[Role of echoendoscopy in diagnostic and therapeutic strategies in gastrointestinal oncology].
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Decision Trees↗
Biomedical subjects
A Soriano
Publications and source records attributed to A Soriano.
The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection.
BACKGROUND: Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy. METHODS: We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. RESULTS: In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004). CONCLUSIONS: Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.
Adult↗
Predictors of progression in chronically infected naive patients with plasma viraemia below 5000 copies/ml and CD4 T lymphocytes greater than 500 x 10(6)/I.
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CD4 Lymphocyte Count↗
Practice of nuclear medicine in Spain.
This survey presents the results of a poll sent to all Spanish nuclear medicine departments between July 1999 and March 2000, with the aim of clarifying the current situation of nuclear medicine in Spain. This survey is believed to be the first of its kind, and it is anticipated that the data will be of assistance to health authorities in ensuring that the needs of the population with regard to nuclear medicine facilities are met.
Nuclear Medicine↗
Differential role of selectins in experimental colitis.
BACKGROUND AND AIMS: The role of selectins in experimental colitis remains unknown. The aims of this study were to characterize the time-course expression of selectins in trinitrobenzene sulfonic acid (TNBS)-induced colitis, the functional role of selectins in colonic leukocyte-endothelial cell interactions, and the therapeutic usefulness of selectin blockade in this model. METHODS: Control and TNBS-induced colitic rats were studied. Expression of P- and E-selectin was assessed by the radiolabeled antibody technique, and L-selectin by flow cytometry. Leukocyte-endothelial cell interactions were studied in colonic venules by using intravital microscopy under basal conditions and after P-, E-, or L-selectin immunoblockade. Additional groups of animals were treated with anti-P-selectin antibody, a nonbinding antibody, or dexamethasone, for 7 days. RESULTS: P-selectin and E-selectin expression were markedly up-regulated in colitic rats. Increased leukocyte rolling was abrogated by anti-P-selectin, but only attenuated by anti-E- or anti-L-selectin antibodies. Only pretreatment with anti-P- selectin decreased leukocyte adhesion. Animals chronically treated with dexamethasone, but not with anti- P-selectin, had significantly lower macroscopic and histologic damage scores, colon weight, and myeloperoxidase (MPO) activity than those treated with nonbinding antibody. CONCLUSIONS: P-selectin plays a key role on leukocyte rolling and its blockade attenuates leukocyte adhesion in TNBS-induced colitis. However, treatment with an anti-P-selectin antibody does not significantly improve colitis.
Animals↗
Brain endothelial adhesion molecule expression in experimental colitis.
OBJECTIVES: 1) To determine if endothelial expression of adhesion molecules involved in leukocyte recruitment is increased in the brain and other organs in four different models of experimental colitis, and 2) to investigate whether leukocyte infiltration occurs in the brain of colitic animals. METHODS: Endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was quantified, using the dual radiolabeled antibody technique in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis, in mice with dextran sulfate sodium (DSS)-induced colitis, in SCID mice reconstituted with CD45RBhigh T-cells, and in IL-10-/- mice. Leukocyte infiltration in the brain of TNBS-induced colitic rats was assessed by myeloperoxidase activity and immunohistochemical staining with anti-CD45 monoclonal antibody. RESULTS: Marked upregulation of brain endothelial VCAM-1 (2- to 5.5-fold) was consistently found in colitic animals in the four models studied. Brain VCAM-1 strongly correlated with colon VCAM-1 and colon weight. By contrast, upregulation of brain ICAM-1 in colitic animals was only observed in the CD45RBhigh transfer (3-fold) and the TNBS-induced (1.5-fold models). Heart and muscle VCAM-1 and ICAM-1 were not upregulated in colitic animals in the majority of models studied. There was no leukocyte infiltration into the brain of TNBS-induced colitic rats. CONCLUSIONS: Our study demonstrates a marked and specific upregulation of endothelial VCAM-1 in the brain of colitic animals. This activation of cerebral endothelial cells was not associated with an infiltration of leukocytes into brain tissue.
Animals↗
[Distribution of hepatitis C virus genotypes among the hemodialysis population in the province of Alicante].
UNLABELLED: Hepatitis C virus (HCV) genotypes are irregularly distributed among the different geographic area and groups at risk. OBJECTIVE: To study the different HCV genotypes and subtypes of hemodialyzed patients from Alicante. METHODS: We studied 640 patients on haemodialysis (HD) and we determined the RNA-HCV and the genotypes in the 120 patients with antibodies against HCV (HCV-Ab). We compared the results with the genotypes of 1,370 patients from other groups at risk in the same geographic area. RESULTS: RNA-HCV was not found in the serum in 15% (18/120) of the patients on HD who were HCV-Ab positive. Prevalence of the different genotypes in the 102 patients with positive viral RNA was the following: 1b: 56.8% (58/102), 1a: 19.6% (20/102), 3: 17% (17/102), 2a-2c: 1.9 (2/102), 2b: 0.9% (1/102) 4: 2.9 (3/102), 5: 0.9% (1/102). In conclusion, the genotype 1b was the most frequent in the patients studied in all these areas, and was the same as in the rest of the country. This genotype has been associated with the most severe hepatic disease and poor response to treatment, affecting the prognosis of these patients. The most frequent genotypes in HD in Alicante were 1b, 3 and 1a. HCV genotypes distribution among the HD units was not uniform in the different geographic areas. HCV genotypes distribution in the HD population is similar to other groups at risk from the same geographic area.
Adult↗
Dose-finding study of once-daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients.
BACKGROUND: Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels. METHODS: Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half. RESULTS: In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily. CONCLUSION: Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.
Adult↗
UreE stimulation of GTP-dependent urease activation in the UreD-UreF-UreG-urease apoprotein complex.
The activation of metal-containing enzymes often requires the participation of accessory proteins whose roles are poorly understood. In the case of Klebsiella aerogenes urease, a nickel-containing enzyme, metallocenter assembly requires UreD, UreF, and UreG acting as a protein chaperone complex and UreE serving as a nickel metallochaperone. Urease apoprotein within the UreD-UreF-UreG-urease apoprotein complex is activated to wild-type enzyme activity levels under physiologically relevant conditions (100 microM bicarbonate and 20 microM Ni2+) in a process that requires GTP and UreE. The GTP concentration needed for optimal activation is greatly reduced in the presence of UreE compared to that required in its absence. The amount of UreE provided is critical, with maximal activation observed at a concentration equal to that of Ni2+. On the basis of its ability to facilitate urease activation in the presence of chelators, UreE is proposed to play an active role in transferring Ni2+ to urease apoprotein. Studies involving site-directed variants of UreE provide evidence that His96 has a direct role in metal transfer. The results presented here parallel those obtained from previous in vivo studies, demonstrating the relevance of this in vitro system to the cellular metallocenter assembly process.
Apoproteins↗
Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection.
OBJECTIVES: To assess whether an almost complete restoration of immune system can be achieved when antiretroviral therapy is initiated at very early stages of asymptomatic chronic HIV-1 infection. DESIGN: T cell subsets and cell-mediated responses were analysed at baseline and after 12 months of either a double or a triple antiretroviral therapy in 26 asymptomatic HIV-1-infected patients with CD4 T cell counts > 500 x 10(6) cells/l and a baseline plasma viral load > 10000 copies/ml. RESULTS: Triple therapy was significantly more effective in reducing plasma HIV RNA to undetectable levels, in returning CD4:CD8 ratio to nearly normal levels, in reducing activated cells (CD38) and in increasing naive (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4 cells. Both double and triple therapies caused a clear decrease in memory (CD45RA-CD45RO+) CD8 cells as well as a significant increase in the CD28 subset of CD8 cells. At baseline, there was an important increase in cells producing interferon-gamma (IFNgamma) with no significant abnormalities in T lymphocytes producing interleukin 2 (IL-2), tumour necrosis factor alpha and interleukin 4. Both types of therapy reduced IFNgamma- and IL2-producing CD4 T lymphocytes while IFNgamma-producing CD8 cells remained increased. Even before therapy, these HIV-1-positive patients lacked significant abnormalities in the T cell responsiveness to polyclonal stimuli as well as in the secretion of CCR5 chemokines by peripheral blood mononuclear cells. CONCLUSIONS: Initiating highly active antiretroviral therapy at very early stages of chronic HIV-1 infection allows rapid and almost complete normalization of T cell subsets and preservation of T cell functions. These early-treated patients could be excellent candidates for receiving additional HIV-specific immune-based therapies, which might be essential for the control of HIV infection.
ADP-ribosyl Cyclase↗
VCAM-1, but not ICAM-1 or MAdCAM-1, immunoblockade ameliorates DSS-induced colitis in mice.
Adhesion molecule immunoneutralization is envisioned as a promising therapy for inflammatory bowel disease, but the relative value of selective blockade of different adhesion molecules has not been established. The aims of this study were to measure expression and functional relevance of endothelial intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in leukocyte recruitment in experimental colitis and to compare the therapeutic effectiveness of their selective blockade. For this purpose, cell adhesion molecule expression was measured by the dual radiolabeled antibody technique in mice with dextran sulfate sodium-induced colitis and controls. Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. Therapeutic effects of chronic treatment with anti-ICAM-1, anti-VCAM-1, or anti-MAdCAM-1 antibodies were also assessed. Whereas colonic endothelial ICAM-1 was constitutively expressed and had a mild up-regulation in colitic animals, constitutive expression of VCAM-1 and MAdCAM-1 was low, but markedly increased after induction of colitis. Leukocyte adhesion was abrogated by immunoneutralization of VCAM-1 or MAdCAM-1 but not by treatment with an anti-ICAM-1 antibody. Chronic administration of anti-VCAM-1 antibody, but not anti-ICAM-1 or anti-MAdCAM-1, resulted in significant attenuation of colitis in terms of disease activity index, colon length, ratio of colon weight to length, and myeloperoxidase activity. In conclusion, VCAM-1 plays a central role in leukocyte recruitment in colitis and blockade of this adhesion molecule has higher therapeutic effect than immunoneutralization of ICAM-1 or MAdCAM-1 in this experimental model.
Animals↗
Pathogenic significance of methicillin resistance for patients with Staphylococcus aureus bacteremia.
To assess whether methicillin resistance is a microbial characteristic associated with deleterious clinical outcome, we performed a cohort study on 908 consecutive episodes of Staphylococcus aureus bacteremia and a case-control study involving 163 pairs of patients matched for preexisting comorbidities, prognosis of the underlying disease, length of hospitalization, and age. Of 908 bacteremic episodes, 225 (24.8%) were due to methicillin-resistant S. aureus (MRSA). Multivariate analysis did not reveal that methicillin resistance was an independent predictor for mortality when shock, source of bacteremia, presence of an ultimately or rapidly fatal underlying disease, acquisition of the infection in an intensive care unit (ICU), inappropriate empirical therapy, female sex, and age were taken into account. Nonetheless, methicillin resistance was an independent predictor for shock. The case-control study could not confirm that shock was linked to MRSA when prior antimicrobial therapy, inappropriate treatment, ICU residence, and female sex were considered. Our data suggest that cohort studies tend to magnify the relationship of MRSA with clinical markers of microbial pathogenicity and that this effect is a shortcoming of these kind of studies that is caused by inadequate control for underlying diseases.
Adult↗
Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism.
BACKGROUND: In addition to its anticoagulant properties, heparin has anti-inflammatory effects, the molecular and mechanistic bases of which are incompletely defined. AIMS: The current studies were designed to test the hypothesis that heparin abrogates the expression or function of leucocyte-endothelial adherence molecules which are fundamental to the acute inflammatory response. METHODS: The effects of heparin on tumour necrosis factor alpha (TNF-alpha) induced leucocyte rolling, adhesion, and migration as well as vascular permeability were assessed in rat mesenteric venules using intravital microscopy. Expression of adhesion molecules was quantitated using a double radiolabelled monoclonal antibody (mAb) binding technique in vivo (P-selectin, intercellular cell adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1)) or flow cytometry (CD11a, CD11b, and L-selectin). Ex vivo binding of heparin to neutrophils was assessed by flow cytometry. RESULTS: TNF-alpha induced a significant increase in leucocyte rolling, adhesion, and migration, and vascular permeability, coincident with a significant increase in expression of P-selectin, ICAM-1, and VCAM-1. Ex vivo assessment of blood neutrophils showed significant upregulation of CD11a and CD11b and significant downregulation of L-selectin within five hours of TNF-alpha administration. Heparin pretreatment significantly attenuated leucocyte rolling, adhesion, and migration but did not affect expression of cell adhesion molecules or vascular permeability elicited by TNF-alpha administration. Binding of heparin was significantly increased on blood neutrophils obtained five hours after TNF-alpha administration. Preincubation with an anti-CD11b mAb but not with an anti-CD11a or anti-L-selectin antibody significantly diminished heparin binding ex vivo. CONCLUSIONS: Our results support the concept that the anti-inflammatory effects of heparin involve attenuation of a CD11b dependent adherent mechanism.
Animals↗
New therapeutic strategies for lung cancer: biology and molecular biology come of age.
The current understanding of the biology and molecular biology of lung cancer pathogenesis and progression is reviewed. Awareness of the influence of growth factors, oncogenes, and tumor suppressor genes as well as signal transduction and angiogenesis pathways on the natural history of cancer cells has led to attempts to develop new therapeutic strategies directed at interrupting tumor cell growth. Treatments utilizing monoclonal antibodies, matrix metalloproteinase inhibitors, and gene transfer and alteration are currently being investigated. The rationale and effectiveness of these treatments in early trials are explored, and recommendations for future directions in cell biology research are presented. Interest in the biology and molecular biology of tumor cells has led to some important findings that may provide opportunities for new treatments. Several of these new directions for anticancer therapy are already being examined in phase I clinical trials.
Antineoplastic Agents↗
[Tolerability and safety of levofloxacinin long-term treatment].
Levofloxacin is a useful quinolone for patients infected with osteomyelitis or tuberculosis. There is little information on the tolerance and safety of levofloxacin in long-term treatment. Fifteen patients (10 men and 5 women) with prosthetic joint infection or chronic osteomyelitis were analyzed. The treatment was levofloxacin (500 mg/d) and rifampicin (600 mg/d). Controls were performed monthly during the treatment, and after that every six months. Problems that were likely related to medication were noted by medical interview. Analyses of hepatic and renal function were performed at each visit. The mean age was 64 years. Ten patients had prosthetic joint infection, two chronic osteomyelitis, two osteosynthetic device infection and one silicone graft infection. Staphylococcus aureus was isolated in eight cases, staphylococcus coagulase being negative in five, and the cultures negative in two cases. The mean duration of treatment was 3.6 months (range 2-6 months). No adverse reactions were observed in seven patients (46%). Occasional digestive symptoms were reported in six patients (40%), and two cases (13%) presented light diarrhea. These patients also took antiinflammatory treatment. Sleeplessness was observed in one patient (6%). Tendinitis or alterations in hepatic function were not observed. In no case was the treatment changed due to adverse reactions. It was concluded that levofloxacin is well tolerated and safe and could be an option for infections that require long-term treatment.
Aged↗
[Evaluation of partners of women with HPV infection].
BACKGROUND: The authors report the results of a clinical-peniscopic study of the genital regions in the male sexual partners of woman with proven genital Human Papilloma Virus (HPV) infection because of its contagiousness, incidence rate and relation with premalignant lesions. METHODS: From January 1998 to March 1999, 137 sex partners of women with HPV genital infection were investigated by clinical evaluation, cytologic examination of a urethral brushing and peniscopy at the Cervico-vaginal Pathology Center of the Gynecology and Obstetrics Institute of the Second University of Naples. All patients with a clinical and/or peniscopic evidence of infection were submitted to biopsy for histologic examination. RESULTS: On peniscopy 29.9% (41 patients) of men presented lesions either typical of suspicious for HPV infection at the first and/or at the second control. CONCLUSIONS: These data confirm that HPV infection, as all sexually transmitted diseases, needs a prevention and control program involving male and female to obtain a good recovery rate and a lowest diffusion.
Female↗
GTP-dependent activation of urease apoprotein in complex with the UreD, UreF, and UreG accessory proteins.
Syntheses of metal-containing enzymes often require the participation of accessory proteins. The roles played by many of these accessory proteins are poorly characterized. Klebsiella aerogenes urease, a nickel-containing enzyme, provides an ideal system to study metallocenter assembly. Here, we describe a method for isolating a complex containing urease apoprotein and the UreD, UreF, and UreG accessory proteins. We demonstrate that urease apoprotein in this complex is activated to near wild-type enzyme levels when incubated with nickel ions and high (approximately 100 mM) concentrations of bicarbonate. Significantly, we also observed nickel-dependent activation at physiologically relevant (approximately 100 microM) bicarbonate levels, but only in the presence of GTP. Based on studies involving a nonhydrolyzable analog of GTP, we conclude that nucleotide hydrolysis, not just binding, is required for this process. The critical nucleotide-binding site was localized to UreG on the basis of experiments using a variant complex. These studies highlight the relevance of the UreD-UreF-UreG-urease apoprotein complex to nickel metallocenter assembly and explain the previously identified in vivo energy requirement for urease activation.
Apoenzymes↗