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Biomedical subjects

V Costa

Publications and source records attributed to V Costa.

At least 19 recordsLinked to original sources
PubMed2002

Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.

Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.

Acute Disease↗
PubMed2002

Antisense oligonucleotides to the integrin receptor subunit alpha(5) decrease fibronectin fragment mediated cartilage chondrolysis.

OBJECTIVE: To investigate involvement of the integrin alpha(5) subunit of the classical fibronectin receptor in cartilage chondrolytic activities of fibronectin fragments (Fn-f). DESIGN: Bovine chondrocytes and cartilage explants were cultured in the presence of antisense oligonucleotide (ASO), or sense (SO) or scrambled sequence oligonucleotide (SCO) corresponding to the bovine alpha(5) subunit. The effects of the oligonucleotides on mRNA and protein expression of the alpha(5) subunit were analysed by rtPCR and Western blotting, respectively. To test effects on Fn-f activities, three different Fn-f were first added to serum or serum-free cultures, followed by addition of oligonucleotides and the effects on Fn-f mediated proteoglycan (PG) degradation, cartilage PG depletion and PG and general protein synthesis suppression were tested. RESULTS: The ASO decreased alpha(5) mRNA and protein expression to 69% and 55%, respectively, in monolayer cultures and decreased protein expression 67% in cartilage explants, while SO and SCO were ineffective. The ASO partially reversed the ability of the Fn-fs to suppress PG and general protein synthesis in cartilage explant and high density chondrocyte cultures. Concentrations of ASO from 1 nM to 5 microM effectively suppressed Fn-f activities in particular assays and the effects were reversible, while SO and SCO were not significantly effective. ASO also suppressed, in a dose-dependent and reversible fashion, the ability of the Fn-fs to enhance degradation and release of PG from cartilage explants. The ASO were also effective in suppressing the ability of an antibody to the alpha(5) subunit to enhance PG degradation, but were ineffective in blocking endotoxin or IL-1beta enhanced degradation. CONCLUSIONS: These data implicate the alpha(5) integrin subunit in Fn-f mediated activities, consistent with a role for the alpha(5)beta(1) integrin in this pathway.

Animals↗
PubMed2002

Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross-linked to the alpha5 integrin receptor subunit.

OBJECTIVE: To determine whether fibronectin fragments (Fn-f) known to enhance cartilage matrix degradation and to alter chondrocyte metabolism, bind on the chondrocyte cell surface close enough to the alpha(5)beta(1) fibronectin (Fn) receptor to be chemically cross-linked to it. DESIGN: Biotinylated Fn-fs were added to chondrocytes, followed by cross-linking with dithiobissulfosuccinimidyl propionate, and the resultant alpha(5) complexes trapped on to antialpha(5)-agarose. Adherent material was analysed by probing with avidin-HRP. In a more specific approach in which only proximal targets could be cross-linked, photoaffinity labeled Fn-fs or Fn were added to cells, the derivatives activated and the cross-linked material analysed. Interaction of biotinylated Fn-fs and Fn with insolubilized alpha(5)beta(1) receptor was also visualized and quantified. RESULTS: Biotinylated Fn-fs and Fn, but not a control of BSA, were cross-linked to alpha(5) protein in the presence of the propionate. Photoaffinity label Fn-f and Fn, but not BSA, were cross-linked to alpha(5) protein as well. Interaction was decreased by addition of an excess of unlabeled Fn-f or Fn. Fn-fs bound to alpha(5)beta(1)-agarose, although the affinity was 30-fold weaker and the stoichiometry 20-fold greater when the smallest Fn-f was compared to native Fn. CONCLUSIONS: These data are consistent with a role for the alpha(5) subunit in Fn-f activities and suggest that the Fn-fs bind proximal or directly to alpha(5) receptors. The weaker, higher stoichiometry interaction of Fn-fs with receptor suggests that fragmentation has allowed de novo interactions not possible in native Fn.

Animals↗
PubMed2000

Adaptive response of the yeast Saccharomyces cerevisiae to reactive oxygen species: defences, damage and death.

The yeast Saccharomyces cerevisiae has been extensively utilised to address the mechanisms underlying the oxidative stress response. The antioxidant defences can be induced either by respiratory growth or in the presence of pro-oxidants. The cell response involves the transcriptional control of genes by protein regulators that have been recently identified and post-translational activation of pre-existing defences. The current state of the art regarding the induction of antioxidant defences during respiratory growth and by exposure to hydrogen peroxide is reviewed.

Adaptation, Physiological↗
PubMed2000

Effects of emotional reactivity on inhibitory avoidance in the elevated T-maze.

The possibility of the presence of inter-individual emotional differences and the memory performance of rats was examined in the elevated T-maze. Two kinds of aversively motivated behaviors, inhibitory avoidance and escape learning, were measured. Based on the number of trials to achieve a learning criterion, rats were divided into two subgroups with either low or high avoidance reactivity (LAR or HAR, respectively). Retention test avoidance latencies showed that HAR animals had better avoidance memory (Mann-Whitney rank sum test, P = 0.0035). No such differences were found for the escape component of this test. These data suggest that individual emotional differences affect inhibitory avoidance performance, which may help to explain the dispersion of the data observed in other studies using this paradigm.

Animals↗
PubMed2000

Intraventricular administration of substance p increases the dendritic arborisation and the synaptic surfaces of Purkinje cells in rat's cerebellum.

Substance P was infused in the lateral ventricles of twenty Lewis rats for twenty days. On the twentieth day the animals were sacrificed and the cerebellar cortex was processed for electron microscopy. The ultrastructural morphometric analysis revealed that the Purkinje cell dendritic arborisation and the number of the synapses between the parallel fibres and the Purkinje cell dendritic spines were much higher than in control animals. Numerous unattached spines of the secondary and tertiary dendritic branches of the Purkinje cells were also seen in the molecular layer either free or surrounded by astrocytic sheath. The increased number of synapses between the Purkinje cell dendrites and the parallel fibres in the animals, which received substance P intraventricularly, in correlation to control animals, supports a neurotrophine-like activity of the substance P in the mammalian cerebellum, enforcing the pre-programmed capability of the Purkinje cells to develop new synaptic surfaces.

Animals↗
PubMed2000

Clinical trial with Secnidazole in a single dose in Venezuelan children infected by Giardia intestinalis.

The aim of this work was to evaluate in an open, noncomparative study the use of secnidazole in oral suspension given to Venezuelan children infected with Giardia intestinalis, from a community in Carapita, a slum area in Caracas. Seventy children from 2 to 11 years old (38 males and 32 females) were treated with a single oral dose of secnidazole (30 mg/Kg of body weight), after clinical and parasitological evaluation to make the diagnosis of active giardiasis. The effectiveness of treatment was determined by clinical examination and parasitological evaluation of feces samples 15 days after treatment. The results showed 95% of clinical cure with a significant decrease of the frequency of gastrointestinal symptoms. The parasitological cure was 98%, there were 4 failures at the end of treatment. Side effects observed after treatment were of mild intensity, lasting only few hours. These results show that a simple dose of secnidazole in an oral suspension is an effective, safe and well tolerated treatment for giardiasis in children and that this drug may be used as a mass treatment in risk populations.

Administration, Oral↗
PubMed1999

Measuring emotional memory in the elevated T-maze using a training-to-criterion procedure.

The elevated T-maze, an ethologically based test, has been used to investigate the effects of anxiolytic drugs on memory and the relationships between neural systems involved in such modulation. This test allows the measurement in the same rat of two kinds of aversively motivated behaviors--inhibitory avoidance and one-way escape. The apparatus consists of three arms of equal dimensions, elevated 50 cm from the floor. One arm is enclosed by walls and stands perpendicular to the two open arms. Placing the rat at the end of the enclosed arm and recording the time to withdraw from this arm during three consecutive trials assesses inhibitory avoidance. Soon afterwards, the rat is placed at the end of one of the open arms and the time to leave this arm recorded as escape response. Three days later memory is assessed by reexposing the rats to the maze. One critical question raised by these studies is whether the anterograde amnesia induced by anxiolytic drugs could be due to insufficient learning during training or to amnesia. The present work investigated whether the introduction of a multitrial training-to-criterion procedure could overcome this question. For this purpose, rats were tested as many times as needed to stay in the enclosed arm continuously for 300 s (avoidance learning to criterion). Results from Experiment 1 showed that rats trained to a learning criterion shows significantly better retention performance. Experiment 2 evaluated the effects of pretraining diazepam (DZP) treatment on this training-to-criterion protocol. The results indicate that DZP did not affect acquisition performance but induced a dose-dependent impairment of the inhibitory avoidance in the memory test. One-way escape (latency to enter the enclosed compartment from the open arms) was not affected by DZP. These results rule out the possibility that the impairment of inhibitory avoidance memory in the elevated T-maze could be due to lack of learning during training, and support the hypothesis that the disruptive effects of DZP are on processes involved in long-term storage of information.

Amnesia↗
PubMed1999

Selective advantages created by codon ambiguity allowed for the evolution of an alternative genetic code in Candida spp.

Several species of the genus Candida decode the standard leucine CUG codon as serine. This and other deviations from the standard genetic code in both nuclear and mitochondrial genomes invalidate the notion that the genetic code is frozen and universal and prompt the questions 'why alternative genetic codes evolved and, more importantly, how can an organism survive a genetic code change?' To address these two questions, we have attempted to reconstruct the early stages of Candida albicans CUG reassignment in the closely related yeast Saccharomyces cerevisiae. These studies suggest that this genetic code change was driven by selection using a molecular mechanism that requires CUG ambiguity. Such codon ambiguity induced a significant decrease in fitness, indicating that CUG reassignment can only be selected if it introduces an evolutionary edge to counteract the negative impact of ambiguity. We have shown that CUG ambiguity induces the expression of a novel set of stress proteins and triggers the general stress response, which, in turn, creates a competitive edge under stress conditions. In addition, CUG ambiguity in S. cerevisiae induces the expression of a number of novel phenotypes that mimic the natural resistance to stress characteristic of C. albicans. The identification of an evolutionary advantage created by CUG ambiguity is the first experimental evidence for a genetic code change driven by selection and suggests a novel role for codon reassignment in the adaptation to new ecological niches.

Adaptation, Biological↗
PubMed1999

Haemoglobin concentrations and infection by Giardia intestinalis in children: effect of treatment with secnidazole.

The blood concentrations of haemoglobin were investigated in 82 children aged 2-9 years. Fifty-seven (31 boys and 26 girls) were stool-positive for Giardia intestinalis but the other 25, used as controls, were negative. The mean (S.D.) haemoglobin concentration among the infected children was significantly lower pre-treatment than that for the control group [11.6 (1.2) v. 12.6 (1.5) g/dl; P < 0.05]. Treatment of the infected children with a single oral dose of secnidazole (30 mg/kg) led to a significant increase in their mean haemoglobin level 15 days later, from 11.6 (1.2) g/dl pre-treatment to 12.4 (1.2) g/dl post-treatment (P < 0.05). The results indicate that the therapeutic control of giardiasis could be important in programmes to combat anaemia in children living in endemic areas.

Anemia↗
PubMed1999

Comparative Study of the Efficacy and Tolerability of Secnidazole Suspension (single dose) and Tinidazole Suspension (two days dosage) in the Treatment of Amebiasis in Children.

Amebiasis caused by Entamoeba histolytica may be considered the most aggressive parasitic disease affecting human intestine, causing acute amoebic colitis and extra-intestinal diseases of high morbidity and mortality. 5-nitroimidazoles are the drugs of choice. In this multicenter, open and random clinical trial, the efficacy and tolerability of secnidazole suspension in a single oral dose of 1ml/kg was compared with 0.5ml/kg doses of tinidazole suspension given for 2 consecutive days to 303 Entamoeba histolytica-positive children aged 2 to 13. Patients with extra-intestinal complications were excluded from the study. Clinical and parasitological follow-up using the Faust and Kato-Katz method were carried out 7, 14, and 21 days after treatment. Clinical improvement/cure was observed in 93% of the patients in the secnidazole group and 91% in the tinidazole group. Parasitological success was reported for 77% and 63% of the secnidazole and tinidazole patients, respectively, showing a significant statistical difference between the two groups (p=0.007). Both drugs were well tolerated, and the adverse effects reported were mild, consisting mainly of digestive disturbances. This comparative study showed that a single oral dose of 1ml/kg of secnidazole produced a significantly higher parasitological cure rate than 2 doses of tinidazole. Secnidazole is a safe and effective drug for the treatment of uncomplicated intestinal amebiasis.

Journal Article↗
PubMed1998

Effects of tibolone on the breast.

OBJECTIVE: to evaluate the effect of hormone replacement therapy and tibolone on the breast. STUDY DESIGN: prospective, controlled, randomized study. SETTING: Outpatient Menopause Clinic of the Second University of Naples. PARTICIPANTS: forty four women in spontaneous menopause without any risk factor for breast cancer were randomly allocated to three groups: 15 patients (group A) were treated with transdermal oestrogens 50 microg, 2 patches/week for 3 weeks per month, plus acetate nomegestrolo per os 5 mg/die for 12 days per cycle, 17 patients (group B) were treated with tibolone 2.5 mg/die. Twelve patients not given any medication represented the control group (group C). METHODS: at the time of recruitment and after at least 12 months of therapy the patients were subjected to a questionnaire aimed at quantifying the slight, moderate or severe presence of the tension/mastodynia symptoms and to a mammographic test to assess the parenchymal pattern according to a quantitative method: type 1 (less than 25% of mammary gland covered by dense tissue), type 2 (from 25% to 75% of total glandular area covered by dense tissue), type 3 (more than 75% of mammary parenchyma covered by dense tissue). Statistical analysis was carried out by means of Fisher's exact test. RESULTS: after at least 12 months of treatment in Group A 5 out of 15 patients (33%) showed a trend of increase in mammographic density not statistically significant (P=0.22) when compared with group B in which one patient showed a swift from type 1 to type 2 and another from type 2 to type 3. The analysis of tension/mastodynia symptoms revealed a significantly difference between the two groups (P=0.02): in group A mastodynia appeared in three previously asymptomatic women and increased in five women, with a total increase in the symptomatology in 8 out of 15 patients (53.3%), in group B only in one case (5%) mastodynia turned from slight to moderate. CONCLUSION: in postmenopausal women oestroprogestogenic replacement therapy may be associated with an increase in mammographic density and with the onset or increase in mastodynia. On the contrary tibolone does not seem to affect normostructured mammas and may be considered a first-rate replacement therapy in case of mammas showing particular density or benign mastopathies.

Anabolic Agents↗
PubMed1998

[Skin cancer].

The authors, using the Cancer Registry data of S. Antonio General Hospital in Oporto, selected the cancer cases from 1981 to 1993. Distribution according to age, sex, topography and morphology is presented. Seven point nine percent of the 12,124 cases mentioned in the Registry were skin cancers (n = 883). They were mostly on the face (56.8%), trunk (11.7%) and scalp and neck (7.7%). As for the type of tumour, 472 basaliomas, 231 squamous cell carcinomas and 63 melanomas were recorded. One may conclude that basaliomas and squamous cell cancers arise at a later age than melanomas; melanomas are more frequent on the lower limbs and on the trunk; squamous cell carcinomas are more frequent on the face and lips. Basalioma is more frequent on the face. These results are in accordance with those published internationally.

Adolescent↗
PubMed1997

Mitochondrial superoxide dismutase is essential for ethanol tolerance of Saccharomyces cerevisiae in the post-diauxic phase.

This work reports the role of both superoxide dismutases-CuZnSOD (encoded by SOD1) and MnSOD (encoded by SOD2)-in the build-up of tolerance to ethanol during growth of Saccharomyces cerevisiae from exponential to post-diauxic phase. Both enzyme activities increase from the exponential phase to the diauxic shift and from the diauxic shift to the post-diauxic phase. The levels of mRNA-SOD1 and mRNA-SOD2 increase from the exponential phase to the diauxic shift; however, during the post-diauxic phase mRNA-SOD1 levels decrease while mRNA-SOD2 levels remain unchanged. These data indicate the existence of two regulatory mechanisms involved in the induction of SOD activity during growth: synthesis de novo of the proteins (until the diauxic shift), and post-transcriptional or post-translational regulation (during the post-diauxic phase). Ethanol does not alter the activities of either enzyme in cells from the diauxic shift or post-diauxic-phases, although the respective mRNA levels decrease in post-diauxic-phase cells treated with ethanol (14% or 20%). Results of experiments with sod1 and sod2 mutants show that MnSOD, but not CuZnSOD, is essential for ethanol tolerance of diauxic-shift and post-diauxic-phase cells. Evidence that ethanol toxicity is correlated with the production of reactive oxygen species in the mitochondria is obtained from results with respiration-deficient mutants. In these cells, the induction of superoxide dismutase activity by ethanol is low; also, the respiratory deficiency restores the capacity of sod2 cells to acquire ethanol tolerance.

Enzyme Induction↗
PubMed1996

The molecular defences against reactive oxygen species in yeast.

There is rapidly expanding interest into the protective systems against reactive oxygen species (ROS) in the eukaryotic cell, now that the links between oxidative damage, various disease states, and ageing, are firmly established in higher organisms. Yeast molecular genetics should be able to provide powerful insight into these mechanisms; this potential is now starting to be exploited. A number of primary antioxidant activities and systems of metal-ion homeostasis or detoxification have now been demonstrated to contribute to oxidative-stress protection in yeast. Also, evidence is emerging that the oxidative-stress response of this organism is complex, involving separate transcription-factor responses to peroxide, superoxide anion and metal ions.

Oxidative Stress↗