Biomedical subjects

W F White

Publications and source records attributed to W F White.

At least 19 recordsLinked to original sources

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↗

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↗

PubMed1994

A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death.

The neurologic mutant mouse, oscillator, is characterized by a fine motor tremor and muscle spasms that begin at 2 weeks of age and progressively worsen, resulting in death by 3 weeks of age. We report the localization of the oscillator mutation to the central region of mouse Chr 11, and demonstrate its allelism with spasmodic, a recessive viable neurological mutation which displays excessive startle. Oscillator is caused by a microdeletion in the gene coding for the alpha 1 subunit of the adult glycine receptor (Glra1). Glra1 assembles into a pentameric complex with the beta subunit of the glycine receptor (3 alpha (1)2 beta 5) to form a glycine-gated chloride channel. This receptor is the major adult glycine receptor, and the site of action of the poison strychnine. The oscillator deletion causes a frameshift resulting in loss of the highly conserved third cytoplasmic loop and fourth transmembrane domain of the protein. Membranes isolated from oscillator homozygote spinal cords display a 90% reduction in glycine-displaceable strychnine binding. This lack of ligand binding function confirms that oscillator is a complete loss of function allele. The oscillator mutation provides evidence that although at least four different alpha subunits exist for the glycine receptor, none of the other subunits can compensate for the loss of alpha 1 function. Mutations which impair GLRA1 function in humans have been shown to cause dominant familial startle disease. The identification of the oscillator mutation suggests that severe loss of function alleles in humans would result in prenatal or neonatal lethality.

Amino Acid Sequence↗

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↗

PubMed1991

Opioid receptors localize to the external granular cell layer of the developing human cerebellum.

The distribution of opioid receptors in the developing human cerebellum was determined by tissue autoradiography using [3H]naloxone. In infants, opioid receptors were heavily concentrated in the external granular layer, a matrix of germinal cells, and were substantially less concentrated in the internal granular layer, differentiating progeny of external granular cells. In the mature internal granular layer of the child and adult, opioid receptors were negligible. Thus, in the human cerebellum, opioid receptors localize to a population of germinal cells and are negligible in their mature progeny. These data support the idea that endogenous opioids play a role in human brain development and may function as receptor-mediated growth factors. The cerebellum provides a model site to examine abnormal opioid effects upon human brain development, particularly in infants exposed to narcotics in utero.

Cell Differentiation↗

PubMed1990

A 3,4-dihydroxyphenylalanine oxidation product is a non-N-methyl-D-aspartate glutamatergic agonist in rat cortical neurons.

Applications of solutions of 2,4,5-trihydroxyphenylalanine (TOPA or 6-hydroxyDOPA) to rat cortical neurons in culture monitored under whole-cell voltage clamp with patch electrodes resulted in currents which could be nearly completely blocked by the non-N-methyl-D-aspartate (non-NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but only weakly antagonized by the NMDA antagonist D.L-2-amino-5-phosphonovalerate (APV). Thus, TOPA can generate glutamatergic responses by interacting preferentially with non-NMDA receptors in cortical neurons. As these results show that a product closely related to the catecholamine precursor 3,4-dihydroxyphenylalanine (DOPA) has glutamatergic agonist properties, it is conceivable that catecholamine-containing brain areas may be at special risk for excitotoxic damage under certain conditions.

2-Amino-5-phosphonovalerate↗

PubMed1990

Three-dimensional distribution of 3H-naloxone binding to opiate receptors in the human fetal and infant brainstem.

Despite the putative role of opioids in disorders of the developing human brainstem, little is known about the distribution and ontogeny of opioid-specific perikarya, fibers, terminals, and/or receptors in human fetuses and infants. This study provides baseline information about the quantitative distribution of opiate receptors in the human fetal and infant brainstem. Brainstem sections were analyzed from three fetuses, 19-21 weeks gestation, and seven infants, 45-68 postconceptional weeks, in whom the postmortem interval was less than or equal to 12 hours. Opiate receptors were localized by autoradiographic methods with the radiolabelled antagonist 3H-naloxone. Computer-based methods permitted quantitation of 3H-naloxone binding in specific nuclei, as well as three-dimensional reconstructions of binding patterns. High 3H-naloxone binding corresponds primarily to sensory and limbic nuclei, and to nuclei whose functions are known to be influenced by opioids, e.g., trigeminal nucleus (pain), nucleus tractus solitarii and nucleus parabrachialis medialis (cardio-respiration), and locus coeruleus (arousal). The regional distribution of opiate receptors as determined by 3H-naloxone binding is similar in human infants to that reported in human adults and animals and corresponds most closely to that of mu receptors. We found, however, that opiate receptor binding is high in the fetal and infant inferior olive, in comparison to low binding reported in this site in adult humans, primates, and rodents. In addition, opiate receptors are sparse in the fetal and infant substantia nigra, as in reports of the adult human substantia nigra, compared to moderate densities reported in primates and rodents. By midgestation, the regional distribution of 3H-naloxone binding in human fetuses is similar, but not identical, to that in infants. Highest 3H-naloxone binding occurs in the inferior olive in fetuses at midgestation, compared to the interpeduncular nucleus in infants. Tritiated naloxone binding quantitatively decreases in virtually all nuclei sampled over the last trimester, but not to the same degree. The most substantial binding decrease (two- to fourfold) occurs in the inferior olive and may reflect programmed regressive events, e.g., neuronal loss, during its development. Definitive developmental trends in 3H-naloxone binding are not observed in the postnatal period studied. The heterogeneous distribution of opiate binding in individual brainstem nuclei underscores the need for volumetric sampling in quantitative studies.

Brain Stem↗

PubMed1990

Intravenous treosulfan versus intravenous treosulfan plus cisplatinum in advanced ovarian carcinoma.

In a prospective, multicentre, randomized trial, the efficacy and tolerance of treosulfan alone was compared with that of treosulfan plus cisplatinum in 135 women with advanced ovarian carcinoma. No statistically significant difference was found between the two treatments in terms of median survival. Combined treatment was associated with significantly greater side-effects and haematological toxicity. Optimal survival with minimal toxicity can be achieved by using treosulfan alone in patients (mainly stages Ic or II) with minimal postoperative residual disease. Patients (likely to be stage III or IV) with greater residual disease should receive treosulfan plus cisplatinum.

Adult↗

PubMed1990

Three-dimensional autoradiographic localization of quench-corrected glycine receptor specific activity in the mouse brain using 3H-strychnine as the ligand.

The autoradiographic analysis of neurotransmitter receptor distribution is a powerful technique that provides extensive information on the localization of neurotransmitter systems. Computer methodologies are described for the analysis of autoradiographic material which include quench correction, 3-dimensional display, and quantification based on anatomical boundaries determined from the tissue sections. These methodologies are applied to the problem of the distribution of glycine receptors measured by 3H-strychnine binding in the mouse CNS. The most distinctive feature of this distribution is its marked caudorostral gradient. The highest densities of binding sites within this gradient were seen in somatic motor and sensory areas; high densities of binding were seen in branchial efferent and special sensory areas. Moderate levels were seen in nuclei related to visceral function. Densities within the reticular formation paralleled the overall gradient with high to moderate levels of binding. The colliculi had low and the diencephalon had very low levels of binding. No binding was seen in the cerebellum or the telencephalon with the exception of the amygdala, which had very low levels of specific binding. This distribution of glycine receptors correlates well with the known functional distribution of glycine synaptic function. These data are illustrated in 3 dimensions and discussed in terms of the significance of the analysis techniques on this type of data as well as the functional significance of the distribution of glycine receptors.

Animals↗

PubMed1989

Radiotherapy for Paget's disease of the nipple: a conservative alternative.

The case records of 28 patients with Paget's disease of the nipple treated by radio-therapy alone were reviewed retrospectively. 16 of 19 patients who had no palpable underlying tumour and who were mammographically normal at the time of original treatment remain free of disease with a median follow-up of 5 years 3 months. In this selected group, radical radiotherapy with small fields localised to the involved skin is an effective alternative to mastectomy.

Adult↗

PubMed1989

Glycine binding to rat cortex and spinal cord: binding characteristics and pharmacology reveal distinct populations of sites.

Glycine is the principal inhibitory neurotransmitter in posterior regions of the brain. In addition, glycine serves as an allosteric regulator of excitatory neurotransmission mediated by the N-methyl-D-aspartate (NMDA) acidic amino acid receptor subtype. The studies presented here characterize [3H]glycine binding to washed membranes prepared from rat spinal cord and cortex, areas enriched in glycine inhibitory and NMDA receptors, respectively, in an attempt to define the glycine recognition sites on the two classes of receptors. Specific binding for [3H]glycine was seen in both cortex and spinal cord. Saturation analyses in cortex were best fitted by a two-site model with respective equilibrium dissociation constants (KD values) of 0.24 and 5.6 microM and respective maximal binding constants (Bmax values) of 3.4 and 26.7 pmol/mg of protein. Similar analyses in spinal cord were best fitted by a one-site model with a KD of 5.8 microM and Bmax of 20.2 pmol/mg of protein. Na+ had no effect on [3H]glycine binding to cortical membranes but increased the binding to spinal cord membranes by greater than 15-fold. This Na+-dependent binding may reflect glycine binding to the recognition site of the high-affinity, Na+-dependent glycine uptake system. Several short-chain, neutral amino acids displaced [3H]glycine binding from both cortical and spinal cord membranes. The most potent displacers of [3H]glycine binding to cortical membranes were D-serine and D-alanine, followed by the L-isomers of serine and alanine and beta-alanine. In contrast, D-serine and D-alanine were similar in potency to L-serine in spinal cord membranes. Compounds active at receptors for the acidic amino acids had disparate effects on the binding of [3H]glycine. At 10 microM, NMDA resulted in a 25% increase, whereas D- and L-2-amino-5-phosphonovaleric acid at 100 microM resulted in a 30% decrease, in [3H]glycine binding to cortical membranes. Kynurenic acid was the most potent of the acidic amino acid-related compounds at displacing [3H]glycine binding. In cortical membranes, kynurenic acid displacement was resolved into a high- and a low-affinity component; the high-affinity component displaced the high-affinity component of [3H]glycine binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗

PubMed1988

Distribution of muscarinic receptor subtypes within architectonic subregions of the primate cerebral cortex.

The regional distributions of muscarinic receptor subtypes (M1 and M2) in the macaque brain were investigated by in vitro receptor autoradiography. Putative muscarinic receptor subtypes were distinguished by their differential affinities for pirenzepine and carbachol in competition with [3H]-quinuclidinyl benzilate. Autoradiographic visualization of muscarinic receptor subtypes demonstrated marked regional and laminar variations that respected architectonic boundaries. The M1 receptor subtype was widely distributed throughout most cortical areas and was most intense over the superficial layers. Almost all limbic and paralimbic regions including the amygdala, hippocampus, orbitofrontal, temporopolar, parahippocampal, cingulate, and parolfactory areas displayed peak densities of the M1 receptor subtype. The M2 receptor subtype was selectively elevated in the primary sensory areas of all five sensory modalities, including the visual (area 17, V1), auditory (A1), and somatosensory (3b, S1) koniocortices, the anterior olfactory nucleus, and the gustatory area. The primary motor area also displayed a relative peak of M2 receptor subtype labeling. In the hippocampal formation, M1, M2, and nicotine receptors were distributed differentially, with each subdivision having a specific complement of cholinergic receptor subtype. The M1 receptor subtype was prevalent in the dentate gyrus, the CA4-CA3 region, and the CA1 ammonic sector. The M2 receptor subtype was concentrated in the CA2 sector, the subiculum, the rhinal cortices, and the parasubiculum. Putative neural nicotinic receptors, tagged with L-[3H]-nicotine, were most concentrated within the presubiculum.

Animals↗

PubMed1988

Quantitative comparisons of gamma-aminobutyric acid neurons and receptors in the visual cortex of normal and dark-reared cats.

Physiological studies suggest that the function of the visual cortical gamma-aminobutyric acid (GABA) system is abnormal in cats reared in total darkness. The present study asked whether visual input is necessary for the normal postnatal anatomical development of the GABA system by comparing GABA neurons and receptors in the visual cortex of normal and dark-reared cats. Immunohistochemical techniques (anti-GABA) were used to localize GABA neurons. In both rearing conditions, GABA neurons were stained rather uniformly in all cortical layers. Counts of GABA cells indicated a marked increase in density in dark-reared compared to normal cats. Counts of total cellular density in cresyl-stained sections, however, indicated a comparable increase in dark-reared cats. When corrected for total cellular density, there were no differences between dark-reared and normal cats in the density of GABA cells per layer, or the relative proportion of GABA cells across cortical layers. In vitro receptor binding of 3H-muscimol was used to compare GABAA receptors in the two rearing conditions. When corrected for total cellular density, saturation kinetics indicated no difference in the total number or affinity of receptors. Similarly, autoradiographic histology indicated no difference in the laminar distribution of receptors across cortical layers between dark-reared and normal cats. These results indicate that the postnatal development of GABA neurons and receptors occurs normally in the absence of visual input.

Aging↗

PubMed1987

A washing apparatus for microcentrifugation assays.

The use of centrifugation techniques for separating labeled compounds that are bound to tissue fractions from unbound substrate is widespread in biochemistry. An apparatus is described for simultaneously washing 24 microcentrifuge tubes. The apparatus provides for removing solutions from the tubes and filling tubes with washing solution. This apparatus permits the rapid and reproducible analysis of large numbers of samples.

Cell Fractionation↗

PubMed1987

Once weekly irradiation in breast cancer.

Eighty-four elderly patients with carcinoma of the breast were treated with a once-weekly schedule using 650 cGy per fraction to a total of six fractions. According to the TNM classification there were 8 patients with Stage I, 29 patients with Stage II, 45 patients with Stage III, and 2 patients with Stage IV disease. Primary surgical treatment included biopsy, that is, truecut needle biopsy or open biopsy in 53 patients and excision biopsy in 13 patients; the remaining 18 patients had mastectomy. The average age of patients was 69.2 years with the oldest 91 years of age. Ten patients died of concomitant causes during the follow-up period at an average age of 84.5 years. Patients included in this report had at least a 36 month follow-up period with the longest being 94 months. Acute reactions were noticeably less than those with daily treatment. Only one of the 36 patients, where the breast was preserved, had severe delayed skin reaction. Of the 37 patients with Stage I and II, 24 were alive and disease-free at the time of reporting. Three died of concomitant causes, 2 are alive with disease, and the remaining 8 patients died of recurrent of progressive disease. There were 45 patients with Stage IIIA and IIIB and in this group 11 are alive and disease-free, 7 died of concomitant causes, 12 died of progressive breast cancer, and the remaining 4 patients are alive with disease. The two remaining Stage IV patients died of their disease. Once-weekly treatment was well tolerated by all patients and the early local control result is encouraging. We are continuing to assess this type of fractionation in selected elderly patients, especially in those who live away from our center.

Adult↗

PubMed1987

Behavior, genetics and biochemistry of an allele of the mutant mouse spastic, spaAlb.

A new autosomal recessive mutation, characterized by an early defect in righting reflex and stiffened gait, progression to severe spasticity, tremor and rigidity, and death before weaning, appeared spontaneously on the C57BL/6 background. It was shown to be an allele of the mutant spastic spa, and shall be known as spaAlb. Mutant levels of [3H]strychnine binding are less than 10% of control levels in the brainstem and spinal cord. Autoradiographic examination of the distribution of [3H]strychnine binding sites in the mutant confirm a greatly reduced level of binding compared to control in all areas of the spinal cord, brainstem, and midbrain.

Alleles↗