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BACKGROUND: There is a critical period for visual development, conventionally considered to be the first 6 years of life. Children aged 7 years and older are significantly less responsive to amblyopia treatment. This study investigated the efficacy of binocular vision therapy in amblyopic children aged 7-10 years. METHODS: This retrospective study enrolled 36 children with unilateral amblyopia who were divided into a case group (receiving vision therapy, optical correction, and part-time patching of the weaker eye) and a control group (receiving optical correction and part-time patching of the weaker eye). Visual acuity (VA) was measured at baseline, at the 3-month, 6-month, and 9-month visits, and 3 months after cessation of treatment. RESULTS: There were 19 subjects in the case group and 17 subjects in the control group. Mean VA in the case group improved from 0.39 ± 0.24 logMAR at baseline to 0.10 ± 0.23 logMAR at the endpoint of treatment (p < 0.001, paired t-test). Mean VA in the control group improved from 0.64 ± 0.30 logMAR at baseline to 0.52 ± 0.27 logMAR at the endpoint of treatment (p = 0.015, paired t-test). The improvement was significantly greater in the case group than in the control group (p = 0.006, two-samples independent t-test). All subjects underwent follow-up examinations within 6 to 12 months. There was no regression of VA in the case group 3 months after cessation of vision therapy. The patients in the case group who received visual therapy were with better VA improvement then patients with only optic correction and patching. CONCLUSIONS: Vision therapy combined with conventional treatment (optical correction and part-time patching) is more effective than conventional treatment alone in children aged 7-10 years with unilateral refractive amblyopia. The treatment results not only in greater vision gain, but also in shorter duration of treatment.
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Ambliopia , Ambliopia/terapia , Criança , Humanos , Estudos Retrospectivos , Privação Sensorial , Visão Binocular , Acuidade VisualRESUMO
BACKGROUND: This study aimed to investigate the association between early-onset cataract and tinnitus using a population-based database. METHODS: Retrospective claims data from the Taiwan National Health Insurance Research Database were analysed. Study subjects comprised patients with early-onset cataract, aged 20-55 years and diagnosed between 2000 and 2010 (n = 2084) and a comparison cohort without the disease (n = 8336). Both cohorts were followed until 2010 to estimate the incidence of tinnitus. To calculate the risk of tinnitus in the case and control groups, Cox proportional hazards models were used and presented as hazard ratios (HRs), adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS: Patients with early-onset cataract had 1.53-fold increased risk (HR = 1.53, 95% CI = 1.17-2.01, p < 0.01) of developing tinnitus than controls. The number of patients with vertigo (p < 0.0001), insomnia (p < 0.0001), anxiety (p < 0.0001) and hearing loss (p < 0.0001) as comorbidities was also significantly higher in the case group. After adjusting for age, sex and all listed comorbidities, patients with increasing age (aHR = 1.04, 95% CI = 1.02-1.07), early-onset cataract (aHR = 1.32, 95% CI = 1.01-1.74), vertigo (aHR = 1.75, 95% CI = 1.15-2.67), insomnia (aHR = 1.48, 95% CI = 1.14-1.93) and hearing loss (aHR = 6.20, 95% CI = 3.58-10.70) had significantly higher risk of tinnitus. CONCLUSIONS: Patients with early-onset cataract are at an increased risk of developing tinnitus in subsequent years and should receive further evaluation for early diagnosis and management if any signs of tinnitus occur.
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Catarata/complicações , Vigilância da População , Zumbido/epidemiologia , Adulto , Idade de Início , Estudos de Casos e Controles , Catarata/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Zumbido/etiologiaRESUMO
Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin's lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses. Here, we describe a novel mechanism to induce DHFR degradation through cofactor depletion in neoplastic cells by inhibition of NAD kinase, the only enzyme responsible for generating NADP, which is rapidly converted to NADPH by dehydrogenases/reductases. We identified an inhibitor of NAD kinase, thionicotinamide adenine dinucleotide phosphate (NADPS), which led to accelerated degradation of DHFR and to inhibition of cancer cell growth. Of importance, combination treatment of NADPS with MTX displayed significant synergy in a metastatic colon cancer cell line and was effective in a MTX-transport resistant leukemic cell line. We suggest that NAD kinase is a valid target for further inhibitor development for cancer treatment.
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NADP/análogos & derivados , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Linhagem Celular Tumoral , Meia-Vida , Humanos , Metotrexato/farmacologia , NADP/metabolismo , NADP/farmacologia , Proteólise/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
BACKGROUND: In this study we aim to determines the effect of our vision therapy program for 7- to 10-year-old patients who exhibit bilateral amblyopia that is no longer responsive to conventional treatment. METHODS: Children with bilateral amblyopia between the ages of 7 and 10 treated with vision therapy at the China Medical University Hospital between 2016 and 2019 were retrospectively reviewed. Age and visual acuity-matched bilateral amblyopes are included as a control group. The visual acuity for both groups showed no improvement for more than 3 months with part-time patching and full refraction correction. The initial and final visual acuity, stereopsis, and refractive status were analyzed. RESULTS: Here, 15 cases were included as the treatment group and 16 cases as a control group. At the endpoint, the study group shows a significant improvement in BCVA, with a mean of 0.32 ± 0.15 logMAR (3 lines improvement) versus 0.003 ± 0.19 logMAR (nearly no improvement) for the control group (p < 0.001). The benefits of treatment are most obvious in the first 3 months after treatment (p < 0.001) and last until the end point. Stereoacuity also improves from 190.00 ± 163.34 to 85.00 ± 61.24 arc seconds, which is a 55.26% improvement. CONCLUSIONS: Vision therapy, comprising orthoptic therapy, perceptual learning and dichoptic training, is a successful program for increasing visual acuity and stereoacuity in 7- to 10-year-old children with bilateral amblyopia that is unresponsive to conventional treatment.
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Multiple vaccines are now being used across the world, and several studies have described cases of corneal graft rejection following the administration of the COVID-19 vaccine. The purpose of this article is to review the corneal adverse event that occurred following COVID-19 vaccine administration. The literature search was conducted in March 2022 using MEDLINE, PubMed, and the Cochrane Database of Systematic Reviews. A total of 27 articles, including 37 cases, have documented corneal adverse events that occurred following COVID-19 vaccination. The mean age was 60 ± 14.9 years (range, 27-83 years). The most common events were acute corneal graft rejection (n = 21, 56.8%), followed by herpes zoster ophthalmicus (n = 11, 29.7%) and herpes simplex keratitis (n = 2, 5.4%). The mean time from vaccination to the event was 10 ± 8.5 days (range, 1-42 days) after the first or second dose of vaccine. All patients with corneal graft rejection, immune-mediated keratolysis, and peripheral ulcerative keratitis (PUK) (n = 24, 64.9%) were managed topically with or without oral corticosteroids. Patients with herpes zoster ophthalmicus and herpes simplex keratitis were managed with oral antiviral agents. Two patients received penetrating keratoplasty due to keratolysis after invalid topical treatment. Disease resolution was noted in 29 patients (78.3%), whereas 3 (8.1%) had persistent corneal edema after graft rejection, 1 (2.7%) had corneal infiltration after HZO, and 4 (10.8%) were not mentioned in the articles. Corneal adverse events could occur after COVID-19 vaccination. After timely treatment with steroids or antiviral agents, most of the events were mild and had a good visual outcome. Administrating or increasing steroids before vaccination may be useful for the prevention of corneal graft rejection. However, the prophylactic use of antiviral treatments in patients with a herpes viral infection history is not recommend.
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Opacificação da Cápsula , Corpos Estranhos no Olho , Degeneração Hepatolenticular/diagnóstico , Adulto , Opacificação da Cápsula/diagnóstico , Opacificação da Cápsula/etiologia , Diagnóstico Diferencial , Corpos Estranhos no Olho/complicações , Corpos Estranhos no Olho/diagnóstico , Feminino , HumanosRESUMO
BACKGROUND: The aim was to investigate the effect of inferior oblique (IO) operation (IO myectomy or graded recession and anteriorization) for unilateral and bilateral superior oblique muscle palsy (SOP); Methods: A total of 167 eyes undergoing IO surgery by a single surgeon between 2008 and 2015 were retrospectively reviewed. The method for treating symmetric bilateral SOP was bilateral IO myectomy (n = 102) and the method for treating unilateral SOP or non-symmetric bilateral SOP was IO-graded recession and anteriorization (n = 65). Associated clinical results and other factors were analyzed; Results: Head tilt, vertical deviation, IO overaction, SO underaction degree and ocular torsion angle were all clearly changed, but there was no statistically significance between these two procedures. Mean preoperative torsional angle was 15.3 ± 6.4 degree, which decreased to 5.3 ± 2.7 degree after surgery. Preoperative torsional angle, IOOA and SOUA degree were all significantly affected in postoperative torsional angle (p = 0.025, 0.003 and 0.038). Horizontal rectus muscle and IO muscle operation did not interfere with each other's results (p = 0.98); Conclusions: Symmetric bilateral SOP could be treated with bilateral IO myectomy and IO-graded recession and anteriorization should be reserved for unilateral SOP or non-symmetric bilateral SOP.
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Increasing evidence suggested that a number of ubiquitin enzymes, including ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, E3 ubiquitin ligases and deubiquitination enzymes contribute to therapeutic resistance in triple-negative breast cancer (TNBC) cells. Inhibition of these enzymes with small molecule inhibitors may restore therapeutic sensitivity. Here, we demonstrated ubiquitin conjugating enzyme UbcH5b strongly supports HECTD3 auto-ubiquitination in vitro. Based on this, we developed a Fluorescence Resonance Energy Transfer (FRET) assay and identified three Schisandraceae triterpenoids, including PC3-15, to block HECTD3/UbcH5b auto-ubiquitination. Furthermore, we revealed that PC3-15 directly binds to UbcH5b and also inhibits UbcH5b-mediated p62 ubiquitination. We found that the UbcH5b-p62 axis confers TNBC cells resistance to lapatinib by promoting autophagy. Consistently, PC3-15 inhibits lapatinib-induced autophagy and increases lapatinib sensitivity in TNBC in vitro and in mouse xenografts. These findings suggest that the UbcH5b-p62 axis provides potential therapeutic targets and that Schisandraceae triterpenoids may be used for TNBC treatment in combination with lapatinib.
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Antineoplásicos/farmacologia , Lapatinib/farmacologia , Schisandra/química , Neoplasias de Mama Triplo Negativas/patologia , Triterpenos/farmacologia , Enzimas de Conjugação de Ubiquitina/efeitos dos fármacos , Animais , Humanos , Camundongos , Relação Estrutura-Atividade , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/enzimologia , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To evaluate the thickness and shape of the posterior lamellar graft in Descemet stripping and automated endothelial keratoplasty after long-term observation. METHODS: All patients who underwent Descemet stripping and automated endothelial keratoplasty including simple and triple Descemet stripping and automated endothelial keratoplasty between August 2009 and May 2014 were enrolled in this retrospective study. To assess postoperative thickness and shape of the Descemet stripping and automated endothelial keratoplasty graft, images of the graft taken at the center (C), mid-periphery at 4 mm optical zone (P1), and periphery at 6 mm optical zone (P2) at 1, 2, and 3 years postoperatively were obtained using anterior segment optical coherence tomography. RESULTS: C:P1 was 0.96, 0.96, and 0.95 at 1, 2, and 3 years postoperatively, respectively. C:P2 was 0.85, 0.84, and 0.83 at 1, 2, and 3 years postoperatively, respectively. There was a greater thinning of the central graft thickness compared with the peripheral graft thickness. The shapes of the posterior lamellar graft were variable, such as concave, asymmetrical, planar, irregular, and convex meniscus shapes. The most common shape was asymmetrical shape at 1 year postoperatively and concave at 2 and 3 years postoperatively. The most common shape of the posterior lamellar grafts was asymmetrical shape (38.18%) at 1 year postoperatively, followed by concave (34.54%), planar (20.00%), irregular (5.45%), and convex (1.81%) shapes. The most common shape was concave shape (44.44% and 57.14% for 2 and 3 years postoperatively, respectively), followed by asymmetrical (27.77% and 17.85%, respectively), planar (16.66% and 17.85%, respectively), and irregular (11.11% and 7.14%, respectively) shapes. CONCLUSION: In our study, concave meniscus was not the only observed shape of the graft. The shape and thickness of the graft did not stabilize even 3 years postoperatively in some patients. These findings should be taken into consideration in a combination of Descemet stripping and automated endothelial keratoplasty and cataract surgery.
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Doenças da Córnea/cirurgia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Endotélio Corneano/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Adulto , Idoso , Idoso de 80 Anos ou mais , Endotélio Corneano/transplante , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo , Doadores de TecidosRESUMO
We have observed that rodent cell lines (mouse, hamster) contain approximately 10 times the levels of dihydrofolate reductase as human cell lines, yet the sensitivity to methotrexate (ED(50)), the folate antagonist that targets this enzyme, is similar. Our previous studies showed that dihydrofolate reductase protein levels increased after methotrexate exposure, and we proposed that this increase was due to the relief of feedback inhibition of translation as a consequence of methotrexate binding to dihydrofolate reductase. In the current report, we show that unlike what was observed in human cells, dihydrofolate reductase (DHFR) levels do not increase in hamster cells after methotrexate exposure. We provide evidence to show that although there are differences in the putative mRNA structure between hamster and human mRNA in the dihydrofolate reductase binding region previously identified, "hamsterization" of this region in human dihydrofolate reductase mRNA did not change the level of the enzyme or its induction by methotrexate. Further experiments showed that human dihydrofolate reductase is a promiscuous enzyme and that it is the difference between the hamster and human dihydrofolate reductase protein, rather than the DHFR mRNA, that determines the response to methotrexate exposure. We also present evidence to suggest that the translational up-regulation of dihydrofolate reductase by methotrexate in tumor cells is an adaptive mechanism that decreases sensitivity to this drug.
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Regulação Enzimológica da Expressão Gênica , Biossíntese de Proteínas , Tetra-Hidrofolato Desidrogenase/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Células CHO , Cricetinae , Cricetulus , Primers do DNA , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , RNA Mensageiro/química , RNA Mensageiro/genética , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Tetra-Hidrofolato Desidrogenase/químicaRESUMO
Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) structural proteins (S, E, M, and NC) localize in different subcellular positions when expressed individually. However, SARS-CoV M protein is co-localized almost entirely with S, E, or NC protein when co-expressed in the cells. On the other hand, only partial co-localization was observed when S and E, S and NC, or E and NC were co-expressed in the cells. Interactions between SARS-CoV M and other structural proteins but not interactions between S and E, S and NC, or E and NC were further demonstrated by co-immunoprecipitation assay. These results indicate that SARS-CoV M protein, similar to the M proteins of other coronaviruses, plays a pivotal role in virus assembly. The cytoplasmic C-terminus domain of SARS-CoV M protein was responsible for binding to NC protein. Multiple regions of M protein interacted with E and S proteins. A model for the interactions between SARS-CoV M protein and other structural proteins is proposed. This study helps us better understand protein-protein interactions during viral assembly of SARS-CoV.
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Síndrome Respiratória Aguda Grave/virologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas Estruturais Virais/metabolismo , Animais , Chlorocebus aethiops , Proteínas M de Coronavírus , Deleção de Genes , Ligação Proteica , Mapeamento de Interação de Proteínas , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/metabolismo , Células VeroRESUMO
SARS-CoV M gene fragment was cloned and expressed as a recombinant protein fused with a V5 tag at the C-terminus in Vero E6 cells. In addition to un-glycosylated and glycosylated proteins, one product with smaller size initiated in-frame from the third Met residues probably through ribosomal re-initiation was also detected. Translation initiated in-frame from the third Met is unusual since the sequence around the first Met of SARS-CoV M protein contains the optimal consensus Kozak sequence. The function of this smaller translated product awaits further investigation. Similar to other N-glycosylated proteins, glycosylation of SARS-CoV M protein was occurred co-translationally in the presence of microsomes. The SARS-CoV M protein is predicted as a triple-spanning membrane protein lack of a conventional signal peptide. The second and third trans-membrane regions (a.a. 46-68 and 78-100) are predicted to be the primary type helices, which will be able to penetrate into membrane by themselves, while the first trans-membrane region (a.a. 14-36) is predicted to be the secondary type helix, which is considered to be stabilized by the interaction with other trans-membrane segments. As expected, the second and third trans-membrane regions were able to insert a cytoplasmic protein into the endoplasmic reticulum membrane more efficiently than the first one. These results should be important for the study of SARS-CoV morphogenesis.
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Fusão de Membrana , Proteínas da Matriz Viral/metabolismo , Animais , Sequência de Bases , Western Blotting , Membrana Celular/virologia , Chlorocebus aethiops , Proteínas M de Coronavírus , Primers do DNA , Glicosilação , Biossíntese de Proteínas , Frações Subcelulares/metabolismo , Células Vero , Proteínas da Matriz Viral/genéticaRESUMO
Imp4p is a component of U3 snoRNP (small nucleolar ribonucleoprotein) involved in the maturation of 18S rRNA. We have shown that Imp4p interacts with Cdc13p, a single-stranded telomere-binding protein involved in telomere maintenance. To understand the role of Imp4p in telomeres, we purified recombinant Imp4p protein and tested its binding activity towards telomeric DNA using electrophoretic mobility-shift assays. Our results showed that Imp4p bound specifically to single-stranded telomeric DNA in vitro. The interaction of Imp4p to telomeres in vivo was also demonstrated by chromatin immunoprecipitation experiments. Significantly, the binding of Imp4p to telomeres was not limited to yeast proteins, since the hImp4 (human Imp4) also bound to vertebrate single-stranded telomeric DNA. Thus we conclude that Imp4p is a novel telomeric DNA-binding protein that, in addition to its role in rRNA processing, might participate in telomere function.
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Proteínas de Ligação a DNA/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Proteínas Ribossômicas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Telômero , Sequência de Bases , Imunoprecipitação da Cromatina , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Ligação Proteica , Proteínas Recombinantes/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
PURPOSE: To build a decision tree for patients suspected of having prostate cancer using classification and regression tree (CART) analysis. PATIENTS AND METHODS: Data were uniformly collected on 1,433 referred men with a serum prostate-specific antigen (PSA) levels of < or = 10 ng/mL who underwent a prostate biopsy. Factors analyzed included demographic, laboratory, and ultrasound data (ie, hypoechoic lesions and PSA density [PSAD]). Twenty percent of the data was randomly selected and reserved for study validation. CART analysis was performed in two steps, initially using PSA and digital rectal examination (DRE) alone and subsequently using the remaining variables. RESULTS: CART analysis selected a PSA cutoff of more than 1.55 ng/mL for further work-up, regardless of DRE findings. CART then selected the following subgroups at risk for a positive biopsy: (1) PSAD more than 0.165 ng/mL/cc; (2) PSAD < or = 0.165 ng/mL/cc and a hypoechoic lesion; (3) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and prostate volume < or = 44.0 cc; and (4) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and 50.25 cc less than prostate volume < or = 80.8 cc. In the validation data set, specificity and sensitivity were 31.3% and 96.6%, respectively. Cancers that were missed by the CART were Gleason score 6 or less in 93.4% of cases. Receiver operator characteristic curve analysis showed that CART and logistic regression models had similar accuracy (area under the curve = 0.74 v 0.72, respectively). CONCLUSION: Application of CART analysis to the prostate biopsy decision results in a significant reduction in unnecessary biopsies while retaining a high degree of sensitivity when compared with the standard of performing a biopsy of all patients with an abnormal PSA or DRE.
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Neoplasias da Próstata/diagnóstico , Análise de Regressão , Adulto , Idoso , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias da Próstata/classificação , Neoplasias da Próstata/diagnóstico por imagem , UltrassonografiaRESUMO
Prevention and treatment of myopia is an important public problem worldwide. We found a higher incidence of myopia among patients with inflammatory diseases such as type 1 diabetes mellitus (7.9%), uveitis (3.7%), or systemic lupus erythematosus (3.5%) compared to those without inflammatory diseases (p<0.001) using data from children (<18years old) in the National Health Insurance Research database. We then examined the inhibition of myopia by atropine in Syrian hamsters with monocular form deprivation (MFD), an experimental myopia model. We found atropine downregulated inflammation in MFD eyes. The expression levels of c-Fos, nuclear factor κB (NFκB), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were upregulated in myopic eyes and downregulated upon treatment with atropine. The relationship between the inflammatory response and myopia was investigated by treating MFD hamsters with the immunosuppressive agent cyclosporine A (CSA) or the inflammatory stimulators lipopolysaccharide (LPS) or peptidoglycan (PGN). Myopia progression was slowed by CSA application but was enhanced by LPS and PGN administration. The levels of c-Fos, NF-κB, IL-6, and TNF-α were upregulated in LPS- and PGN-treated eyes and downregulated by CSA treatment. These findings provide clinical and experimental evidence that inflammation plays a crucial role in the development of myopia.
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Inflamação/complicações , Miopia/etiologia , Miopia/patologia , Adolescente , Animais , Anti-Inflamatórios/uso terapêutico , Atropina/uso terapêutico , Técnicas de Cultura de Células , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Cricetinae , Modelos Animais de Doenças , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Incidência , Lactente , Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Masculino , Miopia/diagnóstico , Miopia/epidemiologia , Vigilância da População , Taiwan/epidemiologiaRESUMO
PURPOSE: Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. PATIENTS AND METHODS: Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. RESULTS: Forty-nine (new or worsened) symptoms were detected by both physician and QLQ, 48 symptoms were detected by the physician alone, and 55 symptoms were detected by the QLQ alone. They agreed on the absence of a symptom in 102 instances of 254 possible opportunities. Their uncorrected agreement was 59.4%, but Cohen's kappa, a coefficient of agreement that corrects for chance, was 0.15, indicating only slight agreement. Using the QLQ as the standard, overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptoms. CONCLUSION: Even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy adverse effects. Tools for collecting patient-reported adverse event data in chemotherapy clinical trials should be developed.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Médicos/normas , Qualidade de Vida , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Sensibilidade e Especificidade , Inquéritos e QuestionáriosRESUMO
PURPOSE: Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. PATIENTS AND METHODS: The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. RESULTS: SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor-associated protein (GABARAP) gene expression predict decreased survival among all patients. GABA(A) delta receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABA(A) receptor subunits was identified (GABA(A) profile [GAP score]). Patients with a higher GAP score (> -1) had a survival advantage. Multivariate analysis showed that GABARAP and GABA(A) alpha2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators. CONCLUSION: Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.
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Proteínas Associadas aos Microtúbulos/genética , Neuroblastoma/genética , Receptores de GABA-A/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Biomarcadores Tumorais/análise , Expressão Gênica , Humanos , Lactente , Análise Multivariada , Hibridização de Ácido Nucleico , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
BACKGROUND AND OBJECTIVES: Imatinib induces complete cytogenetic responses (CCR) in the majority of patients with chronic myeloid leukemia (CML) in chronic phase (CP). However, a subgroup of patients is refractory at the cytogenetic level. Clinically, it would be advantageous to identify such patients a priori, since they may benefit from more aggressive therapy. DESIGN AND METHODS: To elucidate mechanisms underlying cytogenetic refractoriness, we used Affymetrix oligonucleotide arrays to determine the transcriptional signature associated with cytogenetic refractoriness in unselected white blood or bone marrow cells from 29 patients with CML in first CP prior to treatment with imatinib. Patients with CCR within 9 months were defined as responders (n = 16) and patients lacking a major cytogenetic response (> 35% Philadelphia-positive metaphases) after 1 year were defined as non-responders (n = 13). RESULTS: Differences in gene expression between responders and non-responders were subtle. Stringent statistical analysis with multiple comparison adjustments revealed very few differentially expressed genes. Differentially expressed genes could not be confirmed in an independent test set. INTERPRETATION AND CONCLUSIONS: We conclude that transcriptional profiling of unselected white cells is of limited value for identifying genes consistently associated with cytogenetic refractoriness to imatinib.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , RNA Neoplásico/sangue , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , RNA Ribossômico/sangue , RNA Ribossômico/genética , RNA Ribossômico/isolamento & purificaçãoRESUMO
To investigate the prevalence of Helicobacter pylori (H. pylori) infection in adolescents and children in Changhua and to compare the differences between urban and rural areas, we used enzyme immunoassay to detect H. pylori stool antigen for feco-prevalence study. In addition, a questionnaire was designed to obtain demographic and clinical information. Children and adolescents under 18 years of age living in Changhua city and Yung-Chin village were divided into 6 groups respectively, ie. 0-3, 3-6, 6-9, 9-12, 12-15, and 15-18 years. A minimum of 30 persons were investigated in each group. A total of 567 subjects (M/F 295/272) were included in this study. There was no significant difference in H. pylori infection with regard to residential area, gender, education of the mother, occupation of parents, family history of peptic ulcer, and number of family members, except for epigastralgia of the subjects (p=0.001) and education of the father (p=0.039). The overall prevalence was 13.75%. A low prevalence was noted in the group 0-3 years (2.0%). The prevalence increased with age and reached its maximum of 23.8% in the age group of 9-12 years and then declined. The multiple logistic regression analysis revealed that only age (odds ratio (OR)=1.3, 95% confidence interval (C.I.)=1.1-1.5) and epigastralgia (OR=1.71, 95% C.I.=1.0-3.0) were the most important risk factors for H. pylori infection after adjusting for participating gender, place of residence and father's age. The difference in age pattern of H. pylori infection between our results and other studies needs further investigation.
Assuntos
Antígenos de Bactérias/análise , Fezes/microbiologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Prevalência , Taiwan/epidemiologiaRESUMO
The purpose of this study was to investigate the effects of an epidermal growth factor (EGF) intervention on improving the inflammatory response of rats fed an ethanol-containing diet. Eight-week-old male Wistar rats were divided into ethanol (E) and control (C) groups. Rats in the E group were fed an ethanol liquid diet, while rats in the C group were pair-fed an isoenergetic diet without ethanol. After a 4-week ethanol-induction period, both the C and E group were respectively subdivided into 2 groups: a normal liquid diet without (C group, n = 8) or with EGF supplementation (C + EGF, n = 8), and the ethanol-containing diet without (E group, n = 8) or with EGF supplementation (E + EGF group, n = 8). The EGF (30 µg/kg body weight/day) intervention period was carried out for the following 8 weeks. At the end of the experiment, activity of aspartate transaminase (AST) and alanine transaminase (ALT) and hepatic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 in group E were significantly higher than those in group C. In addition, alterations in the gut microbiota profile were found in group E. In contrast, activity of AST and ALT and levels of TNF-α, IL-1ß, and IL-6 in group E + EGF were significantly lower than those in group E. Significantly lower intestinal permeability and lower numbers of Escherichia coli in the fecal microbial culture were also found in group E + EGF. These results suggest that EGF improved the intestinal integrity by decreasing E. coli colonization and lowering intestinal permeability, which then ameliorated the inflammatory response under chronic ethanol exposure.