Biomedical subjects

G M Halliday

Publications and source records attributed to G M Halliday.

At least 145 records · Page 8Linked to original sources

PubMed1995

Quantitative analysis of the variability of substantia nigra pigmented cell clusters in the human.

At present there is no consensus concerning the internal organization of the human substantia nigra, despite its pivotal role in neurodegenerative conditions. We have quantitatively analysed the variability in the pattern of clusters of melanin-pigmented neurons in the human substantia nigra using serial section analysis and computer reconstructions. The substantia nigra pars compacta showed a bilaminar organization consisting of the pars medialis and pars lateralis, as well as dorsal and ventral tiers as described previously [D. A. McRitchie et al. (1995) J. comp. Neurol. (in press)]. Both the dorsal and ventral tiers could be further subdivided into three mediolateral cell columns based on position and cell density. The presence and arrangement of these cell clusters was most variable in transverse sections (the plane currently used for diagnostic neuropathology). Quantitative assessment of the topographical pattern of cell loss within single transverse sections of the human substantia nigra should therefore be treated with some caution. In contrast, the full rostrocaudal extent of the cell columns could be seen in horizontal sections. Thus, consistent samples of larger numbers of pigmented neurons per region were found in this section plane, although only two cell columns were found in most sections. Our results show that greater quantitative reliability can be achieved with horizontal sections of the substantia nigra.

Adult↗

PubMed1995

CD4+ T lymphocyte infiltration correlates with regression of a UV-induced squamous cell carcinoma.

It is currently unknown which arm of the immune system is responsible for regression of tumours. We have studied the T lymphocytes infiltrating a spontaneously regressing murine squamous cell carcinoma during the growth, plateau and regression phases of tumour development. In the plateau phase, where tumour growth is partially controlled by the immune system so that tumour size remains static, there was a considerable influx of CD4+ cells into the tumour. There was also an increase in the number of cells expressing the receptor for interleukin 2 (IL-2R), indicating that these cells were probably activated. The number of CD4+ cells remained high during the regression phase, where immunological destruction exceeded tumour growth. In contrast, CD8+ cells were only present in low numbers, and did not change during growth or regression of the tumours. These results indicate that CD4+ cells are probably responsible for tumour destruction. Thus CD4+ T lymphocytes are able to mediate tumour rejection and should be given more consideration for immunotherapy.

Animals↗

PubMed1995

Sunscreen protection of contact hypersensitivity responses from chronic solar-simulated ultraviolet irradiation correlates with the absorption spectrum of the sunscreen.

This study compares the ability of two ultraviolet (UV) B-absorbing sunscreens, 2-ethylhexyl p-methoxycinnamate (2-EHMC) and 2-ethylhexyl p-aminobenzoate (Padimate O), and two physical sunscreens, microfine titanium dioxide (MTD) and zinc oxide, to protect the skin immune system from chronic (4 weeks) solar-simulated UV irradiation. Mice were exposed to suberythemal doses of UV before assessing local and systemic immunosuppression and tolerance to a contact sensitizer. Using a UV protocol that induced local but not systemic immunosuppression or tolerance in BALB/c mice, it was shown that Padimate O made the immunosuppression worse, whereas 2-EHMC and MTD protected the immune system. When the cumulative dose was increased by 12.7%, causing systemic immunosuppression and tolerance, none of the sunscreens protected from immunosuppression, but 2-EHMC provided partial, and MTD gave complete protection from tolerance. To examine this apparent lack of protection from systemic immunosuppression, C3H/HeJ mice were used. These mice had a minimal erythema dose similar to that of the BALB/c mice but were systemically immunosuppressed, with only 44% of the UV dose required to immunosuppress BALB/c mice. 2-EHMC provided some protection, whereas MTD provided complete protection from systemic immunosuppression in C3H/HeJ mice. Hence, sunscreens can protect from local and systemic immunosuppression, although this protection is limited and is not related to the sun protection factor of the sunscreens or the minimal erythema dose of the mouse strain. Instead, protection seems to be related to the sunscreens' having a broad absorption spectrum.

4-Aminobenzoic Acid↗

PubMed1995

Comparison of the number of vasopressin-producing hypothalamic neurons in rats and humans.

The aim of this study was to assess the number and proportion of vasopressin-producing neurons in the hypothalamic magnocellular nuclei in rats and humans. Accurate and unbiased neuronal counts were estimated using the optical disector method. Arginine vasopressin-containing neurons were immunohistochemically visualized in formalin-fixed tissue sections. The magnocellular neurons were similar in size and morphology in both species. While the human hypothalamus contained significantly more vasopressin-containing neurons compared with the rat (36-fold increase), the proportion of vasopressin-containing neurons between species was similar. In both species, the majority of supraoptic neurons contained vasopressin, however the proportion of vasopressin-containing neurons in the human paraventricular nucleus was double that of the rat (nearly a 100-fold increase in number). These results suggest that the paraventricular nucleus contributes significantly to the release of vasopressin from the posterior pituitary in humans, whereas in rats vasopressin is mainly released by supraoptic neurons.

Animals↗

PubMed1995

Neurofibrillary tangles in chronic alcoholics.

Magnocellular neurons in the cholinergic nucleus basalis appear to be vulnerable in a variety of pathological conditions, including chronic alcoholism. While neurofibrillary degeneration of these neurons has been noted in a number of disorders characterized by dementia, the mechanism of cell death in thiamine-deficient chronic alcoholics has not been identified. In the present post-mortem investigation, multiple brain regions of seven thiamine-deficient chronic alcoholics, three neurologically asymptomatic chronic alcoholics and seven non-alcoholic age matched controls were screened for neurofibrillary pathology using both tau-immunohistochemistry and a modified Bielschowsky silver stain. In chronic alcoholics with thiamine deficiency, neurofibrillary pathology was found in the nucleus basalis, but not any other brain region. Neurofibrillary tangles were not seen in age-matched controls and were infrequent in alcoholics without neuropathological signs of thiamine-deficiency. Neurofibrillary tangles were most numerous in those cases with cell loss in the nucleus basalis. These findings suggest that neurodegeneration of the nucleus basalis in chronic alcoholics proceeds through the formation of neurofibrillary tangles.

Aged↗

PubMed1994

Practical considerations for the use of the optical disector in estimating neuronal number.

The aim of this study was to establish methodological variability in the estimation of the total number of neurones using the optical disector. Variations in the 3 dimensions of the disector probe were analysed under uniform sampling conditions in 50-microns-thick frozen sections of the human mediodorsal thalamic nucleus. There was no significant difference between the estimated neuronal number using samples of variable height (fractionator vs. non-fractionator sampling). In addition, different methods of volume calculation (individual sample vs. an average) did not significantly change the estimated total neuronal number. Large variations in the estimated total neuronal number occurred when the x and y dimensions of the disector probe were altered. In this study, accurate and reproducible estimates were achieved when the disector probe was large enough to have a probability of sampling at least 2 cells per frame. We conclude that the variables in the x-y plane (the disector frame size as well as the sample interval) significantly contribute to differences in the estimated total neuronal number. Several practical measurements to estimate this probability and enhance experimental design are discussed.

Cell Count↗

PubMed1994

Changes in epidermal Langerhans cells, gamma delta T cells and CD4 T cells after intradermal infection with recombinant vaccinia virus expressing cytokine genes.

Langerhans cells (LC) play a critical role in cutaneous immunity, and whereas Thy-1+ dendritic epidermal cells (Thy-1+ dEC) are also present in murine epidermis, their role remains unknown. Antigens and cytokines influence the number of LC found in the epidermis. However, there has been no investigation into the effects of particular cytokines during resolution of a viral infection. In order to study this we infected mice subcutaneously with vaccinia virus (VV) constructs containing the genes encoding TNF-alpha, IL-6 or IFN-gamma and the density of LC, THY-1+ dEC and CD4+ cells was determined. In this system the cytokines were produced locally at the site of viral replication. Cell densities were examined at day 1, while the response was being initiated, and at day 5 as the infection was being resolved. Infection with VV, like exposure to other antigens, decreased the density of epidermal LC at day 1, and they remained depressed at day 5. Production of TNF-alpha during VV growth did not influence this response by LC, whereas IFN-gamma and IL-6 both increased the number of epidermal Ia+ LC at day 1 but then caused a reduction at day 5. Thy-1+ dEC were not affected by VV infection at any time-point examined, nor did any cytokine influence the density of these cells at day 1. However, by day 5 IFN-gamma and IL-6, but not TNF-alpha, decreased the number of Thy-1+ dEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Regression in basal cell carcinoma: an immunohistochemical analysis.

Spontaneous regression of some cutaneous tumours is well recognized, and is thought to result from an immunological response to the tumour. Regression has previously been noted in basal cell carcinomas, but no studies defining the role of the immune response in the regression of this malignancy have been performed. We have examined 45 primary basal cell carcinomas (BCCs) (20 nodular, 25 superficial) and identified the cellular phenotypes and activation states of the cells infiltrating primary regressing and non-regressing BCCs, by immunocytochemistry. We have found a significantly increased number of CD3+ and CD4+ T cells infiltrating regressing compared with non-regressing tumours, and the expression of interleukin-2 receptor (an early activation marker for T cells) was also increased. There were no significant differences in class II major histocompatibility complex (MHC), CD1, or macrophage antigen expression in these groups. These findings suggest that activated CD4+ cytokine-secreting cells are important in the regression of BCCs.

CD4-CD8 Ratio↗

PubMed1994

Evidence that regression in keratoacanthoma is immunologically mediated: a comparison with squamous cell carcinoma.

Recent research observations suggest that the keratoacanthoma (KA) is a form of resolving squamous cell carcinoma (SCC). The mechanism by which this resolution takes place has not been fully explored, although it may have an immunological basis. To investigate this, we compared 15 clinically and histologically diagnosed KAs and 15 SCCs with regard to cellular infiltrate and keratin expression. We found that KAs have significantly higher numbers of CD3+ and CD4+ cells invading their epidermal component than SCCs. The T lymphocytes infiltrating KAs were more immunologically active, as greater numbers expressed the interleukin-2 receptor (IL-2R) than those in SCCs. It is of interest that CD36 was expressed by a significantly greater proportion of tumour cells within KAs than SCCs. This was also the case for the intercellular adhesion molecule ICAM-1, and the differentiation marker keratin 10. Overall, these findings suggest that KA regression is immunologically mediated, with activated (IL-2R+) CD4+ T lymphocytes and adhesion molecules playing a pivotal role in the immune response.

Aged↗

PubMed1994

Effect of chronic alcohol consumption on the human locus coeruleus.

Despite reduced levels of noradrenaline and increased cortical beta-adrenergic receptor binding, there is controversy regarding the effect of chronic alcohol consumption on the noradrenergic neurons of the locus coeruleus (LC). The aim of this study is to investigate the effects of chronic alcohol consumption on the LC; in particular, to determine whether or not there is any alteration in the size or number of neurons, or other significant changes in this nucleus. Eight chronic alcoholics without additional medical complications and eight age-matched controls were selected for this study. Immunohistochemistry with antibodies against tyrosine hydroxylase (TH) was used to visualize TH-positive neurons in spaced serial 50-microns sections throughout the length of the LC. These neurons were counted and no correction factors applied. There was no significant loss of TH-positive neurons in the LC of alcoholics compared with controls who had up to 20% variation in the number of neurons between individuals. This confirms published results from one alcoholic without complications, but contradicts recent findings of a significant neuronal loss in five alcoholics, all with liver pathology. Our analysis suggests that central noradrenergic neurons in alcoholics without significant medical complications are not susceptible to alcohol neurotoxicity.

Aged↗

PubMed1994

All-trans retinoic acid induces functional maturation of epidermal Langerhans cells and protects their accessory function from ultraviolet radiation.

Retinoids provide some protection against ultraviolet radiation-induced skin damage. We have previously shown that topical all-trans retinoic acid prevents ultraviolet light from reducing the density of epidermal Langerhans cells in the epidermis but does not inhibit the development of immunosuppression to a locally applied contact sensitizer. We therefore investigated the ability of all-trans retinoic acid to modulate Langerhans cell induction of allogeneic T-cell proliferation in the mixed epidermal cell lymphocyte reaction. Langerhans cells isolated from all-trans retinoic acid-treated mice induced an enhanced mixed epidermal cell lymphocyte reaction. This is similar to Langerhans cells cultured with granulocyte-macrophage colony stimulating factor. Retinoic acid treatment also enhanced the allogeneic cell-stimulating capability of Langerhans cells isolated from ultraviolet-irradiated mice. Langerhans cells from all-trans retinoic acid-treated, ultraviolet-irradiated mice which were "matured" by 3 days in culture induced a larger mixed epidermal cell lymphocyte reaction than mice treated with solvent and ultraviolet irradiation. Thus all-trans retinoic acid treatment of mice causes Langerhans cell maturation and inhibits ultraviolet light from reducing their density or impairing their allogeneic cell-stimulating capacity. However, these mice remained immunosuppressed upon application of a contact sensitizer to irradiated or unirradiated skin. It is thus likely that, whereas all-trans retinoic acid protects local Langerhans cell numbers and function, it does not inhibit the production of an ultraviolet radiation-induced photoproduct which causes immunosuppression.

Animals↗

PubMed1994

Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon.

We have analyzed glial changes in forebrain and diencephalic regions in 19 alcoholics with different histories of chronic alcohol consumption and related medical complications including Wernicke's encephalopathy and alcoholic liver disease. Cases with postmortem evidence of hepatic encephalopathy were excluded. Two of the alcoholic patients had ceased drinking for several years prior to death. Brains were obtained postmortem and fixed in formalin. Serial 50 microns sections of the forebrain and diencephalon at 750 microns intervals were stained with standard histochemical stains (haematoxylin and eosin, luxol fast blue, cresyl violet and silver), as well as immunohistochemically for glial fibrillary acidic protein (GFAP). In control tissue, GFAP-positive astrocytes were intimately associated with ependymal, pial, and vascular surfaces. In alcoholic cases, the morphology of these cells was markedly changed showing enlargement of the cell bodies and beading of the cellular processes. In contrast to controls, GFAP-positive astrocytes were seen within and surrounding clusters of magnocellular neurons in the basal forebrain and hypothalamus. In thiamine-deficient alcoholics, glial scarring in the vicinity of the large branches of the cerebral arteries disrupted the normal forebrain architecture. A patchy loss of GFAP immunostaining was seen in most severe cases. A remarkable number of corpora amylacea also rimmed blood vessels, pial and ependymal surfaces in all alcoholics compared to controls. The beaded fibers were seen in alcoholics drinking at the time of death as well as in those who had ceased drinking alcohol several years prior to death. These results indicate that chronic alcoholics have prominent glial changes which persist despite the cessation of alcohol consumption and are not exclusive to alcoholics with liver pathology.

Adult↗

PubMed1993

Carcinogen-treated skin allografts rejected by T lymphocytes specific for class I but not class II MHC antigens.

Treatment of skin with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), which reduces the density of epidermal class II MHC-expressing Langerhans cells (LC), enhances its survival when transplanted onto histoincompatible hosts. We have examined the ability of T lymphocytes which reject DMBA-treated skin to lyse P388D1 cells expressing either only class I or class I and II antigens. Lymphocytes isolated from solvent-treated grafts showed greater cytotoxicity for the targets expressing both antigens, indicating that some of these lymphocytes were specific for class II MHC antigens. In contrast, lymphocytes isolated from carcinogen-treated grafts lysed both targets similarly and hence did not contain any cells specific for class II MHC antigens. Anti-class I MHC antibody blocked cytotoxicity by both leukocyte populations to similar extents, but anti-class II MHC antibodies preferentially blocked T cells isolated from the solvent-treated grafts. There was no difference in the phenotype of the cytotoxic cells isolated from solvent- and carcinogen-treated grafts. Thus, whereas solvent-treated skin grafts are rejected by T cells specific for class I and II MHC antigens, DMBA-treated skin grafts are only rejected by class I MHC-specific T cells which may account for the enhanced survival of the carcinogen-treated grafts.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1993

Parvalbumin as an anatomical marker for discrete subregions of the ambiguus complex in the rat.

The topography of parvalbumin-immunoreactive neurons within the ventrolateral medulla of rats was investigated. Parvalbumin is a member of the 'EF-hand' family of Ca-binding proteins and is present in certain cell types within the central nervous system (fast-firing neurons with high metabolic rates). Parvalbumin-immunoreactive neurons were located in discrete rostrocaudal divisions of the ambiguus complex corresponding to regions containing respiratory-related neurons. Based on the location of physiologically characterized respiratory-related neurons reported in the literature, parvalbumin immunoreactivity does not appear to distinguish inspiratory- from expiratory-related neurons.

Animals↗

PubMed1993

Quantitation and three-dimensional reconstruction of Ch4 nucleus in the human basal forebrain.

The basal nucleus of Meynert, incorporating the Ch4 group of cholinergic neurons, was examined in six patients with no signs of neurological abnormalities. The ages of the patients ranged from 20 to 80 years. Despite a number of descriptions of these neurons, few age-related studies have been dedicated to the analysis of the entire anteroposterior extent of the nucleus. Staining with cresyl violet and acetylcholinesterase histochemistry, alone or in combination, was used to identify the cytoarchitectural organization of the Ch4. Computer-assisted morphometry was used for three-dimensional visualization and quantitation. The three-dimensional computer reconstructions revealed a continuous ribbon of neurons with a highly variable density. Four distinct subregions could be clearly identified in all cases by their cytoarchitecture and cellular morphology, although these subgroups were different to those previously described. There were no quantitative differences between the hemispheres in volume, density or cell number of the Ch4, although equivalent levels varied in area and density. The measures were similar in all cases with the exception of the case aged 80 years old. The data demonstrate individual variability in three dimensions and confirm previous studies that found only a mild decline of the Ch4 in old age.

Acetylcholinesterase↗

PubMed1993

Protein kinase C transduces the signal for Langerhans' cell migration from the epidermis.

Langerhans' cells (LC) take up antigen in the epidermis and then migrate to the local lymph nodes where they present the antigen to T lymphocytes, initiating cutaneous immune responses. However the intracellular mechanisms which mediate LC migration from the epidermis are unknown. We have demonstrated that activation of protein kinase C (PKC) induces this LC migration. An analogue of diacylglycerol (DAG), the physiological activator of PKC, L-alpha-dioctanoyl glycerol (oDAG), applied topically onto the skin of mice caused a significant depletion in the density of Ia+ and J11d+ epidermal LC. oDAG decreased the density of LC in both BALB/c and C57BL mice 24 hr following application, over a dose range of 0.5-24 microM; 200 or 0.05 microM being ineffective. LC density remained depressed for up to 7 days and oDAG increased the number of fluorescein isothiocyanate (FITC) positive cells in the local lymph nodes of mice treated topically with FITC, indicating that oDAG induced LC migration from the epidermis. Additionally, LC migration from the epidermis induced by the contact sensitizer 2,4,6-trinitrochlorobenzene (TNCB) was blocked when PKC was inhibited by palmitoyl-DL-carnitine chloride (PCC) or D-Sphingosine (Sph), indicating that LC cannot migrate from the epidermis when PKC is inhibited. However, PCC did not inhibit the induction of contact sensitivity. Thus PKC transduces the signal which leads to LC migration from the epidermis, and disruptions in this secondary messenger may interfere with the induction of immune responses in the skin by disturbing LC migration from the epidermis to the local lymph nodes.

Administration, Topical↗

PubMed1992

Rostrocaudal differences in morphology and neurotransmitter content of cells in the subretrofacial vasomotor nucleus.

The rostral ventrolateral medulla (RVLM) contains sympathoexcitatory neurons that exert a powerful control over the sympathetic outflow to the cardiovascular system. In the cat there is a concentration of such neurons (but not neurons subserving other functions) within a narrow longitudinal column in the RVLM termed the subretrofacial (SRF) nucleus. Furthermore, it has been suggested that there are subgroups of cells, located at different rostrocaudal levels of the SRF nucleus, that preferentially or exclusively control different vascular beds (e.g. in the kidney and hindlimb). The aim of this study was to map quantitatively the rostrocaudal distribution within the nucleus of different cell types, defined according to morphological and/or chemical criteria, and to correlate this with the regional vasomotor effects (in hindlimb and kidney) evoked by stimulation of SRF cells at the corresponding rostrocaudal levels. SRF cells were highly heterogeneous with respect to both their morphology and chemical properties. They varied greatly in size (equivalent diameter ranging from 10-40 microns) as well as in shape and orientation. An immunohistochemical examination using the avidin-biotin procedure revealed that many SRF cells (estimated 57% of all SRF cells) were immunoreactive for tyrosine hydroxylase (TH, a marker of catecholamine cells). In addition, there were SRF cells immunoreactive for neuropeptide Y (NPY, 11% of total), enkephalin (ENK, 16% of total), and serotonin (5HT, 10% of total), but not for substance P, galanin or somatostatin. Different cell types, defined according to their morphology and/or chemical properties, were unevenly distributed throughout the nucleus. In the most caudal part of the SRF nucleus, virtually all cells were TH-positive, and the large majority (estimated 80%) were NPY-positive, suggesting that many cells at this level contained both TH and NPY. In contrast, in the most rostral part of the SRF nucleus, only 30% of cells were TH-positive, and no NPY-positive cells were observed. Both 5HT- and ENK-positive cells were found throughout the rostrocaudal extent of the nucleus, but predominantly within its rostral part. Furthermore, TH-positive cells in the rostral SRF nucleus were on average significantly larger (mean equivalent diameter 18-43% greater) than TH/NPY-positive cells in the caudal part of the nucleus, but smaller than 5HT- or ENK-positive cells at the same level. Overall, rostral cells (regardless of their chemical type) were larger than caudal cells within the SRF nucleus (mean equivalent diameter 13-28% greater).(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia↗

PubMed1992

The dorsal, posterodorsal, and ventral tegmental nuclei: a cyto- and chemoarchitectonic study in the human.

In order to verify the existence of the ventral and posterodorsal tegmental nuclei and to extend previous findings regarding the dorsal tegmental nucleus in the human brainstem, studies were conducted using cyto- and chemoarchitectonics, and computer reconstruction techniques. Serial sections of five brainstems from adults with no known neurological disorders were stained for Nissl substance, acetylcholinesterase, and substance P. The topography, cytoarchitecture, and acetylcholinesterase reactivity of the tegmental nuclei were presented in a mini-atlas depicting sections cut in transverse and sagittal planes. The dorsal and posterodorsal tegmental nuclei were identified fully within the central grey matter while the ventral tegmental nucleus extended across the medial longitudinal fasciculus into the pontine reticular formation. The dorsal tegmental nucleus featured a cell-poor pericentral part, strongly positive for acetylcholinesterase, and a central part comprised of densely packed small neurons that displayed moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The posterodorsal tegmental nucleus, located in the same transverse plane as the rostral part of the motor nucleus of the trigeminal nerve, was composed of diffusely arranged small to medium neurons with its neuropil displaying moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The ventral tegmental nucleus, identified as a prominent structure in the pontine tegmentum immediately rostral to the genu of the facial nerve, contained predominantly large neurons and displayed intensive acetylcholinesterase reactivity and substance P-like immunoreactivity. These studies showed that the tegmental nuclei, which displayed distinctive cyto- and chemoarchitectonic features, were fully present in adult human brainstem.

Acetylcholinesterase↗