RESUMO
Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve-induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.
Assuntos
Sistema Imunitário/inervação , Imunomodulação/efeitos dos fármacos , Baço/imunologia , Sistema Nervoso Simpático/imunologia , Nervo Vago/imunologia , Animais , Feminino , Expressão Gênica , Humanos , Sistema Imunitário/efeitos dos fármacos , Inflamação , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Microcirculação/efeitos dos fármacos , Microcirculação/genética , Microcirculação/imunologia , Norepinefrina/farmacologia , Ratos , Especificidade da Espécie , Baço/efeitos dos fármacos , Baço/inervação , Baço/patologia , Suínos , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Nervo Vago/efeitos dos fármacos , Estimulação do Nervo Vago/métodosRESUMO
Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG). The docking data suggested that AKT1 binding may require residues Asn54, Trp80, Tyr272, Asp274, and Asp292, whereas AKT2 binding would expect residues Phe163 and Glu279, and AKT3 binding would favor residues Glu17, Trp79, Phe306, and Glu295. These findings may help guide AKT1-selective or AKT3-selective molecular design while sparing the inhibition of AKT2 to minimize the cutaneous toxicity.
Assuntos
Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores da AngiogêneseRESUMO
Carbon nanotubes (CNTs) have unique physical and chemical properties that drive their use in a variety of commercial and industrial applications. CNTs are commonly oxidized prior to their use to enhance dispersion in polar solvents by deliberately grafting oxygen-containing functional groups onto CNT surfaces. In addition, CNT surface oxides can be unintentionally formed or modified after CNTs are released into the environment through exposure to reactive oxygen species and/or ultraviolet irradiation. Consequently, it is important to understand the impact of CNT surface oxidation on the environmental fate, transport, and toxicity of CNTs. In this review, we describe the specific role of oxygen-containing functional groups on the important environmental behaviors of CNTs in aqueous media (e.g., colloidal stability, adsorption, and photochemistry) as well as their biological impact. We place special emphasis on the value of systematically varying and quantifying surface oxides as a route to identifying quantitative structure-property relationships. The role of oxygen-containing functional groups in regulating the efficacy of CNT-enabled water treatment technologies and the influence of surface oxides on other carbon-based nanomaterials are also evaluated and discussed.
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Nanotubos de Carbono/química , Oxigênio/metabolismo , Poluentes Químicos da Água/metabolismo , Adsorção , Humanos , Óxidos/química , Óxidos/metabolismo , Oxigênio/química , Propriedades de Superfície , Poluentes Químicos da Água/química , Poluentes Químicos da Água/farmacologiaRESUMO
The ultraviolet (UV)-induced degradation of graphene/polymer nanocomposites was investigated in this study. Specifically, the effect of few-layer graphene nanofillers on the degradation of a thermoplastic polyurethane (TPU) and the release potential of graphene from the degraded nanocomposite surfaces were assessed. Graphene/TPU (G/TPU) nanocomposites and neat TPU were UV-exposed under both dry and humid conditions in the NIST SPHERE, a precisely controlled, high intensity UV-weathering device. Neat TPU and G/TPU were characterized over the time course of UV exposure using color measurements and infrared spectroscopy, for appearance and chemical changes, respectively. Changes in thickness and surface morphology were obtained with scanning electron microscopy. A new fluorescence quenching measurement approach was developed to identify graphene sheets at the nanocomposite surface, which was supported by contact angle measurements. The potential for graphene release from the nanocomposite surface was evaluated using a tape-lift method followed by microscopy of any particles present on the tape. The findings suggest that graphene improves the service life of TPU with respect to UV exposure, but that graphene becomes exposed at the nanocomposite surface over time, which may potentially lead to its release when exposed to small mechanical forces or upon contact with other materials.
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INTRODUCTION: Equine recurrent laryngeal neuropathy (RLN) is a naturally occurring model of length-dependent axonopathy characterized by asymmetrical degeneration of recurrent laryngeal nerve axons (RLn). Distal RLn degeneration is marked, but it is unclear whether degeneration extends to include cell bodies (consistent with a neuronopathy). METHODS: With examiners blinded to RLN severity, brainstem location, and side, we examined correlations between RLN severity (assessed using left distal RLn myelinated axon count) and histopathological features (including chromatolysis and glial responses) in the nucleus ambiguus cell bodies, and myelinated axon count of the right distal RLn of 16 horses. RESULTS: RLN severity was not associated with RLn cell body number (P > .05), or degeneration. A positive correlation between the left and right distal RLn myelinated axon counts was identified (R2 = 0.57, P < .05). DISCUSSION: We confirm that RLN, a length-dependent distal axonopathy, occurs in the absence of detectable neuronopathy.
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Corpo Celular/patologia , Bulbo/patologia , Fibras Nervosas Mielinizadas/patologia , Neurônios/patologia , Nervo Laríngeo Recorrente/patologia , Paralisia das Pregas Vocais/patologia , Animais , Atrofia , Contagem de Células , Cavalos , Nervo Laríngeo Recorrente/fisiopatologia , Paralisia das Pregas Vocais/fisiopatologiaRESUMO
Active muscle performs various mechanical functions during locomotion: work output during shortening, work absorption when resisting (but not preventing) lengthening, and impulse (force-time integral) whenever there is active force. The energetic costs of these functions are important components in the energy budget during locomotion. We investigated how the pattern of stimulation and movement affects the mechanics and energetics of muscle fibre bundles isolated from wild rabbits (Oryctolagus cuniculus). The fibres were from muscles consisting of mainly fast-twitch, type 2 fibres. Fibre length was held constant (isometric) or a sinusoidal pattern of movement was imposed at a frequency similar to the stride frequency of running wild rabbits. Duty cycle (stimulation duration×movement frequency) and phase (timing of stimulation relative to movement) were varied. Work and impulse were measured as well as energy produced as heat. The sum of net work (work output-work input) and heat was taken as a measure of energetic cost. Maximum work output was produced with a long duty cycle and stimulation starting slightly before shortening, and was produced quite efficiently. However, efficiency was even higher with other stimulation patterns that produced less work. The highest impulse (considerably higher than isometric impulse) was produced when stimulation started while the muscle fibres were being lengthened. High impulse was produced very economically because of the low cost of producing force during lengthening. Thus, locomotion demanding high work, high impulse or economical work output or impulse requires a distinct pattern of stimulation and movement.
Assuntos
Metabolismo Energético/fisiologia , Locomoção/fisiologia , Músculo Esquelético/fisiologia , Coelhos/fisiologia , Animais , Fenômenos Biomecânicos , Feminino , Masculino , Termogênese/fisiologiaRESUMO
An increase in production of commercial products containing graphene-family nanomaterials (GFNs) has led to concern over their release into the environment. The fate and potential ecotoxicological effects of GFNs in the environment are currently unclear, partially due to the limited analytical methods for GFN measurements. In this review, the unique properties of GFNs that are useful for their detection and quantification are discussed. The capacity of several classes of techniques to identify and/or quantify GFNs in different environmental matrices (water, soil, sediment, and organisms), after environmental transformations, and after release from a polymer matrix of a product is evaluated. Extraction and strategies to combine methods for more accurate discrimination of GFNs from environmental interferences as well as from other carbonaceous nanomaterials are recommended. Overall, a comprehensive review of the techniques available to detect and quantify GFNs are systematically presented to inform the state of the science, guide researchers in their selection of the best technique for the system under investigation, and enable further development of GFN metrology in environmental matrices. Two case studies are described to provide practical examples of choosing which techniques to utilize for detection or quantification of GFNs in specific scenarios. Because the available quantitative techniques are somewhat limited, more research is required to distinguish GFNs from other carbonaceous materials and improve the accuracy and detection limits of GFNs at more environmentally relevant concentrations.
Assuntos
Grafite , Nanoestruturas , Ecotoxicologia , Limite de Detecção , ÁguaRESUMO
The biodegradation rates of carbon nanotube (CNT)/ polymer nanocomposites (PNCs) containing poly-ε-caprolactone (PCL) were investigated using Pseudomonas aeruginosa, a microorganism commonly found in the environment. CNT/PCL nanocomposite mass loss profiles revealed that the rate of PCL matrix biodegradation decreased systematically as the CNT loading increased from 0.1 to 10% w/w. Addition of even a low CNT loading (<1% w/w) caused the CNT/PCL biodegradation rate constant to decrease by more than 50%. Similar trends in biodegradation rate were observed for both pristine and oxidized multiwall CNTs embedded in PCL. During PCL matrix biodegradation, CNT accumulation was observed at the surface of CNT/PCL nanocomposites and single particle inductively coupled-mass spectrometry experiments revealed no measurable CNT release to the culture fluid. Experimental data indicated that biodegradation proceeded as a result of biofilm formation on the CNT/PCL nanocomposites and decreased as a function of CNT loading due to the cytotoxicity of CNTs toward P. aeruginosa and the physical barrier presented by the surface-accumulated CNTs to the underlying PCL substrate. As the CNT loading in the CNT/PCL nanocomposites increased, the microbial proliferation of planktonic cells in the surrounding media also decreased as did the biodegradation rate of PCL samples present in the same reactors. Results from this study demonstrate that the inclusion of CNTs into polymer matrices could increase the environmental persistence of polymers in lakes, landfills, and surface waters.
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Nanocompostos , Nanotubos de Carbono , Biodegradação Ambiental , Polímeros , Pseudomonas aeruginosaRESUMO
PURPOSE: To report outcomes of a conjoined tendon transfer procedure in a small case series of young active patients of various activity levels with recurrent traumatic anterior shoulder instability. METHODS: A retrospective chart review identified 10 consecutive patients who underwent conjoined tendon transfer (8 open and 2 arthroscopic) for anterior glenohumeral instability from January 2009 through December 2012. The indications were traumatic anterior shoulder instability with 25% or greater anterior glenoid bone loss, engaging Hill-Sachs lesion, or absent anterior-inferior labral tissue with anterior capsular tissue that did not readily hold sutures or a combination of these deficiencies. Patients did not undergo the procedure if they had healthy capsulolabral tissue and small bony defects or if they competed in high-level collision sports or were overhead throwers. The American Shoulder and Elbow Surgeons (ASES) questionnaire and a physical examination were completed preoperatively. Postoperatively, patients answered questions about shoulder stability and completed ASES and Western Ontario Shoulder Index questionnaires. A physical examination was performed postoperatively to assess range of motion. RESULTS: Of 10 patients, 9 were available for follow-up. The mean age was 33.0 years (range, 18-51 years) at the time of surgery. Eight of nine patients underwent a physical examination at 31.3 ± 10.5 months (range, 24-58 months) postoperatively. There were no revisions or complications except for recurrent instability in 1 patient who underwent the arthroscopic procedure and reported gross deviation from the postoperative protocol. The ASES score improved significantly (62.8 ± 21.2 at baseline vs 89.2 ± 11.5 at final follow-up, P = .01). The postoperative Western Ontario Shoulder Index score was 74.5 ± 19.7. No significant change was found in external rotation in 90° of abduction (80.6° ± 12.9° at baseline vs 88.4° ± 6.1° at final follow-up, P = .11) or in flexion (145.6° ± 14.9° at baseline vs 153.1° ± 16.4° at final follow-up, P = .19). All patients returned to their previous activity level. CONCLUSIONS: Stability was restored and no significant range-of-motion loss was observed in noncollision athletes who underwent conjoined tendon transfer. Recurrent instability occurred in 1 patient who underwent the arthroscopic procedure. There were no other complications. LEVEL OF EVIDENCE: Level IV, therapeutic case series.
Assuntos
Artroscopia/métodos , Instabilidade Articular/cirurgia , Lesões do Ombro/cirurgia , Transferência Tendinosa/métodos , Adolescente , Adulto , Atletas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Amplitude de Movimento Articular , Estudos Retrospectivos , Articulação do Ombro/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. RESULTS: Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. CONCLUSIONS: The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.
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Ouro/toxicidade , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas , Dióxido de Silício/toxicidade , Prata/toxicidade , Baço/efeitos dos fármacos , Animais , Biomarcadores/sangue , Feminino , Ouro/administração & dosagem , Ouro/metabolismo , Injeções Intravenosas , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Nanopartículas Metálicas , Camundongos Endogâmicos BALB C , Medição de Risco , Dióxido de Silício/administração & dosagem , Dióxido de Silício/metabolismo , Prata/administração & dosagem , Prata/metabolismo , Baço/metabolismo , Baço/patologia , Fatores de Tempo , Distribuição TecidualRESUMO
INTRODUCTION: A unilateral neurectomy model was used to study the relationship between histologic and ultrasonographic tissue characteristics during muscle atrophy over time. METHODS: This investigation was an in vivo experimental study in an equine model (n = 28). Mean pixel intensity of ultrasonographic images was measured, a muscle appearance grade was assigned weekly, and muscles were harvested from 4 to 32 weeks. Minimum fiber diameter, fiber density per unit area, percent collagen, percent fat, and fiber type profile were measured from muscle cryosections and correlated with the ultrasonographic parameters. RESULTS: A significant relationship was identified between collagen content, minimum fiber diameter, and ultrasonographic muscle appearance by as early as 8 weeks. There was no apparent association between fat content of muscle and the ultrasonographic appearance of atrophy before 28 weeks. CONCLUSIONS: Early muscle atrophy before fatty infiltration is detectable with ultrasound. The effect of muscle collagen content on echointensity may be mediated by reduced fiber diameter.
Assuntos
Músculos Laríngeos/diagnóstico por imagem , Músculos Laríngeos/patologia , Modelos Animais , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/patologia , Animais , Feminino , Cavalos , Masculino , UltrassonografiaRESUMO
In the central nervous system, nitric oxide (NO) transmits signals from one neurone to another, or from neurones to astrocytes or blood vessels, but the possibility of oligodendrocytes being physiological NO targets has been largely ignored. By exploiting immunocytochemistry for cGMP, the second messenger generated on activation of NO receptors, oligodendrocytes were found to respond to both exogenous and endogenous NO in cerebellar slices from rats aged 8 days to adulthood. Atrial natriuretic peptide, which acts on membrane-associated guanylyl cyclase-coupled receptors, also raised oligodendrocyte cGMP in cerebellar slices. The main endogenous source of NO accessing oligodendrocytes appeared to be the neuronal NO synthase isoform, which was active even under basal conditions and in a manner that was independent of glutamate receptors. Oligodendrocytes in brainstem slices were also shown to be potential NO targets. In contrast, in the optic nerve, oligodendrocyte cGMP was raised by natriuretic peptides but not NO. When cultures of cerebral cortex were continuously exposed to low NO concentrations (estimated as 40-90 pM), oligodendrocytes responded with a striking increase in arborization. This stimulation of oligodendrocyte growth could be replicated by low concentrations of 8-bromo-cGMP (maximum effect at 1 µM). It is concluded that oligodendrocytes are probably widespread targets for physiological NO (or natriuretic peptide) signals, with the resulting rise in cGMP serving to enhance their growth and maturation. NO might help coordinate the myelination of axons to the ongoing level of neuronal activity during development and could potentially contribute to adaptive changes in myelination in the adult.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Diferenciação Celular/fisiologia , Óxido Nítrico/metabolismo , Oligodendroglia/fisiologia , Animais , Encéfalo/citologia , Células Cultivadas , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos Natriuréticos/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Oligodendroglia/citologia , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Técnicas de Cultura de TecidosRESUMO
Graphene oxide (GO) is promising in scalable production and has useful properties that include semiconducting behavior, catalytic reactivity, and aqueous dispersibility. In this study, we investigated the photochemical fate of GO under environmentally relevant sunlight conditions. The results indicate that GO readily photoreacts under simulated sunlight with the potential involvement of electron-hole pair creation. GO was shown to photodisproportionate to CO2, reduced materials similar to reduced GO (rGO) that are fragmented compared to the starting material, and low molecular-weight (LMW) species. Kinetic studies show that the rate of the initially rapid photoreaction of GO is insensitive to the dissolved oxygen content. In contrast, at longer time points (>10 h), the presence of dissolved oxygen led to a greater production of CO2 than the same GO material under N2-saturated conditions. Regardless, the rGO species themselves persist after extended irradiation equivalent to 2 months in natural sunlight, even in the presence of dissolved oxygen. Overall, our findings indicate that GO phototransforms rapidly under sunlight exposure, resulting in chemically reduced and persistent photoproducts that are likely to exhibit transport and toxic properties unique from parent GO.
Assuntos
Grafite/química , Óxidos/química , Luz Solar , Dióxido de Carbono/química , Cinética , Fotoquímica , Água/químicaRESUMO
In many environmental scenarios, the fate and impact of polymer nanocomposites (PNCs) that contain carbon nanotubes (CNT/PNCs) will be influenced by their interactions with microorganisms, with implications for antimicrobial properties and the long-term persistence of PNCs. Using oxidized single-wall (O-SWCNTs) and multi-wall CNTs (O-MWCNTs), we explored the influence that CNT loading (mass fraction≤0.1%-10%) and type have on the initial interactions of Pseudomonas aeruginosa with O-CNT/poly(vinyl alcohol) (PVOH) nanocomposites containing well-dispersed O-CNTs. LIVE/DEAD staining revealed that, despite oxidation, the inclusion of O-SWCNTs or O-MWCNTs caused PNC surfaces to exhibit antimicrobial properties. The fraction of living cells deposited on both O-SWCNT and O-MWCNT/PNC surfaces decreased exponentially with increasing CNT loading, with O-SWCNTs being approximately three times more cytotoxic on a % w/w basis. Although not every contact event between attached microorganisms and CNTs led to cell death, the cytotoxicity of the CNT/PNC surfaces scaled with the total contact area that existed between the microorganisms and CNTs. However, because the antimicrobial properties of CNT/PNC surfaces require direct CNT-microbe contact, dead cells were able to shield living cells from the cytotoxic effects of CNTs, allowing biofilm formation to occur on CNT/PNCs exposed to Pseudomonas aeruginosa for longer time periods.
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Nanotubos de Carbono/microbiologia , Pseudomonas aeruginosa/fisiologia , Anti-Infecciosos/química , Biofilmes , Meio Ambiente , Nanocompostos , OxirreduçãoRESUMO
Mild injury of the exocrine pancreas is often asymptomatic and can be under- or mis-diagnosed. The pancreas-enriched microRNAs miR-216a and miR-217 were evaluated as potential serum biomarkers of exocrine pancreas injury in rodent models of acute pancreatitis induced by caerulein, l-arginine, and pancreatic duct ligation. Both microRNAs showed time- and dose- relevant responses to pancreatic injury and wider dynamic ranges of response than serum amylase or lipase. Pancreas-selective microRNAs were found to be relatively sensitive serum biomarkers of pancreatic injury in rodents with potentially greater specificity than the current standard assays.
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MicroRNAs/sangue , Pâncreas/patologia , Pancreatite/sangue , Amilases/sangue , Animais , Arginina , Biomarcadores/sangue , Ceruletídeo , Masculino , Camundongos Endogâmicos C57BL , Pancreatite/induzido quimicamente , Curva ROC , Ratos Sprague-DawleyRESUMO
Previously we found that regulation of eNOS is an important part of the pathogenic process of Drug-induced vascular injury (DIVI) for PDE4i. The aims of the current study were to examine the phosphorylation of eNOS in mesentery versus aorta at known regulatory sites across DIVI-inducing drug classes and to compare changes across species. We found that phosphorylation at S615 in rats was elevated 35-fold 2 hr after the last dose of CI-1044 in mesentery versus 3-fold in aorta. Immunoprecipitation studies revealed that many of the upstream regulators of eNOS activation were associated with eNOS in 1 or more signalosome complexes. Next rats were treated with drugs from 4 other classes known to cause DIVI. Each drug was given alone and in combination with SIN-1 (NO donor) or L-NAME (eNOS inhibitor), and the level of eNOS phosphorylation in mesentery and aorta tissue was correlated with the extent of vascular injury and measured serum nitrite. Drugs or combinations produced altered serum nitrite levels as well as vascular injury score in the mesentery. The results suggested that phosphorylation of S615 may be associated with DIVI activity. Studies with the species-specific A2A adenosine agonist CI-947 in rats versus primates showed a similar pattern.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Óxido Nítrico Sintase Tipo III/metabolismo , Lesões do Sistema Vascular/induzido quimicamente , Lesões do Sistema Vascular/patologia , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Animais , Aorta/metabolismo , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Relação Dose-Resposta a Droga , Masculino , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/genética , Nitritos/sangue , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
Multiwalled carbon nanotubes (MWNTs) are utilized in a number of sectors as a result of their favorable electronic properties. In addition, MWNT antimicrobial properties can be exploited or considered a potential liability depending on their intended application and handling. The ability to tailor electrochemical and antimicrobial properties using economical and conventional treatment processes introduces the potential to significantly enhance product performance. Oxygen functional groups are known to influence several MWNT properties, including redox activity. Here, MWNTs were functionalized with oxygen groups using standard acid treatments followed by selective reduction via annealing. Chemical derivatization coupled to X-ray photoelectron spectroscopy was utilized to quantify specific surface oxygen group concentration after variable treatment conditions, which were then correlated to observed trends in electrochemical and antimicrobial activities. These activities were evaluated as the potential for MWNTs to participate in the oxygen reduction reaction and to have the ability to promote the oxidation of glutathione. The compiled results strongly suggest that the reduction of surface carboxyl groups and the redox activity of carbonyl groups promote enhanced MWNT reactivity and elucidate the opportunity to design functional MWNTs for enhanced performance in their intended electrochemical or antimicrobial application.
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Anti-Infecciosos/farmacologia , Técnicas Eletroquímicas/métodos , Nanotubos de Carbono/química , Elétrons , Glutationa/metabolismo , Oxirredução/efeitos dos fármacos , Oxigênio/química , Espectroscopia FotoeletrônicaRESUMO
The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis and literature precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 open reading frame 2 induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human LINE-1 open reading frame 2 (96% identity with macaque), as well as simian endogenous retrovirus-K Gag and Env, induced polyfunctional T cell responses to all Ags, and Ab responses to simian endogenous retrovirus-K Env. There were no adverse safety or pathological findings related to vaccination. These studies provide the first evidence, to our knowledge, that immune responses can be induced safely against this class of self-antigens and pave the way for investigation of them as HIV- or tumor-associated targets.
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Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Elementos de DNA Transponíveis/imunologia , Retrovirus Endógenos/imunologia , Vacinas contra a AIDS/genética , Adulto , Sequência de Aminoácidos , Animais , Vacinas Anticâncer/genética , Elementos de DNA Transponíveis/genética , Modelos Animais de Doenças , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Columnar thin films of undoped ceria were grown by metal-organic chemical vapor deposition. The films, deposited on Pt-coated MgO(100) substrates, display a columnar microstructure with nanometer scale grain size and ~30% overall porosity. Through-plane (thickness mode) electrical conductivity was measured by AC impedance spectroscopy. Proton conduction is observed below 350-400 °C, with a magnitude that depends on gas-phase water vapor pressure. The overall behavior suggests proton transport that occurs along exposed grain surfaces and parallel grain boundaries. No impedance due to grain boundaries normal to the direction of transport is observed. The proton conductivity in the temperature range of 200-400 °C is approximately four times greater than that of nanograined bulk ceria, consistent with enhanced transport along aligned grain surfaces in the CVD films.
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PURPOSE: Elbow arthroscopy has had an emerging role in the management of many disorders of the elbow. In patients with chronic elbow instability, several arthroscopic techniques have been described in the diagnosis and management of posterolateral rotatory instability and valgus instability. METHODS: We performed a systematic review investigating the role of arthroscopy in posterolateral rotatory instability and valgus instability in the elbow using the PubMed and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases, and the Cochrane Database of Systematic Reviews, consisting of articles from peer-reviewed journals published in the English language after January 1, 1991. RESULTS: Search criteria initially identified 249 articles. Twenty-five articles met criteria for inclusion. This included 17 review articles, 4 cadaveric studies, 3 retrospective studies, and 1 prospective study. Two of the retrospective studies compared arthroscopic and open techniques. Articles included in this systematic review concluded that arthroscopy is an accurate adjunct to physical examination and imaging in the diagnosis of chronic elbow instability and affords an exceptional view of the joint with the ability to address intra-articular pathologic conditions. Arthroscopic surgical techniques have shown equivalent clinical outcomes in a comparison of arthroscopic and open techniques. CONCLUSIONS: Elbow arthroscopy is a valuable tool in the diagnosis and management of chronic elbow instability. Patients treated arthroscopically benefit from additional diagnostic techniques, improved visualization of the elbow joint, the ability to address coexisting intra-articular pathologic conditions, and minimal soft tissue injury with no clinical consequences in outcomes. With such significant advantages, the use of elbow arthroscopy is likely to expand in the management of chronic elbow instability. LEVEL OF EVIDENCE: Level IV, systematic review.