Biomedical subjects

W F White

Publications and source records attributed to W F White.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1986

[3H]muscimol binding of GABA receptors in the visual cortex of normal and monocularly deprived cats.

In vitro receptor binding techniques were used to compare the total number, affinity and regional distribution of GABA receptors in visual cortex, as revealed by [3H]muscimol binding, in 5 normal and 5 monocularly deprived (MD) cats. Analysis of saturation kinetics and pharmacological specificity indicated that binding was to a single site having the characteristics of the GABAA receptor. No differences were found between normal and MD cats in either number or affinity of receptors. Within visual cortex, there were laminar differences in the density of binding, but no evidence for a lateral (columnar) organization. Label was densest in the superficial layers (I-IV), lowest in layer V and intermediate in layer VI. This pattern of label varied with incubation parameters with layer IV showing the densest label when high concentrations of [3H]muscimol and short rinse times were used. There were no differences between normal and MD cats in regional distribution of receptors under any incubation condition.

Animals↗

PubMed1986

A multimodal system for reconstruction and quantification of neurologic structures.

The utility of computers and computer graphics as aids in the study of nervous system architecture is growing. However, modern histologic, immunocytologic and biochemical methods for revealing the underlying microarchitecture and macroarchitecture of the nervous system yield data formats requiring disparate computer acquisition, analysis and display approaches, capable of spanning many orders of magnitude of scale. This paper describes the Image Graphics Laboratory data acquisition, processing and display system, whose various components and programs may be used singly or in concert to enable definition of various tissue properties at different levels of resolution and integration. Examples are given of the system's use in light microscopic two-dimensional and three-dimensional reconstructions, autoradiographic reconstructions, reconstructions from projected images, reconstructions of impregnated cells (e.g., whole neurons) and peripheral nerve image analysis.

Animals↗

PubMed1985

The glycine receptor in the mutant mouse spastic (spa): strychnine binding characteristics and pharmacology.

There is a marked deficit in the binding of the glycine receptor antagonist strychnine to the CNS of the mutant mouse spastic. The characteristics and pharmacology of [3H]strychnine binding to washed homogenates of spastic and littermate control spinal cord and brainstem were investigated to determine the nature of this defect. The maximal binding of [3H]strychnine to spastic homogenates is approximately 20% the value obtained from littermate control homogenates; the affinity of [3H]strychnine binding is approximately 25% lower than littermate control values. The pharmacology of [3H]strychnine binding has the same rank order of potency in spastic and littermate control mice; however, there are small differences in the potency of several compounds in spastic vs littermate control animals. These results indicate that the glycine receptor alteration seen in the spastic mutant mouse is primarily due to a decrease in receptor number. They also suggest that the pharmacological characteristics of the glycine receptor in spastic are different from littermate control. The data do not permit a distinction between whether the strychnine binding sites found in spastic represent the same population seen in littermate control animals or are a subpopulation that is spared by the mutation.

Animals↗

PubMed1985

The picrotoxinin binding site and its relationship to the GABA receptor complex.

The binding characteristics of [3H] alpha-dihydropicrotoxinin to the picrotoxinin binding site were investigated in membrane preparations of adult rat forebrain and living cultures of rat cerebral cortex. The binding of [3H]alpha-dihydropicrotoxinin to rat forebrain was decreased by lysing, treating with Triton X-100, and heating. Coincubation with gamma-aminobutyric acid (GABA), benzodiazepines, or alterations in the Na+ or Cl- composition of the media had no effect on the binding to the rat brain preparation. However, in the living neurons in tissue culture both GABA and diazepam significantly decreased the binding of [3H]alpha-dihydropicrotoxinin. The dose-response relationships for GABA antagonism of [3H]alpha-dihydropicrotoxinin binding and for picrotoxinin antagonism of the GABA enhancement of [3H]flunitrazepam binding in cultured cortical neurons were also investigated. The Hill coefficients for these actions were reciprocal, suggesting that they result from complementary interactions between the binding sites for GABA and picrotoxinin. These data support the association of the picrotoxinin binding site with the postsynaptic GABA receptor complex.

Acetates↗

PubMed1985

Tryptophan metabolism in patients with breast cancer.

Plasma levels of total tryptophan were significantly lower in 51 patients with breast cancer than in 14 women with benign breast cancer following surgery and after 12 weeks. The urinary excretion of xanthurenic and 5-hydroxyindoleacetic acids were similar in patients with cancer and benign disease but the excretion of N'-methylnicotinamide (NMN) was significantly higher (P less than 0.001) in the cancer patients. It is suggested that the elevated urinary excretions of NMN is due to higher NAD activity reflecting elevated glycolysis through the Cori cycle.

Breast Neoplasms↗