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BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.
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Células-Tronco Mesenquimais , Infarto do Miocárdio , Humanos , Ácido Hialurônico/farmacologia , Células Endoteliais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteômica , Infarto do Miocárdio/terapia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Células-Tronco Mesenquimais/metabolismo , FibroseRESUMO
Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 109 /l) and 38/44 patients (86%) achieved a complete response (≥100 × 109 /l). In all patients, the median platelet count on eltrombopag or romiplostim was 45 × 109 /l vs 114 × 109 /l on avatrombopag (p < 0.0001); in patients switched for ineffectiveness of romiplostim/eltrombopag, it was 28 × 109 /l on romiplostim/eltrombopag vs 88 × 109 /l on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before switching discontinued them after switching, including 63% of patients receiving chronic corticosteroids. In a heavily pretreated chronic ITP population, avatrombopag was effective following therapy with romiplostim or eltrombopag, with high response rates even in patients with inadequate response to a prior TPO-RA.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Benzoatos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Tiazóis , Tiofenos , Trombocitopenia/tratamento farmacológico , TrombopoetinaRESUMO
Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-γ2 (PLC-γ2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-α and IL-4. Finally, we found that SP significantly inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-γ2/MAPK signaling in mast cells.
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Imunoglobulina E/imunologia , Mastócitos/efeitos dos fármacos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Fosfolipase C gama/metabolismo , Quercetina/análogos & derivados , Animais , Linhagem Celular/efeitos dos fármacos , Citocinas/metabolismo , Imunoglobulina E/farmacologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos Endogâmicos BALB C , Anafilaxia Cutânea Passiva/imunologia , Fosforilação/efeitos dos fármacos , Quercetina/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
Background and Aims: Patients with health-related social needs (HRSNs) experience barriers to health care services. To identify areas of intervention, we need to understand the impact of HRSN in patients with gastroparesis. This study aimed to 1) determine types of HRSN present in patients with gastroparesis; 2) analyze relationship between HRSN and gastroparesis symptom severity and health-related quality of life (HRQL); and 3) evaluate which HRSN domains most significantly affect symptom severity and HRQL. Methods: Patients with gastroparesis were enrolled and completed questionnaires to assess the following: 1) severity of gastroparetic symptoms using Gastroparesis Cardinal Symptom Index (GCSI); 2) HRSN using screening questionnaire; and 3) HRQL using the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL). Results: Three hundred twenty-one patients with gastroparesis participated in this study. Two hundred twelve patients completed GCSI and HRSN questionnaires, and 109 additional patients completed PAGI-QOL questionnaire. Of the 321 total patients, the most common HRSN were mental health, financial strain, and food insecurity. Overall, 43% had at least one HRSN and 22% had at least 2 HRSN. The number of HRSN was directly correlated to the GCSI total symptom score (r = 0.284, P < .05) while inversely correlated to the PAGI-QOL score (r = -0.650, P < .05). Of the 7 HRSN domains studied, patients with mental health HRSN, in particular, reported more severe gastroparesis symptoms and lower quality of life. Conclusion: A large number (43%) of patients with gastroparesis had at least 1 HRSN. Patients with HRSN reported more severe gastroparesis symptoms and lower quality of life than patients without HRSN.
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BACKGROUND: Obesity is a known risk factor for the development of osteoarthritis and the subsequent need for joint replacement. Weight loss has been shown to reduce pain, disability, and the need for joint replacement, particularly in patients with knee osteoarthritis. The aim of this study was to investigate pre-operative weight change in patients with hip, knee, and shoulder osteoarthritis at a regional, public hospital in Australia, to identify opportunities for pre-operative weight-loss intervention. METHODS: A retrospective review of patients who underwent elective primary total hip (THR), knee (TKR), and shoulder (TSR) replacement for osteoarthritis was conducted between December 2019 and December 2022. BMI data were collected at three time points: (1) general practitioner (GP) referral; (2) orthopaedic clinic review; and (3) pre-admission clinic (PAC) assessment. RESULTS: A total of 496 patients were included in the study, of which 205 underwent THR, 251 underwent TKR, and 40 underwent TSR. The mean patient age was 67 years, and 46.4% were female. At the time of GP referral, the mean body mass index (BMI) was 31.4 kg/m2. Across the study period, only 2% of patients experienced clinically significant weight loss pre-operatively (≥5% of total body weight). CONCLUSION: This study has demonstrated that very few patients lose weight prior to undergoing joint replacement in the public sector in Australia. This highlights the need for targeted non-surgical weight loss interventions for patients currently awaiting joint replacement.
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UNLABELLED: Activation of v-akt murine thymoma viral oncogene homolog (AKT) and Ras pathways is often implicated in carcinogenesis. However, the oncogenic cooperation between these two cascades in relationship to hepatocellular carcinoma (HCC) development remains undetermined. To investigate this issue, we generated a mouse model characterized by combined overexpression of activated forms of AKT and neuroblastoma Ras viral oncogene homolog (N-Ras) protooncogenes in the liver by way of hydrodynamic gene transfer. The molecular mechanisms underlying crosstalk between AKT and N-Ras were assessed in the mouse model and further evaluated in human and murine HCC cell lines. We found that coexpression of AKT and N-Ras resulted in a dramatic acceleration of liver tumor development when compared with mice overexpressing AKT alone, whereas N-Ras alone did not lead to tumor formation. At the cellular level, concomitant up-regulation of AKT and N-Ras resulted in increased proliferation and microvascularization when compared with AKT-injected mice. Mechanistic studies suggested that accelerated hepatocarcinogenesis driven by AKT and N-Ras resulted from a strong activation of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, elevated expression of FOXM1/SKP2 and c-Myc also contributed to rapid tumor growth in AKT/Ras mice, yet by way of mTORC1-independent mechanisms. The biological effects of coactivation of AKT and N-Ras were then recapitulated in vitro using HCC cell lines, which supports the functional significance of mTORC1, FOXM1/SKP2, and c-Myc signaling cascades in mediating AKT and N-Ras-induced liver tumor development. CONCLUSION: Our data demonstrate the in vivo crosstalk between the AKT and Ras pathways in promoting liver tumor development, and the pivotal role of mTORC1-dependent and independent pathways in mediating AKT and Ras induced hepatocarcinogenesis.
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Carcinoma Hepatocelular/fisiopatologia , Fatores de Transcrição Forkhead/fisiologia , Neoplasias Hepáticas/fisiopatologia , Proteína Oncogênica v-akt/fisiologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Proteína Forkhead Box M1 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos , Neovascularização Patológica/fisiopatologia , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Global surgery broadly refers to a rapidly expanding multidisciplinary field concerned with providing better and equitable surgical care across international health systems. Global surgery initiatives primarily focus on capacity building, advocacy, education, research, and policy development in low- and middle-income countries (LMICs). The inadequate surgical, anesthetic, and obstetric care currently contributes to 18 million preventable deaths each year. Hence, there is a growing interest in the rapid growth of artificial intelligence (AI) that provides a distinctive opportunity to enhance surgical services in LMICs. AI modalities have been used for personalizing surgical education, automating administrative tasks, and developing realistic and cost-effective simulation-training programs with provisions for people with special needs. Furthermore, AI may assist with providing insights for governance, infrastructure development, and monitoring/predicting stock take or logistics failure that can help in strengthening global surgery pillars. Numerous AI-assisted telemedicine-based platforms have allowed healthcare professionals to virtually assist in complex surgeries that may help to improve surgical accessibility across LMICs. Challenges in implementing AI technology include the misrepresentation of minority populations in the datasets leading to discriminatory bias. Human hesitancy, employment uncertainty, automation bias, and role of confounding factors need to be further studied for equitable utilization of AI. With a focused and evidence-based approach, AI could help several LMICs overcome bureaucratic inefficiency and develop more efficient surgical systems.
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BACKGROUND: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV. OBJECTIVE: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. METHODS: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scoresâ<â1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. RESULTS: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. CONCLUSIONS: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.
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Doença de Alzheimer , Disfunção Cognitiva , Microbioma Gastrointestinal , Infecções por HIV , Humanos , Feminino , Infecções por HIV/complicações , Microbioma Gastrointestinal/genética , Doença de Alzheimer/complicações , Estudos Transversais , Cognição , Disfunção Cognitiva/genéticaRESUMO
BACKGROUND & AIMS: Aberrant activation of the AKT oncogenic pathway and downregulation of the Sprouty 2 (Spry2) tumor suppressor gene are frequently observed molecular events in human hepatocarcinogenesis. The goal of the present study was to investigate the eventual biochemical and genetic crosstalk between activated AKT and inactivation of Spry2 during liver cancer development by using in vivo and in vitro approaches. METHODS: Activated AKT and/or Spry2Y55F, a dominant negative form of Spry2, were overexpressed in the mouse liver via hydrodynamic gene delivery. Histological and biochemical assays were applied to characterize the molecular features of AKT and AKT/Spry2Y55F liver tumors. The human HLE hepatocellular carcinoma (HCC) cell line, stably overexpressing AKT, was transfected with Spry2Y55F to study the molecular mechanisms underlying hepatocarcinogenesis driven by Spry2 loss. RESULTS: Spry2Y55F overexpression significantly accelerated AKT-induced hepatocarcinogenesis in the mouse. AKT/Spry2Y55F liver lesions had increased proliferation and glycolysis and decreased lipogenesis when compared with AKT corresponding lesions. At the molecular level, AKT/Spry2Y55F HCCs exhibited a significantly stronger induction of activated mitogen-activated protein kinase (MAPK) and pyruvate kinase M2 (PKM2) pathways than in AKT corresponding lesions. This phenotype was reproduced in HLE cells overexpressing AKT following transfection with Spry2Y55F. Furthermore, we found that concomitant suppression of the MAPK cascade and PKM2 strongly inhibited the growth induced by Spry2Y55F in AKT-overexpressing cells. CONCLUSIONS: Inactivation of Spry2 accelerates AKT-induced hepatocarcinogenesis via activation of MAPK and PKM2 pathways.
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Adenoma/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adenoma/metabolismo , Adenoma/patologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Regulação para Baixo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Camundongos , Plasmídeos , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Piruvato Quinase/metabolismo , TransfecçãoRESUMO
BACKGROUND & AIMS: De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC). METHODS: We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. RESULTS: In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. CONCLUSIONS: De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.
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Carcinoma Hepatocelular/enzimologia , Lipogênese , Neoplasias Hepáticas/enzimologia , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais , Animais , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Endopeptidases/metabolismo , Ácido Graxo Sintases/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-akt/genética , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Serina-Treonina Quinases TOR , Fatores de Tempo , Transfecção , Ubiquitina Tiolesterase , Ubiquitinação , Regulação para CimaRESUMO
Morbidity and mortality due to preventable medical errors are a disastrous reality in medicine. Debriefing, a process that allows individuals to discuss team performance in a constructive, supportive environment, has been linked to improved performance in various medical and surgical fields, including improvements in specific procedures, teamwork and communication, and error identification. However, the neurosurgical literature on this topic is limited. The authors review the debriefing literature in the field of medicine, with a specific emphasis on the operating room, and they report their own institutional experience with a debriefing module, from invention to pilot implementation, at Vanderbilt University Medical Center. The authors share the challenges and lessons learned from their quality improvement project. The field of neurosurgery would undoubtedly benefit from embracing debriefing, as its potential has been established in other medical specialties and can serve as a valuable role in immediately learning from mistakes. The authors hope that their colleagues can learn from this experience and improve their own.
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Intervenção em Crise , Erros Médicos/prevenção & controle , Procedimentos Neurocirúrgicos/normas , Segurança do Paciente/estatística & dados numéricos , Humanos , Cuidados Pós-Operatórios , Gestão da SegurançaRESUMO
UNLABELLED: Sprouty2 (Spry2), a negative feedback regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway, is frequently down-regulated in human hepatocellular carcinoma (HCC). We tested the hypothesis that loss of Spry2 cooperates with unconstrained activation of the c-Met protooncogene to induce hepatocarcinogenesis via in vitro and in vivo approaches. We found coordinated down-regulation of Spry2 protein expression and activation of c-Met as well as its downstream effectors extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) in a subset of human HCC samples with poor outcome. Mechanistic studies revealed that Spry2 function is disrupted in human HCC via multiple mechanisms at both transcriptional and post-transcriptional level, including promoter hypermethylation, loss of heterozygosity, and proteosomal degradation by neural precursor cell expressed, developmentally down-regulated 4 (NEDD4). In HCC cell lines, Spry2 overexpression inhibits c-Met-induced cell proliferation as well as ERK and AKT activation, whereas loss of Spry2 potentiates c-Met signaling. Most importantly, we show that blocking Spry2 activity via a dominant negative form of Spry2 cooperates with c-Met to promote hepatocarcinogenesis in the mouse liver by sustaining proliferation and angiogenesis. The tumors exhibited high levels of activated ERK and AKT, recapitulating the subgroup of human HCC with a clinically aggressive phenotype. CONCLUSION: The occurrence of frequent genetic, epigenetic, and biochemical events leading to Spry2 inactivation provides solid evidence that Spry2 functions as a tumor suppressor gene in liver cancer. Coordinated deregulation of Spry2 and c-Met signaling may be a pivotal oncogenic mechanism responsible for unrestrained activation of ERK and AKT pathways in human hepatocarcinogenesis.
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Carcinoma Hepatocelular/etiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neoplasias Hepáticas/etiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas c-met/fisiologia , Regulação para Cima , Proteínas Adaptadoras de Transdução de Sinal , Animais , Humanos , Camundongos , Proteínas Serina-Treonina Quinases , Células Tumorais CultivadasRESUMO
OBJECTIVE: To determine whether there might be an increased prevalence of undiagnosed celiac disease among a population of infertile women using serologic screening. STUDY DESIGN: A prospective cohort study was performed at an academic infertility clinic in the United States. RESULTS: The overall prevalence of celiac disease in this population was 2.1% (4/188). There was a significantly increased prevalence (5.9%) of undiagnosed celiac disease among women presenting with unexplained infertility (n = 51). CONCLUSION: Women with unexplained infertility are at increased risk for having undiagnosed celiac disease, which may be a potentially modifiable (and treatable) risk factor.
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Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Infertilidade Feminina/epidemiologia , Adulto , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Feminino , Humanos , Síndrome do Intestino Irritável/epidemiologia , Minnesota/epidemiologia , Gravidez , Taxa de Gravidez , Prevalência , Estudos ProspectivosRESUMO
Objective. To hold a storytelling event and assess its effect on Doctor of Pharmacy (PharmD) students' perspectives on and attitudes toward reflection. Methods. Story Slam, a four-hour storytelling competition, was incorporated into the spring semester of the first professional year of a PharmD program. The event featured short first-person stories told by faculty members as well as students. Students were invited to participate in a pre- and post-intervention survey and focus group. An inductive qualitative analysis of the resulting data was conducted using textual and audio artifacts. Results. All 136 first professional year (P1) students participated in the 2019 Story Slam. Eleven students submitted qualitative pre- and post-intervention survey instruments and participated in a semi-structured recorded focus group. Thematic analysis revealed nine themes. Students' perspectives regarding the importance of self-reflection changed after participating in Story Slam, with students expressing a greater willingness to engage in self-reflection in the context of professional practice following the event. Students believed Story Slam created an environment conducive to reflection and engagement, resulting in strengthened relationships with peers and faculty members. Students expressed feeling a wide range of emotions as they shared their story and listened to the stories of others. Conclusion. Story Slam is an effective strategy for introducing P1 students to reflection, while also strengthening the school's reflective culture. Additionally, sharing stories may foster positive relationships and cultivate trust and respect between students and faculty members.
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Atitude do Pessoal de Saúde , Educação em Farmácia , Conhecimentos, Atitudes e Prática em Saúde , Narração , Estudantes de Farmácia/psicologia , Anedotas como Assunto , Comportamento Competitivo , Emoções , Grupos Focais , Humanos , Relações Interpessoais , Pesquisa Qualitativa , Autoimagem , RedaçãoRESUMO
BACKGROUND AND PURPOSE: Cognitive dysfunction occurs in 9% to 23% of patients during the first month after carotid endarterectomy (CEA). A 4-basepair (AAAT) tandem repeat polymorphism (either 3 or 4 repeats) has been described in the promoter region of inducible nitric oxide synthase (iNOS), a gene with complex roles in ischemic injury and preconditioning against ischemic injury. We investigated whether the 4-repeat variant (iNOS(+)) affects the incidence of cognitive dysfunction after CEA. METHODS: One-hundred eighty-five CEA and 60 spine surgery (control) subjects were included in this nested cohort analysis. Subjects underwent a battery of 7 neuropsychometric tests before and 1 day and 1 month after surgery. Multivariate logistic regression analyses were performed to determine if the iNOS promoter variant was independently associated with the incidence of cognitive dysfunction at 1 day and 1 month. Further, all right-hand-dominant CEA subjects were grouped by operative side and performance on each test was compared between iNOS(+) and iNOS(-) groups. RESULTS: Forty-four of 185 CEA subjects had at least 1 iNOS promoter allele containing 4 copies of the tandem repeat (iNOS(+)). iNOS(+) status was significantly protective against moderate/severe cognitive dysfunction 1 month after CEA. Right-hand-dominant iNOS(+) CEA subjects undergoing left-side CEA performed significantly better than iNOS(-) subjects on a verbal learning test and those undergoing right-side CEA performed significantly better on a test of visuospatial function. CONCLUSIONS: We demonstrate an iNOS promoter polymorphism variant provides protection against moderate/severe cognitive dysfunction 1 month after CEA. Further, this protection appears to involve cognitive domains localized ipsilateral to the operative carotid artery.
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Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Endarterectomia das Carótidas/efeitos adversos , Óxido Nítrico Sintase Tipo II/genética , Complicações Pós-Operatórias/psicologia , Regiões Promotoras Genéticas/genética , Idoso , Alelos , Apolipoproteínas E/genética , Transtornos Cognitivos/psicologia , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Testes Neuropsicológicos , Óxido Nítrico/biossíntese , Óxido Nítrico/fisiologia , Polimorfismo Genético/genéticaRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) is 1 of the leading causes of cancer-related deaths worldwide, yet the molecular genetics underlying this malignancy are still poorly understood. In our study, we applied statistical methods to correlate human HCC gene expression data obtained from complementary DNA (cDNA) microarrays and corresponding DNA copy number variation data obtained from array-based comparative genomic hybridization. We have thus identified 76 genes that are up-regulated and show frequent DNA copy number gain, and 37 genes that are down-regulated and show frequent DNA copy loss in human HCC samples. Among these down-regulated genes is Sprouty2 (Spry2), a known inhibitor of receptor tyrosine kinases. We investigated the potential role of Spry2 in HCC by expressing dominant negative Spry2 (Spry2Y55F) and activated beta-catenin (DeltaN90-beta-catenin) in the mouse liver through hydrodynamic injection and sleeping beauty-mediated somatic integration. When stably expressed in mouse hepatocytes, Spry2Y55F cooperates with DeltaN90-beta-catenin to confer a neoplastic phenotype in mice. Tumor cells show high levels of expression of phospho-extracellular signal-regulated kinase (ERK), as well as deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. CONCLUSION: We identified a set of candidate oncogenes and tumor suppressor genes for human HCC. Our study provides evidence that inhibition of Spry activity cooperates with other oncogenes to promote liver cancer in mouse models, and Spry2 may function as a candidate tumor suppressor for HCC development in vivo. In addition, we demonstrate that the integration of genomic analysis and in vivo transfection is a powerful tool to identify genes that are important during hepatic carcinogenesis.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Dosagem de Genes , Expressão Gênica , Perfilação da Expressão Gênica , Genes Supressores de Tumor , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Oncogenes , Proteínas Serina-Treonina Quinases , Transfecção , Proteínas Supressoras de Tumor/genética , beta Catenina/metabolismoRESUMO
BACKGROUND/OBJECTIVE: Regular physical activity (PA) has been associated with improved cognitive function, but its effect on postoperative delirium (POD) has not been established. Our objectives were to determine the effect of baseline PA on the incidence of POD in older patients undergoing elective orthopedic surgery and to determine whether these effects were independent of cognitive reserve. We hypothesize that PA protects against POD by bolstering physiologic reserve needed to withstand the stressors of surgery. DESIGN: Secondary analysis of a prospective, single-center, cohort study. SETTING: Urban academic hospital. PARTICIPANTS: A total of 132 nondemented, English-speaking adults older than 60 years undergoing elective orthopedic surgery. MEASUREMENTS: Subjects were screened for POD and delirium severity using the Confusion Assessment Method and the Memorial Delirium Assessment Scale. Baseline cognitive activities and PAs were assessed with a validated Leisure Activity Scale. Regular PA was categorized as 6 to 7 days per week. The association of regular PA with incidence of POD was assessed using multivariable logistic regression, adjusting for age, sex, Charlson Comorbidity Index, cognitive reserve, and cognitive function. Linear regression was used to assess the association of delirium severity with regular PA. RESULTS: Of 132 patients, 41 (31.1%) developed POD. Regular PA was associated with a 74% lower odds of developing POD (odds ratio [OR] = 0.26; 95% confidence interval [CI] = 0.08-0.82). There was no significant interaction between PA and cognitive reserve (P = .70). Of 85 women, 25 (29.4%), and of 47 men, 16 (34.0%) developed POD. In stratified analysis, women who engaged in regular PA had dramatically lower odds of POD (OR = 0.08; 95% CI = 0.01-0.63) compared with men (OR = 0.93; 95% CI = 0.18-4.97). CONCLUSIONS: Regular PA is associated with decreased incidence of POD, especially among women. Future studies should address the basis of sex differences in PA benefits on delirium. J Am Geriatr Soc 67:2260-2266, 2019.