Biomedical subjects
Publications and source records attributed to M Navarro.
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Animal models have revealed that psychoactive cannabinoids induce both anxiolytic and anxiety-like reactions which are dose- and context-dependent. In the present study we examined the acute actions of the CB1 cannabinoid receptor antagonist SR 141716A in both the defensive withdrawal test and the elevated plus-maze in rats. Acute administration of SR 141716A (0.1, 1 and 3 mg kg-1) induced defensive responses in both anxiety tests, at a dose of 3 mg kg-1. This dose had no effect on horizontal locomotor activity and did not activate the hypothalamus-pituitary-adrenal axis, although several cannabinoid withdrawal-like behavioural symptoms were observed. These results demonstrate that blockade of the endogenous cannabinoid tone might induce anxiety-like responses in rats.
BACKGROUND: In the chick embryo, both mesonephros and metanephros have a renal portal system. The classical literature gives uncertain answers about the development and degeneration of the meso- and metanephric portal venous system. Some mesonephric vessels present angiogenic processes to colonize the metanephros, while others show signs of degeneration and disappear together with the mesonephros. The adult avian kidney has a conspicuously placed valve, the renal portal valve. The development of this functionally important renal portal valve has not yet been studied in detail. METHODS: Scanning electron microscopy of vascular corrosion casts has been used in this study. Strong mesonephric degeneration as well as metanephric growth and maturation occur in the developmental stages selected for this investigation (7.5, 9, 11, 14, and 21 days of incubation). RESULTS: The mesonephric afferent venous system in the chick embryo is supplied by two vessels, the posterior and the anterior mesonephric portal veins. The posterior mesonephric portal veins show a similar pattern to the anuran (amphibian) kidney. The anterior mesonephric portal vein has not previously been described. Constrictions were found in this vessel, a probable sign of subsequent degeneration. The metanephric afferent venous system is also supplied by two vessels: the caudal and cranial metanephric portal veins. The caudal metanephric portal vein is derived from the postcardinal vein. The cranial metanephric portal vein grows independently throughout the development of the mesonephric vascular system. It is connected to the vertebral venous sinus already at the beginning of its development. The renal portal valve first appears as a capillary network that communicates with the developing afferent and efferent metanephric venous systems. This capillary network later develops to a venous valve. The metanephric afferent venous system shows typical angiogenic signs in corrosion cast, such as nodular protrusions, holes, and enlarged vessels. CONCLUSIONS: The postcardinal vein first supplies only the mesonephric tissue as a portal vessel. Then it becomes a common source for both kidney generations. Finally it supplies only the metanephric tissue with venous blood. However, two independent vessels were found to supply the cranial renal regions: the anterior mesonephric portal vein and the cranial metanephric portal vein.
The purpose of this study was to determine the cytologic and histologic features that differentiate benign from squamous intraepithelial lesion (SIL)-associated cervical abnormal keratinization, defined as hyperkeratosis, parakeratosis, or individual cell dyskeratosis. Fifty-four cervical Papanicoloau (Pap) smears that contained abnormally keratinized cells were reviewed without knowledge of the concurrent biopsy. Twenty-three Pap smears were diagnosed as SIL and the corresponding biopsy showed SIL in 21 (91%) of these cases. Of the 23 Pap smears diagnosed as negative for SIL, the corresponding biopsy in 20 cases (87%) showed benign (SIL negative) abnormal keratinization. Eight Pap smears showed squamous atypia, of these 5 showed SIL on biopsy, and the other 3 revealed benign keratinization. The Pap smear correlates of the 25 biopsies that were negative for SIL included marked hyperkeratosis (18/25-72 vs. 5/29-17% for biopsies with SIL) and regular nuclear membranes (16/18-89% cases with nucleated dyskeratotic cells vs. 5/29-17% for biopsies with SIL). The cytologic correlates of the 29 biopsies that showed SIL included irregular chromatin clumping (27/29-93% vs. 3/18-17% for biopsies without SIL), and a disorganized growth pattern (24/29-83 vs. 5/25-20% for biopsies without SIL). It is concluded that the cytologic distinction between benign and SIL-related Pap smears with abnormal keratinization can be reliably made by the degree of hyperkeratosis, nuclear chromaticity pattern and contour, and the growth pattern of the dyskeratotic cells.
Plasmapheresis and low-density lipoprotein (LDL)-apheresis are recognized procedures for the treatment of hyperlipidemia resistant to diet and lipid-lowering drugs and provide information on cholesterol synthesis in hypercholesterolemic patients. However, cholesterol synthesis after acute cholesterol removal from plasma has never been investigated in normocholesterolemic patients. In this study, cholesterol synthesis was evaluated in three normocholesterolemic patients by determination of plasma lathosterol, lathosterol-to-cholesterol ratio, and plasma mevalonic acid. In a short-term kinetic study, samples were collected before and after plasmapheresis and every 6 hours during 24 hours. In the second part of the study, cholesterol synthesis was evaluated daily for 3 days. In normocholesterolemic patients, cholesterol returns to basal levels in 3 days. However, cholesterol removal did not result in a significant increase in lathosterol-to-cholesterol ratio or in plasma mevalonic acid, despite a slight increase in lathosterol. In contrast, when repeated plasma exchanges induced a dramatic hypocholesterolemia (< 1 mmol/liter), an acute but transient stimulation of cholesterol synthesis was observed (lathosterol/cholesterol ratio and MVA, respectively, increase from 8.2 to 22.3 and from 28 nmol/liter to 98 nmol/liter). This study shows that cholesterol synthesis is not stimulated by plasmapheresis in normocholesterolemic patients but is enhanced in dramatic hypocholesterolemic patients (< 1 mmol/liter).
Netobimin (NTB), a benzimidazole prodrug with a good anthelmintic spectrum, was administered orally to female rats at a dose of 59.5 mg NTB/kg, to study its pharmacokinetic behavior and the disposition of its most important metabolites, albendazole (ABZ), albendazole sulfoxide (ABZSO), and albendazole sulfone (ABZSO2). ABZ was found in plasma after 6 hr. Peak plasma concentrations (Cmax) and areas under curves (AUC) of ABZSO were eight- and fourfold higher, respectively, than those of ABZSO2. To study NTB disposition in pregnant rats, three different drug doses (50, 59.5, and 70.7 mg/kg) were given. No significant differences were found between plasma concentrations for each metabolite at the three doses studied. Only ABZ concentrations rose slightly as dose increased. ABZ, ABZSO, and ABZSO2 were found in amniotic sacs and embryos at concentrations that were higher than plasma at the same times. The fetuses obtained after administration of each of the doses of NTB were studied to detect developmental toxicity. A significant correlation was found between rate of developmental toxicity and metabolite concentration. ABZSO embryo concentrations could be the main factor accounting for toxicity.
BACKGROUND: Available information suggests that IgE levels are elevated in adults infected with human immunodeficiency virus (HIV), and that increased IgE levels correlate with allergic disease, with decreased CD4 counts, and with a poor prognosis. Data with respect to these factors in children are scant. OBJECTIVE: We investigated whether serum IgE levels are elevated in children with HIV and, if so, whether the serum IgE level correlates with the degree of immunodeficiency and/or objective indicators of allergic disease. METHODS: Serum IgE levels, CD4 counts, absolute eosinophil counts, and immediate hypersensitivity skin test (IHST) results were collected from 43 children with symptomatic HIV infection (mean age 7.2 years). Associations between serum IgE levels, CD4 counts, and eosinophil counts were investigated by multiple stepwise linear regression analysis. Data were stratified according to IHST positivity, and analysis of variance was used to compare mean values for age, CD4 counts, IgE levels, and eosinophil counts between the two groups. RESULTS: Serum IgE values were elevated more than 2 SDs above control age-matched mean values in 17 of 43 patients (40%). IHST results were positive in 12 of 43 patients (28%). CD4 counts were less than 200/mm3 in 17 of 43 patients (40%). Stepwise linear regression failed to demonstrate any correlation between serum IgE levels and either CD4 or eosinophil counts. With data divided into two groups according to IHST results (positive vs negative), analysis of variance failed to reveal significant differences between means for patient age, CD4 counts, IgE levels, or eosinophil counts. CONCLUSIONS: Our findings confirm that serum IgE levels are increased in children infected with HIV, just as in adults. However, an elevated serum IgE level did not correlate with allergic disease as measured by IHST results and eosinophil counts, nor with the degree of immune dysfunction as approximated by CD4 counts. The mechanism and significance of elevated serum IgE levels remain unclear in children with HIV, and warrant further investigation.
Sub-diabetogenic doses of streptozotocin (STZ) produce insulitis, beta cell destruction and diabetes in mice. Since kinin have been proposed as an inflammatory mediator in several diseases, we decided to evaluate the role of the kallikrein-kinin system in the evolution of insulitis. Male C 57 BL/KsJ mdb mice were injected with STZ (40 mg/kg) for 5 consecutive d. Aprotinin (4000 KIU/d) was injected simultaneously with STZ during 10 d. Plasma and urine samples collected on day 15 were assayed for glucose concentration and proteins, nitrites and kallikrein. Diabetic mice showed hyperglycemia and increased diuresis, marked proteinuria, nitrites and kallikrein. Administration of aprotinin, a potent tissue kallikrein inhibitor, to STZ mice, reduced the hyperglycemia and the altered renal function of the diabetic mice to level no different from normal mice. The present studies are consistent with the hypothesis that the over-production of tissue kallikrein in insulitis could be controlled by the effect of aprotinin.
BACKGROUND: Helicobacter pylori infection is the major pathogenic factor for peptic ulcer disease. Its epidemiology is not fully known; few data are available in patients with chronic liver disease. AIMS: To investigate the seroprevalence and factors associated with Helicobacter pylori infection in a series of liver cirrhosis patients. METHODS: Two hundred and twenty consecutive patients were prospectively included in a study aimed to evaluate the effect of dietary intervention on cirrhosis complications and survival. At inclusion, an epidemiological and clinical questionnaire was completed. Sera were obtained and stored at -70 degrees C until analyzed. They were tested for Helicobacter pylori antibodies using a commercial ELISA kit. RESULTS: Eleven out of 220 patients had borderline anti-Helicobacter pylori IgG titers. Of the remaining 209 patients, 105 (50.2%) showed positive titers of Helicobacter pylori IgG. Univariate analysis showed that Helicobacter pylori infection was more frequent in older patients, those born outside Catalonia, and in patients with a low educational level. Past ethanol consumption and current smoking correlated negatively with Helicobacter pylori infection. Multivariate analysis selected age (OR 3.1. 95% CI 1.46-6.45), educational level (OR 2.2. 95% CI 1.18-4.2) and alcohol consumption (OR 0.7. 95% CI 0.45-0.99) as the variables independently related to Helicobacter pylori infection. CONCLUSIONS: Helicobacter pylori infection in cirrhosis has the same epidemiological pattern as in the general population. Suggestions that the etiology or the severity of the liver disease could be related to Helicobacter pylori infection were not confirmed by our study.
In order to use the chicken embryo in teratogenic studies, it is necessary to know the internal volume in which a xenobiotic distributes. The inoculation of a xenobiotic in one of the compartments of the fertilized egg is the usual technique used in these studies. Neither the concentration nor the moment in which the xenobiotic comes into contact with the chicken embryo have been considered. Predicting the internal volume of distribution in the egg from some of the external parameters that do not interfere with the normal development is necessary. A simple method to calibrate these external parameters and their correlation with the different compartments of the fertilized eggs as well as the different distribution of the xenobiotic in these compartments has been successfully demonstrated. After injection of ABZ-SO, the maximum concentration in the embryo is reached by 36 h. The mean AUC for the albumen (sharp and obtuse end), yolk, and embryo were 78.4, 40.7, 79.2, and 10.8 micrograms.h/ml respectively. The results obtained about the kinetics of the diffusion of ABZ-SO indicate that this compound does not have a homogeneous distribution in all the compartments of the fertilized egg. These results highlight that whenever fertilized eggs are used as a screening for the possible toxicity of a drug or other substances, the dose of the xenobiotic to be injected has to be precisely determined in accordance with the total volume and the stage of embryonic development selected to be affected, starting from the previous knowledge of when and how much substance accedes to the embryo.
OBJECTIVE: To investigate the prevalence and characteristics of anti-endothelial cell antibodies (AECA) in a large cohort of patients with several well defined systemic autoimmune diseases, in order to determine their relationship with the clinical and laboratory features of these diseases. METHODS: Clinical and laboratory features of 216 consecutive Caucasian patients were prospectively studied. One hundred and seven patients had been diagnosed as having a primary systemic vasculitis-specifically, 39 had temporal arteritis (TA), 25 polyarteritis nodosa (PAN), 9 Wegener's granulomatosis (WG), and 34 Behcet's disease (BD)-, 90 patients had systemic lupus erythematosus (SLE), and 19 had a primary Sjogren's syndrome (SS). The AECA were determined by ELISA. RESULTS: One hundred and four (48%) patients with systemic autoimmune diseases were found to have a positive titre of AECA. Specifically, AECA were detected in 41 (38%) patients with a primary systemic vasculitis (13 (33%) with TA, 14 (56%) with PAN, 5 (56%) with WG and 9 (26%) with BD), in 58 (63%) patients with SLE, and in 5 (26%) patients with a primary SS. In patients with a primary systemic vasculitis, those with AECA were found to have an increased prevalence of disease activity (P < 0.05). In SLE patients, those with AECA were found to have an increased prevalence of vascular lesions (P < 0.05), lupus nephropathy (P < 0.05), and anticardiolipin antibodies (aCL) (P < 0.001). CONCLUSIONS: Patients with systemic autoimmune diseases have a high prevalence of AECA and they are associated with the presence of vascular lesions, nephropathy, and aCL in SLE, as well as with disease activity in several primary systemic vasculitis (TA, PAN, WG and BD).
Insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of myogenic cell lines, and these actions are mostly mediated through the type I IGF receptor (type I IGF-R). To further investigate the role of this receptor in phenotypic characteristics of C2 murine myoblasts, we overexpressed the human type I IGF-R in the inducible clone of C2 cells, which requires IGFs in the differentiation medium to undergo terminal differentiation. Inducible myoblasts were transfected with either the eukaryotic expression vector pNTK or pNTK containing the human type I IGF-R complementary DNA, and we isolated two clones named Ind-Neo and Ind-R, respectively. Binding and autophosphorylation experiments indicate that Ind-R cells express about 10 times as much type I IGF-R compared with Ind-Neo control cells and that the transfected type I IGF-R is functional in Ind-R cells. We show that overexpression of the human type I IGF-R makes inducible myoblasts able to differentiate spontaneously, as assessed by expression of the myogenic transcription factors MyoD and myogenin, detection of the muscle-specific protein troponin T, and myotube formation. Moreover, when exposed to IGF-I, Ind-R cells lose contact inhibition, grow in the presence of a low level of growth factors and form colonies in soft agar, which is characteristic of a ligand-dependent transformed phenotype. It emerges from this study that 1) the type I IGF-R is strongly involved in the phenotypic differences between inducible and permissive cells with respect to the differentiation program; and 2) overexpression causes this receptor to act as a ligand-dependent transforming protein in muscle cells. We suggest that type I IGF-R abundance and level of activation may determine the efficiency of the autocrine mode of action of IGFs and discriminate their biological functions.
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The oral fluoropyrimidines have proved to be active in colorectal cancer in Japan and, recently, in the United States and Europe. Continuous oral administration simulates protracted fluorouracil (5-FU) continuous intravenous infusion. The purpose of this trial was to evaluate the tolerability and potential advantages of oral treatment for colorectal cancer in the elderly. The main inclusion criterion was age over 72 years. Patients were treated with UFT (tegafur plus uracil) 400 mg/24 hours (fixed doses) continuously plus folinic acid 45 mg/24 hours until toxicity. If grade 3 or 4 toxicity appeared, treatment was stopped until recovery. From September 1994 to November 1996, 126 patients were included. For the analysis in November 1996, 77 patients were evaluable for response, toxicity, and survival. The patients, including 34 women and 43 men, had a median age of 74 years (range, 72 to 82 years of age). The Karnofsky performance status was 60% to 80% for 41 patients and 90% to 100% for 36 patients. Liver metastasis was present in 48% of the cases, and 42% were locoregional and peritoneal. Toxicity was mild, with only one patient having grade 3 thrombocytopenia, 11 (14%) grade 3 or 4 nausea/vomiting, seven (9%) grade 3 or 4 diarrhea, and one grade 3 mucositis. Four patients (5%) had complete responses and nine (11.6%) partial responses, for an objective response rate of 16.9% (95% confidence interval, 9% to 27%). Twenty-two patients (28.6%) showed no change. The number of patients in whom disease did not progress (ie, patients with complete plus partial responses plus those with stable disease) was 35 (45.4%) (95% confidence interval, 34% to 57%). With a maximum follow-up of 24 months, the median actuarial survival is 14.4 months. The number without disease progression and the median survival in this preliminary analysis suggests that this schedule is a moderately effective, comfortable, treatment with only mild toxicity, that can be recommended for use in the elderly, and it warrants further study.
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