[Embracing change].
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Biomedical subjects
Publications and source records attributed to J Costa.
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Transforming growth factor (TGF)-beta has several downregulatory functions on the immune system: inhibition of interleukin-2 receptor induction, decrease of interferon-gamma-induced class II antigen expression, inhibition of macrophage activation, as well as cytotoxic and lymphokine-activated killer cell generation. TGF-beta has also been recognized as an important immunoregulator in murine leishmaniasis, for which it increases susceptibility to disease. In the present study we evaluate the involvement of TGF-beta in human leishmaniasis in vitro and in patients with cutaneous leishmaniasis. Human macrophages produce active TGF-beta after infection by Leishmania amazonensis (480 +/- 44.7 pg/ml; mean +/- SEM), L. donovani chagasi (295 +/- 7.6 pg/ml), or L. braziliensis (196 +/- 15.7 pg/ml). When TGF-beta was added to cultures of human macrophages infected with L. braziliensis it led to an increase of approximately 50% in parasite numbers as compared with untreated cultures. Exogenous TGF-beta added to macrophage cultures was able to reverse the effect of interferon-gamma in controlling Leishmania growth. Even at 100 IU/ml interferon-gamma the presence of TGF-beta increases the number of intracellular parasites. On the other hand, TNF-alpha at high concentration (100 IU/ml) totally blunts the suppressive effect of TGF-beta. Immunostaining for TGF-beta was observed in the dermis, produced by fibroblasts and occasionally by inflammatory cells in the biopsies from human leishmaniasis lesions, being present in most of the biopsies taken from patients with early cutaneous leishmaniasis (less than 2 months of ulcer development) and in cases of active mucosal leishmaniasis. Taken together these observations suggest an important role for TGF-beta in human leishmaniasis, with its production by infected macrophages being probably related to parasite establishment in the early stages of the disease.
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BACKGROUND: The aim of the present was to study the rate of exposure to the hepatitis A virus (HAV) in the young adult Spanish population. METHODS: A transversal observational study was performed to evaluate the prevalence of anti-HAV antibodies (IgG) in a representative sample of the Spanish population between the ages of 20-40 years. Information on demographic variables (age, place of residence, education, number of children and number of brothers or sisters) and history of hepatitis was collected. A blood sample was also obtained from the umbilical cord or heel of newborns. The level of total anti-HAV antibodies was measured by the ELISA method. RESULTS: A total of 1,204 pregnant women the ages of 20-40 years with deliveries in 71 hospitals in 14 autonomic regions were included in the study. A total of 606 positive anti-HAV were reported representing a prevalence of 50.4% (CI 95% = 48-52%). The prevalence was seen to significantly increase in relation to age, from 39% (group from 20-25 years) up to 60% (groups from 31-35 and 36-40 years of age). The factors of "education" and "number of children" were not associated to greater risk of previous contact with HAV. A non significant increase in prevalence was observed in relation with "number of brothers or sisters of the parturient". 86.3% (CI 95% = 83-93) of the positive anti-HAV subjects reported not having had clinical history of hepatitis. CONCLUSIONS: Half of the young Spanish adult population does not show antibodies against the hepatitis A virus, with an increase in morbidity by clinical hepatitis A being foreseen in this age group.
We developed a chimeric human-severe combined immunodeficient mouse model to study human allograft rejection. Mice received first partial thickness human skin grafts and then, after anastomosis of the mouse with graft human microvessels, human lymphocytes allogeneic to the skin. By 2 weeks, the skin grafts uniformly developed changes that resemble first-set skin rejection in humans. Vascular cell adhesion molecule 1 and major histocompatibility complex class II molecules were induced on the human vascular endothelium at day 6, prior to significant T-cell infiltration. Perivascular human CD4+ and CD8+ T-cell infiltrates were marked by day 11. Some T cells, adjacent to injured human vessels, expressed the cytolytic granule protein perforin. The human microvessels were destroyed by day 16 without significant damage to human keratinocytes or adjacent mouse microvessels. This small animal model may permit evaluation of potential therapeutic reagents that inhibit human T-cell-mediated injury.
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The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)
The authors report an unusual bronchial papillary tumor found in the right lower lobe of a 89-year-old woman at the time of postmortem examination. The lesion was difficult to classify and did not fit well into any lung neoplasm category. Light and electron microscopic features were consistent with a papillary variant of low-grade mucoepidermoid carcinoma. Differential diagnoses mainly included the papillary bronchial mucous gland adenoma and the mixed epithelial-cell-type papilloma. Histogenetically, the tumor appeared to originate from the surface epithelium. Because the lesion showed features of low malignant potential, lobectomy would constitute an appropriate therapy whenever possible.
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A randomised crossover study was undertaken to compare the quality and cost of controlled versus empirical sedation with midazolam in critically ill patients. Patients (n = 40) entering the ICU were enrolled provided they satisfied the strict entry criteria. During 90 hours of midazolam sedation, patients received randomly allocated 10-hour periods of controlled or empirical sedation. With empirical sedation, the mean dose of midazolam and the cost of sedation were almost double those with controlled sedation. The quality of sedation was superior with the controlled method. In a separate study on 352 patients, a cost-benefit analysis of controlled sedation with midazolam or propofol infusion or bolus injections of morphine plus diazepam showed that the quality of sedation achieved with propofol was superior to the other two regimens and that, with morphine plus diazepam, the quality of sedation was unacceptably poor. Although the direct purchase price of propofol was higher than that of other agents, the total cost of sedation with propofol was lower than that for midazolam for short-term intensive care (less than 24 hours) and comparable to midazolam for longer-term use. However, indirect benefits of sedation with propofol include a much shorter ICU stay with the attendant reduced nursing costs and greater throughout the patients, and this more than compensates for the higher purchase price of the agent.
Steady-state blood clozapine concentrations in 58 schizophrenic patients varied more than 45-fold (40-1911 ng/mL) after fixed-dose treatment (400 mg/day). Discriminant function analysis determined that a blood clozapine concentration of 420 ng/mL optimally distinguished responders from nonresponders. After 4 weeks of treatment, only 8% of those patients with a blood clozapine concentration < 420 ng/mL responded compared with 60% of those who had a blood clozapine concentration > 420 ng/mL. When plasma concentrations were increased above 420 ng/mL (by a double-blind random assignment procedure), nonresponders increased their response rate to 73% if their plasma concentrations at Week 12 exceeded 420 ng/mL compared with a response rate of 29% if their Week 12 levels remained below 420 ng/mL (chi 2 = 4.2, p < .04).
Eighteen patients with schizophrenia had cerebral metabolic rates assessed with positron emission tomography during a double-blind, placebo-controlled crossover study of clozapine treatment. Relative metabolic rates were increased in the basal ganglia, especially on the right side. In the frontal lobe, metabolic rates were lowered, more on the left than on the right. The anterior nuclei of the thalamus also showed lower metabolic rates after clozapine. We have previously observed patients with schizophrenia to have low metabolic rates in the basal ganglia and to lack the normal right > left asymmetry; in this study, clozapine normalized striatal activity. In the frontal lobe, asymmetry was normalized, but hypofrontal function was, if anything, exaggerated. This effect in the frontal lobe was not observed with haloperidol in earlier studies. The cortical effects of clozapine may be related to its unique clinical properties and suggest important differences between typical and atypical antipsychotic drugs.
A posttraumatic visual deficit which worsened eleven weeks later, with sudden visual loss, is reported. The neuro-ophthalmologic examination was suggestive of central retina artery occlusion. The intra-arterial angiography revealed a traumatic pseudo-aneurysm of the ipsilateral high extracranial portion of the internal carotid artery. Based upon the clinical examination, the hypothesis of embolization has been considered the most probable mechanism, which is a rarely described etiopathogenesis. The clinical, pathogenic and diagnostic aspects of this situation are discussed. Finally, the authors describe the treatment, which consisted of the occlusion of the internal carotid artery with detachable latex balloons.
We have analyzed K-ras mutations and p53 alterations in 39 tumor and nontumor samples taken from nine patients with longstanding ulcerative colitis and colorectal carcinoma. Two of nine invasive carcinomas contained a K-ras mutation. By a combination of immunohistochemistry and single-strand conformation polymorphism analysis, p53 alterations were found in three of nine carcinomas. Five of 13 dysplastic lesions harbored a mutated K-ras gene, even in the absence of detectable changes in associated invasive tumors. One single focus of dysplastic mucosa harbored concomitant K-ras and p53 gene alterations. In two patients, a K-ras mutation was detected in epithelial lesions considered to be devoid of malignant potential (villous regeneration, active colitis). Our results indicate that: 1) the prevalence of K-ras and p53 genetic alterations found in ulcerative colitis-associated colonic carcinomas appears to be lower than in sporadic carcinomas; 2) K-ras mutations can be detected in dysplasia, villous regeneration, and active colitis and affect a subpopulation of the cells composing the lesions; 3) diverse genetic alterations can be detected in the same patient and the dysplastic lesions can exhibit a different genotype than the carcinomas; and 4) at least part of active colitis and villous regeneration lesions should be considered as preneoplastic in ulcerative colitis.
BACKGROUND: Inequalities in health have been internationally recognized as an important public health problem with a reduction of 25% being the first target of WHO--Europe for the year 2000. It is, therefore, important to describe and monitor the same. METHODS: An ecological study was performed using secondary data from the statistics of mortality (years 1985-1988) and the municipal censuses from the year 1986 to describe and compare inequalities in health in the cities of Valencia and Barcelona with neighborhoods being the unit of observation and analysis. RESULTS: Although the rates of mortality in Barcelona city are slightly inferior and those of Valencia slightly higher to those of Spain, both cities demonstrate important inequalities in regard to mortality in their neighborhoods with respect to standardized mortality which ranged from 78 to 182 in Barcelona and from 63 to 147 in Valencia. The privileged zones in Barcelona are those of Pedralbes and Sant Gervasi and in Valencia in the neighborhoods of Sant Pau and Jaume Roig with the most unfavorable neighborhoods being District I in Barcelona (Gothic Quarter, City Park, Barceloneta and Raval) and the Na Rovella and Fuensanta neighborhoods of Valencia. The level of inequality in both cities is very similar. Statistically significant associations have been found in both cities between the state of health and the level of poverty in the neighborhoods according to an approximation to the Townsend et al indexes. CONCLUSIONS: The description of important inequalities in two large Spanish cities suggests the possibility of its existence in other cities and established the urgent need for a study using comparable methodologies. With the use of routine and presently available data sources it is possible to describe and posteriorly monitor the level of inequality in large cities in Spain. The development of policies to diminish the inequalities in the large cities would provide considerable gains in terms of human lives. The present results support the hypothesis that material conditions in everyday life play an important role as a condition for public health inequality.
BACKGROUND: Mutations at codons 12, 13, and 61 of the ras genes have been found in a variety of human tumors and may have prognostic significance. K-ras mutations have been shown in 40%-50% of colorectal cancers. METHODS: Using a simple nonradioactive polymerase chain reaction-based technique, we have investigated the possible prognostic significance of point mutations of the K-ras gene in patients with human colorectal carcinomas. The prevalence and the type of ras mutations were compared between a group of 35 patients having recurrent disease within 5 years and a group of 64 patients who were disease free 5 years following surgery. RESULTS: First, we found that the overall prevalence of mutations within codons 12 and 13 of the K-ras gene was 25% in the nonrecurring group vs. 71% in the patients with recurrent disease (P < 0.0001) and, second, that mutations other than GGT to GAT occurred, with one exception, exclusively in recurring tumors. CONCLUSIONS: In Dukes' B and C primary tumors, mutations other than GGT to GAT identify patients at very high risk for recurrence. Our results indicate that determining the K-ras mutations provides a good prognostic factor in patients with advanced colorectal carcinoma.