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1.
Comput Methods Programs Biomed ; 194: 105522, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32422474

RESUMO

BACKGROUND AND OBJECTIVE: Post-Stenotic Dilatation (PSD), the common complication of coarctation of the aorta (COA), is a progressive disease involving aortic aneurysm and even rupture. However, there has been no definitive method that could investigate the mechanism of PSD formation, progression and rupture. The purpose of the present work is to analyze the mechanism behind PSD formation and to further assess the risk of COA patients with different coarctation degrees deteriorating into PSD. METHOD: Three-dimensional non-Newtonian (Carreau-Yasuda) hemodynamic simulations are performed throughout the cardiac cycle, and a novel parameter (λci¯ intensity) is proposed to evaluate the intensity of vortices within the aorta. The PSD geometry is reconstructed from Computed Tomography scans. To analyze the formation mechanism and occurrence possibility of PSD, the computer technology is utilized to restore the expansive and/or narrow regions to obtain its previous state (COA) and control group (Normal), and to modify the minimum diameter to obtain the aortas with different coarctation degrees. The clinical cases of pre- and post-operation are further introduced to verify the analysis. RESULTS: Compared with the Normal, the vortical structures with higher swirling strength are generated and accumulated at the downstream of the coarctation segment after COA occurrence, and partially disappear in the wake of PSD formation. The sequence of λci¯ intensity is COA > PSD > Normal and pre-operation > post-operation. With increasing the degree of coarctation, the λci¯ intensity is higher and the jet-flow becomes more drastic. CONCLUSIONS: The formation of PSD is caused by the vortical structures with higher swirling strength accumulating at the downstream of the coarctation segment. An increase in coarctation degree elevates the risk of PSD occurrence and even aneurysmal dilatation.

2.
Ann Thorac Surg ; 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32278750

RESUMO

PURPOSE: This report describes first-in-man experiences and early results of gutter-free chimney stent-graft implantation for aortic arch pathologies. DESCRIPTION: The gutter-free chimney stent-graft consists of an inner stent and an outer skirt fabric to form an integrated structure. The inner and outer layers are nickel-titanium self-expanding skeletal structures with double Polytetrafluoroethylene coated. The outer skirt fabric fits the gutter to prevent endoleak, and the proximal inner stent has larger radial force to ensure the blood flow. All these designs have the advantages to overcome the native defects of current chimney techniques. EVALUATION: We reported two patients who were diagnosed as aortic arch pathologies, received the gutter-free chimney stent-graft implantation during thoracic aortic stent-graft endovascular repair (TEVAR). In all patients, aortic arch lesions were covered, and supra-aortic branches were patent without complications after TEVAR and during the 17-months follow-up. CONCLUSIONS: Novel gutter-free chimney stent-graft may be safely and effectively utilized for endovascular repair in aortic arch pathologies. Long-term durability should be confirmed by larger ongoing researches.

3.
Org Lett ; 22(10): 3775-3779, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32330061

RESUMO

The efficient total synthesis of lycojaponicumin A (1) has been accomplished for the first time. The remarkable features of this novel strategy include the following: (1) rapid construction of tricyclic intermediate 4 through a regio- and stereoselective semipinacol ring expansion, which simplified the construction of rings A and B of 1; (2) the subsequent regio- and stereoselective formation of the highly strained rings C-E of 1 through a tandem oxa-hetero [3 + 2] cycloaddition/N-cycloalkylation.

4.
Neurol Sci ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32323082

RESUMO

BACKGROUND: No standard rehabilitative treatment for coma arousal after traumatic brain injury (TBI) exists. Based on our clinical experience, we hypothesized that sensory stimulation (SS) is a promising protocol to improve outcomes in these patients. METHODS: We performed a literature review on the progress of sensory stimulation to enhance coma arousal after traumatic brain injury. We searched the databases on Medline, Embase, and Cochrane to gain access to relevant publications using the key words "traumatic brain injury," "disorders of consciousness," "sensory stimulation," and "coma scale." RESULTS: We included all original studies published in English with patients presenting severe disorders of consciousness due to traumatic brain injury who had received SS and whose behavioral/neural responses had been measured. We compared data on ten selected studies and analyzed the SS effects in comatose patient outcomes after TBI. Our review outlines the role of SS in patients with TBI and provides guidance for its implementation in the clinical practice. CONCLUSIONS: The literature suggests the SS program improves coma arousal after TBI. However, high-quality clinical trials are needed to establish standard SS protocols.

5.
J Exp Clin Cancer Res ; 39(1): 44, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111229

RESUMO

BACKGROUND: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. METHODS: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. RESULTS: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. CONCLUSIONS: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

6.
Phys Rev Lett ; 124(10): 100501, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32216395

RESUMO

The chain rule for the classical relative entropy ensures that the relative entropy between probability distributions on multipartite systems can be decomposed into a sum of relative entropies of suitably chosen conditional distributions on the individual systems. Here, we prove a chain rule inequality for the quantum relative entropy. The new chain rule allows us to solve an open problem in the context of asymptotic quantum channel discrimination: surprisingly, adaptive protocols cannot improve the error rate for asymmetric channel discrimination compared to nonadaptive strategies.

7.
Int J Surg ; 76: 64-68, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109649

RESUMO

OBJECTIVE: The aim of this study was to evaluate the survival outcomes of different prostate-specific antigens (PSA) levels in men with high-grade prostate cancer. MATERIALS AND METHODS: From 2004 to 2015 in the Surveillance, Epidemiology, and End Results database, men diagnosed with clinically localized prostate cancer and a Gleason score (GS) 8-10 were identified. Patients were divided into the PSA levels <4.0 ng/ml, 4.0-10.0 ng/ml, 10.1-20.0 ng/ml, and >20.0 ng/ml groups. Multivariable Cox regressions and Kaplan-Meier analysis were adopted to analyze the prostate cancer-specific survival (PCSS). RESULTS: 59,336 men with a median age of 70 (63-76) years with a GS 8-10 were included. The PCSS of patients with a PSA <4.0 ng/ml was significantly worse than that of patients with a PSA 4.0-10.0 ng/ml [hazard ratio (HR): 1.43 (1.28-1.58)], but was better than that of patients with a PSA 10.1-20.0 ng/ml [HR: 1.18 (1.06-1.31)]. After stratifying patients by GS, the differences between patients with a PSA <4.0 ng/ml and a PSA 4.0-10.0 ng/ml were only significant in those with a GS 9 and 10 [GS 9 HR: 1.49 (1.28-1.72); GS 10 HR: 1.42 (1.12-1.8)], but not in those with a GS 8 [HR: 1.04 (0.95-1.14)]. Moreover, the PCSS of patients with a PSA <4.0 ng/ml and a PSA 10.0-20.0 ng/ml were similar in patients with GS 9 and 10 diseases [GS 9: HR: 1.06 (0.91-1.23); GS 10: HR: 1.13 (0.89-1.44)]. CONCLUSIONS: Patients with a PSA <4.0 ng/ml had poorer PCSS than patients with a PSA 4.0-10.0 ng/ml. Similar PCSS was found in patients whose PSA levels were 10.1-20.0 ng/ml in patients with GS 9-10 prostate cancer.


Assuntos
Calicreínas/sangue , Gradação de Tumores , Antígeno Prostático Específico/sangue , Neoplasias da Próstata , Idoso , Estudos de Coortes , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos
8.
Interact Cardiovasc Thorac Surg ; 30(2): 280-286, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665309

RESUMO

OBJECTIVES: Our study aims to assess the technical quality and the learning curve of the preclosure technique for a vascular surgeon using Proglide using cumulative sum analysis (CUSUM analysis). METHODS: This study was designed retrospectively and enrolled 81 consecutive patients with 88 access sites who underwent endovascular aortic repair or thoracic endovascular aortic repair with the preclosure technique using Proglide between July 2017 and February 2018. The patients were divided into 2 groups chronologically: (A) the first 40 cases and (B) the latter 41 cases. Logistic regression analysis was used to assess the impact of technical risk factors on the success of the preclosure technique, and the χ2 test and 1-way ANOVA were applied to analyse the distribution of individual characteristics and risk factors between the 2 groups. CUSUM analysis was adapted to analyse the learning curve and to monitor the technical quality, with a predetermined target failure rate of 5%, an alternative failure rate of 20% and calculated 80% 'alert', 95% 'alarm' and 80% 'reassurance' lines. RESULTS: Primary technical success was obtained in 81 (92.05%) access sites. There were no significant correlations between primary technical success and risk factors, including, common femoral artery diameter (P = 0.88), common femoral artery depth from the skin (P =0.94), the level of common femoral artery calcification (P =0.86) and size of sheath (P =0.96). Moreover, the distribution of related risk factors was not significantly different between groups A and B. CUSUM analysis showed that the cumulative failure rate never crossed the 80% 'alert' and 95% 'alarm' lines. Additionally, the failure rate began to approach the 80% 'reassurance' line after ∼22 cases and crossed the 80% 'reassurance' line after 36 cases. CONCLUSIONS: The technique of totally percutaneous access using Proglide is safe and effective for an experienced vascular surgeon, even if the operator has no previous experience with any preclosure techniques. CUSUM analysis showed that 36 cases are necessary to achieve the target failure rate of 5%.

9.
Andrologia ; 52(2): e13475, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31820482

RESUMO

The association of genetic variants and congenital bilateral absence of the vas deferens (CBAVD) has been well acknowledged. By contrast, the link between nonobstructive azoospermia (NOA) or oligospermia and alterations in the cystic fibrosis transmembrane conductive regulator (CFTR) remains inconclusive. To clarify the problem, a meta-analysis was performed out after systematically searching Pubmed, Web of Science, Embase and the Chinese national knowledge infrastructure (CNKI) database. As we know, the ∆F508 and IVS8-5T gene mutations are the most studied genetic variants in CFTR gene. We reviewed the data from male patients who underwent the aforementioned genetic test. Our study revealed that the IVS8-5T mutation may be positively associated with the risk of nonobstructive male infertility (odds ratio (OR) 1.69; 95% CI: 1.12-2.55). This association strengthened when concerning NOA (OR: 2.62; 95% CI: 1.49-4.61). However, the ∆F508 mutation seemed to be a smaller contributing factor to this risk (OR: 1.63; 95% CI: 0.86-3.08). Our study aims to clarify the association between the ∆F508 and IVS8-5T gene mutations and nonobstructive male infertility. Therefore, screening for the IVS8-5T mutation in the CFTR gene may be recommended for men with NOA or severe oligozoospermia seeking assisted reproductive technology (ART).

10.
J Med Chem ; 63(2): 696-713, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31880942

RESUMO

Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.

12.
Technol Cancer Res Treat ; 18: 1533033819896806, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31868118

RESUMO

OBJECTIVE: This study aimed to investigate the effect of tetra-arsenic tetra-sulfide on treating multiple myeloma and its potential regulation on suppressor of cytokine signaling 1 methylation-mediated Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. METHODS: Tetra-arsenic tetra-sulfide with different concentrations were used to treat U266 cells, and cell viability was measured at 12, 24, and 48 hours with 0 µM tetra-arsenic tetra-sulfide treatment as control by Cell Counting Kit-8 assay. Suppressor of cytokine signaling 1 methylation and expression were determined by methylation-specific polymerase chain reaction, quantitative polymerase chain reaction, and Western blot, respectively, in U266 cells and normal plasma cells and in U266 cells treated by tetra-arsenic tetra-sulfide. Then, rescue experiments were performed by transfecting suppressor of cytokine signaling 1 small interfering RNA into tetra-arsenic tetra-sulfide-treated U266 cells. Besides, phosphor-Janus kinase 2, Janus kinase 2, phospho-signal transducer and activator of transcription 3, and signal transducer and activator of transcription 3 expressions were determined by Western blot. RESULTS: Tetra-arsenic tetra-sulfide inhibited U266 cell viability efficiently in a dose- and time-dependent manner. Suppressor of cytokine signaling 1 methylation was higher while suppressor of cytokine signaling 1 expression was lower in U266 cells compared to normal plasma cells; when treated by tetra-arsenic tetra-sulfide, suppressor of cytokine signaling 1 methylation was decreased while suppressor of cytokine signaling 1 expression was increased in U266 cells, along with the reduced phospho-Janus kinase 2 and phospho-signal transducer and activator of transcription 3 expressions. Then, suppressor of cytokine signaling 1 small interfering RNA enhanced the cell viability and phospho-Janus kinase 2 as well as phospho-signal transducer and activator of transcription 3 expressions in both tetra-arsenic tetra-sulfide treatment-free and tetra-arsenic tetra-sulfide-treated U266 cells. CONCLUSION: Tetra-arsenic tetra-sulfide exhibits good killing effect on multiple myeloma cells via repressing suppressor of cytokine signaling 1 methylation and downstream Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, which might serve as a potential treatment option for multiple myeloma.


Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Mieloma Múltiplo/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Janus Quinase 2 , Metilação , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteína 1 Supressora da Sinalização de Citocina/genética
13.
Complement Ther Med ; 47: 102194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31780004

RESUMO

OBJECTIVE: Current conventional treatments for sepsis associated with acute gastrointestinal injury (AGI) have limited efficacy. This study aimed to study traditional Chinese medicine (TCM) bundle therapy (based on TCM syndrome differentiation) as add-on to conventional treatments on the incidence of AGI and on the prognosis of patients with sepsis. DESIGN: This was a prospective multicenter randomized single-blind controlled trial. SETTING: Intensive care units (ICUs) of five university teaching hospitals in Zhejiang Province (China) from December 2012 to December 2014. INTERVENTIONS: The control group received conventional treatment for sepsis and AGI. The intervention group received the conventional treatment combined with TCM bundle therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day mortality. The secondary outcomes included the clinical indicators of sepsis. The 28-day mortality (35.3% vs. 48.3%, P = 0.01) and AGI-attributable mortality (15.1% vs. 36.2%, P = 0.02) in the intervention group were significantly lower than in controls. Duration of mechanical ventilation (17.4 ±â€¯10.4 vs. 19.9 ±â€¯11.1 days, P = 0.049) and duration of ICU stay (17.3 ±â€¯10.2 vs. 20.1 ±â€¯11.5 days) were significantly shorter in the intervention group compared with controls. On days 7 and 14, D-lactate, diamine oxidase, lipopolysaccharides, tumor necrosis factor-α, intra-abdominal pressure, and abdominal circumference in the intervention group were significantly lower than in controls, and serum MTL levels and bowel sounds were significantly higher (all P < 0.05). CONCLUSIONS: TCM bundle therapy in the early stage of sepsis can improve survival and the markers of gastrointestinal function in patients with sepsis associated with AGI.

14.
Sensors (Basel) ; 19(22)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31717949

RESUMO

Considering the inertial measurement unit (IMU) faults risk of an unmanned aerial vehicle (UAV), this paper studies the error overboundings of the state estimation of the extended Kalman filter (EKF) in a tightly coupled IMU/global navigation satellite system (GNSS) integrated architecture under the IMU fault condition, which can be used to assure the integrity of the UAV navigation system. The error overboundings of the error-state inertial navigation equations based EKF (error-state EKF) are obtained according to the IMU faults propagation derivation, which can be expressed as a sum of the terms related to the EKF innovation, the estimated bias, and the remaining position error. It presents the same expression with the error overbounding of the full-state inertial navigation equations based EKF (full-state EKF). Simulation results show that both the error overboundings of the error-state and full-state EKFs can fit the state error against the IMU faults, but the error-state EKF is more suitable for UAV navigation system integrity assurance due to its higher calculation efficiency. This study will be extended to the integrity monitoring of multisensor systems.

15.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31611271

RESUMO

Human α-defensins are 3- to 5-kDa disulfide-bridged peptides with a multitude of antimicrobial activities and immunomodulatory functions. Recent studies show that human enteric α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, aids the highly infectious enteropathogen Shigella in breaching the intestinal epithelium in vitro and in vivo Whether and how HD5 influences Shigella infection of resident macrophages following its invasion of the intestinal epithelium remain poorly understood. Here, we report that HD5 greatly promoted phagocytosis of Shigella by macrophages by targeting the bacteria to enhance bacterium-to-cell contacts in a structure- and sequence-dependent fashion. Subsequent intracellular multiplication of phagocytosed Shigella led to massive necrotic cell death and release of the bacteria. HD5-promoted phagocytosis of Shigella was independent of the status of the type 3 secretion system. Furthermore, HD5 neither inhibited nor enhanced phagosomal escape of Shigella Collectively, these findings confirm a potential pathogenic role of HD5 in Shigella infection of not only epithelial cells but also macrophages, illuminating how an enteropathogen exploits a host protective factor for virulence and infection.


Assuntos
Disenteria Bacilar/microbiologia , Disenteria Bacilar/patologia , Interações Hospedeiro-Patógeno , Shigella/patogenicidade , alfa-Defensinas/metabolismo , Animais , Aderência Bacteriana , Células Cultivadas , Células Epiteliais/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Macrófagos/microbiologia , Camundongos , Fagocitose
17.
Clin Appl Thromb Hemost ; 25: 1076029619868534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31434499

RESUMO

BACKGROUND: Deep venous thrombosis (DVT) is a common complication after stroke. It is easy to identify the patients with symptomatic DVT; however, the tool for asymptomatic high-risk population needs to be further explored. Our aim was to explore the risk factors of acute stroke patients with asymptomatic DVT. METHODS: We performed a prospective observation study among 452 patients with acute stroke who had a stroke within 14 days. Ultrasound examination of deep veins was repeatedly performed in each patient for DVT every 7 days during his admission. The dynamic rate of DVT in acute stroke was analyzed. Then risk factors were compared between DVT patients and non-DVT patients. The predictive model was explored based on thr cox proportion model. RESULTS: Asymptomatic DVT was detected in 52 (11.5%) patients with stroke and 85.9% of thrombi were identified in their distal veins. Patients with longer length of stay (P = .004), more severe stroke (P = 0.001), higher level of D-dimer (P = .003), and higher blood glucose level were associated with higher risk of DVT, while patients with higher triglyceride level (P = .003) were less likely to have DVT, after adjusting age and sex. With the median of D-dimer (0.38 FEU mg/L) as cutoff value. Patients with higher level of D-dimer might have a higher risk of DVT with a significant statistical difference. Also, the severity of stroke differed DVT risk in Kaplan-Meier model. Using cox-proportion hazard regression model, asymptomatic DVT could be predicted (area under the curve 0.852). CONCLUSION: Our data showed that asymptomatic DVT was common in patients with acute stroke and most of thrombosis occurred in distal veins. Combination of clinical manifestation and laboratory results might be helpful predict DVT. DVT prophylaxis should be condisdered in high risk.


Assuntos
Fatores de Risco , Acidente Vascular Cerebral/complicações , Trombose Venosa/etiologia , Idoso , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hospitalização , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ultrassonografia , Trombose Venosa/diagnóstico por imagem
18.
Urol J ; 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31183848

RESUMO

OBJECTIVE: To investigate the safety of electrocoagulation and thulium laser (Tm-laser) sealing methods of distal ureter resection during radical nephroureterectomy (NFU) in a porcine model. METHODS: 9 pigs were used in the study: 6 were used to measure the bursting pressure (BP) and 3 were used to measure the highest pressure during NFU. Twelve ureters were to measure BP after being sealed by electrocoagulation or Tm-laser (n = 6, each). Six experimental NFUs were performed in 3 pigs to measure the intraluminal pressure of all procedures. RESULTS: The mean BP in the electrocoagulation group (104.3 ± 25.0 cmH2O) was similar to that of the Tm-laser group (74.8 ± 23.3 cmH2O, P > 0.05). The peak intraluminal pressure (35.9 ± 7.6 cmH2O) during NFU was significantly lower than the BP (P < 0.05). CONCLUSION: The effectiveness of the sealing was confirmed using both electrocoagulation and Tm-laser during NFU.

19.
Cell Microbiol ; 21(10): e13069, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218775

RESUMO

Human neutrophil peptides (HNPs), also known as human myeloid α-defensins degranulated by infiltrating neutrophils at bacterial infection loci, exhibit broad antomicrobial activities against bacteria, fungi, and viruses. We have made a surprising recent finding that Shigella, a highly contagious, yet poorly adhesive enteric pathogen, exploits human α-defensins including HNP1 to enhance its adhesion to and invasion of host epithelial cells. However, the critical molecular determinants responsible for HNP1-enhanced Shigella adhesion and invasion have yet to be investigated. Using cultured epithelial cells and polarised Caco2 cells as an in vitro infection model, we demonstrated that HNP1 promoted Shigella infection in a structure- and sequence-dependent manner, with two bulky hydrophobic residues, Trp26 and Phe28 important for HNP1 self-assembly, being most critical. The functional importance of hydrophobicity for HNP1-enhanced Shigella infection was further verified by substitutions for Trp26 of a series of unnatural amino acids with straight aliphatic side chains of different lengths. Dissection of the Shigella infection process revealed that bacteria-rather than host cells-bound HNP1 contributed most to the enhancement. Further, mutagenesis analysis of bacterial surface components, while precluding the involvement of lipopolysaccharides (LPS) in the interaction with HNP1, identified outer membrane proteins and the Type 3 secretion apparatus as putative binding targets of HNP1 involved in enhanced Shigella adhesion and invasion. Our findings provide molecular and mechanistic insights into the mode of action of HNP1 in promoting Shigella infection, thus showcasing another example of how innate immune factors may serve as a double-edged sword in health and disease.

20.
Intensive Care Med ; 45(10): 1478-1479, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31069406
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