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H C Kinney

Publications and source records attributed to H C Kinney.

At least 37 records · Page 2Linked to original sources
PubMed1997

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.

Arcuate Nucleus of Hypothalamus↗
PubMed1996

Reciprocal entorhinal-hippocampal connections established by human fetal midgestation.

Little is known about the timing or sequence of genesis of connections between different areas of the developing human cerebral cortex. It has been shown that connections between areas V1 and V2 of the visual isocortex are established at about 37 weeks of gestation (Burkhalter [1993] Cerebr. Cortex 3:476-487), suggesting that cortico-cortical connections appear late in the 40-week human gestational period. However, there are indications from other studies that connections between subdivisions of the hippocampal formation may be established much earlier, by about 20 weeks of human gestation. To investigate this possibility, the lipophilic bidirectional tracer 1,1' dioctadecyl-3,3,3',3-tetramethylindocarbocyanine perchlorate (DiI) was used to study connections between the entorhinal cortex, hippocampus, and temporal lobe neocortex in paraformaldehyde-fixed postmortem fetal tissue. The DiI transport revealed robust reciprocal connections between the entorhinal cortex, hippocampus, and subiculum, which were consistently present at 19 weeks of gestation (the earliest age studied), and which were anatomically similar to those in adult primates. Specifically, projections to the hippocampus and subiculum originated from neurons in the entorhinal cortex (EC) layers 2 and 3, whereas reciprocal projections to the EC originated from pyramidal neurons in the cornu ammonis region CA1 and the subiculum. In contrast, the perforant pathway projection from EC to the dentate gyrus, and all connections with the neocortex, reached only rudimentary stages of development by 22 weeks of gestation (the latest age studied). These findings suggest that hippocampal pathways develop prior to isocortical pathways, and that reciprocal entorhinal-hippocampal projections may be among the first cortico-cortical connections to be established in the human brain.

Brain↗
PubMed1996

Developmental changes in [3H]lysergic acid diethylamide ([3H]LSD) binding to serotonin receptors in the human brainstem.

The ontogeny of serotonin receptors in the human brainstem is largely unknown, despite the putative roles of serotonin in neural development, synaptic transmission, brainstem modulation of vegetative functions, and clinical disorders of serotonergic function. This study provides baseline information about the quantitative distribution of [3H]LSD binding to serotonergic receptors (5-HT1A-1D, 5-HT2) in the human brainstem, from midgestation through maturity, with a focus upon early infancy. Brainstems were analyzed from 5 fetuses (19-25.5 weeks postconception), 5 infants (42-55.5 weeks postconception), and 3 mature individuals (4, 20, and 52 years). Tissue autoradiography was used with [3H]LSD for total serotonergic receptor binding and [3H]LSD and serotonin for nonspecific binding; computer-based quantitation was applied. The highest levels of [3H]LSD binding occurred prenatally throughout the brainstem. At all ages, the highest relative binding localized to the rostral raphe. A marked decline in [3H]LSD binding occurred between the midgestation and infancy in brainstem regions involved in control of cardiovascular function, respiration, and pain. The fetal peak in [3H]LSD binding to 5-HT receptors is consistent with a trophic role of serotonin in immature human brainstem, and a decrease, between midgestation and infancy, in serotonergic modulation of vegetative functions controlled by the brainstem.

Adolescent↗
PubMed1996

Developmental changes in neurotransmitter receptor binding in the human periaqueductal gray.

The periaqueductal gray (PAG) plays a central role in the integration of defense responses to threatening or stressful stimuli. Little is known about the neurochemical development of the human PAG around the time of birth, when the fetus makes the transition to extrauterine life and independent defense responses are needed. We analyzed receptor binding to selected neurotransmitters implicated in PAG function in 7 fetuses (19 to 26 gestational weeks), 9 infants (38 to 74 postconceptional weeks), 1 child (4 years), and 3 adults (20 to 68 years). Tissue autoradiography was used with radioligands for opioid, nicotinic, muscarinic, kainate, and serotoninergic receptors. By midgestation, binding to nicotinic, muscarinic, serotoninergic, opioid, and kainate receptors is already localized to the human PAG. The subsequent developmental profiles are unique for each radioligand. Binding to nicotinic and serotoninergic receptors decreases significantly from the fetal to mature periods, but at different tempos. In contrast, there is no significant change from midgestation to infancy for muscarinic, kainate, and opioid binding: between infancy and the mature period there is a downward trend in binding for muscarinic and kainate receptors and an upward trend for opioid receptors. This study provides baseline information about the neurochemical development of the human PAG in early life. This information is of value in considering the neurochemical substrate of the maturation of defense responses in human infancy, and in evaluating potential neurochemical disorders of the developing human PAG.

Age Factors↗
PubMed1996

Brainstem tegmental necrosis and olivary hypoplasia: a lethal entity associated with congenital apnea.

Previously, we reported an isolated case of a newborn with central apnea at birth, ventilator-dependence, and combined malformative and destructive brainstem lesions (1). We now report 2 additional cases with similar clinicopathologic features. All 3 patients were male (XY karyotype) and required immediate ventilatory support in the delivery room. Perinatal complications included polyhydramnios and breech presentation. Variable cranial nerve palsies and orofacial and limb anomalies were present. The patients dies within minutes of withdrawal of ventilatory support at 2 to 11 weeks after birth. Significant neuropathologic findings were localized to the caudal pons and medulla, and included tegmental necrosis (neuronal loss, gliosis, mineralization) with involvement of respiratory-related nuclei, and anomalies of rhombic lip derivatives (olivary hypoplasia, arcuate nucleus hyperplasia). Three-dimensional computer reconstructions facilitated clinicoanatomic correlations, and underscored the restriction of the lesions to pontine and medullary rhombomeres and rhombic lip. The histopathology of these cases suggests a malformative process occurring at the end of the first trimester (time of rhombic lip migrations), and a superimposed destructive process (tegmental necrosis) in the second half of gestation. Although the etiology is unknown, the segmental nature of the lesions suggests the possibility of an abnormality in homeobox gene regulation. These cases likely represent a distinct clinicopathologic entity that should be considered in the differential diagnosis of Moebius syndrome and failure to breathe at birth.

Apnea↗
PubMed1995

Three-dimensional distribution of [3H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the developing human brainstem.

Acetylcholine has been implicated in brainstem mechanisms of cardiac and ventilatory control, arousal, rapid eye movement (REM) sleep, and cranial nerve motor activity. Virtually nothing is known about the developmental profiles of cholinergic perikarya, fibers, terminals, and/or receptors in the brainstems of human fetuses and infants. This study provides baseline information about the quantitative distribution of muscarinic cholinergic receptors in fetal and infant brainstems. Brainstem sections were analyzed from 6 fetuses (median age: 21.5 postconceptional weeks), 4 premature infants (median age: 26 postconceptional weeks), and 11 infants (median age: 53 postconceptional weeks). One child and three adult brainstems were examined as indices of maturity for comparison. The postmortem interval in all cases was less than or equal to 24 hours (median: 10 hours). Muscarinic receptors were localized by autoradiographic methods with the radiolabeled antagonist [3H]quinuclidinyl benzilate ([3H]QNB). Computer-based methods permitted quantitation of [3H]QNB binding in specific nuclei and three-dimensional reconstructions of binding patterns. By midgestation, muscarinic cholinergic receptor binding is already present and regionally distributed, with the highest binding levels in the interpeduncular nucleus, inferior colliculus, griseum pontis, nucleus of the solitary tract, motor cranial nerve nuclei, and reticular formation. During the last half of gestation, [3H]QNB binding decreases in most, but not all of the nuclei sampled. The most substantial decline occurs in the reticular formation of the medulla and pons, a change that is not fully explained by progressive myelination and lipid quenching. Binding levels remain essentially constant in the inferior olive and griseum pontis. Around the time of birth or shortly thereafter, the relative distribution of binding becomes similar to that in the adult, with the highest levels in the interpeduncular nucleus and griseum pontis, although binding levels are higher overall in the infant. In the rostral pontine reticular formation, paramedian bands of high muscarinic binding are present which do not correspond to a cytoarchitectonically defined nucleus. By analogy to animal studies, these bands may comprise a major cholinoreceptive region of the human rostral pontine reticular formation involved in REM sleep. In the human interpeduncular nucleus in all age periods examined, muscarinic binding localizes to the lateral portions bilaterally, indicative of a heterogeneous chemoarchitecture. Muscarinic binding is high in the arcuate nucleus, a component of the putative respiratory chemosensitive fields along the ventral surface of the infant medulla. This observation is consistent with the known effects of muscarinic agents on chemosensitivity and ventilatory responses applied to the ventral medullary surface in animal models. The nonuniform distribution of muscarinic binding in the caudorostral plane in individual brainstem nuclei, as illustrated by three-dimensional reconstructions, underscores the need for rigorous sampling at precisely matched levels in quantitative studies. This study provides basic information toward understanding the neurochemical basis of brainstem disorders involving dysfunction of autonomic and ventilatory control, arousal, and REM sleep in preterm and full-term newborns and infants and for developing cholinergic drugs for such disorders in the pediatric population.

Adult↗
PubMed1995

Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome.

Muscarinic cholinergic activity in the human arcuate nucleus at the ventral medullary surface is postulated to be involved in cardiopulmonary control. A significant decrease in [3H]quinuclidinyl benzilate binding to muscarinic receptors in the arcuate nucleus is now shown to occur in sudden infant death syndrome (SIDS) infants, compared to infants dying acutely of known causes. In infants with chronic oxygenation abnormalities, binding is low in other nuclei, as well as in the arcuate nucleus. The binding deficit in the arcuate nucleus of SIDS infants might contribute to a failure of responses to cardiopulmonary challenges during sleep.

Acute Disease↗
PubMed1995

Developmental changes in [3H]kainate binding in human brainstem sites vulnerable to perinatal hypoxia-ischemia.

The human brainstem is especially susceptible to hypoxia-ischemia in early life. To test the hypothesis that the period of vulnerability of the developing human brainstem to hypoxia-ischemia correlates with a transient elevation in kainate receptor binding, we compared the quantitative distribution of [3H]kainate binding in brainstem nuclei between four fetuses (19-26 gestational weeks), four infants (one to nine months), and three "mature" individuals (one child and two adults) without neurological disease. Quantitative tissues autoradiography was used. [3H]Kainate binding decreased in all brainstem regions from early life to maturity with the most significant decreases occurring in nuclei thought to be especially vulnerable to perinatal hypoxia-ischemia (e.g. principal inferior olive, griseum pontis, inferior colliculus and reticular core). The highest binding in the fetal and infant period was found primarily in the major cerebellar-relay nuclei. In the inferior olive and arcuate nucleus, binding increased from the fetal to the infant period, and then fell 50-61% to low mature levels. In the griseum pontis, binding decreased 60% between the fetal and mature periods. In the reticular formation, binding fell 67-78% from the fetal to mature period. These data support a correlation between the period of brainstem vulnerability to hypoxia-ischemia in early life to transient elevation in kainate binding, and are particularly relevant to the topographic brainstem patterns in perinatal hypoxia-ischemia of infantile olivary gliosis, pontosubicular necrosis and reticular core damage. Striking localization of [3H]kainate binding to rhombic lip derivatives further suggests that kainate receptors may be involved in the development and function of human brainstem-cerebellar circuitry.

Aged↗
PubMed1995

Control of severe pain in children with terminal malignancy.

OBJECTIVE: To identify the characteristics of the subset of children with malignancy in whom massive opioid infusions are needed during the terminal phase. DESIGN: Retrospective review of the records of the 199 patients who died of malignancy after treatment at Children's Hospital, Boston, from March 1989 to July 1993, identifying characteristics of patients who required massive opioid infusions (operationally defined as infusion of > 3 mg/kg per hour of morphine dose equivalent) during the terminal phase. RESULTS: Twelve patients (6%) required massive opioid infusions, and eight of these patients required extraordinary measures (epidural or subarachnoid infusion and/or sedation) to achieve adequate analgesia. The duration of epidural or subarachnoid infusions in three patients ranged from 3 to 9 days, and minimal complications occurred. The duration of sedation ranged from 1 to 15 days. Maximal intravenous opioid dosing ranged from 3.8 to 518 mg/kg per hour of morphine equivalent. The maximal infusion rate (exceeding all previous published reports) occurred in an infant with an isolated metastasis in the periaqueductal gray matter, a brain-stem site linked to mediating analgesia and defense reactions. The need for massive opioid dosing in 11 of 12 patients was associated with tumor spread to the spinal nerve roots, nerve plexus, large peripheral nerve, or spinal cord compression. CONCLUSIONS: Standard dosing of opioids adequately treats most cancer pain in children; however, a significant group requires more extensive management. These problems occur more commonly among patients with solid tumors metastatic to spine and major nerves.

Adolescent↗
PubMed1994

Neuropathological findings in the brain of Karen Ann Quinlan. The role of the thalamus in the persistent vegetative state.

BACKGROUND: Karen Ann Quinlan had a cardiopulmonary arrest in 1975 and died 10 years later, having never regained consciousness. Her story prompted a national debate about the appropriateness of life-sustaining treatment in patients who are in a persistent vegetative state and led to the development of medicolegal guidelines for the care of such patients. This report describes the neuropathologic features of Quinlan's brain. METHODS: The entire brain and spinal cord were systematically sampled for histologic examination. The brain stem and central cerebrum were embedded en bloc and serially sectioned. Three-dimensional computer reconstructions helped visualize the topographic features of the lesions. RESULTS: Contrary to expectation, the most severe damage was not in the cerebral cortex but in the thalamus, and the brain stem was relatively intact. The neuropathological findings included extensive bilateral thalamic scarring, bilateral cortical scars primarily in the occipital pole and parasagittal parieto-occipital region, and bilateral damage to cerebellar and focal-basal-ganglia regions. The brain stem and basal forebrain and the hypothalamic components of the ascending arousal systems and brainstem regions critical to cardiac and respiratory control were undamaged. The lesions were consistent with hypoxia-ischemia after the cardiopulmonary arrest. CONCLUSIONS: Although the neuropathological findings in the case of Karen Ann Quinlan were complex, the disproportionately severe damage in the thalamus as compared with the cerebral cortex supports the hypothesis that the thalamus is critical for cognition and awareness and may be less essential for arousal.

Adult↗
PubMed1994

Myelination in the developing human brain: biochemical correlates.

To delineate the biochemical sequences of myelination in the human brain, we analyzed the protein and lipid composition of white matter in 18 baseline cases ranging in age from midgestation through infancy, the critical period in human myelination when the most rapid changes occur. Three adult cases were used as indices of maturity, and 4 cases with major disorders of CNS myelination (maple syrup urine disease, severe periventricular leukomalacia, idiopathic central hypomyelination, and metachromatic leukodystrophy) were analyzed. Brain samples were obtained < or = 24 hours after death. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high performance thin-layer chromatography were used to separate and identify proteins and polar and neutral lipids in an average of 10 sites/brain; computer-based densitometry was used to quantify polar lipids. Biochemical sequences, as manifested by the appearance of the myelin-associated lipids and myelin-specific proteins, closely followed previously described anatomic sequences both temporally and by region, and were identical in all sites sampled: sphingomyelin was followed simultaneously by cerebrosides, MBP, PLP, and nonhydroxy-sulfatide, followed by hydroxy-sulfatide. The onset and tempo of the expression of individual constituents, however, were quite variable among sites, suggesting a wide differential in vulnerable periods to insult in biochemically-specific pathways in early life. Cholesterol ester was transiently elevated during late gestation and early infancy, prior to and around the time of the appearance of cerebrosides, sulfatides, PLP, and MBP. Distinctive lipid and protein abnormalities were detected in idiopathic central hypomyelination and metachromatic leukodystrophy. This study underscores the feasibility of the combined biochemical approaches in pediatric brains and provides guidelines for the assessment of disorders of myelination in early human life.

Brain↗
PubMed1994

A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model.

Neuropathologic studies in SIDS victims support the concept that they are not entirely 'normal' prior to death, but rather possess underlying vulnerabilities which put them at risk for sudden death. This concept forms a key link in a triple-risk model for the pathogenesis of SIDS proposed by us. According to this model, sudden death in SIDS results from the intersection of three overlapping factors: (1) a vulnerable infant; (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). An infant will die of SIDS only if he/she possesses all three factors; the infant's vulnerability lies latent until he/she enters the critical period and is subject to an exogenous stressor. According to this model, heterogeneous disorders may make the infant vulnerable to sudden death during the critical period, as potentially exemplified by two previously reported lesions in SIDS brains (arcuate nucleus hypoplasia and subtle hypomyelination). Nevertheless, the triple-risk model does not preclude the possibility that the majority of SIDS deaths will be explained by a single common pathway upon which multiple stressors impinge to produce sudden death during the critical period.

Brain↗
PubMed1993

Early developmental changes in [3H]nicotine binding in the human brainstem.

Little is known about the developmental profile of nicotinic cholinergic receptors in the developing human brain, despite the potential importance of such information in understanding the pathogenesis of neurological abnormalities or increased risk for the sudden infant death syndrome in offspring exposed to nicotine in utero. In this study, we determined the distribution of [3H]nicotine binding in the developing human brainstem by quantitative tissue autoradiography. In midgestational fetuses, [3H]nicotine binding sites were heavily concentrated in tegmental nuclei related to cardiopulmonary integration, arousal, attention, rapid eye movement sleep, and somatic motor control. Over the last half of gestation, [3H]nicotine binding decreased 60-70% in the tegmental nuclei, with a significant difference in binding between midgestation and early infancy. In contrast, there was essentially no change in [3H]nicotine binding in the major cerebellar-relay nuclei (principal inferior olive and griseum pontis) between the same time-points. Tritium quenching by increasing lipid (myelin) content in tissue sections did not account for the decreases in [3H]nicotine binding in tegmental nuclei. Based upon the high levels of [3H]nicotine binding at midgestation, combined with experimental data demonstrating trophic properties for acetylcholine, we postulate that nAChRs a role in the development of the brainstem tegmentum during this period, and that once this role is fulfilled, nicotinic cholinergic binding decreases and remains low thereafter. Alternatively, nicotinic cholinergic receptors may be critical for other developmentally related functions and/or neurotransmission in the brainstem tegmentum at midgestation. The high levels of [3H]nicotine binding in the brainstem tegmentum at midgestation and its rapidly changing profile over late gestation further suggest that mid-to-late gestation is a developmental period during which this region is likely to be most vulnerable to the harmful effects of nicotine in maternal cigarette smoke. The baseline information provided in this study is potentially relevant towards understanding attention deficits and risk for the sudden infant death syndrome in offspring exposed to cigarette smoke in utero.

Arousal↗
PubMed1993

Anatomic distribution of the growth-associated protein GAP-43 in the developing human brainstem.

GAP-43 is a membrane phosphoprotein whose expression is high in neurons undergoing development or remodeling of axonal connections. This study used a monospecific antibody to GAP-43 to investigate the sequences of fiber tract elongation and synaptic development in the human brainstem. Immunocytochemistry was performed in 14 fetal and infant brainstems; two child and adult cases were also examined for comparison. At midgestation, GAP-43 immunostaining was moderately intense across nuclei and fiber tracts, except for the corticospinal tract, where levels were higher, and cranial nerve nucleus VII, superior olive, inferior colliculus, inferior olivary hilum, inferior cerebellar peduncle, medial lemniscus, and medial longitudinal fasciculus, where staining was nearly absent. By the end of the neonatal period, the relative distribution of GAP-43 immunostaining appeared well-established and similar, although not identical, to that in the child and adult brainstem. Immunostaining was absent or negligible in almost all the cranial nerve somato- and branchiomotor nuclei, auditory-relay nuclei, and vestibular nuclei, while remaining intense in visceral-related nuclei, reticular formation, cochlear nucleus, and periaqueductal gray. Staining was also virtually absent in all fiber tracts at birth, except for the corticospinal tract and central tegmental tract. Persistence of GAP-43 staining in the corticospinal tract past the fetal period suggests that this tract remains in a plastic state beyond initial axonal elongation. Intense immunostaining in visceral-related nuclei into adulthood suggests that these regions may continue to undergo synaptic reorganization. This study provides baseline information relevant to understanding developmental brainstem disorders in early human life.

Brain Stem↗
PubMed1992

Arcuate nucleus hypoplasia in the sudden infant death syndrome.

Abnormalities in central respiratory control during sleep, arousal and/or cardiac activity have been reported in some infants who subsequently die of the sudden infant death syndrome (SIDS). We postulate that these abnormalities may result from dysfunction of the ventral and ventrolateral medulla, which, based on animal data, is an integrative site for chemosensitivity, ventilation, autonomic function, and arousal. The arcuate nucleus along the ventral surface of the human medulla has been proposed to facilitate chemosensitivity to carbon dioxide and/or hydrogen ion. In this study, we surveyed serially or extensively sectioned medullae of 41 SIDS and 27 controls, and identified two SIDS victims with isolated hypoplasia of the arcuate nucleus. Three-dimensional reconstructions and volume measurements of each hemimedulla of one of these SIDS victims and three controls were performed from serial sections. The volume of the right arcuate nucleus of the SIDS case was 0.7 mm3, compared to a range of 3.4-26.3 mm3 (median 5 mm3) in three infant controls. On the basis of the anatomic connections of the human arcuate nucleus and of neurons in homologous positions in animals, we postulate that arcuate hypoplasia may lead to death by dyssynergy between cerebellar coordination of ventilation and autonomic/chemosensory/arousal integration, especially during sleep, hypercarbia, and in a critical developmental period.

Arcuate Nucleus of Hypothalamus↗