Biomedical subjects
Publications and source records attributed to A Muñoz.
Onychocola canadensis is a non-dermatophytic mould that may cause distal and lateral subungual or white superficial onychomycosis. It was first reported in 1990. To date, it has been reported only from temperate countries, namely Canada (14 cases), New Zealand (3), France (9) and the United Kingdom (4). We report the first two cases from Spain.
Metabolic responses to exercise differ between Andalusian horses and other breeds, although changes in plasma muscle enzymes have not been reported and most useful information is obtained from animals subjected to different training programmes. The objectives of this study were to 1) describe the changes in plasma enzymes during exercise in different horse breeds in relation to other biochemical parameters (Experiment A) and 2) assess the effect of training duration on these measures (Experiment B). Twenty stallions, 9 Andalusian (AN), 7 Arabian (A) and 4 Anglo-Arabian (AA), age 5-10 years, were studied. They performed 3 exercise tests (ET), consisting of a warm-up of 800 m at 0.7 km/h and 4 workloads at 15, 20, 25 and 30 km/h, at respective distances of 1250, 1670, 2080 and 2500 m, with 5 min active recovery between each workload (Experiment A). Three ETs were performed at the beginning and after 2 and 6 months of training (Experiment B). Venous blood samples were collected during the ETs and plasma glucose (GLU), free fatty acids (FFA), lactate (LA), creatine kinase (CK), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBHD), aspartate aminotransferase (AST), Na+, K+ and Cl- were measured. AN horses responded to exercise with greater increases in GLU, HBHD, LDH, CK and AST compared to the other breeds. An unexpected result in Experiment A was the lack of interbreed differences in plasma peak LA concentrations, since it is commonly accepted that AA and A horses have greater athletic potential. Although the glycolytic response to exercise was reduced after 2 months of training in the AA and A horses, and after 6 months of training in the AN horses, at the end of Experiment B, AN horses produced more lactate than the other 2 breeds. Most of the adaptations linked to training were found in the AN breed. The more striking changes in plasma enzyme activities corresponded to CK in AN horses after 2 months of training. The attenuation of CK response to exercise was related to lower extrafibrilar GLU utilisation with LA formation and greater fat metabolism. The results show that plasma muscle enzyme concentrations for the diagnosis of equine myopathies must be interpreted in relation to breed and training.
STUDY OBJECTIVE: To describe the impact of highly active antiretroviral therapy (HAART) on mortality, morbidity, and markers of HIV disease progression in HIV infected women. DESIGN: Data collected from the Women's Interagency HIV Study, a prospective cohort study that enrolled women between October 1994 and November 1995. SETTING: Six clinical consortia based in five cities in the United States (New York, NY; Washington, DC; Los Angeles, CA; San Francisco, CA; and Chicago, IL). PARTICIPANTS: A total of 1691 HIV seropositive women with a study visit after April 1996. MAIN RESULTS: Beginning in April 1996, the self reported use of HAART increased over time, with more than 50% of the cohort reporting HAART use in 1999. There was a 23% decline per semester in the incidence of AIDS from April 1996 (95% confidence intervals (CI) -29% to -16%). Furthermore, there was a 21% decline of the semiannual mortality rates among those with AIDS at baseline (95% CI -27% to -14%) and an 11% decline among those AIDS free at baseline (95% CI -3% to -18%). CD4+ lymphocyte counts either increased (women with baseline AIDS) or stabilised (women without baseline AIDS) after April 1996, and HIV RNA levels dramatically declined in both groups, although the percentage of women with HIV RNA above 4000 cps/ml remained stable at approximately 40% since mid-1997. CONCLUSIONS: Despite concerns regarding the use of antiretroviral therapies in this population, the use of therapies led to improved immunological function, suppressed HIV disease activity, and dramatic declines in morbidity and mortality.
PURPOSE: It is well known that vertebrates Central Nervous System reacts to a wide variety of hormones, and growth factors. However the basic maturation mechanisms and remodelling processes remain in general unknown. Thyroid hormones tri-iodothyronine (T(3)) and thyroxine (T(4)) modulate this metabolism, playing a role in cell differentiation and proliferation and in gene expression during growth. The aim of the present study was to investigate whether or not low levels of thyroid hormone in blood, obtained with an experimental model of congenital neonatal hypothyroidism referred to herein, may induce changes in optic nerve development, mainly in processes of macroglial cell genesis and myelination. MATERIAL AND METHOD: We used an experimental model of materno-foetal hypothyroidism (MFHP) set up in a rat through chemical thyroidectomy. A solution of methyl-mercapto-imidazole and KClO(4) was administered with drinking water to pregnant rats and their offspring during gestation and lactancy. A group of rats was maintained in parallel as controls (C-G). Optic nerves were excised from both groups at key postnatal developmental stages (P) and these were prepared for light and transmission electron microscopy. RESULTS: Cross-sectional areas of optic nerves in the MFHP-G group appeared significantly smaller compared to C-G, this, during the perinatal phase as well as P25 (p<0.01). Macroglial cell nuclear cross-sectional areas showed increasing values in both groups. Data from MFHP-G, however, showed significantly lower than those of C-G (p<0.01). Between 4 to 6 days delayed myelination was at all times observed in the treated group. CONCLUSIONS: All results suggest that T(3) and T(4) regulate optic nerve development by stimulating glial cells function at cell nuclear level, probably through specific receptor binding sites, as suggested in earlier literature (Pinazo-Durán et al. Arch. Soc. Esp. Oftalmol., 1997).
INTRODUCTION: Pregnancy produces multiple changes in the mother's body, most of which have been studied. However, changes in hepatosplenic circulation are not well-known. The routine use of ultrasonography and of echo-Doppler has created new possibilities for the knowledge of splenic circulation during pregnancy. MATERIAL AND METHOD: We studied 30 healthy pregnant women who had given their informed consent. To evaluate the morphological and hemodynamic changes that might occur in the splenic vessels during pregnancy and immediate puerperium, laboratory investigations, obstetric and hepatic ultrasonography, and hepatosplenic echo-Doppler were performed between weeks 8-12, 20-24, and 32-36, as well as in the immediate puerperium. RESULTS: The caliber of the vena porta and its tributaries, as well as that of its intrahepatic branches, increased while the caliber of the suprahepatic vessels slightly decreased during pregnancy. The hemodynamic changes detected by Doppler ultrasonography were: progressive flattening of the pulsed Doppler trace of the suprahepatic vessels during the course of pregnancy; a progressive reduction in mean portal velocity, which was more marked in the third trimester, and a decrease in the markers of resistance in the hepatic artery and superior mesenteric artery. CONCLUSIONS: Hemodynamic changes in hepatosplenic circulation are produced during pregnancy that can be safely and effectively evaluated in real time by ultrasonography and echo-Doppler. Knowledge of these changes is required to evaluate these vessels in pathological conditions.
BACKGROUND: Currently employed high-dose regimens for patients with breast carcinoma consist mainly of single-cycle combinations of alkylating agents. In a previous Phase I trial, the authors developed a tandem high-dose combination of two cycles of mitoxantrone and cyclophosphamide for the treatment of patients with metastatic breast carcinoma (MBC) and high-risk breast carcinoma (HRBC). Treatment was delivered with granulocyte-colony stimulating factor (G-CSF) but without stem cell support to avoid potential tumor cell reinfusion. The objective was to validate the safety and obtain preliminary efficacy assessment of this combination in a Phase II trial. METHODS: Fifty-three patients were included: 27 patients with MBC and 26 patients with HRBC. After standard induction treatment, patients received two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 separated by a 4-week interval. Patients received G-CSF and ciprofloxacin until hematologic recovery. Follow-up was performed in an outpatient setting. RESULTS: One hundred one of 106 projected cycles (95%) were delivered. The mean dose intensities achieved were mitoxantrone 5.8 mg/m2 per week and cyclophosphamide 933 mg/m2 per week. Infection developed in 46% of the cycles, and platelet transfusions were required in 42%. Nonhematologic toxicity was mainly Grade 3 emesis. There were no toxic deaths. In 17 evaluable patients with MBC, 13 patients (77%) had response improvements, including 7 complete responses (41%). CONCLUSIONS: Treatment with two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 with G-CSF but without stem cell support was well tolerated. The dose intensities achieved approach those obtained with conventional high-dose therapy. This combination warrants further investigation as an alternative to conventional high-dose regimens.
We studied a 57-year-old female patient with clinical and biochemical evidences of McArdle's disease. Her muscle biopsy also revealed signs of mitochondrial proliferation, scattered RRF, and a deficit in complex I of the respiratory chain. Molecular genetic analysis showed that the patient was heterozygous for the most common mutation at codon 49 in the myophosphorylase gene. Mitochondrial DNA analysis of muscle tissue revealed an additional G-to-A transition at nucleotide position 7444 in the cytochrome c oxidase subunit I (COI) gene.
OBJECTIVE: To characterize predictors and consequences of discontinuing antiretroviral therapy (ART) in terms of CD4 cell count, HIV RNA, and reported side-effects in a large cohort of HIV-infected women. DESIGN: Cohort study. METHODS: A total of 1058 HIV-infected women initiated potent ART before September 1999. For each 6 month period after October 1996 we determined the proportion of potent ART users who downshifted to non-potent ART and who discontinued all ART. We examined the role of CD4 cell count and HIV RNA with regard to ART discontinuation. RESULTS: Between October 1996 and September 1999, 1058 individuals contributed 3362 visits at which potent ART was reported in the previous 6 months. Overall rates of 6 month downshifting and discontinuation were 10.0% and 6.7%. The proportion of individuals discontinuing all ART increased from 2.9% in late 1996 to 9.1% in mid 1999 (P < 0.001). Individuals with high HIV RNA levels were more likely to discontinue (P < 0.05). Compared to those who continued on potent ART, individuals who discontinued experienced large declines (P < 0.001) in CD4 cell counts and were more than three times more likely (P < 0.001) to experience HIV RNA increases. However, over one-third of those discontinuing ART reported side-effects and this subset had smaller CD4 cell count declines as compared to discontinuers not reporting side-effects (P = 0.147). CONCLUSIONS: In a large cohort of HIV-infected women, an increasing proportion of potent ART users discontinued ART over 3 years. Higher HIV RNA levels predicted discontinuation. Immediate immunological/virological deleterious consequences were observed. Side-effects were the most common reason for discontinuation and CD4 cell count declines were larger among those who did not cite side-effects as the reason for discontinuation.
Two methods are presented for measuring population effectiveness (i.e., reduction of disease in a population in which only some receive treatment) of antiretroviral therapy among human immunodeficiency virus (HIV)-infected men at risk for acquired immunodeficiency syndrome (AIDS) and followed between January 1, 1986, and June 30, 1999, in the Multicenter AIDS Cohort Study. Method I, requiring use of a seroincident cohort, estimates relative hazards of AIDS for persons at equal duration of infection. Method II, allowing use of a seroprevalent cohort, estimates relative hazards since the beginning of therapy eras for persons starting at equal levels of prognostic markers of disease stage (CD4 cell count and HIV type 1 RNA). The follow-up interval was divided into four calendar periods to characterize different eras of antiretroviral therapy. For method I, the relative hazards were 1.52 (95% confidence interval (CI): 0.93, 2.49), 0.91 (95% CI: 0.66, 1.26), and 0.30 (95% CI: 0.18, 0.51) for the eras of no therapy, dual nucleoside therapy, and potent combination antiretroviral therapy, respectively (monotherapy was the reference era). For method II, the corresponding relative hazards were 1.52 (95% CI: 1.10, 2.09), 1.03 (95% CI: 0.77, 1.38), and 0.31 (95% CI: 0.21, 0.45). These results extend the measurement of population effectiveness from incident to prevalent cohorts and demonstrate the ability of cohort studies to complement information provided by clinical trials.
Longitudinal measurements of plasma HIV RNA were analyzed using novel segmented regression models for 62 men in the Multicenter AIDS Cohort Study who at enrollment in 1985 were HIV seropositive and who had stable CD4+ lymphocyte counts and no clinical disease progression for a 6-year period between 1985 and 1991. Through 1996, 20 of the men developed clinical AIDS or died (late progressors) and 42 remained asymptomatic (nonprogressors). Using segmented regression model methods, we estimated, for each individual, the time when a change in HIV RNA trajectory was most likely to have occurred. Prior to this time, late progressors and nonprogressors had stable plasma HIV RNA levels, although the mean level in late progressors was 0.42 log10 copies/ml higher than in nonprogressors (p = 0.018). Furthermore, late progressors showed significant increases in HIV RNA levels of 0.23 log10 copies/ml/year (1.7-fold increase/year). This increase in HIV RNA in the late progressors began approximately 1.1 years prior to the onset of their decline in CD4+ lymphocytes, and 4.8 years prior to the onset of AIDS. These results provide evidence that an increase in the slope of plasma levels of HIV RNA is a sign of incipient progression of HIV disease.
The beta-catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1alpha,25-dehydroxyvitamin D(3)) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (SW480-ADH) but not that of a malignant subline (SW480-R) or metastasic derivative (SW620) cells lacking VDR. 1alpha,25(OH)2D(3) induced the expression of E-cadherin and other adhesion proteins (occludin, Zonula occludens [ZO]-1, ZO-2, vinculin) and promoted the translocation of beta-catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane. Ligand-activated VDR competed with T cell transcription factor (TCF)-4 for beta-catenin binding. Accordingly, 1alpha,25(OH)2D(3) repressed beta-catenin-TCF-4 transcriptional activity. Moreover, VDR activity was enhanced by ectopic beta-catenin and reduced by TCF-4. Also, 1alpha,25(OH)2D(3) inhibited expression of beta-catenin-TCF-4-responsive genes, c-myc, peroxisome proliferator-activated receptor delta, Tcf-1, and CD44, whereas it induced expression of ZO-1. Our results show that 1alpha,25(OH)2D(3) induces E-cadherin and modulates beta-catenin-TCF-4 target genes in a manner opposite to that of beta-catenin, promoting the differentiation of colon carcinoma cells.
Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.
We evaluated CD4 cell counts over a 3(1/2) year period following the initiation of potent antiretroviral therapy (ART) in the Multicenter AIDS Cohort Study. The study population included 314 HIV-infected gay men who provided CD4 cell counts for at least 2 years after the initiation of potent ART. Trends in CD4 cell counts and plasma HIV-RNA were analyzed by regression methods that incorporated the statistical dependencies of outcomes measured over time within individuals. Regardless of CD4 cell count at initiation of potent ART, CD4 cell counts increased significantly (p <.05) in the first 2 years after initiation. However, between 2 and 3(1/2) years after initiation, these counts neither increased nor decreased. The pattern of the proportion with plasma HIV-RNA <400 copies/ml was similar to CD4 cell count (i.e., increased significantly after initiation and plateau in the subsequent 1(1/2) years). The single most important predictor of the steady state CD4 cell count that was maintained between 2 and 3(1/2) years after initiation was the change in plasma HIV-RNA in the first year after initiation of potent ART.
Various mechanisms are thought to control excitation of pyramidal cells of the cerebral cortex. With immunocytochemical methods, we found that the proximal portions of numerous pyramidal cell axons (Pyr-axons) in the human and monkey neocortex are immunoreactive for the serotonin (5-HT) receptor 5-HT-(1A). With double-labeling experiments and confocal laser microscopy, we found that most (93.4%) of the 5-HT(1A)-immunoreactive Pyr-axons present in layers II and III were innervated by parvalbumin-immunoreactive chandelier cell axon terminals. In addition, Pyr-axons were compartmentalized: 5-HT-(1A) receptors were found proximal to inputs from chandelier cells. Although we found close appositions between GABAergic chandelier cell axon terminals and Pyr-axons, suggesting synaptic connections, we did not observe 5-HT-immunoreactive fibers in close proximity to the Pyr-axons. These results suggested that Pyr-axons are under the influence of 5-HT in a paracrine manner (via 5-HT-(1A) receptors) and, more distally, are under the influence of gamma-aminobutyric acid (GABA) in a synaptic manner (through the axons of chandelier cells). The local axonal specialization might represent a powerful inhibitory mechanism by which the responses of large populations of pyramidal cells can be globally controlled by subcortical serotonin afferents, in addition to local inputs from GABAergic interneurons.
OBJECTIVES: To evaluate prior antiretroviral therapy experience and host characteristics as determinants of immunologic and virologic response to highly active antiretroviral therapy (HAART). METHODS: We studied 397 men from the Multicenter AIDS Cohort Study (MACS) who initiated HAART between October 1995 and March 1999. CD4 cell count and HIV-1 RNA responses to HAART were measured at the first visit following HAART (short-term) and extending from the first visit to approximately 33 months after HAART (long-term). Prior antiretroviral experience was classified into three groups based on antiretroviral therapy use during the 5 years prior to HAART. Age, race and host genetic characteristics also were assessed for their effects on treatment response. RESULTS: Better short- and long-term CD4 cell and HIV-1 RNA responses were observed in the treatment-naive users. Intermittently and consistently experienced users did not significantly differ in response. Whereas race did not independently affect response, among those initiating HAART with > 400 x 10(6) CD4 cells/l, younger age and the Delta32 CCR5 genotype were associated with a better short-term CD4 cell response. There was a suggestion that having the protective CCR5 genotype also was associated with a better long-term CD4 cell response. CONCLUSION: Immunologic and virologic response to HAART was stronger in individuals who had no prior experience with the antiretroviral therapy agents subsequently included in their initial HAART regimen. Age, level of immune competence and immunogenetics appeared to play a role in the subsequent immune reconstitution following use of highly effective HIV therapy.
OBJECTIVES: To determine the effectiveness of potent antiretroviral therapy in reducing opportunistic infections (OI) as both a presenting event and subsequent to an AIDS-defining event. DESIGN AND METHODS: A total of 543 seroconverters and 1470 men with AIDS were compared for the time to development of OI as the presenting AIDS event and as a subsequent event in the 1984-1989, 1990-1992, 1993-1995, and 1996-1998 periods, when the major treatments were no therapy, monotherapy, combination therapy, and potent antiretroviral therapy, respectively. RESULTS: The seroconverters suffered 132 OI and the participants with AIDS had 717 OI. The relative hazard (RH) of OI as the presenting AIDS event declined by 81% in the calendar period when potent antiretroviral therapy was available compared with the monotherapy period. Declines were observed for Mycobacterium avium complex, cytomegalovirus disease, and esophageal candidiasis, but were statistically significant only for Pneumocystis carinii pneumonia. The RH of OI as a secondary infection dropped by 77% in the last calendar period compared with the monotherapy period. A significant decline was observed for all four OI. Prophylactic drug use did not increase in the era of potent antiretroviral therapy. CONCLUSION: The hazard of OI in the era of potent antiretroviral therapy has declined dramatically compared with the era of monotherapy, despite the concurrent decrease in the use of prophylactic drugs. Physicians should consider whether it is necessary to include prophylactic drugs as part of the complex drug regimen for patients on potent antiretroviral therapy.
This prospective study of 2960 injection drug users investigated the dynamic nature of HIV behavioral risk factors between 1988 and 1994. Behavioral risks were assessed semi-annually. Robust regression models of time-dependent covariates were used to identify longitudinal predictors of behavior change. Maintenance of risky behaviors varied over time, with risk reduction seen more among HIV infected participants than among HIV seronegatives. Those at highest risk for HIV transmission were least likely to cease engaging in these behaviors. Interventions staged according to risk behaviors, targeting incremental risk reduction rather than only promoting abstinence, may be more successful in reducing HIV transmission among drug injectors.
A field test was carried out in different production systems to evaluate the effect of vaccination against swine enzootic pneumonia with an inactivated vaccine. A total of 13,691 pigs of four different genetic origins were used, of which 7,351 were vaccinated and 6,340 were used as controls. The animals were housed in 16 fattening units, in which the 'one-site', 'two-site' and 'three-site' production systems were represented. There were the following statistically significant differences in favour of the vaccinated animals: a 1.89 per cent lower mortality (P<0.001), a 0.09 lower feed conversion ratio (P<0.030), a 3.12 per cent lower cost per kilogram gained in fattening (P<0.031), a 4.02 per cent lower cost per kilogram of carcase (P<0.018), a 3.77 per cent lower cost of feed per kilogram gained in fattening (P<0.012) and a 56.75 per cent lower potential loss of profit per kilogram gained in fattening due to mortality (P<0.001). An analysis of variance of the effects of genetic origin, treatment and production system on the different parameters showed that only the treatment had any statistically significant effect on the percentage mortality (P<0.002), feed conversion ratio (P<0.030), cost per kilogram gained in fattening (P<0.019), cost per kilogram of carcase (P<0.020), cost of feed per kilogram gained in fattening (P<0.015) and potential loss of profit per kilogram gained in fattening due to mortality (P<0.002).