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Biomedical subjects

Francesca Moretti

Publications and source records attributed to Francesca Moretti.

At least 19 recordsLinked to original sources
PubMed2006

Influence of folate serum concentration on plasma homocysteine levels in HIV-positive patients exposed to protease inhibitors undergoing HAART.

BACKGROUND: Homocysteinemia (Hcy) increase and risk factors in HIV-positive patients are not clear yet. METHODS: HIV-positive patients on stable highly active antiretroviral therapy (HAART) regimens for at least 6 months were enrolled in this cross-sectional study. Among other factors, vitamin B12, folate and length of exposure to protease inhibitors (PIs) were evaluated for their possible correlation with hyper-Hcy (>13 micromol/l in females; >15 micromol/l in males) by logistic regression analysis. RESULTS: Ninety-eight HIV-positive patients were recruited. Twenty-eight (28.6%) had hyper-Hcy. Length of exposure to antiretroviral therapy and PIs did not result to be significantly associated with hyper-Hcy risk. Normal folate level was the only factor associated with the outcome, resulting protective from hyper-Hcy, either at univariate (OR = 0.22; CI 95% = 0.06-0.86; p = 0.029) and multivariable (OR = 0.24; CI 95% = 0.06-0.94; p = 0.04) logistic regression analysis. Folate predictive value of hyper-Hcy risk was driven by levels in the lowest quartiles of the study population (i.e. <10.9 nmol/l). CONCLUSIONS: No significant correlations were observed between hyper-Hcy and length of exposure to antiretroviral therapy or PIs. Folate could be a confounding factor in the association between hyper-Hcy and PI exposure found by others. The potential value of folate supplementation, in those who are deficient and in those with hyper-Hcy, merits study.

Adult↗
PubMed2006

Highly active antiretroviral therapy reduces the age-associated risk of dementia in a cohort of older HIV-1-infected patients.

Historically, older patients have shown a higher risk of HIV-1-associated dementia (HIVD). The objective of this study was to evaluate the association of aging with HIVD and minor cognitive motor disorders (MCMDs) during the late-highly active antiretroviral therapy (HAART) era and to analyze characteristics, predictive factors, and survival of older HIV-1-infected individuals affected by these disorders. A nested longitudinal study was designed for a cohort of HIV-1-infected individuals with neurological diseases. Multiple logistic regression and Cox regression for survival were employed. From 2000 to 2003, 195 patients with HIVD (53%) or MCMD (47%) were enrolled. The cumulative prevalence of these two disorders was 21%, with an increasing rate for calendar year (p < 0.001). Previous antiretroviral exposure occurred in 46% of patients. Mean CD4(+) cell count and plasma HIV-1 RNA were 144 cells/microl and 4.5 log10 copies/ml, respectively. The mean age was 44 years (SD, 9.9), with 35% of patients aged 20-39 years (I), 45% aged 40-49 years (II), and 20% aged >/=50 years (III). Among drug-naive patients, the prevalence of HIVD progressively increased in older subjects: 7.2% (I), 15.3% (II), and 27.3% (III) (p < 0.001), whereas no significant increase in HIVD with older age was observed in drug-treated subjects. Older age was independently associated with an increased risk of HIVD (odds ratio, 6.44; 95% confidence interval, 2.82-14.69) in naive but not in experienced individuals, but had no significant effect on survival. No significant effect of age was observed for MCMD. We conclude that in our cohort, HAART seems to alter the relationship between aging and HIVD, conferring a neuroprotective effect to older patients. These results may have significant implications for the clinical management of the older HIV population.

AIDS Dementia Complex↗
PubMed2005

A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes.

The p53 protein plays a pivotal role in determining the quality of the response to DNA damage through its transcriptional activity. Upon DNA damage, p53 is activated by post-translational modifications, binds its cognate sequences on the promoters of its target genes and stimulates transcription. In proliferating keratinocytes, the activity of p53 is blunted by its inhibitor DeltaNp63alpha. Here, we describe a novel mechanism through which DeltaNp63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of DeltaNp63, which precedes DeltaNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated DeltaNp63 has a lower affinity for p53REs and detaches from cell cycle arrest and apoptotic promoters, thus allowing the rapid activation of p53-dependent transcriptional apoptotic program.

Apoptosis↗
PubMed2005

A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study.

BACKGROUND: It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy. METHODS: In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study. RESULTS: Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response. CONCLUSIONS: The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.

Adult↗
PubMed2005

Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. METHODS: JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. RESULTS: The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. CONCLUSIONS: Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

Adult↗
PubMed2004

Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy.

BACKGROUND: Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. METHODS: Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. RESULTS: With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. CONCLUSIONS: TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed2004

The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene.

Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.

Animals↗
PubMed2004

Modifications in SENV DNA detection and/or SENV subtype determination over a prospective follow-up in a cohort of HIV-positive patients: is this a moving target?

SEN virus (SENV) is a new family of single-stranded DNA viruses with eight different strains, A-H. The modifications in SENV DNA detection and subtype distribution were studied over a long-term follow-up (48 +/- 32.5 months) in 52 HIV-infected patients. 46% of the patients in the first sample and 34.6% in the second sample were found to have detectable SENV viremia. While the most prevalent variant in the first sample was found to be genotype A (83.3%), the second sample revealed a broader subtype diversification. Several epidemiological and clinical variables were tested in univariate model for clearance of detectable SENV viremia, but none of them reached statistical significance. In conclusion, a high degree of instability of both SENV DNA detection and subtype distribution in a cohort of HIV-infected patients was suggested, which may have important implications for further studies on both SENV epidemiology and its clinical impact.

Adult↗
PubMed2004

[Communication strategies to motivate patients to follow doctor's advice].

The growing attention to the preventive aspects of health care has raised the question how to motivate patients to modify potentially health damaging habits such as smoking, alcohol abuse, wrong diet or poor exercise. The present paper examines the theory and the techniques of the motivational interview and proposes practical examples which illustrate how the physician may overcome patient's resistance. The authors describe the principal aspects of the process of motivational change and some of the corresponding attitudes and skills which the physician has to adopt in each phase of this process. The basic assumptions are that the patient is the main agent of change and that the physician's task is to facilitate this process and to sustain the patient's efforts.

Communication↗
PubMed2003

HIV susceptibility to amprenavir: phenotype-based versus rules-based interpretations.

OBJECTIVES: The objective was to study genotypic correlates of discordant interpretations of amprenavir (APV) resistance between a rules-based algorithm and either recombinant phenotype or virtual phenotype. METHODS: HIV resistance mutations found in patients from the GenPheRex study were interpreted with VGI-TRUGENE (version 5.0; VGI) and compared with either recombinant-phenotype (Antivirogram, r-PHT) or virtual-phenotype (Virtual-Phenotype, v-PHT) interpreted through Virco biological cut-offs. RESULTS: Among 180 samples available, 56 (31.1%) were discordant with the observed genotype interpretation results, as a result of being judged as sensitive by r-PHT or v-PHT but resistant by VGI (S/R). Only the I84V mutation was almost invariably found in concordant resistant isolates compared with S/R isolates (60% versus 0%, respectively; P < 0.0001). Notwithstanding this, the number of multi-protease inhibitor-associated mutations (PAMs) was significantly higher in the concordant resistant isolates; the prevalence of >3 PAMs was 56.52% versus 33.93% in R/R and S/R isolates, respectively (P = 0.01). Correspondence analysis confirmed the relevance of PAMs, although additional mutations appeared to be correlated with APV resistance. CONCLUSIONS: The rate of discordance between rules-based and either r-PHT or v-PHT interpretations for APV was high. Mutation I84V and accumulation of >3 PAMs were found to be associated with resistance as interpreted with all systems tested. However, our results indicate that a number of mutations may have an impact on APV resistance, but that they are missed by current interpretation algorithms and this merits further investigations.

Algorithms↗
PubMed2003

Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin.

Angiotensin-II (AII), the dominant effector of the renin-angiotensin system, is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines through nuclear factor kappa B (NFkappaB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFkappaB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFkappaB activation by AII is mediated by the NFkappaB-inducing kinase (NIK), a common mediator of NFkappaB activation by inflammatory cytokines, such as TNF-alpha. However, NFkappaB stimulation by AII differs from that of TNF-alpha since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFkappaB activation. In analogy with TNF-alpha-dependent activation of NFkappaB, treatment with either the anti-oxidant N-acetyl cysteine (NAC) or the cyclooxygenase (COX) inhibitor acetyl salicylic acid (aspirin), but not indometacin, prevents the induction of NFkappaB-dependent transcription by AII. Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFkappaB. AII also activates the inflammatory p38 kinase in endothelial cells, an effect inhibited by exposure to either NAC or asp. Pharmacological interference of the p38 pathway, with the inhibitor SB 202190, prevented AII-mediated activation of the NFkappaB target V-CAM, without affecting degradation of IkappaBalpha. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways-NFkappaB and p38-both of which are sensitive to asp and antioxidants.

Angiotensin II↗
PubMed2003

Modifications of health resource-use in Italy after the introduction of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection. Pharmaco-economic implications in a population-based setting.

OBJECTIVE: To assess the impact of highly active antiretroviral therapy (HAART) on health resource utilisation (HRU) and to estimate associated direct costs in a population based setting. DESIGN: Retrospective study of all patients in the Institute of Infectious and Tropical Diseases (Brescia, Northern Italy) during a 4 years period related to the prescription of HAART has been performed: from 1997 (before HAART) to 2000 (after substantial period of HAART prescription). MAIN OUTCOME MEASURES AND RESULTS: HIV inpatient admissions (IA's) decreased from 506.8/1000 patients (pts) in 1997 to 246.3/1000 pts in the year 2000. Day care admissions (DCA's) also decreased from 1658.3/1000 pts to 942/1000 pts, while outpatient consultations (OC's) increased from 2046.9/1000 pts to 2590.6/1000 pts in the same years, respectively. By contrast, a relative increase of IA's and DCA's of patients whose serostatus was HIV-negative or unknown has been found. Cost of antiretroviral therapy increased by 2582 Euro (2272 US Dollars), while cost of HIV care (IA+DCA+OC) decreased by 1546 Euro (1360.4 US Dollars) per patient, resulting in a saving in direct cost equal to 60% of the increase in the expenditure for antiretroviral drugs. CONCLUSIONS: Our results demonstrate the shift of HIV care from inpatient to outpatient services that occurred after HAART had been introduced into clinical practice. Despite persisting clinical benefits, an increase in total direct cost for HIV pts has been seen for the first time during the HAART era in the year 2000, probably due to an over-prescription of HAART, according to actual Guideline for antiretroviral therapy use, to pts who were not at risk of clinical progression in the short term. Pharmacoeconomical surveillance of HAART is necessary while a favourable impact on the saving in cost is expected from the new treatment guidelines that suggest a relative delay in starting HAART.

Ambulatory Care↗
PubMed2003

Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA).

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Acquired Immunodeficiency Syndrome↗
PubMed2003

SENV infection in HIV-positive patients: prevalence, subtype characterization, and impact on HIV disease progression.

Among 165 HIV-infected patients, prevalence of SEN virus (SENV) infection was 51.5%, with subtype A predominance and unique SENV variant (67%), but also SENV superinfections with multiple variants were frequent. High prevalence, superinfection and broad SENV subtype diversification have been demonstrated, all linked to intravenous drug use (IVDU) as a risk factor for HIV acquisition. At multivariate analysis, SENV infection did not appear to have any negative impact on survival, while a possible protective effect needs further investigation.

Adult↗
PubMed2003

Persistence of HIV-1 drug resistance mutations and emergence during antiretroviral treatment interruption: considerations from a clinical case.

BACKGROUND: HIV drug resistance (HDR) represents a crucial problem in antiretroviral therapy today. HDR mutations can accumulate, persist in the proviral genome and re-emerge, promoting further failure of rescue regimens. Resistance testing on the proviral genome has been suggested in order to detect the presence of archived resistance mutations and to guide drug prescription. CASE REPORT: We report the persistence of HDR mutations to protease inhibitors (PIs) during effective highly active antiretroviral therapy (HAART) not including PIs and their transient re-emergence after treatment interruption. Further follow-up has demonstrated a progressive reversion toward the wild type. At that point in time, proviral DNA analysis was not more sensitive in detecting mutations than tests of the plasma viral load. CONCLUSIONS: This case demonstrates that HDR mutations can persist even though plasma viral load is undetectable, implying the ability of HIV to escape from treatment recycling and the use of drugs to which HIV is cross-resistant. Also, this case suggests that plasmatic and intracellular HIV compartments find a balance under conditions of active viral replication, which could hamper detection of resistance mutations in the proviral DNA. Therefore, in the case of active viral replication, proviral analysis may not actually provide more information than testing the plasma viral load. The clinical utility and specific indications for testing proviral DNA require further investigation.

Anti-HIV Agents↗
PubMed2002

DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest.

p53 and p73 genes are both activated in response to DNA damage to induce either cell cycle arrest or apoptosis, depending on the strength and the quality of the damaging stimulus. p53/p73 transcriptional activity must be tightly regulated to ensure that the appropriate biological response is achieved and to allow the cell to re-enter into the cell cycle after the damage has been repaired. In addition to multiple transcriptionally active (TA) isoforms, dominant negative (DN) variants, that lack the amino-terminal transactivation domain and function as trans-repressors of p53, p63 and p73, are expressed from a second internal promoter (P2-p73Pr). Here we show that, in response to a non apoptotic DNA damage induced by low doses of doxorubicin, p53 binds in vivo, as detected by a p53-specific chromatin immunoprecipitation assay, and activates the P2-p73 promoter. DN-p73alpha protein accumulates under the same conditions and exogenously expressed DN-p73alpha is able to counteract the p53-induced activation of the P2-p73Pr. These results suggest that DN-p73 may contribute to the autoregulatory loops responsible for the termination of p53/p73 responses in cells that do not undergo apoptosis. Accordingly, the activation of the P2-p73Pr is markedly enhanced in both p73-/- murine fibroblasts and in human cells in which p73 transcripts are selectively knocked-out by p73-specific small interfering RNAs.

Apoptosis↗