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Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme polynucleotide kinase 3'-phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.
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Neoplasias Encefálicas , Glioma , Histonas , Niño , Humanos , Neoplasias Encefálicas/patología , Reparación del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Glioma/patología , Histonas/genética , Histonas/metabolismo , Mutación , Fosfotransferasas (Aceptor de Grupo Alcohol)/genéticaRESUMEN
In this review, the current state of research on textile-based temperature sensors is explored by focusing on their potential use in various applications. The textile-based sensors show various advantages including flexibility, conformability and seamlessness for the wearer. Integration of the textile-based sensors into clothes or fabric-based products enables continuous and sensitive monitoring of change in temperature, which can be used for various medical and fitness applications. However, there are lacks of comprehensive review on the textile-based temperature sensors. This review introduces various types of textile-based temperature sensors, including resistive, thermoelectric and fibre-optical sensors. In addition, the challenges that need to be addressed to fully realise their potential, which include improving sensitivity and accuracy, integrating wireless communication capabilities, and developing low-cost fabrication techniques. The technological advances in textile-based temperature sensors to overcome the limitations will revolutionize wearable devices requiring function of temperature monitoring.
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Cancer predisposition syndromes are associated with an increased risk of developing primary malignancies. Here we discuss those which are associated with an increased risk of tumors of the central nervous system (CNS) and gastrointestinal (GI) tract. These can be grouped into those in which the CNS tumors predominate versus those in which the GI cancers predominate. The former include constitutional mismatch repair deficiency (CMMRD) syndrome, Li-Fraumeni syndrome (LFS), and Cowden syndrome (CS) while the latter include familial adenomatosis polyposis 1 (FAP1), Lynch syndrome and polymerase proofreading-associated polyposis syndrome (PPAP). Tumor specificity does exist as medulloblastoma occur in FAP, LFS and CMMRD while glioma are most commonly seen in all replication repair-deficient genes and LFS. Choroid plexus carcinoma is strictly observed in LFS while Cowden syndrome patients develop Lhermitte Duclos disease or meningioma. In each syndrome, specific types of low-grade and high-grade gastrointestinal cancers can occur, but these will be discussed elsewhere. Underlying cancer predisposition syndromes are important to consider when faced with brain tumors, particularly in the pediatric and young adult age groups, as identification of an underlying germ line mutation may change the upfront management of the patient and has implications for future cancer surveillance for both the patient and potentially affected family members. Considerations of family history, presence of skin lesions and consanguinity provide valuable information in identifying patients at potential increased risk.
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Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/patología , Neoplasias Encefálicas/genética , Predisposición Genética a la Enfermedad , HumanosRESUMEN
Childhood exposure to traumatic events, termed early life stress (ELS), is now widely recognized for causing long-term negative health effects that may not manifest until adulthood. Allostatic load (AL) describes the cumulative "wear-and-tear" effects of chronic stress on the body that may adversely affect human health by accelerating other disease processes. Recent epidemiological studies have reported higher stress levels in industrialized countries and trends of increasing prevalence in autoimmune diseases during recent decades. To elucidate mechanisms of stress-related immune dysregulation, most animal studies up to now have focused on AL and stress-triggered events occurring in adults but have not explored ELS in the context of autoimmune disorders. We have identified a current gap in understanding the impact of ELS on immune system ontogeny and its potential for priming genetically susceptible individuals who are at increased risk for autoimmune diseases later in life, through mechanisms involving neuroendocrine-immune cross talk. In this review, we highlight the intersection between stress and immune function, with a focus on ELS as consequential for increased autoimmune disorder risks later in life.
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Enfermedades Autoinmunes/inmunología , Estrés Psicológico/inmunología , Adulto , Animales , Enfermedades Autoinmunes/epidemiología , Niño , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Prevalencia , Estrés Psicológico/epidemiologíaRESUMEN
BACKGROUND: Both the type I insulin-like growth factor receptor (IGF1R) and Src pathways are associated with the development and progression of numerous types of human cancer, and Src activation confers resistance to anti-IGF1R therapies. Hence, targeting both IGF1R and Src concurrently is one of the main challenges in combating resistance to the currently available anti-IGF1R-based anticancer therapies. However, the enhanced toxicity from this combinatorial treatment could be one of the main hurdles for this strategy, suggesting the necessity of developing a novel strategy for co-targeting IGF1R and Src to meet an urgent clinical need. METHODS: We synthesized a series of 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitors, selected LL28 as an active compound and evaluated its potential antitumor effects in vitro and in vivo using the MTT assay, colony formation assays, flow cytometric analysis, a tumor xenograft model, and the Kras G12D/+ -driven spontaneous lung tumorigenesis model. RESULTS: LL28 markedly suppressed the activation of IGF1R and Src and significantly inhibited the viability of several NSCLC cell lines in vitro by inducing apoptosis. Administration of mice with LL28 significantly suppressed the growth of H1299 NSCLC xenograft tumors without overt toxicity and substantially reduced the multiplicity, volume, and load of lung tumors in the Kras G12D/+ -driven lung tumorigenesis model. CONCLUSIONS: The present results suggest the potential of LL28 as a novel anticancer drug candidate targeting both IGF1R and Src, providing a new avenue to efficient anticancer therapies. Further investigation is warranted in advanced preclinical and clinical settings.
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Pirimidinas/química , Pirimidinas/uso terapéutico , Receptores de Somatomedina/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dasatinib/uso terapéutico , Humanos , Imidazoles/uso terapéutico , Inmunohistoquímica , Células MCF-7 , Pirazinas/uso terapéutico , Receptor IGF Tipo 1 , Receptores de Somatomedina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/metabolismoRESUMEN
c-Jun N-terminal kinase (JNK), a member of stress-induced mitogen-activated protein (MAP) kinase family, has been shown to modulate a variety of biological processes associated with neurodegenerative pathology of the retina. In particular, various retinal cell culture and animal models related to glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa indicate that JNK signaling may contribute to disease pathogenesis. This mini-review discusses the impact of JNK signaling in retinal disease, with a focus on retinal ganglion cells (RGCs), photoreceptor cells, retinal pigment epithelial (RPE) cells, and animal studies, with particular attention to modulation of JNK signaling as a potential therapeutic target for the treatment of retinal disease.
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Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Sistema de Señalización de MAP Quinasas , Degeneración Retiniana/enzimología , Trastornos de la Visión/enzimología , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Glaucoma/enzimología , Glaucoma/genética , Glaucoma/fisiopatología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/deficiencia , Degeneración Macular/enzimología , Degeneración Macular/genética , Degeneración Macular/fisiopatología , Ratones , Terapia Molecular Dirigida , Células Fotorreceptoras de Vertebrados/enzimología , Células Fotorreceptoras de Vertebrados/fisiología , Degeneración Retiniana/genética , Degeneración Retiniana/terapia , Epitelio Pigmentado de la Retina/enzimología , Epitelio Pigmentado de la Retina/fisiología , Trastornos de la Visión/genética , Trastornos de la Visión/terapiaRESUMEN
Understanding how Munc18 proteins govern exocytosis is crucial because mutations of this protein cause severe secretion deficits in neuronal and immune cells. Munc18-2 has indispensable roles in the degranulation of mast cell, partly by binding and chaperoning a subset of syntaxin isoforms. However, the key syntaxin that, crucially, participates in the degranulation whose levels and intracellular localization are regulated by Munc18-2 remains unknown. Here, we demonstrate that double knockdown of Munc18-1 and Munc-2 in mast cells results in greatly reduced degranulation accompanied with strikingly compromised expression levels and localization of syntaxin-3. This phenotype is fully rescued by wild-type Munc18 proteins but not by the K46E, E59K and K46E/E59K mutants of Munc-18 domain 1, each of which exhibits completely abolished binding to 'closed' syntaxin-3. Furthermore, knockdown of syntaxin-3 strongly impairs degranulation. Collectively, our data argue that residues Lys46 and Glu59 of Munc18 proteins are indispensable for mediating the interaction between Munc18 and closed syntaxin-3, which is essential for degranulation by chaperoning syntaxin-3. Our results also indicate that the functional contribution of these residues differs between immune cell degranulation and neuronal secretion.
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Mastocitos/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas Munc18/metabolismo , Unión Proteica/genética , Proteínas Qa-SNARE/metabolismo , Animales , Exocitosis , Humanos , RatasRESUMEN
Oxidative injuries, such as those related to reactive oxygen species (ROS), have been implicated in various retinal and optic nerve disorders. Many ROS detection methods have been developed. Although widely utilized, many of these methods are useful only in post mortem tissues, or require relatively expensive equipment, or involve intraocular injection. In the present study, we demonstrated and characterized a chemiluminescent probe L-012 as a noninvasive, in vivo ROS detection agent in the mouse retina. Using optic nerve crush (ONC) and retinal ischemia/reperfusion (I/R) as injury models, we show that L-012 produced intensive luminescent signals specifically in the injured eyes. Histological examination showed that L-012 administration was safe to the retina. Additionally, compounds that reduce tissue superoxide levels, apocynin and TEMPOL, decreased injury-induced L-012 chemiluminescence. The decrease in L-012 signals correlated with their protective effects against retinal I/R-induced morphological and functional changes in the retina. Together, these data demonstrate the feasibility of a fast, simple, reproducible, and non-invasive detection method to monitor in vivo ROS in the retina. Furthermore, the results also show that reduction of ROS is a potential therapeutic approach for protection from these retinal injuries.
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Traumatismos del Nervio Óptico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Neuronas Retinianas/metabolismo , Animales , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Sustancias Luminiscentes/metabolismo , Luminol/análogos & derivados , Luminol/metabolismo , Ratones , Ratones Endogámicos C57BL , Compresión Nerviosa , Estrés Oxidativo , Reproducibilidad de los ResultadosRESUMEN
Munc18-1 plays essential dual roles in exocytosis: (i) stabilizing and trafficking the central SNARE protein, syntaxin-1 (i.e. chaperoning function), by its domain-1; and (ii) priming/stimulating exocytosis by its domain-3a. Here, we examine whether or not domain-3a also plays a significant role in the chaperoning of syntaxin-1 and, if so, how these dual functions of domain-3a are regulated. We demonstrate that introduction of quintuple mutations (K332E/K333E/P335A/Q336A/Y337L) in domain-3a of Munc18-1 abolishes its ability to bind syntaxin-1 and fails to rescue the level and trafficking of syntaxin-1 as well as to restore exocytosis in Munc18-1/2 double knockdown cells. By contrast, a quadruple mutant (K332E/K333E/Q336A/Y337L) sparing the Pro-335 residue retains all of these capabilities. A single point mutant of P335A reduces the ability to bind syntaxin-1 and rescue syntaxin-1 levels. Nonetheless, it surprisingly outperforms the wild type in the rescue of exocytosis. However, when additional mutations in the neighboring residues are combined with P335A mutation (K332E/K333E/P335A, P335A/Q336A/Y337L), the ability of the Munc18-1 variants to chaperone syntaxin-1 and to rescue exocytosis is strongly impaired. Our results indicate that residues from Lys-332 to Tyr-337 of domain-3a are intimately tied to the chaperoning function of Munc18-1. We also propose that Pro-335 plays a pivotal role in regulating the balance between the dual functions of domain-3a. The hinged conformation of the α-helix containing Pro-335 promotes the syntaxin-1 chaperoning function, whereas the P335A mutation promotes its priming function by facilitating the α-helix to adopt an extended conformation.
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Exocitosis/fisiología , Chaperonas Moleculares/metabolismo , Proteínas Munc18/metabolismo , Sustitución de Aminoácidos , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Chaperonas Moleculares/genética , Proteínas Munc18/genética , Mutación Missense , Prolina/genética , Prolina/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Sintaxina 1/genética , Sintaxina 1/metabolismoRESUMEN
BACKGROUND: Trunk co-contraction during lifting may reflect a guarded motor response to a threatening task. This work estimated the impact of pain catastrophizing on trunk co-contraction during lifting, in people with and without low back pain. METHODS: Adults with high pain catastrophizing (back pain: n = 29, healthy: n = 7) and low pain catastrophizing (back pain: n = 20, healthy: n = 11), performed 10 repetitions of a lifting task. Electromyography data of rectus abdominis, erector spinae and external oblique muscles were collected, bilaterally. Co-contraction indices were determined for rectus abdominis/erector spinae and external oblique/erector spinae pairings, bilaterally. Pain catastrophizing was measured using the pain catastrophizing scale and task-specific fear using the Photograph series of daily activities scale. Three-way mixed ANOVAs tested the effects of group (back pain vs. healthy), pain catastrophizing (high vs. low), lifting phase (lifting vs. replacing) and their interactions. RESULTS: There were no main effects of pain catastrophizing, lifting phase, nor any interactions (p > 0.05). Group effects revealed greater co-contraction for bilateral erector spinae/rectus abdominis pairings (but not erector spinae-external oblique pairings) in people with back pain, compared to healthy participants, independent of pain catastrophizing and lifting phase (p < 0.05). Spearman correlations associated greater task-specific fear and greater erector spinae-left external oblique co-contraction, only in people with back pain (p < 0.05). CONCLUSIONS: Greater co-contraction in the back pain group occurred independent of pain catastrophizing, as measured with a general questionnaire. A task-specific measure of threat may be more sensitive to detecting relationships between threat and co-contraction. SIGNIFICANCE STATEMENT: This work contributes evidence that people with back pain commonly exhibit trunk co-contraction when lifting. The lack of a relationship between pain catastrophizing and trunk co-contraction, however, challenges evidence linking psychological factors and guarded motor behaviour in this group. Together, this suggests that other factors may be stronger determinants of co-contraction in people with LBP or that a general construct like pain catastrophizing may not accurately represent this relationship.
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PURPOSE: Profiling gene expression in human ocular tissues provides invaluable information for understanding ocular biology and investigating numerous ocular diseases. Accurate measurement of gene expression requires high-quality RNA, which often is a challenge with postmortem ocular tissues. METHODS: We examined the effect of various death to preservation (DP) times on the RNA quality of ten different ocular tissues. We used 16 eyes from eight different human donors. The eyes were preserved immediately in RNAlater or preserved after initial storage at 4 °C to create a range of DP times from 2 to 48 h. Ten ocular tissues were dissected from each eye. After total RNA was extracted from each dissected ocular tissue, the RNA integrity number (RIN) was determined using an Agilent Bioanalyzer. RESULTS: The RIN values from corneal and trabecular meshwork tissues were significantly (p<0.05) higher than those from the ciliary body at an earlier DP time (<6 h), but were not different among all tissues after 8 h. Interestingly, the RIN values from non-vascularized tissues were significantly (p=0.0002) higher than those from vascularized ocular tissues at early DP times (<6 h). The RIN value from the cornea was significantly (p<0.05) higher at short DP times compared to longer DP times. The RIN values from corneal tissues were significantly correlated to DP time according to regression analysis (p<0.05). CONCLUSIONS: In this study, we determined RNA quality from postmortem ocular tissues with various DP times. Our results emphasize the need for rapid preservation and processing of postmortem human donor eye tissues, especially for vascularized ocular tissues.
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Ojo/metabolismo , Cambios Post Mortem , ARN/normas , Femenino , Humanos , Masculino , Factores de Tiempo , Donantes de Tejidos , Conservación de TejidoRESUMEN
BACKGROUND: We tested whether fatty liver, brachial-ankle pulse wave velocity (baPWV) and conventional cardiovascular risk factors were associated with a coronary artery calcium (CAC) score > 0 (as a marker of the presence of early atherosclerosis) in a cohort of healthy Korean adults. METHOD: The study population consisted of individuals who underwent a comprehensive health examination in 2010 at Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University in South Korea. The 6009 subjects of total 7371 participants who had an assigned CAC score following coronary computed tomography (CT) scanning and baPWV were analyzed. RESULTS: Among the study subjects, 39.2% of the population had evidence of fatty liver by ultrasound and 4.6% of the population had evidence of CAC score > 0. Among individuals with a CAC score = 0, 38% of the individuals had fatty liver compared with 58% of the individuals with a CAC score > 0. The individuals with a CAC score > 0 also had higher blood pressure and had more metabolic abnormalities. The prevalence of CAC score > 0 was increased according to baPWV quartiles and was higher in the fatty liver group in comparison with those without fatty liver. The odds ratio for CAC score > 0, after adjusting for clinical risk factors, showed a significant elevation with increasing quartiles of baPWV and the presence of fatty liver. CONCLUSION: We showed that both fatty liver and baPWV are independently associated with the presence of CAC, a marker of preclinical atherosclerosis. These associations are independent of conventional risk factors and medical history.
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Enfermedad de la Arteria Coronaria/epidemiología , Hígado Graso/epidemiología , Calcificación Vascular/epidemiología , Rigidez Vascular , Adulto , Índice Tobillo Braquial , Estudios de Cohortes , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Hígado Graso/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de la Onda del Pulso , República de Corea/epidemiología , Tomografía Computarizada por Rayos X , Ultrasonografía , Calcificación Vascular/diagnóstico por imagenRESUMEN
Resolution of acute of infection caused by capsular Streptococcus pneumoniae infection in the absence of effective antibiotic therapy requires tight regulation of immune and inflammatory responses. To provide new mechanistic insight of the requirements needed for innate host defenses against acute S. pneumoniae infection, we examined how IL-23 deficiency mediated acute pulmonary resistance. We found that IL-23 deficient mice were more susceptible to bacterial colonization in the lungs corresponding with greater bacterial dissemination. The lack of IL-23 was found to decrease IL-6 and IL-12p70 cytokine levels in bronchiolar lavage within the initial day after infection. Pulmonary leukocytes isolated from infected IL-23 deficient mice demonstrated a dramatic decrease in IL-17A and IFN-γ in response to heat-killed organisms. These findings corresponded with significant abrogation of neutrophilic infiltrate in the lungs compared to IL-23 competent mice. Whereas previous studies have shown opposing influences of IL-12/IL-23 regulation, our findings suggest a concordant dependency of IL-23 expression on Th1 and Th17-related responses.
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Subunidad p19 de la Interleucina-23/deficiencia , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Femenino , Inmunidad Innata , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunologíaRESUMEN
Caudal articular process (CAP) dysplasia is a congenital vertebral malformation that results from the failure of ossification center of articular process located in vertebrae, which includes aplasia or hypoplasia. In previous studies, it was reported to be common in small and chondrodystrophic dogs however, investigated in limited breeds. So we aimed to confirm the prevalence and the characteristics of CAP dysplasia in various breeds, and also to investigate the association of CAP dysplasia and spinal cord myelopathy in neurologically abnormal dogs. In this multicenter, retrospective study, the clinical records and thoracic vertebral column computed tomographic (CT) images of 717 dogs between February 2016 and August 2021 were included and 119 dogs which also underwent magnetic resonance imaging (MRI) examination were evaluated. Overall, 337 of 717 dogs (47.0%) had at least one thoracic CAP dysplasia and the prevalence of CAP dysplasia was significantly higher in dogs with a lower body weight (P < 0.0001). A total of 66.4% of toy breeds, 39.0% of small breeds, 20.2% of medium breeds, and 6.0% of large breeds were affected by at least one CAP dysplasia. The most affected vertebra was T4 in toy (48.1%) and small breeds (20.8%), and T5 in medium (20.8%) and large breeds (5.0%). In all groups, prevalence of CAP dysplasia between T1 and T9 was higher than post-diaphragmatic vertebrae (T10-T13). Fifty nine of 119 dogs which underwent both CT and MRI examination had symptoms of spinal cord myelopathy of T3-L3 and twenty-five of 59 dogs (42.3%) had at least one thoracic CAP dysplasia. In that 25 neurologically abnormal dogs, 41 sites of intervertebral disc disease (IVDD) were detected. However, only one dog had both CAP dysplasia and herniated disc at the same level. Also, CAP dysplasia associated non-compressive spinal myelopathy at the same level was found in the other dog. Association CAP dysplasia with spinal myelopathy is speculated but is not confirmed by this study.
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Introduction: Transarterial embolization (TAE) is one of the treatment options for liver masses that are not suitable for surgery and they have been applied in veterinary medicine for about 20 years, but surgical resection is considered as the first treatment option, and only a few case reports and articles about TAE in dogs have been published. Although understanding of vascular anatomy for the procedure is important, previous studies lack of the information about hepatic artery anatomy in small and toy-breed dogs. Due to the introduction of 3D print in veterinary medicine, it is now possible to make 3D models for preoperative planning. The purpose of this study is to understand the hepatic arterial vascular structure of various sizes and breeds of dogs, and to develop 3D-printed canine artery models with and without hepatic tumors to simulate TAE procedure. Methods: CT images of a total of 84 dogs with normal hepatic arteries were analyzed, and the mean value and standard deviation of body weight, celiac artery size, and hepatic artery size were 6.47 ± 4.44 kg, 3.28 ± 0.77 mm, and 2.14 ± 0.43 mm, respectively. Results: It was established that type 2-2-1, which has two separate hepatic branches-the right medial and left branch and the right lateral branch that runs to the right lateral lobe and caudate process-is the most prevalent of the hepatic artery branch types, as it was in the previous study. The review of 65 CT images of dogs with hepatic tumors showed that 44.6% (29/65) had multifocal lesions in multiple lobes, for which TAE can be recommended. Discussion: Based on the result, a 3D model of the normal canine hepatic artery and the hepatic tumor was made using one representative case from each group, and despite the models having some limitations in reflecting the exact tactile and velocity of blood vessels, TAE procedure was successfully simulated using both models.
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Myrrh has been used as an antibacterial and anti-inflammatory agent. However, effect of myrrh on peritoneal macrophages and clinically relevant models of septic shock, such as cecal ligation and puncture (CLP), is not well understood. Here, we investigated the inhibitory effect and mechanism(s) of myrrh on inflammatory responses. Myrrh inhibited LPS-induced productions of inflammatory mediators such as nitric oxide, prostaglandin E(2), and tumor necrosis factor-α but not of interleukin (IL)-1ß and IL-6 in peritoneal macrophages. In addition, Myrrh inhibited LPS-induced activation of c-jun NH(2)-terminal kinase (JNK) but not of extracellular signal-regulated kinase (ERK), p38, and nuclear factor-κB. Administration of Myrrh reduced the CLP-induced mortality and bacterial counts and inhibited inflammatory mediators. Furthermore, administration of Myrrh attenuated CLP-induced liver damages, which were mainly evidenced by decreased infiltration of leukocytes and aspartate aminotransferase/alanine aminotransferase level. Taken together, these results provide the evidence for the anti-inflammatory and antibacterial potential of Myrrh in sepsis.
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PURPOSE: Macular edema including cystoid macular edema is one of the main causes of unfavorable visual outcomes after cataract surgery. The macular thickness and the occurrence of macular edema after uncomplicated cataract surgery was evaluated using optical coherence tomography (OCT) in this study. METHODS: Macular map images were taken by OCT before surgery and at 1 week, 1 month, and 2 months postsurgery. The subjects were classified into two groups (group 1, patients with no macular edema; group 2, patients with macular edema). Group 2 was defined as increase in central macular thickness (CMT) by 30% compared with that before surgery. The risk factors for macular edema were evaluated. Group 2 was divided into two subgroups: subclinical macular edema (group 2A) and cystoid macular edema (group 2B) and they were assessed in terms of the clinical course of best-corrected visual acuity and CMT. RESULTS: A total of 376 patients were enrolled in this study, of which 36 (9.57%, group 2) showed macular edema measured by OCT after the surgery. Univariate analysis for group 1 and 2 revealed that intracameral injection of epinephrine during phacoemulsification was associated with the development of macular edema. In group 2, five patients (1.33%) developed cystoid macular edema. Statistically significant differences in the clinical course of CMT were observed at 2 months (201.2 ± 23.1, 250.0 ± 29.8, and 371.0 ± 160.3 in group 1, group 2A, and group 2B, respectively; p < 0.001) and 1 month postoperatively (198.5 ± 23.6, 237.8 ± 40.9, and 314.0 ± 104.5 in group 1, group 2A, and group 2B, respectively; p < 0.001). Group 2B required additional treatment and eventually achieved best-corrected visual acuity of >0.2 with CMT in the normal range. CONCLUSIONS: The intracameral injection of epinephrine may cause macular edema after uncomplicated cataract surgery. Examination of CMT using OCT is recommended for the early detection of macular edema.
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Catarata , Edema Macular , Facoemulsificación , Catarata/complicaciones , Edema/etiología , Epinefrina , Humanos , Implantación de Lentes Intraoculares/efectos adversos , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Facoemulsificación/efectos adversos , Facoemulsificación/métodos , Estudios Prospectivos , Tomografía de Coherencia Óptica/métodos , Agudeza VisualRESUMEN
Acute pancreatitis (AP) is an inflammatory disease involving acinar cell injury and rapid production and release of inflammatory cytokines, which play a dominant role in local pancreatic inflammation and systemic complications. 2',4',6'-Tris (methoxymethoxy) chalcone (TMMC), a synthetic chalcone derivative, displays potent anti-inflammatory effects. Therefore, we aimed to investigate whether TMMC might affect the severity of AP and pancreatitis-associated lung injury in mice. We used the cerulein hyperstimulation model of AP. Severity of pancreatitis was determined in cerulein-injected mice by histological analysis and neutrophil sequestration. The pretreatment of mice with TMMC reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (activity of amylase, lipase, trypsin, trypsinogen, and myeloperoxidase and production of proinflammatory cytokines). In addition, TMMC inhibited pancreatic acinar cell death and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 by inhibiting NF-κB and extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation. Neutralizing antibodies for TNF-α, IL-1ß, and IL-6 inhibited cerulein-induced cell death in isolated pancreatic acinar cells. Moreover, pharmacological blockade of NF-κB/ERK1/2 reduced acinar cell death and production of TNF-α, IL-1ß, and IL-6 in isolated pancreatic acinar cells. In addition, posttreatment of mice with TMMC showed reduced severity of AP and lung injury. Our results suggest that TMMC may reduce the complications associated with pancreatitis.
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Antiinflamatorios/uso terapéutico , Chalconas/uso terapéutico , Lesión Pulmonar/prevención & control , Pancreatitis/tratamiento farmacológico , Amilasas/sangre , Animales , Ceruletida , Interleucina-1beta/sangre , Interleucina-6/sangre , Lipasa/sangre , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Pancreatitis/inducido químicamente , Pancreatitis/complicaciones , Pancreatitis/patología , Peroxidasa/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Piperine is a phenolic component of black pepper (Piper nigrum) and long pepper (Piper longum), fruits used in traditional Asian medicine. Our previous study showed that piperine inhibits lipopolysaccharide-induced inflammatory responses. In this study, we investigated whether piperine reduces the severity of cerulein-induced acute pancreatitis (AP). Administration of piperine reduced histologic damage and myeloperoxidase (MPO) activity in the pancreas and ameliorated many of the examined laboratory parameters, including the pancreatic weight (PW) to body weight (BW) ratio, as well as serum levels of amylase and lipase and trypsin activity. Furthermore, piperine pretreatment reduced the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 during cerulein-induced AP. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti-inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs. Thus, piperine may have a protective effect against AP.