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Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.
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AIMS: This study identified the distinct magnetic resonance imaging findings of cervical gastric-type adenocarcinoma (GAS) that can help differentiate it from squamous cell carcinoma (SCC) and usual-type endocervical adenocarcinoma (UEA) and reveal the radiologic-pathologic correlation. MATERIALS AND METHODS: All consecutive patients with cervical GAS treated at our hospital from November 2009 to August 2021 were included. The SCC and UEA cases were considered controls. Tumor location, tumor shape, presence and size of cysts, presence of uterine fluid, and apparent diffusion coefficient (ADC) were evaluated. RESULTS: Overall, 18 GAS, 55 SCC, and 23 UEA cases were evaluated. The tumor was located in the entire cervix in 13/18 GAS cases, whereas it was predominantly located in the lower cervix in 38/55 SCC cases and 14/23 UEA cases. Most GAS cases exhibited a diffuse infiltration growth pattern (17/18), whereas most SCC and UEA cases exhibited a mass-forming pattern (39/55 and 20/23, respectively). Moreover, the percentages of cases presenting microcysts or macrocysts and undergoing uterine fluid collection were significantly higher in the GAS group (14/18 and 13/18) than in the SCC and UEA groups. ADC was significantly higher in the GAS group than in the SCC group (1.092 × 10-3 vs. 0.819 × 10-3 mm2/s). CONCLUSION: This study revealed that GAS is characterized by tumor presence in the entire cervix, infiltrative growth pattern, intrauterine fluid collection, and frequent microcyst or macrocyst formation. Moreover, ADC was significantly higher in the GAS group than in the SCC group.
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BACKGROUND AND PURPOSE: Patients with SAH due to a ruptured intracranial aneurysm occasionally show reversible high-signal lesions in the splenium of the corpus callosum on DWI. These lesions are called cytotoxic lesions of the corpus callosum. This study retrospectively reviewed cases of aneurysmal SAH and investigated clinical features of cytotoxic lesions of the corpus callosum associated with SAH. MATERIALS AND METHODS: Participants comprised 259 patients with aneurysmal SAH who had undergone curative treatment at our hospital. We examined the following items related to cytotoxic lesions of the corpus callosum: occurrence rate, timing of appearance and disappearance of the lesions, lesion size, aneurysm location, severity of SAH, treatment method, clinical course, and outcome. RESULTS: Among the 259 cases, DWI detected cytotoxic lesions of the corpus callosum in 33 patients (12.7%). The mean periods from the onset of SAH to detection and disappearance of cytotoxic lesions of the corpus callosum were 6.3 days (range, 0-25 days) and 35.7 days (range, 9-78 days), respectively. Cytotoxic lesions of the corpus callosum were classified into 2 types: a small type localized in the splenium in 26 cases (78.9%) and a large type spread along the ventricle in 7 cases (21.2%). The severity of SAH, coiling, hydrocephalus, and poor mRS score at discharge were significantly higher in the group with cytotoxic lesions of the corpus callosum. However, multivariate analysis did not identify cytotoxic lesions of the corpus callosum as a risk factor for poor outcome. CONCLUSIONS: Cytotoxic lesions of the corpus callosum appear at a frequency of 12.7% in patients with aneurysmal SAH. Cytotoxic lesions of the corpus callosum associated with SAH take several days to appear and subsequently resolve within about a month. Cytotoxic lesions of the corpus callosum were likely to occur in patients with high-grade SAH but did not represent a predictor of poor outcome.
Assuntos
Hemorragia Subaracnóidea , Idoso , Aneurisma Roto , Corpo Caloso/diagnóstico por imagem , Feminino , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico por imagem , Estudos Retrospectivos , Hemorragia Subaracnóidea/diagnóstico por imagem , Resultado do TratamentoRESUMO
Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higher-dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.
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Anticorpos Monoclonais/uso terapêutico , Antígenos CD40/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/imunologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Antígenos CD40/antagonistas & inibidores , Ligante de CD40/antagonistas & inibidores , Ligante de CD40/imunologia , Rejeição de Enxerto/imunologia , Humanos , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Macaca fascicularis , Masculino , Modelos Animais , Transdução de Sinais/imunologiaRESUMO
High-resolution ultrasound may be able to detect pressure ulcers before clinical signs emerge. This retrospective study found that one such early indicator is inflammatory oedema in the subcutaneous fat, which resolves as healing occurs.
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Úlcera por Pressão/diagnóstico por imagem , Gordura Subcutânea/diagnóstico por imagem , Adulto , Diagnóstico Precoce , Edema/diagnóstico por imagem , Edema/etiologia , Edema/patologia , Feminino , Humanos , Inflamação , Japão , Masculino , Pessoa de Meia-Idade , Necrose , Avaliação em Enfermagem , Pesquisa em Avaliação de Enfermagem , Valor Preditivo dos Testes , Úlcera por Pressão/complicações , Úlcera por Pressão/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Gordura Subcutânea/patologia , Ultrassonografia , CicatrizaçãoRESUMO
We report the characterization of the first successful treatment of neuronal ischemic injury in vivo by cell-permeant Ca2+ chelators. The chelators attenuated glutamate-induced intracellular Ca2+ increases and neurotoxicity in neuronal explant cultures. When infused intravenously in rats, permeant fluorescent BAPTA analogs accumulated in neurons in several brain regions. BAPTA-AM, infused in vivo, reduced Ca(2+)-dependent spike frequency adaptation and post-spike train hyperpolarizations in CA1 neurons taken from treated animals. This effect was reproduced by direct injections of BAPTA into untreated neurons. The effects of three different chelators (BAPTA, 5,5'-difluoro BAPTA, and 4,4'-difluoro BAPTA) on Ca(2+)-dependent membrane excitability varied with their Ca2+ affinity. When the chelators' permeant forms were used to treat rats prior to the induction of focal cortical ischemia, they were highly neuroprotective, as gauged by significant reductions in cortical infarction volumes and neuronal sparing. The chelators' protective effects in vivo also reflected their affinity for Ca2+. This report provides the most direct evidence to date that intracellular Ca2+ excess triggers early neurodegeneration in vivo and contributes a novel therapeutic approach to neuronal ischemia of potential clinical utility.
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Isquemia Encefálica/patologia , Cálcio , Quelantes/farmacologia , Neurônios/patologia , Neurotoxinas/farmacologia , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular , Quelantes/farmacocinética , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Glutamatos/farmacologia , Ácido Glutâmico , Camundongos , Camundongos Endogâmicos , Neurônios/efeitos dos fármacos , Neurotoxinas/antagonistas & inibidores , Ratos , Ratos Endogâmicos F344 , Medula Espinal/citologiaRESUMO
In order to obviate a small-for-size graft syndrome (SFSGS), a portacaval (PC) shunt had been considered in a case of adult-to-adult living donor liver transplantation (AA-LDLT). In a recent AA-LDLT case, we adopted the PC shunt to resolve SFSGS; however, graft atrophy was observed in the late period of LDLT, thereby resulting in liver dysfunction. Due to the surgical closure of the PC shunt at 11 months post-LDLT, the graft regenerated gradually and resulted in the recovery of the liver function. This experience indicates that the portacaval shunt would overcome SFSGS in the early period of LDLT, while it would cause the graft atrophy and the graft dysfunction in the late period of LDLT.
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Transplante de Fígado , Fígado/patologia , Doadores Vivos , Derivação Portocava Cirúrgica , Adulto , Atrofia , Feminino , Humanos , Fígado/fisiopatologia , Testes de Função Hepática , Transplante de Fígado/efeitos adversos , Transplante de Fígado/patologia , Masculino , Tamanho do Órgão , Derivação Portocava Cirúrgica/efeitos adversos , SíndromeRESUMO
Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c.-191C>A and c.-216G>T) and the c.2073A>T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A>T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26-0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A>T polymorphism could play a role in future therapeutic approaches to astrocytoma.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Receptores ErbB/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Astrocitoma/etnologia , Neoplasias Encefálicas/etnologia , Brasil , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Resultado do TratamentoRESUMO
Malignant brain tumor experimental models tend to employ cells that are immunologically compatible with the receptor animal. In this study, we have proposed an experimental model of encephalic tumor development by injecting C6 cells into athymic Rowett rats, aiming at reaching a model which more closely resembles to the human glioma tumor. In our model, we observed micro-infiltration of tumor cell clusters in the vicinity of the main tumor mass, and of more distal isolated tumor cells immersed in normal encephalic parenchyma. This degree of infiltration is superior to that usually observed in other C6 models.
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Neoplasias Encefálicas/patologia , Glioma/patologia , Animais , Modelos Animais de Doenças , Feminino , Invasividade Neoplásica , Ratos , Ratos NusRESUMO
An in vitro culture of FLEB14 cells, an Epstein-Barr virus-transformed B cell precursor containing the germ line immunoglobulin genes, gave rise to a uniclonally expanded variant, FLEB14 delta 3, which was rearranged at the immunoglobulin heavy-chain gene locus. Cytogenetic analysis showed that FLEB14 delta 3 had a novel reciprocal translocation, t(6;14)(q15;q32). Molecular cloning of the rearranged DNA fragments and determination of their nucleotide sequence revealed that the recombination event was reciprocal, imprecise, and nonhomologous and took place in the S mu region, like those found in Burkitt's lymphoma cells. We propose a molecular model to explain this genetic event which may be relevant to class switch recombination. The translocated sequence of chromosome 6 did not contain any known oncogenes, although the sequence is conserved among mammals. FLEB14 delta 3 did not show tumorigenicity.
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Linfócitos B/fisiologia , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 6 , Translocação Genética , Sequência de Bases , Linhagem Celular , Transformação Celular Viral , Clonagem Molecular , Genes , Herpesvirus Humano 4 , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulinas/análise , Imunoglobulinas/genética , Cariotipagem , FenótipoRESUMO
Clarification of TP53 alterations is important to understand the mechanisms underlying the development of diffuse astrocytomas. It has been suggested that the alleles of TP53 at codon 72 differ in their ability to induce apoptosis in human cancers. The aim of this study was to analyze the possible association of TP53 mutation, p53 overexpression, and p53 codon 72 polymorphism with susceptibility to apoptosis in adult Brazilian patients with diffuse astrocytomas. We analyzed 56 surgical specimens of diffuse astrocytomas for alterations of TP53, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) direct sequencing. p53 and cleaved caspase 3 protein expression were assessed by immunohistochemistry. We found TP53 mutations in 19.6% (11 out of 56) of tumors tested, with the lowest mutation rate found in the cases of glioblastomas (8.8%) (p = 0.03). Only 16.1% of tumors tested showed cleaved caspase 3-positive staining, demonstrating that apoptosis is very inhibited in these tumors. All tumors having TP53 mutation and p53 accumulation had no expression of cleaved caspase 3. Additionally, no association was observed in tumors having proline and arginine alleles and expression of cleaved caspase 3. We concluded that clarification of the TP53 alterations allows a better understanding of the mechanisms involved in the progression of diffuse astrocytomas, and the allele status at codon 72 was not associated with apoptosis in these tumors.
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Apoptose/genética , Astrocitoma/genética , Genes p53/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Astrocitoma/patologia , Biomarcadores Tumorais/análise , Caspase 3 , Caspases/análise , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Proteína Supressora de Tumor p53/biossínteseRESUMO
It has recently been reported that the human myeloma cell line U266 proceeds to undergo apoptosis after cultivation with the antiestrogen tamoxifen, thus raising the possibility that antiestrogens may be candidates for use in myeloma therapy. To obtain basic information on the effects of antiestrogens on myeloma cells, we investigated the mRNA expression levels of estrogen receptor (ER)-alpha, ER-beta, and coactivators and corepressors in nine human myeloma cell lines and compared them with those of seven human breast cancer cell lines including four ER-positive and three ER-negative lines. The alterations in cell growth and mRNA expression of the target genes of ER or those of cytokines in the myeloma lines by estradiol or antiestrogens (tamoxifen and toremifene) were also investigated. In addition, effects on membrane Fas expression, appearance of apoptosis, and cell cycle perturbation were analyzed. It was revealed that ER-beta and corepressors were dominantly expressed in myeloma cells, and antiestrogens induced growth inhibition through apoptosis mediated by a Fas-related pathway and G1 arrest of the cell cycle in myeloma cell lines.
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Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Mieloma Múltiplo/metabolismo , Receptores de Estrogênio/metabolismo , Antineoplásicos Hormonais/metabolismo , Primers do DNA , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/metabolismo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Células Tumorais CultivadasRESUMO
Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc-finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL.
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Caspase 8/genética , Proteínas de Ligação a DNA/genética , Proteína de Domínio de Morte Associada a Fas/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Nucleares/genética , Adulto , Animais , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Caspase 8/metabolismo , Morte Celular , Linhagem Celular , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Feminino , Regulação Leucêmica da Expressão Gênica , Vetores Genéticos , Células HEK293 , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lentivirus/genética , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , Camundongos , Camundongos Endogâmicos NOD , Transplante de Neoplasias , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Carga Tumoral , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
A new human thyroid carcinoma cell line, KTC-1, was established from the malignant pleural effusion of a recurrent thyroid carcinoma patient. Cytogenetic analysis revealed a normal karyotype, and no p53 mutation in exons 5-9 was detected. This cell line is tumorigenic in athymic nude mice. Histological findings by light and electron microscopy, such as the absence of follicular structures and the existence of intranuclear cytoplasmic inclusions and psammoma bodies, indicated transplanted tumors to be a poorly differentiated papillary thyroid carcinoma. A low expression level of thyroglobulin was detected by immunocytochemistry and RT-PCR. Messenger ribonucleic acid (mRNA) expression of thyroid transcription factor-1 and PAX-8 was also detected. No mRNA expression of TSH receptors, thyroid peroxidase, or Na+/I- symporter was detected. Interleukin-6 and leukemia inhibitory factor were secreted into the medium. These findings suggest this cell line to be functionally poorly differentiated. Moreover, all-trans-retinoic acid increased the mRNA expression of thyroglobulin and decreased both the mRNA expression and secretion of interleukin-6 and leukemia inhibitory factor while significantly stimulating growth. RT-PCR analysis of retinoic acid receptors (RARs) revealed that KTC-1 cells express a moderate level of RARalpha and -gamma, but a low level of RARbeta. This cell line may be useful for studying redifferentiation therapy for thyroid carcinoma.
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Carcinoma Papilar/genética , Citocinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/genética , Transcrição Gênica , Tretinoína/farmacologia , Animais , Carcinoma Papilar/patologia , Carcinoma Papilar/ultraestrutura , Diferenciação Celular , Divisão Celular , Proteínas de Ligação a DNA/genética , Genes p53 , Inibidores do Crescimento/genética , Humanos , Interleucina-6/genética , Fator Inibidor de Leucemia , Linfocinas/genética , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/ultraestrutura , Fator Nuclear 1 de Tireoide , Transativadores/genética , Fatores de Transcrição/genética , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The termination of protein synthesis in bacteria requires codon-specific polypeptide release factors RF-1 (UAG/UAA specific) and RF-2 (UGA/UAA specific). We have proposed that release factors mimic tRNA and recognize the stop codon for polypeptide release (Nakamura et al (1996) Cell 87, 147-150). In contrast to the textbook view, genetic experiments have indicated that Escherichia coli RF-2 terminates translation very weakly at UAA while Salmonella RF-2 decodes this signal efficiently. Moreover, an excess of E coli RF-2 was toxic to cells while an excess of Salmonella RF-2 was not. These two RF-2 proteins are identical except for 16 out of 365 amino acids. Fragment swap experiments and site-directed mutagenesis revealed that a residue at position 246 is solely responsible for these two phenotypes. Upon substituting Ala (equivalent to Salmonella RF-2) for Thr-246 of E coli RF-2, the protein acquired increased release activity for UAA as well as for UGA. These results led us to conclude that E coli RF-2 activity is potentially weak and that the amino acid at position 246 plays a crucial role, not for codon discrimination, but for stop codon recognition or polypeptide release, presumably constituting an essential moiety of tRNA mimicry or interacting with peptidyltransferase centers of the ribosome.
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Escherichia coli/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , RNA de Transferência/metabolismo , Salmonella typhimurium/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA , Escherichia coli/genética , Teste de Complementação Genética , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Terminação Traducional da Cadeia Peptídica , Fatores de Terminação de Peptídeos/biossíntese , Fatores de Terminação de Peptídeos/química , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , RNA de Transferência/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Salmonella typhimurium/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
UNLABELLED: The aim of this SPECT study was to investigate the effects of donepezil on regional cerebral blood flow (rCBF) in patients with mild to moderate Alzheimer's disease (AD) using statistical parametric mapping. METHODS: rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer in 35 AD patients with a Mini-Mental State Examination score > 16 on initial evaluation. Baseline and follow-up SPECT studies with a mean interval of 12 mo were performed on these patients. We used the adjusted rCBF images in the relative flow distribution (normalization of global cerebral blood flow for each patient to 50 mL/100 g/min with proportional scaling) to compare these groups through statistical parametric mapping. RESULTS: In the follow-up study, the adjusted rCBF was significantly preserved in the right and left anterior cingulate gyri, right middle temporal gyrus, right inferior parietal lobules, and prefrontal cortex of donepezil-treated AD patients, compared with placebo-treated AD patients. CONCLUSION: Treatment with donepezil for 1 y appears to reduce the decline in rCBF, suggesting preservation of functional brain activity.
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Doença de Alzheimer/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Donepezila , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
UNLABELLED: The aim of this SPECT study was to determine the initial abnormality and longitudinal changes in regional cerebral blood flow (rCBF) in early Alzheimer's disease (AD) using statistical parametric mapping (SPM). METHODS: rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer SPECT in 32 patients complaining of mild cognitive impairment, with a Mini-Mental State Examination score more than 24 at the initial study, and 45 age-matched healthy volunteers. All patients satisfied the diagnostic criteria of AD during the follow-up period of at least 2 y. Follow-up SPECT studies were performed on the patients at a mean interval of 15 mo. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images of relative flow distribution (normalization of global cerebral blood flow [CBF] for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM. RESULTS: In the baseline study, the adjusted rCBF was significantly and bilaterally decreased in the posterior cingulate gyri and precunei of patients compared with healthy volunteers. In the follow-up study, selected reduction of the adjusted rCBF was observed in the left hippocampus and parahippocampal gyrus. These areas showed the most prominent reduction in absolute rCBF on each occasion. Moreover, further decline of the absolute rCBF was longitudinally observed in extensive areas of the cerebral association cortex. CONCLUSION: SPM analysis showed the characteristic early-AD rCBF pattern of selective decrease and longitudinal decline, which may be overlooked by a conventional region-of-interest technique with observer a priori choice and hypothesis. This alteration in rCBF may closely relate to the pathophysiologic process of this disease.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Previously, we showed that transgenic expression of the MHC (major histocompatibility complex) class II I-E molecules prevented insulitis in non-obese diabetic (NOD) mice at the age of 19 weeks. To rule out the possibility that the I-E expression merely delays the onset of insulitis, we have further characterized the expression and function of the I-E molecule expressed in transgenic NOD mice and confirmed our previous observations. Northern blot analysis showed that the transgenic E alpha d gene was expressed in a pattern similar to the endogenous E alpha d gene in BALB/c mice. The newly expressed I-E molecules were recognized as an alloantigen by the T lymphocytes of normal NOD mice as shown by mixed lymphocyte reaction (MLR). Transgenic NOD mice were resistant to the treatment by cyclophosphamide, which effectively induces diabetes in normal NOD mice, and did not develop diabetes up to 40 weeks of age. On the basis of these findings, we discuss the role of I-E molecules in the prevention of diabetes in NOD mice.
Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Expressão Gênica , Terapia Genética , Antígenos de Histocompatibilidade Classe II/genética , Animais , Animais Geneticamente Modificados , Ilhotas Pancreáticas/patologia , Linfócitos/fisiologia , Camundongos , Camundongos Mutantes , Monócitos/fisiologiaRESUMO
To evaluate putative risk factors for Alzheimer's disease (AD), we conducted a case-control study with exposure assessment performed after disease onset. In this study, we evaluated the effect of recalled habitual napping according to its duration and examined whether APOE genotype modifies the effect. The subjects were 337 patients (144 men, 193 women, age at onset and the time of study (years): 69+/-10, 73+/-9) with a diagnosis of probable AD based on the NINCDS-ADRDA criteria. Two hundred and sixty spouses of the subjects (94 men, 166 women, age at the time of study: 69+/-9) served as controls. We asked retrospectively about habitual (3 or more days per week) napping and its duration observed between 5 and 10 years before the onset of AD for cases, and between 5 and 10 years before the time of the study for controls. The analysis revealed that limited napping for up to 60 min had an apparently protective effect against the development of AD, especially for carriers of the APOEepsilon 4 allele. By contrast, napping for more than 60 min increased the risk of AD morbidity among the carriers of the allele. Habitual napping may modulate or disturb the physiological functions of sleep and circadian time-keeping according to its duration, and this might be associated with some mechanism that leads to the development of AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Sono/fisiologia , Idoso , Alelos , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Transtornos Cognitivos/diagnóstico , Feminino , Genótipo , Humanos , Masculino , Testes Neuropsicológicos , Estudos Retrospectivos , Fatores de Risco , Sono REM/fisiologia , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
Nasopharyngeal carcinoma (NPC) is characterized by its association with Epstein-Barr virus (EBV) infection. Unlike other upper aerodigestive tract squamous cell carcinomas, clinical and pathologic features are unable to predict outcome in NPC. EBV has been demonstrated to have transforming potential in B-cell systems so that its infection can rapidly and efficiently induce sustained lymphocyte proliferation in vitro. However, the relationship between cell proliferation and EBV infection in NPC has not been previously reported. This study was designed to determine the association of EBV infection and NPC tumor cell proliferation. Cell proliferation index, as measured by two markers, PCNA and Ki-67, were moderately correlated (r=0.534, p=0.033). Quantitative analysis of EBV positivity was highly correlated with both cell proliferation indices (r=0.802, p=0.0039 and r=0.720, p=0.0174 for PCNA and Ki-67, respectively). TNM staging did not demonstrate prognostic significance. NPC patients whose tumors were EBV positive demonstrated increased survival compared with patients whose tumors were EBV negative (p=0.043). These results indicate that EBV infection may regulate cell proliferation in NPC and the presence of EBV can be used as a positive prognostic factor.