From a 16th century monastery to a 21st century orthopaedic hospital.
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Christianity↗
Biomedical subjects
A Viganò
Publications and source records attributed to A Viganò.
Analysis of bone mineral content in horizontally HIV-infected children naïve to antiretroviral treatment.
Low bone mass is a frequent finding in HIV-infected individuals. Reduced bone mass has been found in vertically infected children who are receiving antiretroviral treatment. Little is known about bone mass in horizontally infected young patients who are naïve to antiretroviral therapy. We measured the bone mineral content (BMC) at the lumbar spine and in the whole skeleton by using dual-energy X-ray absorptiometry (DXA) in 16 HIV-infected children (age 9.3 +/- 3.9 years) naïve to antiretroviral treatment, and in 119 healthy children (age 9.7 +/- 3.3 years). Thirteen patients were also pair-matched by anthropometric measures, sex, and age with healthy children. Median spine BMC of HIV-infected children was 14.9 g (8.2-39.2 g), and whole body BMC was 1106.1 g (55.5-2344.1 g). Spine BMC of healthy children was 18.6 g (6.8-52.2 g), and whole body BMC was 1213.5 g (541.0-2722.0 g). Multivariate analysis showed a mean difference of spine BMC values of 0.004 g (P = 0.64) between the two groups. Similarly, the whole body BMC difference between the two groups (0.001 g) was not statistically significant (P = 0.55). Mean spine BMC measurements in the case-control evaluation were 21.1 g (9.7 g) (patients), and 22.3 g (6.9 g) (controls). Whole body BMC measurements of patients and controls were 1258.5 g (539.6 g) and 1311.1 g (479.2 g), respectively. In both cases the differences were not significant. The duration of HIV infection did not relate to BMC values. In conclusion, horizontally HIV-infected children naïve to antiretroviral therapy have bone mineral measurements comparable to those of healthy children.
Absorptiometry, Photon↗
Adherence to antiretroviral therapy and its determinants in children with human immunodeficiency virus infection: a multicentre, national study.
AIM: To investigate rates and determinants of adherence to antiretroviral therapy in Italian children infected with the human immunodeficiency virus (HIV). METHODS: An observational, cross-sectional multicentre study was performed through a structured interview with the caregivers of HIV-infected children. The interview included quantitative information on adherence in the 4 d before interview. Sociodemographic, clinical and psychosocial characteristics of children were recorded. RESULTS: 129 children (median age 96 mo) were enrolled, of whom 94 were on highly active antiretroviral therapy (HAART). Twenty-one (16%) omitted more than 5% of total doses in 4 d and were considered non-adherent. However, only 11% of caregivers reported that therapy had been administered at the correct times. No significant difference was found between age and the stage of HIV infection. Children aware of their HIV status were less adherent. Individual drugs showed a broad adherence pattern and children who received HAART were more adherent. Children receiving therapy from foster parents were more adherent than those receiving drugs from biological parents or relatives. CONCLUSIONS: Adherence is a major problem in children. Psychological rather than clinical or sociodemographic features and types of drug are major determinants of adherence.
Adolescent↗
Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy.
BACKGROUND: Combined use of dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) allows a precise estimate of regional body composition and intra-abdominal adipose tissue (IAT). Data on body composition in HIV-infected children (HIV+) receiving highly active antiretroviral therapy (HAART) with (LD+) and without (LD-) lipodystrophy are lacking. METHODS: DXA scans were performed in 34 HIV+: six LD+, 28 LD- and 34 pair-matched (age, sex and body mass index) healthy controls (HC): six for LD+ (HC+) and 28 for LD- (HC-). MRI scans were performed in 16 HIV+: six LD+, 10 LD- and 16 pair-matched (age and sex) HC. Data were analysed by analysis of variance, post hoc Fisher test and Mann-Whitney test. RESULTS: LD+ and LD- were similar for: previous exposure to zidovudine/zidovudine + didanosine, months on HAART (stavudine + lamuvidine + one protease inhibitor), CD4+ cells, patients with HIV-RNA < 50 copies/ml. In HIV+ and HC, fat mass and distribution were significantly different, whereas lean mass was comparable. Thus, LD+ and LD- as compared to HC+ and HC- respectively showed: (1) reduced fat amount and percentage; (2) lower truncal fat mass; (3) markedly reduced limbs fat mass. Within the HIV+ group, (4) LD+ showed higher fat trunk/fat total (P = 0.04) and lower fat limbs/ fat total ratios (P = 0.009) than LD-; (5) LD+ showed larger IAT areas than LD- and HC (P < 0.0003). CONCLUSIONS: Increased central fat and peripheral lipoatrophy are distinctive features of all HAART-treated children. Changes in body fat composition are detectable by DXA even in the absence of signs of Lipodystrophy. Only LD+ show true central obesity.
Absorptiometry, Photon↗
Bone mineral loss through increased bone turnover in HIV-infected children treated with highly active antiretroviral therapy.
OBJECTIVES: To evaluate the occurrence and define the aetiology of osteopenia in children receiving highly active antiretroviral therapy (HAART). METHODS: Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and five naive to any antiretroviral treatment (untreated). Six HAART-treated children showed clinical evidence of lipodystrophy. N-terminal propeptide of type-I procollagen (PINP), bone-specific alkaline phosphatase (BALP) and N-terminal telopeptide of type I collagen (NTx) were measured. Results were compared with those obtained in 314 healthy controls. Differences between HIV-positive and healthy children and within the HIV-positive group were assessed by multivariate analyses, controlling for confounding variables (age, sex, weight and height). RESULTS: HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children. Total body BMD was lower (P < 0.005) in HAART-treated children with lipodystrophy than in untreated patients, while children on HAART but without lipodystrophy had intermediate values. BALP, PINP and NTx were similar among untreated and healthy children. HAART-treated children had higher BALP levels than healthy (P = 0.0007) and untreated (P = 0.045) children. PINP values showed the same trend as BALP. HAART-treated children had higher NTx urine levels than healthy (P < 0.0001) and untreated (P = 0.041) children. CONCLUSIONS: HAART seems a new risk factor for life-long osteoporosis in children. An increased rate of bone turnover causes BMD decrease. Severity of osteopenia seems to be related to lipodystrophy.
Absorptiometry, Photon↗
Protein analysis by capillary zone electrophoresis utilizing a trifunctional diamine for silica coating.
A novel method is here reported for the analysis of mixture of proteins with pI ranging from pH 3-9.5 in an ample pH interval (pH 2.5-9.0) without adsorption onto the naked silica wall. It consists of treating the capillary surface at alkaline pH, typically 9.0, with small amounts (2-4 mM) of a quaternarized piperazine derivative: (N-methyl-N-omega-iodobutyl)-N'-methylpiperazine (Q-PzI). It appears that this compound is able to dock onto the wall via trifunctional links: a salt bridge via the quaternary nitrogen, a hydrogen bond via the tertiary nitrogen, and finally, a covalent link via the terminal iodine in the butyl chain and a neighboring ionized silanol. This last reaction seems to be completed in a few minutes of incubation of the capillary at room temperature. Because the compound is permanently affixed to the wall, its presence is not needed during protein/peptide separations. By properly dosing the level of Q-PzI in the preconditioning step, it is possible to strongly reduce the electroendoosmotic flow (EOF), zero it, or reverse it. Unlike dynamic coatings with oligoamines, which are most effective only at acidic pH values and are required as additives during separations, Q-PzI is effective in an ample pH interval (pH 2.5-9.0) and is not needed during the CZE analysis. A broad pI (pH 3-10) protein mix can be separated according to protein mobility in free phase, suggesting a strong modulating capacity of the functionalized wall. The same separation is not obtained in capillaries permanently coated with neutral, hydrophilic polymers (such as polyacrylamide), even if the quality of a single protein/peptide profile in Q-PzI-conditioned capillaries is equivalent to those obtained in capillaries permanently coated. Although there is strong indirect evidence of the ability of Q-PzI to alkylate the silica wall, to which it is then irreversibly bound, such an alkylation event does not occur with proteins on potentially reacting sites, such as the free -SH of Cys or the -OH group of Tyr, as demonstrated by incubating them overnight in a large molar excess at strongly alkaline pH values and analyzing such proteins by MALDI-TOF mass spectrometry.
Diamines↗
Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders?
Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.
Adult↗
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↗
Survival prediction in terminal cancer patients: a systematic review of the medical literature.
The clinical significance of studies on survival predictors in terminal cancer patients is hindered by both methodological limitations and the difficulty of finding common predictors for all final events in cancer related deaths. To evaluate the published medical literature concerned with the survival of patients with terminal cancer and identify potential prognostic factors, major electronic databases including MEDLINE (1966-), CANCERLIT (1983-) and EMBASE (1988-) were searched up to September 1999. Studies were included in our review if published in English, were cohort studies, addressed the identification of clinical prognostic factors for survival and looked at samples with median survival of < or = 3 months. Data extracted from selected papers included: sample size, median survival, type of study, sampling frame, cohort type, type of statistical analysis (univariate or multivariate), choice of models and underlying assumptions, predictors examined and their reported level of statistical significance. A total of 24 studies were found and reviewed. On the basis of these studies, performance status and the presence of cognitive failure, weight loss, dysphagia, anorexia and dyspnoea appear to be independent survival predictors in this population. Clinical estimation of survival by the treating physician appeared independently associated with survival but the magnitude of the association generally appeared small. Clinical predictions should be considered as one of many criteria, rather than as a unique criterion by which to choose therapeutic interventions or health care programmes for terminally ill cancer patients. The use of convenient samples as opposed to more representative inception cohorts, the inclusion of different variables in the statistical analyses and inappropriate statistical methods appear to be major limitations of the reviewed literature. Methodological improvements in the design and conduction of future studies may reduce the prognostic uncertainty in this population.
Data Collection↗
The relative accuracy of the clinical estimation of the duration of life for patients with end of life cancer.
BACKGROUND: Although the prediction of the duration of life of patients with end of life cancer most often relies on the clinical estimation of survival (CES) made by the treating physician, the accuracy and practical value of CES remains controversial. METHODS: The authors prospectively evaluated the accuracy of CES in an inception and population-based cohort of 233 cancer patients who were seen at the onset of their terminal phase. They also systematically reviewed the literature on CES in advanced or end-stage cancer patients in MEDLINE, CANCERLIT, and EMBASE data bases, using two search strategies developed by a research librarian. RESULTS: CES had low sensitivity in detecting patients who died within shorter time frames (< or =2 months), and a tendency to overestimate survival was noted. A moderate correlation was observed between actual survival (AS) and CES (Pearson correlation coefficient = 0.47, intraclass correlation coefficient = 0.46, weighted kappa coefficient = 0.42). CONCLUSIONS: Treating physicians appear to overestimate the duration of life of end of life ill cancer patients, particularly those patients who die early in the terminal phase and who may potentially benefit from earlier participation in palliative care programs. CES should be considered one of many criteria, rather than a unique criterion, by which to choose therapeutic intervention or health care programs for patients in the end of life cancer phase.
Adult↗
Clinical and immuno-virologic characterization of the efficacy of stavudine, lamivudine, and indinavir in human immunodeficiency virus infection.
Clinical, virologic, and immunologic outcomes were analyzed in children with vertically transmitted human immunodeficiency virus (HIV) infection (n = 25) and clinical symptoms and evidence of immunosuppression to establish the efficacy of 18 months' treatment with stavudine, lamivudine, and indinavir. Children were naive for treatment with protease inhibitors and lamivudine and had minimal exposure to stavudine. At 1, 6, 12, and 18 months, the proportions of patients with HIV-RNA <400 copies/mL were 79%, 100%, 94%, 87% in Centers for Disease Control and Prevention (CDC) immunologic class 2 and 50%, 67%, 67%, 72% in CDC immunologic class 3. At 12 months, the median CD4(+) count and percent increased significantly in both CDC immunologic class groups, but to a greater extent in the class 3 group. In the 12- to 18-month period, there were no significant changes within the groups. In both groups there was a steady increase in the proportion and number of children with positive skin test responses. Children in class 2 were more likely to have a positive delayed-type hypersensitivity response and a greater number of positive responses. Lymphocyte proliferative response to recall antigens improved significantly in all patients. The rate of increase in positive test results was faster in children in class 2 than in those in class 3. Only minor clinical events occurred during 18 months of therapy. Potent antiretroviral therapy achieves a sustained benefit in HIV-infected children, but immune reconstitution is more likely achieved in children with less advanced disease.
Adolescent↗
A manuscript worth a villa: Vittorio Putti's acquisition of the Guy de Chauliac manuscript.
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France↗
Terminal cancer syndrome: myth or reality?
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Aged↗
Immunization with both T cell-dependent and T cell-independent vaccines augments HIV viral load secondarily to stimulation of tumor necrosis factor alpha.
Vaccination of HIV-infected individuals increases HIV viral load, reduces CD4 cell counts, and might influence disease progression. Because these deleterious effects are postulated to be secondary to a direct activation of T lymphocytes induced by the immunogen, we compared immunologic and virologic effects of a T cell-dependent and a T cell-independent vaccine. Seventeen HIV-infected children were immunized with influenza (FLU) (T cell-dependent) or pneumococcal (PNEUMO) (T cell-independent) vaccines. HIV viral load and type 1 (IL-2 and IFN-gamma) and type 2 (IL-4 and IL-10) cytokine production were evaluated before and 7, 14, and 28 days after vaccination. Slopes of CD4 cell counts analyzed 6 months before and 6 months after vaccination were not significantly different. HIV viral load increased in both groups of children despite the fact that type 1 cytokine production and the type 1-to-type 2 ratio increased in FLU-vaccinated but not in PNEUMO-vaccinated patients. Thus, an increase in HIV viral load in the absence of T cell activation (as measured by cytokine production) was observed in PNEUMO-vaccinated children. Because polysaccharides of the bacterial cell wall stimulate TNF-alpha production by monocyte-macrophages and TNF-alpha was shown to stimulate HIV replication directly on activation of NF-kappa b after binding the long terminal repeat (LTR) sequences of HIV, we measured TNF-alpha production and observed a significant increase in both groups of vaccines. These data suggest that an increase in HIV viral load can be observed in vaccinated HIV-infected children even independent of direct antigen-induced activation of T lymphocytes, and that augmented production of TNF-alpha might play a role in this phenomenon.
Bacterial Vaccines↗
Subtle occurrence of indinavir-induced acute renal insufficiency.
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Acute Kidney Injury↗
Regulatory interactions between the human HOXB1, HOXB2, and HOXB3 proteins and the upstream sequence of the Otx2 gene in embryonal carcinoma cells.
Vertebrate Hox and Otx genes encode homeodomain-containing transcription factors thought to transduce positional information along the body axis in the segmental portion of the trunk and in the rostral brain, respectively. Moreover, Hox and Otx2 genes show a complementary spatial regulation during embryogenesis. In this report, we show that a 1821-base pair (bp) upstream DNA fragment of the Otx2 gene is positively regulated by co-transfection with expression vectors for the human HOXB1, HOXB2, and HOXB3 proteins in an embryonal carcinoma cell line (NT2/D1) and that a shorter fragment of only 534 bp is able to drive this regulation. We also identified the HOXB1, HOXB2, and HOXB3 DNA-binding region on the 534-bp Otx2 genomic fragment using nuclear extracts from Hox-transfected COS cells and 12.5 days postcoitum mouse embryos or HOXB3 homeodomain-containing bacterial extracts. HOXB1, HOXB3, and nuclear extracts from 12.5 days postcoitum mouse embryos bind to a sequence containing two palindromic TAATTA sites, which bear four copies of the ATTA core sequence, a common feature of most HOM-C/HOX binding sites. HOXB2 protected an adjacent site containing a direct repeat of an ACTT sequence, quite divergent from the ATTA consensus. The region bound by the three homeoproteins is strikingly conserved through evolution and necessary (at least for HOXB1 and HOXB3) to mediate the up-regulation of the Otx2 transcription. Taken together, our data support the hypothesis that anteriorly expressed Hox genes might play a role in the refinement of the Otx2 early expression boundaries in vivo.
Animals↗
Plasma viremia and virus phenotype are correlates of disease progression in vertically human immunodeficiency virus type 1-infected children.
OBJECTIVE: To analyze the relationships among HIV-1 plasma viremia, phenotype and CD4 T cell counts in vertically infected children. METHODS: Plasma viremia was quantified in 37 vertically infected children at different stages of the disease by a standardized molecular assay. Virus isolation and non-syncytia-inducing or syncytia-inducing (SI) HIV-1 phenotype evaluation were performed in parallel. RESULTS: HIV-1 RNA genomes were found to be significantly different in CDC clinical classes N, A, B and C (P = 0.0135) and in immunologic classes 1, 2 and 3 (P = 0.0110). None of the children in Class N or A harbored HIV-1 isolates with SI phenotype, whereas SI primary isolates were detected in 2 of 7 (29%) and 7 of 10 (70%) Class B and C children, respectively. Similarly SI variants were present in only 9 of 13 children in immunologic Class 3 (70%). When stratified according to the increasing severity of virologic status, the children showed a significant difference (P = 0.0458) in viral burden. CONCLUSIONS: Clinical symptoms, the most dramatic being reduction in the number of CD4 lymphocytes, and the highest plasma viremia levels were observed in the children in whom fast replicating, highly cytopathic SI variants were isolated. These data extend the virologic characterization of vertically HIV-1 infected children and suggest that both the plasma viremia levels and phenotype of primary isolates are viral correlates of disease progression in vertically infected children.
Anti-HIV Agents↗
HIV type 1 phenotype correlates with the stage of infection in vertically infected children.
A cohort of 39 vertically infected children (class N, A, B, and C of the CDC HIV classification for pediatric infection) was studied by virus isolation and non-syncytium inducing (NSI)/syncytium inducing (SI) HIV-1 phenotype evaluation. The HIV-1 isolates were recovered from PBMCs and the MT-2 cell line was used to perform the syncytium assay. HIV-1 could be isolated in 34 of 39 (87%) infected children, regardless of the clinical and immunological stage of the disease. Class N and A subjects harbored exclusively NSI strains, whereas the SI phenotype was detected in two of eight class B and five of nine class C patients. All of the SI variants were observed in severely CD4-depleted children (class 3 patients). The capability of pediatric HIV-1 isolates to induce a cytopathic effect is associated with the clinical status and the degree of CD4 depletion. These data suggest that the biological properties of HIV-1 isolates in children do not differ from those observed in adults, and that viral phenotype strictly correlates with disease progression in vertically infected children.
Cell Line↗