla (caudal, intermediate, and rostral), to investigate whether the proportion of neurons positive for these enzymes differs amongst the diagnostic subgroups of SIDS compared to those with an explained cause of Sudden unexpected death in infancy (eSUDI), and whether there were any associations with SIDS risk factors (male gender, cigarette smoke exposure, co-sleeping/bed sharing, and prone sleeping). Results showed that ChAT-positive neurons were lower in the rostral DMNV in the SIDS II cohort, and within the caudal and intermediate DMNV of infants who were exposed to cigarette smoke. These findings suggest altered cholinergic regulation in the brainstem of SIDS infants, with potential contribution of cigarette smoke exposure, presumably via the nicotinic acetylcholinergic receptor system.

Changes in background characteristics and risk factors among SIDS infants in England: cohort comparisons from 1993 to 2020

ObjectivesUsing the National Child Mortality Database, this work aims to investigate background characteristics and risk factors in the sleeping environment associated with sudden infant death syndrome (SIDS) and compare the...

Age-related cytokine imbalance in the thymus in sudden infant death syndrome (SIDS)

BackgroundSudden infant death syndrome (SIDS) has been considered to be triggered by a combination of underlying immune dysregulation and infections. The thymus is a crucial lymphatic organ responsible for T cell development in infancy. We hypothesized that an altered thymic immune status may be detectable by intrathymic cytokine profiling in SIDS.Methods27 cytokines in protein lysates of thymus tissue and thymus weights were assessed in 26 SIDS cases and 16 infants who died of other reasons.ResultsSeventeen out of 27 cytokines were increased in thymic tissue of SIDS compared to controls without infections, and the most significant discrepancy was in infants younger than 20 weeks. The thymic cytokine profiles in SIDS cases were similar to those in controls with severe infection; however, the magnitude of the cytokine concentration elevation in SIDS was less pronounced, indicating sub-clinical infections in SIDS. In contrast to SIDS, intrathymic cytokine concentrations and thymus weight were increased with age in control children.ConclusionsElevated thymic cytokine expression and thymus weight, as well as impaired age-related alterations in SIDS, may be influenced by subclinical infection, which may play a role in initiating SIDS in infants with a compromised immune response.Impact StatementIncreased thymic weight and cytokine concentration may suggest possible subclinical infection in SIDS.Elevated thymic weight and cytokine concentration mainly in SIDS cases aged <20 weeks.Age-related impairment in the thymic weight and cytokine expression may be impaired by subclinical infection in SIDS.

Assessment of mothers' awareness of sudden infant death syndrome and safe infant sleep practices in Palestine

ObjectiveOne of the major public health mysteries around the world is a subcategory of infant sleep-related deaths of unknown etiology termed Sudden Infant Death Syndrome (SIDS) which is a common leading cause of infant mortality worldwide and targets infants under a year of age while sleeping. Sleep environment plays a significant role in the risk of SIDS, mothers actions for creating safe infant sleep practices play a protective role in reducing SIDS occurrence. The knowledge gap centered on SIDS is not adequately researched or investigated in Palestine. Correspondingly, the study aims to assess mothers' awareness of SIDS and safe infant sleep practices. MethodsA cross-sectional quantitative design was used. A self-reported questionnaire containing 30 items was distributed to childbearing mothers in various rural and urban areas in Palestine. The 1116 participants were selected based on a non-probability, convenience method in duration from April 1st, 2023 to June 19th, 2023. ResultThe data were analyzed through the SPSS program version 20; specifically, one-way ANOVA, independent sample T-tests, and Pearson's correlation test. The mother's total awareness and practice scores were coded into two categories: 1 signifying poor awareness or practice, and 2 signifying good awareness or practice. The mean total awareness was calculated to be 1.444, while the standard deviation came out to 0.497. The mean total practice was calculated to be 8.0789, while the standard deviation came out to 2.223. To further elaborate, 55.6% of the mothers showed poor awareness regarding SIDS. Moreover, 84.5% of the mothers revealed they had poor practices regarding safe infant sleep practices. ConclusionThe study displayed a positive-moderate correlation between the mothers' awareness and practices. Specifically, mothers’ had poor awareness in addition to poor practices.

Cell death in the lateral geniculate nucleus, and its possible relationship with nicotinic receptors and sudden infant death syndrome (SIDS)

The role of the lateral geniculate nucleus (LGN) in vision has been extensively studied, yet its extraretinal capacities are still being investigated, including its role in arousal from sleep. The β2 nicotinic acetylcholine receptor (nAChR) subunit is involved in the laminal organisation of the LGN with magnocellular (MC) and parvocellular (PC) neurons. Sudden infant death syndrome (SIDS) occurs during a sleep period and, neuropathologically, is associated with increased neuronal cell death and altered nAChRs. A recent qualitative pilot study from our group implicates the possibility of increased neuronal death/apoptosis in the SIDS LGN. The present study used quantitative analysis to report the baseline expression of apoptotic and nAChR subunits α7 and β2 in the PC and MC layers of the LGN, to determine correlations amongst these markers within layers and across layers, and to evaluate changes in the expression of these markers in the LGN of SIDS infants, along with associations with SIDS risk factors, such as age, sex, cigarette smoke exposure, bed-sharing, and presence of an upper respiratory tract infection (URTI). Tissue was immunohistochemically stained for cell death markers of active caspase-3 (Casp-3) and TUNEL, and for the α7 and β2 nAChR subunits. Amongst 43 cases of sudden and unexpected deaths in infancy (SUDI), classifications included explained deaths (eSUDI, n = 9), SIDS I (n = 5) and SIDS II (n = 29). Results indicated a strong correlation of the apoptotic markers and β2 nAChR subunit between the LGN layers, but not across the markers within the layers. Amongst the diagnostic groups, compared to eSUDI, the SIDS II cases had decreased Casp-3 expression while β2 nAChR expression was increased in both PC and MC layers. Amongst the SIDS risk factors, URTI and bed-sharing were associated with changes in neuronal death but not in the α7 and β2 markers. In conclusion, our findings do not support a role for the α7 and β2 nAChRs in apoptotic regulation of the LGN layers during infancy. However, for SIDS victims, an inverse correlation between the changes for markers of apoptosis and the β2 nAChR subunit expression suggests altered LGN function.

Sudden infant death syndrome

The sudden death of infants younger than one year is known as SIDS. It is a major cause of mortality among infants less than one year of age. There is little focus in the literature on sudden infant death syndrome (SIDS). Thus, this review aims to provide new insights on the incidence, risk factors and prevention of SIDS in infants. Following preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, this review explored eligible articles from PubMed, Google Scholar, and research gate databases. Several keywords were used for the search to obtain all possible related articles. The inclusion criteria were reviews and original articles focused on the current subject and written in English. The eligible articles used to compile this review were published between 2007 and 2021. Three main titles were discussed in this review: incidence, risk factors, and prevention. SIDS is the most common reason for death among infants aged less than one year. There is great variation in the global incidence of SIDS. Factors related to the sleeping environment are the major risk factors for SIDS and should be the focus. Hence, following the recommendations of the American academy of pediatrics can reduce incidence of SIDS.

Postmortem delay and stress/hypoxia markers in the sudden infant death syndrome (SIDS)

Measure markers of stress and in particular hypoxia taking into account the postmortem delay (PMD) in the sudden infant death syndrome (SIDS). We studied in children who died of SIDS different stress and PMD markers by immunoanalysis such as RIA/IRMA with groups of 30–50 SIDS compared to age paired controls ( n > 30). We chose (i) erythropoietin (EPO) which is regulated by tissue O 2 pressure, (ii) stress hormones: cortisol, ACTH, beta endorphin, adrenergic markers: catecholamines (by HLPC) and their co-factors i.e. neuropeptide Y (NPY) and Chromogranin A (CGA), (iii) the most reliable markers of the PMD to measure the variations of the biological markers according to the PMD. We studied K+, lactate/glucose ratio and NSE (neuron-specific enolase) in CSF. After establishing the physiological levels of EPO according to the age of the infants, we showed that there was a significant difference in the EPO of SIDS and age-matched control infants (Le Le Cam-Duchez V, et al., Biol Neonate 1999;76:1–9); pre-mortem anemia was excluded in SIDS because the fetal hemoglobin % was normal. At the same time, we have shown that SIDS have an increase in the CSF and the serum of the couple ACTH and beta-endorphin (BE) whose secretion is equimolar and of serum cortisol (M ± SEM: 874 ± 74 nM vs normal < 250 nM). Unlike ACTH, which is labile (CSF: 28 ± 7 pM; blood: 7 ± 3; normal < 15 pM), BE remains stable during postmortem time (CSF: 123 ± 21 pM; blood: 24 ± 9; normal < 15 pM). During agonal stress Cortisol and BE are both greatly increased signifying maximal stress (Coquerel A, et al. Neurochem Int 1992;20:97–102). For adrenergic markers, catecholamines cannot be interpreted because they are very labile; nevertheless, HPLC-MSMS makes it possible to characterize and quantify toxins and drugs. On the other hand, neuropeptide Y and especially Chromogranin A (CGA), which are co-released by the adrenal medulla, are stable in PMD (CGA: m ± SEM: 265 ± 22 vs. control infants 105 ± 18 ng/mL). They are greatly increased among the SIDS. As for the DPM markers for PM times > 12 h, the most reliable is the NSE. It also seems necessary to look for toxins and drugs in biological fluids because they can contribute to fatal apnea (Kahn A, et al. Biol Neonate 1994;65:235–39; Pathman L, et al. J Vascular Anom 2022;1–3). Most SIDS cases are characterized by stress markers related to long-lasting hypoxic episodes with EPO, cortisol + endorphin and CGA, which are quantitatively assayed up to 48 h postmortem and PMD could be specified by K+, Lactate and NSE in CSF.

Home Cardiorespiratory Monitoring in Infants at Risk for Sudden Infant Death Syndrome (SIDS), Apparent Life-Threatening Event (ALTE) or Brief Resolved Unexplained Event (BRUE).

Sudden infant death syndrome (SIDS) is defined as the sudden death of an infant younger than one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history. About 90% of SIDS occur before six months of age, the peak incidence is between two and four months, and the median age for death is elven weeks. The clinical, social, and economic relevance of SIDS, together with the evidence that prevention of this syndrome was possible, has significantly stimulated research into risk factors for the development of SIDS in the hope of being able to introduce new effective preventive measures. This narrative review discusses the potential relationships between apparent life-threatening events (ALTE) or brief resolved unexplained events (BRUE) and SIDS development, and when a home cardiorespiratory monitor is useful for prevention of these conditions. A literature analysis showed that home cardiorespiratory monitoring has been considered a potential method to identify not only ALTE and BRUE but SIDS also. ALTE and BRUE are generally due to underlying conditions that are not detectable in SIDS infants. A true relationship between these conditions has never been demonstrated. Use of home cardiorespiratory monitor is not recommended for SIDS, whereas it could be suggested for children with previous ALTE or severe BRUE or who are at risk of the development of these conditions. However, use of home cardiorespiratory monitors assumes that family members know the advantages and limitations of these devices after adequate education and instruction in their use.

Neurological repercussions of neonatal nicotine exposure: A review.

Smoking during pregnancy is hazardous to both the mother and the foetus, according to a substantial amount of recorded data. Exposure to nicotine and other compounds in cigarette smoke increases the risk of sudden infant death syndrome (SIDS) by two to five times during pregnancy. Serotonergic abnormalities have been discovered in SIDS infants in the zone of the medulla oblongata, which is known to control cardio-respiratory function. SIDS establishes a connection between depression, learning difficulties and behavioural disorders. Prenatal nicotine intake during the second trimester affects the dopaminergic neurological system, making the foetal brain more susceptible to nicotine and developing ADHD symptoms not just in a foetus but in adolescents also. Prenatal nicotine exposure alters the neurological route of neurotransmitters, acetylcholine and dopamine. Nicotine enhances neuronal activity in adults but desensitizes these processes in babies and young children exposed prenatally. The impact of a neurotoxin like nicotine is determined by the amount and duration of exposure. Continued exposure throughout pregnancy will influence a wide range of activities in the neurodevelopment, whereas exposure confined to a single stage of pregnancy may only affect the processes that are forming at that stage. To decrease the effect of nicotine on neonates due to maternal smoking strategies like nicotine replacement therapy (NRT), folic acid treatment and other behavioural treatments have been studied. Hence, this review focuses on the impact of exposure to nicotine on neonates, which results in various neurological consequences and smoking cessation therapies.

A systematic review of the burden and risk factors of sudden infant death syndrome (SIDS) in Africa.

BackgroundWhile sudden infant death syndrome (SIDS) has long been recognized as a leading preventable cause of infant mortality in high-income countries, little is known about the burden of SIDS in Africa. To address this knowledge gap, we conducted the first systematic review of SIDS-related publications in Africa. Our objective was to assess the prevalence of SIDS and its risk factors in Africa.MethodsWe systematically searched PubMed, Embase, Web of Science, Cochrane, and Google Scholar to identify studies published until December 26, 2020. Review authors screened titles and abstracts, and selected articles independently for full-text review. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) or a modification. Data on the proportion of infants who died of SIDS and reported prevalence of any risk factors were extracted using customized data extraction forms in Covidence.ResultsOur analysis rested on 32 peer-reviewed articles. Nine studies presented prevalence estimates on bedsharing and prone sleeping, suggesting near-universal bedsharing of infants with parents (range, 60 to 91.8%) and frequent use of the prone sleeping position (range, 26.7 to 63.8%). Eleven studies reported on the prevalence of SIDS, suggesting high rates of SIDS in Africa. The prevalence of SIDS ranged from 3.7 per 1000 live births in South Africa, 2.5 per 1000 live births in Niger, and 0.2 per 1000 live births in Zimbabwe. SIDS and other sudden infant deaths accounted for between 2.5 to 21% of infant deaths in South Africa and 11.3% in Zambia.ConclusionsAfrica may have the highest global rate of SIDS with a high burden of associated risk factors. However, majority of the studies were from South Africa which limits generalizability of our findings to the entire continent. There is an urgent need for higher quality studies outside of South Africa to fill this knowledge gap.Protocol registrationProspero Registration Number: CRD42021257261

Safe sleep after 1 year of age.

Safe sleep after 1 year of age.

Maternal Age, the Disparity across Regions and Their Correlation to Sudden Infant Death Syndrome in Taiwan: A Nationwide Cohort Study.

Sudden infant death syndrome (SIDS) has always been a regrettable issue for families. After sleeping in the supine position was proposed, the incidence of SIDS declined dramatically worldwide. However, SIDS still accounts for the top 10 causes of infant deaths in Taiwan. Recognizing the risk factors and attempting to minimize these cases are imperative. We obtained information on cases with SIDS from the National Health Insurance Research Database in Taiwan and interconnected it with the Taiwan Maternal and Child Health Database to acquire infant–maternal basal characteristics between 2004 and 2017. The SIDS subjects were matched 1:10 considering gestational age to normal infants. After case selection, a total of 953 SIDS cases were included. Compared with healthy infants, SIDS infants had younger parents, lower birth weight, and lower Apgar scores. After adjusting for potential confounders, infants with mothers aged <20 years had 2.81 times higher risk of SIDS. Moreover, infants in the non-eastern region had a significantly lower risk of SIDS than those in the eastern region. We concluded that infants of young mothers (especially maternal age <20 years) and infants in the eastern region of Taiwan had a higher risk of SIDS than their counterparts.

Forensic Autopsy Findings in Sudden Infant Death Syndrome: A Study in a Tertiary Care Hospital, Rajshahi, Bangladesh

Introduction: Sudden Infant Death Syndrome (SIDS) is the general diagnosis given when it is not possible to identify the cause of infant death, even after a complete forensic study and death site investigation. SIDS is a term that was first proposed in 1969 for a distinctive subgroup of unexpected infant deaths that occurred during the postneonatal period with relatively consistent clinical, epidemiological, and pathological features. SIDS remains a diagnosis of exclusion, according to the definition proposed in 1969. Although this syndrome has several distinctive features, including age distribution such as only affecting those younger than 1 year of age, and apparent occurrence during sleep, there has been reluctance to include these features in the definition. The aim of this study was to research the findings of SIDS in infants after a detailed forensic autopsy, and determine the importance of forensic autopsy. Methods: This cross-sectional analytical study conducted at Emergency and the department of Orthopaedic Surgery, Rajshhi Medical College Hospital, Rajshahi, Bangladesh during the period from January 2019 to December 2019 with a sample size of 75. Data were analyzed using statistical software SPSS. Study taken permission from the guardians of the infants. Result: Over half of the study population was male and 43% were female. 60% of the patients died at home. For 56% of the cases no information was available regarding their activity at the time of death. Of the available information, 26.67% died while sleeping, 14.67% were involved in other activities at home, and 2.66% were involved with some other form of activity. Post analysis showed that 48% were natural death. 38.67% of cases were still under study at the time of data collection. After a proper autopsy, 76% of the cases were ruled with SIDS as the cause of death. SIDS was determined as the cause of death in 57 out of 75 cases. 82.46% of the 57 cases had no available history. 8.77% had a history .....

The parental role before and after SIDS

Role confusion is a prominent constituent symptom of Prolonged Grief Disorder in parents after their infants die from sudden infant death syndrome (SIDS). We interviewed 31 parents of SIDS infants 2–5 years post-loss examining the parental role before death, at the time of loss, and in bereavement. Thematic analysis found disruption of the role and re-imagined responsibilities for their child’s physical security, emotional security, and meaning. Tasks within these domains changed from concrete and apparent to representational and self-generated. Parents in bereavement locate ongoing, imperative parental responsibilities, particularly asserting their child’s meaningful place in the world and in their family.

Increased brainstem microglia is associated with an attenuated hypercarbic ventilatory response in a rat model of neonatal opioid withdrawal syndrome

Background Infants born with neonatal opioid withdrawal syndrome (NOWS) display abnormal respiratory patterns including tachypnea, apnea and impaired ventilatory responses to hypoxia and hypercarbia challenges. Infants with NOWS are also at an increased risk of sudden infant death syndrome (SIDS), which is associated with impairments in respiratory control and increased gliosis in key brainstem respiratory control regions including the nucleus tractus solitarius (nTS). Objective Use a rat model of neonatal opioid withdrawal syndrome to assess whether pre- and postnatal morphine exposure attenuates the ventilatory responses to hypoxia and hypercarbia challenges in the offspring and whether they are associated with increased nTS microglia expression. Design/Methods Pregnant female rats (dams) received twice-daily subcutaneous injections of morphine (5mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. After birth, the pups received once-daily subcutaneous injections of morphine (1mg/kg), through postnatal day 10 to simulate postnatal morphine therapy. Whole-body plethysmography was used precisely 24 hours later to assess ventilatory defense responses to acute hypoxia (HVR) and hypercapnia (HCVR) challenge (5 minutes at 10% O2 and 5% CO2, respectively). Brainstems were removed to assess nTS microglia expression using immunohistochemistry and a glial (Iba-1) marker. Results Compared to saline-treated pups, morphine exposure attenuated the HCVR, but not the HVR (Fig. 1A). Morphine-exposed offspring also expressed increased number of microglia in the nTS (Fig. 1B). Conclusion The disturbances in neonatal hypercarbia challenge are associated with increased brainstem microglia expression, which could contribute to the etiology underlying the increased risk of SIDS in infants with NOWS.

Airway basal stem cells generate distinct subpopulations of PNECs.

SUMMARYPulmonary neuroendocrine cells (PNECs) have crucial roles in airway physiology and immunity by producing bioactive amines and neuropeptides (NPs). A variety of human diseases exhibit PNEC hyperplasia. Given accumulated evidence that PNECs represent a heterogenous population of cells, we investigate how PNECs differ, whether the heterogeneity is similarly present in mouse and human cells, and whether specific disease involves discrete PNECs. Herein, we identify three distinct types of PNECs in human and mouse airways based on single and double positivity for TUBB3 and the established NP markers. We show that the three PNEC types exhibit significant differences in NP expression, homeostatic turnover, and response to injury and disease. We provide evidence that these differences parallel their distinct cell of origin from basal stem cells (BSCs) or other airway epithelial progenitors.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002–0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla—a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

The Unfolded Protein Response in the Human Infant Brain and Dysregulation Seen in Sudden Infant Death Syndrome (SIDS).

Low orexin levels in the hypothalamus, and abnormal brainstem expression levels of many neurotransmitter and receptor systems in infants who died suddenly during a sleep period and diagnosed as sudden infant death syndrome (SIDS), may be linked to abnormal protein unfolding. We studied neuronal expression of the three unfolded protein response (UPR) pathways in the human infant brainstem, hypothalamus, and cerebellum: activating transcription factor 6 (ATF6), phosphorylated inositol-requiring enzyme 1 (IRE1), and phosphorylated protein-kinase (PKR)-like endoplasmic reticulum (ER) kinase (pPERK). Percentages of positively stained neurons were examined via immunohistochemistry and compared between SIDS (n = 28) and non-SIDS (n = 12) infant deaths. Further analysis determined the effects of the SIDS risk factors including cigarette smoke exposure, bed-sharing, prone sleeping, and an upper respiratory tract infection (URTI). Compared to non-SIDS, SIDS infants had higher ATF6 in the inferior olivary and hypoglossal nuclei of the medulla, higher pIRE1 in the dentate nucleus of the cerebellum, and higher pPERK in the cuneate nucleus and hypothalamus. Infants who were found prone had higher ATF6 in the hypoglossal and the locus coeruleus of the pons. Infants exposed to cigarette smoke had higher ATF6 in the vestibular and cuneate nuclei of the medulla. Infants who were bed-sharing had higher pPERK in the dorsal raphe nuclei of the pons and the Purkinje cells of the cerebellum. This study indicates that subgroups of SIDS infants, defined by risk exposure, had activation of the UPR in several nuclei relating to proprioception and motor control, suggesting that the UPR underlies the neuroreceptor system changes responsible for these physiological functions, leading to compromise in the pathogenesis of SIDS.