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BACKGROUND: The role of radiology in the diagnosis of interstitial lung diseases (ILDs) has evolved over time, in part replacing histology. Radiology now represents a pillar of diagnostics and monitoring in ILDs. OBJECTIVE: To what extent does radiology influence diagnostics and treatment in ILDs? MATERIALS AND METHODS: A literature review was conducted, and current findings were discussed in the context of clinical data. RESULTS: Radiology plays a crucial role in the diagnosis of ILDs. Within the framework of the multidisciplinary conference, it provides specific CT patterns such as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP), or helps in identifying cystic lung diseases. Multicompartment diseases can be detected, and pulmonary hypertension or extrapulmonary involvement of the respective diseases can be suspected. Progressive pulmonary fibrosis requires radiologic assessment as one of the required criteria. Interstitial lung abnormalities are usually detected by radiological studies performed for an unrelated indication. CONCLUSION: Radiology plays an important role within the multidisciplinary conference to determine both diagnosis and treatment with antifibrotic or anti-inflammatory drugs, or a combination of both.
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Enfermedades Pulmonares Intersticiales , Tomografía Computarizada por Rayos X , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/terapia , Enfermedades Pulmonares Intersticiales/diagnóstico , Humanos , Tomografía Computarizada por Rayos X/métodos , Diagnóstico DiferencialRESUMEN
BACKGROUND: Excess reactive oxygen species generated by NADPH oxidase 2 (Nox2) in response to ethanol exposure mediate aspects of skeletal toxicity including increased osteoclast differentiation and activity. Because perturbation of chondrocyte differentiation in the growth plate by ethanol could be prevented by dietary antioxidants, we hypothesized that Nox2 in the growth plate was involved in ethanol-associated reductions in longitudinal bone growth. METHODS: Nox2 conditional knockout mice were generated, where the essential catalytic subunit of Nox2, cytochrome B-245 beta chain (Cybb), is deleted in chondrocytes using a Cre-Lox model with Cre expressed from the collagen 2a1 promoter (Col2a1-Cre). Wild-type and Cre-Lox mice were fed an ethanol Lieber-DeCarli-based diet or pair-fed a control diet for 8 weeks. RESULTS: Ethanol treatment significantly reduced the number of proliferating chondrocytes in the growth plate, enhanced bone marrow adiposity, shortened femurs, reduced body length, reduced cortical bone volume, and decreased mRNA levels of a number of osteoblast and chondrocyte genes. Conditional knockout of Nox2 enzymatic activity in chondrocytes did not consistently prevent any ethanol effects. Rather, knockout mice had fewer proliferating chondrocytes than wild-type mice in both the ethanol- and control-fed animals. Additional analysis of tibia samples from Nox4 knockout mice showed that loss of Nox4 activity also reduced the number of proliferating chondrocytes and altered chondrocyte size in the growth plate. CONCLUSIONS: Although Nox enzymatic activity regulates growth plate development, ethanol-associated disruption of the growth plate morphology is independent of ethanol-mediated increases in Nox2 activity.
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Additively manufactured (AM) degradable porous metallic biomaterials offer unique opportunities for satisfying the design requirements of an ideal bone substitute. Among the currently available biodegradable metals, iron has the highest elastic modulus, meaning that it would benefit the most from porous design. Given the successful preclinical applications of such biomaterials for the treatment of cardiovascular diseases, the moderate compatibility of AM porous iron with osteoblast-like cells, reported in earlier studies, has been surprising. This may be because, as opposed to static in vitro conditions, the biodegradation products of iron in vivo are transported away and excreted. To better mimic the in situ situations of biodegradable biomaterials after implantation, we compared the biodegradation behavior and cytocompatibility of AM porous iron under static conditions to the conditions with dynamic in situ-like fluid flow perfusion in a bioreactor. Furthermore, the compatibility of these scaffolds with four different cell types was evaluated to better understand the implications of these implants for the complex process of natural wound healing. These included endothelial cells, L929 fibroblasts, RAW264.7 macrophage-like cells, and osteoblastic MG-63 cells. The biodegradation rate of the scaffolds was significantly increased in the perfusion bioreactor as compared to static immersion. Under either condition, the compatibility with L929 cells was the best. Moreover, the compatibility with all the cell types was much enhanced under physiomimetic dynamic flow conditions as compared to static biodegradation. Our study highlights the importance of physiomimetic culture conditions and cell type selection when evaluating the cytocompatibility of degradable biomaterials in vitro. STATEMENT OF SIGNIFICANCE: Additively manufactured (AM) degradable porous metals offer unique opportunities for the treatment of large bony defects. Despite the successful preclinical applications of biodegradable iron in the cardiovascular field, the moderate compatibility of AM porous iron with osteoblast-like cells was reported. To better mimic the in vivo condition, we compared the biodegradation behavior and cytocompatibility of AM porous iron under static condition to dynamic perfusion. Furthermore, the compatibility of these scaffolds with various cell types was evaluated to better simulate the process of natural wound healing. Our study suggests that AM porous iron holds great promise for orthopedic applications, while also highlighting the importance of physio-mimetic culture conditions and cell type selection when evaluating the cytocompatibility of degradable biomaterials in vitro.
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Células Endoteliales , Hierro , Hierro/farmacología , Porosidad , Materiales Biocompatibles/farmacología , MetalesRESUMEN
RATIONALE: Nox4 is a constitutively active NADPH oxidase that constantly produces low levels of H2O2. Thereby, Nox4 contributes to cell homeostasis and long-term processes, such as differentiation. The high expression of Nox4 seen in endothelial cells contrasts with the low abundance of Nox4 in stem cells, which are accordingly characterized by low levels of H2O2. We hypothesize that Nox4 is a major contributor to endothelial differentiation, is induced during the process of differentiation, and facilitates homeostasis of the resulting endothelial cells. OBJECTIVE: To determine the role of No×4 in differentiation of murine inducible pluripotent stem cells (miPSC) into endothelial cells (ECs). METHODS AND RESULTS: miPSC, generated from mouse embryonic wildtype (WT) and Nox4-/- fibroblasts, were differentiated into endothelial cells (miPSC-EC) by stimulation with BMP4 and VEGF. During this process, Nox4 expression increased and knockout of Nox4 prolonged the abundance of pluripotency markers, while expression of endothelial markers was delayed in differentiating Nox4-depleted iPSCs. Eventually, angiogenic capacity of iPSC-ECs is reduced in Nox4 deficient cells, indicating that an absence of Nox4 diminishes stability of the reached phenotype. As an underlying mechanism, we identified JmjD3 as a redox target of Nox4. iPSC-ECs lacking Nox4 display a lower nuclear abundance of the histone demethylase JmjD3, resulting in an increased triple methylation of histone 3 (H3K27me3), which serves as a repressive mark for several genes involved in differentiation. CONCLUSIONS: Nox4 promotes differentiation of miPSCs into ECs by oxidation of JmjD3 and subsequent demethylation of H3K27me3, which forced endothelial differentiation and stability.
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BACKGROUND: Retinal arterial occlusive events in young patients are rare. However, because of physiological multifactorial adaptations during pregnancy, retinal vascular occlusive disease may occur spontaneously. In addition, a patent foramen ovale is a risk factor for an ischemic thromboembolic event. Since fluorescein angiography, a central tool in the evaluation of these occlusions, should be avoided during pregnancy, optical coherence tomography angiography, a novel technique, offers a good opportunity for visualizing vascular perfusion of retinal tissue. CASE PRESENTATION: Here we present a case series of three patients (Caucasian, nonsmoker) who visited our clinic owing to acute visual impairment and central scotoma. Using regular optical coherence tomography and optical coherence tomography angiography, retinal vascular occlusions were detected, thus initiating the evaluation of systemic risk factors. We report two patients (30 and 32 years old) who developed cilioretinal artery occlusion but whose etiology differed: one was of thromboembolic origin associated with patent foramen ovale, while the other was caused by hemodynamic blockade secondary to central retinal vein occlusion. In both cases, optical coherence tomography angiography revealed reperfusion of the cilioretinal artery occlusion. However, transient ischemia led to retinal atrophy after a few weeks. In the third patient (32 years old), 8 weeks after onset of scotoma, optical coherence tomography angiography revealed atrophy of the middle layers and impaired perfusion in the deep capillary plexus, and thus a paracentral acute middle maculopathy was diagnosed. All patients regained normal visual acuity and had otherwise uncomplicated pregnancies, and laboratory blood tests did not reveal any defects or alterations. CONCLUSIONS: As shown here, optical coherence tomography angiography enables risk-free imaging of retinal vessel perfusion during pregnancy. Together with regular optical coherence tomography, it allows one to predict functional outcome according to the existing retinal occlusion-related atrophy.
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Foramen Oval Permeable , Oclusión de la Arteria Retiniana , Enfermedades de la Retina , Adulto , Atrofia/complicaciones , Atrofia/patología , Femenino , Angiografía con Fluoresceína/métodos , Foramen Oval Permeable/complicaciones , Humanos , Isquemia/diagnóstico , Embarazo , Oclusión de la Arteria Retiniana/diagnóstico por imagen , Oclusión de la Arteria Retiniana/etiología , Enfermedades de la Retina/etiología , Vasos Retinianos/patología , Escotoma , Tomografía de Coherencia Óptica/métodosRESUMEN
The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.
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Macrófagos/metabolismo , NADPH Oxidasa 4/metabolismo , FN-kappa B/metabolismo , Animales , Polaridad Celular/fisiología , Fibrosarcoma/enzimología , Fibrosarcoma/patología , Humanos , Interferón gamma/farmacología , Interleucinas/farmacología , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/antagonistas & inhibidores , NADPH Oxidasa 4/deficiencia , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Personal de Salud/psicología , Errores Médicos/psicología , Administración de la Seguridad , Apoyo Social , Estrés Psicológico/psicología , Agotamiento Profesional/psicología , Dinamarca , Miedo , Frustación , Culpa , Humanos , Grupo Paritario , Gestión de Riesgos/legislación & jurisprudencia , Autoimagen , Grupos de AutoayudaRESUMEN
The next generation magnetic spectrometer in space, AMS-100, is designed to have a geometrical acceptance of 100 m2 sr and to be operated for at least ten years at the Sun-Earth Lagrange Point 2. Compared to existing experiments, it will improve the sensitivity for the observation of new phenomena in cosmic rays, and in particular in cosmic antimatter, by at least a factor of 1000. The magnet design is based on high temperature superconductor tapes, which allow the construction of a thin solenoid with a homogeneous magnetic field of 1 Tesla inside. The inner volume is instrumented with a silicon tracker reaching a maximum detectable rigidity of 100 TV and a calorimeter system that is 70 radiation lengths deep, equivalent to four nuclear interaction lengths, which extends the energy reach for cosmic-ray nuclei up to the PeV scale, i.e. beyond the cosmic-ray knee. Covering most of the sky continuously, AMS-100 will detect high-energy gamma rays in the calorimeter system and by pair conversion in the thin solenoid, reconstructed with excellent angular resolution in the silicon tracker.
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An ideal bone substituting material should be bone-mimicking in terms of mechanical properties, present a precisely controlled and fully interconnected porous structure, and degrade in the human body to allow for full regeneration of large bony defects. However, simultaneously satisfying all these three requirements has so far been highly challenging. Here we present topologically ordered porous magnesium (WE43) scaffolds based on the diamond unit cell that were fabricated by selective laser melting (SLM) and satisfy all the requirements. We studied the in vitro biodegradation behavior (up to 4â¯weeks), mechanical properties and biocompatibility of the developed scaffolds. The mechanical properties of the AM porous WE43 (Eâ¯=â¯700-800â¯MPa) scaffolds were found to fall into the range of the values reported for trabecular bone even after 4â¯weeks of biodegradation. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), electrochemical tests and µCT revealed a unique biodegradation mechanism that started with uniform corrosion, followed by localized corrosion, particularly in the center of the scaffolds. Biocompatibility tests performed up to 72â¯h showed level 0 cytotoxicity (according to ISO 10993-5 and -12), except for one time point (i.e., 24â¯h). Intimate contact between cells (MG-63) and the scaffolds was also observed in SEM images. The study shows for the first time that AM of porous Mg may provide distinct possibilities to adjust biodegradation profile through topological design and open up unprecedented opportunities to develop multifunctional bone substituting materials that mimic bone properties and enable full regeneration of critical-size load-bearing bony defects. STATEMENT OF SIGNIFICANCE: The ideal biomaterials for bone tissue regeneration should be bone-mimicking in terms of mechanical properties, present a fully interconnected porous structure, and exhibit a specific biodegradation behavior to enable full regeneration of bony defects. Recent advances in additive manufacturing have resulted in biomaterials that satisfy the first two requirements but simultaneously satisfying the third requirement has proven challenging so far. Here we present additively manufactured porous magnesium structures that have the potential to satisfy all above-mentioned requirements. Even after 4â¯weeks of biodegradation, the mechanical properties of the porous structures were found to be within those reported for native bone. Moreover, our comprehensive electrochemical, mechanical, topological, and biological study revealed a unique biodegradation behavior and the limited cytotoxicity of the developed biomaterials.
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Materiales Biocompatibles/farmacología , Magnesio/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Electroquímica , Humanos , Porosidad , Propiedades de Superficie , Andamios del Tejido/química , Microtomografía por Rayos XRESUMEN
Seasonal allergic conjunctivitis (SAC) is a frequent disease, which is often associated with allergic rhinitis and subsequently manifested as allergic rhinoconjunctivitis. In contrast to other types of chronic allergic conjunctivitis, the course of SAC is not sight-threatening. Pathogenetically, the underlying cause of SAC is an immunoglobulin E (IgE) mediated, Th2-driven type 1 hypersensitivity reaction. Clinically it presents with itching, light-red conjunctival injection as well as chemosis that exceeds the extent of conjunctival injection. The goals of treatment are relief of acute signs and symptoms, control of the underlying inflammatory process and utilization of preventive options. Dually effective local therapeutics combine the advantages of rapid action with a relatively long-lasting effect by a two-fold active approach. Specific immunotherapy is useful in selected patients.
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Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/inmunología , Conjuntivitis Alérgica/terapia , Diagnóstico Diferencial , Humanos , Inmunoglobulina E/sangre , Inmunoterapia , Células Th2/inmunologíaRESUMEN
Due to rising demand worldwide it is becoming increasingly more difficult to satisfy the needs for human corneal transplants. At this point transplantation is the only possible cure for endothelial diseases, such as Fuchs endothelial dystrophy. In this article we present descemetectomy, a circumscribed removal of Descemet's membrane (DMx) without subsequent transplantation, as new possible treatment option on the basis of a clinical case.
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Lámina Limitante Posterior/cirugía , Distrofia Endotelial de Fuchs/cirugía , Anciano , Trasplante de Córnea , Lámina Limitante Posterior/patología , Estudios de Seguimiento , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/patología , Humanos , Masculino , Complicaciones Posoperatorias/diagnóstico , Agudeza Visual/fisiologíaRESUMEN
Seasonsal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90% of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivitity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection,watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.
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Conjuntivitis Alérgica/diagnóstico , Rinitis Alérgica Perenne/diagnóstico , Rinitis Alérgica Estacional/diagnóstico , Administración Tópica , Corticoesteroides/administración & dosificación , Conjuntivitis Alérgica/tratamiento farmacológico , Combinación de Medicamentos , Antagonistas de los Receptores Histamínicos/administración & dosificación , Humanos , Gotas Lubricantes para Ojos/administración & dosificación , Mastocitos/efectos de los fármacos , Calidad de Vida , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Estacional/tratamiento farmacológicoRESUMEN
The NLRP3 inflammasome is a key component of the innate immune system that induces pro-inflammatory cytokine production and cell death. Although NLRP3 is activated by many pathogens, it only appears to be critical for host defense for a limited number of specific infections. NLRP3 is however strongly associated with the initiation and pathology of many inflammatory diseases. If NLRP3 function is largely redundant for host defense, but drives a number of inflammatory diseases, this raises the important question of why evolution has elected to maintain NLRP3 function. We propose that the primary physiological functions of NLRP3 in health are to engage pathways to clear noxious substances (e.g. protein aggregates and crystals), and to regulate metabolism. We discuss the newly identified functions for NLRP3 in metabolic homeostasis, and how NLRP3 beneficial functions in homeostasis may become detrimental during the onset of inflammatory and metabolic diseases. A common feature of most NLRP3-driven diseases is that they are associated with ageing or metabolic excess, and indeed, Nlrp3 deficiency promotes 'healthspan' in ageing mice. This suggests that beneficial functions of NLRP3 in youth may become increasingly countered by NLRP3-dependent pathology as an individual ages, and we propose a general model by which ageing or nutrient excess may provide a tipping point to switch NLRP3 function from beneficial to pathological. The physiological role of NLRP3 in healthy individuals remains incompletely understood and future research will need to address this if NLRP3 is to become a successful therapeutic target for the clinical management of inflammatory diseases.
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The majority of repeated dose toxicity studies are available for the oral route. For risk assessment, however, data are needed from the relevant exposure route, i.e. inhalation or dermal. Instead of conducting additional animal studies, route-to-route (R2R) extrapolation may be performed. To explore uncertainties associated with this approach, we derived extrapolation factors (EF) based on no/lowest effect levels (NOELs/LOELs) in the Fraunhofer RepDose® database. For R2R extrapolation oral-to-inhalation 246 study pairs on 110 chemicals were analyzed. Systemic effects triggered the LOELs in the underlying inhalation studies in 49.2%, local effects in 21.9% and both local and systemic effects in 30.9% of the data pairs. For systemic effects in inhalation studies an EF of 2.2 (95% confidence interval: 1.2-3.1) was derived, for local effects, the EF was 4.4 (95% confidence interval: 2.0-8.6), and the EF without distinguishing local or systemic effects (any EF) was 3.2 (95%, confidence interval: 1.7-5.0). Calculation with LOELs instead of NOELs, exposure duration and intrinsic properties of the chemical (toxicity or physicochemical properties) did not influence the EF significantly. For R2R extrapolation oral-to-dermal 46 study pairs on 28 chemicals were analyzed. An overall EF of 0.4 (95%, confidence interval: 0.2-0.9) was obtained. Here, we found a significant difference of EFs for low and high toxic chemicals. Overall, we conclude that reliable systemic NOELs/LOELs can be obtained for inhalation studies via R2R extrapolation from oral studies. Based on the data for any EF we propose to use an EF of 3, which covers also the uncertainty that unexpected local effects may occur in an inhalation study. For the dermal route, our dataset was too small to allow general conclusions, but the results so far do suggest that the current ECHA guidance is conservative when assuming that dermal absorption is as high as oral absorption.
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Bases de Datos Factuales , Pruebas de Toxicidad/métodos , Animales , Interpretación Estadística de Datos , Vías de Administración de Medicamentos , Proyectos de Investigación , Medición de RiesgoAsunto(s)
Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica/métodos , Inmunosupresores/uso terapéutico , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/terapia , Medicina Basada en la Evidencia , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Even though macular edema (ME) in patients with retinal vein occlusion (RVO) is resolved after intravitreal treatment with anti-vascular endothelial growth factor (VEGF), impairment of visual acuity (VA) often persists. OBJECTIVE: A qualitative and quantitative evaluation of spectral domain optical coherence tomography (SD-OCT) images was carried out in patients with RVO and resolved ME to investigate a correlation between retinal morphology and functional results. MATERIAL AND METHODS: Foveal SD-OCT scans of 13 patients with RVO and resolved ME after treatment were retrospectively evaluated. The thickness of inner retinal layers up to the external limiting membrane (ELM) and up to the photoreceptors in the retinal pigment epithelium (RPE) was measured by automatic segmentation software. Foveal continuity of the four outer hyperreflective bands, the ellipsoid zone of the inner segments (ISe), the ELM, the interdigitation zone (IZ), the RPE and the location of the initial ME were evaluated. Patients with good (≤ 0.3 logMAR, n = 10) and poor VA (≥ 1.0 logMAR, n = 3) were compared. RESULTS: Inner retinal layers up to ELM were thinner in the the poor VA group. In the good VA group the initial ME was significantly more often above the ISe and after resolution of ME the ISe tended to be intact more frequently. CONCLUSION: In patients with poor VA despite resolved ME the inner retinal layers up to the ELM were significantly thinner, which could be a sign of atrophy. Qualitative differences were seen at the photoreceptor level, which could be explained by ischemia or an involvement of the outer retina during initial ME that leads to permanent destruction of the ISe.
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Edema Macular/complicaciones , Edema Macular/terapia , Oclusión de la Vena Retiniana/diagnóstico por imagen , Oclusión de la Vena Retiniana/etiología , Tomografía de Coherencia Óptica/métodos , Trastornos de la Visión/diagnóstico , Agudeza Visual , Anciano , Femenino , Humanos , Edema Macular/diagnóstico por imagen , Masculino , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , Trastornos de la Visión/etiologíaRESUMEN
Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTIs). Little is known about interactions between UPEC and the inflammasome, a key innate immune pathway. Here we show that UPEC strains CFT073 and UTI89 trigger inflammasome activation and lytic cell death in human macrophages. Several other UPEC strains, including two multidrug-resistant ST131 isolates, did not kill macrophages. In mouse macrophages, UTI89 triggered cell death only at a high multiplicity of infection, and CFT073-mediated inflammasome responses were completely NLRP3-dependent. Surprisingly, CFT073- and UTI89-mediated responses only partially depended on NLRP3 in human macrophages. In these cells, NLRP3 was required for interleukin-1ß (IL-1ß) maturation, but contributed only marginally to cell death. Similarly, caspase-1 inhibition did not block cell death in human macrophages. In keeping with such differences, the pore-forming toxin α-hemolysin mediated a substantial proportion of CFT073-triggered IL-1ß secretion in mouse but not human macrophages. There was also a more substantial α-hemolysin-independent cell death response in human vs. mouse macrophages. Thus, in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1ß secretion pathway in human macrophages. This has important implications for understanding UTI in humans.
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Proteínas Portadoras/inmunología , Inflamasomas/efectos de los fármacos , Interleucina-1beta/inmunología , Macrófagos/inmunología , Escherichia coli Uropatógena/inmunología , Animales , Toxinas Bacterianas/toxicidad , Proteínas Portadoras/genética , Muerte Celular/efectos de los fármacos , Regulación de la Expresión Génica , Proteínas Hemolisinas/toxicidad , Interacciones Huésped-Patógeno , Humanos , Inflamasomas/inmunología , Interleucina-1beta/genética , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR , Cultivo Primario de Células , Transducción de Señal , Especificidad de la Especie , Escherichia coli Uropatógena/patogenicidadRESUMEN
Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.