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1.
Theranostics ; 11(16): 7879-7895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335970

RESUMO

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Timosina/farmacologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , China , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco/métodos , Suínos , Timosina/metabolismo , Timosina/fisiologia
3.
Neuroradiology ; 62(12): 1553-1564, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32715357

RESUMO

PURPOSE: Hyperintense parasellar signal on time-of-flight MR angiography (TOF-MRA) in asymptomatic patients may be due to a variety of nonpathological causes and mimic parasellar high flow signal in pathological arteriovenous shunts at the cavernous sinus (CSAVS). This creates a clinical conundrum between diagnosing an aggressive yet asymptomatic CSAVS subtype against exposing patients without CSAVS to potential complications of an invasive angiographic evaluation. We reviewed common nonpathological causes of hyperintense parasellar signal and contrast their imaging features against those of pathological CSAVS and proposed a systemic approach to resolve such conundrum. METHODS: The anatomy of the cavernous sinus (CS) and causes of nonpathological parasellar hyperintense TOF-MRA signal are described and explained with case reviews, illustrations, and reference to published literature where appropriate. Imaging features of proven CSAVS are juxtaposed to aid in radiological differentiation. An algorithm is proposed to manage patients with such incidental TOF-MRA findings. RESULTS: The margins, contour, extent, intensity, and stippling appearance aid in evaluation of pathological versus incidental TOF-MRA parasellar signal, and differentiation of CSAVS from nonpathological causes. Pertinent radiological features are summarized in a table. For unresolved cases suspected for CSAVS, further evaluation with dynamic time-resolved contrast-enhanced MRA is proposed and depicted in a decision tree flow chart. CONCLUSION: Familiarity with the differentiating radiological features and a systematic management workflow could aid in resolving the clinical conundrum of findings of cryptic asymptomatic parasellar TOF-MRA high signal, while facilitating timely detection of the asymptomatic CSAVS.

4.
BMJ Case Rep ; 12(1)2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30610031

RESUMO

A 56-year-old teetotaller man with hypertension and gout presented with a week duration of painless worsening diplopia on a background of loss of weight and appetite, generalised lethargy and weakness for 1 year. On examination, he was noted to be hypothermic and tachycardic with generalised muscle wasting. Proximal myopathy, lower limb fasciculations and areflexia, restricted bilateral eye abduction and nystagmus were observed. Blood investigations demonstrated compensated lactic acidosis, acute kidney injury and leucocytosis. A nerve conduction study showed severe length-dependent axonal sensorimotor polyneuropathy. This was a diagnostic dilemma until an MRI brain revealed symmetrical signal abnormality and enhancement in the periaqueductal area indicative of Wernicke's encephalopathy, caused by thiamine deficiency from poor nutrition. Beriberi, also caused by thiamine deficiency, accounted for his tachycardia, polyneuropathy, areflexia, hypothermia and biochemical abnormalities. Both beriberi and Wernicke's encephalopathy are medical emergencies, which were treated with intravenous thiamine to good effect.


Assuntos
Beriberi/complicações , Diplopia/diagnóstico , Debilidade Muscular/diagnóstico , Tiamina/uso terapêutico , Encefalopatia de Wernicke/diagnóstico por imagem , Beriberi/diagnóstico , Diagnóstico Diferencial , Diplopia/etiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Doenças Raras , Tiamina/administração & dosagem , Deficiência de Tiamina/complicações , Resultado do Tratamento , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/uso terapêutico , Encefalopatia de Wernicke/complicações , Encefalopatia de Wernicke/patologia
5.
Sci Rep ; 8(1): 17125, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459473

RESUMO

Animal models that recapitulate the human pathophysiology have been developed as useful research tools. Although laboratory mice are widely used, they are phylogenetically "distant" to humans. New world monkeys, such as the common marmoset (Callithrix jacchus) have steadily gained prominence. In this report, marmosets are explored as an alternate in vivo model to investigate infection and immunity of Zika virus (ZIKV). Multimodal platforms, including ultrasound and magnetic resonance imaging (MRI), flow cytometry, and multiplex microbead immunoassays were established to comprehensively decipher immune responses and pathophysiological outcomes. While ZIKV-infected marmosets had detectable ZIKV RNA load in various body fluids, animals did not develop any observable lesions in their testes and brains as shown by ultrasound and MRI. Immune-phenotyping detected differences in the numbers of B cells, CD8+ T cells and HLADR+ NK cells during the first two weeks of infection. Neutralizing ZIKV-specific antibodies were elicited to high levels and targeted epitopes in the E protein. This study presents a one-stop-shop platform to study infection and pathophysiology in marmosets. While marmoset-specific research tools are being refined, the research values of these animals present them as a good model for immune-based therapies.


Assuntos
Callithrix/imunologia , Callithrix/virologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , RNA Viral/imunologia , Infecção por Zika virus/virologia
6.
Singapore Med J ; 59(12): 634-641, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30631881

RESUMO

A 68-year-old man presented with a three-week history of rapidly progressive dementia, gait ataxia and myoclonus. Subsequent electroencephalography showed periodic sharp wave complexes, and cerebrospinal fluid assay revealed the presence of a 14-3-3 protein. A probable diagnosis of sporadic Creutzfeldt-Jakob disease was made, which was further supported by magnetic resonance (MR) imaging of the brain showing asymmetric signal abnormality in the cerebral cortices and basal ganglia. The aetiology, clinical features, diagnostic criteria, various MR imaging patterns and radiologic differential diagnosis of sporadic Creutzfeldt-Jakob disease are discussed in this article.


Assuntos
Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Idoso , Encéfalo/patologia , Córtex Cerebral , Líquido Cefalorraquidiano/metabolismo , Demência/fisiopatologia , Diagnóstico Diferencial , Eletroencefalografia , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Masculino , Doenças Priônicas/fisiopatologia
8.
Hepatology ; 61(1): 227-37, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24638991

RESUMO

UNLABELLED: Both liver resection (LR) and cadaveric liver transplantation (CLT) are potentially curative treatments for patients with hepatocellular carcinoma (HCC) within the Milan criteria and with adequate liver function. Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of LR against CLT for patients with HCC within the Milan criteria using a decision analytic model. A Markov cohort model was developed to simulate a cohort of patients aged 55 years with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, undergoing LR or CLT, and followed up over their remaining life expectancy. Analysis was performed in different geographical cost settings: the USA, Switzerland and Singapore. Transition probabilities were obtained from systematic literature reviews, supplemented by databases from Singapore and the Organ Procurement and Transplantation Network (USA). Utility and cost data were obtained from open sources. LR produced 3.9 quality-adjusted life years (QALYs) while CLT had an additional 1.4 QALYs. The incremental cost-effectiveness ratio (ICER) of CLT versus LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland, and was above thresholds for cost-effectiveness in all three countries. Sensitivity analysis revealed that CLT-related 5-year cumulative survival, one-time cost of CLT, and post-LR 5-year cumulative recurrence rates were the most sensitive parameters in all cost scenarios. ICERs were reduced below threshold when CLT-related 5-year cumulative survival exceeded 84.9% and 87.6% in Singapore and the USA, respectively. For Switzerland, the ICER remained above the cost-effectiveness threshold regardless of the variations. CONCLUSION: In patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, LR is more cost-effective than CLT across three different costing scenarios: the USA, Switzerland, Singapore.


Assuntos
Carcinoma Hepatocelular/cirurgia , Técnicas de Apoio para a Decisão , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/economia , Modelos Econômicos , Carcinoma Hepatocelular/economia , Análise Custo-Benefício , Humanos , Neoplasias Hepáticas/economia , Cadeias de Markov , Pessoa de Meia-Idade , Singapura , Suíça , Estados Unidos
9.
Ann Surg ; 254(1): 108-13, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21527845

RESUMO

OBJECTIVE: To compare microvascular invasion (McVI) with parameters defined by the Milan criteria in predicting tumor recurrence and overall survival (OS) in patients with surgical resection (SR) for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Although the Milan criteria is discriminatory for selecting patients with good outcomes in liver transplantation and SR for HCC, it neither adequately predict tumor recurrence nor explain differences in survival for patients with good liver function. McVI is a strong indicator of intrahepatic metastasis in HCC, but its relative significance for predicting clinical outcomes compared to the Milan criteria is unclear. METHODS: Patients undergoing SR with curative intent from January 2000 to March 2009 at the Singapore General Hospital were followed up for long-term outcomes till January 1, 2010. They were stratified first by the Milan criteria and then by the presence of McVI and compared relative to OS. RESULTS: Altogether, 454 of the 515 patients received curative SR. There were stratified into 4 groups (Milan+, McVI-), (Milan+, McVI+), (Milan-, McVI-), and (Milan-, McVI+). All pair-wise comparisons between groups relative to OS were significant except (Milan+, McVI-) (OS, 90%, 73%, and 60% at 1, 3, and 5 years) with (Milan-, McVI-) (OS, 86%, 71%, and 61% at 1, 3, 5 years) and (Milan+, McVI+) with (Milan-, McVI+). Multivariate Cox regression analysis showed that McVI was predictive of OS, after which Milan status did not add additional discriminative information. CONCLUSIONS: McVI is a better predictor of tumor recurrence and OS than the Milan criteria after SR for HCC. Assessment of McVI should aid in patient selection for adjuvant treatments to improve outcomes after SR.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Carcinoma Hepatocelular/irrigação sanguínea , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Microvasos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Fatores de Tempo
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