RESUMEN
Expansion of the lysosomal apparatus occurs in subcortical white matter in brains from persons with AIDS. This study examined whether HIV-associated subcortical dementia (HAD) is significantly related to this lysosomal anomaly. Brain cortex and adjacent white matter from the middle frontal gyrus were obtained from the National NeuroAIDS Tissue Consortium. Lysosomal hydrolase activity was assayed in 57 subjects who underwent neuropsychological testing within 6 months prior to autopsy. Decedents were evaluated from 4 geographical sites in the United States: Galveston/Houston, Texas (n = 36), Los Angeles, California (n = 5), New York, New York (n = 5), and San Diego, California (n = 11). Increased beta-glucuronidase activity, a representative lysosomal glycosidase, was correlated with the amount of neurocognitive impairment. Significant correlation was present in 5 of 7 functional testing domains, including some that draw upon frontal lobe output (r = 0.419; P < 0.002). The biochemical anomaly was negligible in cerebral cortex and cerebrospinal fluid and was not correlated with brain dysfunction in those compartments. Glycosidase activation was associated significantly with increased HIV RNA concentration in brain tissue (r = 0.469; P < 0.021) and possibly with HIV RNA in cerebrospinal fluid (r = 0.266; P < 0.067). HIV RNA in blood plasma was not correlated. These results support the suggestion that abnormal metabolism in white matter glial cells contributes to cognitive slowing in persons with HAD. Because membrane turnover is routed through the endosome-lysosome apparatus, these data are in agreement with brain spectroscopic data that have suggested that there is an increase in membrane turnover in white matter glia.
Asunto(s)
Complejo SIDA Demencia/fisiopatología , Lóbulo Frontal/fisiopatología , Lisosomas/enzimología , Complejo SIDA Demencia/enzimología , Terapia Antirretroviral Altamente Activa , Trastornos del Conocimiento/fisiopatología , Lóbulo Frontal/enzimología , Lóbulo Frontal/ultraestructura , VIH-1 , Humanos , ARN Viral/líquido cefalorraquídeoRESUMEN
A gene expression profile of the human brain cortex was performed in people with HIV-1-associated dementia (HAD) using Affymetrix HG-U133 chips. Messenger RNA transcripts in middle frontal gyrus from subjects with HAD or milder neurocognitive dysfunction were compared to HIV-negative people. The analysis focused on ionic conductance carriers that control membrane excitation. Overexpressed ionic channel genes in brain cortex of subjects with dementia included (1) a calcium-driven K+ channel that prolongs afterhyperpolarization (AHP) current, (2) a leak type of K+ channel that prolongs the AHP, (3) an adenosine receptor that modulates cationic current via G proteins, (4) a G protein-coupled serotonin receptor that modulates cyclic AMP-linked current transduction, (5) a G protein-coupled dopamine receptor, (6) a GABA receptor subunit that conducts chloride current. Underexpressed current generators in the demented subjects included (1) two voltage-gated K+ channels that influence refractory periods and the onset of AHP, (2) a Na+ channel subunit that modifies current inactivation and the onset of the AHP, (3) a neuronal type of voltage-sensitive Ca+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Galpha protein that transduces metabotropic cationic current, (6) an NMDA receptor subunit, (7) a glycine receptor subunit that modulates chloride current. These gene expression shifts probably occurred in neurons because they were not present in gyral white matter. Acquired neuronal channelopathies were not associated with a generalized shift of neuronal or glial cell markers, which suggest that they were not an artifact produced by neurodegeneration and/or glial cell proliferation. Channelopathies were not correlated with a generalized increase of inflammatory cell transcripts and were present in demented people without, and with HIV encephalitis (HIVE). We surveyed experimentally induced perturbations of these channels to determine the implications for brain function. Eleven experimental channelopathies produced decreased neuronal firing frequencies and pacemaker rates in model neurons; seven channelopathies increase neuronal firing rates experimentally. The implied disruption of neuronal excitability is consistent with some features of HAD, including its potential reversibility after HIV-1 replication is suppressed, the abnormal electroencephalographic recordings, the lack of clear-cut correlation with neurodegeneration and the lack of strict correlation with brain inflammation. The channelopathy concept may have wide relevance to the subcortical dementias.
Asunto(s)
Complejo SIDA Demencia/complicaciones , Trastornos del Conocimiento/etiología , Canales Iónicos/metabolismo , Receptores de Superficie Celular/metabolismo , Complejo SIDA Demencia/genética , Complejo SIDA Demencia/metabolismo , Adulto , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Canales Iónicos/clasificación , Canales Iónicos/genética , Masculino , Persona de Mediana Edad , Examen Neurológico , Pruebas Neuropsicológicas , Cambios Post Mortem , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo , Receptores de Superficie Celular/clasificación , Receptores de Superficie Celular/genéticaRESUMEN
An 81-year-old female received voriconazole in a 7-day treatment course for a symptomatic Candida krusei urinary tract infection. Four days after the last dose, she developed toxic epidermal necrolysis. She was treated with intravenous immunoglobulin, and her symptoms promptly resolved.
Asunto(s)
Antifúngicos/efectos adversos , Inmunoglobulinas Intravenosas/uso terapéutico , Pirimidinas/efectos adversos , Síndrome de Stevens-Johnson/etiología , Triazoles/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Síndrome de Stevens-Johnson/fisiopatología , Síndrome de Stevens-Johnson/terapia , VoriconazolRESUMEN
OBJECTIVES: Dyslipidemia associated with antiretroviral therapy is a common clinical problem among HIV-infected patients. Considering that the challenge of adherence to drugs (both antiretroviral and lipid lowering) may be substantial in routine HIV care, our objective was to evaluate the lipid-lowering effects of statins and fibrates in the management of HIV dyslipidemias in clinical practice setting. METHODS: Retrospective review of 103 ethnically diverse dyslipidemic HIV patients on antiretroviral therapy treated with lipid-lowering drugs (using National Cholesterol Education and Prevention II [NCEP II] guidelines) who were followed for a median of 70 weeks. RESULTS: An overall mean reduction of 16% in total cholesterol, 20% non-HDL cholesterol, and 18% in triglycerides was noted. There were no significant changes in HDL levels. On evaluation of the different drug classes, the mean (median) change in total cholesterol, were -9 (-7)% with fibrates, -11 (-14)% with statins and -23 (-22)% for dual therapy with fibrates and statins. The triglycerides decreased by -11 (-40)% in those treated with fibrates; -1 (-21)% in those with statins alone, and -32 (-42)% in those with dual therapy. Overall less than a fifth of patients reached the defined NCEP target goal reduction. On logistic regression analysis, only stopping protease inhibitors/ritonavir was independently associated with significant cholesterol reduction (OR: 10.14; 95% CI: 2.1-48.9; p < 0.005). CONCLUSION: In a primary care setting, the use of statins and/or fibrates may add to the complexity of HIV care, with only modest lipid lowering effects.
Asunto(s)
Ácido Clofíbrico/uso terapéutico , Infecciones por VIH/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Lípidos/sangre , Adulto , Terapia Antirretroviral Altamente Activa , Colesterol/sangre , Estudios de Cohortes , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Hiperlipidemias/inducido químicamente , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
Ethnic minority, female, and drug-using patients may be less likely to receive highly active antiretroviral therapy (HAART), despite its proven benefits. We reviewed the medical records of a consecutive population of 354 patients entering care in 1998 at the Thomas Street Clinic, an academically affiliated, public, HIV-specialty clinic in Houston, to determine the factors associated with not receiving HAART as recorded in pharmacy records. Ninety-two patients (26.0%) did not receive HAART during at least 6 months of follow-up. Patients who did not receive HAART were more likely to be women and to have missed more than two physician appointments and were less likely to have a CD4 count <200 cells/microL or a viral load > or = 10 copies/mL. In multivariate logistic analysis, missed appointments (OR = 5.85, p<.0001), female sex (OR = 2.53, =.001), and CD4 count > or = 200 cells/microL (OR = 2.50, p=.001) were independent predictors of not receiving HAART. More than half the patients who never received HAART never returned to the clinic after their first appointment. Among patients new to care, women and those with poor appointment adherence were less likely to receive HAART. Efforts to improve clinic retention and further study of the barriers to HAART use in women are needed.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Servicios de Salud Comunitaria , Infecciones por VIH/tratamiento farmacológico , Adulto , Recuento de Linfocito CD4 , Etnicidad , Femenino , Infecciones por VIH/inmunología , Humanos , Masculino , Grupos Minoritarios , Pobreza , Caracteres Sexuales , Texas , Resultado del Tratamiento , Negativa del Paciente al Tratamiento , Población UrbanaRESUMEN
BACKGROUND: Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS: We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS: 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION: Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.