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Biomedical subjects

A Costa

Publications and source records attributed to A Costa.

At least 127 records · Page 7Linked to original sources
PubMed1999

The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation.

CONTEXT: Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. OBJECTIVE: To determine whether women taking raloxifene have a lower risk of invasive breast cancer. DESIGN AND SETTING: The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe. PARTICIPANTS: A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded. INTERVENTION: Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets. MAIN OUTCOME MEASURES: New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review. RESULTS: Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). CONCLUSION: Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

Aged↗
PubMed1999

The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families.

Out of 90 Portuguese patients with mitochondrial cytopathy, six harbored the A3243G mutation in the mtDNA tRNA(Leu(UUR)) gene ('MELAS mutation'). They had heterogeneous clinical features, including myopathy with stroke-like episodes, progressive external ophthalmoparesis, diabetes mellitus, and subacute encephalopathy. Histochemical and biochemical analyses of muscle biopsies showed abundant ragged-red fibers reacting positively with the cytochrome oxidase stain, and decreased respiratory chain enzyme activities. On average, the proportion of mutated mtDNA was 67% (20-88%) in tissues from patients and 21% (0-49%) in blood from 20 maternal relatives. The proportion of mutated mitochondrial genomes in muscle did not correlate with clinical presentation or duration of disease. This study, the first in Portuguese patients, confirms the frequent occurrence of the A3243G mutation in patients with mitochondrial diseases, and emphasises the usefulness of genetic testing in reaching a correct diagnosis.

Adolescent↗
PubMed1999

[The usefulness of basal blood glucose and glycosylated hemoglobin for the detection of abnormal glucose tolerance in the relatives of patients with type-2 diabetes mellitus].

BACKGROUND: Type 2 diabetes mellitus (DM 2) constitutes today one of the most important problems in terms of health. Nowadays, there is special interest to identify those subjects with a high risk for developing the disease. Our study aimed to evaluate fasting glycemia and glycated hemoglobin in the screening of defects in oral glucose tolerance, in relatives of patients with DM 2. SUBJECTS AND METHODS: 111 relatives of patients with DM 2 were consecutively included in the study. Glycated hemoglobin (HbA1c, DCA 2000) was measured, afterwards an oral glucose tolerance test (OGTT) was performed. 120 min glycemia (G120) classified oral glucose tolerance as: normal (NGT), impaired glucose tolerance (IGT) and DM. In a first subgroup (n = 80) the equation to predict G120 was obtained (G120 estimated) from the basal glycemia (GO) and HbA1c. In a second subgroup (n = 31), G120 observed after the OGTT (G120 observed) and G120 estimated were compared. Finally, sensitivity, specificity and positive predictive value (PPV) for different cutpoints of GO and G120 were estimated, in order to identify those subjects with abnormal glucose tolerance (IGT and DM). RESULTS: Considering the results from the first subgroup of subjects, G120 was independently related with GO (R2 = 0.64) and with HbA1c (R2 = 0.62). When GO and HbA1c were considered altogether R2 value was 0.73. When data from the second subgroup of subjects was analysed we did not find any differences between observed G120 and G120 estimated by the equation. The sensitivity, specificity and PPV to detect abnormalities in oral glucose tolerance of estimated G120 were 80, 76 and 61%, respectively. Optimal values of these parameters were obtained with GO 98-102 mg/dl and Hba1c 5.6-5.8%. CONCLUSIONS: Our results confirm that the measurement of GO and HbA1c in first degree relatives of patients with DM 2 is extremely useful to identify those subjects in which abnormal oral glucose tolerance is highly probable.

Adult↗
PubMed1999

An Effective Fluorescent Sensor for Choline-Containing Phospholipids.

A set of weak CH small middle dot small middle dot small middle dotO interactions is responsible for the recognition of tetraalkylammonium ions (ball-and-stick structure) by the tripodal receptors depicted in the diagram, in which the binding pocket is lined with squaramide units. The association constants of the fluorescent receptors are remarkably high at about 10(5) M(-1) and can be used for signaling the presence of selected choline phospholipids. Z=RNH, where R=alkyl, arylamino; X(-)=BH(4)(-), Cl(-), Br(-), I(-).

Journal Article↗
PubMed1999

Localization and mobility of coenzyme Q in lipid bilayers and membranes.

We have studied the mobility of coenzyme Q (CoQ) in lipid bilayers and mitochondrial membranes in relation to the control of electron transfer activities. A molecular dynamics computer simulation in the vacuum yielded a folded structure for CoQ10, with a length of only 21 A. Using this information we were able to calculate diffusion coefficients in the range of 10(-6) cm2/s in good agreement with those found experimentally by fluorescence quenching of pyrene derivatives. To investigate if CoQ diffusion may represent the rate-limiting step of electron transfer, we reconstituted complexes I and III and assayed the resulting NADH-cytochrome c reductase activity in presence of different CoQ10 levels and at different distances between complexes; the experimental turnovers were higher than the collision frequencies calculated using diffusion coefficients of 10(-9) cm2/s but compatible with values found by us by fluorescence quenching. Since the experimental turnovers are independent of the distance between complexes, we conclude that CoQ diffusion is not rate-limiting for electron transfer.

Animals↗
PubMed1999

Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.

BACKGROUND: Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. OBJECTIVE: We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. METHODS: A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. RESULTS: One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. CONCLUSIONS: On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.

Adult↗
PubMed1999

FAK and PYK2/CAKbeta in the nervous system: a link between neuronal activity, plasticity and survival?

A major aim of neurobiology today is to improve understanding of the signaling pathways that couple rapid events, such as the action potential and neurotransmitter release, to long-lasting changes in synaptic strength and increased neuronal survival. These adaptations involve interactions of neurons with other cells and with the extracellular matrix. They use, in part, the same molecular machinery that controls adhesion, motility or survival in non-neuronal cells. This machinery includes two homologous non-receptor tyrosine kinases, FAK and PYK2/CAKbeta, and the associated SRC-family tyrosine kinases. Specific brain isoforms of FAK with distinct properties are regulated by neurotransmitters, whereas PYK2/CAKbeta is highly sensitive to depolarization. The multiplicity of the pathways that can be activated by these tyrosine kinases indicates their importance in signal transduction in the adult brain.

Adult↗
PubMed1999

[Cerebral ischemic infarction in newborn infants. Diagnosis using pulsed and color Doppler imaging].

In newborn infant, cerebral infarction is often difficult to distinguish from cerebral hemorrhage, both pathologies being moreover frequently associated. We report a left anterior stroke in a fullterm newborn who had seizures on the third day of life. Ultrasound scanning showed a hyperechogenic zone in the territory of the left anterior cerebral artery. Pulsed and color Doppler imaging showed a decreased blood flow velocity in comparison to the opposite side, thus enabling the diagnosis.

Blood Flow Velocity↗
PubMed1999

Effect of tamoxifen on lipoprotein(a) and insulin-like growth factor-I (IGF-I) in healthy women.

Studies in breast cancer patients have shown that tamoxifen decreases circulating levels of lipoprotein(a) (Lp(a)), an independent risk factor for premature coronary heart disease, and insulin-like growth factor-I (IGF-I), a promising surrogate biomarker for breast cancer. Since a common hormone regulatory pathway has been suggested for both biomarkers, we measured Lp(a) levels for 6 months in 68 healthy women participating in a chemoprevention trial of tamoxifen and correlated its changes with IGF-I. After 1 month, mean Lp(a) levels decreased by 23% with tamoxifen and increased by 6% with placebo (P = 0.033). No further change was observed after 2 and 6 months. Women with abnormal values at baseline (i.e. > 30 mg/dl) showed the highest reduction. The mean levels of IGF-I decreased by 23.5% with tamoxifen and remained stable with placebo, but the changes induced by tamoxifen in Lp(a) and IGF-I levels were uncorrelated. Our results support the observation that tamoxifen may be a suitable preventive option for women with multiple disease risk factors.

Adult↗
PubMed1999

Caring About Women and Cancer (CAWAC): a European survey of the perspectives and experiences of women with female cancers.

This paper reports on the findings of the largest ever European survey of female patients' perceptions of their cancer treatment. It has provided clarification of what women consider important in relation to their management and has identified several areas where more research is needed. It has shown that women's knowledge about cancer before diagnosis is poor and the number undergoing regular screening could be improved. Women are not being adequately prepared and educated about what to expect from treatment and steps should be taken as a matter of urgency to redress this shortcoming. It was revealed that whilst families were the primary source of support to female cancer patients, women also derive considerable support from healthcare professionals, particularly senior doctors; more attention should be paid by specialists and nurses to developing psychological skills to cope with this. In this context, further research is needed into how support groups may best meet patient needs.

Attitude to Health↗
PubMed1999

Effect of fenretinide on bone mineral density and metabolism in women with early breast cancer.

Prolonged administration of natural or synthetic retinoids has been associated with significant skeletal abnormalities, including osteoporosis. We studied the effects of the synthetic retinoid fenretinide (N-4-hydroxyphenylretinamide, or 4-HPR) administered for a mean of 40 months on bone mineral density and metabolism in 66 consecutive women with early breast cancer belonging to a secondary prevention trial. The mean (+/-SD) bone mineral density at the distal and ultradistal forearm were, respectively, 0.61+/-0.08 and 0.30+/-0.05 g/cm2 in 33 treated women and 0.62+/-0.07 and 0.29+/-0.07 g/cm2 in 33 control women (p = ns for both). Also, no significant difference was observed in markers of bone formation such as bone alkaline phosphatase and osteocalcin, nor in urinary bone resorption markers such as calcium, hydroxyproline, and type I bone collagen cross-linked N-telopeptide (NTx). However, a border-line higher excretion of urinary calcium and NTx was found in the 4-HPR group after adjustment for menopausal status. We conclude that prolonged administration of 4-HPR is not associated with significant alterations of bone mineral density of the forearm. However, a trend towards an increase in bone resorption markers suggests the need for further assessment at different skeletal sites.

Aged↗
PubMed1999

START: a European state-of-the-art on-line instrument for clinical oncologists.

START ('State-of-the-Art Oncology in Europe'), a freely available resource on the Internet, is a European 'information base' of current clinical approaches to human tumours. Its aim is to help clinical oncologists make appropriate clinical decisions by providing them with updated information reflecting state-of-the-art cancer treatment as perceived by the European oncology community. It is based upon contributions from authors and internal reviewers from all over Europe as selected by START's editorial board under the supervision of an advisory board and a scientific committee. Close collaborations with the main European cancer societies are ongoing. An external feedback process augments the mechanisms for rendering START a truly European instrument. START is concerned with evidence-based cancer medicine, and the main clinical options are thus codified and their bases indicated in accord with a scale worked out from the perspective of clinical decision-making. Therapeutic options may be 'standard', 'investigational', or 'suitable for individual clinical use' (within the context of a decision made jointly by the patient and the physician). The goal of instruments such as START is to improve the quality of patient care. In addition, START hopes to make contributions to the methodology by which medical research is transformed into clinical decisions.

Decision Making↗
PubMed1999

The effect of growth hormone secretagogues and neuropeptide Y on hypothalamic hormone release from acute rat hypothalamic explants.

Growth hormone (GH) secretagogues (GH-releasing peptides and their non-peptide analogues) stimulate growth hormone release via specific G-protein coupled receptors both directly from the pituitary gland and through stimulation of the hypothalamus. The exact mechanism of action in the hypothalamus is not known. The presence of endogenous GH releasing hormone (GHRH) seems to be necessary for the in-vivo actions of growth hormone secretagogues (GHSs), but data suggest that further factors must be involved as well. The effect of GHSs is not entirely specific for the GH axis; they release prolactin and stimulate the hypothalamo-pituitary-adrenal axis causing elevations in circulating ACTH and cortisol levels in both animal and human studies. Recently, it has also been suggested that GHSs stimulate hypothalamic neuropeptide Y (NPY) neurones. In the present study, we have therefore investigated the direct effect of several GHSs (GHRP-6, hexarelin and the non-peptide analogues L-692, 429 and L-692, 585) on GHRH, somatostatin (SS), corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) release in vitro in an acute rat hypothalamic incubation system. We also assessed the effect of NPY on GHRH, SS and AVP release. Freshly removed hypothalami were incubated in control media for 20 min and then in 1-4 consecutive 20-min periods in each of the test substances at different concentrations. There was no significant change in either the basal or potassium-stimulated release of GHRH or SS at low concentrations of any of the secretagogues; however, at millimolar doses a paradoxical inhibition of GHRH was observed with GHRP-6, hexarelin and L-692 585 (data are expressed as the ratio of treated to preceding basal release; at 20 min control group: 0.97+/-0.02, GHRP-6: 0.55+/-0.04, P<0.001 compared to control group; hexarelin: 0. 56+/-0.06, P<0.001, L-692,585: 0.70+/-0.03, P<0.001), while SS was stimulated after 60 or 80 min (at 80 min control: 0.80+/-0.03, hexarelin: 1.23+/-0.07, P<0.05 and L-692,585: 1.37+/-0.11, P<0.05). GHSs stimulated hypothalamic AVP release (at 20 min control: 0. 99+/-0.06 ratio to basal release, 10-4 M concentration of GHRP-6: 6. 31+/-1, P<0.001, hexarelin: 1.88+/-0.4, P<0.01, L-692,429: 1.90+/-0. 5, P<0.05 and L-692,585: 2.34+/-0.96, P<0.01), while no stimulatory effect was found on CRH release. NPY significantly stimulated SS and inhibited basal and potassium-stimulated GHRH release, while potentiating potassium-evoked AVP secretion. The Y1 receptor antagonist BIBP 3226 did not inhibit the effects of NPY on SS, GHRH or AVP release. We therefore conclude that, in this in-vitro rat hypothalamic incubation model, growth hormone secretagogues stimulate the release of AVP but have no effect on either GHRH, SS or CRH at low doses; at high doses paradoxically they inhibit the hypothalamic GH axis similar to in-vivo data in the rat. We speculate that these effects might be mediated by NPY.

Animals↗
PubMed1999

Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor 1.

Chemokines are a family of proteins that chemoattract and activate cells by interacting with specific receptors on the surface of their targets. The chemokine stromal cell-derived factor 1, (SDF1), binds to the seven-transmembrane G protein-coupled CXCR4 receptor and acts to modulate cell migration, differentiation, and proliferation. CXCR4 and SDF1 are reported to be expressed in various tissues including brain. Here we show that SDF1 and CXCR4 are expressed in cultured cortical type I rat astrocytes, cortical neurons, and cerebellar granule cells. In cortical astrocytes, prolonged treatment with lipopolysaccharide induced an increase of SDF1 expression and a down-regulation of CXCR4, whereas treatment with phorbol esters did not affect SDF1 expression and down-modulated CXCR4 receptor expression. We also demonstrated the ability of human SDF1alpha (hSDF1alpha) to increase the intracellular calcium level in cultured astrocytes and cortical neurons, whereas in the same conditions, cerebellar granule cells did not modify their intracellular calcium concentration. Furthermore, in cortical astrocytes, the simultaneous treatment of hSDF1alpha with the HIV-1 capside glycoprotein gp120 inhibits the cyclic AMP formation induced by forskolin treatment.

AIDS Dementia Complex↗
PubMed1999

Psychological distress in cancer patients attending the European Institute of Oncology in Milan.

BACKGROUND: The determination of the extent and specific features of the psychological distress to be expected in a cancer centre may influence the choice of interventions to be implemented for addressing these problems. This study was aimed at estimating the prevalence of psychological distress in patients attending a second reference cancer centre in Milan (Italy), and at identifying associated factors. PATIENTS AND METHODS: 190 consecutive patients were assessed within 3 days of hospital discharge using the Hospital Anxiety and Depression Scale. RESULTS: Major depressive disorders or generalised anxiety disorders were estimated in 16% of the patients. Only 2 of these patients were referred to the psycho-oncology unit, hence the psychological distress of many patients was not considered during their hospital stay. In the multiple regression analysis, independent predictors of psychological distress were female gender, experience of disturbance in family and social life due to illness, nausea and vomiting, and perception of being in a poor state of health (R(2) = 0.31, p value < 0.001), while physical functioning, fatigue and pain, significant factors in univariate analysis (p < 0. 05), sociodemographic and clinical factors were not predictors. CONCLUSIONS The psycho-oncology team should focus on helping doctors and nurses identify the patients' psychological problems, dealing with them or making a referral.

Adult↗
PubMed1999

Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women.

PURPOSE: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction. PATIENTS AND METHODS: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer. RESULTS: The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 mg every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations. CONCLUSION: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.

Antineoplastic Agents, Hormonal↗