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In this work, we report the first example of the PCET reactivity for a boron cluster compound, the zwitterionic nido-carboranyl diphosphonium derivative 7-P(H)tBu2-10-P(H)iPr2-nido-C2B10H10. This main-group reagent efficiently transfers two electrons and two protons to quinones to yield hydroquinones and regenerate a neutral closo-carboranyl diphosphine, 1-PtBu2-2-PiPr2-closo-C2B10H10. As we have previously reported the conversion of this closo-carboranyl diphosphine into the zwitterionic nido- derivative upon reaction with main group hydrides, the transformation reported herein represents a complete synthetic cycle for the metal-free reduction of quinones, with the redox-active carboranyl diphosphine scaffold acting as a mediator. The proposed mechanism of this reduction, based on pKa determination, electrochemical studies, and kinetic isotope effect determination, involves the electron transfer from the nido- cluster to the quinone coupled with the delivery of protons.
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We present our discovery of switchable high explosives (HEs) as a new class of energetic material that cannot detonate unless filled with a fluid. The performance of fluid-filled additive-manufactured HE lattices is herein evaluated by analysis of detonation velocity and Gurney energy. The Gurney energy of the unfilled lattice was 98% lower than that of the equivalent water-filled lattice and changing the fluid mechanical properties allowed tuning of the Gurney energy and detonation velocity by 8.5% and 13.4%, respectively. These results provide, for the first time since the development of HEs, a method to completely remove the hazard of unplanned detonations during storage and transport.
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Background: Medical cannabis currently dominates the U.S. cannabis advertising landscape. The public is increasingly exposed to outdoor cannabis advertising, which increases positive attitudes about and intentions to use cannabis. Research is lacking regarding outdoor cannabis advertising content. This article characterizes the content of outdoor cannabis advertising in Oklahoma, one of the fastest growing U.S. medical cannabis markets. Methods: We conducted a content analysis of cannabis advertising billboard images (n = 73) from Oklahoma City and Tulsa, photographed May 2019-November 2020. We followed a primarily inductive, iterative team approach to thematically analyze billboard content in NVIVO. We reviewed all images, identified a broad coding taxonomy, and then incorporated emergent codes and those related to advertising regulation (e.g. youth/children). We totaled frequencies of code application across billboards and reexamined billboards for final themes. Results: Major themes were social meanings related to cannabis subculture, formal medical systems, and nature, and the presence of company contact information. Minor themes related to convenience, price promotions, store proximity, U.S. affiliation, product quality, and spirituality. State advertising regulation violations were rare, with the exception of content that may promote curative or therapeutic effects (4%) and misrepresentation of product state of origin (1.4%). Conclusion: Outdoor medical cannabis advertising in Oklahoma blurs boundaries between formal medical discourses and cannabis subculture that is suspicious of messaging from authorities and regards cannabis as harmless and natural. Increased monitoring of advertising regulation compliance and greater understanding of social discourses within emerging markets is needed to promote public health within the context of cannabis advertising.
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Cannabis , Maconha Medicinal , Adolescente , Criança , Humanos , Publicidade , OklahomaRESUMO
Due to the lack of new antimicrobial drug discovery in recent years and an ever-growing prevalence of multidrug-resistant "superbugs", there is a pressing need to explore alternative ways to combat pathogenic bacterial and fungal infections. Building upon our previous work in the field of medicinal phytochemistry, the present study is focused on designing, synthesizing, and testing the altered bioactivity of new variants of two original bioactive molecules found in the Argemone mexicana plant. Herein, we report upon 14 variants of berberine and four variants of chelerythrine that have been screened against a pool of 12 microorganisms (five Gram-positive and four Gram-negative bacteria, and three fungi). Additionally, the crystal structures of two berberine variants are described. Several berberine variants show enhanced antibacterial activity compared to the unaltered plant-derived molecule. We also report promising preliminary tumor cytotoxicity effects for a number of the berberine derivatives.
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The south Florida pine rocklands is a critically endangered, fire-dependent ecosystem dominated by the overstory tree Pinus densa (South Florida slash pine). Because pine recruitment in this ecosystem has proven problematic, restoration efforts need to include replanting slash pine trees. Even though ectomycorrhizal fungi are known to be critical symbionts of young pines and are necessary for the development of healthy pines, virtually nothing is known about these mutualists and their role in pine establishment and survival in the pine rocklands. One approach to improve pine establishment is to grow seedlings in a nursery before outplanting, facilitating early associations with ectomycorrhizae, and therefore improving seedling health. In this study, we compared health metrics (height, stem diameter, final needle length, root length, root colonization, needle greenness, root volume, and root:shoot ratio) of seedlings grown in soil amended with five commercially available mycorrhizal inocula versus field soil collected from three pine rockland fragments. Seedlings grown with native field soil from the pine rocklands generally performed better than those grown with commercial inoculum in all metrics except root length. According to their labels, each commercial inoculum contained between 4 and 10 ectomycorrhizal fungi species. However, no ectomycorrhizal fungi were recovered from two of the inoculum products and only three ectomycorrhizal fungi in total were recovered from the other three products. In contrast, seedlings grown with field soil are associated with ten ectomycorrhizal species. Our results highlight the importance of incorporating native ectomycorrhizal fungi into pine seedling replanting as part of restoration efforts in the pine rocklands.
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Micorrizas , Pinus , Ecossistema , Pinus/microbiologia , Plântula/microbiologia , SoloRESUMO
BACKGROUND: The nonlesional skin of children with atopic dermatitis (AD) with peanut allergy (PA) is associated with increased transepidermal water loss; low urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), both of which are filaggrin breakdown products; and a reduced ratio of esterified ω-hydroxy fatty acid sphingosine ceramides (EOS-CERs) to nonhydroxy fatty acid sphingosine ceramides (NS-CERs) in the skin. The skin barrier of subjects with PA without AD (AD-PA+) has not been studied. OBJECTIVE: Our aim was to explore whether AD-PA+ is associated with skin barrier abnormalities. METHODS: A total of 33 participants were enrolled, including 13 AD-PA+, 9 AD+PA+, and 11 nonatopic (NA) participants. RESULTS: The PCA content in the stratum corneum of AD-PA+ subjects was significantly reduced versus that in NA subjects (median level, 67 vs 97 µg/mg protein [P = .028]). The ratio between cis- and trans-UCA decreased significantly from being highest in the NA group (1.62) to lowest in AD+PA+ group (0.07 [P < .001 vs in the NA group; P = .006 vs in the AD-PA+ group]), with the AD-PA+ group having an intermediate cis/trans-UCA ratio (1.17 [P = .024 vs in the NA group]). The TEWL in AD-PA+ subjects did not differ from that in the group with NA skin. Interestingly, AD-PA+ subjects had an increased EOS/NS-CER ratio versus that in the group of subjects with NA skin (1.9 vs 1.3 [P = .008]), whereas the AD+PA+ group had a decreased proportion of EOS-CERs (0.8 [P = .001] vs in the AD-PA+ group). CONCLUSION: Our data demonstrate that irrespective of AD, PA is associated with decreased skin cis-UCA and PCA content. An increase in skin EOS-CER/NS-CER ratio separates the AD-PA+ group from the AD+PA+ and NA groups.
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Dermatite Atópica , Anormalidades da Pele , Pele , Criança , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Feminino , Proteínas Filagrinas , Humanos , Masculino , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/patologia , Pele/imunologia , Pele/patologia , Anormalidades da Pele/imunologia , Anormalidades da Pele/patologiaRESUMO
Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.
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Mycobacterium tuberculosis , Tiazinas , Tuberculose , Animais , Camundongos , Camundongos Endogâmicos C3H , Piperazinas , Tuberculose/tratamento farmacológicoRESUMO
Two natural auxins, phenylacetic acid (PAA) and indole-3-acetic acid (IAA), play crucial roles in plant growth and development. One route of IAA biosynthesis uses the glucosinolate intermediate indole-3-acetaldoxime (IAOx) as a precursor, which is thought to occur only in glucosinolate-producing plants in Brassicales. A recent study showed that overproducing phenylacetaldoxime (PAOx) in Arabidopsis increases PAA production. However, it remains unknown whether this increased PAA resulted from hydrolysis of PAOx-derived benzyl glucosinolate or, like IAOx-derived IAA, is directly converted from PAOx. If glucosinolate hydrolysis is not required, aldoxime-derived auxin biosynthesis may occur beyond Brassicales. To better understand aldoxime-derived auxin biosynthesis, we conducted an isotope-labelled aldoxime feeding assay using an Arabidopsis glucosinolate-deficient mutant sur1 and maize, and transcriptomics analysis. Our study demonstrated that the conversion of PAOx to PAA does not require glucosinolates in Arabidopsis. Furthermore, maize produces PAA and IAA from PAOx and IAOx, respectively, indicating that aldoxime-derived auxin biosynthesis also occurs in maize. Considering that aldoxime production occurs widely in the plant kingdom, aldoxime-derived auxin biosynthesis is likely to be more widespread than originally believed. A genome-wide transcriptomics study using PAOx-overproduction plants identified complex metabolic networks among IAA, PAA, phenylpropanoid and tryptophan metabolism.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Ácidos Indolacéticos , Oximas , Zea mays/genéticaRESUMO
PURPOSE: Patient-Specific Quality Assurance (PSQA) measurement analysis depends on generating metrics representative of calculation and measurement agreement. Considering the heightened capability of discrete spot scanning protons to modulate individual dose voxels, a dose plane comparison approach that maintained all of the capabilities of the well-established γ test, but that also provided a more intuitive error parameterization, was desired. METHODS: Analysis was performed for 300 dose planes compared by searching all calculated points within a fixed radius around each measured pixel to determine the dose deviation. Dose plane agreement is reported as the dose difference minimum (DDM) within an empirically established search radius: ΔDmin(r). This per-pixel metric is aggregated into a histogram binned by dose deviation. Search-radius criteria were based on a weighted-beamlet 3σ spatial deviation from imaging isocenter. Equipment setup error was mitigated during analysis using tracked image registration, ensuring beamlet deviations to be the dominant source of spatial error. The percentage of comparison points with <3% dose difference determined pass rate. RESULTS: The mean beamlet radial deviation was 0.38mm from x-ray isocenter, with a standard deviation of 0.19mm, such that 99.9% of relevant pencil beams were within 1 mm of nominal. The dose-plane comparison data showed no change in passing rate between a 3%/1mm ΔDmin(r) analysis (97.6 +/- 3.6%) and a 3%/2mm γ test (97.7 +/- 3.2%). CONCLUSIONS: PSQA dose-comparison agreements corresponding to a search radius outside of machine performance limits are likely false positives. However, the elliptical shape of the γ test is too dose-restrictive with a spatial-error threshold set at 1 mm. This work introduces a cylindrical search shape, proposed herein as more relevant to plan quality, as part of the new DDM planar-dose comparison algorithm. DDM accepts all pixels within a given dose threshold inside the search radius, and carries forward plan-quality metrics in a straightforward manner for evaluation.
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Terapia com Prótons , Prótons , Algoritmos , Humanos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
Metal nitrides are strong refractory ceramic materials known for applications in the coatings, catalysis, and semiconductor industries. Lanthanide nitrides are difficult to prepare in high purity and often require high temperatures and sophisticated equipment. In this work, we present an approach to the synthesis of high-purity f-element nitrides through the use of simple lanthanide salts and the nitrogen-rich ligand 5,5'-bis(1H-tetrazolyl)amine (H2BTA) to form lanthanide complexes of 5,5'-bis(tetrazolato)amine (BTA2-). We have demonstrated that, when dehydrated, these types of complexes undergo a self-sustained combustion reaction under an inert atmosphere to yield nanostructured f-element nitride foams for lanthanum and cerium. The synthesis, characterization, and single-crystal X-ray crystallography of the BTA2- complexes of lanthanum, cerium, praseodymium, neodymium, and europium are also discussed.
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This case is, to the authors' knowledge, the first reported case in the literature of bilateral orbital abscesses as result of an infected nasal dermoid. The baby presented with what proved to be bilateral supraorbital subperiosteal abscesses with associated frontal osteitis/osteomyelitis and soft tissue infection of the glabella. Methicillin-sensitive staphylococcus aureus infection was found in the setting of a midline nasal dermoid with tuft of hair and infected sinus tract that was at least initially missed on diagnosis.
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Abscesso/etiologia , Coristoma/complicações , Cisto Dermoide/complicações , Infecções Oculares Bacterianas/etiologia , Cabelo , Doenças Nasais/complicações , Infecções Estafilocócicas/etiologia , Abscesso/diagnóstico , Abscesso/microbiologia , Coristoma/diagnóstico , Cisto Dermoide/diagnóstico , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/microbiologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Doenças Nasais/diagnóstico , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Tomografia Computadorizada por Raios XRESUMO
CONTEXT: It is important to validate single-leg squat visual rating criteria used in clinical practice and research. Foot orthoses may improve single-leg squat performance in those who demonstrate biomechanics associated with increased risk of lower limb injury. OBJECTIVE: Validate visual rating criteria proposed by Crossley et al, by determining whether athletes rated as poor single-leg squat performers display different single-leg squat biomechanics than good performers; and evaluate immediate effects of foot orthoses on single-leg squat biomechanics in poor performers. DESIGN: Comparative cross-sectional study. SETTING: University laboratory. PARTICIPANTS: 79 asymptomatic athletes underwent video classification of single-leg squat performance based on established visual rating criteria (overall impression, trunk posture, pelvis "in space," hip movement, and knee movement), and were rated as good (n = 23), fair (n = 41), or poor (n = 15) performers. INTERVENTION: A subset of good (n = 16) and poor (n = 12) performers underwent biomechanical assessment, completing 5 continuous single-leg squats on their dominant limb while 3-dimensional motion analysis and ground reaction force data were recorded. Poor performers repeated the task standing on prefabricated foot orthoses. MAIN OUTCOME MEASURES: Peak external knee adduction moment (KAM) and peak angles for the trunk, hip, knee, and ankle. RESULTS: Compared with good performers, poor performers had a significantly lower peak KAM (mean difference = 0.11 Nm/kg, 95% confidence interval = 0.02 to 0.2 Nm/kg), higher peak hip adduction angle (-4.3°, -7.6° to -0.9°), and higher peak trunk axial rotation toward their stance limb (3.8°, 0.4° to 7.2°). Foot orthoses significantly increased the peak KAM in poor performers (-0.06 Nm/kg, -0.1 to -0.01 Nm/kg), with values approximating those observed in good performers. CONCLUSIONS: Findings validate Crossley et al's visual rating criteria for single-leg squat performance in asymptomatic athletes, and suggest that "off-the-shelf" foot orthoses may be a simple intervention for poor performers to normalize the magnitude of the external KAM during single-leg squat.
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Órtoses do Pé , Articulação do Quadril/fisiologia , Articulação do Joelho/fisiologia , Amplitude de Movimento Articular , Adulto , Atletas , Fenômenos Biomecânicos , Estudos Transversais , Feminino , Articulação do Quadril/fisiopatologia , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Movimento , Postura , TroncoRESUMO
BACKGROUND: Although preoperative risk assessment is multifactorial, subcutaneous fat thickness at the incision site has been associated with postoperative complications in studies of total hip arthroplasty (THA) and other procedures. This study compared subcutaneous fat thickness encountered in THA approaches using a lateral hip incision with that of approaches using an anterior incision and examined the relationship between body mass index (BMI) and fat distribution based on sex and age. METHODS: Subcutaneous fat measurements were obtained from 2004 patient CT images at positions that correspond with lateral and anterior incision sites for common approaches to THA. A thickness ratio (lateral/anterior) was calculated, and BMI, sex, and age were collected via chart review. RESULTS: Males and females had significantly different thickness ratio averages at 1.97 and 2.68, respectively. Thickness ratios were not significantly different between BMI groups. Lateral thickness averages were significantly different for males and females, and the interaction between sex and BMI group was significant. The relationship between BMI and the thickness ratio in males aged ≥65 years was significantly different from males of <65 years and females of all ages. CONCLUSION: Regardless of BMI, sex, or age, incision site soft tissue thickness was greater for approaches using a lateral hip incision than for those with an anterior incision, and a positive relationship between BMI and both measurements was identified. The predominance of lateral fat was more pronounced in females of all age and BMI groups and less pronounced in obese males aged ≥65 years.
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Artroplastia de Quadril/métodos , Obesidade/complicações , Gordura Subcutânea/diagnóstico por imagem , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Feminino , Quadril/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores Sexuais , Gordura Subcutânea/patologia , Tomografia Computadorizada por Raios XRESUMO
Both dorsolateral prefrontal and posterior parietal cortex have been implicated in spatial working memory and representation of task information. Prior experiments training animals to recall the first of a sequence of stimuli and examining the effect of subsequent distractors have identified increased ability of the prefrontal cortex to represent remembered stimuli and filter distractors. It is unclear, however, if this prefrontal functional specialization extends to stimuli appearing earlier in a sequence, when subjects are cued to remember subsequent ones. It is also not known how task information interacts with persistent activity representing remembered stimuli and distractors in the two areas. To address these questions, we trained monkeys to remember either the first or second of two stimuli presented in sequence and recorded neuronal activity from the posterior parietal and dorsolateral prefrontal cortex. The prefrontal cortex was better able to represent the actively remembered stimulus, whereas the posterior parietal cortex was more modulated by distractors; however, task effects interfered with this representation. As a result, large proportions of neurons with persistent activity and task effects exhibited a preference for a stimulus when it appeared as a distractor in both areas. Additionally, prefrontal neurons were modulated to a greater extent by task factors during the delay period of the task. The results indicate that the prefrontal cortex is better able than the posterior parietal cortex to differentiate between distractors and actively remembered stimuli and is more modulated by the task; however, this relative preference is highly context dependent and depends on the specific requirements of the task.
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Memória de Curto Prazo/fisiologia , Neurônios/fisiologia , Lobo Parietal/fisiologia , Córtex Pré-Frontal/fisiologia , Percepção Visual/fisiologia , Potenciais de Ação , Animais , Antecipação Psicológica/fisiologia , Sinais (Psicologia) , Macaca mulatta , Masculino , Rememoração Mental/fisiologia , Microeletrodos , Testes Neuropsicológicos , Estimulação Luminosa , Percepção do Tempo/fisiologiaRESUMO
Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.
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Técnicas de Apoio para a Decisão , Transplante de Coração , Cadeias de Markov , Transplantados , Listas de Espera , Aloenxertos , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Transplante de Coração/mortalidade , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Medição de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Fatores de Tempo , Listas de Espera/mortalidadeRESUMO
Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone.
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Redução de Custos , Transplante de Coração/economia , Transplante de Coração/métodos , Teste de Histocompatibilidade/economia , Listas de Espera , Criança , Pré-Escolar , Estudos de Coortes , Análise Custo-Benefício , Bases de Dados Factuais , Emergências , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Coração/efeitos adversos , Teste de Histocompatibilidade/métodos , Custos Hospitalares , Humanos , Lactente , Masculino , Cadeias de Markov , Seleção de Pacientes , Pediatria , Prognóstico , Sistema de Registros , Medição de Risco , Sensibilidade e Especificidade , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: This study focused on how catheter size affects transseptal puncture, what transseptal indication means, and whether the swine model is predictive for humans. BACKGROUND: Transseptal puncture is a common procedure that gains access to the left atrium, allowing percutaneous mitral valve repair, left atrial appendage closure, and left-sided ablations. The basic approach has not changed in many years; however, the frequency of transseptal punctures and the size of devices are increasing with emerging treatments. METHODS: A broad range of devices (4 F to 18 F) were advanced through atrial septa of swine hearts; some devices were inserted in both swine and human hearts using 10 F catheters. RESULTS: Greater forces were required to puncture through the septa of human hearts compared to those of swine. Larger catheters used in swine hearts required greater force to advance them through the septa, causing greater dilation of tissue and sometimes tearing the floor of the fossa ovalis; analyses indicated an exponential increase in the size of the iatrogenic atrial septal defect. Specific tissue property testing of the septum primum showed that this tissue sheared at a lower exerted force in a superior to inferior direction. CONCLUSIONS: Results may provide physicians with important knowledge about what to expect when treating a possible iatrogenic atrial septal defect or help them understand the consequences of transseptal punctures. Comparative data between swine and human atrial septal tissue properties provide critical insights between the species and offer clinicians and device designers important information relative to differences in tissue behaviors.
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Septo Interatrial/fisiologia , Septo Interatrial/cirurgia , Punções , Animais , Catéteres , Feminino , Humanos , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Modelos Animais , SuínosRESUMO
Receptors for advanced glycation end-products (RAGE) are members of the immunoglobulin superfamily of cell-surface receptors implicated in mechanisms of pulmonary inflammation. In the current study, we test the hypothesis that RAGE mediates inflammation in primary alveolar macrophages (AMs) exposed to diesel particulate matter (DPM). Quantitative RT-PCR and immunoblotting revealed that RAGE was up-regulated in Raw264.7 cells, an immortalized murine macrophage cell line and primary AMs exposed to DPM for 2 h. Because DPM increased RAGE expression, we exposed Raw264.7 cells and primary AMs isolated from RAGE null and wild-type (WT) mice to DPM prior to the assessment of inflammatory signaling intermediates. DPM led to the activation of Rat sarcoma GTPase (Ras), p38 MAPK and NF-κB in WT AMs and, when compared to WT AMs, these intermediates were diminished in DPM-exposed AMs isolated from RAGE null mice. Furthermore, cytokines implicated in inflammation, including IL-4, IL-12, IL-13 and TNFα, were all significantly decreased in DPM-exposed RAGE null AMs compared to similarly exposed WT AMs. These results demonstrate that diesel-induced inflammatory responses by primary AMs are mediated, at least in part, via RAGE signaling mechanisms. Further work may show that RAGE signaling in both alveolar epithelial cells and resident macrophages is a potential target in the treatment of inflammatory lung diseases exacerbated by environmental pollution.
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Poluentes Atmosféricos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Receptores Imunológicos/biossíntese , Transdução de Sinais/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Linhagem Celular , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Mutantes , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Receptors for advanced glycation end-products (RAGE) are immunoglobulin-like pattern recognition receptors abundantly localized to lung epithelium. Our research demonstrated that primary tobacco smoke exposure increases RAGE expression and that RAGE partly mediates pro-inflammatory signaling during exposure. However, the degree to which RAGE influences developing lungs when gestating mice are exposed to secondhand smoke (SHS) has not been determined to date. METHODS: Timed pregnant RAGE null and wild type control mice were exposed to 4 consecutive days of SHS from embryonic day (E) 14.5 through E18.5 using a state of the art nose-only smoke exposure system (Scireq, Montreal, Canada). RAGE expression was assessed using immunofluorescence, immunoblotting, and quantitative RT-PCR. TUNEL immunostaining and blotting for caspase-3 were performed to evaluate effects on cell turnover. Matrix abnormalities were discerned by quantifying collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. Lastly, TNF-α and IL-1ß levels were assessed in order to determine inflammatory status in the developing lung. RESULTS: Pulmonary RAGE expression was elevated in both dams exposed to SHS and in fetuses gestating within mothers exposed to SHS. Fetal weight, a measure of organismal health, was decreased in SHS-exposed pups, but unchanged in SHS-exposed RAGE null mice. TUNEL assessments suggested a shift toward pulmonary cell apoptosis and matrix in SHS-exposed pups was diminished as revealed by decreased collagen IV and increased MMP-9 expression. Furthermore, SHS-exposed RAGE null mice expressed less TNF-α and IL-1ß when compared to SHS-exposed controls. CONCLUSIONS: RAGE augmentation in developing pups exposed to maternal SHS weakens matrix deposition and influences lung inflammation.