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In eukaryotic cells, pre-mRNA splicing is catalyzed by the spliceosome, a highly dynamic molecular machinery that undergoes dramatic conformational and compositional rearrangements throughout the splicing cycle. These crucial rearrangements are largely driven by eight DExD/H-box RNA helicases. Interestingly, the four helicases participating in the late stages of splicing are all DEAH-box helicases that share structural similarities. This review aims to provide an overview of the structure and function of these DEAH-box helicases, including new information provided by recent cryo-electron microscopy structures of the spliceosomal complexes.
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RNA Helicases DEAD-box , Precursores de RNA , Microscopia Crioeletrônica , RNA Helicases DEAD-box/genética , Precursores de RNA/genética , Splicing de RNA , Spliceossomos/metabolismoRESUMO
The molecular mechanisms of exon definition and back-splicing are fundamental unanswered questions in pre-mRNA splicing. Here we report cryo-electron microscopy structures of the yeast spliceosomal E complex assembled on introns, providing a view of the earliest event in the splicing cycle that commits pre-mRNAs to splicing. The E complex architecture suggests that the same spliceosome can assemble across an exon, and that it either remodels to span an intron for canonical linear splicing (typically on short exons) or catalyses back-splicing to generate circular RNA (on long exons). The model is supported by our experiments, which show that an E complex assembled on the middle exon of yeast EFM5 or HMRA1 can be chased into circular RNA when the exon is sufficiently long. This simple model unifies intron definition, exon definition, and back-splicing through the same spliceosome in all eukaryotes and should inspire experiments in many other systems to understand the mechanism and regulation of these processes.
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Éxons , Íntrons , Modelos Moleculares , Splicing de RNA , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Microscopia Crioeletrônica , Estrutura Quaternária de Proteína , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/ultraestrutura , Spliceossomos/metabolismo , Spliceossomos/ultraestruturaRESUMO
Human PRPF39 is a homolog of the yeast Prp39 and Prp42 paralogs. We have previously shown that human PRPF39 forms a homodimer that interacts with the CTD of U1C, mirroring the yeast Prp39/Prp42 heterodimer. We demonstrate here that PRPF39 knockdown in HEK293 cells affects many alternative splicing events primarily by reducing the usage of weak 5'ss. Additionally, PRPF39 preferentially binds to a GC-rich RNA, likely at the interface between its NTD and CTD. These data indicate that PRPF39 potentially recruits U1 snRNP to a weak 5' ss, serving as a previously unrecognized alternative splicing factor. We further demonstrate that human TIA1 binds to U1C through its RRM1 and RRM3+Q domains but has no significant binding to PRPF39. Finally, all three human LUC7L isoforms directly interact with U1C. These results reveal significant parallels to the yeast U1 snRNP structure and support the use of yeast U1 snRNP as a model for understanding the mechanism of human alternative splicing.
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The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.
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Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapiaRESUMO
Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.
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Neoplasias Vulvares , Feminino , Humanos , Adenocarcinoma/patologia , Neoplasias dos Genitais Femininos , Doença de Paget Extramamária/diagnóstico , Doença de Paget Extramamária/etiologia , Doença de Paget Extramamária/terapia , Neoplasias Cutâneas , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/epidemiologia , Neoplasias Vulvares/etiologiaRESUMO
The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/terapia , Melanoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Estadiamento de Neoplasias , Oncologia/normas , Oncologia/métodosRESUMO
Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.
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Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Estados Unidos/epidemiologia , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/etiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etiologia , Luz Solar , Oncologia , IncidênciaRESUMO
The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.
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Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Point-of-care ultrasound (POCUS) can aid geriatricians in caring for complex, older patients. Currently, there is limited literature on POCUS use by geriatricians. We conducted a national survey to assess current POCUS use, training desired, and barriers among Geriatrics and Extended Care ("geriatric") clinics at Veterans Affairs Medical Centers (VAMCs). METHODS: We conducted a prospective observational study of all VAMCs between August 2019 and March 2020 using a web-based survey sent to all VAMC Chiefs of Staff and Chiefs of geriatric clinics. RESULTS: All Chiefs of Staff (n=130) completed the survey (100% response rate). Chiefs of geriatric clinics ("chiefs") at 76 VAMCs were surveyed and 52 completed the survey (68% response rate). Geriatric clinics were located throughout the United States, mostly at high-complexity, urban VAMCs. Only 15% of chiefs responded that there was some POCUS usage in their geriatric clinic, but more than 60% of chiefs would support the implementation of POCUS use. The most common POCUS applications used in geriatric clinics were the evaluation of the bladder and urinary obstruction. Barriers to POCUS use included a lack of trained providers (56%), ultrasound equipment (50%), and funding for training (35%). Additionally, chiefs reported time utilization, clinical indications, and low patient census as barriers. CONCLUSIONS: POCUS has several potential applications for clinicians caring for geriatric patients. Though only 15% of geriatric clinics at VAMCs currently use POCUS, most geriatric chiefs would support implementing POCUS use as a diagnostic tool. The greatest barriers to POCUS implementation in geriatric clinics were a lack of training and ultrasound equipment. Addressing these barriers systematically can facilitate implementation of POCUS use into practice and permit assessment of the impact of POCUS on geriatric care in the future.
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Geriatria , Sistemas Automatizados de Assistência Junto ao Leito , Humanos , Idoso , Instituições de Assistência Ambulatorial , Hospitais , GeriatrasRESUMO
Hydrofluoroethers (HFEs), such as CF3CH2OCH3 (HFE-263fb2), CHF2CF2CH2OCH3 (HFE-374pcf), and CF3CF2CH2OCH3 (HFE-365mcf3), have been proposed in the last few decades as the third-generation replacements for perfluorocarbons (PFCs) and hydrofluorocarbons (HFCs) because of their zero stratospheric ozone depletion potentials and relatively low global warming potentials (GWPs). These GWPs depend on the radiative efficiency (RE) and the atmospheric lifetime (τOH) of HFEs due to the reaction with hydroxyl (OH) radicals. The temperature and pressure dependencies of the OH-rate coefficient (kOH(T)) for HFE-263fb2, HFE-374pcf, and HFE-365mcf3 are not known. Therefore, in this paper, we present the first study on the temperature (263-353 K) and pressure (50-500 torr of helium) dependence of kOH(T) for the titled HFEs. No pressure dependence of kOH(T) was observed in the investigated range. From kOH(298 K), estimated τOH are 17 days (for HFE-263fb2), 12 days (for HFE-374pcf), and 13 days (for HFE-365mcf3). The observed T-dependencies of kOH(T) (in cm3 molecule-1 s-1) are well described by (3.88 ± 0.89) × 10-12 exp[-(508 ± 69)/T] for HFE-263fb2, (2.81 ± 0.33) × 10-12 exp[-(312 ± 35)/T] for HFE-374pcf, and (2.60 ± 0.31) × 10-12 exp[-(319 ± 35)/T] for HFE-365mcf3. A correlation between log kOH(298 K) and the activation energy (Ea) of the process is presented, allowing the prediction of Ea for OH-reactions with other HFEs, exclusively investigated at room temperature. In addition to the kinetic measurements, the infrared absorption cross sections of HFE-263fb2, HFE-374pcf, and HFE-365mcf3 were determined between 520 and 3100 cm-1. Lifetime corrected REs and GWPs relative to CO2 at 100 years' time horizon were reexamined. The impact of the investigated HFEs on the radiative forcing of climate change would be negligible.
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Nitrogen-bearing molecules, like methylamine (CH3NH2), can be the building blocks of amino acids in the interstellar medium (ISM). At the ultralow temperatures of the ISM, it is important to know its gas-phase reactivity towards interstellar radicals and the products formed. In this work, the kinetics of the OH + CH3NH2 reaction was experimentally and theoretically investigated at low- and high-pressure limits (LPL and HPL) between 10 and 1000 K. Moreover, the CH2NH2 and CH3NH yields were computed in the same temperature range for both pressure regimes. A pulsed CRESU (French acronym for Reaction Kinetics in a Uniform Supersonic Flow) apparatus was employed to determine the rate coefficient, k(T), in the 11.7-177.5 K range. A drastic increase of k(T) when the temperature is lowered was observed in agreement with theoretical calculations, evaluated by the competitive canonical unified statistical (CCUS) theory, below 300 K in the LPL regime. The same trend was observed in the HPL regime below 350 K, but the theoretical k(T) values were higher than the experimental ones. Above 200 K, the calculated rate coefficients are improved with respect to previous computational studies and are in excellent agreement with the experimental literature data. In the LPL, the formation of CH3NH becomes largely dominant below ca. 100 K. Conversely, in the HPL regime, CH2NH2 is the only product below 100 K, whereas CH3NH becomes dominant at 298 K with a branching ratio similar to the one found in the LPL regime (≈70%). At T > 300 K, both reaction channels are competitive independently of the pressure regime.
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Crystallography is a powerful tool to determine the atomic structures of proteins and RNAs. X-ray crystallography has been used to determine the structure of many splicing related proteins and RNAs, making major contributions to our understanding of the molecular mechanism and regulation of pre-mRNA splicing. Compared to other structural methods, crystallography has its own advantage in the high-resolution structural information it can provide and the unique biological questions it can answer. In addition, two new crystallographic methods - the serial femtosecond crystallography and 3D electron crystallography - were developed to overcome some of the limitations of traditional X-ray crystallography and broaden the range of biological problems that crystallography can solve. This review discusses the theoretical basis, instrument requirements, troubleshooting, and exciting potential of these crystallographic methods to further our understanding of pre-mRNA splicing, a critical event in gene expression of all eukaryotes.
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Cristalografia por Raios X/métodos , Microscopia Eletrônica de Transmissão/métodos , Conformação de Ácido Nucleico , Precursores de RNA/química , Splicing de RNA , Cristalografia por Raios X/instrumentação , Microscopia Eletrônica de Transmissão/instrumentação , Nanopartículas/química , Precursores de RNA/genética , Precursores de RNA/metabolismoRESUMO
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.
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Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologiaRESUMO
The kinetic study of the gas-phase reactions of hydroxyl (OH) radicals and chlorine (Cl) atoms with CF3CHFCF2OCH3 (HFE-356mec3) and CHF2CHFOCF3 (HFE-236ea1) was performed by the pulsed laser photolysis/laser-induced fluorescence technique and a relative method by using Fourier Transform infrared (FTIR) spectroscopy as detection technique. The temperature dependences of the OH-rate coefficients (kOH(T) in cm3s-1) between 263 and 353 K are well described by the following expressions: 9.93 × 10-13exp{-(988 ± 35)/T}for HFE-356mec3 and 4.75 × 10-13exp{-(1285 ± 22)/T} for HFE-236ea1. Under NOx-free conditions, the rate coefficients kCl at 298 K and 1013 mbar (760 Torr) of air were determined to be (2.30 ± 1.08) × 10-13 cm3s-1and (1.19 ± 0.10) × 10-15 cm3s-1, for HFE-356mec3 and HFE-236ea1, respectively. Additionally, the relative kinetic study of the Cl + CH2ClCHCl2 reaction was investigated at 298 K, as it was used as a reference reaction in the kinetic study of the Cl-reaction with HFE-356mec3 and discrepant rate coefficients were found in the literature. The global atmospheric lifetimes were estimated relative to CH3CCl3 at the tropospheric mean temperature (272 K) as 1.4 and 8.6 years for HFE-356mec3 and HFE-236ea1, respectively. These values combined with the radiative efficiencies for HFE-356mec3 and HFE-236ea1 derived from the measured IR absorption cross sections (0.27 and 0.41 W m-2 ppv-1) yield global warming potentials at a 100-yrs time horizon of 143 and 1473, respectively. The contribution of HFE-356mec3 and HFE-236ea1 to global warming of the atmosphere would be large if they become widespread increasing their atmospheric concentration.
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OBJECTIVE: Withdrawal syndrome stands out as the strongest risk factor for Prescription Opioid-Use Disorder (POUD) and is related to psychological and pain impairment in chronic pain population. This study aimed to identify profiles of chronic pain patients with opioid withdrawal based on psychological factors, and to explore the association between the classes and demographic, clinical, and substance use variables. METHOD: This cross-sectional descriptive study involved 391 patients, 221 of them with interdose withdrawal (mean age=57.91±13.61 years; 68.3% female). Latent Class Analysis (LCA) and bivariate and logistic regression analyses were performed. RESULTS: Two latent classes were identified (BIC=4020.72, entropy=0.70, LRTs p<0.01): Withdrawal syndrome with No Psychological Distress (WNPD; 45.2%, n=100) and Withdrawal syndrome with Psychological Distress (WPD; 54.8%, n=121). The WPD class was more likely to experience craving, anxiety, and depression, and to report higher levels of pain intensity and interference (p<0.01). Patients in this class were younger, visited a higher number of specialists, and showed higher rates of high-dose opioid use, misuse, moderate-severe POUD, and tobacco and anxiolytics use (p<0.05). Only moderate-severe POUD (OR=2.64) and tobacco use (OR=2.28) increased the risk of WPD class membership. CONCLUSIONS: Although it is common for chronic pain patients to experience withdrawal symptoms during opioid treatment, more than a half of the participants reported concomitant psychological distress. Establishing differential profiles can help to improve withdrawal syndrome management during the treatment of chronic pain with opioids.
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An assessment of the different aspects of tobacco addiction is central to adapting interventions to the profiles and needs of smokers. The Glover−Nilsson Smoking Behavioral Questionnaire (GN-SBQ) is one of the few and most used scales to evaluate the behavioral aspects of tobacco addiction. However, few studies involve the validation of the GN-SBQ in clinical settings. Thus, this study aimed to analyze the psychometric properties of the GN-SBQ in a sample of Spanish smokers. A total of 341 smokers attending clinical services in Spain participated in this cross-sectional study. Measures included the psychological factors related to tobacco addiction, assessed with the GN-SBQ, the physical factors of nicotine addiction, withdrawal symptoms, smoking-related variables, and alcohol use. Data analysis included descriptive statistics, internal consistency coefficients, confirmatory factor analyses, Spearman correlations, and the Kruskal−Wallis test. The GN-SBQ showed adequate reliability (α = 0.76 and ω = 0.76) and a unidimensional structure. GN-SBQ scores also provided evidence of convergent and concurrent validity. GN-SBQ scores significantly correlated with the physical symptoms of addiction, age, number of cigarettes, and withdrawal symptoms. The results of discriminant validity were also adequate, as no correlation was observed between GN-SBQ scores and CO levels or alcohol use. Significant differences were found between all levels of psychological addiction based on the GN-SBQ scores regarding physical nicotine addiction, withdrawal symptoms, and age. Thus, this questionnaire is a reliable and valid instrument to assess the psychological aspects of tobacco addiction in smokers in clinical settings. The short length of the GN-SBQ proves advantageous for its use in time-limited assessments, which are common in public health services.
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Síndrome de Abstinência a Substâncias , Tabagismo , Humanos , Tabagismo/psicologia , Reprodutibilidade dos Testes , Estudos Transversais , Fumar/epidemiologia , Fumar/psicologia , Psicometria , Inquéritos e QuestionáriosRESUMO
Opioid withdrawal is characterized by a set of physical and psychological symptoms that depend on both opioid and patient specific characteristics. The present study aims to identify different latent classes of chronic pain patients according to the type of opioid withdrawal symptoms experienced, and to analyze the relationships between the classes and demographic, opioid therapy, psychological and substance use variables. This cross-sectional descriptive study included 391 chronic pain patients on long-term opioid therapy. A Latent Class Analysis (LCA) identified 3 classes (BIC = 7051.89, entropy = .87, LRTs P < .01). The mild withdrawal class showed low probabilities of presenting physical and psychological symptoms, the moderate withdrawal class was characterized by experiencing psychological symptoms, and the severe withdrawal class stood out for high probabilities of presenting both types of symptoms. The classes differed from each other, with higher rates of moderate-severe POUD, opioid misuse, anxiety, depression, and greater pain intensity and interference in more severe withdrawal classes (P < .05). The multinomial logistic regression showed that moderate-severe POUD and anxiety were the strongest variables related to moderate (ORPOUD = 3.34, ORAnxiety = 2.58) and severe withdrawal classes (ORPOUD = 4.26, ORAnxiety = 5.15). Considering that POUD and anxiety were strongly related to a more severe withdrawal syndrome, the inclusion of psychological interventions in pain management seems critical in this population. PERSPECTIVE: Although interdose opioid withdrawal is common in chronic pain patients, this study shows 3 different patterns in its experience (mild, moderate, and severe withdrawal). A more severe withdrawal may result in reduced effectiveness of opioids in relieving pain and increased negative consequences, such as higher risk of POUD. Findings that could help improve chronic pain management.
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Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Analgésicos Opioides/efeitos adversos , Dor Crônica/psicologia , Estudos Transversais , Humanos , Análise de Classes Latentes , Entorpecentes , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
Chronic granulomatous disease (CGD) is an inborn error of immunity that affects the functionality of phagocytosis; specifically, there's lack of production of oxygen-free radicals by NADPH oxidase. CGD manifests as severe and recurring bacterial and fungal infections, as well as local and systemic hyperinflammation. In countries where tuberculosis is endemic and the BCG vaccine is mandatory at birth, patients with CGD may present local or systemic reactions to this vaccine as first manifestation; besides, recurrent infections by M. tuberculosis may be present throughout their life. The susceptibility of these patients to mycobacteria is due to the excessive production of pro-inflammatory cytokines and the formation of granulomas that are inefficient in containing mycobacteria. In developed countries, patients with CGD do not present this type of infectious manifestations, except for migrants who come from developing countries. In this review, we present the characteristics of infections by BCG, M. tuberculosis, and other types of mycobacteria. Interestingly, there are no guidelines regarding anti-tuberculosis treatments in patients with CGD, so we propose the realization of a consensus by experts in order to establish guidelines for the treatment of mycobacterial disease in CGD.
La enfermedad granulomatosa crónica (ECG) es un error innato de la inmunidad que afecta la funcionalidad de la fagocitosis, específicamente hay una falta de producción de radicales libres de oxígeno por la NADPH oxidasa. La EGC se manifiesta con infecciones bacterianas y fúngicas, recurrentes y graves e hiperinflamación local y sistémica. En países en donde la tuberculosis es endémica y la vacuna BCG es obligatoria al nacer, los pacientes con EGC pueden presentar como primera manifestación las reacciones locales o sistémicas a esta vacuna y además a lo largo de su vida infecciones recurrentes por M. tuberculosis. La susceptibilidad de estos pacientes a micobacterias es debida a la producción excesiva de citocinas proinflamatorias y la formación de granulomas ineficientes en la contención de la micobacteria. En los países desarrollados, los pacientes con EGC no presentan este tipo de manifestaciones infecciosas, salvo los migrantes de países en desarrollo. En esta revisión, presentamos las características de las infecciones por BCG, M. tuberculosis y otras micobacterias. Interesantemente no existen lineamientos en cuanto a los tratamientos antituberculosos en pacientes con EGC, por lo que proponemos realizar un consenso por expertos para establecer lineamientos para el tratamiento de la enfermedad por micobacterias en EGC.
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Doença Granulomatosa Crônica , Tuberculose , Vacina BCG , Humanos , Recém-Nascido , NADPH Oxidases , Fagocitose , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologiaRESUMO
Chronic granulomatous disease (CGD) is an inborn error of immunity caused by a defect in one of the components of the NADPH oxidase complex, which is responsible for generating reactive oxygen species (ROS) during the respiratory burst in phagocytes. The absence of ROS produced by NADPH oxidase in neutrophils and in macrophages leads to greater susceptibility to certain bacterial and fungal infections, and also to inflammatory manifestations due to a deregulated inflammatory response, which suggests that the ability to adequately regulate inflammatory signaling depends on ROS produced by NADPH oxidase. The disease course in patients with X-linked CGD is more severe, with recurrent invasive infections; in contrast, patients with non-classic CGD do not present invasive bacterial or fungal infections, but have more prominent inflammatory manifestations. The most frequent gastrointestinal manifestations are stomatitis, gingivitis, chronic diarrhea, liver abscesses that are similar to inflammatory bowel disease (IBD), and granulomas that can cause obstruction or stenosis in the esophagus, stomach or intestine. It has been observed that the deficiency of p40phox and ROS (non-classic CGD) are associated with greater susceptibility to colitis and the development of severe inflammation; therefore, it is presented that these proteins participate in the resolution of inflammation. In general, the inflammatory findings in CGD, including gastrointestinal manifestations, are seldom described. In international cohorts, manifestations that are similar to IBD are reported in up to 58% of patients with CGD; however, in the only Mexican cohort, its finding is described in only 4 out of 93 patients (4.3%). In this review, we summarize the gastrointestinal clinical findings of CGD, including infectious and inflammatory manifestations, emphasizing on the latter.
La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad causado por un defecto en uno de los componentes del complejo NADPH oxidasa, responsable de generar especies reactivas de oxígeno (ERO) durante el estallido respiratorio en los fagocitos. La ausencia de ERO producidos por la NADPH oxidasa en los neutrófilos y en los macrófagos produce mayor susceptibilidad a infecciones bacterianas y fúngicas, además de manifestaciones inflamatorias por una respuesta inflamatoria desregulada, lo que sugiere que la capacidad para regular adecuadamente la señalización inflamatoria depende de las ERO derivadas de la NADPH oxidasa. Los pacientes con EGC ligada al cromosoma X tienen un curso de enfermedad más grave con infecciones invasivas recurrentes, a diferencia de los pacientes con EGC no clásica, quienes no presentan infecciones bacterianas o fúngicas invasivas, pero con manifestaciones inflamatorias más prominentes. Las manifestaciones gastrointestinales más frecuentes son estomatitis, gingivitis, diarrea crónica, abscesos hepáticos, similares a las de la enfermedad inflamatoria intestinal (EII) y granulomas, que pueden provocar obstrucción o estenosis en esófago, estómago o intestino. Se ha observado que la deficiencia de p40phox y EROS (EGC no clásica) se asocia a mayor susceptibilidad a colitis y al desarrollo de inflamación severa, por lo que se plantea que estas proteínas participan en la resolución de la inflamación. En general, los hallazgos inflamatorios en la EGC, incluyendo los gastrointestinales, han sido poco descritos. En las cohortes internacionales se reportan manifestaciones similares a EII hasta en 58 % de los pacientes con EGC; en cambio, en la única cohorte mexicana se describe su hallazgo solo en cuatro de 93 pacientes (4.3 %). En esta revisión resumimos los hallazgos clínicos gastrointestinales de la EGC, incluidas las manifestaciones infecciosas e inflamatorias, con énfasis en las últimas.
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Doença Granulomatosa Crônica , Humanos , Inflamação/etiologia , Macrófagos , NADPH Oxidases , NeutrófilosRESUMO
BACKGROUND: The DSM-5 diagnostic criteria for Prescription Opioid-Use Disorder (POUD) have undergone some significant changes. One of the most controversial changes has been the elimination of the withdrawal symptoms criterion when opioid use is under appropriate medical supervision. For this reason, the goal of this study was to analyze factors associated with opioid withdrawal in patients with chronic non-cancer pain (CNCP). METHODS: This cross-sectional descriptive study involved 404 patients who use prescription opioids for long-term treatment (≥90 days) of CNCP. Measures included sociodemographic and clinical characteristics, POUD, withdrawal symptoms, craving, anxiety-depressive symptoms, and pain intensity and interference. RESULTS: Forty-seven percent (n = 193) of the sample reported moderate-severe withdrawal symptoms, which were associated with lower age, higher daily morphine dose and duration of treatment with opioids, moderate-severe POUD, use of psychotropic drugs, higher anxiety-depressive symptoms, and greater pain intensity and interference (p < .05). Binary logistic regression analysis showed that moderate-severe POUD (OR = 2.82), anxiety (OR = 2.21), depression (OR = 1.81), higher pain interference (OR = 1.05), and longer duration of treatment with opioids were the strongest factors associated with moderate-severe withdrawal symptoms (p < .05). CONCLUSION: Psychological factors seem to play a key role in the severity of withdrawal symptoms. Since greater intensity of these symptoms increases the risk of developing POUD, knowing the factors associated with withdrawal may be useful in developing preventive psychological interventions.