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Biomedical subjects

R Penny

Publications and source records attributed to R Penny.

At least 91 records · Page 5Linked to original sources
PubMed1991

Allergic manifestations of human immunodeficiency virus (HIV) infection.

Drug allergy is the most common and significant allergic manifestation of HIV3 infection. Initially described in patients treated with SMX-TMP for PCP, allergy is now known to involve a multitude of drugs. The pathogenesis of, and risk factors for, allergy in HIV infection are poorly understood, although there is evidence suggesting that allergy is more common with advancing immunodeficiency. HIV-negative subjects with sulfonamide allergy may have drug-specific antibodies and drug metabolite-induced lymphocyte cytotoxicity, abnormalities that could partly explain the allergic mechanisms and which may have future diagnostic potential; these abnormalities have not been described in HIV-infected subjects. Therapy includes avoidance, suppressive agents such as corticosteroids, and desensitization, although the appropriate role for each is not entirely clear. Serum IgE levels have been shown to rise with progressive disease; those patients with higher levels may have a worse prognosis. The mechanisms of this rise are multifactorial, probably a combination of altered T-lymphocyte regulation of IgE synthesis and of production of specific IgE directed against microbial antigens.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Sulphadiazine desensitization in patients with AIDS and cerebral toxoplasmosis.

The objectives of this study were to evaluate the efficacy of a sulphadiazine desensitization protocol to treat patients with AIDS and cerebral toxoplasmosis (CT) and known sulphonamide allergy, to ensure that an adequate dose of sulphadiazine (2-4 g/day) was achieved rapidly (within 4-5 days), and to assess the effect of concurrent corticosteroid (CS) administration on the success rate of the regimen. Sixteen patients with CT and a past history or current manifestations of sulphonamide allergy were desensitized to sulphadiazine from October 1988 to December 1989. The protocol employed the oral administration of gradually increasing increments of sulphadiazine 3-hourly over 5 days. Success was defined as tolerance of 2-4 g oral sulphadiazine per day for at least 7 days until death or the present time without any allergic reactions. Our success rated overall was 10 out of 16 patients (62%). Seven patients achieved a final dose of 4 g/day and three a dose of 2 g/day. Concurrent CS administration did not appear to affect the outcome in the small number of patients studied. Our sulphadiazine regimen rapidly, successfully and safely desensitized patients with CT and sulphonamide allergy, allowing the optimal first-line treatment to continue. The aetiology of allergy in HIV-infected patients and the mechanisms by which desensitization works are unknown.

Acquired Immunodeficiency Syndrome↗
PubMed1991

CD4% is the best predictor of development of AIDS in a cohort of HIV-infected homosexual men.

To determine the relationships between individuals' baseline T-cell subsets, their rates of change with time, and AIDS-free survival time, data were collected at 6-monthly intervals from 379 HIV-seropositive homosexual Sydney men, of whom 31 developed AIDS during the 3-year observation period. Both CD4% and rate of change of CD4% in an individual had significant prognostic value in determining AIDS-free survival time. Compared with subjects whose CD4% remained stable, subjects whose CD4% dropped by 7% or more in a year had a relative hazard of 35.1 (95% confidence interval = 11.7-105.6, P less than 0.001) of developing AIDS. Increasing CD4% had a significant protective effect, reducing the risk of developing AIDS. CD4%, CD4 cell count and CD4: CD8 ratios showed steeper declines in subjects who were later diagnosed with AIDS than in those who remained AIDS-free. The rates of immunological change in AIDS-free seroconverters and seropositives were similar, despite indeterminate differences in durations of infections. In the multivariate Cox regression analysis, baseline CD4%, the rate of change of CD4%, and baseline lymphocyte count were associated with AIDS-free survival time. Baseline CD4% had greater prognostic value than baseline CD4 cell count. Baseline CD8%, baseline CD8 count, their rates of change and their mean square errors were not independently significant in this analysis. These findings are important for clinicians monitoring HIV infection in an individual and for entry criteria and monitoring procedures in clinical trials. They also have implications for resource-poor settings; prognosis based on CD4% can be made with a flow cytometer without a full blood count.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1991

Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha.

Rheumatoid arthritis is characterized by chronic inflammation and proliferation of a number of important elements within the joint including the synovial fibroblasts. Elevated levels of a number of cytokines such as Il-1, IL-2, IL-6, interferon-gamma (IFN-gamma), transforming growth factor-beta and tumour necrosis factor-alpha (TNF-alpha) have been detected in the synovial fluid of patients with rheumatoid arthritis and other inflammatory arthritides. It seems likely that local release of such mediators may be responsible for the proliferation and overgrowth of connective tissue elements in these disorders. In order to ascertain whether there was evidence to suggest local production or release of fibroblast growth factors in the joint in inflammatory arthritis, and to determine their identity, cells were obtained from the synovial fluid of 15 patients with chronic inflammatory arthritides. All subjects' synovial fluid cells spontaneously released growth factor activity for fibroblasts. This was present in large amounts, being detectable in culture supernatants diluted to a titre of at least 1/625. By a series of depletion experiments using solid-phase bound antibodies to cytokines, it was possible to demonstrate that this activity was due to TNF-alpha and platelet-derived growth factor (PDGF). Thus, this study showed for the first time that functionally active PDGF was released from synovial fluid cells. Both PDGF and TNF-alpha appeared to contribute in approximately equal amounts to this fibroblast growth factor activity, and were synergistic in effect. Thus this study provides evidence for the local production and release of these two cytokines and suggests that together they are the dominant factors in fibroblast proliferation within the synovial cavity.

Arthritis, Rheumatoid↗
PubMed1991

Antibody penetration of viable human cells. I. Increased penetration of human lymphocytes by anti-RNP IgG.

Antibody penetration of viable cells and interaction with intracellular antigens may have major consequences for immunopathological processes in connective tissue diseases. We have reported previously that antibody can penetrate viable human lymphocytes. To assess further the role of antinuclear antibodies in this process, peripheral blood lymphocytes (PBMC) were incubated with FITC-conjugated IgG fractions from sera containing anti-RNP (anti-RNP IgG), Ro(SS-A), La(SS-B) and dsDNA antibodies and control sera for 24 h. Using crystal violet to quench cell surface staining, intracellular fluorescence of viable lymphocytes was quantified on the flow cytometer. It was noted that anti-RNP IgG entered 46.4 +/- 7.2% of lymphocytes which was significantly higher than anti-Ro(SS-A) (29.9 +/- 4.1%, P less than 0.05), La(SS-B) (22.0 +/- 7.5%, P less than 0.01) IgG and control IgG (28.8 +/- 2.1%, P less than 0.05) and not statistically different from anti-dsDNA IgG (32.6 +/- 14.3%). Inhibition experiments showed that the increased number of cells penetrated by anti-RNP IgG was a specific process. Time-course studies showed that anti-RNP IgG entry into cells was different from pooled control IgG. With anti-RNP IgG, positive-staining lymphocytes gradually increased in number from 12 to 24 h incubation, whilst with pooled control IgG, the peak was reached within 5 min. Dual staining experiments suggested that whereas both anti-RNP IgG and pooled control IgG entered B and NK cells, anti-RNP IgG also entered T cells. Using IgG F(ab')2 and Fc fragments from either anti-RNP IgG or pooled control IgG to compete with their FITC-conjugated counterparts indicated that the entry of anti-RNP IgG into-viable cells appeared to involve both F(ab')2 and Fc fragments, and pooled control IgG depended exclusively on the Fc portion of IgG. Further investigation by incubating anti-RNP IgG with 35S-methionine-labelled monocyte-depleted PBMC (MD-PBMC) suggested that anti-RNP IgG might react with the corresponding antigens either on the cell surface or within the cytoplasm.

Animals↗
PubMed1991

Interstitial lung disease associated with connective tissue diseases. The use of statistical structure analysis in model development.

Interstitial lung disorders associated with the connective tissue diseases are thought to be quite common, but their precise analysis is fraught with difficulty because of the absence of a Gold Standard that, short of open lung biopsy, is not available. Analysis is hampered by the biologic variability in test results, large overlap between the normal and the disease population for individual tests, the confounding effect of smoking, and the complexities of viewing multidimensional data. In order to better define the pattern of the lung involvement, an entirely different approach has been adopted that is based on the use of graphic and clustering techniques to define the multivariate structure inherent in the data, then discriminant analysis to assign patients into distinct clusters. Using this approach it has been possible to group patients into four distinct clusters based on the result of respiratory function studies, gallium lung scan, bronchoalveolar lavage, and smoking status. These clusters are a normal smoking cluster and a normal nonsmoking cluster, a cluster of patients with active ILD, and a cluster with bronchiolitis. The validity of this method has been verified, and an algorithm has been developed that allows the assignment of any new patient entering the study into one of these clusters. This type of analysis offers a valuable new approach to the categorization of patients into distinct groups based on the results of multiple investigations.

Algorithms↗
PubMed1991

Antibodies to tubulin and actin bind to the surface of a human monocytic cell line, U937.

Intermittent reports of cytoskeleton proteins (actin and tubulin) on the cell surface have appeared over the last 13 years. Whereas most have concentrated on lymphocytes, this study provides evidence for the presence of these proteins on the surface of a human cultured monocyte-like cell line, U937. Both actin and tubulin were detected on the surface of U937 cells by flow cytometry, using an indirect staining procedure based on biotin-streptavidin-phycoerythrin, chosen for greater sensitivity. By use of this procedure, the majority of viable unstimulated U937 cells stained positively for actin and tubulin, although the level of fluorescence intensity was low. With an antibody specific for tyrosine-tubulin, most of the surface tubulin was also found to be tyrosinylated. For vimentin, an intermediate filament protein abundantly present in the cytoplasm of U937 cells, no staining could be detected. Confirmation of the flow cytometry data for surface actin and tubulin on unstimulated U937 cells was achieved by direct vesualization using a confocal laser scanning microscope. When U937 cells were activated with PMA and LPS, a marked reduction in the level of cell surface actin and tubulin occurred. The role of cell surface actin and tubulin on unstimulated U937 cells, in terms of monocyte function, remains to be elucidated.

Actins↗
PubMed1991

Investigation of interleukin 2 receptors on human endothelial cells.

We have demonstrated that both recombinant and purified IL-2 exert a direct effect on quiescent human microvascular endothelial cells in vitro, causing the cells to enter the cell cycle and proliferate (Hicks et al., 1989). In this study we have identified IL-2 receptors (R) on both human umbilical vein (HUVEC) and neonatal foreskin (HCEC) endothelial cells. The techniques used to identify the receptors included proliferation studies, flow cytometry and immunofluorescence. Results indicate that both HUVEC and HCEC possess low numbers of receptors since both cell types proliferate in response to IL-2. The number of receptors on the cell surface vary according to passage number and culture conditions. Immunofluorescent studies show discrete areas of staining on the cell membrane. These combined results suggest that human vascular endothelial cells possess IL-2R.

Cell Division↗
PubMed1990

Interaction of immune and connective tissue cells: I. The effect of lymphokines and monokines on fibroblast growth.

In order to determine if mononuclear cells may be secreting factors capable of modulating fibroblast growth, the in vitro proliferative response of fibroblasts to cytokines known to be secreted by mononuclear cells was measured, using both growth arrested and proliferating cells. Of the cytokines tested, which included interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), platelet derived growth factor (PDGF), and tumor necrosis factor-alpha (TNF-alpha), only TNF-alpha and PDGF had demonstrable growth factor activity. Neither IL-1 alpha nor beta showed any true growth factor activity but were able to enhance the replication of already proliferating cells. No inhibition of proliferation was noted by any of the cytokines with the exception of TNF-alpha and TGF-beta. TNF-alpha in doses greater than 500 ng/ml caused fibroblast death, probably by a prostaglandin related mechanism as fibroblasts remained viable, although non proliferative, when assayed in the presence of indomethacin, a known inhibitor of prostaglandin E2 (PGE2) synthesis. TGF-beta was inhibitory to proliferation at doses greater than 100 ng/ml, while fibroblasts remained viable. This effect was not influenced by indomethacin and hence is unlikely to be PGE2 related.

Cell Division↗
PubMed1990

Definition of two distinct types of AIDS-associated non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) in a human immunodeficiency virus (HIV)-infected person is an AIDS-defining condition. There is both an increased incidence of NHL and a poorer prognosis for the disease in these HIV-infected persons, compared with patients who spontaneously develop NHL. A series of 41 consecutive patients with HIV-associated NHL treated at St Vincent's Hospital, Sydney, between 1984 and September 1989 was assessed. Of these, 36 had NHL proven on biopsy and NHL was diagnosed clinically in the other five. On histologic examination 11 had high-grade malignant lymphoma, small non-cleaved cell (SNCC) type, similar to Burkitt lymphoma, 18 had high-grade lymphoma large cell immunoblastic (LCI) type, and seven could not be classified due to inadequate material for assessment. The clinical features of these two groups were compared. Those patients with LCI had advanced CD4+ immunodeficiency and poor survival (median = 6 weeks). The other group with SNCC had better preserved immune function, and longer survival (median = 18 weeks). Three patients had survived longer than 3 years all of whom had SNCC lymphoma as their first AIDS-defining illness. The clinical features and prognostic factors demonstrated in this study document heterogeneity of NHL in HIV-infected patients and should be used as a guide to treatment of these patients, by reserving more intensive treatment for those persons with better prognostic features.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The gastrointestinal manifestations of AIDS.

Gastrointestinal disease in AIDS is common and is due to opportunistic infections, aggressive malignancy and possible direct HIV enteropathy. Disabling gastrointestinal symptoms are prominent both in patients with established AIDS and in patients with earlier stages of HIV infection. We report the cases of 160 patients with AIDS who underwent gastroenterological investigations at St Vincent's Hospital, Sydney, between November 1983 to October 1987. Of these, 127 had the diagnosis of AIDS established prior to referral and 33 patients had the diagnosis of AIDS established as a result of gastroenterological investigations. Diarrhoea and weight loss (88%) were the most frequent reasons for undertaking gastroenterological investigations. Swallowing disorders (47%), abdominal pain (20%), oral and perianal disease (74%) and evidence of hepatobiliary disease were the other major indications for investigation. In 90% of cases there was evidence of concurrent and active gastrointestinal disease at two or more sites within the alimentary tract. Results from this series reveal a wide range of infectious pathogens: viral (Cytomegalovirus, Herpes simplex), bacterial (Mycobacterium avium intracellulare) and parasitic (Cryptosporidium, Isospora belli). Kaposi's sarcoma and non-Hodgkin's lymphoma were the only malignancies detected in this series. Gastrointestinal disease associated with HIV infection is common, and contributes significantly to its overall morbidity and mortality. Moreover, chronic diarrhoea, weight loss and malnutrition may also contribute to the overall immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Incidence and risk factors for human immunodeficiency virus seroconversion in a cohort of Sydney homosexual men.

By means of prospective cohort data from the Sydney AIDS Project, we report on 55 homosexual or bisexual men who have become infected with human immunodeficiency virus (HIV), as measured by the development of serum HIV antibodies (seroconversion). We have compared the sexual practices, recreational drug abuse, history of sexually-transmissible diseases, and antecedent immunological findings of the men who seroconverted with those of 588 subjects who persistently remained seronegative in the same time-period. The cumulative incidence rate of HIV infection over the three years of observation was 8.5%. The cumulative incidence rate ranged from less than 1% for the six months before August 1, 1984, to a peak of 5% in the six months before August 1, 1985. Of those subjects for whom we had data for the period of seroconversion, all but two of the subjects who seroconverted admitted to a recognized high-risk sexual practice in the six months before the first visit at which they were found to be seropositive. Univariate analysis found that men who seroconverted were significantly more likely to have had a greater number of recent sexual partners (relative risk per partner, 1.02; P less than 0.001), to have engaged in receptive anal intercourse (incidence rate ratio, 3.1; 95% confidence interval [CI], 1.3-7.6; P = 0.01) and to have used nitrite inhalant (incidence rate ratio, 2.6; 95% CI, 1.2-5.9; P = 0.02) and amphetamine (incidence rate ratio, 4.8; 95% CI, 2.2-10.5; P less than 0.001) drugs. The men who seroconverted were significantly (incidence rate ratio, 2.7; 95% CI, 1.2-6.1; P = 0.014) more likely to have antecedent T-suppressor-cell counts of greater than 800 cells/microL. Factors that retained significance in multivariate analysis were the number of recent sexual partners, recent amphetamine abuse and a T-suppressor-cell count of greater than 800 cells/microL.

Adolescent↗