Browsing by Author "Gomes, L"
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- Controversies in the management of hyperglycaemic emergencies in adults with diabetesPublication . Cardoso, L; Vicente, N; Rodrigues, D; Gomes, L; Carrilho, FHyperglycaemic emergencies are associated with significant morbi-mortality and healthcare costs. Management consists on fluid replacement, insulin therapy, and electrolyte correction. However, some areas of patient management remain debatable. In patients without respiratory failure or haemodynamic instability, arterial and venous pH and bicarbonate measurements are comparable. Fluid choice varies upon replenishment phase and patient's condition. If patient is severely hypovolaemic, normal saline solution should be the first option. However, if patient has mild/moderate dehydration, fluid choice must take in consideration sodium concentration. Insulin therapy should be guided by β-hydroxybutyrate normalization and not by blood glucose. Variations of conventional insulin infusion protocols emerged recently. Priming dose of insulin may not be required, and fixed rate insulin infusion represents the best option to suppress hepatic glucose production, ketogenesis, and lipolysis. Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis resolution and prevents rebound hyperglycaemia. Simpler protocols using subcutaneous rapid-acting insulin analogues for mild/moderate diabetic ketoacidosis treatment have proven to be safe and effective, but further studies are required to confirm these results. Treatment with bicarbonate, phosphate, and low-molecular-weight heparin is still disputable, and randomized controlled trials are urgently needed to optimize patient management and decrease the morbi-mortality of hyperglycaemic emergencies.
- Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI studyPublication . Duarte, JV; Pereira, JM; Quendera, B; Raimundo, M; Moreno, C; Gomes, L; Carrilho, F; Castelo-Branco, MType 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes.
- Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancerPublication . Lemos, MC; Carrilho, F; Rodrigues, F; Coutinho, E; Gomes, L; Carvalheiro, M; Regateiro, FJOBJECTIVE: Xenobiotic-metabolizing enzymes are widely polymorphic and confer interindividual variation in the ability to detoxify carcinogens or to activate pro-carcinogens. A common polymorphism of cytochrome P450 2D6 (CYP2D6) results in lack of enzyme activity and has been associated with an altered susceptibility to several cancers. The aim of this study was to investigate the association between the CYP2D6 poor metaboliser genotype and the risk of papillary thyroid cancer (PTC). DESIGN: Retrospective case-control study. PATIENTS: One hundred and eighty-seven patients with PTC and 256 controls. MEASUREMENTS: Genotyping was performed by PCR and restriction enzyme analysis to detect the presence of the common CYP2D6*4 poor metaboliser allele. RESULTS: The frequency of individuals with the homozygous poor metaboliser genotype was lower in the patient group [1.6 vs. 5.5%, P = 0.037, OR = 0.28 (95% CI 0.09-0.93)]. The CYP2D6*4 allele frequency was also lower in the patient group [13.4 vs. 21.7%, P = 0.002, OR = 0.56 (95% CI 0.39-0.80)]. CONCLUSIONS: The results suggest that the poor metaboliser genotype is associated with a protective effect against PTC. This could be explained by a possible role of CYP2D6 on the metabolic activation of putative environmental chemical thyroid carcinogens or by linkage to another cancer-causing gene. Further research may allow the identification of metabolic risk factors and contribute towards understanding the molecular mechanisms involved in thyroid carcinogenesis.
- Hipercortisolismo Recorrente: Após Remoção de Adenoma Hipofisário Secretor de ACTH Associado a Macronódulo da Glândula Supra-RenalPublication . Santos, J; Paiva, I; Gomes, L; Batista, C; Geraldes, E; Rito, M; Velez, A; Oliveira, F; Carvalheiro, MA 29 years old patient was sent to our Outpatient Clinic of Endocrinology presenting clinic of hypercortisolism. Laboratorial study: High urinary free cortisol (UFC); serum cortisol - 25 microg/dl (8 am) (5-25) and 20 microg/dL (11pm); ACTH - 20 pg/mL (9-52) (8 am) and 14 pg/mL (11 pm); serum cortisol after dexamethasone suppression test: 14,9 mg/dL; CRH test: elevation of ACTH; Pituitary MRI: microadenoma; abdominal CT: nodule on the left adrenal. During inferior petrosal sinus sampling with CRH stimulation, ACTH reached 368 pg/mL on the right and 136 pg/mL on the left side. The patient was submitted to transsphenoidal surgery. After surgery, hypertension and physical stigmata improved. In 2006, a relapse of Cushing syndrome was suspected due to worsening of hypertension and increase of weight. A slight increase of UFC, undetectable ACTH and serum cortisol after dexamethasone suppression test equal to 16 microg/dL were found. On abdominal CT, the adrenal nodule kept the same characteristics. In December 2006, the patient was submitted to left adrenalectomy. After surgery, blood pressure normalized, UFC and serum cortisol were reduced, needing substitutive therapy. Progressive tapering of hydrocortisone doses lead to discontinuation in March 2007. He is clinically well, without any treatment. This is an unusual case, in which after surgical cure of Cushing disease, secretory autonomy of a coexisting adrenal nodule occurred. This clinical case is relevant, pointing out the complexity of hypercortisolism cases and the need of long follow-up.
- Hipofisite Auto-imune ou LinfocíticaPublication . Paiva, I; Gomes, L; Ribeiro, C; Carvalheiro, M; Ruas, AThis entity, due to the pituitary lymphoplasmacytic infiltrate, was described for the first time in 1962. The clinical suspicion relies on a rapidly progressing hypopituitarism, particularly with adrenal involvement, affecting women in the peripartum period or patients with previously recognized autoimmune disease. Diabetes insipidus is also often reported. A sellar mass is found in 80% of cases. The diagnosis is confirmed by histology, due to the absence of a specific serological test. The endocrine deficiencies are frequently definitive. Corticotherapy is usually effective in reducing neurological symptoms due to pituitary enlargement, and frequently allows to avoid surgery. The disease-related deaths were due to acute adrenal insufficiency or ineffectively treated hypopituitarism. We are reporting a clinical case of probable lymphocytic hypophysitis in the early post partum of a woman with depression and Graves disease. She has hyperprolactinemia and ACTH deficiency, without pituitary changes in the magnetic resonance imaging. She was treated and her depression and hyperthyroidism were relieved. Hyperprolactinemia recovered spontaneously but she still needs glucocorticoid substitution.
- Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese populationPublication . Lemos, MC; Fagulha, A; Coutinho, E; Gomes, L; Bastos, M; Barros, L; Carrilho, F; Geraldes, E; Regateiro, FJ; Carvalheiro, MThe vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of type 1 diabetes often produced conflicting results in different ethnic backgrounds. The aim of this study was to test for association between common VDR polymorphisms and the genetic susceptibility to type 1 diabetes in the Portuguese population. We genotyped 207 patients with type 1 diabetes and 249 controls for the FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI G>T (rs7975232), and TaqI C>T (rs731236) single nucleotide polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. The distribution of VDR genotype, allele, and haplotype frequencies did not differ significantly between patients and controls. These data suggest that the single nucleotide polymorphisms of the VDR gene are unlikely to contribute significantly to type 1 diabetes susceptibility in the Portuguese population.
- Polimorfismos do gene CYP2D6 estão associados a uma susceptibilidade para os tumores da hipófisePublication . Gomes, L; Lemos, MC; Paiva, I; Ribeiro, C; Carvalheiro, M; Regateiro, FJSeveral polymorphisms of drug-metabolizing enzymes have been implicated in the susceptibility to tumor development. The role of the CYP2D6, GSTM1 and GSTT1 genes has been extensively studied, with alleles conferring different metabolic efficiencies and tumor risk. We studied the relationship between the main polymorphisms of these genes and the susceptibility to develop pituitary tumors, by performing a case-control study comprising 235 patients and 256 controls which were genotyped by means of PCR-RFLP based assays. Frequencies of the CYP2D6*1 and of the poor metabolizer allele CYP2D6*4, were determined along with the frequencies of the GSTM1 and GSTT1 null genotypes. CYP2D6 genotype frequencies were similar in patients and controls (p=0.087). CYP2D6*1 and CYP2D6*4 allele frequencies were 83.8%, 16.2% in cases and 78.3%, 21.7% in controls, showing a significant difference between the two groups (p=0.012). There were no significant differences between the frequencies of the GSTM1 and GSTT1 null genotypes in both groups. No association was found between histological type and any of the studied polymorphisms. Our data suggest an association of the CYP2D6*1 allele and the susceptibility to pituitary adenomas, which could be due to an increased metabolism of unidentified procarcinogens or to linkage disequilibrium with another gene involved in pituitary tumorigenesis.
- PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiencyPublication . Lemos, MC; Gomes, L; Bastos, M; Leite, V; Limbert, E; Carvalho, D; Bacelar, C; Monteiro, M; Fonseca, F; Agapito, A; Castro, JJ; Regateiro, FJ; Carvalheiro, MOBJECTIVE: Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. DESIGN, PATIENTS AND MEASUREMENTS: A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. RESULTS: PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. CONCLUSIONS: This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes
- Radioterapia em tumores hipofisáriosPublication . Baptista, C; Paiva, I; Gomes, L; Gomes, F; Carvalheiro, M; Ruas, AThe aim of this study is to evaluate the use of conventional external radiotherapy in patients with pituitary adenomas. Between October 1970 and May 1998, 27 patients with pituitary adenoma were followed at the Department of Endocrinology and Diabetes of the Hospitais da Universidade de Coimbra. They received radiation therapy at Instituto Português de Oncologia. Seven of those tumors were classified as nonfunctioning adenomas, 17 as growth-hormone-secreting adenomas, 2 as prolactinomas and 1 as adrenocorticotropic adenoma. Twenty-six patients received radiation as adjuvant therapy after incomplete resection and one patient as primary treatment. The majority of these cases were treated using the parallel opposed-field technique with a total dose between 45 and 52 Gy. The patients were submitted, before and after radiotherapy, to a protocol in order to assess the efficacy of this treatment. Some of the results were analyzed. Reduction of tumor mass was achieved in 66.6% of nonfunctioning tumors and in 25% of the secreting ones. Reduction or stabilization of hormonal levels was achieved in 55% of the cases and normalization in 30%. The average duration of follow-up was 126.3 months. Complications observed: hypopituitarism, stroke (3 patients), cerebral edema (1 patient), memory loss (2 patients) and hearing loss (2 patients). None of the patients developed brain tumors
- Relations between Cardiac and Visual Phenotypes in Diabetes: A Multivariate ApproachPublication . Oliveiros, B; Sanches, M; Quendera, B; Graça, B; Guelho, D; Gomes, L; Carrilho, F; Caseiro-Alves, F; Castelo-Branco, MCardiovascular disease and diabetes represent a major public health concern. The former is the most frequent cause of death and disability in patients with type 2 diabetes, where left ventricular dysfunction is highly prevalent. Moreover, diabetic retinopathy is becoming a dominant cause of visual impairment and blindness. The complex relation between cardiovascular disease and diabetic retinopathy as a function of ageing, obesity and hypertension remains to be clarified. Here, we investigated such relations in patients with diabetes type 2, in subjects with neither overt heart disease nor advanced proliferative diabetic retinopathy. We studied 47 patients and 50 controls, aged between 45 and 65 years, equally distributed according to gender. From the 36 measures regarding visual structure and function, and the 11 measures concerning left ventricle function, we performed data reduction to obtain eight new derived variables, seven of which related to the eye, adjusted for age, gender, body mass index and high blood pressure using both discriminant analysis (DA) and logistic regression (LR). We found moderate to strong correlation between left ventricle function and the eye constructs: minimum correlation was found for psychophysical motion thresholds (DA: 0.734; LR: 0.666), while the maximum correlation was achieved with structural volume density in the neural retina (DA: 0.786; LR: 0.788). Controlling the effect of pairwise correlated visual constructs, the parameters that were most correlated to left ventricle function were volume density in retina and thickness of the retinal nerve fiber layers (adjusted multiple R2 is 0.819 and 0.730 for DA and LR), with additional contribution of psychophysical loss in achromatic contrast discrimination. We conclude that visual structural and functional changes in type 2 diabetes are related to heart dysfunction, when the effects of clinical, demographic and associated risk factors are taken into account, revealing a genuine relation between cardiac and retinal diabetic phenotypes.