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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease characterised by arrhythmias of right ventricular origin, due to transmural fatty or fibrofatty replacement of atrophic myocardium. In general, the pathology is seldom diagnosed below the age of 10 years old. We report a case of a 5-year-old female child with Dandy-Walker Syndrome, who died suddenly the night after surgical replacement of the ventriculo-peritoneal shunting catheter. She never had any heart problems and the ECGs have never shown significant alterations. Histological examination of the common myocardium showed focal fatty replacement of the right ventricle, mostly evident in the subepicardial and mid-third of the free wall and of the interventricular septum. Finally, the histological examination of the atrio-ventricular node showed some anomalies of the conduction system. Probably the association of both abnormalities have caused a fatal arrhythmia, occurred after the surgical replacement of the ventriculo-peritoneal shunting catheter. [ABSTRACT FROM AUTHOR]

Objective The goal of this article is to highlight the onset of atheroselerosis in human fetuses of smoker parents and its progression during post-natal life. Methods We examined 46 eases of fetal death (25 males and 21 females) and 43 cases of early neonatal deaths and sudden infant death syndrome (SIDS) (17 males and 26 females) , all died sine causa. All underwent autopsy. 21 eases of 46 fetuses and 21 eases of 43 early neonatal death and SIDS had smoker parents. We examined the four major epicardial coronary arteries , cerebral, common carotids, aorta and the arteries of cords and placenta. All samples were embedded in paraffin and serially cut for histologic examination and immunohistochemical studies (c-Fos,PCNA and apoptosis). Results In 54% of the fetuses and in 63 % of the early neonatal deaths and SIDS structural alterations affecting the arterial wall were evident . In all these eases with atherosclerotie alterations, study of the biological markers showed intense c-Fos positivity of the smooth muscle cells (SMCs). These alterations were constantly observed in the coronary district , mainly in the anterior descending branch, while are less frequent in the other examined arterial district. Very important is also the involvement of fetal adnexa. The immunohistochemical study of the biological markers in the SMCs of atheroselerotic lesions showed intense c-Fos expression in fetuses, and predominant PCNA positivity after birth. Conclusions The birth of atherosclerosis caused by parental smoke and/or air pollution is already detectable in fetal life. It has systemic nature and it is present in different arterial districts. Atherosclerotic lesions are also present in the arteries of medium size. It is also constant the involvement of the arteries of adnexa. In infants, the progression of atheroselerosis determines real atherosclerotic plaques, already recognizable after few weeks of life and closely related to cigarette smoke and formula feeding. During the evolution of the atherosclerotic process a biological modulation of SMCs proliferation is observable, beginning with activation of the c-Fos gene and increasing with high PCNA expressivity. [ABSTRACT FROM AUTHOR]

Sudden infant death syndrome (SIDS) 'gray zone' or borderline cases are defined as those cases in which it is difficult to establish whether the pathological findings are sufficiently severe to have caused the death. Examination of the brainstem in 103 cases of SIDS disclosed five SIDS 'gray zone' cases in which only further investigations of serial sections successfully identified anatomico-pathological findings that likely represent the morphological substrates for a sudden reflexogenic death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system, according to our guidelines. Our five cases are consistent with the triple-risk model of SIDS, a hypothesis postulating an underlying biological vulnerability to exogenous stressors or triggering factors in a critical developmental period. Inflammatory infiltrates (cases 1 and 2), necrotic focus of the solitary tract (case 3), hemangioendothelioma (case 4) and mild pneumonia (case 5) alone might or might not have accounted for the sudden deaths, if it had not been for the location and/or concomitant presence of brainstem abnormalities that could have had a triggering role in causing the sudden death of these babies. [ABSTRACT FROM AUTHOR]

Objectives: To obtain basic information about the expression of somatostatin in the human central nervous system and in particular, to evaluate its possible involvement in unexplained perinatal and in sudden infant death syndrome. Material: Sixty-seven brainstems from subjects aged from 30 gestational weeks to 12 postnatal months, dying of both known and unknown causes, were selected for this study. The unexplained deaths included 17 sudden intrauterinc deaths, 5 sudden neonatal deaths and 28 sudden infant deaths. Method: All brain-stems were fixed in 10% phosphate-buffered fomialin. processed and embedded in paraffin, according to our protocol available on the web site: http://users.unimi.it/~pathol/sids/ riscontro diagnostico e.html. The distribution of the somatostatin in the brainstem was studied by immunohistochemistry on serial sections. Results: We observed an intense somatoslatin positivity in many brainstem nuclei prevalently involved in the respiratory activity (parabrachial/Kölliker-Fuse complex, loeus coenileus, hypoglossus nucleus. dorsal vagus motor nucleus, tractus solitarii nucleus, ambiguus nueleus. reticular formation) in stillbirths. In 10 fetuses with unexplained death the neurons ofthe hypoglossus nucleus were somatostatin-negative. In the postnatal deaths, we observed immuno-positivity in the ventrolateral and ventral subnuclei of the tractus solitary nucleus. Besides, in 15 sudden infant death victims and in 1 control case, somatostatin-positive neurons were also present in the hypoglossus nucleus. In 10 of these 15 cases, a high apoptotic index was also reported. Conclusions: We suggest that abnormalities in the distribution of SS in the hypoglossus nucleus before and after birth may contribute to the induction of both fatal breathing in prenatal life and abnormal ventilatory control after birth leading to irreversible apnea. [ABSTRACT FROM AUTHOR]

Histological studies were made of the conducting system and the myocardium in two cases of torsade de pointes with complex disturbances of impulse conduction and formation. A fairly similar clinicopathological pattern was seen, consisting of an unusual association of non-interruptive, widespread damage to the conducting system with the intermittent and variable electrocardiographic disorders. The inherent desynchronization of cardiac action and the bilateral, uneven, and partial disruptions of the bundle-branches have been tentatively correlated, pathophysiologically, with the re-entry circuit, or mechanism, which is held to be responsible for the cyclic fluctuation of QRS axis, peculiar to torsade de pointes. [ABSTRACT FROM PUBLISHER]

The autoptic procedures in sudden infant death syndrome (SIDS) and sudden intrauterine unexpected death (SIUD) victims requires an in-depth examination of the autonomic nervous system, central and peripheral, as well as of the cardiac conduction system. In these pathologies, our studies have identified frequent developmental abnormalities in the brain stem, particularly hypoplasia of the arcuate nucleus, and accessory atrioventricular pathways in the cardiac conduction system. The law 'Post-mortem Investigation on the SIDS and of Unexplained Late Fetal Death' designated the Institute of Pathology of Milan University as the National Reference Center. The objectives of this law include, in article 4, widespread informative and preventive campaigns and continuous formation of programs for medical personnel. [ABSTRACT FROM AUTHOR]

Abstract Background 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. Methods 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. Results 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. Conclusions 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.

Abstract Background 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. Results 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. Conclusions 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.

Histological examination showed acute haemorrhage of the bifurcating His bundle and of the left bundle branch in a 35 year old man who died after being given external cardiac massage for cardiac arrest. "Hammering" of the ventricular septum crest against the central fibrous skeleton of the heart by compression of the sternum was believed to have caused the haematoma of the junctional tissue. [ABSTRACT FROM PUBLISHER]

Brain-derived neurotrophic factor (BDNF), a neurotrophin of the central nervous system, is able to regulate neuronal differentiation and modulate synaptic plasticity, being particularly involved in the development of the cerebellar cortical structure. The main aim of this study was to delineate, by immunohistochemistry, the BDNF expression in human cerebellar cortex of victims of fetal and infant death. The study was performed on a total of 45 cases, aged between 25 gestational weeks and 6 postnatal months, including 29 victims of sudden fetal and infant death and 16 age-matched subjects who died of known causes (Controls). We observed, in sudden death groups compared with Controls, a significantly higher incidence of defective BDNF expression in granule layers of the cerebellar cortex, which was particularly evident in the posterior lobule, a region that participates in respiratory control. These results were related to maternal smoking, allowing to speculate that nicotine, in addition to the well-known damages, can exert adverse effects during cerebellar cortex development, in particular in hindering the BDNF expression in the posterior lobule. This implies modifications of synaptic transmission in the respiratory circuits, with obvious deleterious consequences on survival., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the α7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1-6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of α7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death.

Stillbirth is one of the most stressful life events affecting over 3 million pregnancies per year throughout the world. An accurate autopsy of the stillborn fetus, including the placenta and umbilical cord examination, should be performed promptly after delivery. A thorough maternal history also should be taken, including exposures to risk factors. In many cases a death cause, attributable to fetal, maternal, or placental pathology, is clearly identified. However, in 50% or more of cases the cause remains unknown. The purpose of this study is to highlight possible developmental alterations of the autonomic nervous system in unexplained stillbirths to provide an explanation of the pathogenetic mechanism of their death. We conducted a careful neuropathological study of the brainstem, where the main vital centers are located, in 85 unexplained stillbirths and 52 age-matched controls died of known cause. Information on the maternal lifestyle, including the smoking habit, was collected in all cases. Hypodevelopment of neuronal centers involved in breathing control, all connected together in a "respiratory network", precisely hypoplasia of the facial/parafacial complex, Kölliker-Fuse nucleus, pre-Bötzinger nucleus and intermediolateral nucleus, were frequently observed in unexplained deaths, significantly related to maternal cigarette smoking. We support the hypothesis of a strong action of maternal smoking during pregnancy on the development of brainstem respiratory nuclei and suggest an explanation of the high incidence of the respiratory network alterations in unexplained fetal death, when breathing not represents a vital function., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

Objectives: As well known, the sudden infant death syndrome (SIDS) is characterized by the sudden death of a seemingly healthy infant during sleep, frequently resulted from a deficit in arousal phase. Awakening from sleep requires a fully developed and functioning neuronal respiratory network to modulate the ventilation as needed. The pontine Kölliker-Fuse nucleus (KFN) plays a pivotal role in breathing control, thanks to its interconnections with the widespread serotonin and noradrenaline neurons in the brainstem. Numerous studies to date have focused on the implication of orexin, a neuropeptide synthesized by neurons of the lateral hypothalamus, with major projections to the brainstem raphé nuclei and locus coeruleus, in arousal, a neurobiological process closely linked to breathing modifications. The aim of our research has been to demonstrate that also the KFN is a fundamental component of the orexin system, actively involved in arousal., Methods: We have evaluated the expression and distribution of the orexin receptors (orexin-1 and orexin-2 receptors) particularly in the rostral pons, where the KFN is located, of 25 SIDS cases and 18 controls., Results: An intense orexin-1 innervation around the KF neurons has been detected in almost all the controls and only in 20% of SIDS cases., Discussion: On the basis of these results, we believe that: (1) the KFN plays a leading role not only in providing a regular breathing rhythm but also in the coordination of the sleep-to-wake transition; (2) a defective orexin expression in the KFN could prevent arousal, thus assuming a crucial importance in causing SIDS.

Aims: The nucleolus is an important cellular component involved in the biogenesis of the ribosome. This study was performed in order to validate the introduction of the argyrophilic nucleolar organiser region (AgNOR) stain technique, specific for the nucleoli detection, in neuropathological studies on sudden fetal and infant death., Methods: In a wide set of fetuses and infants, aged from 27 gestational weeks to eight postnatal months and dead from both known and unknown causes, an in-depth neuropathological study usually applied at the Lino Rossi Research Center of the Milan University was implemented by the AgNOR method., Results: Peculiar abnormalities of the nucleoli, as partial or total disruption above all in Purkinje cells (PCs), were exclusively found in victims of sudden fetal and infant death, and not in controls. The observed nucleolar alterations were frequently related to nicotine absorption in pregnancy., Conclusions: We conclude that these findings represent early hallmarks of PC degeneration, contributing to the pathophysiology of sudden perinatal death., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Sudden Infant Death Syndrome (SIDS), despite the success of campaigns to reduce its risks, is the leading cause of infant death in the Western world. Even though the pathogenesis remains unexplained, brainstem abnormalities of the neuronal network that mediates breathing and protective responses to asphyxia, particularly in the arousal phase from sleep, are believed to play a fundamental role. This is the first study to identify, in SIDS, developmental defects of specific brainstem centers involved in hearing pathways, particularly in the cochlear and vestibular nuclei, in the superior olivary complex and in the inferior colliculus, suggesting a possible influence of the acoustic system on respiratory activity. In 49 SIDS cases and 20 controls an in-depth anatomopathological examination of the autonomic nervous system was performed, with the main aim of detecting developmental alterations of brainstem structures controlling both the respiratory and auditory activities. Overall, a significantly higher incidence of cytoarchitectural alterations of both the auditory and respiratory network components were observed in SIDS victims compared with matched controls. Even if there is not sufficient evidence to presume that developmental defects of brainstem auditory structures can affect breathing, our findings, showing that developmental deficit in the control respiratory areas are frequently accompanied by alterations of auditory structures, highlight an additional important element for the understanding the pathogenetic mechanism of SIDS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We report a noteworthy case of a 7-month-old infant who suddenly and unexpectedly died during her sleep. After a complete postmortem examination, review of the clinical history, and detailed death scene investigation, the death remained unexplained, leading to a diagnosis of sudden infant death syndrome. However, an extensive review of the brainstem neuropathology revealed a severe alteration in the area postrema (a highly vascular structure lying at the base of the fourth ventricle outside of the blood-brain barrier). The alteration was likely due to massive and repeated to a common household insecticide in the last few weeks of life. These results provide an explanation for this sudden infant death, allowing a differential diagnosis from sudden infant death syndrome., (Copyright © 2015 by the American Academy of Pediatrics.)

The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking.

This study indicates the impact of nicotine and pesticides (organochlorine and organophosphate insecticides used in agriculture) on neuronal α7-nicotinic acetylcholine receptor expression in brainstem regions receiving cholinergic projections in human perinatal life. An in-depth anatomopathological examination of the autonomic nervous system and immunohistochemistry to analyze the α7-nicotinic acetylcholine receptor expression in the brainstem from 44 fetuses and newborns were performed. In addition, the presence of selected agricultural pesticides in cerebral cortex samples of the victims was determined by specific analytical procedures. Hypodevelopment of brainstem structures checking the vital functions, frequently associated with α7-nicotinic acetylcholine receptor immunopositivity and smoke absorption in pregnancy, was observed in high percentages of victims of sudden unexpected perinatal death. In nearly 30% of cases however the mothers never smoked, but lived in rural areas. The search for pesticides highlighted in many of these cases traces of both organochlorine and organophosphate pesticides. We detain that exposition to pesticides in pregnancy produces homologous actions to those of nicotine on neuronal α7-nicotinic acetylcholine receptor, allowing to developmental alterations of brainstem vital centers in victims of sudden unexplained death., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Experimental studies have demonstrated that the neurotrophin brain-derived neutrophic factor (BDNF) is required for the appropriate development of the central respiratory network, a neuronal complex in the brainstem of vital importance to sustaining life. The pontine Kölliker-Fuse nucleus (KFN) is a fundamental component of this circuitry with strong implications in the pre- and postnatal breathing control. This study provides detailed account for the cytoarchitecture, the physiology and the BDNF behavior of the human KFN in perinatal age. We applied immunohistochemistry in formalin-fixed and paraffin-embedded brainstem samples (from 45 fetuses and newborns died of both known and unknown causes), to analyze BDNF, gliosis and apoptosis patterns of manifestation. The KFN showed clear signs of developmental immaturity, prevalently associated to BDNF altered expression, in high percentages of sudden intrauterine unexplained death syndrome (SIUDS) and sudden infant death syndrome (SIDS) victims. Our results indicate that BDNF pathway dysfunctions can derange the normal KFN development so preventing the breathing control in the sudden perinatal death. The data presented here are also relevant to a better understanding of how the BDNF expression in the KFN can be involved in several human respiratory pathologies such as the Rett's and the congenital central hypoventilation syndromes.

Endocrine disrupting compounds (EDCs) include organochlorine pesticides (OCPs), organophosphate pesticides (OPPs), carbamate pesticides, and plasticizers, such as bisphenol A (BPA). They persist in the environment because of their degradation resistance and bioaccumulate in the body tissues of humans and other mammals. Many studies are focused on the possible correlation between in utero exposure to EDCs and adverse health hazards in fetuses and newborns. In the last decade, environmental pollution has been considered a possible trigger for Sudden Infant Death Syndrome (SIDS) and Sudden Intrauterine Unexplained Death Syndrome (SIUDS), the most important death-causing syndromes in fetuses and newborns in developed countries. In this work, a rapid and sensitive analytical method was developed to determine the level of OCPs and OPPs, carbamates, and phenols in human fetal and newborn tissues (liver and brain) and to unveil the possible presence of non-targeted compounds. The target analytes where selected on the basis of their documented presence in the Trentino-Alto Adige region, an intensive agricultural area in northern Italy. A liquid-solid extraction procedure was applied on human and animal tissues and the extracts, after a solid phase extraction (SPE) clean-up procedure, were analyzed by gas chromatography coupled to a quadrupole mass spectrometric detector (GC-qMS). A GC-TOFMS (time-of-flight) instrument, because of its higher full-scan sensitivity, was used for a parallel detection of non-targeted compounds. Method validation included accuracy, precision, detection, and quantification limits (LODs; LOQs), and linearity response using swine liver and lamb brain spiked at different concentrations in the range of 0.4-8000.0 ng/g. The method gave good repeatability and extraction efficiency. Method LOQs ranged from 0.4-4.0 ng/g in the selected matrices. Good linearity was obtained over four orders of magnitude starting from LOQs. Isotopically labeled internal standards were used for quantitative calculations. The method was then successfully applied to the analysis of liver and brain tissues from SIUDS and SIDS victims coming from the above mentioned region.

We examined a large number of sudden infant death syndrome victims in order to point out a possible causal relationship between a previous hexavalent vaccination and the sudden infant death. We selected 110 cases submitted to in-depth histological examination of the autonomic nervous system and provided with detailed clinical and environmental information. In 13 cases (11.8%) the death occurred in temporal association with administration of the hexavalent vaccine (from 1 to 7 days). In none of these victims congenital developmental alterations of the main nervous structures regulating the vital functions were observed. Only the hypoplasia of the arcuate nucleus was present in 5 cases. In one case in particular an acquired hyperacute encephalitis of the tractus solitarii nucleus was diagnosed in the brainstem. This study does not prove a causal relationship between the hexavalent vaccination and SIDS. However, we hypothesize that vaccine components could have a direct role in sparking off a lethal outcome in vulnerable babies. In conclusion, we sustain the need that deaths occurring in a short space of time after hexavalent vaccination are appropriately investigated and submitted to a post-mortem examination particularly of the autonomic nervous system by an expert pathologist to objectively evaluate the possible causative role of the vaccine in SIDS.

Background: It is well known that maternal smoking during pregnancy is very harmful to the fetus. Prenatal nicotine absorption, in particular, is associated with alterations in lung development and functions at birth and with respiratory disorders in infancy. Many of the pulmonary disorders are mediated by the interaction of nicotine with the nicotinic receptors (nAChRs), above all with the α7 nAChR subunits that are widely expressed in the developing lung. To determine whether the lung hypoplasia frequently observed in victims of sudden fetal and neonatal death with a smoker mother may result from nicotine interacting with lung nicotinic receptors, we investigated by immunohistochemistry the possible presence of the α7 nAChR subunit overexpression in these pathologies., Methods: In lung histological sections from 45 subjects who died of sudden intrauterine unexplained death syndrome (SIUDS) and 15 subjects who died of sudden infant death syndrome (SIDS), we applied the radial alveolar count (RAC) to evaluate the degree of lung maturation, and the immunohistochemical technique for nAChRs, in particular for the α7 nAChR subunit identification. In the same cases, an in-depth study of the autonomic nervous system was performed to highlight possible developmental alterations of the main vital centers located in the brainstem., Results: We diagnosed a "lung hypoplasia", on the basis of RAC values lower than the normal reference values, in 63% of SIUDS/SIDS cases and 8% of controls. In addition, we observed a significantly higher incidence of strong α7 nAChR immunostaining in lung epithelial cells and lung vessel walls in sudden fetal and infant death cases with a smoker mother than in age-matched controls. Hypoplasia of the raphe, the parafacial, the Kölliker-Fuse, the arcuate and the pre-Bötzinger nuclei was at the same time present in the brainstem of these victims., Conclusions: These findings demonstrate that when crossing the placenta, nicotine can interact with nicotinic receptors of both neuronal and non-neuronal cells, leading to lung and nervous system defective development, respectively. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy.

Purpose: The aim of this study is to provide new molecular approaches to the children with obstructive sleep apnea syndrome by evaluating the possible involvement of the PHOX2B gene, notoriously associated to congenital central hypoventilation syndrome (CCHS), in Class III malocclusion., Methods: Fifty subjects with Class III malocclusion, aged from 8 to 14 years, and with history of sleep apneic episodes, and 20 age-matched controls were submitted to genomic DNA examination from oral cells to specifically analyze the PHOX2B genotype., Results: Point "silent" mutations affecting different nucleotides of the PHOX2B gene were observed in 32 % of patients with Class III malocclusion and never in controls (0 %)., Conclusion: The genetic data obtained in this study in children with Class III malocclusion and sleep-related breathing disorders provide new information useful to the genetic characterization of this pathology. The PHOX2B gene silent mutations can lead to structural and functional modification of their product providing to a group of children with Class III malocclusion similar features to those of CCHS (sleep apnea episodes and craniofacial malformations).

We present a case of sudden death of a 1-month-old male infant with heart, brainstem and genetic polymorphism involvement. Previously considered quite healthy, the child died suddenly and unexpectedly during sleep. The autopsy protocol included an in-depth anatomopathological examination of both the autonomic nervous system and the cardiac conduction system, and molecular analysis of the serotonin transporter gene promoter region, in which a specific genetic condition seems to be associated with sudden infant death. Histological examination revealed the presence of congenital cardiac alterations (hypertrophic cardiomyopathy and an accessory Mahaim fiber in the cardiac conduction system), severe hypodevelopment of all the raphe nuclei and a heterozygous genotype L/S related to the serotonin transporter gene. The sudden death of this infant was the unavoidable outcome of a complex series of congenital anomalies, each predisposing to SIDS., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3480540091031788.

The human choroid plexuses in the ventricular system represent the main source of cerebrospinal fluid secretion and constitute a major barrier interface that controls the brain's environment. The present study focused on the choroid plexus of the fourth ventricle, the main cavity of the brainstem containing important nuclei and/or structures mediating autonomic vital functions. In serial sections of 84 brainstems of subjects aged from 17 gestational weeks to 8 postnatal months of life, the deaths due to both known and unknown causes, we examined the cytoarchitecture and the developmental steps of the fourth ventricle choroid plexus to determine whether this structure shows morphological and/or functional alterations in unexplained perinatal deaths (Sudden Infant Death Syndrome and Sudden Intrauterine Unexplained Death Syndrome). High incidence of histological and immunohistochemical alterations (prevalence of epithelial dark cells, the presence of cystic cells in the stroma, decreased number of blood capillaries, hyperexpression of Substance P and apoptosis) were prevalently observed in unexplained death victims (p<0.05 vs. controls). A significant correlation was found between maternal smoking in pregnancy and choroidal neuropathological parameters (p<0.01). This work underscores the negative effects of prenatal exposure to nicotine on the development of the autonomic nervous system, and in particular of the fourth ventricle choroid plexus that is a very vulnerable structure in the developing CSF-brain system., (Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.)