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Biomedical subjects

S Vella

Publications and source records attributed to S Vella.

At least 19 recordsLinked to original sources
PubMed2003

Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study.

OBJECTIVES: To describe the prevalence and risk factors of poor CD4 count rise despite a good virological response on highly active antiretroviral treatment (HAART). METHODS: The patients from the EuroSIDA study who started HAART with a baseline CD4 count of <350 cells/microL and where all viral load (pVL) measures remained below 500 HIV-1 RNA copies/mL between 6 and 12 months after the start of HAART were included. The risk factors for poor CD4 count rise were analyzed by multiple regression. RESULTS: Seven hundred and eighty patients were included. A low CD4 count response was observed in 225 patients (29%). The risk factors for this condition were older age, lower CD4 count at baseline, higher increase from the nadir to baseline CD4 count and lower pVL at baseline. Patients taking > or =one drug from each of the three antiviral classes were more likely to have a good CD4 response but a minority of the study participants was taking this treatment regimen (3.1%) and the confidence interval was large. CONCLUSIONS: A poor immune reconstitution despite a good virological control is frequent after initiation of HAART among patients with a baseline CD4 count of <350 cells/microL. The underlying mechanisms leading to this condition seems mainly driven by the age and the baseline immunological and virological status of the patients.

Adult↗
PubMed2003

Acute leukoencephalopathy after inhalation of a single dose of heroin.

We describe extended and repeat magnetic resonance (MR) examinations in the case of a 16-year-old male who developed acute left-sided sensorimotor hemiplegia after a single dose of inhaled heroin. MRI revealed symmetrical hyperintense signals in T 2 -weighted images and massive diffusion disorders in the diffusion weighted images predominantly in parieto-occipital subcortical white matter and both ventral globi pallidi with preservation of U fibers and no brain oedema. MR spectroscopy data were compatible with combined hypoxic and mitochondrial damage resulting in axonal injury without demyelination. Normal values and variations had been obtained from spectra of five age-matched subjects. This is the first reported MR follow-up study of leukoencephalopathy occurring acutely after a first inhaled dose of heroin. We postulate that toxic spongiform leukoencephalopathy in heroin addicts may be the outcome of a complex mechanism directly triggered by heroin and causing mitochondrial as well as hypoxic injury in specific and limited areas of white matter.

Acute Disease↗
PubMed2002

HIV-related morbidity and mortality in patients starting protease inhibitors in very advanced HIV disease (CD4 count of < 50 cells/microL): an analysis of 338 clinical events from a randomized clinical trial.

BACKGROUND: AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/microL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be considered equally safe in patients with a previously very low CD4 nadir. METHODS: We evaluated in detail all the AIDS defining events observed during a 48-week clinical trial in 1251 nucleoside reverse transcriptase inhibitor-experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/microL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated. RESULTS: Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per microL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/microL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/microL, with only four deaths occurring in the presence of a CD4 count above 100 cells/microL. CONCLUSIONS: Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/microL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed2001

Vaginal transmission of HIV-1 in hu-SCID mice: a new model for the evaluation of vaginal microbicides.

OBJECTIVE: To develop an animal model of vaginal transmission of HIV-1 for the evaluation of vaginal microbicides. DESIGN: Vaginal infection was performed in SCID mice reconstituted with 4 x 107 human peripheral blood lymphocytes (hu-PBL) by non-invasive vaginal administration. The hu-PBL were previously infected in vitro with a non-syncytium (NSI) strain of HIV-1 (SF162) (hu-PBL-SCID). Lymphocyte migration in vivo was examined using fluorescently labelled human lymphocytes. METHODS: The percentage of CD4 T cells, plasma viral load and p24 antigen were evaluated using fluorescent activated cell sorting (FACS), the Amplicor HIV-1 monitor kit and enzyme-linked immunosorbent assay, respectively. Polymerase chain reaction (PCR) analysis was performed on DNA extracted from spleen and lymph nodes. For in vivo migration of labelled lymphocytes, the mice were sacrificed after 4, 24 and 48 h; vaginae and local lymph nodes were removed, snap frozen with OCT, sectioned and examined by fluorescent microscopy and FACS. RESULTS: HIV transmission was established using virus-infected cells inoculated vaginally, as shown by FACS, HIV viral load, p24 and PCR results. Labelled cells were easily located within the vaginal tissues after 4 h. However, few or no cells could be identified after 24 or 48 h at the vaginal level, whereas labelled cells could be detected at the level of regional lymph nodes. CONCLUSIONS: Because of its simplicity and practical features compared with other animal models, the vaginal HIV-infected hu-SCID mouse model may prove useful to test the activity of compounds against cell-associated HIV and, possibly, other sexually transmitted diseases.

Animals↗
PubMed2001

HIV-protease inhibitors contribute to P-glycoprotein efflux function defect in peripheral blood lymphocytes from HIV-positive patients receiving HAART.

P-glycoprotein (P-gp) has been found expressed in normal human cells, such as bone marrow and peripheral blood cells. The aim of this study was to investigate whether HIV-protease inhibitors (HIV-PIs) interact with P-gp efflux function in normal human peripheral blood lymphocytes (PBLs) and CD34+ progenitor cells. Moreover, we analyzed the in vivo effect of HIV-PIs on P-gp function in PBLs from HIV-infected patients receiving highly active antiretroviral therapy (HAART). We found that HIV-PIs (i.e., ritonavir, saquinavir, nelfinavir and indinavir) interfere with P-gp function in normal PBLs as demonstrated by the reduced efflux of rhodamine 123 (Rh123). This effect was dose-dependent and suggested the following hierarchy: ritonavir > saquinavir > nelfinavir > indinavir. We further analyzed the effect of HIV-PIs on the P-gp function in specific PBLs subsets. Our results show an HIV-PI-induced inhibition of P-gp function in CD4+ and CD8+ T cell subsets, mostly caused by the effect on the naive compartment of both CD4+ and CD8+ T cells. The same inhibitory effect was found in CD34+ hematopoietic progenitor cells. With respect to the in vivo evaluation of P-gp function in PBLs from HIV-infected patients, we found reduced levels of Rh123 efflux that reached the lowest value in AIDS patients receiving HAART. We concluded that HIV-PIs interfere with P-gp function in major cellular targets for HIV infection, such as CD4+ T cells and CD34+ progenitor cells. This ability may contribute to P-gp efflux function defect found in HIV-infected patients and suggests that drug interaction studies are crucial to an overall understanding of the effects of this important group of drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine.

OBJECTIVE: To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents. DESIGN: All patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response. METHODS: Within the three study groups (zidovudine/nevirapine, zidovudine/didanosine or zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving zidovudine/nevirapine/didanosine. RESULTS: After 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30--60 weeks. At 24 weeks, zidovudine resistance developed in 4/40 isolates but was more frequent after 30--60 weeks, especially in patients on two drugs. The degree of zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with zidovudine/didanosine (P = 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C. CONCLUSION: The use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials.

Anti-HIV Agents↗
PubMed2001

High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals.

OBJECTIVE: To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial. METHODS: The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value of k, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively. RESULTS: The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02). CONCLUSIONS: A high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine.

Anti-HIV Agents↗
PubMed2001

Expression of P-170 glycoprotein sensitizes lymphoblastoid CEM cells to mitochondria-mediated apoptosis.

Multidrug resistance caused by P-glycoprotein (P-170) is a phenomenon by which cells exposed to a single drug acquire resistance to other structurally and functionally unrelated drugs. This is a widespread phenomenon described in vivo in the management of infectious as well as non-infectious diseases. Several in vitro models have been developed in order to evaluate physiopathological properties of P-170. Among these are P-170-expressing variants of the human T-lymphoblastoid CEM cell line called VBL100. As a general rule, drug resistance normally results in resistance to apoptosis induction. By contrast, a paradoxical activity is exerted in this cell model by the cytokine tumour necrosis factor-alpha (TNF-alpha), which is capable of inducing apoptosis in P-170-expressing variants better than in wild-type (wt) cells. In the present study we partially address the mechanisms underlying this activity. In fact, the susceptibility of VBL100 cells to TNF-alpha appears to be specifically due to the depolarization of their mitochondrial membrane, a key factor for apoptotic induction. The same was observed with staurosporine, a specific mitochondrion-mediated proapoptotic chemical probe. Conversely, other proapoptotic stimuli, such as Fas/CD95 or the anti-cancer drug etoposide, did induce significant cell death in wild type cells only. Thus, schematically, mitochondrially dependent stimuli appeared to be more effective in VBL100-cell killing, while 'physiological' stimuli showed the opposite behaviour. Importantly, under steady-state conditions, VBL100 cells displayed per se a mitochondrial membrane hyperpolarization that appeared strictly related to their high susceptibility to specific apoptotic stimuli. In conclusion, the study of a well-established cell model such as that represented by the wt/VBL CEM lymphoid cell line seems to suggest that the multidrug resistance phenotype can specifically sensitize cells towards 'unphysiological', mitochondria-associated cell death cascade or, in the same fashion, it could shift cells from type I (mainly plasma membrane-associated) towards type II (mainly mitochondrial membrane-associated) phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Modification of cell perifusion for extended study of hormone release in the rat pituitary.

We use a flow-through cell perifusion system allowing continuous sampling of Luteinizing Hormone (LH) release from excised pituitary tissue. With this system, we are able to sample from viable tissue in primary culture for three days as opposed to a more typical of primary culture of 6-12 hours. Rat pituitary tissue was perifused and challenged with a physiological dose of LHRH. Samples were collected for 3.5 hours on each of 3 consecutive days in a refrigerated fraction collector and assayed for LH concentration by radioimmunoassay. In these experiments we tested two types of media, each with or without fetal calf serum supplementation, for their ability to support pituitary tissue for extended lengths of perifusion. In addition, we broadened the use of aseptic technique, sterile media and equipment to limit microbial contamination. Our results indicate that perifusion of pituitary tissue can be done successfully for 3 or more days at a modest cost, greatly increasing the amount of information that can be collected from each piece of tissue harvested.

Animals↗
PubMed2001

Markers of cell death-activation in lymphocytes of vertically HIV-infected children naive to highly active antiretroviral therapy: the role of age.

BACKGROUND: Apoptosis plays a major role in depleting CD4(+) lymphocytes during infection with HIV-1. Few data exist on its role during HIV infection of children. Sensitivity of peripheral blood lymphocytes (PBLs) to apoptotic stimuli and the importance of the patient's age remain unclear. OBJECTIVES: We sought to analyze the following: (1) markers of cell death-activation (CD95, CD45 isoforms, and CD28) in PBLs from vertically HIV-infected children of different ages before highly active antiretroviral therapy; (2) changes in other PBL populations; (3) PBL sensitivity to cell death and mitochondrial damages; and (4) role of age during progression of infection. METHODS: Cell culture techniques and flow cytometry were used to analyze surface antigens, PBL susceptibility to apoptosis, or PBL susceptibility to change of mitochondrial membrane potential. RESULTS: Donor age had a strong negative correlation with numbers of CD4(+) and CD8(+) T cells. Virgin T lymphocyte (CD45RA(+), CD95(-)) levels and those of CD95(+) cells showed no correlation with the children's clinical status but did show a correlation with patient age. CD28(-) T lymphocytes were markedly augmented in HIV-infected children but were unrelated to stage of infection or age. A relevant decrease in B lymphocytes and an increase in natural killer cells were also found. Finally, PBLs from HIV-positive children had a marked tendency to undergo apoptosis and mitochondrial damage. CONCLUSION: Changes in PBL phenotype, increased expression of CD95, and high sensitivity to apoptosis suggest that a precocious aging of the immune system occurs in HIV-infected children.

Adolescent↗
PubMed2000

A randomized trial comparing the introduction of ritonavir or indinavir in 1251 nucleoside-experienced patients with advanced HIV infection.

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Adult↗
PubMed2000

Quality of life outcomes of combination zidovudine- didanosine-nevirapine and zidovudine-didanosine for antiretroviral-naive advanced HIV-infected patients.

OBJECTIVES: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial). DESIGN: A 48-week randomized, double-blind trial. METHODS: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health. RESULTS: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score. CONCLUSION: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.

Adult↗
PubMed2000

SPECT during sleepwalking.

Sleepwalking is a dissociation between body sleep and mind sleep. We report single photon emission computed tomography (SPECT) in a man with a history of sleepwalking. Our findings suggest that this dissociation arises from activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems.

Adolescent↗