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R Camacho

Publications and source records attributed to R Camacho.

At least 19 recordsLinked to original sources
PubMed2006

Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Bayes Theorem↗
PubMed2006

Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance.

Human Immunodeficiency Virus-1 (HIV-1) antiviral resistance is a major cause of antiviral therapy failure and compromises future treatment options. As a consequence, resistance testing is the standard of care. Because of the high degree of HIV-1 natural variation and complex interactions, the role of resistance mutations is in many cases insufficiently understood. We applied a probabilistic model, Bayesian networks, to analyze direct influences between protein residues and exposure to treatment in clinical HIV-1 protease sequences from diverse subtypes. We can determine the specific role of many resistance mutations against the protease inhibitor nelfinavir, and determine relationships between resistance mutations and polymorphisms. We can show for example that in addition to the well-known major mutations 90M and 30N for nelfinavir resistance, 88S should not be treated as 88D but instead considered as a major mutation and explain the subtype-dependent prevalence of the 30N resistance pathway.

Amino Acid Sequence↗
PubMed2006

Multicenter evaluation of a new 4th generation HIV screening assay Elecsys HIV combi.

Fourth-generation screening assays which permit a simultaneous detection of human immunodeficiency virus (HIV) antigen and antibody reduce the diagnostic window on average by four days in comparison to third-generation antibody assays. Recently, the new automated Elecsys HIV combi was compared in a multicenter study to alternative fourth- and third-generation assays, p24 antigen test and HIV-1 RNA RT-PCR. A total of 104 serocon-version panels, samples of the acute phase of infection after seroconversion (n = 33), anti-HIV-1 positive specimens (n = 572) from patients in different stages of the disease, 535 subtyped samples from different geographical locations, including group M (subtypes A-J) and group O, anti-HIV-2 positive sera (n = 364), dilutions of cell culture supernatants (n = 60) infected with different HIV-1 subtypes, selected performance panels, 8406 unselected samples from blood donors originating from different blood transfusion centers, 3810 unselected sera from daily routine and from hospitalized patients, 9927 unselected samples from South Africa and 1943 potentially interfering samples were tested with the Elecsys HIV combi. Elecsys HIV combi showed a comparable sensitivity to HIV-1 Ag stand-alone assays for early detection of HIV infection in seroconversion panels. The mean time delay of Elecsys HIV combi (last negative sample + 1 day) in comparison to HIV-1 RT-PCR for 92 panels tested with both methods was 3.23 days. The diagnostic window was reduced with Elecsys HIV combi between 1.56 and 5.32 days in comparison to third-generation assays. The specificity of Elecsys HIV combi in blood donors was 99.80% after repeated testing. Our results show that a fourth-generation assay with improved specificity and sensitivity like the Elecsys HIV combi is suitable for blood donor screening due to its low number of false positives and since it detects HIV p24 antigen with a comparable sensitivity to single antigen assays.

Early Diagnosis↗
PubMed2005

Analysis of complex HIV-1 intersubtype recombinants using a Bayesian scanning method.

The increased complexity of HIV-1 genetic heterogeneity raises the issue for reliable classification and analysis of these sequences. Until now, bootscanning analysis has been the main method used for the analysis of potential HIV-1 intersubtype recombinants. We show evidence that in some cases of complex recombinants, where three or more segments with discordant phylogenetic signal may exist in protease (PR) and partial reverse transcriptase (RT) region, Bayesian scanning provides a clearer picture than bootscanning plots about the boundaries of potential recombination. Thus, a recently developed Bayesian scanning tool can facilitate the analysis and classification of HIV-1 mosaic sequences.

Africa, Central↗
PubMed2004

HIV-1 genetic variants circulation in the North of Angola.

Few molecular epidemiological data on HIV-1 in Angola are available. In this study, we analysed 37 pol sequences from patients originated from Luanda and Cabinda in Angola. It was our objective to investigate the circulation of different HIV-1 subtypes in this country. We found a high HIV-1 genetic diversity. The predominant subtypes were C and F, while subtypes A, D, G and H were also detected. Three sequences were untypable and may possibly belong to new subtypes or recombinants of unknown subtypes. Moreover, 13 recombinant sequences were found, most of them with very complex patterns including untypable fragments.

Angola↗
PubMed2004

Updated European recommendations for the clinical use of HIV drug resistance testing.

In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.

Anti-HIV Agents↗
PubMed2002

Plasma agouti-related protein level: a possible correlation with fasted and fed states in humans and rats.

We measured plasma concentrations of agouti-related protein (AGRP) in humans and rats and determined whether these were affected by ingestion of a meal after fasting. In 17 healthy human subjects, the mean plasma concentration of AGRP was lower in the fed state than in the fasted state. Two hours after a breakfast meal, AGRP levels dropped by 39%. By contrast, a continued fast for 2 h increased the average AGRP concentration by 73%. In rats with diet-induced obesity, refeeding resulted in a 50% decrease in plasma AGRP concentrations following a fasting-refeeding protocol. Our results support the notion that plasma AGRP may serve as a biomarker for the transition from a fasted to the satiated state.

Adult↗
PubMed2001

Immune enhancing effect of a growth hormone secretagogue.

Growth hormone (GH) has been known to enhance immune responses, whether directly or through the insulin like growth factor-1, induced by GH. Recently a nonpeptidyl small m.w. compound, a GH secretagogue (GHS), was found to induce the production of GH by the pituitary gland. In this study, we examined the effect of GHS in immunological functions of 5- to 6-wk-old and 16- to 24-month-old mice. In young mice, we observed a significant increase in PBLs, but T and B cell-proliferative responses were not consistently enhanced. The old mice, treated with GHS for 3 wk, did not show increases in peripheral lymphocytes, but they exhibited a statistically significant increase in thymic cellularity and differentiation. When inoculated with a transplantable lymphoma cell line, EL4, the treated old mice showed statistically significant resistance to the initiation of tumors and the subsequent metastases. Generation of CTL to EL4 cells was also enhanced in the treated mice, suggesting that GHS has a considerable immune enhancing effect, particularly in the old mice. We have also found that GHS promoted better thymic engraftment in bone marrow transplant of SCID mice. We found more cycling cells in the spleens of treated mice, suggesting that GHS may exert its immune enhancing effect by promoting cell division in lymphoid cells. These observations ascribe to GHS a novel therapy possible for aging, AIDS, and transplant individuals, whose immune functions are compromised.

Adjuvants, Immunologic↗
PubMed2000

Adherence to antiviral drug regimens in HIV-infected adolescent patients engaged in care in a comprehensive adolescent and young adult clinic.

Inconsistent use of antiviral medications for the treatment of HIV may lead to the emergence of resistant strains in HIV-infected adults. Patterns of adherence with these drug regimens in adolescents remains unknown. Identifying nonadherence in HIV-infected patients to antiviral regimens and developing corrective measures could improve patient outcomes. This study was undertaken to understand adherence in HIV-infected youths engaged in care and to reduce patterns of nonadherence. A retrospective analysis of 25 charts (78%) of HIV-infected youths (n = 32, age 13 to 21 years) were consecutively reviewed from January 1993 to May 1998. Charts were reviewed for documentation of factors previously documented to be associated with adherence: housing stability, social support, prior sexually transmitted diseases (STDs) and/or pregnancy, HIV exposure category, number of clinic visits, number of pills per day, number of medications per day, knowledge of medication schedule, age, gender, race/ethnicity, health status as revealed by CD4 count and viral load, and recorded patterns of adherence to medications and clinic appointments. Thirteen of the 18 (72%) patients who were receiving antiretroviral medication were nonadherent. Sixty-seven percent of the females and 80% of the males reported missing doses. Housing instability (p = 0.031) and/or length of treatment with antiviral medications (months of treatment) (p = 0.043) were significantly correlated with nonadherence. The stability of the adolescents' living situations was the most significant correlate of medication adherence for this population of HIV-infected youth.

Adolescent↗
PubMed1999

Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation.

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.

Animals↗
PubMed1999

Multicenter evaluation of a new rapid automated human immunodeficiency virus antigen detection assay.

Although human immunodeficiency virus (HIV) antigen assays are of limited value for monitoring antiretroviral therapy, they play an important role for confirmatory testing of fourth generation HIV screening enzyme immunoassay (EIA) reactive samples. In a multicenter study, a new automated rapid p24 antigen assay, Elecsys HIV Ag (Roche Diagnostics Boehringer Mannheim GmbH, Penzberg, Germany), was compared to FDA licensed tests (Abbott HIV-1 Ag monoclonal and Coulter HIV-1 p24 antigen assay). In the evaluation 27 seroconversion panels were included, sera from the acute phase of infection, single and follow-up samples from HIV antibody positive patients, dilution series of HIV antigen positive standards, sera and cell culture supernatants infected with different HIV-1 subtypes (A-H, and O) HIV-2 and recombinant HIV-1 (gag/env) isolates. To challenge the specificity of the new assay, 2565 unselected blood donors, sera from pregnant women, dialysis and hospitalized patients and 407 potentially cross-reactive samples were investigated. Acute HIV infection was detected in three to eight seroconversion panels earlier with Elecsys HIV Ag than with the alternative assays. Higher numbers of serum samples from HIV infected patients tested positive by Elecsys HIV Ag than with the comparative assays. All HIV-1 subtypes and HIV-2 isolates were recognized with Elecsys HIV Ag. Abbott HIV-1 Ag monoclonal and Coulter HIV-1 p24 antigen assay showed a variable sensitivity for the different HIV-1 subtypes. The specificity of Elecsys HIV Ag and Coulter HIV-1 p24 antigen assay were 99.8 and 99.93%, respectively. All the eight sera that were false reactive by Elecsys HIV Ag were tested negative with the Elecsys HIV Ag Neutralization Test. In conclusion, Elecsys HIV Ag was more sensitive than the alternative assays and showed a high specificity in combination with the neutralization assay. The very short incubation time of 18 min and the fully automated procedure of Elecsys HIV Ag which permits direct testing from the primary patient blood collection tube, represent a major improvement for routine laboratory diagnosis in comparison to the alternative assays.

Antibodies, Monoclonal↗
PubMed1999

Existence of junction-like structures in large B-cell non-Hodgkin's lymphomas. An ultrastructural study.

The purpose of this work is to study the presence of cell junction-like structures in large B-cell lymphomas. The ultrastructural study, based on 20 cases of this entity proved by immunohistochemistry and flow cytometry, demonstrated four types of junction-like devices easily found between tumor cells. Several explanations are offered about the possible nature of such structures, including the possibility of them being the result of adhesion phenomena. It should also be emphasized that they can potentially complicate the differential diagnosis of those neoplasms. We should, therefore, be careful in rejecting an ultrastructural diagnosis of large B-cell lymphoma based only on the presence of junction-like structures.

Biomarkers, Tumor↗
PubMed1998

Distinctive calcineurin-dependent (FK506-sensitive) mechanisms regulate the production of the CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES vs IL-2 and TNF-alpha by activated human T cells.

Calcineurin (CaN) controls the production of multiple cytokines, including IL-2 and TNF-alpha, during T cell activation. However, its role in chemokine production is unclear. Here, we used the CaN inhibitor FK506 to probe for the contribution of CaN in MIP-1alpha, MIP-1beta, and RANTES production at the protein and mRNA levels in human T cells stimulated via CD3/PMA or CD3/CD28. With both modes of activation, FK506 inhibited RANTES production only partially and late during a 3-day culture, whereas it suppressed both MIP-1alpha and MIP-1beta production throughout the culture. However, FK506 inhibition was more pronounced on MIP-1beta than MIP-1alpha, especially in CD3/CD28-activated T cells. Surprisingly, FK506 also significantly reduced MIP-1beta induction by PMA alone. Furthermore, comparison with IL-2 and TNF-alpha revealed that both were more potently inhibited by the drug upon CD3/PMA or CD3/CD28 induction than either MIP-1alpha or MIP-1beta. These differences in FK506 sensitivity were also observed in CD4(+) and CD8(+) T cell subsets. Therefore, all three chemokines are affected by FK506 distinctly from one another and from IL-2 and TNF-alpha, suggesting that CaN participates to different extents in the induction of these cytokines during T cell activation. Further evidence that this induction relies on distinctive mechanisms, depending on the cytokine, came from analyses of the kinetics and cycloheximide sensitivity of cytokine mRNA expression.

CD28 Antigens↗
PubMed1998

Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production.

Productive T cell activation leading to cytokine secretion requires the cooperation of multiple signaling pathways coupled to the TCR and to costimulatory molecules such as CD28. Here, we utilized two pharmacophores, PD98059 and FK506, that inhibit, respectively, mitogen-activated protein (MAP) kinase kinase 1 (MEK 1) and calcineurin, to determine the relative role of the signaling pathways controlled by these enzymes in T cell activation. Although the two compounds had distinctive effects on CD69 induction, they both suppressed T cell proliferation induced by anti-CD3 mAb, in a manner reversible by exogenous IL-2, suggesting that PD98059, like FK506, affects the production of, rather than the responsiveness to growth-promoting cytokines. Accordingly, IL-2 production by T cells stimulated with anti-CD3 mAb in conjunction with PMA or with anti-CD28 mAb was inhibited by both compounds. However, these compounds differentially affected the production of other cytokines, depending on the mode of activation. PD98059 inhibited TNF-alpha, IL-3, granulocyte-macrophage (GM)-CSF, IFN-gamma, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. FK506 suppressed CD3/PMA-induced production of all cytokines examined here but to a lesser extent IL-13. FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10, TNF-alpha, and IL-6 but augmented that of GM-CSF, IL-5, IFN-gamma, and IL-13. Therefore, the biochemical targets of PD98059 and FK506 contribute differently to the production of various cytokines by T cells, which may have implications for the therapeutic manipulation of this production.

CD28 Antigens↗
PubMed1998

The Cuban National Cancer Registry: 1986-1990.

In Cuba, the illness that produces most deaths among 1-64-year-olds is cancer. Over 65, it is the second cause of death after heart diseases. A National Cancer Registry was created 1964. Its main goals are to register all malignant neoplasms diagnosed in the country, to study this disease from the statistical and epidemiological point of view and to aid in the health control and planning of cancer fighting resources. This paper presents the results based on cases registered from 1986 to 1990. More than 50% of incidence and mortality caused by cancer is confined to the five major primary sites: lung, prostate, colon, breast and cervix. World population standardised rates by 100,000 inhabitants for the period 1986-1990 were 218.2 in males and 183.7 in females for incidence and 138.4 in males and 95.1 in females for mortality. Cancer incidence distribution by provinces shows two major regions: western-central, where higher risks of lung, breast, prostate and colon cancers are found, and eastern where very high risk of cervix cancer is observed. Although an improvement of the information quality indexes has been reported by the National Cancer registry in the studied period of time, quality of the data remained very poor according to the international standards. However, the results obtained by the National Cancer Registry seem to be a valuable tool to evaluate the cancer burden and, in particular, to control and eventually modify the tasks of the National Cancer Control Program in Cuba.

Adolescent↗