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Brain extraction and image quality assessment are two fundamental steps in fetal brain magnetic resonance imaging (MRI) 3D reconstruction and quantification. However, the randomness of fetal position and orientation, the variability of fetal brain morphology, maternal organs around the fetus, and the scarcity of data samples, all add excessive noise and impose a great challenge to automated brain extraction and quality assessment of fetal MRI slices. Conventionally, brain extraction and quality assessment are typically performed independently. However, both of them focus on the brain image representation, so they can be jointly optimized to ensure the network learns more effective features and avoid overfitting. To this end, we propose a novel two-stage dual-task deep learning framework with a brain localization stage and a dual-task stage for joint brain extraction and quality assessment of fetal MRI slices. Specifically, the dual-task module compactly contains a feature extraction module, a quality assessment head and a segmentation head with feature fusion for simultaneous brain extraction and quality assessment. Besides, a transformer architecture is introduced into the feature extraction module and the segmentation head. We utilize a multi-step training strategy to guarantee a stable and successful training of all modules. Finally, we validate our method by a 5-fold cross-validation and ablation study on a dataset with fetal brain MRI slices in different qualities, and perform a cross-dataset validation in addition. Experiments show that the proposed framework achieves very promising performance.
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Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Humanos , Embarazo , Femenino , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Cabeza , Feto/diagnóstico por imagenRESUMEN
INTRODUCTION: Lower respiratory tract infections(LRTIs) in adults are complicated by diverse pathogens that challenge traditional detection methods, which are often slow and insensitive. Metagenomic next-generation sequencing (mNGS) offers a comprehensive, high-throughput, and unbiased approach to pathogen identification. This retrospective study evaluates the diagnostic efficacy of mNGS compared to conventional microbiological testing (CMT) in LRTIs, aiming to enhance detection accuracy and enable early clinical prediction. METHODS: In our retrospective single-center analysis, 451 patients with suspected LRTIs underwent mNGS testing from July 2020 to July 2023. We assessed the pathogen spectrum and compared the diagnostic efficacy of mNGS to CMT, with clinical comprehensive diagnosis serving as the reference standard. The study analyzed mNGS performance in lung tissue biopsies and bronchoalveolar lavage fluid (BALF) from cases suspected of lung infection. Patients were stratified into two groups based on clinical outcomes (improvement or mortality), and we compared clinical data and conventional laboratory indices between groups. A predictive model and nomogram for the prognosis of LRTIs were constructed using univariate followed by multivariate logistic regression, with model predictive accuracy evaluated by the area under the ROC curve (AUC). RESULTS: (1) Comparative Analysis of mNGS versus CMT: In a comprehensive analysis of 510 specimens, where 59 cases were concurrently collected from lung tissue biopsies and BALF, the study highlights the diagnostic superiority of mNGS over CMT. Specifically, mNGS demonstrated significantly higher sensitivity and specificity in BALF samples (82.86% vs. 44.42% and 52.00% vs. 21.05%, respectively, p < 0.001) alongside greater positive and negative predictive values (96.71% vs. 79.55% and 15.12% vs. 5.19%, respectively, p < 0.01). Additionally, when comparing simultaneous testing of lung tissue biopsies and BALF, mNGS showed enhanced sensitivity in BALF (84.21% vs. 57.41%), whereas lung tissues offered higher specificity (80.00% vs. 50.00%). (2) Analysis of Infectious Species in Patients from This Study: The study also notes a concerning incidence of lung abscesses and identifies Epstein-Barr virus (EBV), Fusobacterium nucleatum, Mycoplasma pneumoniae, Chlamydia psittaci, and Haemophilus influenzae as the most common pathogens, with Klebsiella pneumoniae emerging as the predominant bacterial culprit. Among herpes viruses, EBV and herpes virus 7 (HHV-7) were most frequently detected, with HHV-7 more prevalent in immunocompromised individuals. (3) Risk Factors for Adverse Prognosis and a Mortality Risk Prediction Model in Patients with LRTIs: We identified key risk factors for poor prognosis in lower respiratory tract infection patients, with significant findings including delayed time to mNGS testing, low lymphocyte percentage, presence of chronic lung disease, multiple comorbidities, false-negative CMT results, and positive herpesvirus affecting patient outcomes. We also developed a nomogram model with good consistency and high accuracy (AUC of 0.825) for predicting mortality risk in these patients, offering a valuable clinical tool for assessing prognosis. CONCLUSION: The study underscores mNGS as a superior tool for lower respiratory tract infection diagnosis, exhibiting higher sensitivity and specificity than traditional methods.
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Secuenciación de Nucleótidos de Alto Rendimiento , Metagenómica , Infecciones del Sistema Respiratorio , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Metagenómica/métodos , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/epidemiología , Factores de Riesgo , Anciano , Adulto , Líquido del Lavado Bronquioalveolar/microbiología , Líquido del Lavado Bronquioalveolar/virología , Hospitalización , Valor Predictivo de las PruebasRESUMEN
Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and ß3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders.
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Adipocitos Beige/fisiología , Tejido Adiposo Beige/crecimiento & desarrollo , Resistencia a la Insulina , Interleucinas/metabolismo , Macrófagos/fisiología , Agonistas de Receptores Adrenérgicos beta 3 , Animales , Frío , Homeostasis , Interleucina-4/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismo , Proteína Desacopladora 1/fisiologíaRESUMEN
PURPOSE: This study aimed to consolidate the evidence regarding the prognostic influence of sarcopenia in degenerative lumbar spine surgeries. METHODS: A literature search of public databases was conducted up to Nov 15, 2023 using combinations of the key words "sarcopenia" and "lumbar spine surgery". Eligible studies were those that focused on adults undergoing decompression or fusion surgery for degenerative lumbar spine diseases, and compared the outcomes between patients with and without preoperative sarcopenia. Primary outcomes were change in ODI and back and leg pain VAS pain scores. Secondary outcomes were changes in Eq. 5D, JOA, SFHS-p scores, and LOS. RESULTS: Ultimately, nine retrospective studies with a total of 993 patients were included. Sarcopenic patients exhibited significantly worse functional improvement as assessed by ODI compared to non-sarcopenic patients (pooled standardized mean difference [pSMD] = 0.53, 95% confidence interval [CI]: 0.17-0.90). Back pain (pSMD = 0.31, 95% CI:0.15-0.47) and leg pain (pSMD = 0.21, 95% CI:0.02 - 0.39) improvement were also less in sarcopenic patients. Non-sarcopenic patients had greater improvements in Eq. 5D (pSMD = 0.25) and SFHS-p (pSMD = 0.39), and shorter LOS (pSMD = 0.62). CONCLUSIONS: As compared to patients without sarcopenia, those with sarcopenia undergoing lumbar spine surgery for degenerative diseases have lower improvements in functional ability, quality of life, physical health, pain relief and extended hospitalization compared to those without sarcopenia.
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Background and Objectives: Adolescent idiopathic scoliosis (AIS) is a prevalent three-dimensional spinal disorder, with a multifactorial pathogenesis, including genetics and environmental aspects. Treatment options include non-surgical and surgical treatment. Surgical interventions demonstrate positive outcomes in terms of deformity correction, pain relief, and improvements of the cardiac and pulmonary function. Surgical complications, including excessive blood loss and neurologic deficits, are reported in 2.27-12% of cases. Navigation-assisted techniques, such as the O-arm system, have been a recent focus with enhanced precision. This study aims to evaluate the results and complications of one-stage posterior instrumentation fusion in AIS patients assisted by O-arm navigation. Materials and Methods: This retrospective study assesses 55 patients with AIS (12-28 years) who underwent one-stage posterior instrumentation correction supported by O-arm navigation from June 2016 to August 2023. We examined radiological surgical outcomes (initial correction rate, loss of correction rate, last follow-up correction rate) and complications as major outcomes. The characteristics of the patients, intraoperative blood loss, operation time, number of fusion levels, and screw density were documented. Results: Of 73 patients, 55 met the inclusion criteria. The average age was 16.67 years, with a predominance of females (78.2%). The surgical outcomes demonstrated substantial initial correction (58.88%) and sustained positive radiological impact at the last follow-up (56.56%). Perioperative complications, including major and minor, occurred in 18.18% of the cases. Two patients experienced a major complication. Blood loss (509.46 mL) and operation time (402.13 min) were comparable to the literature ranges. Trend analysis indicated improvements in operation time and blood loss over the study period. Conclusions: O-arm navigation-assisted one-stage posterior instrumentation proves reliable for AIS corrective surgery, achieving significant and sustained positive radiological outcomes, lower correction loss, reduced intraoperative blood loss, and absence of implant-related complications. Despite the challenges, our study demonstrates the efficacy and maturation of this surgical approach.
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Cifosis , Tornillos Pediculares , Escoliosis , Fusión Vertebral , Cirugía Asistida por Computador , Femenino , Humanos , Adolescente , Masculino , Escoliosis/cirugía , Escoliosis/complicaciones , Tornillos Pediculares/efectos adversos , Estudios Retrospectivos , Pérdida de Sangre Quirúrgica , Fusión Vertebral/métodos , Imagenología Tridimensional , Tomografía Computarizada por Rayos X/métodos , Cifosis/cirugía , Complicaciones Posoperatorias/etiología , Resultado del Tratamiento , Vértebras TorácicasRESUMEN
As a critical radioactive anionic contaminant, traditional adsorbents primarily remove iodate (IO3 -) through ion exchange or hard acid-hard base interactions, but suffer from limited affinity and capacity. Herein, employing the synergistic effect of ion exchange and redox, we successfully synthesized a redox-active cationic polymer network (SCU-CPN-6, [C9H10O2N5 â Cl]n) by merging guanidino groups with ion-exchange capability and phenolic groups with redox ability via a Schiff base reaction. SCU-CPN-6 exhibits a groundbreaking adsorption capacity of 896â mg/g for IO3 -. The inferior adsorption capacities of polymeric networks containing only redox (~0â mg/g) or ion exchange (232â mg/g) fragments underscore the synergistic "1+1>2" effect of the two mechanisms. Besides, SCU-CPN-6 shows excellent uptake selectivity for IO3 - in the presence of high concentrations of SO4 2-, Cl-, and NO3 -. Meanwhile, a high distribution coefficient indicates its exemplary deep-removal performance for low IO3 - concentration. The synergic strategy not only presents a breakthrough solution for the efficient removal of IO3 - but also establishes a promising avenue for the design of advanced adsorbents for diverse applications.
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Nucleolus, which participates in many crucial cellular activities, is an ideal target for evaluating the state of a cell or an organism. Here, bright red-emissive carbon dots (termed CPCDs) with excitation-independent/polarity-dependent fluorescence emission are synthesized by a one-step hydrothermal reaction between congo red and p-phenylenediamine. The CPCDs can achieve wash-free, real-time, long-term, and high-quality nucleolus imaging in live cells, as well as in vivo imaging of two common model animals-zebrafish and Caenorhabditis elegans (C. elegans). Strikingly, CPCDs realize the nucleolus imaging of organs/flowing blood cells in zebrafish at a cellular level for the first time, and the superb nucleolus imaging of C. elegans suggests that the germ cells in the spermatheca probably have no intact nuclei. These previously unachieved imaging results of the cells/tissues/organs may guide the zebrafish-related studies and benefit the research of C. elegans development. More importantly, a novel strategy based on CPCDs for in vivo toxicity evaluation of materials/drugs (e.g., Ag+ ), which can visualize the otherwise unseen injuries in zebrafish, is developed. In conclusion, the CPCDs represent a robust tool for visualizing the structures and dynamic behaviors of live zebrafish and C. elegans, and may find important applications in cell biology and toxicology.
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Puntos Cuánticos , Pez Cebra , Animales , Carbono/química , Caenorhabditis elegans , Puntos Cuánticos/química , Diagnóstico por Imagen , Colorantes Fluorescentes/químicaRESUMEN
Human disorders associated with amyloid aggregation, such as Alzheimer's disease and Parkinson's disease, afflict the lives of millions worldwide. When peptides and proteins in the body are converted to amyloids, which have a tendency to aggregate, the toxic oligomers produced during the aggregation process can trigger a range of diseases. Nanoparticles (NPs) have been found to possess surface effects that can modulate the amyloid aggregation process and they have potential application value in the treatment of diseases related to amyloid aggregation and fibrillary tangles. In this review, we discuss recent progress relating to studies of nanoparticles that regulate amyloid aggregation. The review focuses on the factors influencing this regulation, which are important as guidelines for the future design of NPs for the treatment of amyloid aggregation. We describe the characterization methods that have been utilized so far in such studies. This review provides research information and characterization methods for the rational design of NPs, which should result in therapeutic strategies for amyloid diseases.
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Enfermedad de Alzheimer , Nanopartículas , Enfermedad de Alzheimer/metabolismo , Amiloide/química , Péptidos beta-Amiloides , Humanos , Nanopartículas/química , PéptidosRESUMEN
OBJECTIVE: To investigate all-cause and cause-specific mortality in SLE patients between two time periods, 1997-2005 and 2006-14. METHODS: We used an administrative health database from the province of British Columbia, Canada to match all incident SLE patients to 10 non-SLE individuals on sex, age and index date. Cohorts were divided into two subgroups, according to diagnosis year: early cohort 1997-2005 and late cohort 2006-14. The outcome was death [all-cause, renal disease, cancer, infection, cardiovascular disease (CVD) and other]. Hazard ratios (HR) and 95% CIs were estimated using univariate and multivariable Cox models. RESULTS: Among 6092 SLE patients and 60 920 non-SLE individuals, there were 451 and 1910 deaths, respectively. The fully adjusted all-cause mortality HR (95% CI) in the overall SLE cohort was 1.85 (1.66, 2.06), with no statistically significant improvement between early and late cohorts [1.95 (1.69, 2.26) vs 1.74 (1.49, 2.04)]. There was excess mortality from renal disease [3.04 (2.29, 4.05)], infections [2.74 (2.19, 3.43)] and CVD [2.05 (1.77, 2.38)], but not cancer [1.18 (0.96, 1.46)], in the overall SLE cohort. There was no statistically significant improvement in cause-specific mortality between early and late cohorts for renal disease [3.57 (2.37, 5.36) vs 2.65 (1.78, 3.93)], infection [2.94 (2.17, 3.98) vs 2.54 (1.84, 3.51)] and CVD [1.95 (1.60, 2.38) vs 2.18 (1.76, 2.71)]. There was no increase in cancer-related mortality in either cohort [1.27 (0.96, 1.69) vs 1.10 (0.82, 1.48)]. CONCLUSION: This population-based study demonstrates a persisting mortality gap in all-cause and cause-specific deaths in SLE patients, compared with the general population.
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Lupus Eritematoso Sistémico/mortalidad , Adulto , Anciano , Colombia Británica/epidemiología , Causas de Muerte , Estudios de Cohortes , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To evaluate the risk of severe infection and infection-related mortality among patients with newly diagnosed SLE. METHODS: We conducted an age- and gender-matched cohort study of all patients with incident SLE between 1 January 1997 and 31 March 2015 using administrative health data from British Columbia, Canada. Primary outcome was the first severe infection after SLE onset necessitating hospitalization or occurring during hospitalization. Secondary outcomes were total number of severe infections and infection-related mortality. RESULTS: We identified 5169 SLE patients and matched them with 25 845 non-SLE individuals from the general population, yielding 955 and 1986 first severe infections during 48 367 and 260 712 person-years follow-up, respectively. The crude incidence rate ratios for first severe infection and infection-related mortality were 2.59 (95% CI: 2.39, 2.80) and 2.20 (95% CI: 1.76, 2.73), respectively. The corresponding adjusted hazard ratios were 1.82 (95% CI: 1.66, 1.99) and 1.61 (95% CI: 1.24, 2.08). SLE patients had an increased risk of a greater total number of severe infections with crude rate ratio of 3.24 (95% CI: 3.06, 3.43) and adjusted rate ratio of 2.07 (95% CI: 1.82, 2.36). CONCLUSION: SLE is associated with increased risks of first severe infection (1.8-fold), a greater total number of severe infections (2.1-fold) and infection-related mortality (1.6-fold).
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Infecciones/etiología , Infecciones/mortalidad , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/mortalidad , Adulto , Colombia Británica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de RiesgoRESUMEN
OBJECTIVES: To estimate the overall risk of venous thromboembolism (VTE), pulmonary embolism (PE) and deep vein thrombosis (DVT) among patients newly diagnosed with RA compared with the general population without RA; and to estimate the risk trends of VTE, PE and DVT after RA diagnosis up to 5 years compared with the general population. METHODS: Using previously validated RA case definition, we conducted a matched cohort study using the population-based administrative health database from the province of British Columbia, Canada. We calculated incidence rates (IRs) and fully adjusted hazard ratios (HRs) for the risk of VTE, DVT and PE after RA index date. RESULTS: Among 39 142 incident RA patients (66% female, mean age 60), 1432, 543 and 1068 developed VTE, PE and DVT, respectively. IRs for the RA cohort were 3.79, 1.43 and 2.82 per 1000 person-years vs 2.70, 1.03 and 1.94 per 1000 person-years for the non-RA cohort. After adjusting for VTE risk factors, the HRs (95% CI) were 1.28 (1.20, 1.36), 1.25 (1.13, 1.39) and 1.30 (1.21, 1.40) for VTE, PE and DVT, respectively. The fully adjusted HRs for VTE during the first five years after RA diagnosis were 1.60, 1.47, 1.40, 1.30 and 1.28, respectively. A similar trend was shown in PE. CONCLUSION: This population-based study demonstrates that RA patients have an increased risk of VTE, PE and DVT after diagnosis compared with the general population. This risk is independent of traditional VTE risk factors and is highest during the first year after RA diagnosis, then progressively declined.
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Artritis Reumatoide/complicaciones , Embolia Pulmonar/etiología , Tromboembolia Venosa/etiología , Trombosis de la Vena/etiología , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Colombia Británica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Embolia Pulmonar/epidemiología , Medición de Riesgo , Factores de Tiempo , Tromboembolia Venosa/epidemiología , Trombosis de la Vena/epidemiologíaRESUMEN
OBJECTIVE: DM and PM are associated with substantial morbidity and mortality. We aimed to examine recent trends. METHODS: Using The Health Improvement Network, we identified patients with incident DM/PM (defined by ≥1 Read diagnosis code) aged 18-89 years with ≥1 year of continuous enrolment prior to the cohort entry date and up to 10 comparators matched on age, sex and entry year. The cohort was divided in two based on the year of DM/PM diagnosis: the early cohort (1999-2006) and late cohort (2007-2014). We calculated multivariable hazard ratios (HR) for death using a Cox-proportional hazards model and multivariable rate differences (RD) using an additive hazard model. RESULTS: We identified 410 DM cases (mean age: 58 years, 66% female) and 407 PM cases (mean age: 59 years, 61% female). Both DM cohorts had excess mortality compared with the comparison cohorts (71.5 vs 12.9 deaths/1000 person-years [PY] in the early cohort and 49.1 vs 10.4 deaths/1000 PY in the late cohort). The multivariable HRs were 7.51 (95% CI: 4.20, 13.42) in the early cohort and 5.42 (95% CI: 3.11, 9.45) in the late cohort (P-value for interaction = 0.59), and multivariable RDs were 56.2 (95% CI: 31.8, 81.2) in the early cohort and 36.3 (95% CI: 19.6, 53.0) in the late cohort (P-value for interaction = 0.15). A similar trend existed in PM. CONCLUSION: The premature mortality gap in DM/PM has not considerably improved in recent years, highlighting an unmet need for therapeutic improvement.
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Dermatomiositis/mortalidad , Polimiositis/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mortalidad Prematura/tendencias , Modelos de Riesgos Proporcionales , Distribución por Sexo , Reino Unido/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To estimate the overall risk and the temporal trend of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) before and after gout diagnosis in an incident gout cohort compared with the general population. METHODS: We conducted a matched cohort study using a province-wide population-based administrative health database in Canada. We calculated incidence rates (IRs) and multivariable adjusted hazard ratios (HRs) for the risk of VTE, DVT and PE before and after gout diagnosis. RESULTS: Among 130 708 incident individuals with gout (64% male, mean age 59 years), 2071 developed VTE, 1377 developed DVT and 1012 developed PE. IRs per 1000 person-years for gout were 2.63, 1.74 and 1.28 compared with 2.03, 1.28 and 1.06 for non-gout, respectively. The fully adjusted HRs (95% CI) for VTE, DVT and PE were 1.22 (1.13, 1.32), 1.28 (1.17, 1.41) and 1.16 (1.05, 1.29). For the pre-gout period, the fully adjusted HRs (95% CI) were 1.51 (1.38, 1.64), 1.55 (1.40, 1.72) and 1.47 (1.31, 1.66) for VTE, DVT and PE. During the third, second and first years preceding gout, the fully adjusted HRs for VTE were 1.44, 1.56 and 1.62. During the first, second, third, fourth and fifth years after gout, the fully adjusted HRs were 1.63, 1.29, 1.33, 1.28 and 1.22. Similar trends were also seen for DVT and PE. CONCLUSION: Increased risks of VTE, DVT and PE were found both before and after gout diagnosis. The risk increased gradually before gout, peaking in the year prior to diagnosis, and then progressively declined. Gout-associated inflammation may contribute to venous thrombosis risk.
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Gota/diagnóstico , Embolia Pulmonar/epidemiología , Tromboembolia Venosa/epidemiología , Trombosis de la Vena/epidemiología , Adulto , Distribución por Edad , Anciano , Canadá/epidemiología , Estudios Transversales , Bases de Datos Factuales , Femenino , Gota/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Pronóstico , Modelos de Riesgos Proporcionales , Embolia Pulmonar/etiología , Embolia Pulmonar/fisiopatología , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Análisis de Supervivencia , Tromboembolia Venosa/etiología , Tromboembolia Venosa/fisiopatología , Trombosis de la Vena/etiología , Trombosis de la Vena/fisiopatologíaRESUMEN
BACKGROUND: The accumulation of M1-polarized macrophages and excessive inflammation are important in the pathogenesis of diabetic foot ulcer (DFU). However, the underlying mechanism of DFU pathogenesis and the crucial regulators of DFU are less well known. Our previous study reported that kallikrein-binding protein (KBP), an angiogenesis inhibitor, was significantly upregulated in diabetic patients compared to its levels in controls. The effects of KBP on monocyte chemotaxis and macrophage M1 polarization were elucidated in this study. METHODS: Plasma KBP levels and monocyte counts were assessed by ELISA and flow cytometry. Wound closure rates in different groups were monitored daily. The phenotype and recruitment of macrophages were measured by real-time PCR, western blot and immunofluorescence assays. The expression of Notch and NF-κB signalling pathway members was determined by the methods mentioned above. ChIP and dual-luciferase reporter gene assays were employed to explore the binding and transcriptional regulation of Hes1 and iNOS. RESULTS: We found that plasma KBP levels and circulating monocytes were elevated in diabetic patients compared to those in nondiabetic controls, and both were higher in diabetic patients with DFU than in diabetic patients without DFU. KBP delayed wound healing in normal mice; correspondingly, KBP-neutralizing antibody ameliorated delayed wound healing in diabetic mice. Circulating monocytes and macrophage infiltration in the wound were upregulated in KBP-TG mice compared to those in control mice. KBP promoted the recruitment and M1 polarization of macrophages. Mechanistically, KBP upregulated iNOS by activating the Notch1/RBP-Jκ/Hes1 signalling pathway. Hes1 downregulated CYLD, a negative regulator of NF-κB signalling, and then activated the IKK/IκBα/NF-κB signalling pathway. CONCLUSIONS: Our findings demonstrate that KBP is the key regulator of excessive inflammation in DFUs and provide a novel target for DFU therapy.
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Pie Diabético/metabolismo , Macrófagos/citología , Serpinas/metabolismo , Cicatrización de Heridas , Animales , Diferenciación Celular , Células Cultivadas , Quimiotaxis , Humanos , Macrófagos/metabolismo , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Receptores Notch/metabolismo , Serpinas/genética , Factor de Transcripción HES-1/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Allopurinol is commonly prescribed for gout, and its clinical use may expand with ongoing trials assessing its potential cardiorenal benefits. Because heart disease has been suggested to be a risk factor for allopurinol-associated severe cutaneous adverse reactions, we sought to confirm this association in a Canadian general population cohort. METHODS: We used population data from British Columbia, Canada, to identify all incident allopurinol users between 1997 and 2015. We examined the association between heart disease (ischemic heart disease and heart failure) and the risk of hospital admission for severe cutaneous adverse reactions, adjusting for known and purported risk factors. We also evaluated the joint effects of combined clinical and demographic risk factors. RESULTS: Among 130 325 allopurinol initiators, 109 hospital admissions occurred for allopurinol-associated severe cutaneous adverse reactions. The multivariable relative risk among those with heart disease was 1.55 (95% confidence interval 1.01-2.37). Patients with heart disease and chronic kidney disease who were started on an allopurinol dosage of greater than 100 mg/d had an 11-fold higher risk. Allopurinol initiation at a lower dosage among patients with heart disease and chronic kidney disease resulted in a fivefold reduction in risk. Older women with heart disease from regions with large Asian populations had a 23-fold higher risk of allopurinol-associated severe cutaneous adverse reactions than younger men without heart disease from other regions. INTERPRETATION: Heart disease is independently associated with risk of allopurinol-associated severe cutaneous adverse reactions, similar to chronic kidney disease, and low-dosage allopurinol initiation may substantially mitigate this risk. Risk factors for these rare but serious reactions should be considered when initiating allopurinol.
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Alopurinol/efectos adversos , Erupciones por Medicamentos/epidemiología , Supresores de la Gota/efectos adversos , Insuficiencia Cardíaca/epidemiología , Hospitalización/estadística & datos numéricos , Isquemia Miocárdica/epidemiología , Factores de Edad , Anciano , Pueblo Asiatico , Colombia Británica/epidemiología , Relación Dosis-Respuesta a Droga , Erupciones por Medicamentos/etiología , Etnicidad , Femenino , Gota/tratamiento farmacológico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
PURPOSE: Sebum is an important shunt pathway for transdermal permeation and targeted delivery, but there have been limited studies on its permeation properties. Here we report a measurement and modelling study of solute partition to artificial sebum. METHODS: Equilibrium experiments were carried out for the sebum-water partition coefficients of 23 neutral, cationic and anionic compounds at different pH. RESULTS: Sebum-water partition coefficients not only depend on the hydrophobicity of the chemical but also on pH. As pH increases from 4.2 to 7.4, the partition of cationic chemicals to sebum increased rapidly. This appears to be due to increased electrostatic attraction between the cationic chemical and the fatty acids in sebum. Whereas for anionic chemicals, their sebum partition coefficients are negligibly small, which might result from their electrostatic repulsion to fatty acids. Increase in pH also resulted in a slight decrease of sebum partition of neutral chemicals. CONCLUSIONS: Based on the observed pH impact on the sebum-water partition of neutral, cationic and anionic compounds, a new quantitative structure-property relationship (QSPR) model has been proposed. This mathematical model considers the hydrophobic interaction and electrostatic interaction as the main mechanisms for the partition of neutral, cationic and anionic chemicals to sebum.
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Fenómenos Químicos , Relación Estructura-Actividad Cuantitativa , Sebo/química , Sebo/fisiología , Aniones , Cationes , Concentración de Iones de HidrógenoRESUMEN
Lymphocyte antigen-6 (Ly6) superfamily is a large family of proteins and characterized by precisely spaced cysteine motifs, termed the three-finger fold. To date, a large number of members of the Ly6/uPAR family were identified among many species. In this study, we first report the identification and characterization of the secreted Ly2.1-3 proteins on the chromosome 2 in zebrafish and determine the expression pattern. Ly2.1-3 all possess a conserved LU domain and adopt similar three-finger structure with human CD59, SLURP1 and other Ly6 family members. Ly2.1-3 cluster on chromosome 2 and share high homology, possibly originated from chromosomal gene duplication. Ly2.1-3 exhibit distinct expression pattern in the endoderm, they were found abundantly and specifically in the digestive tract, liver and pancreas respectively. The differential expression pattern may suggest Ly2.1-3 acquire new function during gene duplication. The expression level of Ly2.1-3 were up-regulating challenged with LPS indicated that they have a role in innate immune responses of the digestive system during endotoxin challenge in early stage.
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Antígenos Ly/genética , Regulación del Desarrollo de la Expresión Génica , Inmunidad Innata , Familia de Multigenes , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Antígenos Ly/metabolismo , Embrión no Mamífero/inmunología , Conformación Proteica , Alineación de Secuencia/veterinaria , Pez Cebra/embriología , Pez Cebra/inmunología , Proteínas de Pez Cebra/metabolismoRESUMEN
Recent studies suggest that copy number variations (CNVs) are also involved in the genetic risk of schizophrenia. Using a Cochran-Mantel-Haenszel (CMH) adjusted meta-analysis in 18,497 schizophrenia patients and 25,522 healthy controls from 14 independent samples, we conducted replication analyses of four chromosomal deletions at 1q21.1, 15q11.2, 15q13.3, and 22q11.2 Loci for their associations with schizophrenia. Only CNVs larger than 100 kb that had >50% reciprocal overlap with the canonical deletion chromosomal regions were considered. We successfully replicate the significant associations at 1q21.1 (P value = 3.101 × 10-7 , odds ratio (OR) = 6.91), 15q13.3 (P value = 4.771 × 10-4 , OR = 7.83), and 22q11.2 (P value = 1.725 × 10-5 , OR = 9.21) deletions, although the effect sizes are relatively smaller than the original studies, which is not unexpected and adds further support for the involvement of these genetic lesions in the risk of schizophrenia. The 15q11.2 deletion, which shows higher frequency in healthy populations than the other three CNV loci, though is not significant in the present meta-analysis (P value = 0.1545, OR = 1.42), it shows the same direction of effects with previous studies. These results further confirm the genetic connections between rare CNVs and schizophrenia, and suggest the importance of adequate sample size in replication analyses for such risk loci with low frequency in general populations. © 2016 Wiley Periodicals, Inc.
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Esquizofrenia/genética , Adulto , Deleción Cromosómica , Variaciones en el Número de Copia de ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Oportunidad Relativa , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
Lymphocyte antigen-6 (Ly-6) superfamily members have been identified in zebrafish, but the expression and function of these Ly-6 genes remain largely unknown. Posterior lateral line (pLL) system is produced by migrating pLL primordium (pLLp). Chemokine signaling, Notch, Wnt, and fibroblast growth factor (FGF) signaling regulate migration of pLLp cells and formation of neuromasts. However, the mechanism of neuromast deposition remains to be explored. Identification of novel genes expressed in pLLp will certainly help the study of such a process. Here we identified a Ly-6 gene called neuromast-expressed gpi-anchored lymphocyte antigen-6 (negaly6), which was specifically expressed in neuromast. Quantitative real-time PCR (qRT-PCR) analysis showed that negaly6 started to be expressed at 24 hpf, and whole-mount in situ hybridization analysis indicated that negaly6 was highly expressed in the trailing zone of pLLp and mature neuromast. Furthermore, negaly6 expression was inhibited by FGF signaling antagonist but not by Wnt signaling agonist or antagonist. Collectively, these data indicate that negaly6 may be associated with the regulation of neuromast deposition via FGF signaling pathway.
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Antígenos Ly/genética , Sistema de la Línea Lateral/metabolismo , Proteínas de Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Antígenos Ly/química , Embrión no Mamífero/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Expresión Génica , Datos de Secuencia Molecular , Alineación de Secuencia , Transducción de Señal , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
BACKGROUND: The quality of treatment plans for breast cancer can vary greatly. This variation could be reduced by using dose prediction to automate treatment planning. Our work investigates novel methods for training deep-learning models that are capable of producing high-quality dose predictions for breast cancer treatment planning. PURPOSE: The goal of this work was to compare the performance impact of two novel techniques for deep learning dose prediction models for tangent field treatments for breast cancer. The first technique, a "glowing" mask algorithm, encodes the distance from a contour into each voxel in a mask. The second, a gradient-weighted mean squared error (MSE) loss function, emphasizes the error in high-dose gradient regions in the predicted image. METHODS: Four 3D U-Net deep learning models were trained using the planning CT and contours of the heart, lung, and tumor bed as inputs. The dataset consisted of 305 treatment plans split into 213/46/46 training/validation/test sets using a 70/15/15% split. We compared the impact of novel "glowing" anatomical mask inputs and a novel gradient-weighted MSE loss function to their standard counterparts, binary anatomical masks, and MSE loss, using an ablation study methodology. To assess performance, we examined the mean error and mean absolute error (ME/MAE) in dose across all within-body voxels, the error in mean dose to heart, ipsilateral lung, and tumor bed, dice similarity coefficient (DSC) across isodose volumes defined by 0%-100% prescribed dose thresholds, and gamma analysis (3%/3 mm). RESULTS: The combination of novel glowing masks and gradient weighted loss function yielded the best-performing model in this study. This model resulted in a mean ME of 0.40%, MAE of 2.70%, an error in mean dose to heart and lung of -0.10 and 0.01 Gy, and an error in mean dose to the tumor bed of -0.01%. The median DSC at 50/95/100% isodose levels were 0.91/0.87/0.82. The mean 3D gamma pass rate (3%/3 mm) was 93%. CONCLUSIONS: This study found the combination of novel anatomical mask inputs and loss function for dose prediction resulted in superior performance to their standard counterparts. These results have important implications for the field of radiotherapy dose prediction, as the methods used here can be easily incorporated into many other dose prediction models for other treatment sites. Additionally, this dose prediction model for breast radiotherapy has sufficient performance to be used in an automated planning pipeline for tangent field radiotherapy and has the major benefit of not requiring a PTV for accurate dose prediction.