RESUMEN
All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions.
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Drosophila/inmunología , Drosophila/microbiología , Inmunidad Mucosa , Pectobacterium carotovorum/fisiología , Simbiosis , Uracilo/metabolismo , Animales , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiología , Homeostasis , Humanos , Inflamación/inmunología , Inflamación/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Madre/metabolismoRESUMEN
BACKGROUND: In response to severe kidney injury, the kidney epithelium displays remarkable regenerative capabilities driven by adaptable resident epithelial cells. To date, it has been widely considered that the adult kidney lacks multipotent stem cells; thus, the cellular lineages responsible for repairing proximal tubule damage are incompletely understood. Leucine-rich repeats and immunoglobulin-like domains protein 1-expressing cells (Lrig1+ cells) have been identified as a long-lived cell in various tissues that can induce epithelial tissue repair. Therefore, we hypothesized that Lrig1+ cells participate in kidney development and tissue regeneration. METHODS: We investigated the role of Lrig1+ cells in kidney injury using mouse models. The localization of Lrig1+ cells in the kidney was examined throughout mouse development. The function of Lrig1+ progeny cells in acute kidney injury repair was examined in vivo using a tamoxifen-inducible Lrig1-specific Cre recombinase-based lineage tracing in three different kidney injury mouse models. Additionally, we conducted single-cell RNA-sequencing to characterize the transcriptional signature of Lrig1+ cells and to trace their progeny. RESULTS: Lrig1+ cells were present during kidney development and contributed to formation of the proximal tubule and collecting duct structures in mature mouse kidneys. In three-dimensional culture, single Lrig1+ cells demonstrated long-lasting propagation and differentiated into the proximal tubule and collecting duct lineages. These Lrig1+ proximal tubule cells highly expressed progenitor-like and quiescence-related genes, giving rise to a novel cluster of cells with regenerative potential in adult kidneys. Moreover, these long-lived Lrig1+ cells expanded and repaired damaged proximal tubules in response to three types of acute kidney injury in mice. CONCLUSIONS: These findings highlight the critical role of Lrig1+ cells in kidney regeneration.
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Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.
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Infección Hospitalaria/etiología , NADH Deshidrogenasa/metabolismo , Choque Séptico/complicaciones , Anciano , Anciano de 80 o más Años , Factores Quimiotácticos/metabolismo , Quimiotaxis , Infección Hospitalaria/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , NADH Deshidrogenasa/fisiología , Activación Neutrófila , Neutrófilos/metabolismo , Péptidos/metabolismo , Receptores de Formil Péptido/metabolismo , Choque Séptico/metabolismo , Choque Séptico/fisiopatologíaRESUMEN
Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.
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Fibroblastos , Interleucinas , Queratinocitos , Material Particulado , Envejecimiento de la Piel , Envejecimiento de la Piel/efectos de los fármacos , Material Particulado/toxicidad , Interleucinas/metabolismo , Interleucinas/genética , Queratinocitos/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Senescencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Factor de Transcripción STAT3/metabolismo , Piel/efectos de los fármacos , Contaminantes Atmosféricos/toxicidadRESUMEN
Previous research demonstrated the potential of using speakers as sensors to detect ear canal conditions. This study continues that effort by using a single speaker to measure electrical impedance across various acoustic loads. Electrical impedance data were collected and preprocessed for machine learning model training. Different image forms were tested, including magnitude only and combined magnitude phase. Using 2100 data samples with convolutional neural network-based models (AlexNet, ResNet, and DenseNet), binary and multiclass classifications achieved average accuracies of 0.9716 and 0.907, respectively. This innovative approach is set to revolutionize acoustic sensing through artificial intelligence.
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Acústica , Inteligencia Artificial , Humanos , Impedancia Eléctrica , Redes Neurales de la Computación , Conducto Auditivo Externo/fisiología , Aprendizaje AutomáticoRESUMEN
BACKGROUND: Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. Pellino-1 (Peli1) belongs to a member of E3 ubiquitin ligase mediating immune receptor signaling cascades, including nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway. OBJECTIVE: We explored the potential role of Peli1 in psoriatic inflammation in the context of skin-resident T17 cells. METHODS: We performed single-cell RNA sequencing of relapsing and resolved psoriatic lesions with analysis for validation data set of psoriasis. Mice with systemic and conditional depletion of Peli1 were generated to evaluate the role of Peli1 in imiquimod-induced psoriasiform dermatitis. Pharmacologic inhibition of Peli1 in human CD4+ T cells and ex vivo human skin cultures was also examined to evaluate its potential therapeutic implications. RESULTS: Single-cell RNA sequencing analysis revealed distinct T-cell subsets in relapsing psoriasis exhibiting highly enriched gene signatures for (1) tissue-resident T cells, (2) T17 cells, and (3) NF-κB signaling pathway including PELI1. Peli1-deficient mice were profoundly protected from psoriasiform dermatitis, with reduced IL-17A production and NF-κB activation in γδ T17 cells. Mice with conditional depletion of Peli1 treated with FTY720 revealed that Peli1 was intrinsically required for the skin-resident T17 cell immune responses. Notably, pharmacologic inhibition of Peli1 significantly ameliorated murine psoriasiform dermatitis and IL-17A production from the stimulated human CD4+ T cells and ex vivo skin explants modeling psoriasis. CONCLUSION: Targeting Peli1 would be a promising therapeutic strategy for psoriasis by limiting skin-resident T17 cell immune responses.
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Dermatitis , Psoriasis , Ratones , Humanos , Animales , Interleucina-17 , FN-kappa B/metabolismo , Piel , Modelos Animales de Enfermedad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Chamaecyparis obtusa (Siebold & Zucc.) Endl. (C. obtusa) belongs to the Cupressaceae family and is native to East Asian regions. Essential oils extracted from the leaves, bark, branches, and roots of C. obtusa have both aesthetic and medicinal properties and are thus widely used. However, detailed analyses of the active ingredients of C. obtusa extract are lacking. In this study, the sabinene content in the hydro-distillation of C. obtusa leaf essential oil (COD) was analyzed using GC-MS, and the anti-inflammatory effect of COD was compared with that of pure sabinene. Cell viability was evaluated by MTT assay, and nitric oxide (NO) production was measured using Griess reagent. Relative mRNA and protein levels were analyzed using RT-qPCR and western blot, and secreted cytokines were analyzed using a cytokine array kit. The results showed that both COD and sabinene inhibited the expression of inducible nitric oxide synthase (iNOS) and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 in lipopolysaccharide (LPS)-induced RAW 264.7 cells. COD and sabinene also reduced the production of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, IL-27, IL-1 receptor antagonist (IL-1ra), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The anti-inflammatory mechanisms of COD and sabinene partially overlap, as COD was shown to inhibit MAPKs and the JAK/STAT axis, and sabinene inhibited MAPKs, thereby preventing LPS-induced macrophage activation.
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Monoterpenos Bicíclicos , Chamaecyparis , Aceites Volátiles , Aceites Volátiles/farmacología , Chamaecyparis/metabolismo , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Citocinas/metabolismo , Hojas de la Planta/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
BACKGROUND: Currently, there is a relative lack of detailed reports regarding clinical presentation and outcome of idiopathic intracranial hypertension in Asians. This study aims to describe the clinical features and treatment outcomes of Korean patients with idiopathic intracranial hypertension. METHODS: We prospectively recruited patients with idiopathic intracranial hypertension from one hospital and retrospectively analyzed the medical records of 11 hospitals in Korea. We collected data regarding preceding medical conditions or suspected medication exposure, headache phenotypes, other associated symptoms, detailed neuroimaging findings, treatments, and outcomes after 1-2 and 3-6 months of treatment. RESULTS: Fifty-nine (83.1% women) patients were included. The mean body mass index was 29.11 (standard deviation, 5.87) kg/m2; only 27 patients (45.8%) had a body mass index of ≥ 30 kg/m2. Fifty-one (86.4%) patients experienced headaches, patterns of which included chronic migraine (15/51 [29.4%]), episodic migraine (8/51 [15.7%]), probable migraine (4/51 [7.8%]), chronic tension-type headache (3/51 [5.9%]), episodic tension-type headache (2/51 [3.9%]), probable tension-type headache (2/51 [3.9%]), and unclassified (17/51 [33.3%]). Medication overuse headache was diagnosed in 4/51 (7.8%) patients. After 3-6 months of treatment, the intracranial pressure normalized in 8/32 (25.0%), improved in 17/32 (53.1%), no changed in 7/32 (21.9%), and worsened in none. Over the same period, headaches remitted or significantly improved by more than 50% in 24/39 patients (61.5%), improved less than 50% in 9/39 (23.1%), and persisted or worsened in 6/39 (15.4%) patients. CONCLUSION: Our findings suggest that the features of Asian patients with idiopathic intracranial hypertension may be atypical (i.e., less likely obese, less female predominance). A wide spectrum of headache phenotypes was observed. Medical treatment resulted in overall favorable short-term outcomes; however, the headaches did not improve in a small proportion of patients.
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Seudotumor Cerebral , Humanos , Femenino , Masculino , República de Corea/epidemiología , Adulto , Resultado del Tratamiento , Seudotumor Cerebral/terapia , Seudotumor Cerebral/tratamiento farmacológico , Seudotumor Cerebral/diagnóstico , Estudios Retrospectivos , Persona de Mediana Edad , Adulto Joven , Estudios ProspectivosRESUMEN
Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.
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COVID-19 , Animales , Cricetinae , Ratones , Humanos , SARS-CoV-2 , Pandemias , Anticuerpos Neutralizantes , Mesocricetus , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besides Helicobacter pylori may also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota. DESIGN: Microbiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year. RESULTS: The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation. CONCLUSION: Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
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Infecciones por Helicobacter , Helicobacter pylori , Microbiota , Neoplasias Gástricas , Animales , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/patología , Humanos , Hiperplasia/patología , Metaplasia/patología , Ratones , Ratones Endogámicos C57BL , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Costal cartilage is commonly employed as a dorsal implant in Asian rhinoplasty. To achieve better outcomes, it is important to know which types of costal cartilage are most appropriate for dorsal augmentation. OBJECTIVES: The authors investigated how various forms of costal cartilage affect the surrounding tissues and their resorption over time, as well as their clinical appearance, using histomorphological analysis. METHODS: Cartilage samples were collected from the anterior chest wall of 10 rabbits. Four forms of cartilage-2-mm solid block, 1-mm solid block, diced, and crushed-were prepared and inserted into the subcutaneous tissue pockets of the nasal dorsum of each rabbit. The animals were killed 3 and 6 months later, and graft specimens were examined. RESULTS: Histomorphological analysis revealed important findings of the cartilage and surrounding tissues. The thickness of thick cartilage significantly decreased over time, but the thickness of thin cartilage did not significantly change (P = 0.038). Additionally, the thick cartilages showed a lower degree of vascularization than the thin cartilages (P < 0.001). A comparison of the cartilage forms revealed that the diced cartilages had better chondrocyte survival than the solid block cartilages (P < 0.001). Fat tissues were prominently observed surrounding the diced cartilages at 3 months (P = 0.01), and fibrosis was more prominently observed in the crushed cartilage than in the other types of cartilages (P = 0.04 and P = 0.005 at 3 and 6 months, respectively). CONCLUSIONS: This study revealed differences in resorption depending on the thickness of the costal cartilage in rabbits. Among the various forms of costal cartilages, diced and thin solid-block cartilage were the best option for dorsal augmentation when considering long-term graft survival.
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Cartílago Costal , Rinoplastia , Tejido Adiposo/trasplante , Animales , Pueblo Asiatico , Cartílago/trasplante , Humanos , Nariz , ConejosRESUMEN
All metazoan guts are in permanent contact with the microbial realm. However, understanding of the exact mechanisms by which the strength of gut immune responses is regulated to achieve gut-microbe mutualism is far from complete. Here we identify a signaling network composed of complex positive and negative mechanisms that controlled the expression and activity of dual oxidase (DUOX), which 'fine tuned' the production of microbicidal reactive oxygen species depending on whether the gut encountered infectious or commensal microbes. Genetic analyses demonstrated that negative and positive regulation of DUOX was required for normal host survival in response to colonization with commensal and infectious microbes, respectively. Thus, the coordinated regulation of DUOX enables the host to achieve gut-microbe homeostasis by efficiently combating infection while tolerating commensal microbes.
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Drosophila/inmunología , NADPH Oxidasas/fisiología , Factor de Transcripción Activador 2/fisiología , Animales , Células CACO-2 , Calcineurina/fisiología , Proteínas Portadoras/fisiología , Regulación Enzimológica de la Expresión Génica , Humanos , Intestinos/inmunología , Intestinos/microbiología , MAP Quinasa Quinasa 3/fisiología , Quinasa 1 de Quinasa de Quinasa MAP/fisiología , NADPH Oxidasas/genética , Fosfolipasa C beta/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Transcripción Genética , Proteínas Quinasas p38 Activadas por Mitógenos/fisiologíaRESUMEN
OBJECTIVE AND BACKGROUND: Post-dural puncture headache is the most common significant adverse event following lumbar puncture. In this study, we investigated the possible systemic factors associated with risk for post-dural puncture headache (PDPH). METHODS: We performed a retrospective cohort study in 969 patients who underwent diagnostic lumbar puncture following a standardized protocol. We compared the clinical and laboratory profiles of the post-dural puncture headache group and non-headache group. We also identified independent factors associated with the incidence of post-dural puncture headache. RESULTS: A total of 48 patients (5%) reported headache; 12 of these patients (25%) received a therapeutic epidural blood patch and the remaining 36 patients improved with conservative treatment. After adjusting for other variables that could be related to PDPH, we found that the development of post lumbar puncture headache was independently associated with age (OR: 0.97, 95% CI: 0.95-0.99, P = .001) and serum glucose levels (OR: 0.98, 95% CI: 0.97-0.99, P = .008).When the patients were classified by age, serum glucose levels were persistently lower in patients with PDPH vs those patients without PDPH in all age groups, with more clearly significant differences observed in the elderly (age <30 years, 103.4 mg/dL vs 106.3 mg/dL, P = .716; >60 years, 111.8 mg/dL vs 137.3 mg/dL, P = .023). CONCLUSIONS: Low glucose levels were inversely associated with risk for post-dural puncture headache. Patients with low serum glucose should be carefully monitored for headache after lumbar puncture.
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Glucemia , Parche de Sangre Epidural , Cefalea Pospunción de la Duramadre/diagnóstico , Cefalea Pospunción de la Duramadre/terapia , Sistema de Registros , Adulto , Factores de Edad , Anciano , Parche de Sangre Epidural/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cefalea Pospunción de la Duramadre/epidemiología , Estudios Prospectivos , RiesgoRESUMEN
The mechanism of perverted vertical responses during horizontal head impulse tests (HITs) requires further elucidation. A 47-year-old woman with a Chiari malformation showed alternating skew deviation, downbeat nystagmus with an increasing slow phase velocity, impaired smooth pursuit, and upward ocular deviation during horizontal HITs and corrective downward saccades in the presence of normal bithermal caloric tests and intact tilt suppressions of the post-rotatory nystagmus. These findings suggest dysfunction of the inferior cerebellum including the tonsil, nodulus, and uvula. We propose that disruption of signals from the medial part of the vestibulocerebellum, which normally inhibits the lateral and anterior canal pathways, may elicit an upward misdirection of the eye velocity during rapid horizontal head rotation. Otherwise, the Chiari malformation may have directly affected the brainstem structures involved in the direction matrix of the vestibulo-ocular reflex.
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Malformación de Arnold-Chiari/fisiopatología , Movimientos Sacádicos/fisiología , Malformación de Arnold-Chiari/complicaciones , Femenino , Prueba de Impulso Cefálico , Humanos , Persona de Mediana Edad , Nistagmo Patológico/etiología , Nistagmo Patológico/fisiopatologíaRESUMEN
BACKGROUND: The mechanisms of pendular seesaw nystagmus (SSN) remain unknown. METHODS: We evaluated modulation of pendular SSN by removal of visual fixation, convergence, and positional changes in 2 patients, one with bitemporal hemianopia due to a traumatic damage of the optic chiasm and the other with platybasia compressing the medulla and lower cerebellum. RESULTS: In both patients, the pendular SSN markedly decreased or disappeared with convergence, without visual fixation in darkness, during static head tilt toward each shoulder while sitting and while supine. CONCLUSIONS: The similar patterns of nystagmus modulation observed in our patients with a different etiology indicate a common role of both visual and otolithic inputs in generating pendular SSN.
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Convergencia Ocular/fisiología , Fijación Ocular/fisiología , Nistagmo Patológico/fisiopatología , Percepción Visual/fisiología , Medidas del Movimiento Ocular , Femenino , Hemianopsia/diagnóstico , Hemianopsia/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Oftalmoscopía , Atrofia Óptica/diagnóstico , Atrofia Óptica/fisiopatología , Platibasia/diagnóstico , Platibasia/fisiopatología , Pruebas del Campo Visual , Adulto JovenRESUMEN
OBJECTIVES: To determine neuroprotective effects and mechanism of the combination therapy of niacin and selenium in cardiac arrest rats. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Rat cortex neurons and male Sprague-Dawley rats (n = 68). INTERVENTIONS: In rat cortex neurons underwent 90 minutes of oxygen-glucose deprivation and 22.5 hours of reoxygenation, effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 µM) were investigated. The role of DJ-1 was determined using DJ-1 knockdown cells. In cardiac arrest rats, posttreatment effects of the combination therapy of niacin (360 mg/kg) and selenium (60 µg/kg) were evaluated. MEASUREMENTS AND MAIN RESULTS: In oxygen-glucose deprivation and 22.5 hours of reoxygenation cells, combination therapy synergistically activated the glutathione redox cycle by a niacin-induced increase in glutathione reductase and a selenium-induced increase in glutathione peroxidase activities and reduced hydrogen peroxide level. It increased phosphorylated Akt and intranuclear Nuclear factor erythroid 2-related factor 2 expression and attenuated neuronal injury. However, these benefits were negated by DJ-1 knockdown. In cardiac arrest rats, combination therapy increased DJ-1, phosphorylated Akt, and intranuclear nuclear factor erythroid 2-related factor 2 expression, suppressed caspase 3 cleavage, and attenuated histologic injury in the brain tissues. It also improved the 7-day Neurologic Deficit Scales from 71.5 (66.0-74.0) to 77.0 (74.-80.0) (p = 0.02). CONCLUSIONS: The combination therapy of clinically relevant doses of niacin and selenium attenuated brain injury and improved neurologic outcome in cardiac arrest rats. Its benefits were associated with reactive oxygen species reduction and subsequent DJ-1-Akt signaling up-regulation.
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Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/etiología , Paro Cardíaco/complicaciones , Niacina/farmacología , Selenio/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Masculino , Oxidación-Reducción/efectos de los fármacos , Proteína Desglicasa DJ-1/biosíntesis , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Psoriasis is largely mediated by interleukin (IL)-23/T helper (Th) 17 axis, and IL-21 is a pleiotropic cytokine expressed by Th17 cells. Despite previously reported possible pathogenic roles of IL-21 in human psoriasis, we found that IL-21 receptor (IL-21R) signalling was not crucial for imiquimod-induced psoriatic inflammation, using IL-21R-/- mice. The severity of imiquimod-induced psoriatic manifestation and pro-inflammatory Th17 cytokine levels, IL-17A-producing γδ T cells and CD4+ T cells, and in vitro IL-17A production by γδ T cells after IL-23 stimulation was comparable between wild-type and IL-21R-/- mice. Collectively, IL-21R signalling was not critically involved in IMQ-induced psoriatic inflammation despite an increased IL-21 expression in the IMQ-treated mouse skin. Our data may represent the significant differences between human psoriasis and murine psoriasis model, and further studies using other models will be required to elucidate the role of IL-21 in psoriasis pathogenesis.
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Dermatitis/genética , Subunidad alfa del Receptor de Interleucina-21/metabolismo , Psoriasis/genética , Receptores de Interleucina-21/metabolismo , Animales , Linfocitos T CD4-Positivos/citología , Dermatitis/metabolismo , Imiquimod , Inflamación , Inductores de Interferón/farmacología , Subunidad alfa del Receptor de Interleucina-21/genética , Subunidad p19 de la Interleucina-23/metabolismo , Linfocitos Intraepiteliales/citología , Ratones , Ratones Noqueados , Ratones Transgénicos , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Receptores de Interleucina-21/genética , Transducción de SeñalRESUMEN
BACKGROUND: Secondary prevention of cardiovascular disease (CVD) has improved immensely during the past decade but controversies persist on cardiovascular benefits among women with diabetes. We investigated 11-year trends in hospital admission rates for acute myocardial infarction (AMI), stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) in people with and without diabetes by gender in England. METHODS: We identified all hospital admissions for cardiovascular disease causes among people aged 17 years and above between 2004 and 2014 in England. We calculated diabetes-specific and non-diabetes-specific rates for study outcomes by gender. To assess temporal changes, we fitted negative binomial regression models. RESULTS: Diabetes-related admission rates remained unchanged for AMI (incidence rate ratio (IRR) 0.99 [95% CI 0.98-1.01]), increased for stroke by 2% (1.02 [1.01-1.03]) and PCI by 3% (1.03 [1.01-1.04]) and declined for CABG by 3% (0.97 [0.96-0.98]) annually. Trends did not differ significantly by diabetes status. Women with diabetes had significantly lower rates of AMI (IRR 0.46 [95% CI 0.40-0.53]) and stroke (0.73 [0.63-0.84]) compared with men with diabetes. However, gender differences in admission rates for AMI attenuated in diabetes compared with the non-diabetic group. While diabetes tripled admission rates for AMI in men (IRR 3.15 [95% CI 2.72-3.64]), it increased it by over fourfold among women (4.27 [3.78-4.93]). Furthermore, while the presence of diabetes was associated with a threefold increased rates for PCI and fivefold increased rates for CABG (IRR 3.14 [2.83-3.48] and 5.01 [4.59-5.05], respectively) in men, among women diabetes was associated with a 4.4-fold increased admission rates for PCI and 6.2-fold increased rates for CABG (4.37 [3.93-4.85] and 6.24 [5.66-6.88], respectively). Proportional changes in rates were similar in men and women for all study outcomes, leaving the relative risk of admissions unchanged. CONCLUSIONS: Diabetes still confers a greater increase in risk of hospital admission for AMI in women relative to men. However, the absolute risk remains higher in men. These results call for intensified CVD risk factor management among people with diabetes, consideration of gender-specific treatment targets and treatment intensity to be aligned with levels of CVD risk.
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Diabetes Mellitus/terapia , Infarto del Miocardio/terapia , Admisión del Paciente/estadística & datos numéricos , Accidente Cerebrovascular/terapia , Anciano , Puente de Arteria Coronaria/métodos , Inglaterra , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Caracteres SexualesRESUMEN
Following the success of antiretroviral therapy, an expanding cohort of adolescents with perinatally acquired HIV (PaHIV) is transitioning into adult care. Dedicated multidisciplinary transitional care HIV services have been established in the UK. However, published data on patient satisfaction with such services are sparse. A single centre survey of patient satisfaction was conducted in January 2014, and results compared to a previous similar survey in 2009. Patients were asked to complete a questionnaire regarding views of their care using a 7-point Likert scale. 51/96 attended within the time period and all completed the survey, compared with 21 in 2009. Ninety-two percent were satisfied with the care provided by the clinic, compared to 100% in 2009. The proportion who felt moving to their current service had a positive effect on their health increased from 68% in 2009 to 81% in 2014. Ninety-two percent were satisfied with the overall care provided by the clinic, compared to 100% in 2009. Ninety-four percent agreed that staff knew how to talk and listen to young people, 96% agreed staff were able to explain their treatments and problems clearly in a way that they could understand. Ninety-six percent felt that a clinic specifically for young people was useful. Despite a marked increase in clinic attendees and unchanged levels of service provision, patient satisfaction remained high. Patients strongly value the provision of dedicated services for young people.
Asunto(s)
Continuidad de la Atención al Paciente/organización & administración , Infecciones por VIH/tratamiento farmacológico , Satisfacción del Paciente , Satisfacción Personal , Transición a la Atención de Adultos , Adolescente , Adulto , Instituciones de Atención Ambulatoria , Estudios de Cohortes , Femenino , Infecciones por VIH/psicología , Encuestas de Atención de la Salud , Humanos , Masculino , Encuestas y Cuestionarios , Reino UnidoRESUMEN
BACKGROUND: While online health social networks (OHSNs) serve as an effective platform for patients to fulfill their various social support needs, predicting the needs of users and providing tailored information remains a challenge. OBJECTIVE: The objective of this study was to discriminate important features for identifying users' social support needs based on knowledge gathered from survey data. This study also provides guidelines for a technical framework, which can be used to predict users' social support needs based on raw data collected from OHSNs. METHODS: We initially conducted a Web-based survey with 184 OHSN users. From this survey data, we extracted 34 features based on 5 categories: (1) demographics, (2) reading behavior, (3) posting behavior, (4) perceived roles in OHSNs, and (5) values sought in OHSNs. Features from the first 4 categories were used as variables for binary classification. For the prediction outcomes, we used features from the last category: the needs for emotional support, experience-based information, unconventional information, and medical facts. We compared 5 binary classifier algorithms: gradient boosting tree, random forest, decision tree, support vector machines, and logistic regression. We then calculated the scores of the area under the receiver operating characteristic (ROC) curve (AUC) to understand the comparative effectiveness of the used features. RESULTS: The best performance was AUC scores of 0.89 for predicting users seeking emotional support, 0.86 for experience-based information, 0.80 for unconventional information, and 0.83 for medical facts. With the gradient boosting tree as our best performing model, we analyzed the strength of individual features in predicting one's social support need. Among other discoveries, we found that users seeking emotional support tend to post more in OHSNs compared with others. CONCLUSIONS: We developed an initial framework for automatically predicting social support needs in OHSNs using survey data. Future work should involve nonsurvey data to evaluate the feasibility of the framework. Our study contributes to providing personalized social support in OHSNs.