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Biomedical subjects

J McMahon

Publications and source records attributed to J McMahon.

At least 19 recordsLinked to original sources
PubMed1996

Expression of the myelin basic protein gene locus in neurons and oligodendrocytes in the human fetal central nervous system.

The myelin basic protein (MBP) gene locus is composed of two overlapping transcription units that share all of the MBP exons. One of these transcription units expresses the MBPs and the other expresses a family of proteins structurally related to the MBPs. This second transcription unit is called the Golli gene, and the entire complex is called the Golli-mbp gene. In this study, the expression of the Golli gene was examined in the human fetal central nervous system (CNS). By using reverse transcriptase-polymerase chain reaction cloning we have identified eight new members of the Golli gene family of transcripts expressed in the human CNS. Golli gene expression was examined by in situ hybridization and immunohistochemistry, and surprisingly, Golli products were found to be expressed in neurons as well as oligodendrocytes. Furthermore, the subcellular distribution of Golli immunoreactivity in fetal spinal cord interneurons shifted between the various laminae. Golli protein was localized within the nuclei of interneurons in the posterior horn, but was found in the cell bodies and processes of interneurons in the anterior horn. Within oligodendrocytes, Golli protein was detected in the cell bodies and processes, including processes which were wrapping axonal segments. Golli mRNA expression was also observed in neurons within the cerebral cortex between 18 and 20 weeks postconception, prior to myelination of this brain region. During this period, there was a striking developmental increase in the numbers and in the locations of neurons expressing Golli mRNAs within the cortical plate. The diverse distribution of Golli proteins within neurons and oligodendrocytes indicates that their function is quite different from that of the MBPs to which they are closely related.

Antibodies↗
PubMed1996

Functional expression of human topoisomerase II alpha in yeast: mutations at amino acids 450 or 803 of topoisomerase II alpha result in enzymes that can confer resistance to anti-topoisomerase II agents.

DNA topoisomerase II is the target of a variety of important antitumor agents, including etoposide, adriamycin, and amsacrine. We have constructed a system for analyzing the action of anti-topoisomerase II agents using the yeast Saccharomyces cerevisiae and have constructed vectors for expressing human topoisomerase II functionally in yeast. We have demonstrated that temperature-conditional yeast TOP2 mutants can be complemented by expression of wild-type human topoisomerase II alpha. Furthermore, expression of human topoisomerase II in yeast results in a quantitatively unique pattern of sensitivity to amsacrine. We also have constructed mutations in human TOP2 based on previously identified mutations from a human cell line selected for resistance to teniposide. Our experiments demonstrate that mutation of either arginine 450 or proline 803 of human topoisomerase II can result in an enzyme that has altered sensitivity to anti-topoisomerase II agents, and that a human enzyme carrying both mutations confers a higher level of drug resistance than enzymes carrying either single mutation.

Alleles↗
PubMed1996

The use of microwave irradiation as a pretreatment to in situ hybridization for the detection of measles virus and chicken anaemia virus in formalin-fixed paraffin-embedded tissue.

Microwave irradiation was investigated as a pretreatment to in situ hybridization on formalin-fixed, paraffin-embedded tissue. Two probe/tissue systems were used: a single-stranded RNA probe for the detection of measles virus nucleocapsid genome in subacute sclerosing panencephalitis brain tissue, and a double stranded DNA probe for chicken anaemia virus in thymus of chicken infected with the virus. Microwaving, when used as sole pretreatment, was not as effective as the more traditional enzyme pretreatments for in situ hybridization. However, when used in combination with existing pretreatments, a significant increase was found in hybridization signal in both brain and thymus tissue. This was emphasized when combination enzyme/microwave pretreatments were used prior to detection of measles virus by in situ hybridization in a series of five archival subacute sclerosing panencephalitis cases. The use of microwave irradiation would be recommended as a means of supplementing in situ hybridization methods, especially when using long-term formalin fixed paraffin-embedded tissue.

Animals↗
PubMed1996

Expression of the myelin proteolipid protein gene in the human fetal thymus.

We have analyzed human fetal thymus and spleen for expression of the proteolipid protein (PLP) gene. We demonstrate that the PLP gene is transcribed in both tissues, and that both the PLP and DM-20 mRNAs are produced. Western blot analyses revealed that both the PLP and DM-20 protein isoforms were present in the fetal thymus and spleen. Immunohistochemical analyses indicated that the PLP/DM-20 proteins were detected in cells which have the distribution and morphology of thymic macrophages. These results provide further evidence that the PLP and DM-20 proteins are expressed in cell types other than myelin forming cells and possess function(s) unrelated to myelin structure. Furthermore, these data demonstrate that the PLP and DM-20 proteins are not shielded from the immune system behind the blood-brain barrier. These observations directly impinge upon the debate concerning acquisition of tolerance and the recognition that the encephalitogenic nature of PLP in diseases, such as Multiple Sclerosis, may not simply be related to its 'sequestration' from a 'naive' immune system.

Alternative Splicing↗
PubMed1996

A comparison of positive and negative alcohol expectancy and value and their multiplicative composite as predictors of post-treatment abstinence survivorship.

Within social learning theory, positive alcohol expectancies represent motivation to drink and negative expectancies, motivation to restrain. It is also recognized that a subjective evaluation of expectancies ought to moderate their impact, although the evidence for this in social drinkers is problematic. This paper addresses the speculation that the moderating effect will be more evident in clinical populations. This study shows that (i) both expectancy and value reliably, independently and equally predict clients' abstinence survivorship following discharge from a treatment programme (and that this is almost entirely confined to the negative rather than positive terms). When (ii) expectancy evaluations are processed against expectancy through multiplicative composites (i.e. expectancy x value), their predictive power is only equivalent to either expectancy or value on its own. However (iii) when the multiplicative composite is assessed following the statistical guidelines advocated by Evans (1991) (i.e. within the same model as its constituents, expectancy and value) the increase in outcome variance explained by its inclusion is negligible and casts doubt upon its use in alcohol research. This does not appear to apply to value, however, and its possible role in treatment is discussed.

Adult↗
PubMed1996

The significance of measles virus antigen and genome distribution in the CNS in SSPE for mechanisms of viral spread and demyelination.

The distribution of measles virus (MV) antigen and genomic RNA in the central nervous system (CNS) in 10 cases of subacute sclerosing panencephalitis (SSPE) was determined using optimized immunocytochemistry and in situ hybridization techniques. As in previous reports neurons and oligodendrocytes were found to be the most frequently infected cells. It was confirmed that MV infection in neuronal processes was predominantly dendritic but there was also some evidence suggestive of occasional axonal involvement, a finding confirmed by electron microscopy. In addition MV genomic RNA was detected in neuronal processes, in some cases in the absence of demonstrable MV antigen. The relationship between myelin destruction and oligodendrocytic infection suggested that the demyelination may be solely the result of virus infection. A possible correlation between viral distribution and form and the clinical duration of disease was examined. Viral antigen and genome were equally abundant in the cerebral cortex in most short duration cases (<6 months). However, in two of these cases viral RNA but not antigen was detected in the spinal cord. In long duration cases (>36 months) viral RNA was abundant in all areas of the CNS examined, frequently in the absence of demonstrable antigen. These findings may suggest viral spread in a cephalo-caudal direction, probably by transneuronal spread.

Child↗
PubMed1996

Changes in alcohol expectancies during treatment relate to subsequent abstinence survivorship.

When negative alcohol expectancies are measured appropriately they form at least as secure associations with measures of consumption as has been demonstrated by mainstream expectancy research for positive alcohol expectancies and they can be usefully used to represent a component of motivation to restrain consumption or recover in dependent drinkers. A study is reported in which (i) negative outcome expectancies assessed at admission to treatment reliably predicted number of days to first drink; (ii) the same relationship is discovered for discharge measures (iii) and, although the change is negative expectancies between admission and discharge does not, itself, predict the number of days to first drink, it does when the corresponding admission measure is also taken into account. The same predictive relationships were not found for positive expectancies. Implications for planning treatment are discussed in terms of treatment enhancement rather than treatment matching.

Adult↗
PubMed1996

The expression of the endothelial cell antigen CD34 in demyelinating disease.

In this study, the antigenic expression of CD34, a 110 kDa glycoprotein which is expressed on human haemopoietic progenitor cells and vascular endothelium, has been assessed in a variety of neuropathological conditions, including infectious and demyelinating disease. Using immunoperoxidase staining on paraffin sections, the immunohistochemical results show that CD34 antigen is expressed widely on human CNS endothelium in grey and white matter, in the eye including retina, and in the anterior and posterior lobes of the pituitary. In demyelinating disease CD34 antigen expression was not detected in acute lesions, whereas strong expression was observed in old lesions. CD34 endothelial positivity was observed in areas of gliosis, vasogenic oedema, vascular disease and in Alzheimer's and Parkinson's disease pathology. A general pattern emerged, with CD34 antigen reactivity predominantly negative in areas of inflammation with demyelination but positive in adjacent non-inflamed tissue, irrespective of myelin pathology. We conclude that perivascular inflammation is a key factor in the absence of immunoreactivity of CD34 in the CNS in demyelinating disease.

Antigens, CD34↗
PubMed1996

Quinidine-induced pigmentation.

Antimalarial agents have long been known to cause a variety of pigmentary disturbances. Quinidine, a cincha alkaloid and D-isomer of quinine, is widely used for the treatment of ventricular arrhythmias. A paucity of literature, however, exists concerning quinidine-associated hyperpigmentation. We describe a case of focal ceruloderma we believe to be secondary to quinidine therapy.

Anti-Arrhythmia Agents↗
PubMed1995

Microwave antigen retrieval for immunocytochemistry on formalin-fixed, paraffin-embedded post-mortem CNS tissue.

Microwave antigen retrieval methods were assessed for a panel of antibodies on formalin-fixed, paraffin-embedded sections from a range of human central nervous system (CNS) tissues taken at post-mortem. The immunoreactivity of a number of antigens (synaptophysin, PGP9.5, GFAP, carbonic anhydrase II, CD68, ferritin, HLA-DR, alpha beta-crystallin, measles and herpes viruses) was markedly enhanced by this procedure compared with other methods of antigen unmasking, such as trypsinization. Enhancement was noted both by an increased number of positive cells and by the intensity of reactions within individual cells and their processes. Furthermore, the microwave method produced uniform immunostaining over large surface area sections with no loss of morphological detail. Large cryostat sections of CNS tissue can be difficult to obtain with good morphology. The ability to retrieve a wide range of antigen in formalin-fixed, paraffin-embedded CNS tissue will greatly increase the range of investigations that can be carried out on this type of stored material.

Antigens↗
PubMed1995

beta-Endorphin enhances the replication of neurotropic human immunodeficiency virus in fetal perivascular microglia.

The effect of an endogenous opiate, beta-endorphin, on the replication of HIV was investigated in brain perivascular microglia. Beta-endorphin enhanced the synthesis of p-24 antigen and transactivation of HIV promoter. Dialysed culture supernatants of endorphin-treated microglia re-activated latent HIV infection. These culture supernatants showed elevated levels of interleukin-1 beta, IL-6 and tumor necrosis factor alpha. Sub-optimal concentration of beta-endorphin potentiated GP-120-induced synthesis of these cytokines. Nalaxone reversed beta-endorphin-induced, but not GP-120-induced, cytokine production and enhanced HIV replication. These results suggest that endogenous opiates may contribute to the progression of AIDS dementia complex.

Cytokines↗
PubMed1995

A comparison of digoxigenin and biotin labelled DNA and RNA probes for in situ hybridization.

A number of in situ hybridization protocols using digoxigenin or biotin labelled probes were assessed for viral nucleic acid detection in formalin fixed, paraffin embedded tissue. Single-step detection protocols for biotin labelled probes produced low sensitivity; however, enzyme based one-step detection protocols for digoxigenin probes produced high sensitivity for both RNA and DNA systems. For both probe types, multistep detection protocols produced equally high sensitivity. Use of an enhanced APAAP procedure for digoxigenin labelled probes achieved maximal sensitivity without use of biotin-strep-tavidin reactions. The sensitivity of nucleic acid detection obtained with a digoxigenin labelled probe is comparable to that obtained using biotin. Digoxigenin labelled probes for nucleic acid detection are recommended for tissues with endogenous biotin.

Animals↗
PubMed1994

Mineralizing pulmonary elastosis in chronic cardiac failure. "Endogenous pneumoconiosis" revisited.

The histopathology, ultrastructure, and clinicopathologic correlations in six patients with cardiac failure and iron encrustation of lung elastic tissue were examined at autopsy. Transmission electron microscopy (TEM) and energy dispersive x-ray analysis were applied to two cases. Of the group, five patients had cardiac failure due to systemic hypertension (4 patients), valvular disease (4 patients), or coronary atherosclerosis (4 patients). Biventricular failure in one patient was associated with sleep apnea. Both iron and calcium, identified by histochemical stains, impregnated degenerated alveolar and vascular elastic fibers and were associated with a foreign body reaction and focal interstitial fibrosis. Energy dispersive x-ray analysis and TEM demonstrated iron and calcium on the microfibrillar portion of elastin. Morphometry indicated vascular changes of pulmonary venous hypertension. The authors concluded that mineral deposition probably represents nonspecific precipitation of metallic ions on altered elastic fibers in patients with cardiac failure. "Mineralizing elastosis" potentially contributes to lung restriction and, occasionally, can be a source of diagnostic confusion.

Adult↗
PubMed1994

Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome.

Forty-nine individuals have been identified with deletions or translocations involving the short arm of chromosome 5. While most display the classical phenotype of the cri-du-chat syndrome, several of the patients do not have the syndrome or have only a subset of the clinical features. Somatic cell hybrids containing the deleted chromosome 5 were derived from each patient. Each somatic cell hybrid was analyzed at the DNA level using 136 chromosome 5p-specific DNA fragments. It was possible to unambiguously order most of the chromosomal breakpoints present in the somatic cell hybrids based on the hybridization patterns of Southern blots. Further comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved the high-pitched cry mapped to 5p15.3, while the chromosomal region involved in the remaining features of the cri-du-chat syndrome mapped to a small region within 5p15.2. Deletions that did not include these two chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype. These results demonstrate the need for careful characterization of a 5p deletion in prenatal cases before clinical predictions are made.

Animals↗
PubMed1994

Negative alcohol expectancy predicts post-treatment abstinence survivorship: the whether, when and why of relapse to a first drink.

Using survival analysis, the association was explored between positive and negative alcohol expectancies measured on admission to a non-residential alcohol dependence treatment unit and post-treatment relapse to a first drink (first slip). A reliable association between negative alcohol expectancy (but not positive) and relapse was found. The active negative alcohol expectancies were distal rather than proximal: proximal expectancies surround consumption ('same day' expectancies) and distal expectancies relate to the 'next-day' following consumption or those longer term expectancies coming from 'continued drinking'. Only the 'next day' component of distal expectancies formed a reliable association with relapse. The use to which negative alcohol expectancy as measured by the Negative Alcohol Expectancy Questionnaire might be put is discussed in terms of (i) a bottom-up representation of motivation for recovery to help treatment match and (ii) a provisor of detailed, client-specific information for structuring motivational interventions.

Adult↗
PubMed1994

Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: a combined in situ hybridization and immunocytochemical investigation.

Neurofibrillary tangle formation, a cardinal characteristic of Alzheimer's disease, is also a feature of several other neurodegenerative disorders, including subacute sclerosing panencephalitis (SSPE). In the present study the association of measles virus genome with neurofibrillary tangle formation has been studied in five cases of SSPE, using in situ hybridization (measles genome) and immunocytochemistry (tau, ubiquitin and beta/A4 amyloid). In two cases with duration of disease less than one year, neurofibrillary tangle formation was not observed. However, in those cases in which the disease was of several years duration, numerous tau- and ubiquitin-positive neurofibrillary tangles were demonstrated. In the two cases of longest duration, double-labelling techniques demonstrated the frequent association of neurofibrillary tangle formation with neuronal measles virus genome positivity. Immunocytochemistry for beta/A4 amyloid failed to demonstrate amyloid in any of the five cases. These findings support the hypothesis that neurofibrillary tangle formation can occur independently of amyloid formation and that this mechanism may operate in both Alzheimer's disease and in virally-induced disease.

Adolescent↗
PubMed1994

Negative and positive alcohol expectancies as predictors of abstinence after discharge from a residential treatment program: a one-month and three-month follow-up study in men.

Male alcohol dependent clients (N = 53), who were given the Alcohol Expectancy Questionnaire and the Negative Alcohol Expectancy Questionnaire upon admission to a residential alcohol treatment program, were successfully followed-up 1 month and 3 months after discharge to assess their compliance with the treatment goal of total abstinence. At 1 month, neither demographic variables nor alcohol expectancies were associated with outcome consumption. At 3 months, however, the demographic variable, age, total negative expectancy (but not total positive) and the two subscales, global positive expectancy and continued-drinking negative expectancy (representing longer term expected negative consequences), were. The potential importance of negative alcohol expectancy in drinking decisions and the limitations of the study were identified.

Adult↗