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Antioxidants agents play an essential role in the food industry for improving the oxidative stability of food products. In the last years, the search for new natural antioxidants has increased due to the potential high toxicity of chemical additives. Therefore, the synthesis and evaluation of the antioxidant activity in peptides is a field of current research. In this study, we performed a Quantitative Structure Activity Relationship analysis (QSAR) of cysteine-containing 19 dipeptides and 19 tripeptides. The main objective is to bring information on the relationship between the structure of peptides and their antioxidant activity. For this purpose, 1D and 2D molecular descriptors were calculated using the PaDEL software, which provides information about the structure, shape, size, charge, polarity, solubility and other aspects of the compounds. Different QSAR model for di- and tripeptides were developed. The statistic parameters for di-peptides model (R2train = 0.947 and R2test = 0.804) and for tripeptide models (R2train = 0.923 and R2test = 0.847) indicate that the generated models have high predictive capacity. Then, the influence of the cysteine position was analyzed predicting the antioxidant activity for new di- and tripeptides, and comparing them with glutathione. In dipeptides, excepting SC, TC and VC, the activity increases when cysteine is at the N-terminal position. For tripeptides, we observed a notable increase in activity when cysteine is placed in the N-terminal position.
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Antioxidantes , Cisteína , Dipéptidos , Oligopéptidos , Relación Estructura-Actividad Cuantitativa , Cisteína/química , Antioxidantes/química , Antioxidantes/farmacología , Dipéptidos/química , Dipéptidos/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Modelos Moleculares , Programas InformáticosRESUMEN
This paper presents an integrated monitoring system for the driver and the vehicle in a single case of study easy to configure and replicate. On-board vehicle sensors and remote sensors are combined to model algorithms for estimating polluting emissions, fuel consumption, driving style and driver's health. The main contribution of this paper is the analysis of interactions among the above monitored features highlighting the influence of the driver in the vehicle performance and vice versa. This analysis was carried out experimentally using one vehicle with different drivers and routes and implemented on a mobile application. Compared to commercial driver and vehicle monitoring systems, this approach is not customized, uses classical sensor measurements, and is based on simple algorithms that have been already proven but not in an interactive environment with other algorithms. In the procedure design of this global vehicle and driver monitoring system, a principal component analysis was carried out to reduce the variables used in the training/testing algorithms with objective to decrease the transfer data via Bluetooth between the used devices: a biometric wristband, a smartphone and the vehicle's central computer. Experimental results show that the proposed vehicle and driver monitoring system predicts correctly the fuel consumption index in 84%, the polluting emissions 89%, and the driving style 89%. Indeed, interesting correlation results between the driver's heart condition and vehicular traffic have been found in this analysis.
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Conducción de Automóvil , Aplicaciones Móviles , Accidentes de Tránsito , Computadores , Teléfono InteligenteRESUMEN
Although many sulfur containing garlic compounds present antioxidant activity, little is known about molecular mechanisms through which these compounds react with reactive oxygen species. In this work, the reactivity and the hydrogen peroxide scavenger reaction mechanisms (including thermodynamics and kinetics aspects) of allyl methyl disulfide in aqueous phase are studied employing density functional theory computational methods. Three reactive sites susceptible for electrophilic attack are found over sulfur atoms and the double bond allyl moiety. For each detected site, one redox reaction is proposed and analyzed. All reactions are thermodynamically feasible, whereas attack over the methyl bound sulfur atom is kinetically favored.
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Antioxidantes/química , Disulfuros/química , Peróxido de Hidrógeno/química , Ajo , Cinética , Modelos Químicos , Electricidad Estática , TermodinámicaRESUMEN
BACKGROUND: The aim of this study is to evaluate the effectiveness of an Enhanced Recovery After Surgery Protocol (ERAS) in relation to reduce the Systemic Inflammatory Response (SIR) to surgery using C-reactive protein (CRP) in the first (POD1), second (POD2) and third (POD3) postoperative day. METHODS: We enrolled 121 patients (ERAS group) that underwent elective colorectal surgery with ERAS, and compared them with 135 patients (preERAS group) that had undergone surgery prior to the implementation. We made a univariate analysis to compare the CRP values in POD1, POD2, and POD3 between preERAS/ERAS group, laparoscopic/open surgery and the presence or not of Clavien Dindo complications. Multivariable lineal regression was used to assess if the ERAS had a decreasing effect on the CRP in POD1, POD2, and POD3, and was adjusted by age, male sex, use of laparoscopy, and complications. RESULTS: The presence of complications was independently associated with an increase in CRP values ââin POD1, POD2, and POD3. Laparoscopy in POD1 and POD2, and ERAS in POD2 was independently associated with a decrease in CRP values. CONCLUSION: The analysis shows an increase in SIR measured as a CRP value in those patients that had complications. The SIR decreased with laparoscopy in POD1 and POD2 and with ERAS in POD2.
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Proteína C-Reactiva/metabolismo , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/cirugía , Anciano , Biomarcadores/metabolismo , Estudios de Cohortes , Colectomía/efectos adversos , Colectomía/métodos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Enfermedades Diverticulares/metabolismo , Enfermedades Diverticulares/cirugía , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/cirugía , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Previously, we have identified a protein in Trypanosoma equiperdum that possesses homology with the regulatory (R) subunits of the mammalian cAMP-dependent protein kinase (PKA). The recombinant T. equiperdum PKA R-like protein was expressed in bacteria and purified to homogeneity. Mice polyclonal antibodies were raised against the recombinant R-like protein to serologically evaluate its humoral immune response. High titers of specific sera antibodies were obtained against the parasite R-like protein by indirect enzyme-linked immunosorbent assay (ELISA), and immunoblots revealed that this protein was specifically recognized by the hyperimmune mice sera. Cellular proliferation assays using splenic B cells from the immunized mice showed higher values when the recombinant T. equiperdum R-like protein was employed than when concanavalin A was utilized as an unspecific mitogen. Two healthy horses that were experimentally infected using either T. equiperdum or Trypanosoma evansi showed a curve response characterized by the appearance of anti-T. equiperdum PKA R-like protein antibody production in sera using indirect ELISA. The recombinant parasite PKA R-like protein was also recognized by sera from naturally trypanosome-infected horses using western blotting. These findings demonstrated that the T. equiperdum PKA R-like protein is an antigen that exhibits cross-reaction with T. equiperdum and T. evansi.
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Proteínas Quinasas Dependientes de AMP Cíclico/química , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Trypanosoma/química , Trypanosoma/inmunología , Animales , Femenino , Caballos , Ratones , Ratones Endogámicos BALB CRESUMEN
Polyclonal immunoglobulin Y (IgY) antibodies were produced in chicken eggs against the purified R(II)-subunit of the cAMP-dependent protein kinase (PKA) from pig heart, which corresponds to the Sus scrofa R(II)α isoform. In order to evaluate whether Trypanosoma equiperdum possessed PKA R-like proteins, parasites from the Venezuelan TeAp-N/D1 strain were examined using the generated anti-R(II) IgY antibodies. Western blot experiments revealed a 57-kDa polypeptide band that was distinctively recognized by these antibodies. Likewise, polyclonal antibodies raised in mice ascites against the recombinant T. equiperdum PKA R-like protein recognized the PKA R(II)-subunit purified from porcine heart and the recombinant human PKA R(I)ß-subunit by immunoblotting. However, a partially purified fraction of the parasite PKA R-like protein was not capable of binding cAMP, implying that this protein is not a direct downstream cAMP effector in T. equiperdum. Although the function of the S. scrofa PKA R(II)α and the T. equiperdum PKA R-like protein appear to be different, their cross-reactivity together with results obtained by bioinformatics techniques corroborated the high level of homology exhibited by both proteins. Moreover, its presence in other trypanosomatids suggests an important cellular role of PKA R-like proteins in parasite physiology.
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Proteínas Quinasas Dependientes de AMP Cíclico/análisis , Proteínas Quinasas Dependientes de AMP Cíclico/inmunología , Subunidades de Proteína/análisis , Subunidades de Proteína/inmunología , Trypanosoma/enzimología , Animales , Pollos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulinas/inmunología , Ratones , Subunidades de Proteína/metabolismo , Trypanosoma/inmunología , Trypanosoma/aislamiento & purificaciónRESUMEN
We predict the soil sorption coefficient for a heterogeneous set of 643 organic non-ionic compounds by means of Quantitative Structure-Property Relationships (QSPR). A conformation-independent representation of the chemical structure is established. The 17,538 molecular descriptors derived with PaDEL and EPI Suite softwares are simultaneously analyzed through linear regressions obtained with the Replacement Method variable subset selection technique. The best predictive three-descriptors QSPR is developed on a reduced training set of 93 chemicals, having an acceptable predictive capability on 550 test set compounds. We also establish a model with a single optimal descriptor derived from CORAL freeware. The present approach compares fairly well with a previously reported one that uses Dragon descriptors.
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Plaguicidas/química , Contaminantes del Suelo/química , Suelo/química , Adsorción , Biodegradación Ambiental , Formaldehído/química , Modelos Químicos , Conformación Molecular , Relación Estructura-Actividad Cuantitativa , Medición de Riesgo , SolubilidadRESUMEN
Background: Coronavirus disease 2019 (COVID-19) has had a significant impact on dermatology, but to date no bibliometric analysis of this field has been identified. Therefore, the aim of this study was to perform a bibliometric indicator analysis of the worldwide scientific production of COVID-19 in dermatology. Materials and Methods: An advanced bibliographic search was performed in the Scopus database to identify articles on COVID-19 and dermatology from 2020 to 2021. The collected information was analysed with SciVal software. Bibliometric data were described through figures and summary tables. Results: A total of 1448 documents were collected and analysed. Torello Lotti was the author with the greatest scientific production; however, Esther Freeman had the greatest impact. Harvard University was the institution with the highest number of published articles. Most papers were published in the first quartiles. The United States and Italy were the leading countries in terms of production. Articles with international collaboration had the highest impact. Conclusion: Articles related to dermatology and COVID-19 are mostly published with American and Italian affiliations. In addition, there has been an increase in the distribution of articles published in the first quartile, which would reflect a growing interest in the community. Publications with international collaboration reported the highest impact, so future authors should take this into account.
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Mycelium is the root-like network of fungi. Mycelium biocomposites prepared by template replication (molding) can function as environmentally friendly alternatives to conventional polystyrene foams, which are energy- and carbon-intensive to manufacture. Recently, several studies have shown that 3D bioprinting technologies can be used to produce high value functional mycelium products with intricate geometries that are otherwise difficult or impossible to achieve via template replication. A diverse range of nutrients, thickeners, and gelling agents can be combined to produce hydrogels suitable for 3D bioprinting. 3D bioprinting with hydrogel formulations infused with living fungi produces engineered living materials that continue to grow after bioprinting is complete. However, a hydrogel formulation optimized for intricate 3D bioprinting of Pleurotus ostreatus mycelium, which is among the strains most commonly used in mycelium biocomposite fabrication, has yet to be described. Here, we design and evaluate a versatile hydrogel formulation consisting of malt extract (nutrient), carboxymethylcellulose and cornstarch (thickeners), and agar (gelling agent), all of which are easily sourced food grade reagents. We also outline a reproducible workflow to infuse this hydrogel with P. ostreatus liquid culture for 3D bioprinting of intricate structures comprised of living P. ostreatus mycelium and characterize the changes in height and mass as well as hardness of the prints during mycelium growth. Finally, we demonstrate that the workflow does not require a sterile bioprinting environment to achieve successful prints and that the same mycelium-infused hydrogel can be supplemented with additives such as sawdust to produce mycelium biocomposite objects. These findings demonstrate that 3D bioprinting using mycelium-based feedstocks could be a promising biofabrication technique to produce engineered living materials for applications such as mushroom cultivation, food preparation, or construction of the built environment.
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Materiales Biocompatibles , Bioimpresión , Hidrogeles , Micelio , Pleurotus , Impresión Tridimensional , Pleurotus/metabolismo , Pleurotus/química , Hidrogeles/química , Materiales Biocompatibles/química , Ensayo de Materiales , Tamaño de la PartículaRESUMEN
Present work employs the QSAR formalism to predict the ED(50) anticonvulsant activity of ringed-enaminones, in order to apply these relationships for the prediction of unknown open-chain compounds containing the same types of functional groups in their molecular structure. Two different modeling approaches are applied with the purpose of comparing the consistency of our results: (a) the search of molecular descriptors via multivariable linear regressions; and (b) the calculation of flexible descriptors with the CORAL (CORrelation And Logic) program. Among the results found, we propose some potent candidate open-chain enaminones having ED(50) values lower than 10 mg·kg(-1) for corresponding pharmacological studies. These compounds are classified as Class 1 and Class 2 according to the Anticonvulsant Selection Project.
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Anticonvulsivantes/química , Compuestos de Nitrógeno/química , Relación Estructura-Actividad Cuantitativa , Anticonvulsivantes/farmacología , Compuestos de Nitrógeno/farmacologíaRESUMEN
This study presents a neuroengineering-based machine learning tool developed to predict students' performance under different learning modalities. Neuroengineering tools are used to predict the learning performance obtained through two different modalities: text and video. Electroencephalographic signals were recorded in the two groups during learning tasks, and performance was evaluated with tests. The results show the video group obtained a better performance than the text group. A correlation analysis was implemented to find the most relevant features to predict students' performance, and to design the machine learning tool. This analysis showed a negative correlation between students' performance and the (theta/alpha) ratio, and delta power, which are indicative of mental fatigue and drowsiness, respectively. These results indicate that users in a non-fatigued and well-rested state performed better during learning tasks. The designed tool obtained 85% precision at predicting learning performance, as well as correctly identifying the video group as the most efficient modality.
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The acid-base reaction of 1,4-benzodioxane 2-carb-oxy-lic acid with calcium carbonate furnished the centrosymmetric title compound, [Ca(C9H7O4)2(H2O)4], in which the metal ion is octa-hedrally coordinated by two monodentate 1,4-benzodioxane 2-carboxyl-ate ligands and four water mol-ecules. In the crystal, O-Hâ¯O and C-Hâ¯O hydrogen bonds link the mol-ecules into a three-dimensional network.
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A detailed study of the phase behavior of n-paraffin C23H48 has been performed by means of real-time variable-temperature experiments with synchrotron radiation. Two detectors were employed for simultaneous analysis of the small-angle (SAXS) and wide-angle X-ray-scattering (WAXS) regions. This paraffin presents a very interesting phase behavior, involving two crystal polymorphs, three rotator phases and the liquid state. The Ostwald rule of stages is invoked to find similarities of the rotator phases with the eventual transient mesomorphic structure in the multistage model of polymer crystallization. That study is complemented by variable-temperature Raman experiments covering frequencies down to 150 cm-1. It was found that the low-frequency region is the most informative regarding the phase transitions, and specifically the intensity of the first overtone. From these analyses, several parameters are evaluated as function of temperature.
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Fibers of poly(4-hydroxybutyrate) (P4HB) have been submitted to both hydrolytic and enzymatic degradation media in order to generate samples with different types and degrees of chain breakage. Random chain hydrolysis is clearly enhanced by varying temperatures from 37 to 55 °C and is slightly dependent on the pH of the medium. Enzymatic attack is a surface erosion process with significant solubilization as a consequence of a preferent stepwise degradation. Small angle X-ray diffraction studies revealed a peculiar supramolecular structure with two different types of lamellar stacks. These were caused by the distinct shear stresses that the core and the shell of the fiber suffered during the severe annealing process. External lamellae were characterized by surfaces tilted 45° with respect to the stretching direction and a higher thickness, while the inner lamellae were more imperfect and had their surfaces perpendicularly oriented to the fiber axis. In all cases, WAXD data indicated that the chain molecular axis was aligned with the fiber axis and molecules were arranged according to a single orthorhombic structure. A gradual change of the microstructure was observed as a function of the progress of hydrolysis while changes were not evident under an enzymatic attack. Hydrolysis mainly affected the inner lamellar stacks as revealed by the direct SAXS patterns and the analysis of correlation functions. Both lamellar crystalline and amorphous thicknesses slightly increased as well as the electronic contrast between amorphous and crystalline regions. Thermal treatments of samples exposed to the hydrolytic media revealed microstructural changes caused by degradation, with the inner lamellae being those that melted faster.
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BACKGROUND: Human cases of Madariaga virus (MADV) infection were first detected during an outbreak in 2010 in eastern Panama, where Venezuelan equine encephalitis virus (VEEV) also circulates. Little is known about the long-term consequences of either alphavirus infection. METHODS: A follow-up study of the 2010 outbreak was undertaken in 2015. An additional survey was carried out 2 weeks after a separate 2017 alphavirus outbreak in a neighboring population in eastern Panama. Serological studies and statistical analyses were undertaken in both populations. RESULTS: Among the originally alphavirus-seronegative participants (n = 35 of 65), seroconversion was observed at a rate of 14.3% (95% CI, 4.8%-30.3%) for MADV and 8.6% (95% CI, 1.8%-23.1%) for VEEV over 5 years. Among the originally MADV-seropositive participants (n = 14 of 65), VEEV seroconversion occurred in 35.7% (95% CI, 12.8%-64.9%). In the VEEV-seropositive participants (n = 16 of 65), MADV seroconversion occurred in 6.3% (95% CI, 0.2%-30.2%). MADV seroreversion was observed in 14.3% (95% CI, 1.8%-42.8%) of those who were originally seropositive in 2010. VEEV seroconversion in the baseline MADV-seropositive participants was significantly higher than in alphavirus-negative participants. In the population sampled in 2017, MADV and VEEV seroprevalence was 13.2% and 16.8%, respectively. Memory loss, insomnia, irritability, and seizures were reported significantly more frequently in alphavirus-seropositive participants than in seronegative participants. CONCLUSIONS: High rates of seroconversion to MADV and VEEV over 5 years suggest frequent circulation of both viruses in Panama. Enhanced susceptibility to VEEV infection may be conferred by MADV infection. We provide evidence of persistent neurologic symptoms up to 5 years following MADV and VEEV exposure.
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UNLABELLED: The literature documents poor concordance between superficial swab and intraoperative tissue cultures in chronic prosthetic joint infections but is less clear in acute postsurgical prosthetic joint infections. We evaluated the relationship between superficial swab and deep intraoperative cultures in 56 patients with acute postsurgical prosthetic joint infections from June 2003 to June 2007; patients receiving antibiotics were excluded. There were 30 hip and 26 knee prostheses. A superficial sample of the wound drainage was taken at admission and three deep samples were obtained during open débridement. Concordance was defined when at least one of the microorganisms isolated in the superficial samples also was found in the deep samples. The analysis also was performed according to the type of microorganism: Staphylococcus aureus, gram-negative bacilli, or other gram-positive microorganisms. Concordance between superficial and deep samples was 80.3% (45 of 56). The sensitivity, specificity, and positive and negative predictive values of superficial cultures to predict the microorganism isolated in deep cultures varied depending on the type of microorganism: 93.7%, 100%, 100%, and 97.5% for S. aureus; 90%, 91.6%, 85.7%, and 94.3% for gram-negative bacilli; and 50%, 75%, 60%, and 66.7% for other gram-positive microorganisms. We therefore believe the superficial swab culture is useful in identifying the etiologic microorganism of acute prosthetic joint infections, especially when S. aureus or gram-negative bacilli were identified. LEVEL OF EVIDENCE: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
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Técnicas de Cultivo/métodos , Prótesis de Cadera/efectos adversos , Prótesis de la Rodilla/efectos adversos , Infecciones Relacionadas con Prótesis/microbiología , Anciano , Anciano de 80 o más Años , Desbridamiento , Drenaje , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones Relacionadas con Prótesis/cirugía , Estudios Retrospectivos , Sensibilidad y Especificidad , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Copolyamides derived from even 1,4-butanediamine and different mixtures of odd dicarboxylic acids with a great difference in the number of methylene groups (i.e., glutaric and azelaic acids with 3 and 7 groups, respectively) have been synthesized, characterized and structurally studied. Calorimetric analyses revealed a complex behavior with multiple melting peaks associated to lamellar reordering and the presence of defective crystals. Equilibrium melting temperatures were evaluated and showed a eutectic behavior with composition. Copolymers were able to crystallize even for samples with comonomer percentages close to 50%. Negative and ringed spherulites from the melt state and small lath-like lamellar crystals from dilute solution crystallizations were attained. Furthermore, calorimetric data pointed out the exclusion of the less abundant monomer from the lattice of the predominant structure. All samples at room temperature showed a similar crystalline structure (form I) defined by two predominant reflections at spacings close to 0.430 and 0.380 nm, which has been related for even-odd nylons with a two-hydrogen bonded structure. Real time synchrotron experiments showed that melt crystallized samples have two polymorphic transitions on heating, which were practically reversible and consequently were also detected during cooling from the melt state. Interestingly, a different behavior was detected among solution crystallized samples and specifically the transition to the intermediate structure (form II) was not detected during heating for samples enriched on the azelate component or more precisely when they were exclusively crystallized in the form I.
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Sorption of l- and d-Tyrosine (Tyr) from aqueous solutions on chiral membranes of chitosan (CH) was studied. A high adsorption in the membrane, with a marked enantioselectivity to l-Tyr, was found. Computational calculations carried out by docking and molecular dynamics (MD) showed a difference in the affinity of the enantiomers and two regions of adsorption in the polymer matrix. The interactions of the enantiomers with the polymer matrix were studied by using FTIR, DRx, DSC and TG measurements. These results indicate that adsorption of Tyr reduces the crystallinity of the membrane and generates a rearrangement of the chains, decreasing the intercatenary spacing. Also, it was observed that the hydrated polymorph to anhydrous polymorph ratio has changed during adsorption, that is, water bound to chitosan is also modified. The energy balance of the system hydrogen bonding, desolvation and the conformational changes resulted in a spontaneous and endothermic process.
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BACKGROUND: Endothelial growth factor receptor (EGFR) mutations are an essential driver of personalized therapy for patients with lung cancer and are detected in approximately 15% of Caucasian and 50% of Asian patients. EGFR tyrosine kinase inhibitors have been developed and used for this set of patients. T790M mutation in exon 20 is usually associated with secondary resistance to EGFR tyrosine kinase inhibitors therapy but is also present in treatment-naïve patients. The frequency for baseline T790M mutation varies from 4 to 35% according to the detection method used. Newer techniques have yielded higher rates, but concerns about false-positive results have been raised. Compound mutations account for 4-14% of all EGFR-mutated tumors, with no studies yet to provide a frequency rate for T790M + 19 deletion association due to the small number of cases. However, there are reports that pretreatment T790M + L858R association is significantly more frequent compared to T790M + exon 19 deletion mutations. Diagnostic challenges, current knowledge on the subject, and therapeutic decisions are discussed. CASE PRESENTATION: We present the case of a 43-year-old Hispanic woman, a treatment-naïve patient, with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19 mutation. The initial symptoms were monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia. In the absence of third-generation tyrosine kinase inhibitors, a platinum-based therapy was initiated with no response and she died 4 months after diagnosis. CONCLUSIONS: Osimertinib seems to be a suitable therapy for treatment-naïve patients with sensitizing and resistant compound EGFR mutations. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.
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Adenocarcinoma del Pulmón/patología , Neoplasias Óseas/secundario , Hipoestesia/patología , Extremidad Inferior/patología , Neoplasias Pulmonares/patología , Adenocarcinoma del Pulmón/diagnóstico por imagen , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adulto , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Análisis Mutacional de ADN , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Exones , Resultado Fatal , Femenino , Humanos , Hipoestesia/diagnóstico por imagen , Hipoestesia/etiología , Extremidad Inferior/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Imagen por Resonancia Magnética , Inhibidores de Proteínas Quinasas/uso terapéutico , Reflejo Anormal , Eliminación de SecuenciaRESUMEN
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.