Ependymal alterations in sudden intrauterine unexplained death and sudden infant death syndrome: possible primary consequence of prenatal exposure to cigarette smoking

<p>Abstract</p> <p>Background</p> <p>The ependyma, the lining providing a protective barrier and filtration system separating brain parenchyma from cerebrospinal fluid, is still inadequately understood in humans. In this study we aimed to define, by morphological and immunohistochemical methods, the sequence of developmental steps of the human ependyma in the brainstem (ventricular ependyma) and thoracic spinal cord (central canal ependyma) of a large sample of fetal and infant death victims, aged from 17 gestational weeks to 8 postnatal months. Additionally, we investigated a possible link between alterations of this structure, sudden unexplained fetal and infant death and maternal smoking.</p> <p>Results</p> <p>Our results demonstrate that in early fetal life the human ependyma shows a pseudostratified cytoarchitecture including many tanycytes and ciliated cells together with numerous apoptotic and reactive astrocytes in the subependymal layer. The ependyma is fully differentiated, with a monolayer of uniform cells, after 32 to 34 gestational weeks. We observed a wide spectrum of ependymal pathological changes in sudden death victims, such as desquamation, clusters of ependymal cells in the subventricular zone, radial glial cells, and the unusual presence of neurons within and over the ependymal lining. These alterations were significantly related to maternal smoking in pregnancy.</p> <p>Conclusions</p> <p>We conclude that in smoking mothers, nicotine and its derivatives easily reach the cerebrospinal fluid in the fetus, immediately causing ependymal damage. Consequently, we suggest that the ependyma should be examined in-depth first in victims of sudden fetal or infant death with mothers who smoke.</p

Neuroanatomical dysmorphology of the medial superior olivary nucleus in sudden fetal and infant death

This study expands our understanding of the organization of the human caudal pons, providing a morphologic characterization of the medial superior olivary nucleus (MSO), component of the superior olivary complex (SOC) that plays an important role in the processing of acoustic information. We examined victims of sudden unexplained fetal and infant death and controls (n = 75), from 25 gestational weeks to 8 months of postnatal age, by complete autopsy and in-depth autonomic nervous system histological examination, particularly of the MSO nucleus, the focus of this study. Peculiar cytoarchitectural features of the MSO nucleus were found in sudden death cases, such as hypoplasia/agenesis and immature hypercellularity, frequently related to dysgenesis of contiguous structures involved in respiratory rhythm-generating circuit, in particular to hypoplasia of the retrotrapezoid and the facial nuclei. We propose the involvement of this nucleus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities. Besides, we highlight the fundamental role of the maternal smoking in pregnancy as etiological factor in the dysmorphic neuroanatomical development of the MSO nucleus. Keywords: sudden infant death syndrome, sudden intrauterine unexplained death syndrome, medial superior olivary nucleus, superior olivary complex, neuropatholog

Neuroanatomical dysmorphology of the medial superior olivary nucleus in sudden fetal and infant death

doi: 10.3389/fnhum.2012.00322 Neuroanatomical dysmorphology of the medial superior olivary nucleus in sudden fetal and infant deat

Massive Amniotic Fluid Aspiration in a Case of Sudden Neonatal Death With Severe Hypoplasia of the Retrotrapezoid/Parafacial Respiratory Group

We report a case of a baby, who, after pregnancy complicated by maternal Addison's disease and Hashimoto's thyroiditis and natural delivery, unexpectedly presented a cardiorespiratory collapse and died 1 hour after birth without responding to prolonged neonatal resuscitation maneuvers. The cause of death was reliably established by carrying out a forensic postmortem examination. More specifically, the histological examination of the lungs showed the presence of abundant endoalveolar and endobronchial cornea scales caused by absorption of amniotic fluid. The neuropathological examination of the brainstem highlighted severe hypodevelopment of the retrotrapezoid/parafacial respiratory group, which is a complex of neurons located in the caudal pons that is involved in respiratory rhythm coordination, especially expiration, in conditions of enhanced respiratory drive, as well as in chemoreception. This neuropathological finding shed new light on the mechanisms underlying the massive amniotic fluid aspiration which led to this early death

Methemoglobinemia as biomarker and precursor of brain capillary oxidative damage link to ferric iron accumulation and originator of neurodegenerative disease

Our main aim is to make a contribution to the establishment of sources of oxidants as the key factors in understanding the role that oxidants and oxidative stress play in the pathogenesis of neurodegeneration, i.e. in the progression of Alzheimer’s disease (AD). Our original observation pointed out the main difference between the hemoglobin and methemoglobin degradation, did from the heme oxygenation when a hemoglobin results in ferrous (Fe2+) iron, but methemoglobin catabolism produces ferric (Fe3+) iron. The methemoglobin plays a role of the carrier, the donor of cytotoxic and redox- active ferric (Fe3+) iron, and it also acts as the originator of neurodegenerative diseases. The abundant and permanent source of redox- active ferric (Fe3+) iron which, without Ferrous-Ferric inversions, has “in situ” direct impact on endothelial small vessels in the brain accumulates and increases the rate of capillary endothelial cell apoptosis and possibly crosses into brain parenchyma to the astrocytes, glia, neurons, and other neuronal cells. Our understanding of the transport and neuronal accumulation of ferric (Fe3+) iron points to how microvessels are organized into a well-structured neurovascular unit with harmful consequences to the brain. Our previously conducted research found that the neonatal jaundice incidence (p=0.034), heart murmur at a later age (p=0.011) and mild disorders in children and adults such as dyslalia and learning/memory impairments (p=0.002) were significantly higher than in children and adults of control mothers without pregnancy methemoglobinemia. The consequence are performed as initial brain iron harmful effects from the mother-fetal pregnancy methemoglobinemia complication, and according to our hypothesis in humans could be followed with the neuronal death, the disease aging process, and leading finally to the severe disorders as AD, PD and other neurodegenerative diseases

Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers-The possible involvement of maternal methemoglobinemia

<p>Abstract</p> <p>Background</p> <p>Iron is involved in important vital functions as an essential component of the oxygen-transporting heme mechanism. In this study we aimed to evaluate whether oxidative metabolites from maternal cigarette smoke could affect iron homeostasis in the brain of victims of sudden unexplained fetal and infant death, maybe through the induction of maternal hemoglobin damage, such as in case of methemoglobinemia.</p> <p>Methods</p> <p>Histochemical investigations by Prussian blue reaction were made on brain nonheme ferric iron deposits, gaining detailed data on their localization in the brainstem and cerebellum of victims of sudden death and controls. The Gless and Marsland's modification of Bielschowsky's was used to identify neuronal cell bodies and neurofilaments.</p> <p>Results</p> <p>Our approach highlighted accumulations of blue granulations, indicative of iron positive reactions, in the brainstem and cerebellum of 33% of victims of sudden death and in none of the control group. The modified Bielschowsky's method confirmed that the cells with iron accumulations were neuronal cells.</p> <p>Conclusions</p> <p>We propose that the free iron deposition in the brain of sudden fetal and infant death victims could be a catabolic product of maternal methemoglobinemia, a biomarker of oxidative stress likely due to nicotine absorption.</p

Harmful Effect of Intrauterine Smoke Exposure on Neuronal Control of &ldquo;Fetal Breathing System&rdquo; in Stillbirths

This article is aimed to contribute to the current knowledge on the role of toxic substances such as nicotine on sudden intrauterine unexplained deaths&rsquo; (SIUDS&rsquo;) pathogenetic mechanisms. The in-depth histopathological examination of the autonomic nervous system in wide groups of victims of SIUDS (47 cases) and controls (20 cases), with both smoking and no-smoking mothers, highlighted the frequent presence of the hypodevelopment of brainstem structures checking the vital functions. In particular, the hypoplasia of the pontine parafacial nucleus together with hypoplastic lungs for gestational age were observed in SIUDS cases with mothers who smoked cigarettes, including electronic ones. The results allow us to assume that the products of cigarette smoke during pregnancy can easily cross the placental barrier, thus entering the fetal circulation and damaging the most sensitive organs, such as lungs and brain. In a non-negligible percentage of SIUDS, the mothers did not smoke. Furthermore, based on previous and ongoing studies conducted through analytical procedures and the use of scanning electron microscopy, the authors envisage the involvement of toxic nanoparticles (such as agricultural pesticides and nanomaterials increasingly used in biomedicine, bioscience and biotechnology) in the death pathogenesis, with similar mechanisms to those of nicotine

Functional neuroanatomy of the human pre-Bötzinger complex with particular reference to sudden unexplained perinatal and infant death

The authors are the first to identify in man the preBötzinger complex, a structure of the brainstem critical for respiratory rhythmogenesis, previously investigated only in rats. The evaluation of the neurokinin 1 receptors and somatostatin immunoreactivity in a total of 63 brains from 25 fetuses, nine newborns and 29 infants, allowed to delineate the anatomic structure and the boundaries of this human neural center in a restricted area of the ventrolateral medulla at the obex level, ventral to the semicompact ambiguus nucleus. The neurons of the pre-Bötzinger complex were roundish in fetuses before 30 gestational weeks and lengthened after birth, embedded in a dendritic system belonging to the reticular formation. Besides, structural and/or functional alterations of the pre-Bötzinger complex were present in a high percentage of sudden deaths (47%), prevalent in late fetal deaths. In particular, different developmental defects (hypoplasia with a decreased neuronal number and/or dendritic hypodevelopment of the reticular formation, abnormal neuronal morphology, immunonegativity of neurotransmitters, and agenesis) were found. The authors suggest that the preBötzinger complex contains a variety of neurons not only involved in respiratory rhythm generation, but more extensively, essential to the control of all vital functions. Sudden death and in particular sudden unexpected fetal death could therefore be ascribed to a selective process when developmental alterations of the pre-Bötzinger complex arise