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Biomedical subjects

A Costa

Publications and source records attributed to A Costa.

At least 55 records · Page 3Linked to original sources
PubMed2003

Parenteral indomethacin (the INDOTEST) in cluster headache.

The interval between indomethacin administration and clinical response may be extremely relevant in the assessment of chronic paroxysmal hemicrania (CPH) and other unilateral headache disorders like cluster headache (CH), with which CPH can be confounded. Indomethacin is inactive in CH; however, in some anecdotal reports in recent years, doubt has been cast on the ineffectiveness of indomethacin in CH. In this study, we have re-assessed the effect of indomethacin treatment in a group of 18 patients with episodic CH (three females and 15 males). From the day 8 of the active period, indomethacin 100 mg i.m. was administered every 12 h, for 2 consecutive days, in an open fashion. The mean daily attack frequency before the test (1.6 +/- 0.6) was not statistically different from that on day 1 (2.1 +/- 0.9) and day 2 (1.9 +/- 0.8) after indomethacin administration. The mean interval between indomethacin injection and the following attack (day 1 and day 2) was 4.6 + 1.1 h. We did not observe any refractory period in any patient after indomethacin. Since the 'expected' attack occurred when there theoretically could have been a protective effect after indomethacin administration, it can be reasonably assumed that there is no such protective effect. The use of a test dose of 100 mg i.m. indomethacin (INDOTEST) appears to provide a clear-cut answer in this situation. It may be a useful tool for a proper clinical assessment of unilateral headache with relatively short-lasting attacks when problems of classification arise. A correct diagnosis of CPH or CH is important, since a CPH diagnosis may imply a lifelong treatment with a potentially noxious drug.

Adult↗
PubMed2003

Nitric oxide pathway and response to nitroglycerin in cluster headache patients: plasma nitrite and citrulline levels.

Nitric oxide (NO) may participate in the mechanisms underlying vascular headaches, such as migraine and cluster headache (CH), by triggering neurogenic inflammation and activation of fibres conveying nociceptive inputs to the trigeminal ganglion. Similarly to migraine, the administration of the NO donor glyceryltrinitrate (GTN) to CH patients is a known model of inducing spontaneous-like attacks. We carried out a GTN test (0.9 mg, sublingually) in 18 patients with episodic CH in active phase and 12 controls. The plasma levels of NO metabolite nitrites (NO2-), after conversion of nitrates to NO2-, were measured spectrophotometrically at baseline, at the maximum intensity of the induced response (or 45 min after GTN in controls), and 120 min after GTN administration. The basal plasma levels of L-citrulline were also assayed in patients and controls using high-performance liquid chromatography. Basal NO2- levels, similar in GTN-responsive patients and controls (48.3 +/- 10.6 and 44.6 +/- 9.5 micromol/l, respectively) were found to be increased significantly at pain peak in patients (76.1 +/- 10.2 micromol/l) and after 45 min in controls (78.2 +/- 9.6 micromol/l) (P < 0.01 vs. respective baseline values), but not after 120 min, without differences between groups. L-citrulline levels in basal conditions showed no differences between groups (patients 64.8 +/- 11.7, controls 67.3 +/- 10.8 micromol/l). These data do not support the presence of a basal hyperactivity of the L-arginine-NO pathway in CH patients. Increased NO production may be of importance in the mechanisms leading to CH attacks, but other factors are likely to render CH patients hyperresponsive to NO, and ultimately to cause the occurrence of pain and associated features.

Adult↗
PubMed2003

Validation of intensity modulation on a commercial treatment planning system.

For two years now, a study on intensity modulated radiotherapy (IMRT) has been in progress at the Antoine Lacassagne Hospital Center for Cancer Therapy (in Nice) in collaboration with the University of Nice-Sophia Antipolis. The kind of intensity modulation that was used is the "step and shoot" technique in which the modulated beam is created both by adding andjoining elementary fields. Before carrying out clinical tests, several problems regarding the production of modulated beams has to be mastered. The current developments of our study enable us to dosimetrically produce (in water phantom and in the PMMA phantom) complexmodulated whose segmentation was calculated by one commercial treatment planning system (TPS). Nevertheless, we showed and studied some critical discrepancies between standard clinical calculations and the calculations using field segmentation. We showed that with nonoptimal conditions of segmentation the discrepancies, which are due to the type of algorithm used, could bring about significant errors inside the field of up to 10% of maximum dose. Another point of our study is the quantification and resolution of differences between measurements and calculations due to the internal segmentation of calculated modulated fields and their realization on Linac. Once again, in none optimal conditions of segmentation and inside the field we obtained discrepancies up to 20% of maximum dose between calculations using field segmentation and measurements. That was mainly due to the tongue and groove effect and penumbra phenomena. This study allows us to show that the discrepancies between segmentation calculations and standard clinical calculations should be solved by the use of penumbra models during segmentation calculations. We will introduce both the study and its near-future perspectives.

Algorithms↗
PubMed2003

Comparison of whole-blood glutathione peroxidase activity, levels of serum selenium, and lipid peroxidation in subjects from the fishing and rural communities of "Rabo de Peixe" village, San Miguel Island, the Azores' Archipelago, Portugal.

The activity of glutathione peroxidase (GSH-Px), serum selenium (Se), and thiobarbituric acid reactive substances (TBARS) were measured in the whole blood of 148 healthy adults aged 20-60 yr from the fishing and rural communities of "Rabo de Peixe," The Azores, Portugal. The subjects did not live in the same household and had different socioeconomic profiles and dietary habits. The serum lipid profile and selected life habits were also considered in this study. No significant differences in the activity of GSH-Px were found in the interpopulation or intrapopulation analyses, classified by age or lipid profile. An age-dependent GSH-Px increase was noted in the younger male (M) subgroups (20-39 yr). The Se levels were higher in fishers (f) of both genders (M, F) than in subjects living in the rural (r) environment: 110+/-25 microg/L (f, M), 89+/-20 microg/L (f, F), 88+/-22 microg/L (r, M) and 80+/-17 microg/L (r, F). In the fishers, but not in the rural population, Se was higher in the males, but it did not show significant variation with age. The levels of TBARS were lower in the f than in the r male group. The Se level was lower and TBARS higher in the hyperlipemic women in the f group, compared to the corresponding controls. Our results suggest that the fishers (mainly men) show a better antioxidant status than that of their rural counterparts, due to differences in dietary habits between the study populations and between genders.

Adult↗
PubMed2002

Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.

AIMS/HYPOTHESIS: The recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility. METHODS: To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha. RESULTS: Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions. CONCLUSION/INTERPRETATION: We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.

Adolescent↗
PubMed2002

The genetic abnormality in the beta cell determines the response to an oral glucose load.

AIMS/HYPOTHESIS: We assessed how the role of genes genetic causation in causing maturity-onset diabetes of the young (MODY) alters the response to an oral glucose tolerance test (OGTT). METHODS: We studied OGTT in 362 MODY subjects, from seven European centres; 245 had glucokinase gene mutations and 117 had Hepatocyte Nuclear Factor -1 alpha ( HNF-1alpha) gene mutations. RESULTS: BMI and age were similar in the genetically defined groups. Fasting plasma glucose (FPG) was less than 5.5 mmol/l in 2 % glucokinase subjects and 46 % HNF-1 alpha subjects ( p < 0.0001). Glucokinase subjects had a higher FPG than HNF-1 alpha subjects ([means +/- SD] 6.8 +/- 0.8 vs 6.0 +/- 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 +/- 2.3 vs 11.2 +/- 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h - fasting) (2.1 +/- 2.3 vs 5.2 +/- 3.9 mmol/l, p < 0.0001). The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used. Fasting and 2-h glucose values were not correlated in the glucokinase subjects ( r = -0.047, p = 0.65) but were strongly correlated in HNF-1 alpha subjects ( r = 0.8, p < 0.001). Insulin concentrations were higher in the glucokinase subjects throughout the OGTT. CONCLUSION/INTERPRETATION: The genetic cause of the beta-cell defect results in clear differences in both the fasting glucose and the response to an oral glucose load and this can help diagnostic genetic testing in MODY. OGTT results reflect not only the degree of hyperglycaemia but also the underlying cause.

Adult↗
PubMed2002

Prevalence of erectile dysfunction in Colombia, Ecuador, and Venezuela: a population-based study (DENSA).

The purpose of this study was to estimate the prevalence of erectile dysfunction (ED) in Colombia, Ecuador, and Venezuela. A 49-item questionnaire was completed by 1946 men aged 40 years and older. The age-adjusted combined prevalence of minimal, moderate, and complete ED for all three countries was 53.4%, with 19.8% of all men reporting moderate to complete ED. Age was the variable most strongly linked to ED; the prevalence of complete ED increased markedly in men older than 79 y of age (31.9%) and 70-79 y (17.2%) compared with men aged 40-49 y (<3%). Several medical conditions, such as hypertension, benign prostatic hyperplasia, and diabetes, and the use of medications to treat these conditions were correlated with the prevalence of ED. This study corroborates earlier studies demonstrating that ED is very common, increases dramatically with age, and has multiple correlates, including some that are also risk factors for cardiovascular disease.

Adult↗
PubMed2002

Efficacy and safety of oral sildenafil citrate (Viagra) in the treatment of male erectile dysfunction in Colombia, Ecuador, and Venezuela: a double-blind, multicenter, placebo-controlled study.

The objective of this work was to assess the efficacy and safety of sildenafil in patients with erectile dysfunction (ED) from Colombia, Ecuador, and Venezuela. One hundred and fifty-eight outpatients with ED participated in a double-blind, flexible-dose, randomized-controlled trial. Efficacy measures included question 3 (achieving an erection) and question 4 (maintaining an erection) from the International Index of Erectile Function (IIEF), the five functional domains of the IIEF, a global efficacy question, and patient event log. Sildenafil increased patients' ability to achieve/maintain erections (P<0.01). Seventy-seven per cent of sildenafil- vs 46% of placebo-treated patients reported improved erections (P<0.001). Sixty-five percent and 35% of intercourse attempts were successful among sildenafil and placebo patients, respectively (P<0.05). Sildenafil patients showed significant improvements in three of the five IIEF functional domains (P<0.05). Adverse events were reported for 51% and 33% of sildenafil and placebo patients, respectively. It can be concluded that sildenafil is an effective, well-tolerated treatment for ED in patients from Latin America.

Administration, Oral↗
PubMed2002

Nitroglycerin-induced activation of monoaminergic transmission in the rat.

When administered to migraine patients, nitroglycerin induces a spontaneous-like migraine attack, with a latency of several hours. Nitroglycerin acts directly and/or indirectly on the central nervous system, through the release of nitric oxide (NO). Systemic administration of the drug to the rat causes neuronal activation in selected subcortical areas, particularly in monoaminergic nuclei of the brainstem. In this study, we sought to investigate whether this activation correlates with changes in monoaminergic neurotransmission. For this purpose, we evaluated the tissue levels of catecholamines and serotonin in the hypothalamus, mesencephalon, pons and medulla of rats treated with systemic nitroglycerin or vehicle, at different time points (1, 2 and 4 h). We also evaluated the peripheral sympathetic response to the drug by measuring the concentrations of plasma catecholamines. Nitroglycerin caused an early (1 h) increase in cerebral (pons) and plasma levels of norepinephrine, followed by a delayed (4 h) decrease in medullary and pontine levels of serotonin. The initial noradrenergic activation may reflect the autonomic response to the rapid cardiovascular effects of the drug, while the delayed response may result from the interaction of nitroglycerin-released NO and 5-HT in central areas devoted to the modulation of nociception. These data might therefore help to clarify the mechanisms underlying the delayed migraine attack observed in migraine sufferers after systemic administration of nitroglycerin.

Animals↗
PubMed2002

Uric acid concentration in subjects at risk of type 2 diabetes mellitus: relationship to components of the metabolic syndrome.

High uric acid concentration is a common finding in subjects with risk factors for cardiovascular disease (CVD), including some characteristics of the metabolic syndrome. However, its exact role in this setting and in the progression to type 2 diabetes mellitus (DM) is not well understood and could be affected by confounding factors such as hypertriglyceridemia. Our study aimed to establish the relationship between uric acid (avoiding the interference of high triglyceride levels), insulin sensitivity, and components of the metabolic syndrome in a group of subjects at high risk of developing DM. Among 201 subjects included in the study, 111 (55.2%) showed an abnormal oral glucose tolerance and uric acid levels higher than those measured in subjects with normal glucose tolerance. Body mass index (BMI), triglycerides, diastolic blood pressure (DBP), and 2-hour glycemia in the oral glucose tolerance test (OGTT) contributed independently to uric acid concentration (R2 =.59). However, uric acid did not affect either insulin sensitivity or glucose tolerance. The recovery tests revealed that a triglyceride concentration > or = 3 mmol/L interfered with the measurement of uric acid level when a colorimetric method was used, but not when a dry-chemistry method was used. In conclusion, uric acid concentration is higher in subjects at high risk of DM with abnormal glucose tolerance and is independently determined by various components of the metabolic syndrome.

Adult↗
PubMed2002

mdm2-p53 Interaction: lack of correlation with the response to 5-fluorouracil in advanced colorectal cancer.

OBJECTIVE: We investigated the relevance of mdm2 and p53 primary tumour expression to the clinical outcome of a consecutive series of advanced colorectal cancer patients treated with a 5-fluorouracil-based chemotherapy. METHODS: The expression of p53 and mdm2 was analyzed by an immunohistochemical assay in 80 formalin-fixed paraffin embedded primary tumour samples and related to the clinical response to 5-fluorouracil therapy and to the prognosis of the patients. In a subgroup of 46 tumours, the apoptotic index (AI) as determined by the Tunel technique was also assessed. RESULTS: Nuclear immunostaining of p53 and mdm2 was present in 42 and 30% of the cases, respectively. No correlation was demonstrated between p53 and mdm2 expression (rs = -0.01; p > 0.05). With regard to the clinical outcome, no statistical association was demonstrated among p53 and mdm2 expression, AI, probability of clinical response to treatment, time to progression, or overall survival. The subgroup of patients with a p53-negative/mdm2-positive tumour showed a worse response rate (15%); however, mdm2-positive/AI-negative tumours showed a 0% (0/7) probability of a clinical response as compared with 30% (9/30) of the remaining tumour patient subgroups; this also translated in a significantly worse overall survival probability (p = 0.01 by log rank). CONCLUSIONS: The analysis of mdm2 expression does not add significant clinical information in colorectal cancers with a different p53 status. Conversely, further analysis of AI seems to give data of a promising prognostic-predictive value.

Adenocarcinoma↗
PubMed2002

Informing the public about advances in cancer therapy.

The word cancer continues to be associated with fear and pessimism among the general public, but they also hear of "new breakthroughs" in the field of oncology. This paper considers whether or not such research advances in cancer are occurring and, if so, is this information being accurately transmitted both within and outside the medical profession. If information is to be given to the public, what preparatory work needs to be achieved in order that this is done effectively.

Communication↗
PubMed2001

Paracrine roles of NAD+ and cyclic ADP-ribose in increasing intracellular calcium and enhancing cell proliferation of 3T3 fibroblasts.

CD38 is a bifunctional ectoenzyme synthesizing from NAD(+) (ADP-ribosyl cyclase) and degrading (hydrolase) cyclic ADP-ribose (cADPR), a powerful universal calcium mobilizer from intracellular stores. Recently, hexameric connexin 43 (Cx43) hemichannels have been shown to release cytosolic NAD(+) from isolated murine fibroblasts (Bruzzone, S., Guida, L., Zocchi, E., Franco, L. and De Flora, A. (2001) FASEB J. 15, 10-12), making this dinucleotide available to the ectocellular active site of CD38. Here we investigated transwell co-cultures of CD38(+) (transfected) and CD38(-) 3T3 cells in order to establish the role of extracellular NAD(+) and cADPR on [Ca(2+)](i) levels and on proliferation of the CD38(-) target cells. CD38(+), but not CD38(-), feeder cells induced a [Ca(2+)](i) increase in the CD38(-) target cells which was comparable to that observed with extracellular cADPR alone and inhibitable by NAD(+)-glycohydrolase or by the cADPR antagonist 8-NH(2)-cADPR. Addition of recombinant ADP-ribosyl cyclase to the medium of CD38(-) feeders induced sustained [Ca(2+)](i) increases in CD38(-) target cells. Co-culture on CD38(+) feeders enhanced the proliferation of CD38(-) target cells over control values and significantly shortened the S phase of cell cycle. These results demonstrate a paracrine process based on Cx43-mediated release of NAD(+), its CD38-catalyzed conversion to extracellular cADPR, and influx of this nucleotide into responsive cells to increase [Ca(2+)](i) and stimulate cell proliferation.

3T3 Cells↗
PubMed2001

Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer.

PURPOSE: To describe the pattern of occurrence of adverse events commonly arising during treatment with fenretinide, a synthetic retinoid under investigation for cancer prevention. PATIENTS AND METHODS: The series includes 2,867 women accrued in a trial aimed at assessing the effect of fenretinide on the prevention of second breast malignancy. Women were randomly assigned to receive no treatment (1,435 patients) or 5-year fenretinide treatment (1,432 patients). In terms of disease recurrence in the breast, the trial showed a possible beneficial effect of the compound in premenopausal women, and an opposite trend in postmenopausal women. End points considered for safety assessment were the occurrence of diminished dark adaptation, dermatologic disorders, gastrointestinal symptoms, disorders of the ocular surface, and abnormal laboratory values. RESULTS: The most common adverse events were diminished dark adaptation (cumulative incidence, 19.0%) and dermatologic disorders (18.6%). Less common events were gastrointestinal symptoms (13.0%) and disorders of the ocular surface (10.9%). In comparison, incidence figures in the control arm were 2.9% for diminished dark adaptation, 2.9% for dermatologic disorders, 5.4% for gastrointestinal symptoms, and 3.2% for disorders of the ocular surface. Symptoms occurring during fenretinide treatment tended to recover with time. No between-group difference was observed for the occurrence of laboratory data abnormalities. Overall, 63 (4.4%) treatment discontinuations were caused by adverse events. CONCLUSION: Given the number of patients involved in the study and the prolonged intake of the drug, the experience on fenretinide tolerability can be considered sufficiently reassuring to justify further testing of the retinoid.

Administration, Oral↗