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Biomedical subjects

A Costa

Publications and source records attributed to A Costa.

At least 19 recordsLinked to original sources
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

[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↗
PubMed1998

Biological markers as indicators of pathological response to primary chemotherapy in oral-cavity cancers.

The predictive role in terms of pathological response and prognostic role of biomarkers such as GST-pi, p53, bcl-2 and bax expression, immuno-histochemically detected, and of the S-phase cell fraction, autoradiographically determined as thymidine labeling index (TLI), were investigated within a prospective randomized phase III clinical trial on squamous-cell carcinoma of the oral cavity, including surgery or primary chemotherapy (PCT), which foresaw the prospective determination of biological markers. Pathological response was defined as the achievement after PCT of a pathological complete remission or the presence of microresidual disease. The study was performed on tumors obtained from a series of 100 previously untreated patients with resectable T2-4N0-2M0 carcinoma. All biomarkers were unrelated, except for an inverse relation between TLI and GST-pi and a direct relation between bcl-2 and bax expression. In patients treated with surgery alone, 3-year disease-free survival (DFS) appeared to be weakly, but not significantly, related only to GST-pi and p53 expression. In patients treated with PCT, pathological response and DFS were independent of p53 expression and cell proliferation. Conversely, low GST-pi and bax expression were indicative of pathological response but lost relevance as predictors of DFS, whereas absence of bcl-2 was associated with high probability of 3-year DFS in the overall series as well as in non-responding patients. Within this latter sub-set, all patients with bcl-2-positive tumors relapsed within 1 year of surgery, whereas a 60% probability of 3-year DFS was observed for patients with bcl-2-negative tumors (p = 0.02). This interim analysis appears to indicate that some biofunctional markers can provide information on pathological response to PCT and could help in understanding treatment efficacy at a cellular level.

Biomarkers↗
PubMed1998

Biologic activity of tamoxifen at low doses in healthy women.

BACKGROUND: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use. METHODS: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/ alternate days (n = 32) (second experiment). Baseline and 2-month measurements of the following parameters were compared: 1) total cholesterol (primary end point) and other surrogate markers of cardiovascular disease, e.g., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) blood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; and, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I), a possible surrogate marker for breast cancer. RESULTS: After adjustment for the baseline values, there were reductions in circulating levels of total cholesterol and IGF-I of the same magnitude in all three tamoxifen treatment arms. A similar pattern was observed for most of the other parameters. In the placebo arm, fibrinogen level, which showed a decrease, was the only parameter exhibiting change. CONCLUSIONS: Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses.

Adult↗
PubMed1998

Identification of a new WT1 mutation in a sporadic Wilms' tumour.

A new mutation in WT1 is described in a sporadic unilateral Wilms' tumour consisting of a 17 bp duplication in exon 7 generating a stop codon. The second allele is either partially deleted or presents the same alteration. LOH analysis at 11p15.5 and at the 16q13-16q24.3 regions indicated retention of heterozygosity in the tumour DNA for the markers analysed. The results are consistent with Knudson's hypothesis and confirm that loss of function of WT1 contributes to the development of at least some Wilms' tumours.

Child, Preschool↗
PubMed1998

Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study.

BACKGROUND: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive. METHODS: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat. FINDINGS: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen. INTERPRETATION: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

Adult↗
PubMed1998

Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients.

Growing evidence substantiates the role of the insulin-like growth factor I (IGF-1) system in breast tumorigenesis. Retinoids have been shown to affect the IGF system several experimental models. We extended our previous data on plasma IGF-1 modulation by the synthetic retinoid fenretinide (4-HPR) and investigated the effect of the retinoid on plasma IGF binding protein (BP)-3, the major protein binding IGFs. IGF-1 and IGFBP-3 were measured on plasma samples obtained at randomization and after an interval of approximately 1 year, from 39 and 33 stage 1 breast cancer patients assigned to receive 4-HPR, and from 39 and 34 untreated controls, respectively. There was a significant decrease in plasma IGF-1 after 4-HPR administration, whereas no significant change was observed in controls. The effect of 4-HPR on IGF-1 levels was modified by menopausal status, inasmuch as the decrease in IGF-1 was particularly pronounced in pre-menopausal women, whereas the reverse was observed in untreated controls. By contrast, treatment induced an increase of IGFBP-3 with respect to controls. As a result of this dual effect, the bioavailability of IGF-1 for interaction with receptors at target levels further decreased in pre-menopausal 4-HPR treated patients compared with controls, suggesting that retinoid administration may result in lower concentrations of biologically active IGF-1. Our findings may have important implications for the clinical preventive activity of this retinoid.

Adult↗
PubMed1998

Endotoxin stimulates an endogenous pathway regulating corticotropin-releasing hormone and vasopressin release involving the generation of nitric oxide and carbon monoxide.

Although the administration of endotoxin in vivo activates the neuroendocrine stress axis in the process of crosstalk between the immune and endocrine axes, the direct application of endotoxin to the hypothalamus in vitro does not stimulate the release of the hypothalamic peptides controlling the hypothalamo-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) and vasopressin. The hypothesis has therefore been tested that endotoxin may also activate inhibitory pathways, specifically those involving the generation of nitric oxide (NO) and carbon monoxide (CO). Studies were performed on the isolated rat hypothalamus using endotoxin in the presence or absence of inhibitors of heme oxygenase (which generates CO) and nitric oxide synthase, and ferrous hemoglobin. Endotoxin alone decreased both CRH and vasopressin secretion from the hypothalamus. However, when applied together with a nitric oxide synthase inhibitor, the inhibitory effect on CRH was lost. Conversely, co-administration with heme oxygenase inhibitors transformed the inhibition of vasopressin to stimulation, while having no effect on the inhibition of CRH. Ferrous hemoglobin reversed the inhibition of vasopressin, but did not lead to stimulation. It is therefore concluded that endotoxin may stimulate endogenous pathways that lead to the generation of NO, which in turn inhibits CRH. In addition, it generates CO, which modulates the release of vasopressin. These gases are thus potential counter-regulatory controls to the activation of the HPA.

Animals↗
PubMed1998

Acute and subacute effects of endotoxin on hypothalamic gaseous neuromodulators.

Although two-way communication between the hypothalamus and the immune system in now well established, particularly for the hypothalamo-pituitary-adrenal axis, the role of the gaseous neurotransmitters nitric oxide (NO) and carbon monoxide (CO) is much less well understood in terms of hypothalamic function. These agents are an important part of the peripheral inflammatory response; and their synthetic enzymes, NO synthase (NOS) and heme oxygenase (HO), respectively, have been localized to the hypothalamic PVN and SON. The induced generation of both NO and CO leads to the suppression of CRH and vasopressin, the major stimulators of the HPA. Thus, the addition of hemin to hypothalamic explants is maximally active at 1 microM in attenuating the release of CRH and vasopressin, and this dose is also most effective in generating biliverdin and associated CO. CO generation is also able to stimulate cyclooxygenase to produce prostaglandin E2, an established intermediary in the cytokine-stimulated activation of the HPA. Finally, inducible NOS mRNA is specifically induced in the hypothalalmus in response to endotoxin, in parallel to interleukin-1. These data provide increasing evidence in favor of NO and CO as counterregulatory agents in the HPA response to immune activation.

Animals↗
PubMed1998

Expression of CD38 increases intracellular calcium concentration and reduces doubling time in HeLa and 3T3 cells.

CD38 is a bifunctional ectoenzyme, predominantly expressed on hematopoietic cells during differentiation, that catalyzes the synthesis (cyclase) and the degradation (hydrolase) of cyclic ADP-ribose (cADPR), a powerful calcium mobilizer from intracellular stores. Due to the well established role of calcium levels in the regulation of apoptosis, proliferation, and differentiation, the CD38/cADPR system seems to be a likely candidate involved in the control of these fundamental processes. The ectocellular localization of the cyclase activity, however, contrasts with the intracellular site of action of cADPR. Here we demonstrate that ectocellular expression of human CD38 in CD38(-) HeLa and 3T3 cells results in intracellular CD38 substrate (NAD+ + NADH) consumption and product (cADPR) accumulation. Furthermore, a causal relationship is established between presence of intracellular cADPR, partial depletion of thapsigargin-sensitive calcium stores, increase in basal free cytoplasmic calcium concentration, and decrease of cell doubling time. The significant shortening of the S phase in CD38(+) HeLa cells, as compared with controls, demonstrates an effect of intracellular cADPR on the mammalian cell cycle.

3T3 Cells↗
PubMed1998

Prevention of breast cancer: focus on chemoprevention.

Present prospects of breast cancer prevention are being developed in three main areas: (a) genetics, to understand the real importance of familial breast cancer and genetic testing; (b) lifestyle, to study various risk factors, including delayed first pregnancies and smaller number of pregnancies, and months of breast feeding; (c) chemoprevention, to identify chemical agents potentially able to inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells. Different target populations for breast cancer chemoprevention may be recognized. Primary chemoprevention may involve a wide population of healthy women with a moderate risk due to nonpenetrant genetic factors (e.g., one first-degree relative with breast cancer) or exposure to known promoting agents (e.g., hormone replacement therapy). A second level of primary chemoprevention may involve a limited population at very high risk because of highly penetrating genetic predisposition to cancer (e.g., BRCA1 mutation carriers). Secondary chemoprevention may involve subjects with premalignant or early malignant lesions, e.g., breast atypical hyperplasia and carcinoma in situ or microinvasive disease. Prevention trials using clinical endpoints are always subject to high costs. Also, the risk of unexpected detrimental effects has recently been high-lighted, and much emphasis has been put on the search for intermediate, surrogate endpoints. Surrogate endpoints are biological markers that may be assessed or observed prior to the clinical appearance of the disease, bearing some relationship to the development of that disease. They are referred to as intermediate since they occur some time between a given intervention that affected the disease process and the time of the clinical diagnosis of the disease. The use of surrogate endpoint biomarkers in pivotal cancer chemoprevention trials may lead to a rational choice of agents which are likely to affect cancer incidence in subsequent phase III trials.

Biomarkers, Tumor↗
PubMed1998

Bcl-2 protein and prognosis in patients with potentially curable non-small-cell lung cancer.

The bcl-2 proto-oncogene functions as a cell death suppressor, and its expression prolongs cell survival by blocking apoptosis. Data available on the clinical relevance of bcl-2 protein expression in patients with non-small-cell lung cancer (NSCLC) are controversial. We analysed the role of bcl-2 protein expression on 6-year relapse-free survival in 229 patients with stage I-IIIa NSCLC (101 squamous cell carcinomas and 128 adenocarcinomas) subjected to surgery, with curative intent. Immunohistochemical analysis was performed on archival material by using a monoclonal antibody anti-bcl-2 (clone 124). Bcl-2 protein expression, which was detected in 22% of the cases, was significantly related to stage, histology and grading, and was an indicator of clinical outcome. The probability of relapse-free survival at 6 years was longer for patients with bcl-2-positive tumours (74%) than for those with bcl-2-negative tumours (57%) (P=0.02). This finding was mainly evident for the subgroups of patients with stage IIIa tumours (P=0.05), squamous cell carcinoma (P=0.03) or moderately/poorly differentiated tumours (P=0.02). However, multivariate analysis by Weibull's regression model indicated that bcl-2 protein expression was not an independent prognostic risk factor in patients with curable NSCLC when the information provided by stage was available.

Adult↗
PubMed1998

High prevalence of abnormal glucose tolerance and metabolic disturbances in first degree relatives of NIDDM patients. A study in Catalonia, a mediterranean community.

Our study aimed to analyse clinical and metabolic characteristics of first degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) in Catalonia. Two hundred and five subjects (39.8 +/- 14.2 year-old, 61% women) were included in the study. An oral glucose tolerance test (OGTT) was performed, obtaining basal plasma glucose and insulin, in order to calculate, %B (HOMA beta cell function) and %S (HOMA insulin sensitivity). A 30.7% of subjects showed an abnormal glucose tolerance, either as impaired glucose tolerance (IGT) (20.5%) or as NIDDM (10.2%). Glycaemia after the OGTT (120 min) was independently determined by fasting glycaemia and age (R2 = 0.50; P < 0.001). As expected, subjects with normal glucose tolerance (NGT) were significantly younger than IGT and NIDDM subjects. The relatives with IGT and NIDDM display more features of syndrome-X when compared to NGT. Likewise, NGT relatives were less insulin sensitive and their basal insulin levels were higher when compared with a control group of subjects without familial history of NIDDM (log %S, 3.6 +/- 0.4 vs. 3.9 +/- 0.4; P = 0.000; log-insulin 2.4 +/- 0.4 vs. 2.1 +/- 0.6 mU/l; P < 0.02). In comparison with the general population, of any age group, NIDDM and IGT were more common in those subjects with a family history of NIDDM. Interestingly, the rates, of abnormal glucose tolerance in the 55-64 and > 64 year groups in the general population were similar to those seen in relatives two decades younger. Our study not only confirms a high prevalence of impaired glucose tolerance (IGT and NIDDM) in subjects with a family history of NIDDM, but also that these abnormalities can be detected at a very early age. Globally, this piece of information corroborates that special attention and precocious detection programs should be addressed to relatives of NIDDM patients.

Adult↗
PubMed1998

Meningo-cortical calcifying angiomatosis and celiac disease.

A woman with ophthalmic migraine was found to have bilateral cerebellar and cerebral calcifications. She progressively developed severe intracranial hypertension, with swelling of the brain and downward transtentorial and tonsillar herniation. Because steroid treatment was ineffective, the right occipital pole was resected. Histological study demonstrated meningo-cortical calcifying angiomatosis. Within 2 months, brain swelling and papilledema disappeared. Subtle signs of malabsorption led to the hypothesis of celiac disease, confirmed by jejunal biopsy. Similar cerebral histological findings have been reported in the brain of two young patients affected by epilepsy and celiac disease. The association between cerebral calcifications and celiac disease is peculiar; the pathogenetic relationship is unknown.

Adult↗
PubMed1998

Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial.

The relationship between plasma transforming growth factor-beta 1 (TGF-beta 1) and second primary breast cancer was explored in a prevention trial of the synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR). Plasma concentrations of TGF-beta 1 were measured by radioimmunoassay in plasma obtained at randomisation and after approximately 1 year of intervention in 28 women treated with 4-HPR and 27 untreated controls with stage I breast cancer. Baseline and 1 year growth factor concentrations were not significantly different between treated and control groups. After a median follow-up of 65 months, an increase in TGF-beta 1 over 1 year was the only significant, independent predictor of a shorter survival free from secondary primary breast cancer. Moreover, the change in TGF-beta 1 levels had a tendency to influence the treatment effect on second breast cancer incidence. Our data suggest that the role of plasma TGF-beta 1 as a surrogate endpoint of breast carcinogenesis should be assessed further.

Adult↗