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  • 1
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    Online Resource
    In Vivo Effects of Highly Active Antiretroviral Therapies Containing the Protease Inhibitor Nelfinavir on Mitochondrially Driven Apoptosis
    SAGE Publications ; 2005
    In:  Antiviral Therapy Vol. 10, No. 8 ( 2005-11), p. 945-951
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 10, No. 8 ( 2005-11), p. 945-951
    Abstract: In vitro studies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear. Patients and methods A cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddI+d4T) - collectively known as HIV+PI - as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochondrial DNA content was measured by real-time PCR. Results BCL2 expression was lower in HIV+ than in HIV-patients ( P 〈 0.01), whereas levels of caspase-9 were higher ( P=0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV- individuals ( P 〈 0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV- patients ( P 〈 0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P 〈 0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddI+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI. Conclusions NFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350501000810
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2005
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  • 2
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    Mitochondrial Effects of Antiretroviral Therapies in Asymptomatic Patients
    SAGE Publications ; 2004
    In:  Antiviral Therapy Vol. 9, No. 1 ( 2004-01), p. 47-55
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 9, No. 1 ( 2004-01), p. 47-55
    Abstract: A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear. Methods We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence. Results Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups. Conclusion Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophy in HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection (Glasgow, UK, November 2002).
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350400900109
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
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  • 3
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    Mitochondrial Assessment in Asymptomatic HIV-Infected Paediatric Patients on Haart
    SAGE Publications ; 2011
    In:  Antiviral Therapy Vol. 16, No. 5 ( 2011-07), p. 719-724
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 16, No. 5 ( 2011-07), p. 719-724
    Abstract: HAART can cause mitochondrial DNA (mtDNA) depletion, which may lead to mitochondrial dysfunction. We aimed to determine whether mtDNA and mitochondrial function abnormalities are present in peripheral blood mononuclear cells from asymptomatic HIV-infected children. Methods A cross-sectional study in peripheral blood mononuclear cells was performed in 47 asymptomatic (free from any HIV- or AIDS-related active condition or HAART-related toxicity), HIV-infected, HAART-treated children and adolescents and 27 uninfected healthy paediatric patients. We measured mtDNA and mitochondrial RNA (mtRNA) content by quantitative real-time PCR. Mitochondrial respiratory chain enzymatic activity of complex-IV (CIV) and mitochondrial mass (estimated by citrate synthase) were measured spectrophotometrically, and CIV protein subunit content was measured with western blot analysis. Results A reduction in mtDNA levels was observed in HIV-infected children compared with controls (mean ±sem 4.47 ±0.31 and 5.82 ±0.48, respectively; 23% depletion; P=0.018), whereas similar levels of mtRNA, CIV protein subunit content and enzymatic activity were found in the two groups. These findings remained unaltered after considering mitochondrial abundance. Among HIV-infected children, mtDNA levels did not correlate with viral load, CD4 + T-cell counts or lactataemia at the time of assessment. No differences were observed when current or past use of individual antiretroviral drugs or HAART regimens were taken into account. Conclusions Depletion in mtDNA from asymptomatic HIV-infected children did not lead to differences in mtRNA levels or mitochondrially-encoded CIV proteins, nor to CIV dysfunction. This may be explained by homeostatic-compensatory mechanisms at the transcription level or by the mild depletion we observed.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.3851/IMP1806
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2011
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  • 4
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    Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens
    SAGE Publications ; 2008
    In:  Antiviral Therapy Vol. 13, No. 3 ( 2008-04), p. 467-468
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 13, No. 3 ( 2008-04), p. 467-468
    Abstract: The authors would like to report an error that appeared in the authorship of the above article. The first and second authors – Eugènia Negredo and Glòria Garrabou – should have been noted as making an equal contribution to this work.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350801300311
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2008
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  • 5
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    Mitochondrial Dna Depletion and Respiratory Chain Enzyme Deficiencies are Present in Peripheral Blood Mononuclear Cells of HIV-Infected Patients with Haart-Related Lipodystrophy
    SAGE Publications ; 2003
    In:  Antiviral Therapy Vol. 8, No. 4 ( 2003-05), p. 333-338
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 8, No. 4 ( 2003-05), p. 333-338
    Abstract: The main objective of the present study was to ascertain if mitochondrial DNA (mtDNA) depletion as reported in HIV-infected patients with highly active antiretroviral therapy (HAART)-related lipodystrophy (LD) implies any degree of mitochondrial respiratory chain (MRC) dysfunction. For this purpose, we evaluated HIV patients on different HAART schedules with LD (group A; n=12) and on HAART but without LD (group B; n=12), and untreated HIV-infected patients as controls (group C; n=24). mtDNA content was determined on peripheral blood mononuclear cells (PBMCs) with a real-time PCR method. Complex II, III and IV activities of the MRC were simultaneously measured spectrophotometrically, as were spontaneous and stimulated oxygen consumption by PBMCs. Compared to controls (group C, 100%), patients with LD (group A) showed a decreased mtDNA content (54%, P 〈 0.001), which was associated with a decline in complex III (62%, P 〈 0.05) and IV activity (69%, P 〈 0.05) (both complexes partially encoded by mtDNA), but not in complex II activity (exclusively encoded by nuclear DNA). Patients in group B showed a similar pattern of mitochondrial dysfunction but to a lesser extent and without statistical significance. Respiratory activities in both treated groups (A and B) did not differ in comparison with controls. We conclude that mtDNA depletion occurring during HAART is associated with deficiencies in MRC complexes partially encoded by mtDNA, which are detectable by PBMCs. Presented in ‘Late Breakers and Hot Topics’ session at 6th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 17–21 November 2002.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350300800410
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2003
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  • 6
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    Effect of Crumb Rubber Bituminous Mixes on Functional Characteristics of Road Pavements
    SAGE Publications ; 2009
    In:  Transportation Research Record: Journal of the Transportation Research Board Vol. 2126, No. 1 ( 2009-01), p. 83-90
    Details
    In: Transportation Research Record: Journal of the Transportation Research Board, SAGE Publications, Vol. 2126, No. 1 ( 2009-01), p. 83-90
    Abstract: The Road Research Laboratory of Spain's Technical University of Catalonia has conducted a study to determine the effects of adding crumb rubber on the functional characteristics of gap-graded mixtures–- particularly the effects on texture and noise. The evaluation was performed on the basis of full-scale measurements of several test sections. All sections were constructed with a gap-graded mixture in which three types of binders were used: bitumen with crumb rubber added by the wet process, the same bitumen with crumb rubber added by the dry process (1% and 2% crumb rubber content), and polymer-modified bitumen acting as the reference. The test sections were located on Road B-140 near Barcelona, Spain. Texture and skid resistance were measured by the side force coefficient routine investigation machine (SCRIM), and noise levels were quantified in a semi-anechoic chamber with the close proximity method. The use of different tires was also analyzed by the Laboratory of Acoustics Applied to Civil Engineering of the University of Castilla-La Mancha (Spain). The results revealed the impact of construction and service conditions on the surface characteristics of pavements and that, in general, the addition of crumb rubber by the dry process may slightly decrease the noise from tire–pavement interaction, while texture levels are decreased and skid resistance is increased, compared with the results obtained with the addition of crumb rubber by the wet process.
    Type of Medium: Online Resource
    ISSN: 0361-1981 , 2169-4052
    URL: Article
    DOI: 10.3141/2126-10
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2009
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  • 7
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    `Ageing in Place'? Exploring Elderly People's Housing Preferences in Spain
    SAGE Publications ; 2009
    In:  Urban Studies Vol. 46, No. 2 ( 2009-02), p. 295-316
    Details
    In: Urban Studies, SAGE Publications, Vol. 46, No. 2 ( 2009-02), p. 295-316
    Abstract: The greater visibility of societal ageing and higher share of individuals with disabilities have created new challenges for housing and urban policies. Housing needs can influence individual choice of living environment and the willingness to undertake housing improvements. This is especially relevant in southern European countries where the family is still the main provider of care for the elderly. This study makes an empirical analysis of the underlying preferences for housing and perceptions of housing suitability in the event of dependency in old age, drawing upon a new representative database of the Spanish population. It explores whether preferences are stable for different age-groups and different levels of individual affluence, calculated in terms of income and housing assets. The study found preferences for `ageing in place', which became stronger as individuals grew older. The effect of affluence, or the `wealth effect', was considerable. Acting independently and exhibiting higher health needs, it restrained individuals from choosing institutional care options. Those respondents who preferred to `age in place' were relatively less affluent. Those with relatively less formal education, preferred living with their relatives.
    Type of Medium: Online Resource
    ISSN: 0042-0980 , 1360-063X
    URL: Article
    DOI: 10.1177/0042098008099356
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2009
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  • 8
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    Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens
    SAGE Publications ; 2008
    In:  Antiviral Therapy Vol. 13, No. 2 ( 2008-02), p. 231-240
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 13, No. 2 ( 2008-02), p. 231-240
    Abstract: Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddI) increases ddI levels causing mitochondrial damage and CD4 + T-cell decline. We assessed whether a simple reduction of the ddI dose in patients receiving ddI (400 mg/day) and TDF could revert this side effect. Methods Immunological and mitochondrial changes were analysed in 20 patients at baseline, after 14 months of receiving ddI (400 mg/day), TDF (300 mg/day) and nevirapine (NVP; 400 mg/day) and 14 months after a ddl dose reduction to 250 mg/day. Immunological analyses measured CD4 + and CD8 + T-cell counts and mitochondrial studies in peripheral blood mononuclear cells assessed mitochondrial DNA content by quantitative real-time PCR, cytochrome c oxidase (COX) activity by spectrophotometry and mitochondrial protein synthesis (COX-II versus β-actin or COX-IV expression) by western blot. Results Treatment with TDF, ddI (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4 + T-cell counts. The reduction in ddI dose resulted in mitochondrial DNA recovery; however, the remaining mitochondrial parameters remained significantly decreased. Levels of CD4 + T-cells were partially restored in 35% of patients. Subjects presenting a significant reduction in CD4 + T-cells during the high ddI dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction. Conclusions Administration of high ddI doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4 + T-cell decay. A reduction of the ddI dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4 + T-cell counts. Other mitochondrial toxicity in addition to DNA γ-polymerase inhibition could be responsible for CD4 + T-cell toxicity.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350801300213
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2008
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  • 9
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    Metabolic and Mitochondrial Effects of Switching Antiretroviral-Experienced Patients to Enfuvirtide, Tenofovir and Saquinavir/Ritonavir
    SAGE Publications ; 2006
    In:  Antiviral Therapy Vol. 11, No. 5 ( 2006-07), p. 625-630
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 11, No. 5 ( 2006-07), p. 625-630
    Abstract: Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity. Patients and Methods Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4 + T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART. Results Switched patients exhibited a mean increase of 26 CD4 + T-cells/mm 3 and a mean decrease of 1.1 log in VL ( P=NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly ( P 〈 0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients ( P 〈 0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P 〈 0.05), complex III activity (127%, P 〈 0.05), complex IV activity (86%, P=0.37) and oxygen consumption (194%, P 〈 0.05). Conclusion Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350601100513
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2006
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  • 10
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    Mitochondrial Effects of a 24-Week Course of Pegylated-Interferon plus Ribavirin in Asymptomatic HCV/HIV Co-Infected Patients on Long-Term Treatment with Didanosine, Stavudine or Both
    SAGE Publications ; 2004
    In:  Antiviral Therapy Vol. 9, No. 6 ( 2004-08), p. 969-977
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 9, No. 6 ( 2004-08), p. 969-977
    Abstract: It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function. Design: Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) α-2b therapy (HCV-treated group). Methods We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy. Results Times on ddI or d4T exposure were 194 ±54.9 and 131 ±66.5 weeks in the HCV-treated and control groups, respectively. There were no differences either in mtDNA content, the enzyme activity of MRC complexes or clinical parameters at baseline. Throughout the study, mitochondrial measurements remained stable within groups and without differences when we compared HCV-treated and control groups. Conclusions In our study, the addition of RBV and PEG-IFN during a 24-week period in HCV/HIV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350400900613
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
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