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Purpose: The osseointegration in dental implants is greatly affected by various surface properties, such as chemistry, texture, and overall cleanliness. This study aimed to investigate the impact of mineral oil lubricants used in rotary instruments on osseointegration within rabbit tibiae, with a specific focus on potential contamination from dental handpices. Materials and Methods: Twelve New Zealand rabbits were included in this study, each receiving two implants in each tibia, resulting in a total of 48 implants across the study. Groups were organized based on the time until euthanasia and the degree of implant contamination. Three contamination levels were defined: the first group received implants without any lubricant in the handpiece (control group); the second group received implants with handpices managed as recommended; the third group had implants placed using fixtures pre-soaked in lubricant. These groups were further subdivided based on euthanization periods of two and four weeks. We measured and analyzed both the removal torque and the bone-implant contact. Results: We observed a non-significant inverse correlation between the severity of fixture contamination and removal torque. However, there was a significant reduction in bone-implant contact associated with higher contamination levels, particularly after four weeks. Conclusions: Even brief exposure to lubricants from handpieces can jeopardize the osseointegration of implants in bone. Therefore, it is imperative to implement thorough procedures for lubricant removal post-application and to employ precise cleaning and suction during implant drilling and placement to minimize residual oil on the implant surface.
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STUDY OBJECTIVES: Severe respiratory distress of neonates with Robin sequence (RS) is traditionally managed by surgery. Stanford Orthodontic Airway Plate treatment (SOAP) is a nonsurgical option. The study aimed to determine if SOAP can improve polysomnography (PSG) parameters of neonates with RS. METHODS: PSG of neonates with RS treated with SOAP at a single hospital were retrospectively analyzed. Patients without PSG at all 4 time points (pre-, start of-, mid-, and post-treatment) were excluded. Data were analyzed using a linear mixed effects model. RESULTS: Sixteen patients were included. All patients had cleft palate (CP). The median age (min, max) at the start of treatment was 1.1 months (0.5, 2.3) with the treatment duration of 4.5 months (3.5, 6.0). The mean obstructive apnea-hypopnea index (95% confidence interval) decreased from 39.3 events/hour (32.9, 45.7) to 12.2 events/hour (6.7, 17.7) (P < 0.001), obstructive apnea index decreased from 14.1 (11.2, 17.0) events/hour to 1.0 (-1.5, 3.5) events/hour (P < 0.001), and oxygen nadir increased from 79.9% (77.4, 82.5) to 88.2% (85.5, 90.8) (P < 0.001) between pre- and start of treatment. Respiratory improvements were sustained during and after the treatment. All patients avoided mandibular distraction osteogenesis or tracheostomy following SOAP. CONCLUSIONS: As being a rare diagnosis, the number of participants was, as expected, low. However, the current study demonstrates that SOAP can improve PSG parameters, demonstrating its potential utility before surgical interventions for neonates with RS and CP experiencing severe respiratory distress.
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BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.
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Objectives: This study investigated the nanoleakage of root canal obturations using calcium silicate-based sealer according to different drying methods. Materials and Methods: Fifty-two extracted mandibular premolars with a single root canal and straight root were selected for this study. After canal preparation with a nickel-titanium rotary file system, the specimens were randomly divided into 4 groups according to canal drying methods (1: complete drying, 2: blot drying/distilled water, 3: blot drying/NaOCl, 4: aspiration only). The root canals were obturated using a single-cone filling technique with a calcium silicate-based sealer. Nanoleakage was evaluated using a nanoflow device after 24 hours, 1 week, and 1 month. Data were collected twice per second at the nanoscale and measured in nanoliters per second. Data were statistically analyzed using the Kruskal-Wallis and Mann-Whitney U-tests (p < 0.05). Results: The mean flow rate measured after 24 hours showed the highest value among the time periods in all groups. However, the difference in the flow rate between 1 week and 1 month was not significant. The mean flow rate of the complete drying group was the highest at all time points. After 1 month, the mean flow rate in the blot drying group and the aspiration group was not significantly different. Conclusions: Within the limitations of this study, the canal drying method had a significant effect on leakage and sealing ability in root canal obturations using a calcium silicate-based sealer. Thus, a proper drying procedure is critical in endodontic treatment.
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BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory condition characterized by the accumulation of reactive oxygen species and the expression of inflammatory factors. Regarding its anti-atopic activity, numerous traditional medicinal materials and secondary metabolic products play pivotal roles in modulating the associated mechanisms. METHODS: This study aimed to utilize Salvia miltiorrhiza Bunge (SMB) as an anti-AD source. In-vitro activity assessments and qualitative and quantitative analyses using UPLC-TQ-MS/MS and HPLC-DAD were conducted in two cultivars ('Dasan' and 'Kosan'). Statistical analysis indicated that the profiles of their secondary metabolites contribute significantly to their pharmacological properties. Consequently, bio-guided fractionation was undertaken to figure out the distinct roles of the secondary metabolites present in SMB. RESULTS: Comparative study of two cultivars indicated that 'Dasan', having higher salvianolic acid A and B, exhibited stronger antioxidant and anti-inflammatory activities. Meanwhile, 'Kosan', containing higher tanshinones, showed higher alleviating activities on anti-AD related genes in mRNA levels. Additionally, performed bio-guided fractionation re-confirmed that the hydrophilic compounds of SMB can prevent AD by inhibiting accumulation of ROS and suppressing inflammatory factors and the lipophilic components can directly inhibit AD. CONCLUSIONS: SMB was revealed as a good source for anti-AD activity. Several bioactive compounds were identified from the UPLC-TQ-MS/MS and different compounds content was linked to biological activities. Characterization of these compounds may be helpful to understand differential role of secondary metabolites from SMB on alleviation of AD.
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Anti-Inflamatórios , Dermatite Atópica , Extratos Vegetais , Salvia miltiorrhiza , Salvia miltiorrhiza/química , Dermatite Atópica/tratamento farmacológico , Extratos Vegetais/farmacologia , Humanos , Anti-Inflamatórios/farmacologia , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: Narrowing of the palatal cleft is often observed in infants with Robin sequence (RS) treated with the Stanford Orthodontic Airway Plate treatment (SOAP) even though SOAP is utilized primarily to establish airway patency. The current study quantified dimensional changes of the cleft palate (CP) in infants with RS treated with SOAP. DESIGN: A retrospective chart review. PATIENTS: Infants with RS and CP who completed SOAP and had maxillary arch models at both pre- and post-treatment time points at a single tertiary referral hospital between September 2019 and July 2023. SETTING AND OUTCOME MEASURE: Maxillary arch models were measured and analyzed using Bivariate statistical analysis. RESULTS: Seventeen infants were included in the study. The median age (min, max) was 6.7 weeks (1.1, 21.9) at pre-treatment and 26.6 weeks (18.7, 37.0) at post-treatment. The median Obstructive Apnea Hypopnea Index was 36.2 events/hour (8.1, 103.1) at pre-treatment and 4.1 events/hour (1.9, 8.6) at post-treatment. The pre-treatment width of CP decreased by an average (± standard diviation) of 6.37 mm (± 3.55, p < 0.001) at post-treatment. The ratio of the posterior cleft width to the total maxillary arch width decreased from 40% (± 9.1) at pre-treatment to 22% (± 11) at post-treatment (p < 0.001). CONCLUSION: The dimensions of CP reduced significantly during SOAP in infants with RS and CP treated for their severe upper airway obstruction. The findings highlight a potential benefit of SOAP that may contribute favorably to the palate repair surgery.
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OBJECTIVES: To investigate the usefulness of super-resolution deep learning reconstruction (SR-DLR) with cardiac option in the assessment of image quality in patients with stent-assisted coil embolization, coil embolization, and flow-diverting stent placement compared with other image reconstructions. METHODS: This single-centre retrospective study included 50 patients (mean age, 59 years; range, 44-81 years; 13 men) who were treated with stent-assisted coil embolization, coil embolization, and flow-diverting stent placement between January and July 2023. The images were reconstructed using filtered back projection (FBP), hybrid iterative reconstruction (IR), and SR-DLR. The objective image analysis included image noise in the Hounsfield unit (HU), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and full width at half maximum (FWHM). Subjectively, two radiologists evaluated the overall image quality for the visualization of the flow-diverting stent, coil, and stent. RESULTS: The image noise in HU in SR-DLR was 6.99 ± 1.49, which was significantly lower than that in images reconstructed with FBP (12.32 ± 3.01) and hybrid IR (8.63 ± 2.12) (P < .001). Both the mean SNR and CNR were significantly higher in SR-DLR than in FBP and hybrid IR (P < .001 and P < .001). The FWHMs for the stent (P < .004), flow-diverting stent (P < .001), and coil (P < .001) were significantly lower in SR-DLR than in FBP and hybrid IR. The subjective visual scores were significantly higher in SR-DLR than in other image reconstructions (P < .001). CONCLUSIONS: SR-DLR with cardiac option is useful for follow-up imaging in stent-assisted coil embolization and flow-diverting stent placement in terms of lower image noise, higher SNR and CNR, superior subjective image analysis, and less blooming artifact than other image reconstructions. ADVANCES IN KNOWLEDGE: SR-DLR with cardiac option allows better visualization of the peripheral and smaller cerebral arteries. SR-DLR with cardiac option can be beneficial for CT imaging of stent-assisted coil embolization and flow-diverting stent.
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Aprendizado Profundo , Procedimentos Endovasculares , Aneurisma Intracraniano , Stents , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Estudos Retrospectivos , Adulto , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/terapia , Aneurisma Intracraniano/cirurgia , Idoso de 80 Anos ou mais , Procedimentos Endovasculares/métodos , Embolização Terapêutica/métodos , Razão Sinal-RuídoRESUMO
BACKGROUND: Sex-related disparities in the prevalence of chronic cough have been consistently reported globally, with varying male-to-female ratios. OBJECTIVES: This study aimed to evaluate sex-related differences by comparing correlations between cough-related symptoms in males and females of different age groups. DESIGN: Adult patients with chronic cough who completed the Leicester Cough Questionnaire (LCQ) were recruited from 16 respiratory centers. METHODS: Correlation networks were constructed based on Spearman's correlation coefficients in males and females of various age groups. The distinct relationships of cough-related symptoms between subgroups were validated by an independent cohort. RESULTS: A total of 255 patients were enrolled in this study (male-to-female ratio, 1:1.71). The following LCQ items were highly correlated: embarrassment and interference with daily work, anxiety, and interference with overall life enjoyment/feeling of being fed up, interference with daily work and overall life enjoyment, interference with overall life enjoyment and feeling of being fed up, and feeling of being fed up and annoyance to partner/family/friends. The patterns of these correlations between LCQ items varied in males and females of different ages. The strongest interrelationship was observed in male patients aged >50 years old, which was similar to those in the validation cohort. CONCLUSION: The correlation patterns between cough-related symptoms vary significantly according to age and sex. Understanding the mechanisms underlying the development of cough-related symptoms may facilitate sex- and age-specific strategies for chronic cough.
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Tosse , Humanos , Tosse/fisiopatologia , Tosse/epidemiologia , Tosse/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Fatores Sexuais , Fatores Etários , Inquéritos e Questionários , Doença Crônica , Disparidades nos Níveis de Saúde , Prevalência , Adulto JovemRESUMO
Vehicular ad hoc networks (VANETs) use multiple channels to communicate using wireless access in vehicular environment (WAVE) standards to provide a variety of vehicle-related applications. The current IEEE 802.11p WAVE communication channel structure is composed of one control channel (CCH) and several service channels (SCHs). SCHs are used for non-safety data transmission, while the CCH is used for broadcasting beacons, control, and safety. WAVE devices transmit data that alternate between CCHs and SCHs, and each channel is active for a duration called the CCH interval (CCHI) and SCH interval (SCHI), respectively. Currently, both intervals are fixed at 50 ms. However, fixed-length intervals cannot effectively respond to dynamically changing traffic loads. Additionally, when many vehicles are simultaneously using the limited channel resources for data transmission, the network performance significantly degrades due to numerous packet collisions. Herein, we propose an adaptive resource allocation technique for efficient data transmission. The technique dynamically adjusts the SCHI and CCHI to improve network performance. Moreover, to reduce data collisions and optimize the network's backoff distribution, the proposed scheme applies reinforcement learning (RL) to provide an intelligent channel access algorithm. The simulation results demonstrate that the proposed scheme can ensure high throughputs and low transmission delays.
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Introduction: Basicervical femoral neck fracture (FNF) is an uncommon type of femoral neck fracture and is associated with an increased risk of fixation failure due to its inherent instability. The purpose of this study was to compare the surgical parameters and reoperation rate between the use of a multiple cannulated screw (MCS) and fixed angle device (FAD) in treating basicervical FNFs. Methods: We retrospectively reviewed the records of 885 patients who underwent internal fixation between May 2004 and August 2019 to determine basicervical FNF with at least 12 months of follow-up. Among the identified 77 patients with basicervical FNF, 17 patients who underwent multiple cannulated screw (MCS) fixation and 36 patients who underwent fixed angle device (FAD) fixation were included. We compared the rates of fracture-site collapse and reoperations according to the fixation device. Results: Among the 53 patients with basicervical FNF, 13 patients (24.5%) sustained surgical complications (8 collapses of fracture site and 5 reoperations). The reoperation rate in the MCS group was significantly higher than that in the FAD group (23.5% vs. 2.8%, p = 0.016), without any significant difference in the collapse of the fracture site (11.8% vs. 16.7%, p = 0.642). Conclusions: Although basicervical FNF was rare among hip fractures, fracture site collapse was prevalent and prone to fixation failure. Surgeons should keep this in mind, and consider FAD for basicervical FNF.
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Parafusos Ósseos , Fraturas do Colo Femoral , Fixação Interna de Fraturas , Humanos , Fraturas do Colo Femoral/cirurgia , Feminino , Masculino , Estudos Retrospectivos , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/estatística & dados numéricos , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Reoperação/estatística & dados numéricos , Idoso de 80 Anos ou mais , Complicações Pós-Operatórias/epidemiologiaRESUMO
This study aimed to compare the nanoleakage of retrograde fillings with premixed calcium silicate-based putty and mineral trioxide aggregate (MTA), using two different techniques (traditional and Lid). Sixty-four extracted human teeth were decoronated, then root canals and ends were instrumented for retrograde filling and divided into four groups according to the retrograde filling technique: the traditional and the Lid technique. Each group (n = 15) was filled with Ceraseal + Well-Root putty, Well-Root putty, Ceraseal + ProRoot MTA, and ProRoot MTA. The nanoleakage was evaluated using the Nanoflow device (IB Systems) on days 1, 3, 7, 15 and 30. Data were collected twice per second at the nanoscale (nL/s) and calculated after archiving the stabilization of fluid flow. The Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. All groups showed enhanced sealing ability over time. Regardless of filling materials, the Well-Root putty, Ceraseal+Well-Root putty, and Ceraseal+ProRoot MTA groups indicated less nanoleakage than the ProRoot MTA group in the first week of evaluation (p < 0.05). Although all groups did not show significant differences after 2 weeks, the Ceraseal+ProRoot MTA group leaked less than ProRoot MTA on Days 3 and 7 (p < 0.05). The scanning electron microscopic examined good adaptation to the cavity wall, which was similar to nanoleakage results. Premixed calcium silicate-based putty retrograde filling material alone and using the "lid technique" were shown to be faster and less prone to nanoleakage when compared to MTA.
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Teriparatide has been effective in treating people diagnosed with medication-related osteonecrosis of the jaw (MRONJ). However, its efficacy is not well established to be accepted as a standard of care. The objective of this paper was to investigate the efficacy of recombinant human parathyroid hormone for the treatment of MRONJ. We report three cases of MRONJ patients with osteoporosis as the primary disease who were treated with a teriparatide agent along with other adjunctive measures. Each patient was administered a teriparatide injection subcutaneously for 16 weeks, 36 weeks, or 60 weeks. Surgical intervention including partial resection, sequestrectomy, decortication, and saucerization took place during the teriparatide administration. Complete lesion resolution was identified clinically and radiographically in all three patients. In patients diagnosed with MRONJ, teriparatide therapy is an efficacious and safe therapeutic option to improve healing of bone lesions. These findings demonstrate that teriparatide in combination with another therapy, especially bone morphogenetic protein, platelet-rich fibrin, or antibiotic therapy, can be an effective protocol for MRONJ.
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There have been previous studies conducted to predict postoperative lung function with pulmonary function tests (PFTs). Computing tomography (CT) can quantitatively measure small airway walls' thickness, lung volume, pulmonary vessel volume, and emphysema area, which reflect the severity of respiratory diseases. These measurements are considered imaging biomarkers. This study aimed to predict postoperative lung function with imaging biomarkers. A retrospective analysis of 79 patients with lung cancer who had undergone lung surgery was completed. Postoperative lung function measured by forced expiratory volume in one second (FEV1) was defined as an outcome. Preoperative clinico-pathological parameters and imaging biomarkers representing airway walls' thickness, severity of emphysema, total lung volume, and pulmonary vessel volume were measured quantitatively in chest CT by an automated segmentation software, AVIEW COPD. Pi1 was defined as the first percentile along the histogram of lung attenuation that represents the degree of emphysema. Wafw was defined as the airway thickness, which was calculated by the full-width at half-maximum method. Logistic and linear regressions were used to assess these variables. If the actual postoperative FEV1 was higher than the postoperative FEV1 projected by a formula, the group was considered to be preserved. Among the 79 patients, 16 of the patients were grouped as a non-preserved group, and 63 of them were grouped as a preserved group. The patients in the preserved FEV1 group had a higher vessel volume than the non-preserved group. Pi1 and Wafw were independent predictors of postoperative lung function. Imaging biomarkers can be considered significant variables in predicting postoperative lung function in patients with lung cancer.
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Three-dimensional microextrusion bioprinting technology uses pneumatics, pistons, or screws to transfer and extrude bioinks containing biomaterials and cells to print biological tissues and organs. Computational fluid dynamics (CFD) analysis can simulate the flow characteristics of bioinks in a control volume, and the effect on cell viability can be predicted by calculating the physical quantities. In this study, we developed an analysis system to predict the effect of a screw-based dispenser system (SDS) on cell viability in bioinks through rheological and CFD analyses. Furthermore, carboxymethylcellulose/alginate-based bioinks were used for the empirical evaluation of high-viscous bioinks. The viscosity of bioinks was determined by rheological measurement, and the viscosity coefficient for the CFD analysis was derived from a correlation equation by non-linear regression analysis. The mass flow rate derived from the analysis was successfully validated by comparison with that from the empirical evaluation. Finally, the cell viability was confirmed after bioprinting with bioinks containing C2C12 cells, suggesting that the developed SDS may be suitable for application in the field of bioengineering. Consequently, the developed bioink analysis system is applicable to a wide range of systems and materials, contributing to time and cost savings in the bioengineering industry.
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Templating is essential in hip arthroplasty preparation, facilitating implant size prediction and surgical rehearsal. It ensures the selection of suitable implants according to patient anatomy and disease, aiming to minimize post-operative complications. Various templating methods exist, including traditional acetate templating on both analog and digital images, alongside digital templating on digital images, which is categorized into 2D and 3D approaches. Despite the popularity of acetate templating on digital images, challenges such as the requirement for physical templates and result preservation persist. To address these limitations, digital templating with software like OrthoSize and Orthoview has been suggested, although not universally accessible. This technical note advocates for Microsoft PowerPoint as an effective alternative for 2D digital templating, highlighting its user-friendly features for image manipulation without needing specialized software. The described method involves scanning acetate templates, adjusting the images in PowerPoint 365 for size, position, and calibration on patient radiographs, and demonstrating reliability through preliminary assessments, with intraclass correlation coefficient (ICC) values indicating a high level of agreement for cup and stem size (ICC = 0.860, 0.841, respectively) but moderate for neck length (ICC = 0.592). We have introduced a method for performing 2D digital templating in the clinical field without the need for specialized software dedicated to digital templating. We believe this method significantly improves the accessibility to 2D digital templating, which was previously limited by the need for digital templating software. Additionally, it enables surgeons to easily establish arthroplasty plans and share them, overcoming the limitations of acetate templates.
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BACKGROUND/AIM: Patients with pneumonia after prolonged neutropenia are at increased risk for acute respiratory distress syndrome (ARDS). The key molecule of endothelial barrier breakdown in sepsis is lipopolysaccharide (LPS), which is a component of the outer membrane of gram-negative bacterial cell walls. Maintaining increased cyclic adenosine monophosphate (cAMP) levels in endothelial cells is effective in preventing endothelial dysfunction and microvascular permeability. The aim of this study was to elucidate whether roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, is effective in LPS-induced acute lung injury (ALI) during neutropenia recovery in a murine model. MATERIALS AND METHODS: To induce neutropenia, all mice were administered intraperitoneal cyclophosphamide. On day 2 after neutropenia, mice were administered LPS by intra-tracheal instillation. In the prevention group, roflumilast was given orally on day 0, when neutropenia was induced. In the treatment group, roflumilast was administered orally 1 hour after LPS injection. RESULTS: Roflumilast attenuated histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of inflammatory cytokines IL-1ß, TNF-α, and IL-6 in bronchoalveolar lavage fluids were inhibited effectively by roflumilast. Also, MMP-9 and TGF-ß expression was attenuated in the roflumilast group. CONCLUSION: Roflumilast significantly attenuated LPS-induced ALI during neutropenia recovery.
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Lesão Pulmonar Aguda , Aminopiridinas , Benzamidas , Ciclopropanos , Modelos Animais de Doenças , Lipopolissacarídeos , Neutropenia , Inibidores da Fosfodiesterase 4 , Animais , Aminopiridinas/farmacologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Neutropenia/tratamento farmacológico , Neutropenia/induzido quimicamente , Inibidores da Fosfodiesterase 4/farmacologia , Citocinas/metabolismo , Masculino , Líquido da Lavagem Broncoalveolar , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Patients with tuberculosis and diabetes have a higher risk of unfavourable anti-tuberculosis treatment outcomes. In the present study, we aimed to evaluate the effects of various diabetes statuses on the outcomes of patients with pulmonary tuberculosis. METHODS: Among the patients with pulmonary tuberculosis enrolled in the Korea Tuberculosis Cohort (KTBC) registry and the multicentre prospective cohort study of pulmonary tuberculosis (COSMOTB), those with diabetes and complicated diabetes were identified. The primary and secondary outcomes were unfavourable outcomes and mortality, respectively. The effect of diabetes and complicated diabetes on the outcomes was assessed using multivariable logistic regression analysis. Using COSMOTB, subgroup analyses were performed to assess the association between various diabetes statuses and outcomes. RESULTS: In the KTBC, diabetes (adjusted odds ratio [aOR] = 1.93, 95% CI = 1.64-2.26) and complicated diabetes (aOR = 1.96, 95% CI = 1.67-2.30) were significantly associated with unfavourable outcomes, consistent with the COSMOTB data analysis. Based on subgroup analysis, untreated diabetes at baseline was an independent risk factor for unfavourable outcomes (aOR = 2.72, 95% CI = 1.26-5.61). Prediabetes and uncontrolled diabetes increased unfavourable outcomes and mortality without statistical significance. CONCLUSION: Untreated and complicated diabetes at the time of tuberculosis diagnosis increases the risk of unfavourable outcomes and mortality.
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Antituberculosos , Estado Pré-Diabético , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/mortalidade , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Antituberculosos/uso terapêutico , Resultado do Tratamento , Estudos Prospectivos , Adulto , República da Coreia/epidemiologia , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/complicações , Fatores de Risco , Sistema de Registros , Diabetes Mellitus/epidemiologia , Idoso , Complicações do DiabetesRESUMO
FAF1 (FAS-associated factor 1) is involved in the activation of Fas cell surface death receptors and plays a role in apoptosis and necrosis. In patients with Parkinson's disease, FAF1 is overexpressed in dopaminergic neurons in the substantia nigra. KM-819, an FAF1 inhibitor, has shown potential for preventing dopaminergic neuronal cell death, promoting the degradation of α-synuclein and preventing its accumulation. This study aimed to develop and validate a quantitative analytical method for determining KM-819 levels in rat plasma using liquid chromatography-tandem mass spectrometry. This method was then applied to pharmacokinetic (PK) studies in rats. The metabolic stability of KM-819 was assessed in rat, dog, and human hepatocytes. In vitro metabolite identification and metabolic pathways were investigated in rat, dog, and human hepatocytes. The structural analog of KM-819, namely N-[1-(4-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(phenylsulfanyl) acetamide, served as the internal standard (IS). Proteins were precipitated from plasma samples using acetonitrile. Analysis was carried out using a reverse-phase C18 column with a mobile phase consisting of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile. The analytical method developed for KM-819 exhibited linearity within the concentration range of 0.002-10 µg/mL in rat plasma. The precision and accuracy of the intra- and inter-day measurements were <15% for the lower limit of quantification (LLOQ) and all quality control samples. KM-819 demonstrated stability under various sample storage conditions (6 h at room temperature (25 °C), four weeks at -20 °C, three freeze-thaw cycles, and pretreated samples in the autosampler). The matrix effect and dilution integrity met the criteria set by the Food and Drug Administration and the European Medicines Agency. This sensitive, rapid, and reliable analytical method was successfully applied in pharmacokinetic studies in rats. Pharmacokinetic analysis revealed the dose-independent kinetics of KM-819 at 0.5-5 mg/kg, with a moderate oral bioavailability of ~20% in rats. The metabolic stability of KM-819 was also found to be moderate in rat, dog, and human hepatocytes. Metabolite identification in rat, dog, and human hepatocytes resulted in the discovery of six, six, and eight metabolites, respectively. Glucuronidation and mono-oxidation have been proposed as the major metabolic pathways. Overall, these findings contribute to a better understanding of the pharmacokinetic characteristics of KM-819, thereby aiding future clinical studies.
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Formiatos , Compostos Orgânicos , Doença de Parkinson , Espectrometria de Massas em Tandem , Ratos , Humanos , Animais , Cães , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massa com Cromatografia Líquida , Acetonitrilas , Reprodutibilidade dos Testes , Cromatografia Líquida de Alta Pressão/métodos , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de ApoptoseRESUMO
BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice. MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration. RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101). CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.
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Lesão Pulmonar Aguda , Neutropenia , Humanos , Camundongos , Ratos , Animais , Galantamina/efeitos adversos , Galantamina/metabolismo , Lipopolissacarídeos/efeitos adversos , c-Mer Tirosina Quinase/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Proteínas Tirosina Quinases/metabolismo , Pulmão/patologiaRESUMO
Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders.