Marie Valdes-Dapena

Decreased Kainate Receptor Binding in the Arcuate Nucleus of the Sudden Infant Death Syndrome

The human arcuate nucleus is postulated to be homologous to ventral medullary surface cells in animals that participate in ventilatory and blood pressure responses to hypercarbia and asphyxia. Recently, we reported a significant decrease in muscarinic cholinergic receptor binding in the arcuate nucleus in victims of the sudden infant death syndrome compared with control patients that died of acute causes. To test the specificity of the deficit to muscarinic cholinergic binding, we examined kainate binding in the arcuate nucleus in the same database. We assessed 3H-kainate binding to kainate receptors with tissue receptor autoradiography in 17 brainstem nuclei. Analysis of covariance was used to examine differences in binding by diagnosis, adjusted for postconceptional age (the covariate). Cases were classified as SIDS, 47; acute control, 15; and chronic group with oxygenation disorder, 17. (Acute controls are infants who died suddenly and unexpectedly and in whom a complete autopsy established a cause of death). The arcuate nucleus was the only region in which there was a significant difference in the age-adjusted mean kainate binding between the SIDS group (37 ± 2 fmol/mg tissue) and both the acute controls (77 ± 4 fmol/mg tissue) (p < 0.0001) and the chronic group (69 ± 4 fmol/mg tissue) (p < 0.0001). There was a positive correlation between the density of muscarinic cholinergic and kainate binding in the SIDS cases only (R = 0.460; p = 0.003). The neurotransmitter deficit in the arcuate nucleus in SIDS victims involves more than one receptor type relevant to carbon dioxide and blood pressure responses at the ventral medullary surface.

Brainstem 3H-Nicotine Receptor Binding in the Sudden Infant Death Syndrome

Maternal cigarette smoking during pregnancy has been shown to be a major risk factor for the sudden infant death syndrome (SIDS). We hypothesized that SIDS is associated with altered 3H-nicotine binding to nicotinic receptors in brainstem nuclei related to cardiorespiratory control and/or arousal. We analyzed 3H-nicotine binding in 14 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 42), acute controls (n = 15), and a chronic group with oxygenation disorders (n = 8). The arcuate nucleus, postulated to be important in cardiorespiratory control and abnormal in at least some SIDS victims, contained binding below the assay detection limits in all (SIDS and control) cases. We found no significant differences among the 3 groups in mean 3H-nicotine binding in the 14 brainstem sites analyzed. When a subset of the cases were stratified by the history of the presence or absence of maternal cigarette smoking during pregnancy, however, we found that there was no expected increase (upregulation) of nicotinic receptor binding in SIDS cases exposed to cigarette smoke in utero in 3 nuclei related to arousal or cardiorespiratory control. This finding raises the possibility that altered development of nicotinic receptors in brainstem cardiorespiratory and/or arousal circuits put at least some infants, i.e. those exposed to cigarette smoke in utero, at risk for SIDS, and underscores the need for further research into brainstem nicotinic receptors in SIDS in which detailed correlations with smoking history can be made.

Tritiated-naloxone binding to brainstem opioid receptors in the sudden infant death syndrome

The sudden infant death syndrome (SIDS) is defined as the sudden death of an infant under 1 year of age that remains unexplained after a thorough case investigation, including a complete autopsy. We hypothesized that SIDS is associated with altered 3H - naloxone binding to opioid receptors in brainstem nuclei related to respiratory and autonomic control. We analyzed 3H - naloxone binding in 21 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 45); acute controls (n = 14); and a chronic group with oxygenation disorders (n = 15). Opioid binding was heavily concentrated in the caudal nucleus of the solitary tract, nucleus parabrachialis medialis, spinal trigeminal nucleus, inferior olive, and interpeduncular nucleus in all cases analyzed (n = 74). The arcuate nucleus on the ventral medullary surface contained negligible binding in all cases (n = 74), and therefore binding was not measurable at this site. We found no significant differences among the three groups in the age-adjusted mean 3H - naloxone binding in 21 brainstem sites analyzed. The only differences we have found to date between SIDS and acute controls are decreases in 3H - quinuclidinyl benzilate binding to muscarinic cholinergic receptors and in 3H - kainate binding to kainate receptors in the arcuate nucleus in alternate sections of this same data set. The present study suggests that there is not a defect in opioid receptor binding in cardiorespiratory nuclei in SIDS brainstems.

A Pathologist's Perspective on Possible Mechanisms in SIDS

The first scientists in the United States to conduct systematic investigations of the sudden infant death syndrome (then known as crib death) were Drs. Werne and Garrow, pathologists at the Office of the Chief Medical Examiner in the Borough of Queens in New York City. Their first joint work on that subject was published exactly 40 years ago. ’,* They stressed the presence of modest inflammation of the upper respiratory tract as having something to do with causation. Those of us who were young and inexperienced at the time were intrigued by their descriptions. What they were suggesting seemed incredible, i.e. the fact that seemingly healthy babies died on account of little more than minimal to moderate inflammation of the upper airway. To this day, I clearly recall reading the first of those articles in absolute disbelief that any such thing could happen. (I was working at the time in an academic institution and had never encountered a crib death.) Soon thereafter, however, I became an employee of the Office of the Medical Examiner of the City of Philadelphia; I saw what they had seen and I certainly had no better explanation to offer. Like a certain popular American cigarette, scientists in general, and anatomic pathologists in particular, have come a long way in the intervening four decades. We all know much more about these babies than we used to. The details of ultimate mechanism of their deaths still elude us, but we have learned a great deal about who they are and where they come from. And much of that knowledge we owe to pathologists. Probably the most important lesson we have learned in those forty years is the fact that there are even more subtle micropscopic changes in the tissues of these infants than Werne and Garrow had ever suspected. So subtle are they that the investigator is obliged to explore them by means of tedious microscopic measurements or morphometry and not in just a few cases but rather large numbers of both cases and controls in order to appreciate their very presence. It is that sort of endeavor, the stretching of ourselves, that has led to a new understanding of the morphology and possible mechanisms of the sudden infant death syndrome.

Pathology Practice: Pediatric Pathology and the Autopsy

The damaging effects of low and declining autopsy rates on the discipline of pediatric pathology are discussed. A survey of autopsy rates in 25 childrens hospitals indicates that current rates are about 51%. Strategies for improving autopsy rates are presented.

Iatrogenic Disease in the Perinatal Period

The ever-changing complexion of iatrogenic perinatal disease dictates the following: 1. Neonatologists and pediatric pathologists must be aware of the current spectrum of these lesions and ever alert to the appearance of new ones. 2. The neonatologist and pediatric pathologist within any given institution should be in regular, systematic communication with each other concerning lesions of this type. 3. There must be a national network for rapid dissemination or exchange of information among institutions regarding these lesions. The Study Group for the Complications of Perinatal Care (SGCPC), established in 1984 as an international, multicenter, multidisciplinary study group, is committed to the prevention of complications of perinatal care by individual and collective effort. Its individual members include perinatologists, neonatologists, pediatric pathologists, and obstetricians. There are institutional members as well. Activities to date include the development of a standardized perinatal autopsy protocol and the initiation of a uniform system for the categorization of perinatal deaths. If the reader is interested in obtaining further information about the organization, contact Trevor Macpherson, MD, in the Department of Pathology at the Magee-Womens Hospital in Pittsburgh, Pennsylvania.

GLOMERULOSCLEROSIS IN THE SUDDEN INFANT DEATH SYNDROME

In the past two decades, two groups of investigators have alleged that infants who die of the sudden infant death syndrome (SIDS) have excess numbers of sclerotic glomeruli in their kidneys. This double blind, case-control study was undertaken to test that assertion. Using microscopic sections of the kidney from 153 autopsies (99 SIDS infants and 54 control infants) in the National Institute of Child Health and Human Development (NICHD) Cooperative Epidemiologic Study of Risk Factors for SIDS, we counted relative numbers of sclerotic glomeruli in four fields of renal cortical tissue in two sections from each infant. Our results indicate that there is no difference between the two groups in regard to the proportion of sclerotic glomeruli.

Insulin-Containing Pancreatic Islet Cells in the Sudden Infant Death Syndrome

In 1976, in a letter to the editor of Lancet, Cox et al1 reported a study of the pancreas in 25 so-called cot deaths, infants who had died of the sudden infant death syndrome (SIDS). Those authors claimed that 9 of the 25 (36%) had islet cell hyperplasia and nesidioblastosis. They attributed those nine deaths to hypoglycemia secondary to pancreatic lesions. They defined nesidioblastosis as multifocal budding of endocrine cells from ductal or ductular epithelium, or interposition of endocrine cells in the midst of ductal or ductular epithelium, together with diffuse proliferation of single endocrine cells or small cell nests in the midst of parenchyma and apart from clearly defined islets. The conviction of these investigators was apparently supported, at least in part, by an earlier report that many SIDS victims have abnormally low levels of glucose in the vitreous humor.2

Cardiac and Respiratory Mechanisms That Might Be Responsible for Sudden Infant Death Syndrome

This international conference sought to piece together what is already known and what should be determined concerning the possible role of cardiac and respiratory mechanisms in the pathogenesis of sudden infant death syndrome (SIDS). Selection of the speakers was designed not only to include researchers who had previously or were now actively engaged in research into SIDS, but also eminent physiologists who, through their understanding of basic cardiac, respiratory, and neural mechanisms, could help guide us into directions likely to further our progress in determining underlying mechanisms. The meeting covered a period of 4 days and was based upon relatively short presentations followed by long periods of discussion. On the fourth day, a series of workshops was held to allow the presenters from the first 3 days of the meeting and their