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Biomedical subjects

R O Weller

Publications and source records attributed to R O Weller.

At least 55 records · Page 3Linked to original sources
PubMed1995

Apoptosis in cerebral astrocytic tumours and its relationship to expression of the bcl-2 and p53 proteins.

Apoptosis is an important determinant of tumour growth which can be regulated by the bcl-2 and p53 genes. This study examines the relationship between apoptosis, growth fraction (Ki-67 immunolabelling index), and accumulation of the bcl-2 and p53 proteins in a spectrum of cerebral astrocytic tumours (n = 81), including fibrillary astrocytomas (n = 16), anaplastic astrocytomas (n = 19), and glioblastomas (n = 46). Median apoptosis indices (AIs) increased across this spectrum of tumours, and a significant (P < 0.0001) correlation was demonstrated between AI and Ki-67 labelling index (LI). Immunolabelling with the bcl-2 antibody was found in 44% of fibrillary astrocytomas, 42% of anaplastic astrocytomas, and 28% of glioblastomas. It was also found in the vascular endothelial proliferation typically seen in glioblastomas, and in the giant, multinucleated cells of some glioblastomas. No clear relationship between AI and bcl-2 accumulation was evident. Immunolabelling with the p53 antibody was found in 56% of fibrillary astrocytomas, 79% of anaplastic astrocytomas, and 50% of glioblastomas. No clear relationship between AI and patterns of p53 immunolabelling was evident. Equal proportions of p53-positive tumours were bcl-2 positive and bcl-2 negative, but a small proportion of p53-negative tumours was bcl-2 positive. The correlation between AI and Ki-67 LI is in line with findings in other malignant tumours. We suggest that the regulation of apoptosis in astrocytic tumours is too complex for a clear association between AI and bcl-2 and p53 protein expression to be demonstrated.

Antibodies, Monoclonal↗
PubMed1995

Prognostic indicators in a range of astrocytic tumours: an immunohistochemical study with Ki-67 and p53 antibodies.

The treatment and prognosis of patients with cerebral astrocytic tumours are currently guided by histopathological classification. This study evaluates immunohistochemistry using Ki-67, an antibody to a nuclear protein expressed in proliferating cells, and DO-7, an antibody to the product of the tumour suppressor gene p53, as prognostic indicators for these tumours. Immunohistochemistry with Ki-67 has been correlated with the behaviour of many different tumours, but its value as a prognostic indicator in astrocytic tumours is diminished by the conflicting results of previous studies. Immunohistochemistry with antibodies to the p53 protein has been used as a prognostic indicator in melanomas and some carcinomas, but the relation between prognosis and accumulation of this protein in astrocytic tumours has not been clarified. We have tested the hypothesis that survival is correlated with Ki-67 immunolabelling indices (LIs) and patterns of p53 immunolabelling in the cerebral astrocytic tumours of a large cohort of patients (n = 123) for whom clinical indices were well documented. Astrocytic tumours were divided into three histological types: fibrillary astrocytoma (n = 24), anaplastic astrocytoma (n = 31), and glioblastoma (n = 68). Histological type and patient age were independent predictors of survival. Median Ki-67 LIs differed significantly (P < 0.0001) between the types of astrocytic tumour, and tumours with a Ki-67 LI < 2% had a significantly (P < 0.0001) better prognosis. Ki-67 LI as a continuous variable carried a significant (P = 0.0043) unadjusted hazard to survival which was lost when adjusted for other variables, notably histological type. By contrast, no relation was found between survival and three categories of p53 labeling (p53-negative, p53 LI < 40%, and p53 LI > 60%). The results indicate that, whereas Ki-67 immunohistochemistry predicts survival in patients with astrocytic tumours, conventional histological appraisal remains the best guide to prognosis, and immunohistochemistry for p53 has no value in the assessment of these tumours.

Adult↗
PubMed1994

Perivascular edema fluid pathway in astrocytic tumors.

Perivascular spaces are anatomical routes for the bulk flow drainage of fluid from the gray matter to the subarachnoid space in normal rat brain. Perivascular cells are the resident scavengers in perivascular spaces. Following focal brain damage, perivascular cells upregulate MHC Class II antigens associated with uptake of edema fluid. Similar cells can be defined in damaged human brain. In the present investigation, the distribution of MHC Class II upregulated perivascular cells was measured in 30 astrocytic tumors and adjacent edematous tissues by immunocytochemistry using the following antibodies: HLA-DR (MHC Class II), PGM1 and MAC387 (macrophages). Perivascular cells were PGM1+/MAC387- and were located in perivascular spaces along blood vessels of all sizes. MHC Class II+ perivascular cells were distributed mainly in the tumors but in some cases (4 of 10 in astrocytomas, 4 of 10 in anaplastic astrocytomas, and 7 of 10 in glioblastomas) they were also found in adjacent edematous brain. The extensive MHC Class II expression on perivascular cells suggests that perivascular cells play a scavenging role in the perivascular spaces in human brain. The results of the present study indicate the similarity between perivascular spaces in human and rat brains and emphasize the significance of perivascular spaces as anatomical routes for edema fluid drainage from human brain tissue.

Animals↗
PubMed1994

Vigabatrin-induced lesions in the rat brain demonstrated by quantitative magnetic resonance imaging.

Rats treated with 250 mg/kg/day vigabatrin showed lesions detected by magnetic resonance imaging (MRI) in the cerebellar white matter in vivo. No lesions were seen in any control animal. As well as these visually apparent lesions, quantitative T2 relaxation time measurements showed a 12 ms increase in cerebellar white matter from 66 +/- 4 ms (SD, n = 5) to 78 +/- 2 ms (SD, n = 7). This region, as expected from previous studies, showed microvacuolation on post-mortem pathology. Additionally, significant increases in T2 relaxation times of 4-9 ms were found in the cerebral cortex, thalamus and hippocampus. Microvacuolation was not detected by post-mortem histopathology in the cerebral cortex or hippocampus, however, immunohistochemical staining for glial fibrillary acidic protein and for macrophages (ED1) showed reactive astrocytes (gliosis) and in more severe cases, microglial proliferation in these regions; such changes were also seen in association with the microvacuoles. No T2 increase was found in the cerebellar grey matter or olfactory bulbs. MRI techniques, including T2 relaxometry, are therefore sensitive for detecting vigabatrin-induced changes, including reactive astrocytosis, microglial proliferation and vacuolation in the rat brain. These results suggest that quantitative MRI should be a useful method for evaluating whether vigabatrin has neuropathological effects when given to patients.

Animals↗
PubMed1994

Histochemical staining of orbicularis oculi muscle in ectropion and entropion.

A histochemical study of orbicularis oculi was undertaken to test the hypothesis that there is a difference in the percentage and size of muscle fibre types which accounts for the development of involutional ectropion or entropion. Wedge excisions from lower lids of patients undergoing repair of these conditions were frozen-sectioned and stained histochemically to reveal muscle fibre types. Five ectropion and five entropion specimens were obtained, and the percentage of type 1 and type 2 fibres, fibre perimeters and fibre diameters were measured. An abundance of type 2 fibres was found in both ectropion (mean 89.6%) and entropion (mean 82.6%). No significant difference was found with respect to fibre type, perimeter or diameter when ectropion was compared with entropion or when either was compared with normals. Type 2 fibres were larger than type 1 in both ectropion and entropion. We conclude that no significant difference could be identified between orbicularis muscle fibres in ectropion, entropion and normals to account for the development of the eyelid malpositions.

Aged↗
PubMed1993

Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages.

Perivascular cells in the rat brain are an immunophenotypically defined group of cells which can be identified by their expression of the ED2 antigen. The present study investigates the role of perivascular cells as scavengers in the perivascular spaces of the rat brain and the relationship of these cells to microglia, macrophages, pericytes and smooth muscle cells. Particulate matter (Indian ink) was injected selectively into the perivascular spaces of the left caudoputamen of 59 rats. Animals were killed by cardiac perfusion of formalin or glutaraldehyde 2 h-2 years after ink injection. Cerebral hemispheres were examined histologically and immunocytochemically using the ED2 antibody for perivascular cells, ED1 for microglia and macrophages and OX-6 directed against Ia antigen [major histocompatibility complex (MHC) class II]. ED2+ perivascular cells ingested Indian ink in the perivascular spaces and expressed MHC class II antigen. Reactive microglia and macrophages in the perivascular parenchyma expressed ED1, but no ED2+ cells were seen outside the perivascular spaces. Transmission electron microscopy distinguished perivascular cells, which ingested carbon particles, from pericytes, which did not. The results of this study suggest that perivascular cells remain distinct from pericytes, microglia and macrophages and that they play a major role as scavengers in the perivascular spaces of the rat brain. This role reflects the importance of perivascular spaces as drainage pathways for soluble and insoluble material from the brain.

Animals↗
PubMed1993

Assessment of neurological injury due to circulatory arrest during profound hypothermia. An experimental study in vertebrates.

To investigate brain changes in induced deep core hypothermia (15 degrees C) with circulatory arrest, five groups of neonatal pigs were subjected to cardiopulmonary bypass (CPB), with circulatory arrest (CA) periods varying from 70-120 min. The parameters analysed were: 1. Histology and electron microscopy of the brain six hours post-CPB, 2. Creatinophosphokinase (CPK) from cerebrospinal fluid (CSF), 3. Vasointestinal neuropeptide (VIP) and 7B2 specific neuropeptide both in plasma and brain tissue. The earliest morphological changes were seen after 90 min CA and were highly significant after 120 min arrest. These changes involved mainly the Purkinje cells of the interior half of the cerebellum with vacuolation in their cytoplasm. A rise in CPK in CSF occurred in all piglet-groups. The differences among the various groups were highly significant at 2 and 5 h post-CPB. (P < 0.05). Statistically significant differences were not exhibited among the various groups both in serum and brain tissue total mean values of VIP and 7B2 neuropeptides. We suggest that 1. The cerebellar region is the most sensitive where ischemic lesions attain their maximal severity and extent; the frequency and pattern of selective vulnerability of the cerebellum may be related primarily to its pattern of blood supply 2. The maximum time of CA without histopathological sequelae should not exceed 70 min.

Anesthesia, General↗
PubMed1993

Neurocytoma/lipoma (neurolipocytoma) of the cerebellum.

We describe a unique tumour that was removed from the posterior fossa of a woman aged 50 years. It was characterized histologically by bland, oval cells with fibrillary cytoplasm and by small groups of lipocytes. Immunocytochemical studies demonstrated expression of synaptophysin, neuron specific enolase and PGP 9.5, but a few cells also expressed glial fibrillary acidic protein and desmin. The combination of neuroectodermal and mesodermal features in this tumour is discussed in relation to primitive neuroectodermal tumours and neurocytoma.

Cerebellar Neoplasms↗
PubMed1993

CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance.

Cerebrospinal fluid (CSF) drainage pathways from the rat brain were investigated by the injection of 50 microliters Indian ink into the cisterna magna. The distribution of the ink, as it escaped from the cranial CSF space, was documented in 2 mm thick slices of brain and skull cleared in cedar wood oil and in decalcified paraffin sections. Following injection of the ink, deep cervical lymph nodes were selectively blackened within 30 min and lumbar para-aortic nodes within 6 h. Within the cranial cavity, carbon particles accumulated in the basal cisterns but were also distributed in the paravascular spaces around the middle cerebral arteries and the nasal-olfactory artery. Carbon particles in the subarachnoid space beneath the olfactory bulbs drained directly into discrete channels which passed through the cribriform plate and into lymphatics in the nasal submucosa. Although ink was distributed along the subarachnoid space of the optic nerves and entered the cochlea, the nasal route was the only direct connection between cranial CSF and lymphatics. Arachnoid villi associated with superior and inferior sagittal sinuses were identified and a minor amount of drainage of ink into dural lymphatics was also observed. This study demonstrates the direct drainage of cerebrospinal fluid through the cribriform plate in anatomically defined channels which connect with the nasal lymphatics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Neuropathological features of profoundly hypothermic circulatory arrest: an experimental study in the pig.

Twenty-four neonatal pigs were exposed to periods of circulatory arrest of between 70 and 120 min under profound hypothermia at 15 degrees C. Brain tissue taken 6h after cardiopulmonary bypass was examined histologically and by electron microscopy for evidence of hypoxic damage. Specimens from control pigs and animals subjected to 70 min arrest showed no morphological changes in the cerebral or cerebellar neurones. The earliest changes were seen after 90-min arrest; these were highly significant after 120 min. The changes involved mainly the Purkinje cells of the cerebellum with vacuolation in the cytoplasm; the inferior half of the cerebellum was particularly affected. The frequency and pattern of selective vulnerability of the cerebellum may be related primarily to the nature of its blood supply.

Animals↗
PubMed1993

Brain damage after profoundly hypothermic circulatory arrest: correlations between neurophysiologic and neuropathologic findings. An experimental study in vertebrates.

Five groups of neonatal pigs were subjected to cardiopulmonary bypass with circulatory arrest periods that varied from 70 to 120 minutes for the investigation of brain changes in induced deep-core hypothermia (15 degrees C) with circulatory arrest. The parameters that were analyzed were (1) microscopy of the brain in animals at 6 hours after bypass procedures and (2) intraoperative monitoring of somatosensory evoked potentials. Microscopic cellular damage appeared in all animals with a circulatory arrest period of more than 70 minutes. These changes involved mainly Purkinje's cells of the cerebellum, and they affected particularly the inferior half of the cerebellum. The prolongation of latency in the cortical responses, which reflects a slowing of the neural transmission with hypothermia, occurred in all animals. The late evoked potentials remained absent in all piglets with circulatory arrest periods of 90, 105, and 120 minutes, but they were fully recovered in all piglets of the control group and those with 70-minute arrest times. We concluded that the cerebellar region is the most sensitive site in which ischemic lesions attain their maximal severity and extent, and the maximum time of circulatory arrest without histopathologic and neurophysiologic sequelae should not exceed 70 minutes.

Animals↗
PubMed1992

Expression of the p53 protein in a spectrum of astrocytic tumours.

Many human cancers are characterized by mutations of p53, a nuclear phosphoprotein which controls elements of the cell cycle. Turnover of p53 in normal cells is rapid, and the minute quantities of protein that are usually present are not detected by immunocytochemical methods. Mutations of the p53 gene in tumour cells are associated with a slower turnover and subsequent accumulation of the protein in both nucleus and cytoplasm. Genetic abnormalities of the short arm of chromosome 17, which is the site of the p53 gene locus, are a feature of astrocytic tumours. Using a panel of five antibodies to p53 and a standard immunocytochemical method, we found detectable quantities of p53 in the cells of 3/16 diffuse astrocytomas, 8/14 anaplastic astrocytomas, and 24/34 glioblastoma multiforme. Progression of one patient's tumour from a diffuse to an anaplastic astrocytoma was characterized by the accumulation of p53. The more malignant histological features of anaplastic astrocytoma and glioblastoma multiforme appear to be reflected by a greater incidence of p53 accumulation.

Astrocytoma↗
PubMed1992

Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain.

Pathways for drainage of interstitial fluid and cerebrospinal fluid from the rat brain were investigated by the injection of 2-5 microliters Indian ink into cerebral white and grey matter and into the subarachnoid space over the vertex of the left frontal lobe. Animals were killed by formalin or glutaraldehyde perfusion 5 min-2 years after injection, and the distribution of ink over the surface of the brain, in 2-mm slices of brain cleared in cedar wood oil, in paraffin sections and by electron microscopy was documented. These investigations showed that carbon particles were distributed diffusely through the interstitial spaces of the white matter whereas they spread selectively along perivascular spaces in the grey matter outlining both arteries and veins and extending to surround capillaries within 1 h. Carbon particles were rapidly ingested by perivascular cells and, to some extent, by meningeal cells surrounding the larger vessels. Very little movement of carbon-labelled perivascular cells and perivascular macrophages was seen after 2 years. Carbon particles entering the subarachnoid space over the vertex of the cerebral hemispheres drained along selected paravascular and subfrontal pathways in the subarachnoid space to the cribriform plate and thence into nasal lymphatics and cervical lymph nodes. These studies demonstrate the diffuse spread of fluidborne tracers through cerebral white matter in the rat, the perivascular spread of tracer in grey matter and the compartmentalised directional flow or tracer through the subarachnoid space to the cribriform plate and nasal lymphatics. Furthermore, particulate matter selectively injected into perivascular spaces in rat grey matter is rapidly and efficiently ingested by perivascular cells.

Animals↗
PubMed1992

Grading of brain tumours. The British experience.

In order to ascertain how widely the Kernohan and WHO numerical grading systems for brain tumours are used in Britain and how uniformly they are applied, a questionnaire was circulated to named neuropathologists in 19 Regional Neuropathology Centres in Britain. Eighty four per cent replied within 10 days. Their replies showed considerable variation in the use of grading systems and revealed that numerical grading was required mainly by clinicians and was not necessarily favoured by pathologists. Although some advantages of a grading system were advanced, it does seem that numerical grading of brain tumours is ill-defined and controversial. Furthermore, the use of historical grading systems may inhibit the incorporation of advances in pathological investigation into the clinical management of patients with brain tumours.

Astrocytoma↗
PubMed1992

Effects of ethanol and various alcoholic beverages on the formation of O6-methyldeoxyguanosine from concurrently administered N-nitrosomethylbenzylamine in rats: a dose-response study.

Consumption of alcoholic beverages has been identified as a major cause of oesophageal cancer in industrialized countries, with an exceptionally high risk associated with apple-based liquors (calvados). In the present study, we have determined the dose--activity relationship of the effects of coincident ethanol on the formation of O6-methyldeoxyguanosine (O6-MEdG) by the oesophageal carcinogen N-nitrosomethylbenzylamine (NMBzA). Male Fischer 344 rats received a single intragastric dose of NMBzA (2.5 mg/kg body wt; 7.4 ml/kg body wt) in tap water containing 0-20% ethanol (v/v). Survival time was 3 h. In controls, concentrations of O6-MEdG were similar in oesophagus, lung and liver (11-14.9 mumol/mol dG). In oesophagus, coincident ethanol increased levels of O6-MEdG from 15.2 mumol/mol (0.1% ethanol) to 46.0 mumol/mol (20%). This increase was dose dependent for 1-20% ethanol; however, low doses produced a larger effect per gram of ethanol than higher doses. In lung, concentrations of O6-MEdG increased from 11 mumol/mol (0.1%) to a plateau value of 24 mumol/mol (greater than or equal to 5%). In nasal mucosa, an increase in O6-MEdG from 3.9 mumol/mol (controls) to 30.7 mumol/mol was observed with 4% ethanol. Effects of ethanol on hepatic DNA methylation were statistically non-significant. Modulation of NMBzA bioactivation by various alcoholic beverages (adjusted to 4% ethanol) was also investigated. Increases in oesophageal O6-MEdG were similar (+50% to +116%) with pear brandy, rice wine (sake), farm-made calvados, gin, Scotch whisky, white wine, Pilsner beer and aqueous ethanol. Significantly higher increases were elicited by commercially distilled calvados (+125%) and red burgundy (+162%). In contrast to its effects at an ethanol content of 4%, farm-made calvados diluted to 20% ethanol produced significantly higher (+200%) increases in oesophageal DNA methylation than aqueous ethanol (+148%). Our results show that ethanol is an effective modulator of nitrosamine bioactivation in vivo at intake levels equivalent to moderate social drinking, and that some alcoholic beverages contain congeners that amplify the effects of ethanol, suggesting that modulation of nitrosamine metabolism by acute ethanol may play a role in the etiology of human cancer.

Alcoholic Beverages↗