Identification of Growth Hormone Receptor in Plexiform Neurofibromas of Patients with Neurofibromatosis Type 1

OBJECTIVE: The aim of this study was to investigate the presence of growth hormone receptor in plexiform neurofibromas of neurofibromatosis type 1 patients. INTRODUCTION: The development of multiple neurofibromas is one of the major features of neurofibromatosis type 1. Since neurofibromas commonly grow during periods of hormonal change, especially during puberty and pregnancy, it has been suggested that hormones may influence neurofibromatosis type 1 neurofibromas. A recent study showed that the majority of localized neurofibromas from neurofibromatosis type 1 patients have growth hormone receptor. METHODS: Growth hormone receptor expression was investigated in 5 plexiform neurofibromas using immunohistochemistry. RESULTS: Four of the 5 plexiform neurofibromas were immunopositive for growth hormone receptor. CONCLUSION: This study suggests that growth hormone may influence the development of plexiform neurofibromas in patients with neurofibromatosis type 1

Genética da neurofibromatose tipo 1

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen´s disease, is the most common form of Neurofibromatosis and account for 90% of all cases. The presence of multiple neurofibromas is one of the main clinical manifestations of NF1. Other clinical characteristics include: café au lait spots, inguinal and axillary ephelides and Lisch nodules. NF1 is an autosomal dominant disorder with a complete penetrance and extreme clinical variability, even in intrafamilial cases. The gene complexity and the diversity of mutations in NF1 gene make the genotype-phenotype correlations very difficult. Although many different mutations have been described, information about genotype-phenotype correlations are still limited. Until now, the only well established genotype-phenotype correlation, reported in many studies, is the association of large deletions (~1.5 mb), involving NF1 gene and contiguous DNA, leading to a more severe phenotype. The aim of this study is to review the literature about the current knowledge of genetic alterations in NF1.A Neurofibromatose tipo 1 (NF1), também conhecida como Doença de von Recklinghausen, é a forma mais freqüente da Neurofibroatose, correspondendo a 90% de todos os casos. A presença de múltiplos neurofibromas constitui uma das principais manifestações clínicas da NF1. Outras características clínicas freqüentemente observadas na NF1 são: manchas café-com-leite, efélides inguinais e axilares e nódulos de Lisch. A NF1 é uma doença autossômica dominante, completamente penetrante e com marcante variabilidade, mesmo nos casos intrafamiliares. A complexidade e a diversidade das mutações do gene NF1 fazem as correlações genótipo-fenótipo muito difíceis. Embora várias mutações diferentes já tenham sido relatadas, ainda são limitadas as informações sobre a correlação genótipo-fenótipo nos pacientes com NF1. Até o momento, a única correlação genótipo-fenótipo que está bem estabelecida e já foi relatada em vários estudos é a associação de grandes deleções (~1,5 mb), envolvendo o gene NF1 e o DNA circunvizinho, que levam a um fenótipo mais grave. O objetivo deste trabalho é fazer uma revisão da literatura sobre o conhecimento atual das alterações genéticas na NF1

Enzimas citocromo P450 e sua correlação com os fatores de risco para o desenvolvimento do câncer de boca – um estado da arte

The development of oral cancer is associated to inherited risk factors and extrinsic risk factors, such as smoking, consumption of alcohol, diet and others. Xenobiotics (foreign substances) biotransformation is mainly catalyzed by enzymes cytochrome P450, present in the liver and in extra-hepatic localization, such as oral cavity and esophagus. and are highly activated in reactive composites that can interact with macromolecules, such as the DNA, leading to mutations, thus participating in carcinogenegis. The aim is to review the role of enzymes Cytochrome P450 in oral carcinogenesis and to discuss their correlation with risk factors involved in the development of oral cancer.O desenvolvimento do câncer de boca está associado a fatores de risco herdados e extrínsecos, como o uso do tabaco, o consumo de álcool, a dieta e outros. Xenobióticos (substâncias estranhas ao organismo) sofrem biotransformação, principalmente por enzimas citocromo P450, que apresentam localização hepática e extra-hepática, como na cavidade oral e no esôfago, e são ativados em compostos altamente reativos, que podem interagir com macromoléculas, como o DNA, causando mutações, o que pode, assim, levar ao aparecimento do câncer. O objetivo deste estudo é realizar uma revisão da literatura sobre o papel das enzimas citocromo P450 na carcinogênese oral e discutir as diversas correlações dessas enzimas com os fatores de risco que estão envolvidos no processo bioquímico e genético de formação neoplásica

Tamoxifen decreases the myofibroblast count in the healing bile duct tissue of pigs

OBJECTIVE: The aim of this study was to evaluate the effect of oral tamoxifen treatment on the number of myofibroblasts present during the healing process after experimental bile duct injury. METHODS: The sample consisted of 16 pigs that were divided into two groups (the control and study groups). Incisions and suturing of the bile ducts were performed in the two groups. Tamoxifen (20 mg/day) was administered only to the study group. The animals were sacrificed after 30 days. Quantification of myofibroblasts in the biliary ducts was made through immunohistochemistry analysis using anti-alpha smooth muscle actin of the smooth muscle antibody. Immunohistochemical quantification was performed using a digital image system. RESULTS: In the animals treated with tamoxifen (20 mg/day), there was a significant reduction in immunostaining for alpha smooth muscle actin compared with the control group (0.1155 vs. 0.2021, p = 0.046). CONCLUSION: Tamoxifen reduced the expression of alpha smooth muscle actin in the healing tissue after bile duct injury, suggesting a decrease in myofibroblasts in the scarred area of the pig biliary tract. These data suggest that tamoxifen could be used in the prevention of biliary tract stenosis after bile duct surgeries

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica

Malignant peripheral nerve sheath tumors are rare and highly aggressive neoplasms. Neurofibromatosis type 1, a syndrome caused by mutations in the NF1 gene, is the major risk factor for the development of these tumors. Malignant peripheral nerve sheath tumors may appear de novo or may develop from the transformation of a benign neural neoplasm, mainly from a plexiform neurofibroma, which occurs almost exclusively in Neurofibromatosis type 1 patients. Nowadays, the knowledge of the factors involved in the oncogenesis of malignant peripheral nerve sheath tumors is still modest. It is believed that the loss of heterozygosity of NF1 gene is sufficient for the development of neurofibromas, but studies have been demonstrated that the pathogenesis of malignant peripheral nerve sheath tumors is a multistage process, involving many molecular alterations in addition to biallelic inactivation of NF1 gene. Many authors have been evaluated alterations in cell proliferation control genes, but the knowledge of apoptosis alterations in these tumors is still scarce. With the aim to evaluate the expression of apoptosis-associated proteins in malignant peripheral nerve sheath tumors, the immunoreactivity of p53, Bcl-2, Bcl-x and cleaved caspase-3 proteins was investigated in 28 malignant peripheral nerve sheath tumors, using tissue microarray, and compared with their immunoreactivity in 38 neurofibromas. The correlation of the expression of these proteins with clinicopathological features and prognosis of malignant peripheral nerve sheath tumors was also investigated. P53, Bcl-2, Bcl-x and cleaved caspase-3 proteins were expressed in 64,3%, 78,6%, 75,0% and 100% of malignant peripheral nerve sheath tumors, respectively, and in 2,6%, 32,4%, 43,2% and 100% of neurofibromas, respectively. Comparing the immunopositive cases, malignant perihperal nerve sheath tumores showed higher positivity indexes for Bcl-2, Bcl-x and cleaved caspase-3 than neurofibromas. In neurofibromas, cleaved caspase-3 expression was only observed in the nucleus of the cells, whereas 50% of malignant peripheral nerve sheath tumors showed nuclear expression and the other 50% expressed cleaved caspase-3 in the nucleus and in the cytoplasm of the cells. There was a correlation between the cytoplasmatic expression of cleaved caspase-3 and the high histological grade, high mitotic index and necrosis. In multivariate Cox analysis, necrosis was an independent predictor factor for lower overall survival and high positivity index for cleaved caspase-3 was an independent risk factor for worse disease-free survival. Our results suggest that alterations of p53, Bcl-2, Bcl-x and cleaved caspase-3 expression are possibly associated to the development of malignant peripheral nerve sheath tumorsTumores malignos da bainha do nervo periférico são neoplasias raras e altamente agressivas. O maior fator de risco para o desenvolvimento destes tumores é a presença da síndrome Neurofibromatose tipo 1, causada por mutações no gene NF1. Os tumores malignos da bainha do nervo periférico podem surgir de novo ou a partir da transformação maligna de uma neoplasia neural benigna, principalmente o neurofibroma plexiforme, que acontece quase que exclusivamente em pacientes com Neurofibromatose tipo 1. Atualmente, o conhecimento sobre os fatores envolvidos na oncogênese dos tumores malignos da bainha do nervo periférico ainda é pequeno. Embora se acredite que a perda da heterozigosidade do gene NF1 seja o suficiente para o surgimento dos neurofibromas, estudos têm demonstrado que o desenvolvimento dos tumores malignos da bainha do nervo periférico, associados ou não à Neurofibromatose tipo 1, é um processo de vários estágios, envolvendo um número variado de alterações moleculares em adição à inativação bialélica do gene NF1. Muitos trabalhos têm avaliado alterações em genes controladores da proliferação celular, porém o conhecimento da alteração da apoptose nestes tumores é escasso. Com o objetivo de avaliar a expressão de proteínas associadas à apoptose nos tumores malignos da bainha do nervo periférico, foi investigada a imunorreatividade, utilizando o tissue microarray, para as proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em 28 tumores malignos da bainha do nervo periférico e os resultados comparados com a expressão destas proteínas em 38 neurofibromas. A correlação da expressão das proteínas estudadas com os dados clínico-patológicos e o prognóstico dos tumores malignos da bainha do nervo periférico também foi investigada. As proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada foram expressas em 64,3%, 78,6%, 75,0% e 100% dos tumores malignos da bainha do nervo periférico, respectivamente, e em 2,6%, 32,4% 43,2% e 100% dos neurofibromas. Comparando os casos imunopositivos, os tumores malignos da bainha do nervo periférico apresentaram maiores índices de positividade para as proteínas Bcl-2, Bcl-x e caspase-3 clivada do que os neurofibromas. A expressão da caspase-3 clivada foi observada apenas no núcleo dos neurofibromas, enquanto que 50% dos tumores malignos da bainha do nervo periférico apresentaram imunomarcação nuclear e a outra metade expressaram a proteína no núcleo e citoplasma. Observou-se correlação entre a presença de marcação citoplasmática da caspase-3 clivada e o alto grau histopatológico, alto índice mitótico e necrose nos tumores malignos da bainha do nervo periférico. A presença de necrose também estava correlacionada com uma menor sobrevida total e o alto índice de positividade para a caspase-3 clivada mostrou-se um fator preditor importante para menor sobrevida livre de doença, na análise multivariada de Cox. Nossos resultados sugerem que a alteração da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada estão possivelmente associadas com o desevolvimento dos tumores malignos da bainha do nervo periférico