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Biomedical subjects

A Webster

Publications and source records attributed to A Webster.

At least 73 records · Page 4Linked to original sources
PubMed1991

Late BCNU lung: a light and ultrastructural study on the delayed effect of BCNU on the lung parenchyma.

We describe eight patients who developed interstitial pulmonary fibrosis following BCNU (carmustine) therapy for cerebral tumours. The fibrosis presented 12-17 (mean 14) years after exposure to the drug. A distinctive pattern of pulmonary fibrosis with involvement of the apices and subpleural areas was seen in one patient dying of the disease. Light microscopy showed interstitial elastosis and intra-alveolar fibrosis which was often focal with an associated mild lymphoplasmacytic infiltrate, intra-alveolar oedema, macrophages, and some neutrophils. Ultrastructural studies showed electron lucency of type I pneumocytes, with breaks in the cytoplasmic membranes leaving a bare basement membrane. Degenerative change was also seen in endothelial cell cytoplasm along with lipofuscin deposition. While BCNU pulmonary fibrosis has been described up to 2 years after treatment, this complication so late after therapy, though rare, has important implications for the follow-up of patients receiving this drug.

Astrocytoma↗
PubMed1991

Eliminating PCR contamination: is UV irradiation the answer?

The sensitivity of the polymerase chain reaction (PCR) can mean that even very low levels of contamination with the target DNA will result in a positive signal. At present this aspect is a major limitation in the use of PCR as a routine diagnostic method. By exposing PCR reagents to UV light, contaminating DNA can be inactivated, thus providing an opportunity to eradicate false positive reactions. UV irradiation was applied to PCR systems used for the detection of human cytomegalovirus (CMV) and human immunodeficiency virus (HIV) and shown to be effective in eradicating both laboratory encountered contamination and plasmid DNA (below 100 pg) added to PCR systems prior to UV exposure. The sensitivity of a PCR system to amplify the long terminal repeat (LTR) sequence of HIV-1 was not affected by the irradiation procedure; however, the ultimate sensitivity of a PCR system for the amplification of an early gene promotor sequence of the CMV genome was reduced 1000-fold. UV irradiation did not affect the size of the PCR product as determined by strand separating polyacrylamide gel electrophoresis of a 32P-labelled amplimer. Thus, a simple pre-exposure to UV light would seem a worthwhile step to incorporate into PCR protocols provided that the effects on sensitivity have been determined empirically for each PCR system.

Base Sequence↗
PubMed1991

Population dynamics of HIV within an individual after treatment with zidovudine.

A new mechanism is proposed for the apparent breakthrough of HIV that occurs approximately 6 months after the commencement of therapy with zidovudine (AZT). Using a simple mathematical model of the interacting population dynamics of HIV and its major host cell in the circulation (the CD4+ lymphocyte), predicted patterns of HIV plasma viraemia in the weeks following treatment with zidovudine are generated. These are in close agreement with observed patterns despite the fact that the model contains no mechanisms for the development of drug-resistant strains of virus. It is suggested that the patterns of viral abundance observed during the first 6 months after treatment may be the result of non-linearities in the interactions between HIV and CD4+ cells, and that it is only after the first post-treatment burst of viral production that drug resistance plays an important role.

AIDS-Related Complex↗
PubMed1991

p24 antigenaemia, CD4 lymphocyte counts and the development of AIDS.

A cohort of 111 HIV-infected haemophiliacs has been followed for up to 11 years, during which time 33 patients have been diagnosed with AIDS. Twenty-seven of the cohort developed detectable p24 antigenaemia while remaining free of AIDS. These patients experienced an increased risk of progression to AIDS compared with those patients who were persistently p24-negative (relative risk 7.24; P less than 0.0001, Cox proportional hazards model). The relative risk was reduced to 5.42 (P less than 0.0001) after adjustment for age and cytomegalovirus seropositivity. After adjustment for the patients' declining CD4 lymphocyte count during follow-up, the relative risk fell dramatically to 1.97 and became non-significant (P = 0.2). p24-antigenaemic patients tended to develop AIDS at levels of similar CD4 lymphocyte counts to those who were persistently p24-antigen-negative (median CD4 lymphocyte counts, 70 and 50 x 10(6)/l, respectively). These results suggests that the association between p24 antigenaemia and the rate of progression to AIDS can be explained largely by a more rapid decline in CD4 lymphocyte count among patients with p24 antigenaemia than in those without. The major pathological effects of increased plasma viral load, as detected by the presence or absence of p24 antigenaemia, appear to act via progressive CD4 lymphocyte depletion.

Acquired Immunodeficiency Syndrome↗
PubMed1991

More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts.

The tendency for older people with HIV infection to progress more rapidly to AIDS than younger people was studied in a group of 111 anti-HIV-positive haemophiliacs followed for up to 10 years from seroconversion. After 7 years of seropositivity, those aged over 30 years at the time of the first positive anti-HIV test had a cumulative progression rate to AIDS of 50%, compared with only 12% for those aged 10-19 years (Kaplan-Meier estimates). Overall, the relative risk of developing AIDS by any given time after seroconversion was 1.45 for each 10 year increase in age (p = 0.002; 95% confidence limits of 1.15, 1.85; Cox proportional hazards model). After adjustment for the CD4+ T-cell count (median of 10 count measurements per patient, fitted as a time-dependent covariate), the relative risk fell to 1.31 but remained statistically significant (p less than 0.05; 95% confidence limits of 1.03, 1.67). This implies that older people may be at higher risk of progression than their younger counterparts, even if their CD4+ T-cell counts are the same. Hence, prophylaxis against opportunistic infections may be indicated at higher CD4+ T-cell counts in older people than in younger people.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Cytomegalovirus as a possible cofactor in HIV disease progression.

It has been suggested that cofactors in human immunodeficiency virus (HIV) disease, particularly other viral infections, may accelerate progression to the acquired immune deficiency syndrome (AIDS). We have shown that in a population of 108 HIV-infected hemophiliacs observed for up to 9 years after the first documented HIV seroconversion, coinfection with cytomegalovirus (CMV) adversely influenced the course of the disease; in particular, logistic regression analysis showed that the age-adjusted relative risk of developing AIDS in CMV-seropositive patients was 2.5 times that in CMV seronegatives (p = 0.02). A number of potential mechanisms for the interaction of HIV and CMV have been proposed. Several groups have reported interaction at a molecular level between HIV and other viruses, including CMV, through transactivation of the HIV genome. Mechanisms by which the two viruses might gain entry to the same cell have been identified in vitro; these include Fc receptor-mediated uptake of antibody-coated HIV by CMV-infected fibroblasts. There is also some evidence that coinfection with HIV and CMV can occur in vivo, within brain cells. Interaction between these two viruses might also occur indirectly through the production of cytokines, such as tumor necrosis factor. Identification of cofactors in HIV infection may help in understanding the pathogenesis of AIDS, and may provide an important opportunity for intervention in the progression of the disease, particularly when an infectious agent for which specific therapy is available is identified.

Cytomegalovirus↗
PubMed1989

Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection.

To examine whether cytomegalovirus (CMV) infection could accelerate progression of human immunodeficiency virus (HIV) infection to AIDS, serological studies were done on 108 HIV-infected haemophiliacs. In the 1.3-9 years from time of first recognised HIV seroconversion, the age-adjusted risk of CDC group IV disease in CMV-seropositive patients was 2.5 times that in CMV-seronegative patients. CMV-seropositive patients were also more likely to have detectable p24 antigenaemia. Survival analysis showed that CMV-seropositive patients were at greater risk of HIV disease than CMV-seronegative patients from about 2 years after HIV seroconversion. Thus CMV infection is associated with a more rapid progression to HIV disease.

Acquired Immunodeficiency Syndrome↗
PubMed1989

A dye-photosensitized reaction that generates stable protein-protein crosslinks.

Irradiation of fibrinogen with visible light for 30 s in the presence of 1-1000 microM fluorescein was found to crosslink fibrinogen both inter- and intramolecularly. Optimum crosslinking was achieved at dye concentrations of around 100 microM and the amount of crosslinking was shown to increase with pH. Crosslinking was inhibited in the presence of 50 microM tryptophan or tyrosine and enhanced in the presence of 5 mM histidine. Twice as much crosslinking was found to take place under anaerobic conditions. These observations are consistent with a dye-photosensitized reaction following the hydrogen abstraction pathway. The subunits of eukaryotic ribosomes and those of phosphorylase a were also crosslinked by the method described.

Amino Acids↗
PubMed1989

The influence of calcium ions on fibrinogen conformation.

The conformation of fibrinogen has been examined using the techniques of dye-photosensitized surface labelling and cross-linking. The results obtained suggest that fibrinogen is a flexible molecule and its conformation is influenced by the concentration of calcium ions. These effects are mediated through binding to the low-affinity calcium binding sites of fibrinogen. In particular the C-terminal regions of the [A]alpha chain are more exposed at higher calcium concentrations creating a molecule which is more liable to form inter-molecular interactions.

Calcium↗
PubMed1989

Titration of IgG antibodies against varicella zoster virus before bone marrow transplantation is not predictive of future zoster.

Serum antibodies to varicella zoster virus (VZV) were measured in 77 patients about to undergo allogeneic bone marrow transplantation, and in 65 of their donors. Ten patients developed zoster within the first 6 months following transplant. There was no significant difference in the mean pretransplant antibody titre between those patients who did or did not subsequently develop zoster. Likewise, the level of antibody to VZV amongst donors had no effect on the subsequent development of zoster. We conclude that the pretransplant level of antibody to VZV is not predictive of subsequent zoster infection, and would not be helpful in identifying patients for trials of antiviral prophylaxis. These results contrast with those previously found for another herpesvirus, herpes simplex (HSV), where antibody level pretransplant is predictive of future HSV recurrence.

Adolescent↗
PubMed1989

Comparison of the reactions of older and younger patients to intensive care.

To determine whether age affected the attitudes of patients to intensive care, we administered a questionnaire to 57 patients who had been hospitalized in our ICU or coronary care unit (CCU). The 28 men and 29 women ranged in age from 20 to 92 yr (mean 58.4). Nineteen patients were greater than or equal to 70 yr and nine were greater than or equal to 80 yr. The "intensity" and "severity" of the treatments were similar in the older and younger patients, both men and women, in the ICU and CCU. The great majority of the patients, both old and young, were satisfied with their treatment and outcome, and expressed willingness to undergo similar treatment(s) in the future, if needed. Only five patients were dissatisfied with their treatment: two were greater than 70 yr, the other three were 27, 62, and 65 yr. We did not interview a large number of patients and thus, cannot draw far-reaching conclusions without additional study. Nevertheless, although we expected that older patients would be particularly distressed about their treatments and hence, say they would decline them in the future, in this study both the older and the younger patients were highly accepting of the treatment they received.

Adult↗
PubMed1989

Characterization of the adenovirus proteinase: development and use of a specific peptide assay.

An assay system has been developed for the adenovirus endoproteinase which utilizes the synthetic peptide MSGGAFSW, derived from the cleavage site of the adenovirus type 2 (Ad2) protein pVI. MSGGAFSW was shown to be cleaved at the G-A bond when incubated with a source of Ad2 proteinase. Digestions were readily monitored by either fast protein liquid chromatography or thin layer electrophoresis, enabling the rapid production of quantitative data. Comparison of the peptide assay with a previously described [35S]methionine assay system showed it to be faster, cleaner and less prone to extreme conditions of pH and ionic strength. The effect on adenovirus proteinase activity of a number of inhibitors was assessed using both the [35S]methionine and peptide assays. Identical inhibitor profiles were obtained and these suggested that the adenovirus enzyme is a cysteine proteinase. The 23K gene product, thought to be the proteinase, contains cysteine and histidine residues at positions 122 and 54, respectively, that could constitute part of the active site of a cysteine proteinase. These amino acids and their surrounding residues are conserved in all serotypes examined and appear to bear some resemblance to those in the putative active sites of the 3C proteinases in picornaviruses.

Adenoviruses, Human↗
PubMed1989

Characterization of the adenovirus proteinase: substrate specificity.

Peptides were synthesized based on the cleavage sites in the adenovirus type 2 proteins pVI and pVII. The synthetic peptides were incubated with disrupted, purified adenovirus as a source of proteinase and specific cleavages were monitored by fast protein liquid chromatography and amino acid analysis. Using this approach it was established that all the peptides cleaved were of the form M(L)XGX decreases G or M(L)XGG decreases X. Thus we have shown that the adenoviral proteinase recognizes a specific secondary structure formed by a sequence of at least five amino acids, the main determinants of specificity being two and four residues to the N-terminal side of the bond cleaved. We were able to examine the relevant structural features of the peptide substrates by utilizing the CHEM-X molecular modelling package. Using our consensus sequence we were able to predict the cleavage sites in the viral proteins pVIII, pre-terminal protein (pTP), 11K and IIIa. Octapeptides containing the predicted sites in pVIII and the pTP were synthesized and shown to be cleaved by the proteinase.

Adenoviruses, Human↗
PubMed1989

Phosphorylation of adenovirus DNA-binding protein.

Evidence is presented here which indicates that the adenovirus DNA-binding protein (DBP) is phosphorylated at a tyrosine residue early in infection. This was suggested by the discovery that a proportion of the label in 32P-labelled DBP was resistant to alkali, and was substantiated by acid hydrolysis of DBP immunoprecipitates and by immunoblotting with a monoclonal antibody against phosphotyrosine. Treatment of [35S]methionine-labelled DBPs with chymotrypsin produced fragments of apparent Mr 45K and 39K whereas digestion of 32P-labelled DBP resulted in fragments of 45K and 26K. Consideration of the distribution of 32P label and its alkali stability in these fragments suggested that chymotrypsin cleaved populations of DBP at different sites depending on their phosphorylation states. The conservation, in all of the seven adenovirus serotypes sequenced, of a tyrosine residue (at amino acid 195 in adenovirus type 2) together with its surrounding residues, suggests that phosphorylation/dephosphorylation at this tyrosine residue may be important in various functions ascribed to the DBP.

Adenoviruses, Human↗
PubMed1989

The psychological, educational and auditory sequelae of early, persistent secretory otitis media.

Previous studies have suggested an association between chronic middle ear disorders due to secretory otitis media and adverse effects on auditory, educational and psychological development in children. Experimental design of such studies has often been poor. In this study, attempts were made to control extraneous variables more rigorously, using matched pairs. A group of children (n = 10) without current hearing problems but with a history of recurrent early secretory otitis media, aged 7-11 yrs, were compared on auditory, educational and psychological measures with a matched group of children with no history of otitis media. The results indicated weak but distinct differences between the two groups on the educational and psychological measures in favour of the control group. The implications for medical and educational services are outlined.

Audiometry, Evoked Response↗