RESUMO
OBJECTIVES: To evaluate the relation between the coronary calcium score and the posterior choice of kilovoltage according to radiologists' criteria in a standard coronary CT angiography protocol to rule out coronary disease. To quantify the reduction in ionizing radiation after linking kilovoltage to patients' body mass index in a low-dose protocol with iterative model reconstruction. To evaluate the image quality and diagnostic performance of the low-dose protocol. MATERIAL AND METHODS: We compared anthropometric characteristics, calcium score, kilovoltage levels, size-specific dose estimates (SSDE), and the dose-length product (DLP) between a group of 50 patients who were prospectively recruited to undergo coronary CT angiography with a low-dose protocol and a historical group of 50 patients who underwent coronary CT angiography with the standard protocol. We correlated these parameters, the number of coronary segments that could not be evaluated with and without temporal padding, the attenuation, and the signal-to-noise ratio in the ascending aorta in the low-dose protocol with excellent imaging quality according to a semiquantitative scale. To calculate the diagnostic performance per patient, we used 24-month clinical follow-up including all tests as the gold standard. RESULTS: In the standard protocol, the presence of coronary calcium correlated with the selection of high kilovoltage (pâ¯=â¯0.02); this correlation was not found in the low-dose protocol (pâ¯=â¯0.47). Median values of SSDE and DLP were significantly (pâ¯<â¯0.001) lower and less dispersed in the low-dose protocol [9.22â¯mGy (IQR 7.84-12.1â¯mGy) vs. 26.5â¯mGy (IQR 21.3-36.3â¯mGy) in the standard protocol] and [97â¯mGyâ¯cm (IQR 78-134â¯mGyâ¯cm) vs. 253â¯mGyâ¯cm (IQR 216-404â¯mGyâ¯cm) in the standard protocol], respectively. The overall quality of the images obtained with the low-dose protocol was considered good or excellent in 96% of the studies. The parameters associated with image quality in a multivariable model (C statisticâ¯=â¯0.792) were heart rate (estimated coefficient, -0,12 [95% confidence interval: -0.2, -0.04]; pâ¯<â¯0.01) and the SSDE (estimated coefficient, -0,26 [95% confidence interval: -0.51, -0.01]; pâ¯<â¯0.05). The CAD-RADS modifier for a not fully evaluable or diagnostic study was used on two occasions (4%); the final measures for the diagnosis of coronary disease were sensitivity 100%, specificity 94%, and efficacy 94%. CONCLUSIONS: In the standard protocol, the radiologist selects higher kilovoltage for CT angiography studies for patients whose previous calcium score indicates the presence of coronary calcium. In the low-dose protocol, linking kilovoltage with body mass index enables the dose of radiation to be reduced by 65% while obtaining excellent or good image quality in 96% of studies and excellent diagnostic performance.
Assuntos
Angiografia por Tomografia Computadorizada , Doença da Artéria Coronariana , Humanos , Índice de Massa Corporal , Cálcio , Redução da Medicação , Doses de Radiação , Doença da Artéria Coronariana/diagnóstico por imagemRESUMO
Infective endocarditis (IE) is a serious condition with a poor prognosis, its mortality unchanged significantly despite diagnostic and therapeutic advances in the last 30years. The diagnostic ability of the modified Duke criteria in prosthetic endocarditis and/or devices does not exceed 50%, so new tools are necessary for the diagnosis of this entity in this context. The 18F-FDG PET/CTA combines a highly sensitive technique to detect inflammatory-infectious activity with a technique with high anatomical resolution to assess the structural lesions associated with endocarditis. With a diagnostic sensitivity between 91-97%, this hybrid technique has become a useful diagnostic tool for patients with prosthetic valves or devices and suspicion of IE, becoming a major criterion in the diagnostic algorithm of current guidelines. This excellent diagnostic ability depends directly on the quality of the obtained exploration and the knowledge at the time of interpreting the images. The aim of this review is to describe and standardize the methodology of cardiac 18F-FDG PET/CTA in the diagnosis of endocarditis in prosthetic valves and intracardiac devices, with special emphasis on the particularities of the patient's preparation, the PET and CT acquisition procedures, and the subsequent imaging postprocessing and interpretation.
Assuntos
Endocardite/diagnóstico por imagem , Próteses Valvulares Cardíacas/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Próteses e Implantes/efeitos adversos , Infecções Relacionadas à Prótese/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Dieta com Restrição de Carboidratos , Gorduras na Dieta , Endocardite/etiologia , Jejum , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Glicólise , Heparina/administração & dosagem , Heparina/farmacologia , Humanos , Leucócitos/metabolismo , Macrófagos/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fosforilação , Compostos Radiofarmacêuticos/farmacocinéticaAssuntos
Abscesso/diagnóstico por imagem , Valva Aórtica/diagnóstico por imagem , Bioprótese/efeitos adversos , Endocardite Bacteriana/diagnóstico por imagem , Próteses Valvulares Cardíacas/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Infecções Relacionadas à Prótese/diagnóstico por imagem , Infecções Estreptocócicas/diagnóstico por imagem , Streptococcus gallolyticus , Abscesso/tratamento farmacológico , Abscesso/cirurgia , Idoso , Antibacterianos/uso terapêutico , Estenose da Valva Aórtica/cirurgia , Terapia Combinada , Remoção de Dispositivo , Ecocardiografia Transesofagiana , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/cirurgia , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Humanos , Masculino , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/cirurgia , Compostos Radiofarmacêuticos , Reoperação , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/cirurgiaRESUMO
The acquisition of a complete neoplastic phenotype requires cancer cells to develop escape mechanisms from the host immune system. This phenomenon, commonly referred to as 'immune evasion,' represents a hallmark of cancers and results from a Darwinian selection of the fittest tumor clones. First reported in solid tumors, cancer immunoescape characterizes several hematological malignancies. The biological bases of cancer immunoescape have recently been disclosed and include: (i) impaired human leukocyte antigen-mediated cancer cell recognition (B2M, CD58, CTIIA, CD80/CD86, CD28 and CTLA-4 mutations); (ii) deranged apoptotic mechanisms (reduced pro-apoptotic signals and/or increased expression of anti-apoptotic molecules); and (iii) changes in the tumor microenvironment involving regulatory T cells and tumor-associated macrophages. These immune-escape mechanisms characterize both Hodgkin and non-Hodgkin (B and T cell) lymphomas and represent a promising target for new anti-tumor therapies. In the present review, the principles of cancer immunoescape and their role in human lymphomagenesis are illustrated. Current therapies targeting these pathways and possible applications for lymphoma treatment are also addressed.
Assuntos
Sistema Imunitário/imunologia , Linfoma/patologia , Evasão Tumoral , Humanos , Linfoma/imunologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologiaRESUMO
Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1ß), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1ß and iNOS induced by 10 µM ß-amyloid1-42 (Aß42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aß42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 µM or 500 µM) or R-flurbiprofen (3 µM or 100 µM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Encéfalo/patologia , Ciclopropanos/uso terapêutico , Flurbiprofeno/análogos & derivados , Neuroglia/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Anti-Inflamatórios não Esteroides/farmacologia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Ciclopropanos/farmacologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Flurbiprofeno/farmacologia , Flurbiprofeno/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Among Western populations, the declining incidence of Helicobacter pylori infection coincides with a growing clinical impact of autoimmune gastritis. AIMS: To describe the histological phenotype of autoimmune gastritis, also to test the prognostic impact of OLGA staging in the autoimmune setting. METHODS: A single-institutional series (spanning the years 2003-2011) of 562 consecutive patients (M:F ratio: 1:3.7; mean age = 57.6 ± 14.4 years) with serologically confirmed autoimmune gastritis underwent histology review and OLGA staging. RESULTS: Helicobacter pylori infection was ascertained histologically in 44/562 cases (7.8%). Forty six biopsy sets (8.2%) featured OLGA stages III-IV; they included all four cases of incidental epithelial neoplasia (three intraepithelial and one invasive; three of these four cases had concomitant H. pylori infection). There were 230 (40.9%) and 139 (24.7%) cases, respectively, of linear and micro-nodular enterochromaffin-like cell hyperplasia; 19 (3.4%) type I carcinoids were detected. The series included 116 patients who underwent repeated endoscopy/biopsy sampling (mean time elapsing between the two procedures = 54 months; range 24-108). Paired histology showed a significant (P = 0.009) trend towards a stage progression [the stage increased in 25/116 cases (22%); it remained unchanged in 87/116 cases (75%)]. CONCLUSIONS: In autoimmune gastritis, the cancer risk is restricted to high-risk gastritis stages (III-IV), and is associated mainly with concomitant H. pylori infection. OLGA staging consistently depicts the time-dependent organic progression of the autoimmune disease and provides key information for secondary gastric cancer prevention strategies.
Assuntos
Doenças Autoimunes/patologia , Gastrite/patologia , Helicobacter pylori/isolamento & purificação , Adulto , Idoso , Doenças Autoimunes/microbiologia , Biópsia , Tumor Carcinoide/patologia , Progressão da Doença , Endoscopia Gastrointestinal/métodos , Feminino , Gastrite/microbiologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Lesões Pré-Cancerosas/patologia , Fatores de Risco , Índice de Gravidade de Doença , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologiaRESUMO
Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Síndrome de Muir-Torre/patologia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/terapia , Feminino , Humanos , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/terapia , Neoplasias Primárias Múltiplas/terapia , Linhagem , Prognóstico , Neoplasias Cutâneas/terapiaRESUMO
The programmed cell death 4 (PDCD4) tumor suppressor is down-regulated in several malignancies, and the (subcellular) expression of its protein product is modulated by both oncomiR miR-21 and protein kinase B (Akt). PDCD4 and activated Akt (phosphorylated Akt [pAkt]) expression were assessed immunohistochemically in 53 tissue samples obtained from 25 endoscopic esophageal mucosal resections performed for squamous intraepithelial neoplasia (IEN) or squamous intramucosal carcinoma (IM-SSC). In total, 33 IEN (low-grade = 15; high-grade = 15) and 20 IM-SSC specimens were considered; 50 additional tissue samples of histologically proven normal esophageal mucosa were considered as normal controls. To further validate the results achieved, miR-21 expression (as assessed by quantitative real-time polymerase chain reaction and in situ hybridization) was tested in another series of 15 normal esophageal tissue samples, 15 high-grade IEN, and 15 IM-SCCs. Normal suprabasal squamous epithelial layers consistently featured strong PDCD4 nuclear immunostaining, which was significantly lower (P < 0.001) in IEN (both low-and high-grade) and in IM-SSC. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. PDCD4 down-regulation, as assessed by immunohistochemistry, is a reliable biomarker of early-stage squamous cell esophageal neoplasia, providing additional information in the histological assessment of these lesions.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Neoplasias Esofágicas/patologia , Humanos , Imuno-Histoquímica , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
Follicular dendritic cell (FDC) sarcoma is a rare tumour with a low-to-intermediate grade of malignancy. It frequently occurs in cervical, mediastinal and axillary lymph nodes. In approximately 30% of cases an extranodal localization has been reported (tonsils, oral cavity, mediastinum, liver, and spleen). Very little is known about possible treatment options and overall prognosis. This case reports a 66 year-old patient, who underwent surgical removal of a persistently enlarged right cervical lymph node. The histopathological examination revealed a spindle cell tumour with lymphocyte and plasma cell infiltrates. Neoplastic cells stained positive for CD21, CD23 and CD35, thus confirming the diagnosis of FDC sarcoma. The neoplasm recurred two years later and partial regression was achieved by IGEV rescue therapy. We briefly discuss clinical history, histopathological differential diagnosis and treatment options of FDC sarcoma.
Assuntos
Sarcoma de Células Dendríticas Foliculares/patologia , Células Dendríticas Foliculares/patologia , Idoso , Biomarcadores Tumorais/análise , Biópsia , Quimioterapia Adjuvante , Sarcoma de Células Dendríticas Foliculares/imunologia , Sarcoma de Células Dendríticas Foliculares/terapia , Células Dendríticas Foliculares/imunologia , Humanos , Imuno-Histoquímica , Excisão de Linfonodo , Masculino , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Receptores de Complemento 3b/análise , Receptores de Complemento 3d/análise , Receptores de IgE/análise , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
A 77-year old patient was admitted for acute coronary syndrome without ST elevation. His risk was stratified using the myocardial perfusion gated SPECT, mild inferior ischemia being observed. Thus, medical therapy was optimized and the patient was discharged. He continued with exertional dyspnea so a coronary CT angiography was performed. It revealed severe lesions in the proximal RCA. SPECT-CT fusion images correlated the myocardial perfusion defect with a posterior descending artery from the RCA, in a co-dominant coronary area. Subsequently, cardiac catheterism was indicated for his treatment. The current use of image fusion studies is limited to patients in whom it is difficult to attribute a perfusion defect to a specific coronary artery. In our patient, the fusion images helped to distinguish between the RCA and the circumflex artery as the culprit artery of ischemia.
Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Tomografia Computadorizada por Emissão de Fóton Único de Sincronização Cardíaca , Angiografia Coronária/métodos , Vasos Coronários/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Síndrome Coronariana Aguda/patologia , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Calcinose/diagnóstico por imagem , Calcinose/patologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Hemodinâmica , Humanos , Masculino , Imagem de Perfusão do MiocárdioRESUMO
The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia.
Assuntos
Isquemia Encefálica/metabolismo , Lisina/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Acetilação , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Isquemia Encefálica/patologia , Proteína de Ligação a CREB/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Sirtuína 1/química , Sirtuína 1/metabolismoRESUMO
We discuss a diabetic obese patient with an extensive necrosis of the ascending and transverse colon plus segmental necrosis of the small bowel incarcerated in a massive median incisional hernia below the umbilicus. After a blood test and an abdominal CT scan (without contrast dial), the patient underwent an urgent operation. We performed an extended right hemicolectomy, multiple segmental small bowel resections and a terminal ileostomy. The defect of the abdominal wall was treated with vacuum-assisted closure (VAC) therapy with good results.
Assuntos
Colo/patologia , Hérnia Ventral/cirurgia , Tratamento de Ferimentos com Pressão Negativa , Idoso , Colo/irrigação sanguínea , Diabetes Mellitus Tipo 2/complicações , Emergências , Feminino , Humanos , Ileostomia , Necrose , Obesidade/complicaçõesRESUMO
Nuclear factor-kappaB (NF-kappaB) is a transcriptional regulator of neuron survival eliciting diverse effects according to the specific composition of its active dimer. While p50/p65 mediates neurodegenerative events, c-Rel-containing dimers promote cell survival. Stimulation of metabotropic glutamate receptors type 5 (mGlu5) reduces neuron vulnerability to amyloid-beta through activation of anti-apoptotic, c-Rel-dependent transcription of Bcl-X(L) pathway. We here evaluated the protective activity of mGlu5 agonists in dopaminergic SK-N-SH cells exposed to 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causing parkinsonism in experimental animals. MPP(+) produced a concentration-dependent cell loss. Activation of mGlu5 receptors by CHPG (1 mM) and 3HPG (50 microM) abolished the toxic effect produced by 3 microM MPP(+). The neuroprotection was associated with activation of NF-kappaB p65/c-Rel dimer and reduction of p50/p65. These effects were prevented by the mGlu5 receptor antagonist MPEP (5 microM). It is suggested that mGlu5 receptor agonists through activation of a c-Rel-dependent anti-apoptotic pathway can rescue dopaminergic cell from mitochondrial toxicity.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Agonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Herbicidas/toxicidade , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-rel/metabolismo , Análise de Variância , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Neuroblastoma , Fenilacetatos/farmacologia , Fatores de TempoRESUMO
Opposite effects of nuclear factor-kappaB (NF-kappaB) on neuron survival rely on activation of diverse NF-kappaB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1beta. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-beta (Abeta), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Abeta toxicity depends on c-Rel activation. Abeta peptide induced NF-kappaB factors p50 and p65. The mGlu5 agonists activated c-Rel, besides p50 and p65, and the expression of manganese superoxide dismutase (MnSOD) and Bcl-X(L). Targeting c-Rel expression by RNA interference suppressed the induction of both antiapoptotic genes. Targeting c-Rel or Bcl-X(L) prevented the prosurvival effect of mGlu5 agonists. Conversely, c-Rel overexpression or TAT-Bcl-X(L) addition rescued neurons from Abeta toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Rel-dependent antiapoptotic pathway responsible for neuroprotection against Abeta peptide.
Assuntos
Peptídeos beta-Amiloides/toxicidade , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-rel/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Deleção de Genes , Inativação Gênica , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Fenilacetatos/farmacologia , Proteínas Proto-Oncogênicas c-rel/deficiência , Proteínas Proto-Oncogênicas c-rel/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Glutamato Metabotrópico/genética , Superóxido Dismutase/metabolismoRESUMO
Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties, and is currently under development for Alzheimer's disease. Recently, it was reported that repeated treatments with sabeluzole protect cultured rat hippocampal neurons against NMDA- and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indirectly, on tau proteins. We found that repeated treatments during development of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resistant to the excitotoxicity induced by glutamate. Also, sabeluzole treatment specifically prevented the glutamate-induced increase of tau expression without modifying the basal pattern of expression of tau proteins, as shown by measurement of mRNA and protein levels. In human neuroblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced cell death. Both effects were prevented by sabeluzole. Our data indicate that increased tau expression is a common response to different types of cells to neurotoxic agents, and that sabeluzole-induced neuroprotection is functionally associated with the prevention of the injury-mediated increase of tau expression.
Assuntos
Morte Celular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Piperidinas/farmacologia , Tiazóis/farmacologia , Proteínas tau/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Ácido Glutâmico/farmacologia , Humanos , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Guidelines, algorithms and recommendations have been issued in the attempt to ensure appropriateness of transfusion practice, but the results are less than satisfactory, mainly due to the difficulty to turn paper procedures into actual practice. In our hospital we have tried to overcome this difficulty through the implementation of a quality assurance programme which includes giving the privilege of nonurgent blood prescription to a limited number of physicians and a computerized prospective audit of blood requests. The latter is performed through verification of the compliance of blood requests, which are designed to include a patient's laboratory and clinical data, with hospital guidelines for the proper use of blood. In the 12 months since implementation of the computerized prospective audit the transfusion service has evaluated 7884 requests. Of these, 63.4% (n = 4998) were for red blood cells, 21.1% (n = 1664) for platelets and 15.5% (n = 1222) for fresh frozen plasma. The prospective audit showed that 96.8% and 98.1% of requests for red units and platelets were appropriate, respectively. Conversely, approximately 27% of plasma requests did not comply with guidelines, mainly because the evidence of coagulopathy was missing. However, inappropriateness of plasma requests for elective general surgery decreased from 39% at the onset of the programme to 14% in the last trimester considered. Moreover, the evaluation by retrospective audit of the proportion of patients transfused with both red blood cells and plasma in the perioperative period out of those transfused with red blood cells only, as an indicator of unwanted reconstitution of whole blood, showed that this proportion decreased from 47.6% (320/672) in the 12 months before implementation of computerized audit to 37.8% (244/646) in the following 12 months (difference = -9.8%, 95% confidence interval of the difference from -4.5% to -15.1%; P < 0.005 by chi 2 test). Our initial experience, together with the present system, shows that (1) the restriction of nonurgent blood prescription to a group of clinicians more educated in transfusion medicine than average clinicians practicing in a large multispecialty hospital is feasible; (2) prospective audit is a useful tool for assuring the quality of blood requesting.
Assuntos
Transfusão de Sangue/estatística & dados numéricos , Auditoria Administrativa , Privilégios do Corpo Clínico , Padrões de Prática Médica , Prescrições , Garantia da Qualidade dos Cuidados de Saúde , Algoritmos , Computadores , Humanos , Guias de Prática Clínica como Assunto , Estudos Prospectivos , SoftwareRESUMO
We have demonstrated recently that in menopausal women and in ovariectomized rats the deficiency of circulating oestrogens impairs vasoactive intestinal peptide (VIP) efficacy in stimulating prolactin (PRL) release. The present study was designed to investigate whether the lack of VIP-induced PRL release after ovariectomy is a consequence of a defect at the receptor-transductional or post-transductional level. For this purpose we evaluated the VIP receptor function, by measuring VIP-stimulated cyclic adenosine monophosphate (AMP) formation, and the efficacy of the cyclic AMP-dependent PRL release in pituitary cells from control and ovariectomized animals. We observed that VIP induced a significantly higher stimulation of adenylate cyclase in pituitary homogenates from ovariectomized rats than in those from control animals. This effect appeared to be linked to an increased efficiency of the Gs coupling protein, because superimposable results were obtained by using the non-hydrolysable guanosine triphosphate (GTP) analogue, 5-guanylylimidodiphosphate. On the contrary, the cyclic AMP analogue, 8-Br-cAMP, that potently stimulated PRL release from control pituitary cells was completely ineffective in cells from ovariectomized rats. The present data indicate that in PRL-secreting cells from ovariectomized rats a defect in the post-transductional mechanism that couples the VIP receptor to PRL secretion, rather than a reduction of receptor function, possibly accounts for the lack of VIP efficacy.
Assuntos
Adeno-Hipófise/metabolismo , Prolactina/metabolismo , Transdução de Sinais , Peptídeo Intestinal Vasoativo/fisiologia , Adenilil Ciclases/análise , Animais , Células Cultivadas , AMP Cíclico/biossíntese , Feminino , Guanilil Imidodifosfato/farmacologia , Ovariectomia , Adeno-Hipófise/citologia , Ratos , Ratos Sprague-DawleyRESUMO
To explore the electroclinical features of temporal lobe epilepsy (TLE) in early childhood, we studied results of video-EEG and other tests of 14 children aged 16 months to 12 years selected by seizure-free outcome after temporal lobectomy. Four children had mesiotemporal sclerosis, 1 had cortical dysplasia, and 9 had low-grade temporal neoplasms. The children had complex partial seizures (CPS) with symptomatology similar to that of adults with TLE, including decreased responsiveness and automatisms. Automatisms tended to be simpler in the younger children, typically limited to lip smacking and fumbling hand gestures. Scalp/sphenoidal EEG showed anterior/inferior temporal interictal sharp waves and unilateral temporal seizure onset in the 4 children with mesiotemporal sclerosis and in the child with cortical dysplasia, but EEG findings in 9 children with low-grade temporal tumors were complex, including multifocal interictal sharp waves or poorly localized or falsely lateralized EEG seizure onset. In children without tumors, video-EEG was critical to localization of the epileptogenic zone for resection, but in patients with tumors video-EEG was less localizing and its main value was to confirm that the reported behaviors were epileptic seizures with semiology typical of temporal lobe onset.
Assuntos
Epilepsia do Lobo Temporal/diagnóstico , Lobo Temporal/cirurgia , Fatores Etários , Encefalopatias/diagnóstico , Encefalopatias/fisiopatologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatologia , Córtex Cerebral/anormalidades , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Eletroencefalografia/estatística & dados numéricos , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/cirurgia , Humanos , Lactente , Imageamento por Ressonância Magnética , Esclerose/diagnóstico , Esclerose/fisiopatologia , Lobo Temporal/fisiopatologia , Resultado do Tratamento , Gravação de VideoteipeRESUMO
Activation of glutamate ionotropic receptors represents the primary event in the neurotoxicity process triggered by excitatory amino acids. We demonstrate here that the concentration-dependent stimulation of metabotropic glutamate receptor (mGluR) by the selective agonist trans-1-aminocyclopentane-1,3-dicarboxylate or by quisqualate counteracts both glutamate- and kainate-induced neurotoxicity in primary cultures of rat cerebellar granule cells. The mGluR-evoked responses are potentiated by aniracetam, which per se also elicits neuroprotection. Aniracetam concentration-dependently counteracted glutamate-, kainate-, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death and greatly facilitated neuroprotective response achieved by different concentrations of both quisqualate and trans-1-aminocyclopentane-1,3-dicarboxylate. In addition, aniracetam potentiated the mGluR-coupled stimulation of phospholipase C, as revealed by the measurement of 3H-inositol phosphate formation. Thus, mGluRs could be a suitable target for novel pharmacological strategies pointing to the treatment of neurodegenerative diseases.