RESUMO
BACKGROUND: Myasthenia gravis (MG) is an uncommon autoimmune disorder affecting the neuromuscular junction and manifesting as muscle weakness. A multitude of stressors can exacerbate MG. When symptoms are exacerbated, muscle weakness can be severe enough to result in respiratory failure, a condition known as myasthenic crisis (MC). OBJECTIVE: This review discusses risk factors, diagnosis, management, and iatrogenic avoidance of MC. DISCUSSION: MC can affect any age, ethnicity, or sex and can be precipitated with any stressor, infection being the most common. MC is a clinical diagnosis defined by respiratory failure caused by exacerbation of MG. Muscle weakness can involve any voluntary muscle. MC can be differentiated from other neuromuscular junction diseases by the presence of normal reflexes, normal sensation, lack of autonomic symptoms, lack of fasciculations, and worsening weakness with repetitive motion. Treatment should target the inciting event and airway support. All acetylcholinesterase inhibitors should be avoided in crisis, including edrophonium testing and corticosteroids initially. Respiratory support can begin with noninvasive positive-pressure ventilation, as this has been successful even in patients with bulbar weakness. If intubation is necessary, consider avoiding paralytics or use a reduced dose of nondepolarizing agents. CONCLUSIONS: MC should be in the differential of any patient with muscular weakness and respiratory compromise. Emergency department management of MC should focus on ruling out infection and respiratory support. Strong consideration should be given to beginning with noninvasive positive-pressure ventilation for ventilatory support. Corticosteroids, depolarizing paralytics, and acetylcholinesterase inhibitors should be avoided in patients with MC in the emergency department.
Assuntos
Miastenia Gravis/complicações , Miastenia Gravis/terapia , Manuseio das Vias Aéreas/métodos , Gerenciamento Clínico , Serviço Hospitalar de Emergência/organização & administração , Humanos , Miastenia Gravis/fisiopatologia , Fatores de RiscoRESUMO
Iron metabolism is essential for many cellular processes, including oxygen transport, respiration and DNA synthesis, and many cancer cells exhibit dysregulation in iron metabolism. Maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which control the expression of iron-related genes by binding iron-responsive elements (IREs) of target mRNAs. Here, we report that mitochondrial SIRT3 regulates cellular iron metabolism by modulating IRP1 activity. SIRT3 loss increases reactive oxygen species production, leading to elevated IRP1 binding to IREs. As a consequence, IRP1 target genes, such as the transferrin receptor (TfR1), a membrane-associated glycoprotein critical for iron uptake and cell proliferation, are controlled by SIRT3. Importantly, SIRT3 deficiency results in a defect in cellular iron homeostasis. SIRT3 null cells contain high levels of iron and lose iron-dependent TfR1 regulation. Moreover, SIRT3 null mice exhibit higher levels of iron and TfR1 expression in the pancreas. We found that the regulation of iron uptake and TfR1 expression contribute to the tumor-suppressive activity of SIRT3. Indeed, SIRT3 expression is negatively correlated with TfR1 expression in human pancreatic cancers. SIRT3 overexpression decreases TfR1 expression by inhibiting IRP1 and represses proliferation in pancreatic cancer cells. Our data uncover a novel role of SIRT3 in cellular iron metabolism through IRP1 regulation and suggest that SIRT3 functions as a tumor suppressor, in part, by modulating cellular iron metabolism.
Assuntos
Antígenos CD/metabolismo , Proteína 1 Reguladora do Ferro/antagonistas & inibidores , Ferro/metabolismo , Neoplasias Pancreáticas/patologia , Receptores da Transferrina/metabolismo , Sirtuína 3/metabolismo , Animais , Antígenos CD/biossíntese , Transporte Biológico , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Proteína 1 Reguladora do Ferro/biossíntese , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Pâncreas/metabolismo , Receptores da Transferrina/biossíntese , Sirtuína 3/genéticaRESUMO
Immunohistochemistry-based biomarkers are commonly used to understand target inhibition in key cancer pathways in preclinical models and clinical studies. Automated slide-scanning and advanced high-throughput image analysis software technologies have evolved into a routine methodology for quantitative analysis of immunohistochemistry-based biomarkers. Alongside the traditional pathology H-score based on physical slides, the pathology world is welcoming digital pathology and advanced quantitative image analysis, which have enabled tissue- and cellular-level analysis. An automated workflow was implemented that includes automated staining, slide-scanning, and image analysis methodologies to explore biomarkers involved in 2 cancer targets: Aurora A and NEDD8-activating enzyme (NAE). The 2 workflows highlight the evolution of our immunohistochemistry laboratory and the different needs and requirements of each biological assay. Skin biopsies obtained from MLN8237 (Aurora A inhibitor) phase 1 clinical trials were evaluated for mitotic and apoptotic index, while mitotic index and defects in chromosome alignment and spindles were assessed in tumor biopsies to demonstrate Aurora A inhibition. Additionally, in both preclinical xenograft models and an acute myeloid leukemia phase 1 trial of the NAE inhibitor MLN4924, development of a novel image algorithm enabled measurement of downstream pathway modulation upon NAE inhibition. In the highlighted studies, developing a biomarker strategy based on automated image analysis solutions enabled project teams to confirm target and pathway inhibition and understand downstream outcomes of target inhibition with increased throughput and quantitative accuracy. These case studies demonstrate a strategy that combines a pathologist's expertise with automated image analysis to support oncology drug discovery and development programs.
Assuntos
Aurora Quinase A/análise , Biomarcadores Farmacológicos/análise , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Animais , Apoptose , Aurora Quinase A/metabolismo , Automação , Azepinas/farmacologia , Biomarcadores Farmacológicos/metabolismo , Biópsia , Ciclopentanos/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Imuno-Histoquímica , Mitose , Neoplasias/metabolismo , Pirimidinas/farmacologia , Pele/metabolismo , Pele/patologiaRESUMO
The aim of this study was to evaluate the detection rate of incidental colorectal malignancies using whole-body 18FDG-PET/CT at an Irish teaching hospital. We performed a retrospective review of the records of 800 consecutive patients undergoing PET-CT scans at our institution from January 2009 - August 2009. The radiologic reports were analysed and all scans with focal colonic FDG uptake were audited. The colonoscopic and histologic records of the patients who underwent further investigation were reviewed for cancerous and pre-cancerous histology. A total of 643 patients were included in the study. Forty-eight patients (7.5%) had scans which demonstrated focal colonic FDG uptake. Of the 21 patients who underwent further investigation with endoscopy, 14 (66.7%) had biopsies which were positive for dysplasia, this represented 2.2% of the total patients undergoing PET-CT. Eight of these fourteen patients (1.2% of the total) had biopsies demonstrating adenocarcinoma. Four of these patients (50%) had TNM stage 1 or 2 colorectal carcinoma and underwent subsequent curative surgical resection. We found a 2.2% rate of incidentally-diagnosed colorectal malignant and premalignant lesions in patients undergoing PET-CT at our institution. A 1.2% rate of adenocarcinoma was identified. This rate is higher than previously described in the literature.
Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Neoplasias Colorretais/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Radiofarmacêuticos , Estudos RetrospectivosRESUMO
BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS). RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months). CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Docetaxel , Gossipol/administração & dosagem , Gossipol/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes , Orquiectomia , Placebos/administração & dosagem , Prednisona/administração & dosagem , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
CONTEXT AND OBJECTIVE: Somnolence and obesity are prevalent in craniopharyngioma patients. We hypothesized that somnolence was because of obstructive sleep apnoea in craniopharyngioma patients. DESIGN, PATIENTS AND MEASUREMENTS: We assessed prevalence of somnolence and sleep apnoea in 28 craniopharyngioma and 23 obese controls attending a tertiary referral centre, by means of the Epworth Sleepiness Score (ESS) and polysomnography. All subjects with sleep apnoea were offered continuous positive airway pressure therapy (CPAP) or modafinil. All craniopharyngioma patients, with unexplained somnolence, were offered modafinil. RESULTS: Somnolence was reported by 20/28 (71·5%) craniopharyngioma patients and 4/23 (17%) obese subjects (P < 0·001). Median ESS was 7·5 (IQR 6, 10·7) in craniopharyngioma patients and 4·0 (4,8) in controls, P < 0·01. Eleven somnolent craniopharyngioma patients had obstructive sleep apnoea, in whom treatment led to a reduction in ESS by 6·4 ± 1·4, P = 0·01. Among the remaining nine patients, five were offered modafinil therapy, of whom four had benefit, three were not compliant with hormone replacement, and one died before intervention. There was no difference in the prevalence of obstructive sleep apnoea between craniopharyngioma (n = 13, 46%) and obese subjects (n = 14, 61%, P = 0·4). Body mass index (BMI) does not correlate with apnoea hypopnoea index [apnoea - hypopnoea index (AHI), r = 0·25, P = 0·08], which suggests that obesity alone does not explain the prevalence of sleep apnoea in craniopharyngioma patients. CONCLUSIONS: Somnolence is common in craniopharyngioma patients and in the majority is because of obstructive sleep apnoea. An additional group of somnolent craniopharyngioma patients benefits from modafinil.
Assuntos
Craniofaringioma/complicações , Neoplasias Hipofisárias/complicações , Síndromes da Apneia do Sono/diagnóstico , Transtornos do Sono-Vigília/diagnóstico , Adulto , Idoso , Compostos Benzidrílicos/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modafinila , Polissonografia , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/terapia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/terapia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. PATIENTS AND METHODS: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. RESULTS: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. CONCLUSION: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Castração , Indóis/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirróis/uso terapêutico , Taxoides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Docetaxel , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Pirróis/efeitos adversos , Qualidade de Vida , Sunitinibe , Taxoides/efeitos adversos , Fatores de Tempo , Falha de TratamentoAssuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Cetoconazol/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Docetaxel , Humanos , Cetoconazol/efeitos adversos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
There have been few investigations into the relationship of smoking to the presentation of anxiety and depression in clients with a primary diagnosis of schizophrenia. Using a survey design, the current study sought to determine if there was a significant difference between smoking and non-smoking clients in this clinical group on self-report measures of anxiety and depression. The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression. One hundred clients (male = 74) with a primary diagnosis of schizophrenia completed the HADS. No significant difference was observed in anxiety and depression scores as a function of smoking status. A logistic regression analysis revealed that gender was a significant predictor of smoking status. The notion that smoking behaviour and mood state are associated with schizophrenia was not supported. However, a high proportion of the cohort were smokers (69%), and male gender was a significant predictive factor in smoking status. Further research in this area is recommended in order to develop strategies which reduce this current level of smoking in clients with a primary diagnosis of schizophrenia.
Assuntos
Afeto , Psicologia do Esquizofrênico , Fumar/psicologia , Adulto , Ansiedade/psicologia , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/efeitos adversos , Fumar/fisiopatologiaRESUMO
BACKGROUND: The aetiology of infantile hypertrophic pyloric stenosis (IHPS) has not been fully elucidated. Since the 1990s, a sharp decline in IHPS has been reported in various countries. Recent research from Sweden reported a correlation between falling rates of IHPS and of sudden infant death syndrome (SIDS). This was attributed to a reduction in the number of infants sleeping in the prone position following the "Back to Sleep" campaign. OBJECTIVES: To describe the changing epidemiology of IHPS in Scotland, to examine the relationship between IHPS and SIDS rates and to examine trends in other factors that may explain the observed reduction in IHPS incidence. DESIGN: Incidence rates of IHPS and SIDS were derived from routine data and their relationship analysed. Trends in mean maternal age, maternal smoking, mean birth weight and breastfeeding rates were also examined. SETTING: The whole of Scotland between 1981 and 2004. RESULTS: IHPS incidence fell from 4.4 to 1.4 per 1000 live births in Scotland between 1981 and 2004. Rates were consistently higher in males, although the overall incidence patterns in males and females were similar. Rates showed a positive relationship with deprivation. The fall in the incidence of IHPS preceded the fall in SIDS by 2 years and the incidence of SIDS displayed less variability than that of IHPS. Significant temporal trends were also observed in other maternal and infant characteristics. CONCLUSION: There has been a marked reduction in Scotland's IHPS incidence, but this is unlikely to be a consequence of a change in infant sleeping position.
Assuntos
Estenose Pilórica Hipertrófica/epidemiologia , Morte Súbita do Lactente/epidemiologia , Aleitamento Materno/epidemiologia , Feminino , Humanos , Incidência , Lactente , Cuidado do Lactente/normas , Masculino , Decúbito Ventral , Estenose Pilórica Hipertrófica/complicações , Fatores de Risco , Escócia/epidemiologia , Sono , Fumar/epidemiologia , Morte Súbita do Lactente/etiologia , Decúbito DorsalRESUMO
Machado-Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP-I and Huntington disease (HD). The present work is a review of our 10-year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Aconselhamento Genético/psicologia , Testes Genéticos/psicologia , Doença de Machado-Joseph/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/psicologia , DNA/análise , DNA/genética , Humanos , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/psicologia , Portugal , Fatores de RiscoRESUMO
OBJECTIVE: To estimate and compare the medical costs of individuals with diabetes and/or hypertension relative to a matched sample of individuals with neither condition, and determine if these costs are significantly influenced by alcohol use. RESEARCH DESIGN AND METHODS: Data were obtained from a sample of 799 patients from eight primary care clinics in south-central Wisconsin between 2001 and 2002. Medical care costs were calculated within four categories [hospital and emergency room (ER) costs, clinic costs, medication costs and total cost] for three chronic disease samples [diabetes only (n = 89), hypertension only (n = 299), and both diabetes and hypertension (n = 209)] as well as a matched sample with neither diabetes nor hypertension (n = 202). Annual medical care costs were estimated using a combination of insurance billing records, self-reported information and chart review. All cost data pertain to a 12-month period in 2001-2002. In addition to a descriptive analysis of costs across medical service categories and samples, we also conducted multivariate analyses of total cost, controlling for patient demographics, education, employment, smoking, and comorbidities, such as heart disease, hyperlipidaemia, liver disease, chronic back pain, asthma, depression, anxiety and bronchitis. RESULTS: The estimated differential in total annual medical cost (relative to the control group) was USD 2183 for diabetes only, USD 724 for hypertension only and USD 3402 for diabetes and hypertension. Alcohol use did not significantly impact medical care costs amongst individuals with diabetes and/or hypertension. CONCLUSIONS: These cost estimates can serve as an important and useful reference source for doctors, insurance companies, health maintenance organizations (HMOs) and policy makers as they try to anticipate the future medical care needs and associated costs for diabetic and hypertensive patients.
Assuntos
Consumo de Bebidas Alcoólicas/economia , Diabetes Mellitus/economia , Angiopatias Diabéticas/economia , Custos de Cuidados de Saúde , Hipertensão/economia , Fatores Etários , Consumo de Bebidas Alcoólicas/efeitos adversos , Doença Crônica , Diabetes Mellitus/terapia , Angiopatias Diabéticas/terapia , Escolaridade , Emprego , Feminino , Humanos , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Modelos EstatísticosRESUMO
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the Western world and its prevalence is increasing. Potential causes of this increase are changes in diet and the increases in obesity seen. This paper looks at the literature surrounding diet and obesity and the links to this increase in CRC. Heralded as a weight loss miracle we investigate whether the literature suggests the Atkins diet may actually do more harm than good by acting to increase an individual's risk of CRC. Obesity has been demonstrated to be a major factor in the increase in CRC although links to changes in diet are more tenuous. Published studies on diet suggest the Atkins diet may help reduce rather than increase the risk of CRC.
Assuntos
Neoplasias Colorretais/etiologia , Dietas da Moda/efeitos adversos , Dieta/efeitos adversos , Obesidade/complicações , Neoplasias Colorretais/epidemiologia , Humanos , Obesidade/dietoterapia , Fatores de RiscoRESUMO
Although the physiological role of tissue-specific translational control of gene expression in mammals has long been suspected on the basis of biochemical studies, direct evidence has been lacking. Here, we report on the targeted disruption of the gene encoding the heme-regulated eIF2alpha kinase (HRI) in mice. We establish that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both alpha- and beta-globins in red blood cell (RBC) precursors by inhibiting the general translation initiation factor eIF2. This inhibition occurs when the intracellular concentration of heme declines, thereby preventing the synthesis of globin peptides in excess of heme. In iron-deficient HRI(-/-) mice, globins devoid of heme aggregated within the RBC and its precursors, resulting in a hyperchromic, normocytic anemia with decreased RBC counts, compensatory erythroid hyperplasia and accelerated apoptosis in bone marrow and spleen. Thus, HRI is a physiological regulator of gene expression and cell survival in the erythroid lineage.
Assuntos
Eritrócitos/citologia , Eritrócitos/enzimologia , Regulação Enzimológica da Expressão Gênica , Deficiências de Ferro , Biossíntese de Proteínas , eIF-2 Quinase/metabolismo , eIF-2 Quinase/fisiologia , Animais , Apoptose , Northern Blotting , Western Blotting , Linhagem da Célula , Separação Celular , Sobrevivência Celular , Clonagem Molecular , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Fator de Iniciação 2 em Eucariotos/metabolismo , Citometria de Fluxo , Biblioteca Gênica , Genótipo , Heme/biossíntese , Ferro/metabolismo , Camundongos , Microscopia Eletrônica , Modelos Biológicos , Fosforilação , Polirribossomos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Protoporfirinas/biossíntese , Reticulócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico , Fatores de TempoRESUMO
Erythropoietin (Epo) controls red cell production in the basal state and during stress. Epo binding to its receptor, EpoR, on erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal liver erythroid progenitors were found in Stat5a(-/-)5b(-/-) mice. However, the role of Stat5 in adult erythropoiesis was not clear. The present study shows that some adult Stat5a(-/-)5b(-/-) mice have a near-normal hematocrit but are deficient in generating high erythropoietic rates in response to stress. Further, many adult Stat5a(-/-)5b(-/-) mice have persistent anemia despite a marked compensatory expansion in their erythropoietic tissue. Analysis of erythroblast maturation in Stat5a(-/-)5b(-/-) hematopoietic tissue shows a dramatic increase in early erythroblast numbers, but these fail to progress in differentiation. Decreased expression of bcl-x(L) and increased apoptosis in Stat5a(-/-)5b(-/-) early erythroblasts correlate with the degree of anemia. Hence, Stat5 controls a rate-determining step regulating early erythroblast survival.
Assuntos
Proteínas de Ligação a DNA/deficiência , Eritropoese/genética , Proteínas do Leite , Transativadores/deficiência , Anemia/genética , Animais , Apoptose , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Eritroblastos/química , Eritroblastos/patologia , Contagem de Eritrócitos , Células Precursoras Eritroides/patologia , Eritropoetina/fisiologia , Doenças Fetais/genética , Genótipo , Hematócrito , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/análise , Receptores da Eritropoetina/fisiologia , Fator de Transcrição STAT5 , Baço/química , Baço/patologia , Estresse Fisiológico/fisiopatologia , Transativadores/genética , Transativadores/fisiologia , Proteína bcl-XRESUMO
The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2(-/-) embryos are severely deficient in erythropoiesis and die at an early stage of development from fetal anemia. The binding of erythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosphorylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study explored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and primary erythroid cells expressing BCR-ABL. However, BCR-ABL effectively supports normal erythroid proliferation, differentiation, and maturation in JAK2-deficient fetal liver cells. Using mutants of BCR-ABL, this study shows that certain signaling pathways activated by BCR-ABL segments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2(-/-) progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed.
Assuntos
Eritropoese/fisiologia , Proteínas de Fusão bcr-abl/fisiologia , Proteínas Tirosina Quinases/deficiência , Proteínas Proto-Oncogênicas , Substituição de Aminoácidos , Anemia/sangue , Anemia/embriologia , Anemia/genética , Anemia/patologia , Animais , Diferenciação Celular , Eletroporação , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/patologia , Eritropoese/genética , Morte Fetal/etiologia , Doenças Fetais/sangue , Doenças Fetais/genética , Doenças Fetais/patologia , Proteínas de Fusão bcr-abl/genética , Idade Gestacional , Fatores de Crescimento de Células Hematopoéticas/fisiologia , Janus Quinase 2 , Leucemia Eritroblástica Aguda/patologia , Fígado/embriologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/fisiologia , Receptores da Eritropoetina/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais , Relação Estrutura-Atividade , Transfecção , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Las complicaciones arbitrarias de la sinusitis se deben a la íntima relación entre los senos paranasales y la región arbitraria. Son de evolución rápida y según Chandler, pueden progresar a través de cinco grados hasta la trombosis del seno cavernoso. Una vez instaurada la antibiotecoterapia el drenaje quirúrgico, según sea la severidad del cuadro, responde positivamente. Se presenta el caso de un paciente masculino de 16 años de edad quien fue arrastrado por alud de lodo posterior a desastre natural e ingreso al Hospital" Domingo Luciani" a la Unidad politraumatizados con 48 horas de evolución. Se le realizó amputación supracondilea izquierda por fractura abierta y días después presenta pansinusitis, ameritando maxiloetmoidectomía y esfenoidotomía, posteriormente se asocia a celulitis orbitraria bilateral con proptosis y exposición corneal total (Chandler 2,) realizándosele una segunda maxiloetmoidectomía y por persistir el cuadrado, una tercera intervención días después. Se aislaron gérmenes Gram (-), Gram (+), y hongos. No se realizó drenaje quirúrgico orbitario y recibió tratamiento con Imipenem, Fluconazol y esteroides con respuesta lentamente favorable. Luego de un período de acalmia durante un mes, presentó osteomielitis de la base del cráneo
Assuntos
Humanos , Masculino , Adolescente , Celulite (Flegmão) , Desastres , Sinusite , Otolaringologia , VenezuelaRESUMO
Digital dermatoscopic images are acquired with digital cameras or video camera and frame grabber combinations. These images can be compressed, transmitted, or archived; combined with clinical anamnestic information for medical record purposes; or attached to body surface diagrams for mole mapping applications. Image analysis software, which might interpret the images to produce a computer-assisted or fully automated diagnosis, is under development.