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1.
Obes Surg ; 34(1): 150-162, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37991711

RESUMO

BACKGROUND: Poor weight loss and weight regain are principal challenges following laparoscopic sleeve gastrectomy (LSG). There is a lack of standardised assessments and diagnostic tests to stratify the status post-LSG and determine whether anatomical or physiological problem exists. We aimed to compare nuclear scintigraphy gastric emptying with CT volumetric analysis of sleeve anatomy and determine the impact of anatomy on physiological function and its correlation with weight loss. MATERIALS AND METHODS: Patients greater than 12 months post-LSG were categorised into optimal weight loss (OWL) (n = 29) and poor weight loss groups (PWL) (n = 50). All patients underwent a protocolised nuclear scintigraphy and three-dimensional multi-detector computed tomography (3D-MDCT) gastric volumetry imaging. RESULTS: Post-operative % total weight loss in OWL was 26.2 ± 10.5% vs. 14.2 ± 10.7% in the PWL group (p value < 0.0001). The PWL group had significantly more delayed gastric emptying half-time than OWL (34.1 ± 18.8 vs. 19.5 ± 4.7, p value < 0.0001). Gastric emptying half-time showed statistically significant correlations with weight loss parameters (BMI; r = 0.215, p value 0.048, %EWL; r = - 0.336, p value 0.002 and %TWL; r = - 0.379, p value < 0.001). The median gastric volume on 3D-MDCT did not differ between the OWL (246 (IQR 50) ml) and PWL group (262 (IQR 129.5) ml), p value 0.515. Nuclear scintigraphy gastric emptying half-time was the most highly discriminant measure. A threshold of 21.2 min distinguished OWL from PWL patients with 86.4% sensitivity and 68.4% specificity. CONCLUSION: Nuclear scintigraphy is a potentially highly accurate tool in the functional assessment of sleeve gastrectomy physiology. It appears to perform better as a diagnostic test than volumetric assessment. Gastric volume did not correlate with weight loss outcomes. We have established diagnostic criteria of greater than 21 min to assess sleeve failure, which is linked to suboptimal weight loss outcomes.


Assuntos
Laparoscopia , Obesidade Mórbida , Humanos , Esvaziamento Gástrico , Obesidade Mórbida/cirurgia , Laparoscopia/métodos , Gastrectomia/métodos , Redução de Peso/fisiologia , Tomografia Computadorizada por Raios X , Cintilografia , Tomografia , Resultado do Tratamento , Estudos Retrospectivos
2.
Artigo em Inglês | MEDLINE | ID: mdl-37549431

RESUMO

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2023;25(4):22f03471. Author affiliations are listed at the end of this article.


Assuntos
Catatonia , Transtornos Mentais , Psiquiatria , Trombose dos Seios Intracranianos , Humanos , Catatonia/diagnóstico , Catatonia/terapia , Comorbidade , Trombose dos Seios Intracranianos/complicações , Trombose dos Seios Intracranianos/diagnóstico , Trombose dos Seios Intracranianos/terapia , Encaminhamento e Consulta , Hospitais Gerais
3.
Ther Adv Urol ; 14: 17562872221139109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36504599

RESUMO

Introduction: One of the most challenging aspects of inflatable penile prosthesis (IPP) surgery is reservoir placement. The traditional space of Retzius (SOR) is not suitable for all patients. For example, radical cystectomy or prostatectomy may alter the anatomical SOR. Hence, traditional placement of the reservoir in this space increases the risk of bowel or vascular injury. Also, patients with bilateral inguinal hernias repaired with mesh, or those with previous reservoirs that have been retained, are not eligible for a Retzius reservoir. Our study reports on the use of midline sub-rectus muscle placement of a penile prosthesis reservoir in these patients as an alternative to high submuscular placement commonly used. Methods: A retrospective chart review of male patients who underwent IPP surgery between June 2017 and 2021 was conducted. Patients were divided into two groups based on the location of the reservoir: SOR versus Midline Submuscular Reservoir (MSMR). Complication rates were compared, including herniated reservoirs, infections, bowel injuries, and vascular injuries. Results: Our cohort included 461 patients who underwent IPP surgery between June 2017 and 2021 in one tertiary center. SOR was used in 89% of patients and MSMR in 11% of patients (n = 413 and 48, respectively). Median follow-up for all patients was 28 months. The mean age was 67 ± 8 years. There was no statistically significant difference between the two groups regarding age or comorbidities (BMI, diabetes mellitus, hypertension, hyperlipidemia, and coronary artery disease). The complication rate was low in both the SOR and MSMR groups, with device malfunction being the most common (2% versus 4%, respectively; p = 0.32). The infection rate was 0.5% in the SOR group with no infections in the MSMR group (NS). There was only one case of herniation requiring surgical revision in the SOR group and no cases of bowel or vascular injury. Conclusion: Placement of a penile prosthesis reservoir within a midline rectus submuscular space is a safe and effective technique when the SOR is compromised by previous surgery or bilateral inguinal canals are not accessible.

4.
Urol Oncol ; 40(2): 60.e11-60.e16, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34334292

RESUMO

OBJECTIVE: To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance. METHODS: We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy. RESULTS: Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence. CONCLUSIONS: The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.


Assuntos
Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Gradação de Tumores , Prognóstico , Estudos Retrospectivos
5.
Front Immunol ; 12: 686439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616392

RESUMO

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-ζ signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.


Assuntos
Anticorpos/metabolismo , Antígeno HLA-A2/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T Reguladores/transplante , Tolerância ao Transplante , Animais , Engenharia Celular , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Imunoterapia Adotiva , Masculino , Camundongos , Camundongos Endogâmicos NOD , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
6.
Front Immunol ; 12: 639818, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833759

RESUMO

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG4) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG4-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.


Assuntos
Antígenos CD28/imunologia , Domínios Proteicos/imunologia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/imunologia , Dimerização , Humanos , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
7.
World J Urol ; 39(9): 3685-3690, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33398426

RESUMO

PURPOSE: To investigate the parameters of renal trauma, including emergent intervention type, that predict the mortality of patients with traumatic renal injury. METHODS: A retrospective database analysis was performed on patients who sustained a traumatic renal parenchymal injury identified by the 2017 National Trauma Data Bank. Data were analyzed to identify differences in hospital length of stay, ER and hospital disposition, and mortality based on patient age, gender, race, Injury Severity Score, renal injury grade, and need for emergent intervention (angioembolization versus open surgery). Logistic regression was used to correlate intervention type and trauma parameters to mortality. RESULTS: A total of 4,876 of 1,004,440 trauma patients (0.49%) had a traumatic renal injury. Of those, 220 (4.5%) underwent an emergent intervention-29 (0.59%) angioembolization and 191 (3.9%) open renal surgery. 83 patients with a blunt renal trauma (2.0%) underwent renal intervention, whereas 136 (21.0%) with a penetrating injury required a procedure. Forty-five of the 220 patients (20.5%) who had a renal intervention died, while 377 of 4,656 (8.1%) who did not have an intervention died. Multiple logistic regression identified black race, age > 45 years, penetrating trauma, and ISS > 15 to be independent predictors of mortality. Neither angioembolization nor open renal surgery was associated with a significantly higher likelihood of mortality in the multivariable model. CONCLUSION: While procedural interventions are associated with higher mortality for patients with traumatic renal injury, other factors, such as race, age, trauma type, and injury severity may be more predictive of death under care.


Assuntos
Rim/lesões , Ferimentos não Penetrantes/mortalidade , Ferimentos Penetrantes/mortalidade , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
Cells ; 8(8)2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426448

RESUMO

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Doença de Parkinson , Polifenóis/farmacologia , Animais , Dopamina/análogos & derivados , Dopamina/toxicidade , Drosophila , Células HEK293 , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Extratos Vegetais , Chá
9.
J Bronchology Interv Pulmonol ; 26(4): 290-292, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31107295

RESUMO

Malignant pleural effusions' (MPEs) treatment goals focus on optimizing the quality of life and decreasing time spent in health care facilities in this patient population with limited life expectancy. Numerous pleural palliation options and combination of these exist and continue to undergo studies to identify safe, superior and ideally patient-centered care. We report a cohort of 13 patients with symptomatic MPE managed with iodopovidone intrapleural instillation via an indwelling pleural catheter (IPC) in the ambulatory setting. Successful complete pleurodesis was achieved in 10 of 13 (76.9%) patients at a median time of 5 days with IPC removal at a median of 16 days. Two patient obtained partial pleurodesis with IPC removal, 1 required IPC reinsertion due to symptom recurrence. Complications were limited to intraprocedural pain in 4 patients (31%). Iodopovidone pleurodesis via IPC may represent a safe, feasible, and effective ambulatory-based option for pleural palliation in MPE.


Assuntos
Derrame Pleural Maligno/terapia , Pleurodese/métodos , Povidona-Iodo/administração & dosagem , Soluções Esclerosantes/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/métodos , Cateteres de Demora , Drenagem , Feminino , Humanos , Instilação de Medicamentos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Qualidade de Vida
10.
Curr Opin Chem Biol ; 40: 57-64, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28628856

RESUMO

The recent expansion of molecular tool kits has propelled synthetic biology toward the design of increasingly sophisticated mammalian systems. Specifically, advances in genome editing, protein engineering, and circuitry design have enabled the programming of cells for diverse applications, including regenerative medicine and cancer immunotherapy. The ease with which molecular and cellular interactions can be harnessed promises to yield novel approaches to elucidate genetic interactions, program cellular functions, and design therapeutic interventions. Here, we review recent advancements in the development of enabling technologies and the practical applications of mammalian synthetic biology.


Assuntos
Edição de Genes/métodos , Medicina de Precisão/métodos , Biologia Sintética/métodos , Animais , Sistemas CRISPR-Cas , Terapia Baseada em Transplante de Células e Tecidos/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Engenharia Genética/métodos , Humanos , Imunoterapia/métodos
11.
ACS Synth Biol ; 6(8): 1484-1495, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28510446

RESUMO

Targeted therapies promise to increase the safety and efficacy of treatments against diseases ranging from cancer to viral infections. However, the vast majority of targeted therapeutics relies on the recognition of extracellular biomarkers, which are rarely restricted to diseased cells and are thus prone to severe and sometimes-fatal off-target toxicities. In contrast, intracellular antigens present a diverse yet underutilized repertoire of disease markers. Here, we report a protein-based therapeutic platform-termed Cytoplasmic Oncoprotein VErifier and Response Trigger (COVERT)-which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. We demonstrate that fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. We further demonstrate the rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp), highlighting the COVERT platform's modularity and adaptability to diverse protease targets. As an initial step toward engineering COVERT-T cells for adoptive T-cell therapy, we verified that primary human T cells can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. Our findings set the foundation for future intracellular-antigen-responsive therapeutics that can complement surface-targeted therapies.


Assuntos
Técnicas de Química Sintética/métodos , Granzimas/síntese química , Granzimas/imunologia , Terapia de Alvo Molecular/métodos , Peptídeo Hidrolases/imunologia , Engenharia de Proteínas/métodos , Proteínas Recombinantes de Fusão/imunologia , Granzimas/genética , Células HEK293 , Humanos , Peptídeo Hidrolases/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética
12.
J Paediatr Child Health ; 48(2): 99-102, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22320270

RESUMO

It is known that the refugee population in Australia is at risk of tuberculosis (TB) and children with TB infection can develop active disease with devastating consequence. Currently, in New South Wales (NSW) and possibly other Australian States and Territories, there are different and complex health-screening pathways for newly arrived refugees. This is compounded by various factors, such as social and language difficulties for refugees to access healthcare and limited pre-embarkation screening. In this Viewpoint article, we present a child refugee in Australia with TB and use this case to reason why a universal post-arrival health screening programme should be established.


Assuntos
Programas de Rastreamento , Refugiados , Tuberculose/diagnóstico , Austrália , Criança , Pré-Escolar , Feminino , Humanos , Saúde Pública , Sudão/etnologia
13.
Invest Ophthalmol Vis Sci ; 50(11): 5384-95, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19515999

RESUMO

PURPOSE: To evaluate the effect of KV11, a novel 11-mer peptide from human apolipoprotein(a), against retinal neovascularization and to study its penetration and the possible toxicity to the retina. METHODS: Wound-healing, a modified Boyden chamber, and MTS assays were used to evaluate the effect of KV11 on the migration and proliferation of bovine retinal capillary endothelial cells (BRCECs) induced by vascular endothelial growth factor (VEGF) in vitro. The antiangiogenic effect of KV11 was also studied with a mouse model of oxygen-induced retinopathy. Then, FITC-labeled KV11 was injected into the vitreous of normal rabbits, the retinal penetration was determined by confocal laser-scanning microscope, and further confirmed by UPLC/MS analysis of KV11 in tissue extracts. Electrophysiological tests and histologic examinations were used to study the possible toxicity of KV11 against rabbit neuroretina after intravitreal administration. RESULTS: KV11 inhibited VEGF-induced BRCEC migration but not proliferation and reduced the pathologic neovascularization in a mouse model, without affecting normal retinal vasculature. FITC-labeled KV11 appeared in the retina within 30 minutes after injection and diffused to all layers 3 hours later. The transfer of KV11 from the vitreous to the retina was confirmed by UPLC/MS data. Electrophysiologic tests and histologic examinations revealed no evident functional or morphologic abnormalities in rabbit neuroretina after KV11 injection. CONCLUSIONS: It is concluded that the novel peptide KV11 is an effective inhibitor of retinal pathologic angiogenesis with a sufficient retinal penetration and a favorable safety profile and may provide a promising alternative for ocular antiangiogenic therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Apolipoproteínas A/farmacologia , Fragmentos de Peptídeos/farmacologia , Neovascularização Retiniana/prevenção & controle , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/toxicidade , Animais , Apolipoproteínas A/síntese química , Apolipoproteínas A/farmacocinética , Apolipoproteínas A/toxicidade , Bovinos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/citologia , Feminino , Injeções , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Oxigênio/toxicidade , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/toxicidade , Coelhos , Retina/efeitos dos fármacos , Retina/metabolismo , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/metabolismo , Vasos Retinianos/citologia , Corpo Vítreo/metabolismo , Cicatrização/efeitos dos fármacos
14.
Diabetes ; 58(4): 954-64, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19188429

RESUMO

OBJECTIVE: This study aimed to verify whether the decreased vascular endothelial growth factor (VEGF)-to-pigment epithelium-derived factor (PEDF) ratio can serve as an indicator for the protective effect of angiotensin-converting enzyme inhibitors (ACEIs) on diabetic retinopathy (DR) and to investigate the role of mitochondrial reactive oxygen species (ROS) in the downregulated VEGF-to-PEDF ratio. RESEARCH DESIGN AND METHODS: Diabetic rats and control animals were randomly assigned to receive perindopril or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without perindopril. VEGF, PEDF, PPARgamma, and uncoupling protein-2 (UCP-2) in the rat retinas or BREC extracts were examined by Western blotting and real-time RT-PCR. The levels of VEGF and PEDF in cell culture media were examined by ELISA. Mitochondrial membrane potential (Deltapsim) and ROS production were assayed using JC-1 or CM-H2DCFDA. RESULTS: The VEGF-to-PEDF ratio was increased in the retina of diabetic rats; perindopril lowered the increased VEGF-to-PEDF ratio in diabetic rats and ameliorated the retinal damage. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF-to-PEDF ratio by reducing mitochondrial ROS. We found the decreased ROS production was a result of perindopril-induced upregulation of PPARgamma and UCP-2 expression and the subsequent decrease of Deltapsim. CONCLUSIONS: It is concluded that the protective effect of ACEI on DR is associated with a decreased VEGF-to-PEDF ratio, which involves the mitochondria-ROS pathway through PPARgamma-mediated changes of UCP-2. This study paves a way for future application of ACEI in treatment of DR.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Retinopatia Diabética/prevenção & controle , Proteínas do Olho/fisiologia , Mitocôndrias/fisiologia , Fatores de Crescimento Neural/fisiologia , Perindopril/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Serpinas/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Bovinos , Diabetes Mellitus Experimental/fisiopatologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Proteínas do Olho/genética , Glucose/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Membranas Mitocondriais/fisiologia , Fatores de Crescimento Neural/genética , Perindopril/farmacologia , Ratos , Ratos Sprague-Dawley , Vasos Retinianos/citologia , Vasos Retinianos/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serpinas/genética , Sobreviventes , Fator A de Crescimento do Endotélio Vascular/genética
15.
BMC Med Genomics ; 1: 54, 2008 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-18950519

RESUMO

BACKGROUND: Overall gastric cancer survival remains poor mainly because there are no reliable methods for identifying highly curable early stage disease. Multi-protein profiling of gastric fluids, obtained from the anatomic site of pathology, could reveal diagnostic proteomic fingerprints. METHODS: Protein profiles were generated from gastric fluid samples of 19 gastric cancer and 36 benign gastritides patients undergoing elective, clinically-indicated gastroscopy using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry on multiple ProteinChip arrays. Proteomic features were compared by significance analysis of microarray algorithm and two-way hierarchical clustering. A second blinded sample set (24 gastric cancers and 29 clinically benign gastritides) was used for validation. RESULTS: By significance analysyis of microarray, 60 proteomic features were up-regulated and 46 were down-regulated in gastric cancer samples (p < 0.01). Multimarker clustering showed two distinctive proteomic profiles independent of age and ethnicity. Eighteen of 19 cancer samples clustered together (sensitivity 95%) while 27/36 of non-cancer samples clustered in a second group. Nine non-cancer samples that clustered with cancer samples included 5 pre-malignant lesions (1 adenomatous polyp and 4 intestinal metaplasia). Validation using a second sample set showed the sensitivity and specificity to be 88% and 93%, respectively. Positive predictive value of the combined data was 0.80. Selected peptide sequencing identified pepsinogen C and pepsin A activation peptide as significantly down-regulated and alpha-defensin as significantly up-regulated. CONCLUSION: This simple and reproducible multimarker proteomic assay could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy for gastric cancer and pre-malignant lesions.

16.
Ophthalmologica ; 222(1): 32-6, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18097178

RESUMO

Diabetic macular edema (DME) is the major cause of vision loss in patients with diabetic retinopathy (DR). The purpose of this study was to assess the prevalence of DR and DME in a community in China and to analyze the characteristics of their optical coherence tomography (OCT) images. This study was an incidence survey based on data from 108,132 residents living in the Beixinjing District, Shanghai, China. Patients with DME came from the local health network. OCT was performed in 151 eyes of 100 type 2 diabetes patients with DR and 102 eyes of normal control subjects. Totally 795 cases were examined, and 215 of them were diagnosed to have DR. The average thickness of the macular fovea was 195.56 microm in 151 eyes from 100 random samples. Forty-six eyes had macular thickening. The statistical analysis showed that there was a positive correlation between the thickness of the macular fovea and -log of best-corrected visual acuity (r = 0.2869, p = 0.0004) as well as the severity of DR (p = 0.0003). However, there was no statistical significance between DME and posterior vitreous detachment. The images of OCT in DME included 3 types. Best-corrected visual acuity moderately correlated with retinal thickness. The macular thickness correlated with the severity of DR but not with posterior vitreous detachment.


Assuntos
Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/epidemiologia , Edema Macular/epidemiologia , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , China , Estudos Transversais , Complicações do Diabetes/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Angiofluoresceinografia , Fóvea Central/patologia , Inquéritos Epidemiológicos , Humanos , Incidência , Macula Lutea/patologia , Edema Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Retina/patologia , Fatores de Risco , Tomografia de Coerência Óptica , Ultrassonografia , Testes Visuais , Acuidade Visual/fisiologia
17.
Ophthalmologica ; 222(1): 58-61, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18097183

RESUMO

PURPOSE: To investigate the expression of nerve growth factor (NGF) and its receptor TrkA on the retina at different time points after retinal detachment (RD) and the protection effect of NGF in experimental RD. METHODS: Sprague-Dawley rats were used as an RD animal model by injection of 0.1% sodium hyaluronate under the neurosensory retina. The expression of endogenous NGF and its receptor TrkA in the rat retina was detected using immunohistochemistry. The NGF (5 mug/eye) or phosphate-buffered saline were injected separately into vitreous every 4 days after the RD. The rat eyes were then observed at various time points. Morphologic changes were investigated by light microscopy. Retinal gliosis was detected by glial fibrillary acidic protein labeling. RESULTS: The expression of endogenous NGF and TrkA was upregulated during RD procedure. Most of the NGF-treated retina had a well-organized structure. In NGF-treated RD eyes, the cells were still significantly more numerous than in phosphate-buffered-saline-treated retina. Glial fibrillary acidic protein labeling increased quickly after RD; the NGF-treated retina had less reactive gliosis than the control groups. CONCLUSIONS: Intravitreal injection of exogenous NGF can protect retinal cells from degeneration in experimental RD. It may exert its protective action by preventing the apoptosis of retinal cells after RD.


Assuntos
Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacologia , Receptor trkA/metabolismo , Descolamento Retiniano/patologia , Animais , Apoptose/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/patologia , Injeções , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Retina/efeitos dos fármacos , Retina/patologia , Degeneração Retiniana/patologia , Regulação para Cima/fisiologia , Corpo Vítreo
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