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Introduction: The purpose of this study was to describe cases presenting with fibromuscular hyperplasia of the pulmonary arteries that could belong to the group of sudden infant death syndrome (SIDS) and sudden unexpected perinatal death "gray zone" or borderline cases., Methods: In a total of 12 cases, eight females and four males, ranging in age from 39 gestational weeks to 93 postnatal days, dying suddenly and unexpectedly, a fibromuscular hyperplasia of the pulmonary artery was detected. Postmortem examinations were requested with a clinical SIDS or sudden unexpected perinatal death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system., Results: Histological examination showed the presence of various degrees of fibromuscular hyperplasia with fibrosis of the right (six cases), left (five cases) or both (one case) pulmonary arteries., Conclusions: In our cases, fibromuscular hyperplasia of the pulmonary artery alone might or might not have accounted for the sudden deaths, if it had not been for the concomitant presence of hypoplasia of the arcuate nucleus in the brainstem and/or cardiac conduction system abnormalities. Therefore, they were classified as SIDS/sudden unexpected perinatal death gray zone or borderline cases. Necropsy studies of sudden infant and perinatal death should always include an accurate gross and histological examination of the pulmonary arteries, as well as of the brainstem and cardiac conduction system.

This study, besides to delineate the cytoarchitecture and the localization in the brainstem of the human raphé nuclei, aims to evaluate the correlation between neuropathological raphé defects and serotonin transporter gene (5-HTT) promoter region polymorphisms in a cohort of 28 SIDS victims, 12 sudden intrauterine unexplained deaths (SIUD), and 17 controls. Hypoplasia of one or more nuclei of both the rostral and caudal raphé groups was found in 57% of SIDS, in 67% of SIUD, and only in 12% of controls. Furthermore, a significant correlation among 5-HTT Long (L) allele, hypoplasia of the raphé nuclei, and maternal smoking in pregnancy was observed in sudden fetal and infant deaths. The presence of the L allele represents a predisposing factor for sudden fetal and infant death in association with morphologic developmental defects of the raphé nuclei and prenatal smoke exposure. A further consideration of the authors is that SIUD should not be regarded as a separate entity from SIDS, given the potentially shared neuropathological and genetic bases.

The present study was undertaken to evaluate the possible alterations of the triangle of Guillain and Mollaret (G-Mt), a neuronal brainstem/cerebellum network (from the dentate nucleus to red nucleus and inferior olivary nucleus) already known for its involvement in the pathogenesis of the palatal myoclonus, in sudden unexplained perinatal and infant death. In 44 cases of perinatal and infant death victims, aged from 26 gestational weeks to 10 months of life, we investigated, besides the histological morphology of the three nuclei, the c-fos and apoptotic expression, as well as the possible effects elicited by maternal cigarette smoking.A significant increase of lesions (hypoplasia and/or increased c-fos and apoptotic neuronal immunopositivity) of the three nuclei was found in unexplained death victims, compared with age-matched controls. These alterations were related to maternal cigarette smoking habit.We postulated that the G-Mt is an important network involved in the pathogenesis of a wide spectrum of pathological manifestations and that maternal smoking during pregnancy can exert an adverse influence on this complex, even leading to sudden death in vulnerable periods of perinatal or infant development.

Recent anatomo-pathological studies have revealed a frequent associated hypoplasia of both arcuate nucleus and lungs in stillbirths. The purpose of this study is to analyze the lung and brainstem development in sudden unexplained perinatal death and sudden infant death syndrome (SIDS). A total of 51 cases were investigated. A complete autopsy was performed in each case. Anatomo-pathologic examination of the central autonomic nervous system included an in-depth study on histological serial sections of the brains where the main structures participating in control of the vital functions are located. The stage of lung development was evaluated by macroscopic and microscopic criteria. In 52.9% of cases, a pulmonary hypoplasia was detected. The pulmonary hypoplasia was significantly more frequent in the SIDS group compared to the sudden perinatal unexplained death groups (p < 0.05). In 72.5% of cases, histological examination of the brainstem on serial sections showed hypodevelopment of the brainstem nuclei, particularly hypoplasia, of the arcuate nucleus (60.8%). In 47.1% of cases, pulmonary hypoplasia was associated with brainstem hypodevelopment.

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

The aim of this study was to investigate the developmental patterns of the human prefrontal cortex involved in breathing control in a wide cohort of fetal and infant death victims, aged from the 22(nd) gestational week to 10 months of life, and to evaluate whether morpho-functional disorders are present in this specific cortical area in victims of sudden unexplained death. A further aim was to determine whether prenatal absorption of nicotine could also affect the maturational processes of the prefrontal cortex. A pronounced radial organization of the cerebral wall was evident from the 26(th) gestational week. By 36 gestational weeks this columnar structure disappeared, coinciding with the formation of a laminar cyto-architecture. The mature cortex, observable from the 4(th) month of life, was organized horizontally into six laminae. In 33% of the sudden death victims the prefrontal cortex showed morphological alterations with anomalous laminar patterns and delayed neuronal maturation. A significant correlation with prenatal cigarette exposure was found.

Background: Carotid barochemoreceptor pathological lesions have been studied in animals, but few human necropsies have been performed. Therefore, data rely on case patients following surgery, radiotherapy and carotid endarterectomy. Almost no data are available regarding whether the effect of aging prevails over pathological conditions, despite the classic description that glomic fibrosis increases with age., Objective: To morphometrically characterize the alterations of the carotid barochemoreceptors and their supplying arteries., Methods: Patients (n=23) who had suffered and died from stroke, with and without complicated internal carotid atheromatosis, were divided by age (group 1: older than 80 years; group 2: 65 to 80 years; and group 3: younger than 65 years). Carotid segments were obtained at autopsy. The specimens were stained for light microscopy and immunohistochemistry., Results: Carotid glomus presented from moderate-to-severe atrophy and fibrosis. A focal decrease in vascularization (CD34-positive) of the glomus (greater than 50%) was observed in areas of atrophy and fibrosis. Damaged nerve endings (S100 protein-positive) were observed at the media of the carotid sinus. Morphometric data showed no differences between groups for glomus area, number of type 1 and 2 cells, and the wall to lumen arteriole ratio. No statistical differences were demonstrated in the pathological findings of the carotid glomus when comparing complicated with noncomplicated plaques or age groups., Conclusion: Severe carotid chemoreceptor damage exists in patients who have died from stroke and suffered from carotid atheromatosis. These findings were independent from aging and plaque type. However, damage was correlated with a marked narrowing of the supplying arterioles as a consequence of hemodynamic and/or metabolic alterations (dyslipidemia, diabetes).

The sudden unexpected death of a person believed healthy has occasionally been followed by a detailed postmortem examination that revealed no cause of death except for the unexpected presence of a medullary brain lesion. Our review of all available cases of sudden unexpected death related to medullary brain lesions (SUD-MBL) revealed the absence of any specific constellation of ante-mortem disease characteristics, together with the finding that major motor and sensory pathways were grossly preserved in most cases. The wide variety in ages of the victims, and in specific types of tissue pathology affecting the medulla, makes this illness extremely difficult to anticipate when the medullary lesions are not otherwise known to exist during life. SUD-MBL may be a specific clinico-neuropathologic disease entity, having significant importance for forensic investigators trying to establish the cause of sudden unexpected death in a victim of any age. Because victims often harbor their medullary lesions for days or weeks before SUD-MBL, clinical physicians as well need to consider the possibility of medullary brain involvement by any disease process, neurologic or systemic, while managing their patients.

Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.

Background: Sudden intrauterine unexplained death (SIUD) is one of the most heartbreaking tragedies that any parent can experience. It remains poorly understood and incompletely examined both morphologically and functionally. The aim of this work is to examine the likely role of cardiac conduction system in relation to sudden and unexplained fetal death., Methods: We analyzed and compared the autopsy results in 15 cases of SIUD (6 males and 9 females, ranging in age from 35 to 40 weeks) and 11 cases of intrauterine explained death (IED). A complete autopsy was performed, focusing on the examination of the cardiac conduction system on serial sections., Results: The following findings were observed: resorptive degeneration (33% of SIUD, 36% of IED), dispersion or septation of the atrioventricular (AV) junction (60% of SIUD, 64% of IED), islands of the conduction system in the central fibrous body (80% of SIUD, 73% of IED), Mahaim fibers (20% of SIUD), cartilaginous metahyperplasia (20% of SIUD, 18% of IED), an AV node (AVN) tongue (13% of SIUD), hemorrhage of the cardiac conduction system (7% of SIUD, 9% of IED), left-sided bifurcation (7% of SIUD), an intramural right bundle (7% of SIUD), central fibrous body hypoplasia (7% of SIUD), and thickening of the conduction system arteries (13% of SIUD)., Conclusions: Most of the abnormal cardiac conduction findings were detected only in SIUD and were absent in controls, i.e., Mahaim fibers, AVN tongue, left-sided bifurcation, intramural right bundle, and central fibrous body hypoplasia. We are convinced that these cardiac conduction abnormalities, in association with altered neurovegetative stimuli, could underlie potentially malignant arrhythmias.

The aim of the present study is to give a review of the postnatal development of peripheral chemoreceptors - carotid body, paraganglia, and pulmonary neuroendocrine cells (PNEC) - with implications in Sudden Infant Death Syndrome (SIDS). In the postnatal period, the hypoxic chemosensitivity of the carotid body gradually develops. Changes include proliferation of type I and II cells, increased numbers of dense core vesicles and K+ channels, and modifications of neurotransmitter/neuromodulator and receptor expression. Chromaffin paraganglia show increased expression of nitric oxide synthase and neuropeptides, and increased innervation. Innervation of PNEC develops fully only in the first postnatal period, after which their density falls. The neuropeptides produced by PNEC also changes, with increased expression of calcitonin gene-related peptide and neuropeptide YY and reduced expression of calcitonin and gastrin-releasing peptide. Most of the findings in the carotid body of SIDS victims, i.e., decrease in type I cells and dense cytoplasmic granules, and increase in progenitor cells, indicates immaturity of the carotid body, which may play a role in SIDS in the form of underlying biologic vulnerability. Aorticopulmonary paraganglia hyperplasia and increase of PNEC are also found in SIDS, and may be epiphenomena of alterations of the respiratory function with a pathogenetical role in SIDS. A comprehensive view of the pathogenesis of SIDS should also arise from the integration of peripheral chemoreceptors findings with neuro- and cardiopathologic ones.

Objective: Because the fetal origin of coronary artery lesions is controversial, early atherosclerotic coronary artery lesions in late fetal stillborns and infants, as well as the possible atherogenic role of maternal cigarette smoking, were studied., Methods: Twenty-two fetal death and 36 sudden infant death syndrome victims were examined by autopsy. In 28 of 58 cases, the mothers were smokers. Serially cut sections of coronary arteries were stained for light microscopy and immunotypified for CD68, CD34, alpha-smooth muscle actin, proliferating cell nuclear antigen, c-fos and apoptosis., Results: Multifocal coronary lesions were detected in 10 of 12 fetuses and in 15 of 16 infants whose mothers smoked. Arterial lesions in infants with nonsmoking mothers were observed in only five cases (two of 10 fetuses and three of 20 infants) (P<0.001). Alterations ranged from focal areas with mild myointimal thickening in prenatal life to early soft plaques in infants. Smooth muscle cells infiltrated into the subendothelium. These early lesions demonstrated c-fos gene activation in the smooth muscle cells of the media, and in some of these, positivity for apoptosis was observed, suggesting that c-fos overexpression may promote proliferation, as evidenced by proliferating cell nuclear antigen-positive cells., Conclusions: Early intimal alterations of the coronary arteries are detectable in the prenatal and infancy period, and may be significantly associated with maternal smoking.

The authors are the first to identify in man the pre-Bötzinger 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 pre-Bötzinger 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.

Objective: To evaluate the involvement of alterations of the central autonomic nervous system, particularly of the brainstem and cerebellum, in a wide set of victims of sudden and unexplained perinatal and infant death., Material and Methods: The study population consisted of 63 stillbirths, 28 neonatal deaths and 140 suspected SIDS. The victims were subjected to in-depth anatomopathological examination following appropriate guidelines. The protocol included, in particular, the histological evaluation on serial sections of the cardiorespiratory autonomic nervous system., Results: A diagnosis of "unexplained death" was established for 217 of the 231 victims (59 stillbirths, 28 newborns and 130 SIDS). In a very high percentage of these deaths (84%) we observed one or more anomalies of the nuclei and/or structures of the brainstem and cerebellum related to vital functions., Conclusion: Unexpected perinatal loss should not be regarded as a separate entity from SIDS, given the common neuropathological substrates.

In light of the growing information on the pathophysiology and clinical aspects of unexpected perinatal loss and sudden infant death syndrome (SIDS), a novel approach to the inherent problems by pathologists has become necessary. Herein, we propose an up-to-date protocol for accurate examination of the central autonomic nervous system and of the cardiac conduction system, which can encompass morphological and/or functional abnormalities of reliable epicritical value in unexplained perinatal loss and SIDS, particularly in those cases (still quite numerous) lacking adequate clinical documentation. Anatomo-pathologic examination of the central autonomic nervous system includes an in-depth study on histological serial sections of the brainstem, cerebellum, and spinal cord, where the main structures participating in control of the vital functions are located. For the histological study of the cardiac conductions system, serial sections were obtained from two blocks, including the sino-atrial node and the atrio-ventricular system, respectively. This type of updated investigation is yielding important arguments for a broader discussion of the pathogenesis of unexpected stillbirth, early neonatal death, and SIDS, besides allowing a more complete forensic-medical documentation of individual cases.

Objectives: The present study was aimed to evaluate the possible presence of cytohistologic and/or biologic modifications of the human dentate-olivary complex in sudden unexplained perinatal and infant deaths., Methods: We investigated the histologic morphology of the dentate and inferior olivary nuclei, the glial index, the c-fos and apoptotic immunopositivity, as well as the possible effects elicited by maternal cigarette smoking, in 44 cases of perinatal and infant death victims, aged from the 26th gestational week to 10 months of life., Results: We observed subtle alterations of both the medullary inferior olivary nucleus and of the cerebellar dentate nucleus, represented by a significant increase in the reactive astrocyte density and in the neuronal c-fos and apoptotic expression in unexplained death victims, compared with age-matched controls. These alterations were closely related to a maternal cigarette smoking habit., Discussion: We postulate that maternal smoking, besides inducing the previously demonstrated morpho-functional alterations of the autonomic central nervous system, could also exert an adverse influence on the dentate-olivary complex, leading to sudden death in vulnerable periods of perinatal development or early infancy.

The aims of this study were to investigate in the human cerebellar cortex the structural and biological ontogenetic features, the possible presence of alterations in cases of sudden unexplained fetal and infant death, and the involvement of the maternal cigarette smoking in developmental abnormalities. We analyzed 52 brains of fetal and infant death victims, aged from the second gestational trimester to 12th postnatal month. In the cerebellar cortex we evaluated, besides the morphological aspects, the expression of several biomarkers implicated in proliferative processes (c-fos, proliferating cell nuclear antigen, and apoptosis) as well as the presence of the neurotransmitter somatostatin, which is strongly implicated in central nervous system differentiation, and of EN2 gene. The observed features of the cerebellar cortex, mainly confined to the transient external granular layer, were high proliferative activity and high expression of both somatostatin and EN2 gene in prenatal life and high apoptotic index after birth. In 41% of the sudden unexplained death victims, in the greater part with smoking mothers, we observed different biopathological alterations of the cerebellar cortex. Maternal smoking is increasingly being demonstrated to be one of the main contributors to developmental neurological alterations in the offspring.

Various risk factors have been postulated to be related to sudden infant death syndrome (SIDS). Despite its reduction, thanks to the "Back to Sleep" campaign, SIDS is still a major cause of infant mortality in the first year of life. The purpose of this study was to correlate the different risk factors with the autopsy results and thus to determine if one or more of these variables is really specific for SIDS. We collected 128 sudden infant death victims with clinical diagnosis of SIDS and performed a complete autopsy with in-depth histology on serial sections, particularly of the brainstem, in accordance with our necropsy protocol. Histopathologic and immunohistochemical examination of the central autonomic nervous system revealed, in 78 cases of the SIDS group, the following anomalies: hypodevelopment of the arcuate nucleus, somatostatin positive hypoglossus nucleus, tyrosine hydroxylase negativity in the locus coeruleus, gliosis, and hypoplasia of the hypoglossus nucleus. A significant relation was found between maternal smoke and brainstem alterations.

The aim of this study was to investigate the histological and biological features of the human cerebellar cortex development and differentiation. We analyzed 52 brains of fetal and infant death victims, aged from 17 gestational weeks to 12th postnatal month. In particular, in the cerebellar cortex at different ages we evaluated, besides the structural aspects, the expression of several biomarkers implicated in proliferative processes (c-fos, PCNA and apoptosis). We observed morphological patterns progressively evolving every month, from the indefinite structure of the second gestational trimester to the four-layered structure (external granular layer, molecular layer, Purkinje cell layer, internal granular layer) of the late fetal cortex and subsequently to the three-layered postnatal definitive morphology, due to involution of the external granular layer. The evaluation of the biological features of the cerebellar cortex showed high proliferative activity mainly confined to the transient external granular layer in prenatal life, and high apoptotic index after birth. Thus, the histological examination, better with the support of biomarker investigations, allows with accuracy to describe the dynamic sequence of steps that occur in human cerebellar cortex development and to establish in each case the age, namely the pre- or postnatal month of life. Consequently, we can diagnose delayed or altered processes of differentiation during the development of the human cerebellar cortex.

This article intends to show how the cerebellum, a structure ordinarily not considered in mediating breathing or cardiovascular control, may play a critical role in compensatory responses particularly to hypoxic insults occurring pre and/or postnatally and thus may be involved in the sudden unexplained perinatal and infant death. Besides the ontogenesis of the cerebellar cortex in man, we reported alterations of biopathological features (neuronal immaturity, altered apoptotic programs, negative expression of somatostatin and EN2 gene, intense c-fos expression positivity, astrogliosis) in the cortex and in the dentate nucleus of the 63% of sudden deaths, and only in 10% of the controls. The correlation of these results with the mother's smoking habit was highly significant. Therefore, we support the hypothesis, already expressed in previous studies on brainstem, of a close relation between maternal cigarette smoking and a wide range of morpho-physiological defects of the brain, leading to unexplained sudden death in stillbirths, newborns, and Sudden Infant Death Syndrome (SIDS) victims.

Experts from panels of the European Agency for the Evaluation of Medical Products have investigated whether there might be a link between hexavalent vaccines and some cases of deaths that occurred. Participants included pathologists with experience in the field of vaccines and sudden infant death syndrome who conducted autopsies. However, to the best of our knowledge, little, if any, attention was paid to examination of the brainstem and the cardiac conduction systems on serial sections, nor was the possibility of a triggering role of the vaccine in these deaths considered. Herein we report the case of a 3-month-old female infant dying suddenly and unexpectedly shortly after being given a hexavalent vaccination. Examination of the brainstem on serial sections revealed bilateral hypoplasia of the arcuate nucleus. The cardiac conduction system presented persistent fetal dispersion and resorptive degeneration. This case offers a unique insight into the possible role of hexavalent vaccine in triggering a lethal outcome in a vulnerable baby. Any case of sudden unexpected death occurring perinatally and in infancy, especially soon after a vaccination, should always undergo a full necropsy study according to our guidelines.

We aimed to study the consequences of chronic exposure to tobacco smoke in utero on the morphological and functional maturation of the brainstem by comparing stillbirths of smoker mothers versus nonsmoker mothers. A total of 42 stillbirths, aged 25-40 gestational weeks, underwent autopsy according to our guidelines (). The brainstem was studied on serial sections and by immunohistochemistry to assay the expression of the EN2 gene, somatostatin (SS) and the tyrosine hydroxylase enzyme (TH). We observed a significant correlation between maternal smoking and sudden intrauterine unexplained death (SIUD), hypoplasia of the ArcN, no immunostaining of the EN2 in the arcuate nucleus (ArcN), and of TH in the locus coeruleus (LC) (P < 0.05). An increased incidence of maternal smoking was also observed in fetuses with SS negativity in the hypoglossus nucleus (HypoglN). Exposure in utero to maternal smoking may strongly interfere with brain biological parameters, giving rise not only to structural developmental abnormalities of the arcuate nucleus, but also to a decrease of noradrenergic activity in the LC, of EN2 gene expression in the ArcN and of SS in the HypoglN.

For each case of sudden infant and perinatal death, a full review of clinical and epidemiologic data and a complete necropsy study were performed according to the necropsy protocol devised by the Institute of Pathology, University of Milan, Milan, Italy (available at: http://users.unimi.it/~pathol/sids&#95;e.html). Histopathologic examination of unexpected late fetal and neonatal death and SIDS cases allowed us to identify frequent alterations, mainly congenital, of the autonomic nervous system, modulating respiratory, cardiovascular, arousal, and upper digestive activities. The data and arguments presented herein provide a brief survey tending to open, rather than conclude, a far-reaching subject and to motivate medicolegal specialists and pathologists to perform more in-depth study.

Cigarette smoking is associated with an increased incidence of atherosclerotic diseases. The aim of this study was to examine the progression of the pre atherosclerotic lesions previously observed by us in coronary arteries of fetuses of smoker mothers and in infants with smoker parents. We examined the coronary arteries of 34 infants, aged 1-36 months, and the histological and biological [c-fos, proliferating cell nuclear antigen (PCNA), and apoptosis] features of the early atherosclerotic lesions. In 17 infants (50%), at least one parent smoked, generally more than five cigarettes a day. In 18 cases (53%), we observed variable thickening of the coronary walls from pre-atherosclerotic lesions to juvenile atherosclerotic plaques, related to parental smoking habit. This morphological progression of the lesions was accompanied by a sequence of biological changes in the smooth muscle cells of the tunica media. We suggest that the oxidants present in the gas phase of the parental cigarette smoke pass through the endothelium and induce at first the c-fos gene activation and subsequently the PCNA positivity, that is, a proliferative process.

This work intends to be a review of the recent histopathological findings elicited by research into sudden and unexpected perinatal death and sudden infant death syndrome (SIDS) that have dictated a novel approach to the inherent problems by pathologists, especially those entrusted with forensic medical authority. The new approach stems from the recent advances made in the understanding of neuro- and/or cardiac-conduction-system diseases present in unexpected perinatal death and SIDS. These demand that an accurate morphologic examination be performed of these structures, which modulate respiratory, cardiovascular, digestive, and arousal activities, in all victims of sudden death. A histopathologic study of an ample register of cases of victims of sudden death, either perinatally or in early infancy, has demonstrated frequent alterations both of the autonomic nervous system (especially hypoplasia of the arcuate nucleus) and of the cardiac conduction system (accessory atrioventricular pathways). The present research provides an in-depth study of the many still-controversial aspects underlying perinatal unexpected death and SIDS and is recommended for professionals working in the forensic field, whose greater insight into this problem will allow more complete medicolegal documentation.

Background: Physiopathology of barochemoreception is hindered by the scarce information on its morphology in disease. The baroreflex is of major importance for the maintenance of arterial pressure during orthostatic stress. The purpose of this paper was to characterize the morphological alterations of carotid glomus in old patients who died from stroke and suffering obstructive carotid atheromatosis., Methods: Bilateral carotid segments were obtained at autopsy from 17 patients (51-89 years old). Specimens were stained with hematoxylin and eosin; Azan trichrome, Grimelius silver stain for catecholamine detection, and were immunophenotyped for CD34 and S-100. Similar segments of both carotid arteries of six patients (62-77 years old) who died by accidents were used as controls., Results: The carotid glomus of patients who died from stroke presented atrophy and fibrosis (2.59+/-0.5 vs. 1.17+/-0.39 in the control group; p<0.0001). There was a loss of chief cells and of the argyrophilic staining granules. A focal diminution of glomus vascularization was observed in the areas of atrophy and fibrosis (2.73+/-0.45 vs. 1.5+/-0.52 in the control group; p<0.0001). The arterioles to glomus showed severe fibrointimal proliferation, disruption of internal elastic lamina and luminal narrowing, and luminal thrombi., Conclusion: A severe carotid glomic damage does exist in old patients who died from stroke and suffering from carotid atheromatosis, independent from aging, of note, a "culprit" marked narrowing of the corresponding arterioles was observed.

In this study, we wanted to evaluate whether the engrailed EN-2 gene, a homeobox gene with an essential role in the development of the rhombic lip derivatives in different species, is (1) expressed also in man in the differentiation process of the medullary arcuate nucleus (ArcN) and (2) involved in sudden unexplained perinatal and infant death, frequently related to developmental defects of the ArcN. We evaluated by means of the monoclonal antibody 4D9, exclusively recognizing engrailed-2 protein, the expression of the EN-2 gene in the ArcN on histological sections of the brainstems of 30 subjects aged from 17 gestational weeks to 10 postnatal months, who had died of known (17 cases) and unknown causes (13 cases). We observed in the greater number of the cases that the expression of the EN-2 gene is very high in the ArcN neurons from the 17th to the 22nd gestational week, then decreases up to the first days after birth and later disappears. Moreover, in eight of the 13 sudden deaths (61%), a hypoplasia of the ArcN was present. In almost all of these cases, EN-2 expression was negative. In conclusion, we support the role of the EN-2 gene in the normal neuronal development and in the anatomic organization of the human ArcN as well as the possible existence of EN-2 mutations related to hypoplasia of this nucleus.

The aim of this study was to reconstruct dynamic biological steps of human atherosclerosis at different ages of life and, in particular, to clarify the role of the smooth muscle cells (SMCs) by means of evaluation of several markers implicated in proliferative diseases (c-fos, proliferating cell nuclear antigen: PCNA, apoptosis, chromosome 7). We examined the biological features of 67 atherosclerotic arterial lesions obtained from fetuses, infants, young people and adults. From each case serial sections were stained for histological examination, PCNA, c-fos and apoptosis detection by immunohistochemical methods and for chromosome 7 number evaluation by fluorescence in situ hybridization. In coronary specimens of fetuses we observed SMCs with c-fos positivity. In infant lesions the predominant result was positivity for PCNA. Similar results were obtained from the plaques from young subjects with a greater presence of PCNA-positive cells. In adult subjects numerous apoptotic cells were present in the stable plaques, whereas in the unstable plaques we frequently detected joint positivity for both PCNA and c-fos gene and supernumerary chromosomes 7. During the evolution of the atherosclerotic process we observed a biological modulation of SMC proliferation, which begins after activation of the c-fos gene, increases during progression of the lesion and declines in stable plaques, when apoptosis increases. In unstable plaques, the same early steps observed in fetus and infant arteries occur. The observation in some cases of chromosome 7 alterations, markers of tumorigenesis, suggests the possible transformation of an advanced atherosclerotic plaque into a neoplastic-like process.

We investigated the immunohistochemical expression of the tyrosine hydroxylase (TH) enzyme and the morphometric parameters of the human locus coeruleus (LC) in the brainstems of 32 subjects aged from 17 gestational weeks to 12 postnatal month, died of unknown (sudden unexplained perinatal and infant deaths) and known causes. The goals of this study were: (1) to obtain basic information about the structure and physiology of the LC during the first phases of human nervous system development; (2) to evaluate whether there is altered expression of TH and/or structural alterations of the LC in cases of sudden perinatal and infant death; and (3) to verify if morphological and/or physiological abnormalities of the LC could be related to maternal cigarette smoking. Morphometric analysis showed homogeneous data in cases of sudden perinatal and infant death and in age-matched controls who had died of known aetiology. However, immunohistochemistry demonstrated in a wide subset of sudden and unexplained deaths a negativity or low positivity of TH. High distribution of TH protein were instead detectable in the LC neurons of foetuses aged 17-18 gestational weeks who had died of known causes. Therefore, we postulate the functional importance of the LC in the early phases of central nervous system development. Besides, the observation of a significant correlation between sudden unexplained death, negativity of TH staining and maternal smoking, prompted us to suppose a close relation between smoking in utero and a decrease of the noradrenergic activity of the LC, leading to sudden death in the last part of pregnancy and in the first year of life.

Maternal smoking during pregnancy is the most important risk factor for sudden perinatal and infant death in more industrialized countries. The frequent observation of hypoplasia of the arcuate nucleus in the brainstem of these victims prompted the verification of whether maternal cigarette smoking could be related to defective development of this nucleus during intrauterine life, by affecting the expression of specific genes involved in its developmental process. In serial sections of the brainstem of 54 cases of sudden and unexplained fetal and infant deaths (13 stillbirths, 7 neonatal deaths and 34 sudden infant death syndrome (SIDS) victims), morphological and morphometrical analysis was used to observe the different structural alterations of the arcuate nucleus (bilateral hypoplasia, monolateral hypoplasia, partial hypoplasia, delayed neuronal maturation and decreased neuronal density) detected in 24 cases (44%). Correlating this finding with smoking in pregnancy, a significantly increased incidence of cytoarchitectural alterations of the arcuate nucleus was found in stillborns and SIDS victims with smoker mothers compared to victims with non-smoker mothers. Moreover, the observation of a wide range of developing morphological defects of the arcuate nucleus related to maternal smoking led to the hypothesis that the constituents of the gas phase in cigarette smoke could directly affect the expression of genes involved in the development of this nucleus, such as the homeobox En-2 gene.

The factors underlying the sudden infant death syndrome (SIDS) are still unknown, but in recent years much attention has been focused on the central cardiorespiratory control system. In the present work we analyzed the nucleus tractus solitarii (nTS) of 23 SIDS victims and 17 age-matched control cases. We studied the functional and morphological alterations of neurons and glial cells to evaluate the results of possible hypoxic-ischemic injury that could have led to sudden death. Morphometric and immunohistochemical analyses were performed on medullary sections. In the nTS of SIDS victims we observed modifications of both neuronal and glial cells. Brain injury triggers the activation of both astrocytes and microglia, which respond to neuronal damage by characteristic changes that could explain our observations in the nTS of SIDS victims. In our investigation of the nTS of SIDS victims we found a significant increase of reactive astrocytes density, a significantly higher percentage of necrotic cells, an increase of reactive microglial cells density, a significantly higher expression of substance P and the presence of NMDA receptors immunoreactivity. Our results support the hypothesis that there is injury of the nTS neurons in SIDS victims, even if the causes of this damage are still unknown. This neuronal damage may explain why adequate ventilation is often not maintained during hypoxia. Such histological findings have never been thought sufficient to explain SIDS, but the tissue findings could be an indication of the impairment of several pathophysiological mechanisms which may underlie brainstem dysfunction, affecting cardiorespiratory control.

Introduction: Although several studies have described initial atherosclerotic lesions of the coronary arteries, already detectable in infancy and even during the intrauterine life, little, if any, attention has been given to the possible involvement of the cardiac conduction system arteries. In particular, to the best of our knowledge, none has considered the lesions of the cardiac conduction arteries as an initial stage of atherosclerosis., Methods: The cardiac conduction system of 70 infants dying suddenly and unexpectedly was removed in two blocks for paraffin embedding and serially cut., Results: The histological study of the cardiac conduction arteries of the 70 cases examined showed a normal structure in 55 cases (78.57%). In 15 cases (21.43%), there was a thickening of the sinoatrial node and/or atrioventricular artery associated with a thickening of varying severity in coronary artery walls. The lesions were marked by thickening and deposits of amorphous material and mainly lipids in the intima, as well as fragmentation of the elastic fiber system. A significant correlation was evident between early atherosclerotic lesions and both formula feeding and parental cigarette smoking (P<.05, chi(2) test)., Conclusions: The combination of both the considered risk factors seems to increase the early atherogenic effect of each noxa because the coronary lesions were more diffused in formula-fed infants whose parents both smoked.

While the parabrachial/Kölliker-Fuse complex has been described in a variety of animal species it has not been characterized in human brainstem. In the present study we investigated fetal and infant brainstems, focusing particularly on the dorsolateral part of the pontine tegmentum, with the aim of defining the precise cytoarchitecture of the medial parabrachial, lateral parabrachial, and Kölliker-Fuse nuclei in man, and analyzing the developmental stages of this complex. In serial sections of 28 human brainstems of subjects aged between 32 gestational weeks and 1 year we made a morphologic and morphometric analysis of the shape and size of the parabrachial/Kölliker-Fuse complex. We observed a homogeneous morphology in all cases, which enabled us to define the structure of the three nuclei. The features of the parabrachial nuclei are largely consistent with those reported in experimental studies. However, the Kölliker-Fuse nucleus appears to be more developed in human beings than in other animal species, showing a greater extension and a more complex structure. The neuronal maturation of these nuclei was seen to occur between the 35th and the 36th gestational weeks.

The parabrachial/Kölliker-Fuse complex has been defined, in different animal species, to lie in the dorsolateral part of the pontine tegmentum and to be subdivided into three well-defined regions: the medial parabrachial nucleus, the lateral parabrachial nucleus, and the Kölliker-Fuse nucleus. Experimental studies have shown that the parabrachial/Kölliker-Fuse complex is involved in a variety of functional activities and above all plays an important role in respiratory modulation. In human brainstem, the cytoarchitecture and physiology of this complex have not yet been fully characterized. The aim of the present study was to examine fetal and infant human brainstems in order to define the precise morphology of the three nuclei of the parabrachial/Kölliker-Fuse complex, and to determine whether this nervous center shows morphologic alterations in sudden infant death syndrome (SIDS) and in sudden intrauterine unexplained death (SIUD). In serial sections of 31 brainstems of subjects aged from 32 gestational wk to 10 months of life, we studied, by morphologic and morphometric analyses, the cytoarchitecture and the extension of the three nuclei of the parabrachial/Kölliker-Fuse complex. All the morphometric parameters were very similar in SIUD and SIDS cases to those of the respective control group, as shown by the absence of significant statistical differences between the two fetus and infant groups. We observed that the features of both the lateral and the medial parabrachial nuclei are largely consistent with those reported in experimental studies. In contrast, the Kölliker-Fuse nucleus appears to be more developed in human beings than in other animal species, showing a greater extension and a more complex structure, as well as subdivision into two subnuclei (compactus and dissipatus).

Complete examination of the brainstem involves transverse serial 5-microm sections made throughout the entire brainstem. The number of serial sections varies from 360 in sudden intrauterine unexplained death (SIUD) to 600 in term fetuses to over 1400 sections in sudden infant death syndrome (SIDS) victims. The procedure is not applicable in all histopathological laboratories, owing to the need for additional technical personnel. The simplified procedure allows a remarkable reduction of the number of sections. The brainstem is divided into 3 blocks. The first, cranial block, extends from the border between the medulla oblongata and pons up to the upper pole of the olivary nucleus. The second, intermediate block, corresponding to the submedian area of the inferior olivary nucleus, has as reference point the obex and extends 2 to 3 mm above and below the obex itself. The third, caudal block, includes the lower pole of the inferior olivary nucleus and the lower adjacent area of the medulla oblongata. Examinations of the brainstems from 106 SIDS victims, 30 controls, and 51 stillborns underlined a remarkable variability, particularly of the arcuate nucleus. The simplified examination of the brainstem makes it possible to evaluate the structures, examining 3 specific levels, defined by morphologic reference points.

Cot death is the commonest form of death among babies in the first year of life. The authors report the unusual case of a 2-month-old female infant dying suddenly and unexpectedly in whom a postmortem histological examination demonstrated a cardiac multifocal Purkinje cell tumor. Necroscopy studies of sudden infant death should always include an accurate histological examination of the cardiac conduction system and brainstem using serial sections.

A term male fetus suddenly and unexpectedly died in utero at the 40th week of gestation. The mother had a regular and unremarkable pregnancy except for an anticardiolipin antibodies positivity. The histological examination of the cardiac conduction system showed islands of conduction tissue in the central fibrous body, known as persistent fetal dispersion. The brainstem examination revealed a severe bilateral hypoplasia of the arcuate nucleus. This morphological finding has been described in more than 35% of our stillborn as well as sudden infant death syndrome (SIDS) cases, independently from the presence of anticardiolipin antibodies. Some authors have given emphasis to the possible lethal association of maternal autoantibodies and QT prolongation. Our findings emphasize the need of an accurate postmortem examination including the study of brainstem and cardiac conduction system in every case of unexpected late intrauterine death, following the same standardized autopsy protocol adopted in SIDS cases.

High serologic lipid levels, infections, and genetic susceptibility have been proposed as possible etiologic factors of initial atherosclerotic lesions of the coronary arteries in infancy. At a recent WHO annual meeting, it was stated that breast milk substitutes cause irreparable damage in infants. This prompted us to verify whether formula feeding and parental cigarette smoking might play a role in the pathogenesis of early atherosclerotic alterations in infancy. The major epicardial coronary arteries from 36 infants dying suddenly and unexpectedly (sudden infant death syndrome) were embedded in paraffin and serially cut for histologic examination. In 67% of the cases, multifocal coronary early atherosclerotic lesions of varying entities were detected. The alterations ranged from focal plaques with mild myointimal thickening to juvenile soft plaques reducing the arterial lumen. A significant correlation was observed between the early atherosclerotic lesions and the risk factors considered. In particular, we noted different morphologic patterns related to formula feeding and cigarette smoking. Baby formula feeding and parental cigarette smoking might have an atherogenic effect on the coronary walls as from the first months of life. The lesions appear to be larger and more diffuse when both these atherogenic factors are present.

We report the first observation of perinatal death attributable to morphological alterations of the parabrachial/Kölliker-Fuse complex. In an infant, born at 41 weeks of gestation with severe signs of asphyxia and dead 20 h after delivery, we observed the presence of rare and immature neurons in the brain stem areas of both lateral and medial parabrachial nuclei and the absence of the characteristic neurons of the Kölliker-Fuse nucleus. Such hypoplasia was associated with severe hypoplasia of the arcuate nucleus and pulmonary hypoplasia., (Copyright 2004 S. Karger AG, Basel)

The distribution of the somatostatin was studied by immunohistochemistry on serial sections of the 56 brain stems from subjects aged from 30 gestational weeks to 12 postnatal months, dying of both known and unknown causes. The unexplained deaths included 13 sudden intrauterine deaths, 4 sudden neonatal deaths and 24 sudden infant deaths. We observed intense somatostatin positivity in the cell bodies and fibres of many brainstem nuclei prevalently involved in the respiratory activity (parabrachial/Kölliker-Fuse complex, locus coeruleus, hypoglossus nucleus, dorsal vagus motor nucleus, tractus solitarii nucleus, ambiguus nucleus, and reticular formation) in stillbirths. Only in 8 foetuses with unexplained death the hypoglossus nucleus was somatostatin-negative. In the postnatal deaths, the immunopositivity was prevalently limited to the ventrolateral and ventral subnuclei of the tractus solitarii nucleus. In 13 sudden infant death victims and in one case of death due to pneumonia, somatostatin-positivity was also present in the hypoglossus nucleus. We concluded that: 1) the somatostatin is an important foetal breathing-inhibitor, but it becomes important for the physiological control of respiration immediately after delivery; 2) functional alterations of the hypoglossal nucleus can occur in both sudden perinatal and infant deaths and contribute to the induction of both fatal breathing movements in foetuses and abnormal ventilatory control in infants leading to irreversible apneic phenomena.

Recently, quantitative abnormalities in neuronal populations derived from the rhombic lip (inferior olive nucleus of the brain stem and external granular layer of the cerebellum) have been reported in victims of the sudden infant death syndrome (SIDS). In this study we examined the arcuate nucleus (ARCn) of 35 SIDS victims and 25 controls, to determine neuronal abnormalities involving this nucleus in SIDS. Computer-assisted cell evaluation was made on sections stained with hematoxylin and eosin to study the neuronal dimensions (nuclear and cytoplasmic area, nuclear/cytoplasmic ratio), the form factor and the density of reactive astrocytes. There was a significant reduction of the neuronal area (nuclear and cytoplasmic) in SIDS victims compared with controls. The neuronal populations of SIDS victims had a significantly higher form factor, index of immaturity. The SIDS victims were divided into two groups on the basis of ARCn development: 18 SIDS-A cases with a well-developed ARCn and 17 SIDS-B cases with severe bilateral hypoplasia. The results of our research indicate that the developmental defect is characterized by a reduction in size of the ARC neurons and by neuronal depletion. In SIDS the ARCn has the histomorphological features of neuronal immaturity, and there is a marked reduction of all quantitative cell parameters and lower astrocytes density with respect to controls. On the basis of the morphometric results of the arcuate neuronal populations, we hypothesize that infants whose neurons have failed to reach full maturity are at risk for SIDS because they are unable to develop appropriate cardioventilatory control.

Objective: Previously we failed to demonstrate a correlation between plaque type and symptoms in 165 carotid endarterectomy specimens. The purpose of this study was to analyze the relation between the anatomy of the carotid plaques and the presence of symptoms in 281 carotid endarterectomy specimens., Methods: The patients were 213 men (mean age, 68 years) and 68 women (mean age, 68.7 years), with symptomatic disease (n = 133) or asymptomatic disease (n = 148). Specimens were processed for histologic analysis and immunohistochemistry., Results: Plaques were categorized as complicated or noncomplicated, and ruptured or nonruptured. Risk factors could not be correlated with any pathologic or immunohistochemical findings or between plaque type and clinical symptoms., Conclusions: Almost 70% of plaque specimens demonstrated thrombus, intraplaque hemorrhage, or both. Thrombosis was observed in one fourth of specimens, and intraplaque hemorrhage in almost two thirds of specimens. Sixty four percent of plaques demonstrated neovascularization. It was not possible to demonstrate that complicated plaques (plaque rupture, thrombosis, intraplaque hemorrhage) are associated with symptoms, and it appears that such plaques may occur at any time, irrespective of symptoms.

This work intends to be a review of the current status of knowledge on the cardiac conduction system in the crib death as well as remaining challenges, including reflections upon authors' personal works as well as many studies by others. The cardiac conduction system findings of resorptive degeneration, His bundle dispersion, Mahaim fibers, cartilaginous meta-hyperplasia, persistent fetal dispersion, left sided His bundle, hemorrhage of the atrio-ventricular junction, septation of the bifurcation, atrio-ventricular node dispersion, sinus node hypoplasia, Zahn node, His bundle hypoplasia, atrio-ventricular node and His bundle dualism are hereby discussed by the authors. The cardiac hypotheses postulating that crib death could be due to lethal cardiac arrhythmias or heart block were considered of great interest in the 1970s. After a general abandon of the conduction studies in crib death, the cardiac concept of crib death is gathering a renewed interest, as well as the occurrence of infantile junctional tachycardia. Both the morphological and functional derangement underlying crib death remain poorly understood, assuring that it remains to be a major medical and social problem. Despite the non-specificity of most of the cardiac conduction findings in crib death, we believe that they, in association with altered neurovegetative stimuli, could underlie potentially malignant arrhythmias, providing a morphologic support for the cardiac concept of crib death.

The pathogenesis of sudden infant death syndrome (SIDS) is still not understood, although one of the most credited current hypotheses is the respiratory theory. Considerable evidence has been assembled suggesting that hypoxia in human infants produces an initial increase in ventilation, after which respiration is rapidly inhibited. We investigated the expression of the c-fos proto-oncogene, a marker of activated neurons, particularly by hypoxia, in the medulla oblongata nuclei involved in breathing after birth, with special reference to SIDS. We utilized c-fos protein immunohistochemistry on serial transverse sections of medulla oblongata from 22 SIDS victims. In 60% of the analyzed cases, we observed numerous positive c-fos neurons in the dorsal motor nucleus of the vagal nerve. In control cases, the immunohistochemical labeling was negative or very low. The c-fos protein was expressed in the rostral-intermediate portion of the dorsal motor vagal nucleus, where motoneurons with respiratory-related activity are located. The positive c-fos immunoreactivity observed in SIDS suggests that the neurons of the dorsal motor vagal nucleus involved in the regulation of breathing are able to yield an intense, immediate ventilatory response to hypoxia. Our results support the respiratory theory of SIDS.

Background: The process by which a fibrofatty plaque evolves into a fibrotic lesion or into an unstable, lipid-rich plaque is poorly understood. In this study our aim is to deepen the knowledge of the cellular proliferation mechanisms that characterize the initial phases of destabilization of the unstable carotid plaque., Methods: 32 specimens from carotid endarterectomies were employed to assess by immunohistochemical methods, either in stable (n=10) or unstable (n=22) atherosclerotic plaques, the proliferating cell nuclear antigen (PCNA), the proto-oncogene c-fos, and the oncoprotein p53., Results: 18/32 atherosclerotic plaques (all unstable), showed c-fos immunopositivity (P<0.0001). Ten lesions, three stable and seven unstable, were PCNA+, while 13 cases were positive for p53 (three stable and 10 unstable plaques). When comparing symptomatic vs. asymptomatic patients, the most striking finding was the coincidence between c-fos, PCNA and p53 protein positivity observed only in unstable plaques of seven out of eight patients, all with previous episodes of stroke or transient ischemic attacks. On the other hand, none of the above mentioned positivity was detected in the 24 asymptomatic patients (P<0.0001)., Conclusions: These findings indicate an important role of these biomarkers in vascular biology. A series of molecular pathways of disease development and progression common both to atherosclerosis and cancer, support that the world's two most common diseases are more closely aligned than previously believed.

Objective: To investigate lung development and to correlate pulmonary hypoplasia with hypoplasia of the arcuate nucleus in stillbirths., Study Design: We examined 26 stillbirths which occurred after 25 complete gestational weeks. The brainstem and the lung were the particular focus of this study. The brainstem was examined according to the protocol routinely followed in our Institute. As regards the lung examination, the development stage was evaluated on the basis of the correlation between lung and body weight (LW/BW), and according to microscopic parameters, that is, the presence of cartilaginous bronchi up to the distal level and the radial alveolar count (RAC). The normal reference values for the last 3 months of gestation correspond to >0.022 for LW/BW and from 2.2 to 4.4 for RAC., Results: In 17 cases (65%) pulmonary hypoplasia was observed, characterized by a LW/BW value below 0.022 and RAC below 2.2. In nine cases (35%), microscopic examination of brainstem serial sections showed varying degrees of hypoplasia of the arcuate nucleus (ARCn). In eight cases (31%) the pulmonary hypoplasia was associated with hypoplasia/agenesis of the ARCn., Conclusions: This study demonstrated that in about a third of stillbirths there is a congenital hypodevelopment of both lung and arcuate nucleus. In these cases the ARCn hypoplasia would exert a negative effect on respiratory movements in utero and therefore on lung development. When the pulmonary hypoplasia is not accompanied by hypodevelopment of this nucleus the explanation could be a failure to block the inhibitory action of the Kölliker-Fuse nucleus.

We present the case of a 62-year-old white female with a history of previously treated angioimmunoblastic T-cell lymphoma, who died suddenly 1 day after presentation for presumed tumor recurrence. Postmortem gross examination revealed a 4-cm cardiac mass that was adherent to the free wall of the right atrium. Histologic examination showed extensive infiltration of the cardiac conduction system by lymphoma, which likely lead to fatal arrhythmia. Histological examination revealed systemic dissemination by an Epstein-Barr virus (EBV)-positive large B-cell lymphoma. Careful examination of the cardiac conduction system on serial sections was crucial in documenting the cause of death due to lymphomatous infiltration. As in this patient, lymphomatous infiltration of the heart may produce sudden cardiac death without obvious premortem signs of cardiac compromise. This case illustrates the utility of examination of the cardiac conduction system in necroscopy studies of sudden death., (Copyright 2003 Elsevier Inc.)

In the field of reconstructive plastic surgery, grafts of autologous cartilage are sometimes used to replace damaged or pathologic tissues, particularly in the nose, ear, and trachea. However, this procedure is difficult to apply, especially because of the scarcity of donor sites. In this study, we have cultured and characterized human chondrocytes from human nasal septal cartilage biopsies. The proliferative activity was evaluated by incorporation of 3H-thymidine into deoxyribonucleic acid (DNA) both under normal culture conditions and with different growth factors and serum concentrations. Identification of chondrocytes in culture was performed with immunohistochemistry and production of matrix with specific histochemical indicators. We observed a significant increase of cell kinetics of differentiated chondrocytes, embedded with intense metachromatic matrix, in the presence of transforming growth factor beta, and low concentrations of fetal calf serum. Therefore, in suitable conditions, human chondrocytes obtained even from small specimens can produce in vitro considerable quantities of pure autologous cartilaginous tissue within a few days. This newly formed cartilage can be used as a grafting material in reconstructive surgery, particularly in otolaryngology.