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Biomedical subjects

J M Lange

Publications and source records attributed to J M Lange.

At least 19 recordsLinked to original sources
PubMed1992

[Progressive multifocal leukoencephalopathy in AIDS].

This study was carried out to determine clinical features, abnormalities on CT scan and MRI, and course in patients with HIV-I-related progressive multifocal leukoencephalopathy (PML). There were 14 patients with a presumptive diagnosis of PML among 500 HIV-I infected patients with neurological complaints, examined between September 1982 and May 1991 in the University Medical Centre in Amsterdam by a neurologist. In these 14 patients clinical features, imaging abnormalities and course of the disease were analysed retrospectively. All patients presented with progressive focal neurological abnormalities. Cerebrospinal fluid analysis revealed aspecific abnormalities in 5/13 patients. CT scanning of the brain showed hypodense areas in the white matter, without mass effect and with contrast enhancing in only one patient. MR Imaging of the brain showed high signal intensity areas in white matter and in gray matter (10/13), without mass effect, and with contrast enhancement in two. Specimens for neuropathological examination were obtained from 7 patients; in all these cases the diagnosis of PML was confirmed. In patients with AIDS a presumptive diagnosis of PML can be based on clinical features, brain imaging abnormalities and course. However neuropathological confirmation remains the gold standard. Usually the course in these patients was steadily progressive. Most patients died within one year.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects.

The order of appearance in the reverse transcriptase gene of four mutations implicated in the development of resistance to zidovudine was investigated by selective polymerase chain reaction. Serial human immunodeficiency virus isolates were studied from 18 initially asymptomatic individuals who had been treated with zidovudine for 2 years. Most subjects had similar patterns. The first mutation occurred transiently at codon 70; its disappearance was paralleled by the appearance of a mutation at codon 215. Subsequently, in some individuals, the mutation at codon 70 reappeared. During the 2 years of treatment, no mutations developed at codon 219 and only one at codon 67, suggesting that most individuals developed only partly resistant virus. This was confirmed by plaque-reduction assay. Six subjects progressed to AIDS within the 2-year study period, confirming that the development of highly resistant isolates is not required for progression in treated individuals. No clear temporal relationship was found between the development of partial resistance and progression.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men.

The steroid hormone dehydroepiandrosterone (DHEA) has been reported to protect against certain viral infections in animal models and to be a modest inhibitor of human immunodeficiency virus type 1 (HIV-1) infection in vitro. Serum DHEA levels were determined in 41 asymptomatic HIV-1-seropositive subjects, who progressed to AIDS within 5 years after entering a cohort study, in 41 HIV-1-seropositive controls, who remained asymptomatic, and in 41 HIV-1-seronegative controls. At entry, DHEA levels were higher in the seronegative group (median, 13.3 nmol/l) than in either the seropositive nonprogressors (median, 9.2 nmol/l; P = .01) or the progressors (median, 7.2 nmol/l; P less than .001). DHEA levels in the progressors approximately 5 months before the diagnosis of AIDS were lower than the levels in the nonprogressors after the same follow-up (median, 5.6 vs. 8.8 nmol/l; P = .007). DHEA levels less than 7 nmol/l and CD4+ cell counts less than 0.5 x 10(9)/l both proved to be independent predictors for disease progression in HIV-1-infected men.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection.

Nineteen individuals were studied for virologic and immunologic events during primary human immunodeficiency virus type 1 (HIV-1) infection. In 16 individuals only non-syncytium-inducing (NSI) isolates were detected; syncytium-inducing (SI) isolates were obtained from 3. Studies of transmitter-recipient pairs indicated that both NSI variants and SI variants were transmitted and that SI variants may be suppressed in the recipient. CD4+ T cells remained in the normal range in 15 of 16 individuals with NSI isolates but rapidly declined in all 3 individuals with SI variants, 1 of whom was treated with zidovudine. The most marked increase in CD8+ T cells and activated CD8+ T cells was observed in individuals with the most pronounced clinical signs of acute HIV-1 infection. Activated CD8+ T cells were only transiently elevated in individuals with SI variants, suggesting that an impaired cellular anti-HIV-1 immune response plays a role in the rapid progression to AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1992

HIV-1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment.

OBJECTIVE: To determine which parameters are associated with clinical progression during zidovudine treatment of asymptomatic HIV-1-infected individuals. METHODS: Twenty-four initially asymptomatic HIV-1-infected individuals were treated with zidovudine and followed until the development of AIDS or for approximately 3 years. HIV-1 phenotype was determined by cocultivation of patient cells with donor lymphocytes, and by a new assay of direct cocultivation with MT-2 cells. Specific mutations in the HIV-1 reverse transcriptase (RT) gene conferring resistance to zidovudine were detected using a selective polymerase chain reaction. RESULTS: Progression to AIDS was more rapid in individuals harbouring syncytium-inducing (SI) viral isolates or showing a conversion from non-syncytium-inducing (NSI) to SI viral isolates. One out of 20 patients who spent a total of 559 months harbouring an NSI phenotype progressed to AIDS, whereas eight out of 12 patients who spent a total of 223 months harbouring an SI phenotype progressed to AIDS (P < 0.001). There was no significant difference between SI and non-SI isolates in the frequency of five mutations causing zidovudine resistance. However, all SI isolates obtained after 2 years of treatment contained mutations in codons 41 and 215 of the RT gene, whereas only five out of 11 (45%) NSI isolates obtained at that time had this combination of mutations. CONCLUSIONS: Conversion to the SI phenotype cannot be prevented by zidovudine treatment. The presence or appearance of an SI virus heralded disease progression in zidovudine-treated individuals. Further research is required to investigate the relationship between virus phenotype and development of zidovudine resistance.

Cytopathogenic Effect, Viral↗
PubMed1992

The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study.

OBJECTIVE: To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. DESIGN: A Phase I, open-label, single-centre study. METHODS: Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts < 500 x 10(6)/l who had not received previous antiretroviral therapy completed the study. Each patient received a single intravenous dose followed by a single oral dose of 3TC. Four patients were dosed at each of five dose levels (0.25, 1.0, 2.0, 4.0 and 8.0 mg/kg). RESULTS: The most commonly reported adverse event was headache, which was generally reported to be mild. The mean bioavailability of 3TC was 82% following oral administration. The majority of the dose (approximately 70%) was excreted unchanged in the urine. CONCLUSIONS: Overall, 3TC was well tolerated following dosing, and there were no significant changes in the safety parameters measured. Phase I/II clinical trials with 3TC are ongoing to evaluate its safety, pharmacokinetics and preliminary activity.

Administration, Oral↗
PubMed1992

Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population.

The composition of human immunodeficiency virus type 1 (HIV-1) clonal populations at different stages of infection and in different compartments was analyzed. Biological HIV-1 clones were obtained by primary isolation from patient peripheral blood mononuclear cells under limiting dilution conditions, with either blood donor peripheral blood lymphocytes or monocyte-derived macrophages (MDM) as target cells, and the biological phenotype of the clones was analyzed. In asymptomatic individuals, low frequencies of HIV-1 clones were observed. These clones were non-syncytium inducing and preferentially monocytotropic. In individuals progressing to disease, a 100-fold increase in frequencies of productively HIV-1-infected cells was observed as a result of a selective expansion of nonmonocytotropic clones. In a person progressing to AIDS within 19 months after infection, only syncytium-inducing clones were detected, shifting from MDM-tropic to non-MDM-tropic over time. From his virus donor, a patient with wasting syndrome, only syncytium-inducing clones, mostly non-MDM-tropic, were recovered. Parallel clonal analysis of HIV-1 populations in cells present in bronchoalveolar lavage fluid and peripheral blood from an AIDS patient revealed a qualitatively and quantitatively more monocytotropic virus population in the lung compartment than in peripheral blood at the same time point. These findings indicate that monocytotropic HIV-1 clones, probably generated in the tissues, are responsible for the persistence of HIV-1 infection and that progression of HIV-1 infection is associated with a selective increase of T-cell-tropic, nonmonocytotropic HIV-1 variants in peripheral blood.

Acquired Immunodeficiency Syndrome↗
PubMed1992

High potassium diets greatly increase growth-inhibiting agents in aortas of hypertensive rats.

High potassium diets greatly reduce intimal and medial thickening in stroke-prone spontaneously hypertensive rats (SHRSP). In vascular smooth muscle cells, transforming growth factor-beta (TGF-beta) inhibits proliferation. To test whether high potassium diets decrease aortic thickening through TGF-beta, we measured TGF-beta-like activity in medium bathing aortas from rats fed either normal potassium or high potassium diets. Five-week-old SHRSP were fed 6% high NaCl diets containing either normal (0.5%) potassium (11 rats) or high (2.1%) potassium (14 rats) for 7 weeks. Aortas were freshly excised and perfused for 3 hours with tissue culture medium at ordinary arterial pressures. TGF-beta-like activity in the acid-activated perfusing medium was assessed using the growth inhibitory action on mink lung cells. Growth inhibition was assessed by [3H]thymidine incorporation. In the medium perfusing the outside of the aorta, the growth inhibitory rates were 2.5 times higher in high potassium SHRSP than in normal potassium SHRSP (-49% versus -20%, p less than 0.03). Antibodies to TGF-beta 1 and TGF-beta 2 were added to other aliquots and did not alter the results whatsoever. Thus, the difference in growth inhibition was not due to differences in TGF-beta. The high potassium aortas released 2.5 times more growth-inhibiting agents than the normal potassium aortas. The same pattern of growth inhibition was also seen using vascular smooth muscle cells rather than mink lung cells (r = +0.818, p less than 0.001, n = 13). The increased growth inhibition of high potassium aortas was not due to an increased release of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pyrimethamine alone as maintenance therapy for central nervous system toxoplasmosis in 38 patients with AIDS.

We retrospectively assessed the efficacy of maintenance therapy with pyrimethamine alone in 38 patients with AIDS and central nervous system (CNS) toxoplasmosis. The diagnosis was based on clinical presentation and compatible CT scan abnormalities with subsequent response to therapy. Survival analysis was performed by the product limit method of Kaplan-Meier. Fourteen patients received maintenance therapy with 25 mg pyrimethamine per day (group 1), and 24 patients were treated with 50 mg per day (group 2). The median survival from initiation of maintenance therapy until death or end of the study for the entire study population was 32 weeks. Median survival in group 1 was 28 weeks, as compared with 36 weeks in group 2 (p = 0.34). Relapses occurred in 12 patients, six in group 1 and six in group 2. There was no significant difference in failure-free survival between the two treatment groups (p = 0.09). One patient in group 1 and two patients in group 2 experienced severe toxicity, requiring discontinuation of therapy. All three patients relapsed and died. Two patients in group 2 who stopped treatment on their own initiative also had relapses. Thus, all five patients who discontinued therapy had relapses. Five of 13 patients in group 1 and two of 20 patients in group 2 relapsed during continuous therapy with pyrimethamine (p = 0.13); these seven patients responded to reintroduction of combination therapy (n = 6) or treatment with 50 mg pyrimethamine per day (n = 1). The results of our retrospective analysis suggest that maintenance therapy with oral pyrimethamine, 50 mg per day, in AIDS patients with CNS toxoplasmosis is effective.

Acquired Immunodeficiency Syndrome↗
PubMed1991

[Consensus early treatment with zidovudine].

The aim was to reach national consensus on the moment early treatment with the antiretroviral drug zidovudine should be started and on the dosing schedule to be used. On the initiative and under the auspices of the National AIDS Therapy Evaluation Centre a consensus meeting of Dutch AIDS treatment specialists was organised on March 6, 1991. A number of expert-speakers made recommendations on the basis of currently available information. These were amended in a plenary discussion. Subsequently the participants could comment upon a draft consensus document. Premises were that the starting point of treatment should be easily applicable and that the moment chosen should be neither too early nor too late in the course of HIV infection. The zidovudine dose had to be an effective one, and the dosing schedule user-friendly. The consensus was that zidovudine should be started in asymptomatic HIV-infected persons at a peripheral blood CD4+ cell count less than or equal to 0.3 x 10(9)/l. In the presence of additional laboratory indicators of a poor prognosis and in persons with early clinical symptoms of HIV infection, it was preferred to start treatment at a CD4+ cell count less than or equal to 0.4 x 10(9)/l. In view of the natural fluctuation in the number of CD4+ cells it was felt to be injudicious to act upon a single count. The recommended zidovudine dose is 200 mg 3 times daily. In case of serious toxicity the dose should be lowered to 100 mg 3 times daily, although for this dose no long-term efficacy data are available.

Acquired Immunodeficiency Syndrome↗
PubMed1991

[Pneumocystis carinii infection during prophylaxis with nebulized pentamidine in a patient with AIDS].

Since the introduction of aerosolised pentamidine for prophylaxis against Pneumocystis carinii pneumonia (PCP) in HIV-seropositive persons and patients with AIDS, an increasing number of cases of atypical manifestations of infection with Pneumocystis carinii have been reported in the United States, viz. upper lobe pneumonia, extrapulmonary Pneumocystis carinii infection and spontaneous pneumothorax. An association between these atypical manifestations of Pneumocystis carinii infection and the use of aerosolised pentamidine seems likely. This report is the first description in the Netherlands of an atypical Pneumocystis carinii infection in an AIDS patient while using aerosolised pentamidine for prophylaxis against PCP. Since aerosolised pentamidine for prophylaxis against PCP is increasingly being used in the Netherlands, a rise in incidence of atypical manifestations of Pneumocystis carinii infection can be expected.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Differences in clinical course in zidovudine-treated asymptomatic HIV-infected men associated with T-cell function at intake.

Declining CD4+ T-cell numbers and anti-CD3-induced T-cell responsiveness are prognostic markers for progression of HIV infection. We investigated the effect of long-term (2-year) zidovudine treatment on these immunological markers in a group of nine asymptomatic p24-antigenaemic men, five of whom progressed to AIDS. A group of 10 untreated HIV-infected men, five of whom progressed to AIDS, was studied as a control. At intake, 1 year before the start of treatment, CD4+ T-cell numbers in the groups were not significantly different. However, at that time progressors already exhibited an extremely low anti-CD3-induced T-cell responsiveness compared with non-progressors. In all people T-cell responsiveness and the number of CD4+ T-cells had improved 6 months after the start of zidovudine treatment. However, CD4+ T-cell numbers were not persistently elevated, and restoration of T-cell responsiveness was of only short duration. Our results show that zidovudine treatment in the asymptomatic phase of HIV infection did not result in a sustained improvement in T-cell function. Furthermore, they suggest that differences in clinical course among zidovudine-treated asymptomatics may be caused by heterogeneity of this group with respect to T-cell functional capacity at the start of treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Low number of functionally active B lymphocytes in the peripheral blood of HIV-1-seropositive individuals with low p24-specific serum antibody titers.

The in vitro synthesis of HIV-1, p24-, reverse transcriptase (RT)- and gp120-specific immunoglobulin (Ig) G by unstimulated peripheral blood mononuclear cells (PBMC) from 38 asymptomatic and 10 symptomatic HIV-1-seropositive individuals was analysed. In the majority of these individuals, spontaneous production of HIV-1- and gp120-specific IgG from PBMC cultures was demonstrated. In addition, in the majority of the PBMC cultures from individuals with high serum antibody titers to p24, spontaneous production of p24-specific IgG was shown. In contrast, no p24-specific IgG production was detected in PBMC cultures from seropositive individuals with low or no serum antibody titers to p24. A similar relationship between low or absent RT-specific serum antibody titers and the absence of in vitro RT-specific IgG synthesis was not demonstrated. Furthermore, it was shown that the number of p24-specific B lymphocytes in circulation, as calculated by a spot enzyme-linked immunosorbent assay, were significantly lower in individuals with low serum antibody titers to p24. These results suggest that the decline in p24-specific serum antibodies observed during progression towards AIDS is not merely a reflection of the clearance via immune complexes, but may also be attributable, at least in part, to a reduction of p24-specific antibody-producing active B lymphocytes.

Antibody-Producing Cells↗