Abdominal Pain as the First Manifestation of a Systemic Disease

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mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma

CONTEXT: There are several genetic and molecular evidences suggesting dysregulation of the mammalian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphatidylinositol-3-kinase/AKT pathway by RET/PTC and mutant RAS has already been demonstrated, but no data have been reported for the BRAF(V600E) mutation. OBJECTIVE: The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesions and whether it may be correlated with known genetic alterations, as well as to explore the mechanisms underlying mTOR pathway activation in these neoplasias. RESULTS: We observed, by immunohistochemical evaluation, an up-regulation/activation of the mTOR pathway proteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAF(V600E) mutation. Transfection assays with BRAF expression vectors as well as BRAF knockdown by small interfering RNA revealed a positive association between BRAF expression and mTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAF mutation and mTOR pathway up-regulation. When we evaluated the rapamycin in the growth of thyroid cancer cell lines, we detected that cell lines with activating mutations in the MAPK pathway show a higher sensitivity to this drug. CONCLUSIONS: We determined that the AKT/mTOR pathway is particularly overactivated in human cPTC harboring the BRAF(V600E) mutation. Moreover, our results suggest that the mTOR pathway could be a good target to enhance therapy effects in certain types of thyroid carcinoma, namely in those harboring the BRAF(V600E) mutation

Paraquat Intoxication – experience of an Internal Medicine ward for 18 years

Introduction: Paraquat is a contact herbicide commercially available since 1962. Paraquat intoxication (PI) is usually voluntary and highly lethal, since there is no effective antidote. Toxicity occurs through cyclic redox reactions, damaging mainly the kidneys and lungs. Aim, material and methods: featuring the clinical presentation, management and outcome of patients with PI over an 18 years period (from the 01st January 1993 to the 31st December 2010) through the retrospective analysis of clinical files and comparing the survivors and the deceased. Results: Thirty-one cases of Paraquat intoxication were included, with a male: female ratio 1:1. Age range from 13 to 80 years, mean age 42.4years (±18.7).All intoxications were voluntary and by oral route. There was statistical difference in the amount ingested (22.1 mL vs. 72.7 mL, p<0.0005). A non-significant trend to a longer delay until getting medical attention in the deceased group (1.6 h vs. 3.2 h, p=0.091). Statistical significance was found between mortality and leukocytosis, hypocapnea, hypoxemia, LDH, alkaline phosphatase and AST. There was no difference between groups according to treatment options, although hemocarboperfusion was used more often in the deceased group (53.9% vs. 66.7%, p=0.471) and corticosteroids in the survivor group (61.5% vs. 44.4%, p=0.350). Mortality rate was 58.1% (66.7% in the first 72 hours), due to respiratory insufficiency and multiple organ failure. Variable levels of pulmonary fibrosis occurred in 38.5% of the survivors. Discussion & Conclusion: Paraquat intoxication has a poor prognosis with limited efficiency of treatment approaches. The relation between Paraquat in the urine and the time elapsed after ingestion is the main determinant factor in the prognosis. In this study the presence of dyspnea, hypocapnea and hypoxemia was linked to a bad prognosis. There was no statistical difference between the available treatment options

Kalirin: a novel genetic risk factor for ischemic stroke

Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases

Erratum to “Gastroenteropancreatic Neuroendocrine Neoplasia Characterization in Portugal: Results from the NETs Study Group of the Portuguese Society of Endocrinology, Diabetes and Metabolism”

In the article titled "Gastroenteropancreatic Neuroendocrine Neoplasia Characterization in Portugal: Results from the NETs Study Group of the Portuguese Society of Endocrinology, Diabetes and Metabolism"[1], the affiliation for I. Claro was labeled incorrectly. The correct affiliation of the author I. Claro is Instituto Portugûes de Oncologia de Lisboa, Francisco Gentil (IPOLFG), 1099-023 Lisboa, Portugal

Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patient

BACKGROUND: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. METHODS: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. RESULTS: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. CONCLUSION: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample