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Biomedical subjects

J E Bell

Publications and source records attributed to J E Bell.

At least 73 records · Page 4Linked to original sources
PubMed1996

Objective quantification of prion protein in spinal cords of cases of Creutzfeldt-Jakob disease.

A recent investigation into prion protein (PrP) deposition in cases of Creutzfeldt-Jakob disease (CJD) has suggested that the spinal cord is affected in some cases of this disease. In an attempt to measure this phenomenon we have used quantitative image analysis techniques to assess the amount of PrP deposited in the spinal cords of three different cases of CJD. By using an automatic method of image intensity threshold setting we have measured the tissue area occupied by PrP in a non-subjective manner. The ranking of these different cases has confirmed that suggested by visual inspection. This analysis shows a substantial variation in the quantity of PrP positivity observed when a panel of different PrP antibodies was compared, confirming early findings. The distribution of PrP across the spinal cord has also been mapped using the image analysis system.

Antibody Specificity↗
PubMed1995

Prion protein accumulation in the spinal cords of patients with sporadic and growth hormone associated Creutzfeldt-Jakob disease.

An immunohistological study of the spinal cord in 20 cases of sporadic and 4 iatrogenic (growth hormone) cases of Creutzfeldt-Jakob (CJD) disease patients was performed to detect the presence of disease specific prion protein using a number of different antisera. Prion protein was present in all the growth hormone recipients and in 11 of the 20 sporadic CJD cases. Plaque-like deposits of prion protein were found in all the growth hormone cases and three of the sporadic cases. This is the first demonstration of the topographic immunolocalisation of prion protein in the spinal cord of CJD patients, a feature which could help elucidate some important aspects of the pathogenesis of CJD.

Antibodies↗
PubMed1995

Spinal tract pathology in AIDS: postmortem MRI correlation with neuropathology.

Vacuolar myelopathy (VM) and tract pallor are poorly understood spinal tract abnormalities in patients with the acquired immunodeficiency syndrome (AIDS). We studied the ability of magnetic resonance imaging (MRI) to detect these changes in spinal cord specimens postmortem and whether criteria could be formulated which would allow these conditions to be differentiated from other lesions of the spinal cord in AIDS, such as lymphoma, cytomegalovirus (CMV) and human immunodeficiency virus (HIV) myelitis. We imaged 38 postmortem specimens of spinal cord. The MRI studies were interpreted blind. The specimens included cases of VM myelin pallor, CMV myeloradiculitis, HIV myelitis, lymphoma as well as normal cords, both HIV+ve and HIV-ve. MRI showed abnormal signal, suggestive of tract pathology, in 10 of the 14 cases with histopathological evidence of tract changes. The findings in VM and tract pallor on proton-density and T2-weighted MRI were increased signal from the affected white-matter tracts, present on multiple contiguous slices and symmetrical in most cases. The pattern was sufficiently distinct to differentiate spinal tract pathology from other spinal cord lesions in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV-1-positive patients.

Human immunodeficiency virus (HIV)-1-associated dementia is a frequent consequence of HIV infection and is associated with neuronal deficits. Increased concentrations of the kynurenine pathway metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) may contribute to this neuronal damage. We measured 3-HK concentrations and the activity of its catabolising enzyme, 3-hydroxykynureninase, in postmortem brain tissue from eight controls and 32 HIV-positive patients, including a group that exhibited dementia. 3-HK concentrations were significantly increased (over threefold) in the HIV-positive group when compared with controls. This increase was greater in those patients with dementia, but it was still apparent in the nondemented cases. 3-Hydroxykynureninase activity was significantly increased in the HIV-infected group compared with the control values. The effect was apparent in both nondementia and dementia cases, although the latter showed a slightly greater increase. The 3-HK content increase is thus unrelated to a reduction in activity of this enzyme and is likely to reflect an overall increase in the kynurenic metabolic pathway. Elevated levels of the neurotoxin 3-HK may contribute to the neuronal deficits underlying HIV-associated dementia.

AIDS Dementia Complex↗
PubMed1995

A review of endocarditis in acquired immunodeficiency syndrome and human immunodeficiency virus infection.

Non-bacterial thrombotic endocarditis (NBTE) was frequently identified in early post-mortem studies of patients with HIV infection, but has not been reported since 1989. The reason for this apparent decline is not clear, but it is possible that the prevalence of the condition was overestimated in the past. We have found no evidence of NBTE in our series of 110 autopsies on subjects from all major risk groups and at various stages of immune deficiency [intravenous drug user (IVDU)-AIDS 35% (39/110), IVDU-pre AIDS 36% (40/110), homosexual-AIDS 25% (28/110), blood product recipients-AIDS 1.8% 2/110), African 0.9% (1/110)]. Infective endocarditis (IE) in HIV infection occurs almost exclusively in intravenous drug users and is rare in other HIV-positive patients. However, asymptomatic HIV infection appears to have little effect on the susceptibility to or the mortality from endocarditis and it is, therefore, appropriate to institute antimicrobial treatment in these cases. The majority (54.4%) of the 960 HIV-positive individuals in the Lothian region of Scotland are young adults who contracted the virus through IVDU around 1983. However, a prospective echocardiological study of 269 patients over four years (IVDU 69%, homosexual 18%, heterosexual 8%, bisexual 3%, multiple risk factors 1%) has demonstrated only four cases of infective endocarditis. We believe this reflects the prevalence of current parenteral drug use in our cohort which has fallen with the introduction of an oral drug replacement programme.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Opportunistic Infections↗
PubMed1994

Redistribution of HIV outside the lymphoid system with onset of AIDS.

The basis for many of the symptoms and pathological changes found in patients with the acquired immunodeficiency syndrome (AIDS) remains poorly understood. We have used a quantitative polymerase chain reaction technique to investigate the extent to which direct infection with human immunodeficiency virus (HIV) produces the disease manifestations of AIDS. In five patients who died with AIDS-defining illnesses (Centers for Disease Control and Prevention class IV), we found variable, but in many cases extensive, infection by HIV at various sites, including brain, lung, colon, and liver. By contrast, in three HIV-positive subjects who died without HIV-related disease (CDC class II), we found no evidence of significant infection of any non-lymphoid organ. In both groups of patients there were high levels of infection in cells of the spleen, lymph nodes, and peripheral blood. Pathological examination of tissues from the AIDS patients revealed many abnormalities, of which some, such as giant-cell encephalitis in the brain, were specifically associated with the presence of high levels of HIV infection. These findings suggest that spread of HIV outside cells of the immune system is a late event in HIV infection and is extremely sensitive to the degree of immunosuppression in the patient.

Acquired Immunodeficiency Syndrome↗
PubMed1994

CNAD: a potent and specific inhibitor of alcohol dehydrogenase.

CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric and isomeric analogue of NAD, in which the nicotinamide ring is linked to the sugar via a C-glycosyl (C5-C1') bond. CNAD acts as a general dehydrogenase inhibitor but shows unusual specificity and affinity for liver alcohol dehydrogenase (ADH, EC 1.1.1.1). The pattern of inhibition is congruent to 4 nM, with NAD as the variable substrate. These values are 3-5 orders of magnitude smaller than those obtained for CNAD in other dehydrogenases and are comparable to values observed for the tightest binding ADH inhibitors known. The specificity and affinity of CNAD for ADH are likely due to coordination of the zinc cation at the ADH catalytic site by the CNAD pyridine nitrogen. This is supported by kinetic and computational studies of ADH-CNAD complexes. These results are compared with those for a related analogue, CPAD. In this analogue, displacement of the pyridine nitrogen to the opposite side of the ring removes the specificity for ADH.

Alcohol Dehydrogenase↗
PubMed1994

Antenatal detection of neural tube defects: comparison of biochemical and immunofluorescence methods.

The aim of this study was to determine whether identification of glial cells in amniotic fluid samples could form a useful supplementary test in the antenatal diagnosis of neural tube defects (NTDs). In a 5-year study, 1452 samples of middle trimester amniotic fluid were examined blind to the results of other antenatal diagnostic tests and to the outcome of pregnancy. Reason of amniocentesis included raised serum alpha-fetoprotein (329), previous NTD (73), and a family history of NTDs (71). Duplicate cytospin preparations were stained with Giemsa and an antibody to glial fibrillary acidic protein (GFAP), and on this basis a prediction of fetal NTD status was made which was not communicated to clinicians. Subsequent management of pregnancies was influenced only by the results of routine antenatal testing for NTDs. Twenty cases of NTDs occurred among the 1406 cases in which the outcome was subsequently known. Of these 20 cases, only five (four anencephalic, one spina bifida) were correctly predicated by immunofluorescent identification of GFAP-positive cells in the amniotic fluid. The remaining 15 cases (two anencephalic, 13 spina bifida) were not so identified. In a further 18 cases, apparently GFAP-positive cells were identified in the absence of NTDs. We conclude that GFAP immunofluorescence examination of routine amniocentesis samples of amniotic fluid is not a useful predictive test for NTDs.

Acetylcholinesterase↗
PubMed1994

Immunohistochemical localisation of glucose-6-phosphatase in developing human kidney.

The objective of our study was to determine the cellular localisation of glucose-6-phosphatase in developing human kidney using monospecific antiserum and a standard immunohistochemical method (peroxidase-antiperoxidase, PAP) on formalin fixed and paraffin embedded tissue. In embryonic and early fetal development of the metanephric kidney, glucose-6-phosphatase is located primarily in derivatives of the ureteric bud such as the pelvis, calyces and collecting ducts. In mid-fetal life as nephrons evolve and develop they become increasingly immunoreactive to glucose-6-phosphatase, such that in mature metanephric kidney the proximal tubules are highly reactive for glucose-6-phosphatase with other elements of the nephron also immunopositive albeit at lower reactivities. In addition the parietal layer of Bowman's capsule and some cells of the visceral layer are immunopositive. Only with the development of nephrons does the early predominance of glucose-6-phosphatase immunoreactivity to ureteric bud derivatives change: in mature kidney the reactivity in the collecting ducts is a small proportion of the total. In proximal tubular cells the distribution of glucose-6-phosphatase immunoreactivity is relatively uniform throughout development in contrast to collecting ducts where in fetal life this reactivity is displaced to the apices and basal areas by intracellular glycogen deposits. The mesonephric kidney has a similar pattern of glucose-6-phosphatase immunoreactivity to that of metanephric kidney. The availability of monospecific antiserum to glucose-6-phosphatase and immunohistochemical methods now allows an alternative approach to cellular localisation. Many of the difficulties in the fixation of tissue and assay of glucose-6-phosphatase activity inherent in conventional histochemical methods are avoided by such methods.

Female↗
PubMed1994

Prion protein immunocytochemistry: reliable protocols for the investigation of Creutzfeldt-Jakob disease.

Current criteria for the histological diagnosis of Creutzfeldt-Jakob disease (CJD) include features such as spongiform change, neuronal loss and reactive gliosis which are shared to a varying extent with other neuro-degenerative disorders. Reliable visualization of prion protein (PrP) has substantial potential value in diagnostic practice and as a research tool, since accumulation of the disease-associated isoform of this protein is apparently specific for spongiform encephalopathies. A number of antisera against PrP have previously been employed in conjunction with a range of pre-treatments designed to optimize the specificity of immunostaining; such varied usage makes the comparison and interpretation of results difficult. This study was undertaken to identify optimal combinations of each of three PrP antisera and five pre-treatments designed to specifically demonstrate disease-specific PrP in a series of seven CJD cases, six cases of Alzheimer-type dementia and six non-demented control cases. Specific staining of amyloid plaques, spongiform neuropil, neurons and, occasionally, astrocytes was achieved in CJD cases. Alzheimer and control cases were unstained. Use of formic acid with guanidine thiocyanate, and hydrolytic autoclaving with IB3 and SP30 antisera proved most effective and can be recommended for future immunocytochemical studies. PrP immunocytochemistry revealed a greater extent of subcortical neural involvement than routine histological techniques in CJD; the relationship between classical neuropathology in CJD and PrP accumulation as revealed by immunocytochemistry is not clear cut and requires further investigation. These findings may help to broaden our understanding of human spongiform encephalopathies, and have implications for diagnostic practices in neuropathology.

Aged↗
PubMed1994

In vivo distribution and cytopathology of variants of human immunodeficiency virus type 1 showing restricted sequence variability in the V3 loop.

The distribution, cell tropism, and cytopathology in vivo of human immunodeficiency virus (HIV) was investigated in postmortem tissue samples from a series of HIV-infected individuals who died either of complications associated with AIDS or for unrelated reasons while they were asymptomatic. Proviral sequences were detected at a high copy number in lymphoid tissue of both presymptomatic patients and patients with AIDS, whereas significant infection of nonlymphoid tissue such as that from brains, spinal cords, and lungs were confined to those with AIDS. V3 loop sequences from both groups showed highly restricted sequence variability and a low overall positive charge of the encoded amino acid sequence compared with those of standard laboratory isolates of HIV type 1 (HIV-1). The low charge and the restriction in sequence variability were comparable to those observed with isolates showing a non-syncytium-inducing (NSI) and macrophage-tropic phenotype in vitro. All patients were either exclusively infected (six of seven cases) or predominantly infected (one case) with variants with a predicted NSI/macrophage-tropic phenotype, irrespective of the degree of disease progression. p24 antigen was detected by immunocytochemical staining of paraffin-fixed sections in the germinal centers within lymphoid tissue, although little or no antigen was found in areas of lymph node or spleen containing T lymphocytes from either presymptomatic patients or patients with AIDS. The predominant p24 antigen-expressing cells in the lungs and brains of the patients with AIDS were macrophages and microglia (in brains), frequently forming multinucleated giant cells (syncytia) even though the V3 loop sequences of these variants resembled those of NSI isolates in vitro. These studies indicate that lack of syncytium-forming ability in established T-cell lines does not necessarily predict syncytium-forming ability in primary target cells in vivo. Furthermore, variants of HIV with V3 sequences characteristic of NSI/macrophage-tropic isolates form the predominant population in a range of lymphoid and nonlymphoid tissues in vivo, even in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Stereotaxic brain biopsy in AIDS patients: does it contribute to patient management?

The authors analysed all cases of brain biopsy done in AIDS or HIV+patients at the Department of Clinical Neurosciences, Western General Hospital, Edinburgh, during the period 1989-92 to determine the clinical utility of the procedure. Thirteen lesions were biopsied revealing toxoplasmosis in five, lymphoma in four, progressive multifocal leucoencephalopathy in three, HIV encephalitis in two and encephalitis of unknown aetiology in one. One biopsy specimen contained abnormal tissue but was non-diagnostic. The median survival after biopsy was only 7 weeks, but preoperative immunological (median CD4 count 45) and clinical status of the patients were poor. Although the impact of tissue diagnosis on patient survival was minimal it did enable modification of drug therapy. The authors preliminary experience with biopsy in AIDS patients suggests that the diagnostic information obtained is of limited value in prolonging the lives of patients in poor immunological status, but may be useful in refining medical therapies for toxoplasmosis and progressive multifocal leucoencephalopathy. Whether biopsy should be performed earlier in the course of cerebral disease in an effort to prolong survival time remains unclear.

AIDS Dementia Complex↗
PubMed1993

Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide.

Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (11) and C-PAD (12), in which the nicotinamide riboside portion is replaced by a C-nucleoside, were synthesized from 5-(beta-D-ribofuranosyl)nicotinamide (7) and 6-(beta-D-ribofuranosyl)picolinamide (8), respectively. Nucleoside 7 was prepared from the 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-D-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported earlier. Nucleoside 8 was obtained by conversion of the bromo function of the 6-(2,3:4,5-di-O-isopropylidene-D-altro-pentitol-1-yl)-2-bromopyrid ine (14) into a carboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18. Treatment of 18 with CF3COOH/CHCl3 caused deisopropylidenation with simultaneous cyclization into the desired 6-(beta-D-ribofuranosyl)picolinamide (8). NAD analogues, C-NAD (11) and C-PAD (12), were synthesized by imidazole-catalyzed coupling of the corresponding 5'-monophosphates of 7 and 8 with the adenosine-5'-monophosphate. Dinucleotide 11 was found to inhibit the proliferation of L1210 cells (IC50 = 7 microM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 microM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 microM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, Ki = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (Ki = 20 microM) of ADH.

Alcohol Dehydrogenase↗
PubMed1993

Oral teratoma (epignathus) with intracranial extension: a report of two cases.

Epignathi are unusual congenital tumours presenting as oropharyngeal masses, often resulting in rapid asphyxia following birth. Occasionally, intracranial extension of the tumour is present, and two such cases are described. The presence of this complication, diagnosable by ultrasound examination, indicates that aggressive surgical treatment is inappropriate.

Abortion, Therapeutic↗