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Biomedical subjects

Richard W Price

Publications and source records attributed to Richard W Price.

25 records · Page 2Linked to original sources
PubMed2004

The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations.

The urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in extracellular matrix degradation and cell migration in the central nervous system (CNS). To investigate the role of the uPA/uPAR system in the pathophysiology of acquired immunodeficiency syndrome dementia complex (ADC), we measured soluble uPAR (suPAR) levels in cerebrospinal fluid (CSF) and plasma from human immunodeficiency virus (HIV)-1-infected patients and controls. CSF suPAR levels were significantly higher in HIV-1-infected patients than in controls and in patients with ADC or opportunistic CNS infections (CNS-OIs) than in neurologically asymptomatic patients, irrespective of HIV-1 disease stage. The highest levels of suPAR were found in patients with ADC, and among those with CNS-OIs in patients with cytomegalovirus encephalitis or cryptococcosis. Plasma suPAR levels were higher in HIV-1-infected patients than in controls and increased with HIV-1 disease stage regardless of the presence of CNS disease. In patients with ADC or CNS-OIs, CSF suPAR levels correlated with CSF HIV-1 RNA, but not with plasma suPAR concentrations. Highly active antiretroviral therapy was associated with a significant and parallel decrease of both CSF suPAR and HIV-1 RNA. In brain tissue from patients with HIV-1 encephalitis, uPAR was highly expressed by microglial and multinucleated giant cells staining positively for HIV-1. The overexpression of uPAR in the CNS of patients with ADC suggests that the uPA/uPAR system may contribute to the tissue injury and neuronal damage in this disease.

AIDS Dementia Complex↗
PubMed2004

Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease.

The urokinase plasminogen activator (uPA) and its receptor (uPAR) play important physiological functions in extracellular proteolysis, as well as cell adhesion and migration. Through dysregulation of these functions, the uPA/uPAR system might be involved in the pathogenesis of AIDS dementia complex (ADC), and, in fact, uPAR has been found to be overexpressed in the cerebrospinal fluid (CSF) and brain tissues of patients with ADC. On the other hand, its ligand uPA has been shown to down-regulate HIV replication in vitro. In this study, we examined uPAR and uPA expression in the brain of HIV-related lesions, as well as CSF levels of soluble uPAR (suPAR), uPA, and complexes between these two molecules (suPAR/uPA) in patients with HIV infection with or without ADC. uPAR was highly expressed by macrophages in both HIV encephalitis (HIV-E) or leukoencephalopathy (HIV-LE), with a distribution exceeding that of HIV p24 antigen. In contrast, uPA was detected only on rare cells in most of the cases. Both uPA and suPAR/uPA complex concentrations were significantly correlated with CSF suPAR levels, and CSF concentrations of both markers were higher in ADC patients than controls. However, uPA levels were substantially lower than corresponding suPAR levels. Although these findings remain correlative, they add support to the hypothesis that uPAR might be an important participant in the events leading to ADC. Additionally, these findings are consistent with a model in which overexpression of uPAR and overproduction of its soluble form may promote HIV replication via binding and removal of uPA from cell surface.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Antiretroviral drug treatment interruption in human immunodeficiency virus-infected adults: Clinical and pathogenetic implications for the central nervous system.

Interruption of antiretroviral treatment provides a well-defined 'experimental' paradigm to study the dynamics of central nervous system (CNS) infection and host responses in relation to those of systemic infection. We review our experience with 12 subjects (9 who were viremic and three with suppressed infection at baseline) followed longitudinally with serial lumbar punctures and neurological evaluations after stopping their antiretroviral treatments. All but two subjects exhibited an increase in cerebrospinal fluid (CSF) HIV RNA. Approximately half of the cohort developed a substantial, though asymptomatic, CSF lymphocytic pleocytosis with CSF counts rising to 30-60 cells/microL in five of the subjects. Subjects with higher CSF cell counts exhibited higher CSF HIV concentrations. We interpret the relationship of CSF HIV concentrations and pleocytosis in the context of a simple model of virus and cell exchange between blood and CSF. The proportionally greater increase in CSF HIV after treatment interruption indicates that CSF HIV infection is often more effectively suppressed by combination antiretroviral therapy than is systemic infection.

AIDS Dementia Complex↗
PubMed2002

HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy.

Postmortem neuropathologic reports for a consecutive series of 436 HIV-seropositive patients who died between 1985 and 1999 were matched with clinical data for 371 of them. Cases were divided into four groups depending on the date of death. The chosen time periods reflected the type of antiretroviral therapy available: before 1987 (before zidovudine); 1987-1992, the period of monotherapy (nucleoside analog reverse transcriptase inhibitors [NRTIs]); 1993-1995, the era of the use of dual NRTI combinations; and 1996-1999, the era of highly active antiretroviral therapy (HAART) containing protease inhibitors. Fifty-seven percent of our cases in this group had been prescribed HAART. In our study population, accessibility to the latest antiretroviral therapy was widespread. The total number of HIV autopsies declined after the advent of combination therapy. The prevalence of opportunistic infections-cytomegalovirus, toxoplasmosis, cryptococcosis, and central nervous system lymphoma-decreased over time. Cerebral tuberculosis, aspergillosis, herpes, and progressive multifocal leukoencephalopathy showed a downward trend, but the numbers were too low for statistical analyses. The incidence of HIV encephalopathy increased over time (p =.014). The rising prevalence of HIV encephalopathy at time of death may reflect a longer survival time after initial HIV infection in the HAART era. Although combination therapies decrease overall mortality and prevalence of CNS opportunistic infections, these therapies may be less active in preventing direct HIV-1 effects on the brain.

AIDS Dementia Complex↗
PubMed2002

A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy.

To determine whether microbiologic cure of acquired immunodeficiency syndrome (AIDS)-related disseminated cryptococcosis is possible in patients receiving highly active antiretroviral therapy (HAART), antifungal therapy was discontinued in 6 patients with a history of disseminated cryptococcosis who had received > or =12 months of antifungal therapy. All were asymptomatic and had absolute CD4+ T cell counts of >150 cells/microL (range, 178-525 cells/microL). Blood, cerebrospinal fluid (CSF), and urine samples were obtained for fungal culture. Serum and CSF cryptococcal antigen titers were also obtained. All 6 patients had CSF and blood cultures negative for Cryptococcus neoformans and were receiving HAART. All patients' subsequent cultures remained sterile, and all patients were clinically asymptomatic 24 months after ending antifungal therapy. Disseminated cryptococcal disease can be cured by prolonged antifungal therapy in some patients with AIDS who experience sustained CD4 lymphocyte increases while receiving HAART.

AIDS-Related Opportunistic Infections↗