RESUMO
This manuscript presents some artistic and medical considerations about a representation of an individual with apparent dwarfism. He was found in Saqqara by the British Egyptologist James Edward Quibell, in 1910/11. The naked figure of this individual, Djeho, is carved in profile on the lid of his sarcophagus. He has a height of 120 cm and has characteristic clinical features suggesting achondroplasia.
Assuntos
Acondroplasia , Nanismo , Masculino , Humanos , EgitoRESUMO
Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.
Assuntos
Nanismo Hipofisário/congênito , Nanismo Hipofisário/genética , Mutação/genética , Receptores Acoplados a Proteínas G/genética , Sequência de Aminoácidos , Criança , Estudos de Coortes , Simulação por Computador , Feminino , Humanos , Masculino , Receptores Acoplados a Proteínas G/química , Alinhamento de SequênciaRESUMO
The syndrome of Familial Non Medullary Thyroid Carcinoma (FNMTC) includes two or more patients with an isolated non-medullary thyroid cancer (papillary, follicular, anaplastic) within the same family. To diagnose FNMTC, the clinician must exclude a syndromic presentation such as the syndromes of Cowden, Gardner or Werner, and the Carney Complex. Up to now, a hundred families with FNMTC have been genetically studied, including forms with (Ch19p13.2) or without oxyphilia (Ch2q21), in association with a multinodular goiter (Ch14q32), or with a renal cancer (Ch1q21). Several candidate genes of susceptibility have been proposed: SRGAP1, NKX2-1, FOXE1 and HABP2. So far, it is considered that familial cases represent less than 5 % of thyroid cancers. Although rare, these cases represent a unique opportunity to improve our understanding of thyroid cancer. The identification of candidate genes will enrich our knowledge of thyroid cancer pathophysiology. Based on the literature and our experience of the follow-up of eight families with FNMTC, we discuss epidemiological, clinical, pathological and genetic aspects of FNMTC with a view to improve the diagnosis and treatment of this disease.
Le syndrome de «Familial Non Medullary Thyroid Carcinoma¼ (FNMTC) suppose l'existence, au sein d'une même famille, de deux ou plusieurs patients avec un cancer thyroïdien non médullaire isolé (papillaire, folliculaire, anaplasique). Le diagnostic de FNMTC est retenu après exclusion d'une présentation syndromique comme celle liée aux syndromes de Cowden, Gardner, ou Werner et au Complexe de Carney. Une centaine de familles de FNMTC ont été bien caractérisées sur le plan génétique, incluant des formes papillaires avec (Ch19p13.2) ou sans oxyphilie (Ch2q21, 6q22), en association avec un goitre multinodulaire (14q32), ou avec un cancer rénal (Ch1q21). Plusieurs gènes de susceptibilité ont été proposés : SRGAP1, NKX2-1, FOXE1, et HABP2. On estime que les cas familiaux représentent moins de 5 % des cancers thyroïdiens. Bien que minoritaires, ils représentent une occasion exceptionnelle d'approfondir notre compréhension de la tumorigenèse du cancer thyroïdien et d'identifier des gènes candidats pouvant participer à leur physiopathologie. A partir d'une revue de la littérature et de notre expérience sur le suivi de huit familles avec FNMTC, nous discutons des aspects épidémiologiques, cliniques, pathologiques et génétiques permettant d'aboutir à un meilleur diagnostic et à une prise en charge de ce syndrome oncologique.
Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Carcinoma Papilar/terapia , Aberrações Cromossômicas , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Técnicas de Diagnóstico Molecular , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapiaRESUMO
Prolactinomas are the most common hormonally active pituitary tumors and are usually successfully treated with dopamine agonists. A small proportion, however, appears not to respond to such treatment and such cases are termed resistant prolactinomas. Resistance is generally defined as failure to achieve normoprolactinemia and inability to induce tumor shrinkage. Reduced dopamine receptor density on lactotroph cells is currently considered the major underlying mechanism of resistance. Treatment options in resistant cases usually include substitution with another dopamine agonist, increasing the dose of the drug, as well as surgery, radiotherapy, and experimental medical therapies.
Assuntos
Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Humanos , Lactotrofos/metabolismo , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Receptores Dopaminérgicos/metabolismoRESUMO
The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Hipersecreção Hipofisária de ACTH/genética , Neoplasias Hipofisárias/genética , Adolescente , Criança , Cromograninas , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p27 , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Hipersecreção Hipofisária de ACTH/diagnóstico , Neoplasias Hipofisárias/diagnósticoRESUMO
BACKGROUND: The term double pituitary adenomas (DPA) is usually referred to those rare lesions showing two distinct cellular components. Genetic background may sustain the proliferation of more than one cell at the same time but no information is available on the presence of aip mutations in these patients. AIM: We report the prevalence and the endocrinological, neuroradiological, histopathological and genetic features of DPA detected in a large surgical series. The contribution of pituitary transcription factor immunostains in DPA was also evaluated. SUBJECTS AND METHODS: One-hundred-forty-four patients undergoing surgery for tumors of the sellar region were evaluated. Histopathology, immunohistochemistry and the mutational analysis for the entire coding region of the AIP and MEN1 genes were performed. RESULTS: One-hundred-seventeen patients out of 144 had a pituitary adenoma. DPA was found in 3 (2.6%) out of 117 patients with pituitary adenoma. Immunohistochemistry and transcription factors analysis demonstrated two not yet described histotype associations in DPA. The coexistence of somatotroph-lactotroph and silent mammosomatotroph histotype in 1 case and the coexistence of sparsely granulated lactotroph and null cell adenomas in the remaining two cases were first identified. Sequencing data for the coding region of the aip and the menin gene resulted in wild type sequences in all patients with DPA. CONCLUSIONS: The prevalence of DPA observed in our unselected surgical series is not negligible (2.6%). Furthermore, the evaluation of the treatment outcome would suggest that the clinical management of DPAs requires a careful diagnostic approach and follow- up.
Assuntos
Adenoma/epidemiologia , Neoplasias Hipofisárias/epidemiologia , Proteínas Adaptadoras de Transdução de Sinal , Adenoma/genética , Adenoma/cirurgia , Adulto , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Guanilato Quinases , Humanos , Imuno-Histoquímica , Lactotrofos/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/cirurgia , Prolactinoma/genética , Prolactinoma/patologia , Prolactinoma/cirurgia , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Resultado do TratamentoRESUMO
PURPOSE: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). METHODS: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). RESULTS: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA. CONCLUSION: Although most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.
Assuntos
Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias , Neoplasias da Glândula Tireoide , Mutação em Linhagem Germinativa , Humanos , Mutação , Países Baixos , Neoplasias Hipofisárias/genética , Sistema de Registros , Neoplasias da Glândula Tireoide/genéticaRESUMO
The majority of pituitary adenomas occur sporadically, however, about 5% of all cases occur in a familial setting, of which over half are due to multiple endocrine neoplasia type 1 (MEN-1) and Carney's complex (CNC). Since the late 1990s we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named familial isolated pituitary adenomas (FIPA). The clinical characteristics of FIPA vary from those of sporadic pituitary adenomas, as patients with FIPA have a younger age at diagnosis and larger tumours. About 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. This review describes the clinical features of familial pituitary adenomas like MEN1, the MEN 1-like syndrome MEN-4, CNC, FIPA, the tumour pathologies found in this setting and the genetic/molecular data that have been recently reported.
Assuntos
Síndromes Neoplásicas Hereditárias/genética , Neoplasias Hipofisárias/genética , Transformação Celular Neoplásica/genética , Feminino , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , MutaçãoRESUMO
Many causes of thyroxine malabsorption are described in the literature, but the most common cause of failure of thyroxine therapy is poor patient compliance, or pseudomalabsorption. We describe the case of a female patient who underwent total thyroidectomy for Basedow-Graves disease. Post-operatively, several treatment regimens were employed to achieve euthyroidism, but only injectable thyroxine was found to be effective. To exclude levothyroxine malabsorption, the patient was hospitalized in a hypothyroid state while a single oral test dose of levothyroxine (1000 microg) was administered. Within 4 hours a decrease of TSH level (from 59.7 to 55.6 microUI/ml) and a significant increase in free T4 levels (from 0.8 to 15.5 pg/ml) was observed, eliminating a malabsorption problem. The cause of resistance to thyroid hormone therapy was poor patient compliance, leading to the designation of this as a case of pseudomalabsorption.
Assuntos
Absorção Intestinal/fisiologia , Síndromes de Malabsorção/diagnóstico , Hormônios Tireóideos/farmacocinética , Tiroxina/farmacocinética , Idoso , Feminino , Humanos , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.
Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Modelos Biológicos , Somatostatina/análogos & derivados , Somatostatina/administração & dosagem , Acromegalia/sangue , Adulto , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.
Assuntos
Adenoma/genética , Adenoma/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico/genética , Feminino , Gonadotropinas Hipofisárias/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Linhagem , Hormônios Adeno-Hipofisários/metabolismo , Neoplasias Hipofisárias/metabolismo , Prolactinoma/genética , Prolactinoma/patologia , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
BACKGROUND: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of treatment-resistant pituitary tumor growth remains relatively under-explored. METHODS: We assessed the literature for relevant data regarding the surgical, medical and radiotherapeutic treatment of acromegaly in order to identify the factors that were predictive of aggressive or treatment-resistant pituitary tumor behavior in acromegaly and undertook an assessment of the rates of failure to control tumor progression with available treatment modalities. RESULTS: Young age at diagnosis, large tumor size, high growth hormone secretion and certain histological markers are predictors of future aggressive tumor behavior in acromegaly. Significant tumor regrowth occurs in less than 10% of cases thought to be cured surgically, whereas failure to control tumor growth is seen in less than 1% of patients receiving radiotherapy. Somatostatin analogs induce a variable degree of tumor shrinkage in acromegaly but up to 2.2% of somatostatin analog-treated tumors continue to grow. Relative to other therapies, limited data are available for pegvisomant, but these indicate that persistent tumor growth occurs in 1.6-2.9% of cases followed up regularly with serial magnetic resonance imaging scans. CONCLUSIONS: Treatment-resistant tumor progression occurs in a small minority of patients with acromegaly, regardless of treatment modality. Young patients with large tumors or those with high pre-treatment levels of growth hormone particularly warrant close monitoring for continued tumor progression during treatment for acromegaly.
Assuntos
Acromegalia/terapia , Neoplasias Hipofisárias/terapia , Acromegalia/epidemiologia , Acromegalia/cirurgia , Humanos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/cirurgia , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
Parathyroid carcinoma is a rare cause of primary hyperparathyroidism, and the efficacy of medical therapy and chemo- and radiotherapy is poor in recurrent or metastatic disease. We report the first case of PTH immunization in which tumor shrinkage accompanied hormonal, biochemical, and clinical improvements in a patient with metastatic parathyroid carcinoma.A 50-yr-old woman with refractory parathyroid carcinoma and pulmonary metastases was immunized eight times between February 2001 and December 2003 with bovine and modified human PTH fragments and intact human PTH, mixed with Freund's adjuvant. Total and ionized calcium and PTH levels were assayed weekly for 6 months and regularly thereafter. Thoracic computed tomography scans were performed regularly. Antibodies to all PTH fragments were detected after two immunizations. Baseline PTH and total calcium were 213.0 ng/liter and 13.96 mg/dl, respectively, and remained elevated during the first three immunizations. From the fourth immunization onward, PTH and calcium decreased, and the patient's clinical condition improved markedly. PTH and calcium levels have remained controlled for more than 24 months, and the sizes (surface area) of pulmonary metastases decreased from baseline by 39-71%. This is the first evidence that PTH immunization not only can improve clinical, hormonal, and biochemical measures in parathyroid carcinoma but also has an antitumor effect.
Assuntos
Carcinoma/secundário , Carcinoma/terapia , Imunoterapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Hormônio Paratireóideo/imunologia , Neoplasias das Paratireoides/patologia , Animais , Formação de Anticorpos , Cálcio/sangue , Carcinoma/sangue , Carcinoma/diagnóstico por imagem , Bovinos , Feminino , Humanos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico por imagem , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fragmentos de Peptídeos/imunologia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Ischaemia-reperfusion injury (IRI) is caused by endothelial and subendothelial damage by neutrophil-derived oxidants. Vitamin C is an antioxidant which attenuates endothelial injury after IRI. Our aim was to evaluate the effect of oral vitamin C in the prevention of IRI in skeletal muscle. We used a model of cross-clamping (3 hours) and reperfusion (1 hour) of the cremaster muscle in rats. Muscle function was assessed electrophysiologically by electrical field stimulation. Infiltration by neutrophils was determined by the activity of tissue myeloperoxidase (MPO) and tissue oedema by the wet-to-dry ratio. Neutrophil respiratory burst activity was measured in control animals and groups pretreated with vitamin C. IRI significantly decreased muscle function and increased muscle neutrophil MPO activity and muscle oedema. Pretreatment with vitamin C preserved muscle function and reduced tissue oedema and neutrophil infiltration. Neutrophil respiratory burst activity was reduced in the group treated with vitamin C compared with the control group. We conclude that pretreatment with oral vitamin C protects against acute muscle IRI, possibly by attenuating neutrophil respiratory burst activity.
Assuntos
Ácido Ascórbico/uso terapêutico , Músculo Esquelético/fisiopatologia , Traumatismo por Reperfusão/tratamento farmacológico , Doença Aguda , Animais , Músculo Esquelético/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Explosão RespiratóriaRESUMO
Compartment syndrome is a unique form of ischaemia of skeletal muscle which occurs despite patency of the large vessels. Decompression allows the influx of activated leucocytes which cause further injury. Vitamin C is a powerful antioxidant which concentrates preferentially in leucocytes and attenuates reperfusion-induced muscle injury. We have evaluated the use of pretreatment with oral vitamin C in the prevention of injury caused by compartment syndrome in a rat cremasteric muscle model. Acute and delayed effects of pretreatment with vitamin C were assessed at one and 24 hours after decompression of compartment syndrome. Muscle function was assessed electrophysiologically. Vascular, cellular and tissue inflammation was assessed by staining of intercellular adhesion molecule-1 (ICAM-1) and by determination of the activity of myeloperoxidase (MPO) in neutrophils and tissue oedema. Compartment syndrome impaired skeletal muscle function and increased the expression of ICAM-1, activity of MPO and muscle weight increased significantly. Pretreatment with vitamin C preserved muscle function and reduced the expression of ICAM-1, infiltration of the neutrophils and oedema.
Assuntos
Ácido Ascórbico/administração & dosagem , Síndromes Compartimentais/complicações , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Administração Oral , Animais , Síndromes Compartimentais/enzimologia , Edema , Molécula 1 de Adesão Intercelular/metabolismo , Músculo Esquelético/enzimologia , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologiaRESUMO
Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Mutations in the CDKN1B gene, encoding p27(Kip)¹ were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas.
Assuntos
Adenoma/genética , Neoplasias Hipofisárias/genética , Adenoma/complicações , Complexo de Carney/etiologia , Complexo de Carney/genética , Humanos , Neoplasia Endócrina Múltipla Tipo 1/etiologia , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/complicaçõesRESUMO
Clinically-relevant pituitary adenomas occur with a prevalence of approximately 1 per 1000 population in Belgium. Pituitary adenomas that occur in families are likely to have an important genetic pathophysiological basis. Currently about 5% of all pituitary adenoma cases have a family history of pituitary adenomas, classically due to multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Over the last decade we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named 'familial isolated pituitary adenoma' (FIPA). Clinical features of FIPA differ from those of sporadic pituitary adenomas in that patients with FIPA are often younger and have larger tumours at diagnosis. Approximately 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. In this review we examine new findings on the epidemiology of pituitary adenomas and we review familial causes of pituitary adenomas with a particular emphasis on modern clinical testing. In addition, the clinical and genetic features of FIPA are described as FIPA represents a useful framework to study the features of pituitary adenomas that occur in a familial setting.
Assuntos
Adenoma/terapia , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/genética , Acromegalia , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Perda de Heterozigosidade , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Neoplasias Hipofisárias/etiologia , Prolactinoma/tratamento farmacológico , Prolactinoma/genéticaRESUMO
Inherited or familial pituitary tumor syndromes such as multiple endocrine neoplasia type 1 and Carney complex provide an important insight into the genetics and molecular pathology of endocrine cancers. Our understanding of these conditions is expanding rapidly due to the identification of the genes and proteins affected and the availability of murine knockout models. The successes achieved to date in understanding multiple endocrine neoplasia type 1 and Carney complex have helped in the identification and study of new inherited pituitary tumor syndromes such as isolated familial somatotropinomas. This review assesses the current status of research into the clinical features, genetics and molecular pathologies of multiple endocrine neoplasia type 1, Carney complex, and isolated familial somatotropinomas, and details ongoing work to delineate familial isolated pituitary adenomas, a potentially new clinical entity.
Assuntos
Adenoma/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/genética , Adenoma/etiologia , Adenoma/patologia , Animais , Humanos , Camundongos , Camundongos Knockout , Neoplasia Endócrina Múltipla Tipo 1/etiologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/patologiaRESUMO
Historical data indicate that pituitary tumors represent 10% of intracranial tumors, while adenomas are noted in approximately 14-23% of normal subjects on autopsy or magnetic resonance imaging (MRI). About 2.5% of these tumors stain positive for GH in histopathologic studies. In contrast, the prevalence of clinically diagnosed acromegaly is lower at 36-69 per million population. Ongoing studies indicate that the actual prevalence of acromegaly in the community may be higher than previous epidemiologic data suggest. Acromegaly can occur both sporadically and in the setting of familial conditions, such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Isolated familial somatotropinoma has been described and newer data suggest that acromegaly may also occur in non-MEN1/CNC families in combination with other pituitary tumor phenotypes.
Assuntos
Acromegalia/epidemiologia , Acromegalia/genética , Adenoma/epidemiologia , Adenoma/genética , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genéticaRESUMO
BACKGROUND: Desloratadine is a selective H1-antihistamine used in the treatment of allergic rhinitis and chronic idiopathic urticaria. Desloratadine inhibits the release of allergic inflammatory mediators in vitro. We studied the impact of desloratadine on mast cell degranulation due to activation and re-activation by the secretagogue, compound 48/80. METHODS: Rat peritoneal eluate containing 5-6% mast cells were activated by a low concentration of compound 48/80 in a medium containing the vital fluorescent dye, Sulforhodamine-B (SFRM-B, 200 microg/ml), which is engulfed by activated mast cells. The fluorescent image of activated mast cells was captured digitally and the total fluorescent area was analyzed when desloratadine was applied before or after compound 48/80. RESULTS: Mast cells were not activated by desloratadine (10(-4) M), SFRM-B (200 microg/ml), or diluent alone. A low concentration of compound 48/80 (0.125 microg/ml) induced fluorescence, while mast cells lost fluorescent images due to further degranulation on re-exposure to compound 48/80. Desloratadine (10(-8)-10(-4) M), inhibited compound 48/80-induced mast cell degranulation in a concentration-dependent manner. Desloratadine also reduced the loss of fluorescent images due to re-exposure to compound 48/80. CONCLUSIONS: Desloratadine may have a mast cell stabilizing effect at low concentrations in response to repeated mast cell activation in vitro.