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Biomedical subjects

R Penny

Publications and source records attributed to R Penny.

At least 37 records · Page 2Linked to original sources
PubMed1995

Productive in vitro infection of human umbilical vein endothelial cells and three colon carcinoma cell lines with HIV-1.

The objective of this study was to assess the ability of HIV-1 to establish an in vitro infection of primary human umbilical vein endothelial cells (HUVEC). The HUVEC and colon carcinoma cell lines were inoculated with different isolates of HIV-1 (HIV-1SF2, HIV-1Mck and HIV-1LAI) and productive viral infection was assessed by both the detection of p24 core antigen in the culture supernatants and the presence of specific spliced HIV mRNA. The infection which was detected in the inoculated HUVEC and all the colon carcinoma cell lines could not be blocked using an antibody targeted against the CD4 receptor. Furthermore, the HIV-inoculated HUVEC secreted elevated levels of IL-6 and this increase was found to be proportional to the size of the viral inoculum. No changes in the production of IL-1 beta, TNF-alpha, IFN-alpha and IFN-gamma were detected following HIV infection. The colon carcinoma cells, however, did not secrete increased levels of these cytokines following HIV-1 inoculation. These results confirm that non-CD4 expressing cells, such as endothelial cells and certain colon epithelial cells, serve as targets and reservoirs for HIV. Moreover, the production of IL-6 by HIV-infected endothelial cells may be a contributing factor to the aberrant immunoregulation associated with HIV infection in vivo.

Base Sequence↗
PubMed1995

Expression of cytokine genes in T cell leukemias.

Normal T cells secrete cytokines which have important effects on a wide range of other cells. In the present study, the expression of IL-2, IL-4, IL-5, IL-10 and IFN-gamma was assessed in PBMC from 3 cases of T cell leukemia, using reverse transcription and polymerase chain reaction (RT-PCR). The major difference between the leukemia cases and control PBMC samples was that, without in vitro stimulation, IFN-gamma was much more readily detected in 2 of the leukemia cases. IL-2 and IL-5 mRNA were also detected in 2 of the patients but not in the other samples. IL-4 mRNA was not detected in any unstimulated sample, whereas IL-10 was always present. After polyclonal stimulation in vitro, mRNA for all these cytokines was detected in all samples. Thus cytokine expression, particularly of IFN-gamma, may be more prominent in PBMC from adult T cell leukemia cases than in controls.

Adult↗
PubMed1995

Primary structure of the V3 region of gp120 from sequential human immunodeficiency virus type 1 isolates obtained from patients from the time of seroconversion.

V3 loop sequences were compared from 5 human immunodeficiency virus type 1 (HIV-1)-infected patients over time. Three patients remained asymptomatic and 2 became symptomatic with large decrease in CD4 cell counts. The patient isolates were previously evaluated for phenotypic and antigenic properties and had different sensitivities to serum neutralization and changes in phenotype. This study showed a number of amino acid changes for the 2 symptomatic patients, each of whom progressed to AIDS during the study. The only amino acid substitution consistently associated with reduced CD4 cell counts, cytopathic effect, and progression to AIDS was Arg at position 11. Specific amino acid changes could not be correlated with increasing serum neutralization resistance or cytotropism changes. Increased loop charge was associated with a switch from macrophage to T cell tropism and a decrease in the number of CD4 cells. The study shows the importance of naturally occurring mutations in the V3 loop in controlling the biologic properties of HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Effects of primary HIV-1 infection on subsets of CD4+ and CD8+ T lymphocytes.

OBJECTIVE: To analyse changes in T-lymphocyte subsets in patients with primary HIV infection and to determine their specificity (and therefore their diagnostic utility) by comparing these changes with those seen in other acute illnesses as well as in HIV-uninfected patients. METHODS: T-lymphocyte subsets were analysed by two- and three-colour flow cytometry, and compared between HIV seroconverters (n = 16), HIV-infected (n = 18) and uninfected (n = 33) controls, patients with infectious mononucleosis (n = 7), and patients suspected clinically of having primary HIV infection but who were later found to be uninfected (referred to as HIV non-converters; n = 17). RESULTS: CD4+ lymphocyte counts were significantly lower in HIV seroconverters (mean, 444 x 10(6)/l) than in the HIV non-converters (793 x 10(6)/l; P = 0.003), HIV-seronegative controls (888 x 10(6)/l; P < 0.0001) and, to a lesser extent, those with mononucleosis (694 x 10(6)/l; P = 0.045). The reduction in CD4+ lymphocytes occurred in both the CD45RA+ (55%) and CD45R0+ (33%) subsets. CD8+ lymphocyte counts were significantly higher in HIV seroconverters (942 x 10(6)/l) than in HIV non-converters (570 x 10(6)/l; P = 0.003) and seronegative controls (467 x 10(6)/l; P < 0.0001), but significantly lower than in the mononucleosis group (3682 x 10(6)/l; P = 0.004). The CD8+ cells in the HIV seroconverters had increased coexpression of CD45R0, human leukocyte antigen (HLA)-DR, CD38 and CD11a/CD18. The mean CD4: CD8 ratio in the HIV seroconverters was 0.49, versus 1.52 in the non-converters (P < 0.0001), 2.08 in the seronegative patients (P < 0.0001) and 0.37 in the mononucleosis patients (P > 0.2). CONCLUSIONS: Primary HIV infection is characterized by a depletion of CD4+ lymphocytes, especially of the CD45RA+ phenotype, and by an increase in CD8+ lymphocytes with an activated phenotype; the latter was also seen in patients with infectious mononucleosis but not in HIV non-converters or HIV-seronegative patients. Patients suspected clinically of having primary HIV infection but with normal T-cell phenotype are less likely to have primary HIV infection. These phenotypic changes, as well as an inverted CD4: CD8 ratio, can readily distinguish patients with primary HIV infection from HIV-uninfected patients except those with infectious mononucleosis. Therefore, T-cell-subset enumeration may be useful in the diagnosis of primary HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Quinolinic acid production is related to macrophage tropic isolates of HIV-1.

We sought to determine whether the neurotoxin quinolinic acid (QUIN) was produced by macrophages or lymphocytes infected with isolates of HIV-1 with varying degrees of macrophage tropism derived from patients with varying stages of AIDS dementia complex (ADC). Highly macrophage tropic isolates and minimally macrophage tropic isolates were used to inoculate macrophages and QUIN production was measured. Similarly, QUIN production from macrophages was monitored using a purified cell free highly macrophage tropic isolate and laboratory isolates SF33 and SF2. Each of these experiments was also performed with lymphocytes. We found that macrophages infected with macrophage tropic isolates of HIV-1 led to QUIN production while lymphocytes did not produce QUIN. The ability of the HIV-1 infected macrophages to produce QUIN was related to the viral inoculum and the degree of macrophage tropism of the isolate. The severity of ADC in the patient from whom a particular isolate was derived was not per se a determining factor for QUIN production. Purified cell free ADC isolates also led to QUIN production by macrophages thereby suggesting that HIV-1 infection alone is capable of inducing QUIN production.

AIDS Dementia Complex↗
PubMed1994

Neutralizing antibodies against sequential autologous human immunodeficiency virus type 1 isolates after seroconversion.

The emergence of human immunodeficiency virus type 1 (HIV-1) variants with different sensitivities to serum neutralization and biologic phenotype was studied for 2-5 years after primary HIV-1 infection in 5 subjects. In 3 subjects, the initial virus isolate from seroconversion could be neutralized by autologous serum, but isolates obtained at two subsequent times exhibited reduced sensitivity to serum neutralization, decreased replication in primary macrophages, and increased ability to induce syncytia. Two of these 3 subjects progressed to AIDS and died. Sequential virus isolates from the other 2 subjects showed variability in sensitivity to serum neutralization or biologic features. These patients remained relatively stable in clinical status. Thus, viruses isolated at seroconversion appear to be either non-syncytium-inducing, strong macrophage-tropic, serum neutralization-sensitive phenotypes with stable clinical status or to have escaped neutralization by autologous sera over time, have reduced macrophage tropism and increased syncytia formation, and be associated with disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Scleroderma and silicone breast implants.

A 43-yr-old caucasian female presented in July 1992 with an explosive onset of diffuse scleroderma following general anaesthesia for orthopaedic surgery. Her environmental exposures included silicone breast prosthetic surgery and silica exposure, both preceding development of scleroderma. She was DR5-negative, DRw52 positive. All currently available literature relating to breast implants and scleroderma is reviewed and the conclusion drawn that, for currently documented US data, there is no evidence to suggest that patients having had breast augmentation have rates of scleroderma higher than expected to chance alone. However the cause-effect relationship between silicone and scleroderma/other connective tissue disease requires, not just anecdotal reports, but a rigorously designed study.

Adult↗
PubMed1994

Acetylation phenotype and cutaneous hypersensitivity to trimethoprim-sulphamethoxazole in HIV-infected patients.

OBJECTIVE: Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) is more common in patients with HIV infection. In non-infected patients, TMP-SMX hypersensitivity is more common in those with a slow acetylator phenotype. This study was conducted to determine whether the slow acetylation phenotype is associated with an increased risk of hypersensitivity to TMP-SMX in patients with HIV infection. METHODS: Acetylation phenotype was determined in 28 HIV-infected subjects, of whom 16 had prior TMP-SMX hypersensitivity and 12 had received long-term TMP-SMX therapy without hypersensitivity, as well as in 29 healthy controls. Acetylation phenotype was determined by measuring the ratio of two urinary caffeine metabolites, 5-acetylamino-6-amino-3-methyl uracil (AAMU) and 1-methylxanthine (1-MX), after ingestion of a single 200 mg dose of caffeine. RESULTS: Of the 28 HIV-infected subjects, 20 (71%) expressed a slow acetylation phenotype and eight (29%) a fast phenotype. By comparison, of the 29 healthy controls, 15 (52%) expressed a slow phenotype (P = 0.11). Of the 16 HIV-infected subjects with prior TMP-SMX hypersensitivity, 15 (94%) had a slow acetylation phenotype, whereas only five out of 12 (42%) non-hypersensitive subjects had a slow acetylation phenotype (P < 0.01). CONCLUSIONS: A slow acetylation phenotype is a risk factor for hypersensitivity to TMP-SMX in HIV-infected subjects.

Acetylation↗
PubMed1994

Immunohistological assessment of cutaneous drug hypersensitivity in patients with HIV infection.

The pathogenesis of drug hypersensitivity in patients with HIV infection is unknown. To study further the nature of hypersensitivity, the histopathological features of morbilliform drug hypersensitivity reactions were examined in a group of HIV-infected patients. Skin sections from 23 HIV-infected subjects with morbilliform drug hypersensitivity reactions were examined by light microscopy, direct immunofluorescence and immunohistochemistry, to determine the nature of the inflammatory infiltrate and the role of immunoglobulin, complement and cytokines. The principal light microscopic findings were spongiosis, hydropic generation of the basal layer, civatte bodies, an epidermal lymphocytic infiltrate (48%), and a perivascular dermal infiltrate of lymphocytes (87%) and macrophages (52%). Two patients had findings consistent with toxic epidermal necrolysis. Immunohistochemistry demonstrated that the lymphocytic infiltrate consisted of CD8+, HLA-DR+ T lymphocytes (some of which also stained for CD38), a marked depletion of epidermal Langerhans cells (90%), and strong cytoplasmic staining of keratinocytes for IL-6 (60%), IL-1 beta (50%), tumour necrosis factor-alpha (TNF-alpha) (45%) and to a lesser degree, interferon-gamma (IFN-gamma) (35%). Immunofluorescence did not demonstrate any significant deposition of immunoglobulin or complement. The histological findings were independent of the responsible drug, the duration of either therapy or the rash, and of peripheral blood CD4+ and CD8+ cell counts. These findings suggest that activated CD8+ lymphocytes and perhaps epidermal production of cytokines are involved in the pathogenesis of cutaneous drug hypersensitivity in HIV-infected patients. The common histological features, regardless of the causative drug, suggest a common pathogenesis.

Adult↗
PubMed1994

A confocal microscopy study of anticytoskeletal antibody activity in patients with connective tissue disease.

The significance of the presence of antibodies to cytoskeleton proteins in patients with connective tissue diseases is not clear, as there is a high level of these antibodies in healthy controls. In an attempt to improve the visualization of the immunofluorescence binding pattern of autoantibodies to cytoskeletal structures in cultured fibroblasts, we have used confocal microscopy. Of the 256 serum samples tested, 155 (61%) WERE reactive with cytoplasmic structures. These reactive samples could be divided into seven patterns of binding, as determined by double-blind examination of single-section confocal images. While confirming the results of previous immunofluorescence studies which have shown that autoantibodies that bind to filamentous structures in the cytoplasm of cultured cells are common in patients with connective tissue diseases, we were able to identify three patterns of cytoskeletal binding which may be useful as an adjunct to other tests for the diagnosis of some connective tissue diseases, in particular systemic sclerosis (scleroderma) and rheumatoid arthritis/Sjogren's syndrome. None of the seven patterns was exclusive to a particular disease. We conclude that confocal microscopy may be of limited use as an adjunct to other serological assays in the diagnosis of some forms of connective tissue disease.

Actin Cytoskeleton↗
PubMed1994

Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction?

OBJECTIVE: To investigate the circulating levels of endothelin-1 (ET-1) in serum (sET-1) in patients with pulmonary disease [pulmonary fibrosis (PF) and pulmonary hypertension (PHT)], and renal involvement [hypertensive renal crisis (HRC)] in the 2 major subsets of systemic sclerosis (SSc) in order to determine the significance of sET-1 levels in relation to specific organ involvement or to the underlying pathogenic mechanisms of vascular damage and fibrosis. METHODS: In addition to the measurement of ET-1 in serum using a competitive radioimmunoassay, the circulating levels of angiotensin converting enzyme (ACE) and plasma von Willebrand factor (vWF) were measured as markers of endothelial damage in the various disease groups. RESULTS: Levels of sET-1 were significantly increased in 64 patients with diffuse systemic sclerosis (dSSc) and 17 patients with primary Raynaud's phenomenon (RP) compared with 22 healthy individuals. sET-1 levels were equally elevated in diffuse cutaneous disease (dcSSc) with only fibrotic dermal or lung pathology compared with patients with additional PHT or HRC crisis. These observations were in marked contrast to the sET-1 levels seen in patients with the limited cutaneous form of SSc (lcSSc) where only patients with lcSSc with hypertensive lung or renal disease had significantly higher levels of sET-1 than comparable lcSSc patients with only fibrotic dermal and lung disease. sET-1 levels were additionally found to correlate with plasma vWF, skin fibrosis (skin score) and duration of disease in patients with SSc. CONCLUSION: The presence of significantly raised sET-1 levels in patients with dcSSc with widespread fibrosis and patients with lcSSc with hypertensive disease and the relationship seen between sET-1 levels and markers of fibrosis and vascular damage suggest that ET-1 may be important in the pathogenesis of both the fibrotic and vascular manifestations in SSc.

Biomarkers↗
PubMed1993

Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction.

OBJECTIVE: To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields. DESIGN: A prospective, nonrandomized study. PATIENTS: Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis. MEASUREMENTS: History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis. RESULTS: After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies. CONCLUSION: In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.

Adult↗
PubMed1993

Subtypes of Epstein-Barr virus (EBV) in Hodgkin's disease: association between B-type EBV and immunocompromise.

Epstein-Barr virus (EBV) has been associated with Hodgkin's disease (HD) in up to 50% of cases, but the subtype of EBV involved has only recently been studied. In this report, biopsy samples from 30 patients with HD were assessed for EBV sequences using both the polymerase chain reaction (PCR) and in situ hybridization (ISH). EBV sequences were localized to the malignant Reed-Sternberg cells and their mononuclear variants (Hodgkin's cells) in 9 of the 30 cases, with 7 demonstrating A-type and 2 B-type EBV sequences. Both of the patients with B-type EBV-associated HD had features to suggest pre-existing immune compromise: one was infected with human immunodeficiency virus (HIV) and had severe CD4+ T-lymphocyte depletion; the other was a debilitated elderly patient with dementia. A previous study suggested that A-type EBV alone is associated with HD and the finding of predominantly A-type EBV in the present series is in keeping with this report. The presence of B-type EBV in the HD of patients with pre-existing immunodeficiency, taken together with the recent report that B-type EBV occurs in HIV-associated non-Hodgkin's lymphoma, suggests that B-type EBV may be an important human pathogen in immunocompromised patients.

Actins↗
PubMed1993

Clinical and laboratory markers of hypersensitivity to trimethoprim-sulfamethoxazole in patients with Pneumocystis carinii pneumonia and AIDS.

A group of clinical, immunologic, and virologic variables was examined to determine if any predicted the development of hypersensitivity to trimethoprim-sulfamethoxazole (TMP-SMZ) during treatment of Pneumocystis carinii pneumonia in patients with human immunodeficiency virus (HIV) infection. Hypersensitivity occurred in 39 (27%) of 143 patients, who had significantly higher total lymphocyte and CD4+ and CD8+ cell counts and CD4:CD8 ratios than did those who did not develop hypersensitivity. Regression analysis identified having a CD4:CD8 ratio > 0.10 (95% confidence interval [CI], 1.75-3.94; P = .02) and treatment for < 14 days (95% CI, 1.57-3.75; P = .04) as independently predictive of hypersensitivity. Use of corticosteroids tended to reduce the frequency of hypersensitivity (7% vs. 30%; P = .07). T lymphocytes may be important in the pathogenesis of these hypersensitivity reactions. As the frequency of hypersensitivity declines with disease progression, T lymphocytes could be effector cells in these reactions or their sensitivity to TMP-SMZ may decline with HIV disease progression.

AIDS-Related Opportunistic Infections↗