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1.
J Intellect Disabil Res ; 63(9): 1111-1124, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020725

RESUMO

BACKGROUND: Whether individuals with autism spectrum disorder (ASD) have impairments with biological motion perception has been debated. The present study examined the ability to identify point-light-displayed (PLD) human actions in neurotypical (NT) adults and adults with ASD. METHOD: Twenty-seven adults with ASD (mean age = 28.36) and 30 NT adults (mean age = 22.45) were tested. Both groups viewed 10 different biological motion actions contacting an object/tool and 10 without making contact. Each action was presented twice, and participant's naming responses and reaction times were recorded. RESULTS: The ASD group had a significantly lower total number of correct items (M = 29.30 ± 5.08 out of 40) and longer response time (M = 4550 ± 1442 ms) than NT group (M = 32.77 ± 2.78; M = 3556 ± 1148 ms). Both groups were better at naming the actions without objects (ASD group: 17.33 ± 2.30, NT group: 18.67 ± 1.30) than those with objects (ASD group: 11.96 ± 3.57, NT group: 14.10 ± 1.97). Correlation analyses showed that individuals with higher Autism-spectrum Quotient scale scores tended to make more errors and responded more slowly. CONCLUSION: Adults with ASD were able to identify human point-light display biological motion actions much better than chance; however, they were less proficient compared with NT adults in terms of accuracy and speed, regardless of action type.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Percepção de Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
2.
Br J Cancer ; 112(1): 177-84, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25314066

RESUMO

BACKGROUND: As more patients are treated by haematopoietic stem cell transplantation (HSCT), development of secondary malignancy (SM) becomes an increasingly common issue in long-term survivors. METHODS: We conducted a nationwide population-based study of the Taiwanese population to analyse patients who received HSCT between January 1997 and December 2010. Standardised incidence ratios (SIRs) were used to compare the risk of SM in HSCT patients and the general population. Multivariate analysis was performed to identify independent predictors of SM. RESULTS: Patients receiving HSCT had a significantly greater risk of developing SM (SIR 2.00; 95% confidence interval (CI) 1.45-2.69; P<0.001). Specifically, the incidence increased for cancers of the oral cavity (SIR 14.18) and oesophagus (SIR 14.75) after allogeneic HSCT. Multivariate analysis revealed an increased SIR for cancer in patients who received the immunosuppressant azathioprine. The risk of SM also increased with greater cumulative doses of azathioprine. CONCLUSIONS: This study demonstrates an increased incidence of SM in Taiwanese patients who received allogeneic HSCT, especially for cancers of the oral cavity and oesophagus. This finding is different from results in populations of Western countries. Physicians should be cautious about azathioprine use for graft-vs-host disease after HSCT.


Assuntos
Azatioprina/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Segunda Neoplasia Primária/epidemiologia , Adulto , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sobreviventes , Taiwan/epidemiologia , Condicionamento Pré-Transplante/efeitos adversos , Adulto Jovem
4.
Lupus ; 24(14): 1552-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26169478

RESUMO

Protein-losing gastroenteropathy (PLGE), a rare manifestation of primary Sjögren's syndrome (SS), is characterized by profound edema and severe hypoalbuminemia secondary to excessive serum protein loss from the gastrointestinal tract and is clinically indistinguishable from nephrotic syndrome. We report a case of a 30-year-old Taiwanese woman with PLGE-associated SS. In addition to a positive Schirmer's test, she had eye-dryness, thirst, and high levels of anti-SSA antibodies, fulfilling SS criteria. PLGE diagnosis was highly appropriate given the clinical profile of hypoalbuminemia, hypercholesterolemia, pleural effusion, and ascites, with absent cardiac, hepatic, or renal disease. We were unable to perform technetium-99 m-labeled human serum albumin scintigraphy ((99m)Tc-HAS). However, the patient's edema and albumin level improved dramatically in response to a 3-month regime of oral prednisolone followed by oral hydroxychloroquine.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antirreumáticos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Linfangiectasia Intestinal/metabolismo , Prednisolona/administração & dosagem , Enteropatias Perdedoras de Proteínas/tratamento farmacológico , Síndrome de Sjogren/metabolismo , Adulto , Feminino , Humanos , Linfangiectasia Intestinal/patologia , Enteropatias Perdedoras de Proteínas/metabolismo , Enteropatias Perdedoras de Proteínas/patologia , Síndrome de Sjogren/patologia
5.
Br J Cancer ; 111(8): 1562-71, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25093497

RESUMO

BACKGROUND: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. METHODS: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. RESULTS: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. CONCLUSIONS: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.


Assuntos
Antineoplásicos/farmacologia , Ácido Mevalônico/metabolismo , Animais , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Modelos Animais de Doenças , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Técnicas In Vitro , Camundongos , Camundongos Nus
6.
Eur J Clin Microbiol Infect Dis ; 33(6): 941-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24338066

RESUMO

The resistance of Mycobacterium tuberculosis (MTB) to second-line drugs (SLDs) is growing worldwide; however, associations between the appropriateness of treatment for tuberculosis (TB) and whether the directly observed treatment, short course (DOTS)/DOTS-plus programs had an impact on the prevalence of SLD-resistant MTB are still uncertain. We performed a retrospective analysis of resistance profiles among MTB isolates obtained from 6,035 consecutive patients from 2004 to 2011 at two TB referral hospitals in Taiwan. There was a significant decrease (all p-values <0.01) in the prevalence of MTB isolates that were resistant to fluoroquinolones, injectable SLDs, and orally administered SLDs, and multidrug-resistant (MDR) and extensively drug-resistant (XDR) MTB isolates over time. There was a significant increase in the coverage rate of DOTS/DOTS-plus programs and that of administering appropriate first-line and second-line regimens (all p < 0.01). Compared with isoniazid-susceptible isolates, high-level (1.0 mg/L) isoniazid-resistant and MDR isolates showed extensive cross resistance to ofloxacin (5.9%, p < 0.01 and 33.6%, p < 0.01), levofloxacin (9.6%, p < 0.01 and 38.1%, p < 0.01), moxifloxacin (11.1%, p < 0.01 and 26.5%, p < 0.01), kanamycin (6.8 %, p < 0.01 and 16.7 %, p < 0.01), ethionamide (6.4%, p < 0.01 and 16.2%, p < 0.01), and para-aminosalicylic acid (13.1%, p < 0.01 and 20.4%, p < 0.01), but not to capreomycin (2.0%, p = 0.06 and 1.6%, p = 0.08). The decline in prevalence of resistance to SLDs was negatively correlated with the rise in rates of administering appropriate regimens as well as the DOTS/DOTS-plus programs, but not with the increase in usage of second-line regimens. The implementation of DOTS/DOTS-plus programs with appropriate regimens was associated with a decrease in the prevalence of SLD-resistant and XDR TB.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Monitoramento de Medicamentos/métodos , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Prevalência , Estudos Retrospectivos , Taiwan/epidemiologia , Tuberculose/microbiologia
7.
Ann R Coll Surg Engl ; 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38376380

RESUMO

INTRODUCTION: Websites and online resources are increasingly becoming patients' main source of healthcare information. It is paramount that high quality information is available online to enhance patient education and improve clinical outcomes. Upper gastrointestinal (UGI) endoscopy is the gold standard investigation for UGI symptoms and yet little is known regarding the quality of patient orientated websites. The aim of this study was to assess the quality of online patient information on UGI endoscopy using the modified Ensuring Quality Information for Patients (EQIP) tool. METHODS: Ten search terms were employed to conduct a systematic review. for each term, the top 100 websites identified via a Google search were assessed using the modified EQIP tool. High scoring websites underwent further analysis. Websites intended for professional use by clinicians as well as those containing video or marketing content were excluded. FINDINGS: A total of 378 websites were eligible for analysis. The median modified EQIP score for UGI endoscopy was 18/36 (interquartile range: 14-21). The median EQIP scores for the content, identification and structure domains were 8/18, 1/6 and 9/12 respectively. Higher modified EQIP scores were obtained for websites produced by government departments and National Health Service hospitals (p=0.007). Complication rates were documented in only a fifth (20.4%) of websites. High scoring websites were significantly more likely to provide balanced information on risks and benefits (94.6% vs 34.4%, p<0.001). CONCLUSIONS: There is an immediate need to improve the quality of online patient information regarding UGI endoscopy. The currently available resources provide minimal information on the risks associated with the procedure, potentially hindering patients' ability to make informed healthcare decisions.

8.
Ann Oncol ; 24(2): 463-468, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23059959

RESUMO

BACKGROUND: The purpose of this study is to characterize the risk factors of bloodstream infection (BSI) associated with the use of permanent implantable venous ports (Port-A) in solid cancer patients. METHODS: Solid cancer patients implanted with a Port-A were prospectively observed for the occurrence of Port-A-associated BSI (PABSI), defined as BSI without other identifiable infection foci. A PABSI risk score was developed using the Cox proportional hazards model. RESULTS: A total of 415 patients were registered; 88 PABSI episodes occurred in 58 patients (incidence1.05 per 1000 catheter-days). All but one patient had stage IV cancer. Independent predictors of PABSI occurrence included neutropenia, total parenteral nutrition (TPN), chronic steroid use, invasive procedures, postoperative antibiotics, and preoperative antibiotics. A PABSI risk score with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%) was defined for stage IV cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, -0.970; postoperative antibiotics, +0.959; and invasive procedures, +1.098. The median PABSI-free survival was 4.47 months for patients with scores ≥ 0 but not reached for patients with scores <0 (P < 0.0001). CONCLUSION: The PABSI risk score can assist in identifying high-risk solid cancer patients and may assist in designing future preventive strategies.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Nutrição Parenteral Total/efeitos adversos , Sepse/mortalidade , Dispositivos de Acesso Vascular/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neutropenia , Modelos de Riscos Proporcionais , Risco , Sepse/epidemiologia , Sepse/microbiologia , Sobrevida , Adulto Jovem
9.
Eur J Neurol ; 20(4): 616-22, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22672698

RESUMO

BACKGROUND AND PURPOSE: To investigate the risk of stroke development following a diagnosis of Bell's palsy in a nationwide follow-up study. METHODS AND MATERIALS: Information on Bell's palsy and other factors relevant for stroke was obtained for 433218 eligible subjects without previous stroke who had ambulatory visit in 2004. Of those, 897 patients with Bell's palsy were identified. Over a median 2.9 years of follow-up, 4581 incident strokes were identified. We estimated hazard ratios (HR) and 95% confidence intervals [CI] with Cox proportional hazard models adjusting for age, sex, co-morbidities, and important risk factors. Standardized incidence ratio of stroke amongst patients with Bell's palsy was analyzed. RESULTS: Compared with non-Bell's palsy patients, patients with Bell's palsy had a 2.02-times (95% CI, 1.42-2.86) higher risk of stroke. The adjusted HR of developing stroke for patients with Bell's palsy treated with and without systemic steroid were 1.67 (95% CI, 0.69-4) and 2.10 (95%, 1.40-3.07), respectively. CONCLUSIONS: Patients with Bell's palsy carry a higher risk of stroke than the general population. Our data suggest that these patients might benefit from a more intensive stroke prevention therapy and regular follow-up after initial diagnosis.


Assuntos
Paralisia de Bell/complicações , Paralisia de Bell/tratamento farmacológico , Esteroides/uso terapêutico , Acidente Vascular Cerebral/complicações , Adulto , Paralisia de Bell/epidemiologia , Diabetes Mellitus/epidemiologia , Determinação de Ponto Final , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Classificação Internacional de Doenças , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Programas Nacionais de Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Risco , Fatores Sexuais , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Taiwan/epidemiologia
10.
J Clin Pharm Ther ; 38(2): 172-4, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23173909

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Myocarditis that develops because of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disease. We report a case of DRESS-associated myocarditis with cardiac failure that required extracorporeal membrane oxygenation (ECMO) for cardiovascular support. CASE SUMMARY: A 14-year-old boy experienced DRESS-associated myocarditis after anticonvulsive therapy with carbamazepine, clonazepam and phenytoin. The clinical signs included hypotension, cardiac arrhythmia and poor left ventricular (LV) performance. Laboratory investigations showed elevated levels of cardiac enzymes. Systemic corticosteroid pulse therapy for 3 days was administered for treating the DRESS syndrome. The patient required inotropic drugs including dopamine, dobutamine and milrinone because of refractory hypotension and poor LV function. He was placed on ECMO support, and intra-aortic balloon pumping was initiated because of poor response to inotropic drugs and stasis of blood flow in the ventricle on hospital day 17. Plasma exchanges for four separate times over 8 days were also performed during ECMO support on day 22. His condition stabilized 13 days after ECMO support was initiated. The patient was discharged on hospital day 50, and the seizure was controlled by the oral form clonazepam, phenobarbital, topiramate and levetiracetam. Three months later, an echocardiogram showed mild dilated cardiomyopathy. WHAT IS NEW AND CONCLUSION: Drug reaction with eosinophilia and systemic symptoms-associated fulminant myocarditis is a life-threatening disease. Traditionally, systemic corticosteroid administration, plasmapheresis, intravenous immunoglobulin infusion and ventricular assist device implantation have been used for the treatment of this disease. To our knowledge, this is the first case of DRESS-associated fulminant myocarditis treated successfully with ECMO support. However, echocardiogram should be followed regularly because dilated cardiomyopathy may be the late sequela.


Assuntos
Anticonvulsivantes/efeitos adversos , Eosinofilia/tratamento farmacológico , Miocardite/etiologia , Adolescente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Oxigenação por Membrana Extracorpórea/métodos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/terapia , Humanos , Masculino , Miocardite/sangue , Miocardite/induzido quimicamente , Miocardite/terapia
11.
Nat Genet ; 26(1): 64-6, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10973250

RESUMO

A major obstacle to stem-cell gene therapy rests in the inability to deliver a gene into a therapeutically relevant fraction of stem cells. One way to circumvent this obstacle is to use selection. Vectors containing two linked genes serve as the basis for selection, with one gene encoding a selectable product and the other, a therapeutic protein. Applying selection in vivo has the potential to bring a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically modified cells to be inducibly amplified, thereby averting the risks associated with cytotoxic drugs. This system provides a general platform for conditionally expanding genetically modified cell populations in vivo, and may have widespread applications in gene and cell therapy.


Assuntos
Separação Celular , Terapia Genética/métodos , Vetores Genéticos , Proteínas de Neoplasias , Receptores de Citocinas , Animais , Plaquetas/citologia , Plaquetas/metabolismo , Southern Blotting , Transplante de Medula Óssea , Técnicas de Cultura de Células/métodos , Dimerização , Relação Dose-Resposta a Droga , Eritrócitos/citologia , Eritrócitos/metabolismo , Citometria de Fluxo , Granulócitos/citologia , Granulócitos/metabolismo , Proteínas de Fluorescência Verde , Cinética , Proteínas Luminescentes/metabolismo , Camundongos , Proteínas Oncogênicas/química , Proteínas Oncogênicas/metabolismo , Fenótipo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-kit , Receptores da Eritropoetina/química , Receptores da Eritropoetina/metabolismo , Receptores de Trombopoetina , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Retroviridae/genética , Fatores de Tempo , Transgenes
12.
Ann R Coll Surg Engl ; 104(4): 242-248, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34931532

RESUMO

BACKGROUND: Online resources are a fundamental source of healthcare information due to the increasing popularity of the internet. Ensuring accuracy and reliability of websites is crucial to improving patient education and enhancing patient outcomes. Inguinal hernia repair is the most commonly performed general surgical procedure worldwide. This study analyses the quality of online patient information about inguinal hernia repair using the Modified Ensuring Quality Information for Patients (EQIP) tool. METHODS: A systematic review of online information on inguinal hernia repair was conducted using four search terms: 'inguinal hernia', 'groin hernia', 'inguinal hernia repair' and 'inguinoscrotal hernia'. The top 100 websites for each term identified using Google were assessed using the modified EQIP tool (score 0-36). Websites for the paediatric population or intended for medical professional use were excluded from analysis. FINDINGS: A total of 142 websites were eligible for analysis, 52.8% originating from the UK. The median EQIP score for all websites was 17/36 (interquartile range 14-21). The median EQIP scores for content, identification and structure were 8/18, 2/8 and 8/12, respectively. Complications of inguinal hernia repair were included in 46.5% of websites, with only 9.2% providing complication rates and 14.1% providing information on how complications are handled. CONCLUSION: This study highlights that the current quality of online patient information on inguinal hernia repair is poor, with minimal information available on complications, hindering patients' ability to make informed decisions regarding their healthcare. To improve patient education, there is an immediate need for improved quality online resources to meet international standards.


Assuntos
Hérnia Inguinal , Criança , Hérnia Inguinal/cirurgia , Herniorrafia/métodos , Humanos , Reprodutibilidade dos Testes
13.
BMC Microbiol ; 11: 217, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21961456

RESUMO

BACKGROUND: Polymerase chain reaction (PCR) ribotyping is one of the globally accepted techniques for defining epidemic clones of Clostridium difficile and tracing virulence-related strains. However, the ambiguous data generated by this technique makes it difficult to compare data attained from different laboratories; therefore, a portable technique that could supersede or supplement PCR ribotyping should be developed. The current study attempted to use a new multilocus variable-number tandem-repeat analysis (MLVA) panel to detect PCR-ribotype groups. In addition, various MLVA panels using different numbers of variable-number tandem-repeat (VNTR) loci were evaluated for their power to discriminate C. difficile clinical isolates. RESULTS: At first, 40 VNTR loci from the C. difficile genome were used to screen for the most suitable MLVA panel. MLVA and PCR ribotyping were implemented to identify 142 C. difficile isolates. Groupings of serial MLVA panels with different allelic diversity were compared with 47 PCR-ribotype groups. A MLVA panel using ten VNTR loci with limited allelic diversity (0.54-0.83), designated MLVA10, generated groups highly congruent (98%) with the PCR-ribotype groups. For comparison of discriminatory power, a MLVA panel using only four highly variable VNTR loci (allelic diversity: 0.94-0.96), designated MLVA4, was found to be the simplest MLVA panel that retained high discriminatory power. The MLVA10 and MLVA4 were combined and used to detect genetically closely related C. difficile strains. CONCLUSIONS: For the epidemiological investigations of C. difficile, we recommend that MLVA10 be used in coordination with the PCR-ribotype groups to detect epidemic clones, and that the MLVA4 could be used to detect outbreak strains. MLVA10 and MLVA4 could be combined in four multiplex PCR reactions to save time and obtain distinguishable data.


Assuntos
Clostridioides difficile/genética , Clostridioides difficile/isolamento & purificação , Enterocolite Pseudomembranosa/microbiologia , Repetições Minissatélites , Reação em Cadeia da Polimerase/métodos , Ribotipagem/métodos , Clostridioides difficile/classificação , Humanos , Filogenia
14.
Curr Opin Cell Biol ; 9(5): 707-13, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9330875

RESUMO

Mechanical stresses are important environmental cues for both normal cellular functions and pathophysiological changes in conditions such as cardiac hypertrophy and atherosclerosis. There is increasing evidence that mechanotransduction processes in response to mechanical stresses share many common features with processes in cell adhesion, such as an increase in tyrosine phosphorylation of proteins in the focal adhesion sites. Recent findings suggest that integrins may function as mechanotransducers in cells.


Assuntos
Adesão Celular/fisiologia , Integrinas/fisiologia , Estresse Mecânico , Animais , Humanos , Transdução de Sinais/fisiologia
15.
Diabetes Obes Metab ; 13(7): 669-72, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21457428

RESUMO

Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the renal threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Glicosúria/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/farmacologia , Adolescente , Adulto , Canagliflozina , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Glucosídeos/uso terapêutico , Glicosúria/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Tiofenos/uso terapêutico , Adulto Jovem
16.
Gene Ther ; 17(10): 1244-52, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20485382

RESUMO

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética/métodos , Lentivirus/genética , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Anemia de Fanconi/patologia , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Mitomicina/farmacologia , Transdução Genética
17.
J Exp Med ; 181(2): 463-73, 1995 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-7836905

RESUMO

The csk gene encodes a nonreceptor protein tyrosine kinase that acts in part by regulating the activity of src-family protein tyrosine kinases. Since the src-family kinases p56lck and p59fyn play pivotal roles during lymphocyte development, it seemed plausible that p50csk might contribute to these regulatory circuits. Using a gene targeting approach, mouse embryonic stem cell lines lacking functional csk genes were generated. These csknull embryonic stem cells proved capable of contributing to many adult tissues, notably heart and brain. However, although csknull progenitors colonized the developing thymus, T and B cell differentiation were both blocked at very early stages. This represented a relatively selective interdiction of lymphocyte maturation, since csknull hematopoietic progenitors supported the development of normal-appearing MAC-1+ blood leukocytes, and the successful maturation of granulocyte/macrophage-colony-forming units from fetal liver progenitors. We conclude that p50csk regulates normal lymphocyte differentiation, but that it almost certainly does so by acting on targets other than p56lck and p59fyn.


Assuntos
Linfócitos B/citologia , Proteínas de Ligação a DNA , Hematopoese/fisiologia , Proteínas Tirosina Quinases/fisiologia , Linfócitos T/citologia , Quinases da Família src , Alelos , Animais , Sequência de Bases , Proteína Tirosina Quinase CSK , Quimera , Células Clonais , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Proteínas/genética , Timo/citologia
18.
J Exp Med ; 182(3): 811-20, 1995 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-7650487

RESUMO

Previous studies implicate the nonreceptor protein tyrosine kinase (PTK) p59fyn in the propagation of signals from the B cell antigen receptor. To elucidate the functions of this kinase, we examined B cell responsiveness in mice engineered to lack the hematopoietic isoform of p59fyn. Remarkably, antigen receptor signaling was only modestly defective in fynTnull B cells. In contrast, signaling from the interleukin (IL)-5 receptor which ordinarily provides a comitogenic stimulus with antiimmunoglobulin, was completely blocked. Our results document the importance of p59fynT in IL-5 responses in B cells, and they support a general model for cytokine receptor signal transduction involving the simultaneous recruitment of at least three families of PTK.


Assuntos
Linfócitos B/imunologia , Interleucina-5/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores de Antígenos de Linfócitos B/fisiologia , Receptores de Interleucina/fisiologia , Transdução de Sinais/fisiologia , Animais , Antígenos/imunologia , Antígenos T-Independentes/imunologia , Linfócitos B/enzimologia , Feminino , Imunização , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fyn , Receptores de Interleucina/genética , Receptores de Interleucina-5
19.
Sci Rep ; 10(1): 21758, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303895

RESUMO

This study aimed to develop biodegradable calcium alginate microcarriers with uniform particle size and spherical integrity for sustained-release targeting transarterial chemoembolization. To determine related parameters including the ratio of cross-linking volume (sodium alginate: CaCl2), concentrations of sodium alginate and CaCl2 solutions, collection distance, flow rate, stirring speed, syringe needle diameter and hardening time to fabricate the microcarriers, the Taguchi method was applied. Using different conditions, a total of 18 groups were prepared. The average size of microspheres from different groups was estimated as ~ 2 mm (range 1.1 to 1.6 mm). Signal-to-noise ratio analysis showed the optimal spherical integrity (F1) achieved when the above parameters were designed as 0.1, 2.5 wt%, 6 wt%, 8 cm, 30 mL/h, 150 rpm, 0.25 mm and 2 h, respectively. The best (F1), middle (F2) and worst (F3) groups were used for further experiments. Fourier-transform infrared spectroscopy spectrum showed that F1, F2 and F3 conformations were distinct from original sodium alginate. Drug-loaded calcium alginate microcarriers demonstrated rougher surfaces compared to microspheres without drug under transmission electron microscopy. Compared to pH 7.4, swelling rates in PBS were decreased at pH 6.5. Encapsulation and loaded efficiencies of the Dox-loaded microcarriers were estimated as ~ 40.617% and ~ 3.517%. In vitro experiments indicated that the F1 Dox-loaded microcarriers provide a well sustained-release efficacy for about two weeks at 37 °C in PBS. Treatments of calcium alginate microcarriers without the Dox in two distinct hepatocellular carcinoma-derived cell lines, Huh-7 and Hep-3B, indicated that these microcarriers were non-toxic. The Dox-loaded microcarriers displayed sustained-release capacity and reduced cell viabilities to ~ 30% in both cell lines on Day 12.


Assuntos
Alginatos , Cápsulas , Quimioembolização Terapêutica/métodos , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Microesferas , Alginatos/farmacologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Tamanho da Partícula
20.
J Cell Biol ; 101(2): 646-51, 1985 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-4019586

RESUMO

The interactions of human genotype AO erythrocytes (red blood cells) (RBCs) with N-acetylgalactosamine-reactive lectins isolated from Helix pomatia (HPA) and from Dolichos biflorus (DBA) were studied. Binding curves obtained with the use of tritium-labeled lectins showed that the maximal numbers of lectin molecules capable of binding to human genotype AO RBCs were 3.8 X 10(5) and 2.7 X 10(5) molecules/RBC for HPA and DBA, respectively. The binding of one type of lectin may influence the binding of another type. HPA was found to inhibit the binding of DBA, but not vice versa. The binding of HPA was weakly inhibited by a beta-D-galactose-reactive lectin isolated from Ricinus communis (designated RCA1). Limulus polyphemus lectin (LPA), with specificity for N-acetylneuraminic acid, did not influence the binding of HPA but enhanced the binding of DBA. About 80% of LPA receptors (N-acetylneuraminic acid) were removed from RBC surfaces by neuraminidase treatment. Neuraminidase treatment of RBCs resulted in increases of binding of both HPA and DBA, but through different mechanisms. An equal number (7.6 X 10(5) of new HPA sites were generated on genotypes AO and OO RBCs by neuraminidase treatment, and these new sites accounted for the enhancement (AO cells) and appearance (OO cells) of hemagglutinability by HPA. Neuraminidase treatment did not generate new DBA sites, but increased the DBA affinity for the existing receptors; as a result, genotype AO cells increased their hemagglutinability by DBA, while OO cells remained unagglutinable. The use of RBCs of different genotypes in binding assays with 3H-labeled lectins of known specificities provides an experimental system for studying cell-cell recognition and association.


Assuntos
Comunicação Celular , Membrana Eritrocítica/metabolismo , Lectinas/farmacologia , Lectinas de Plantas , Receptores Mitogênicos/efeitos dos fármacos , Sistema ABO de Grupos Sanguíneos/genética , Sítios de Ligação/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Membrana Eritrocítica/fisiologia , Caracois Helix/metabolismo , Testes de Hemaglutinação , Caranguejos Ferradura/metabolismo , Humanos , Lectinas/metabolismo , Neuraminidase/farmacologia , Receptores Mitogênicos/análise
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