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The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.
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Ferroptose/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Neutropenia/patologia , Neutrófilos/imunologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Humanos , Interferon-alfa/imunologia , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis. METHODS: We used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis. RESULTS: Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2-12%). CONCLUSIONS: Our study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association.
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Biomarcadores , Diabetes Mellitus Tipo 2 , Homeostase , Ferro , Cirrose Hepática , Análise da Randomização Mendeliana , Humanos , Diabetes Mellitus Tipo 2/genética , Ferro/sangue , Ferro/metabolismo , Biomarcadores/sangue , Cirrose Hepática/genética , Fígado Gorduroso/genética , Estudo de Associação Genômica Ampla , Glicemia/metabolismoRESUMO
OBJECTIVES: Currently, cardiac involvement is used to describe all eosinophilic granulomatosis with polyangiitis (EGPA) cardiac problems. However, heterogeneity exists among them. We aimed to depict the disease spectrum of EGPA cardiac involvement and identify high-risk population. METHODS: We included EGPA patients hospitalized in our center from 2012 to 2023 and in public databases. Based on the cardiac enzymes, cardiac magnetic resonance imaging, and endomyocardial biopsy results, the patients were divided into 3 groups: eosinophilic myocarditis (EGPA-EM), chronic inflammatory cardiomyopathy (EGPA-ICM) and EGPA-Control. Their clinical, laboratory, imaging results and prognoses were collected and compared. RESULTS: A total of 193 EGPA patients were included, 118 with cardiac involvement (74 EGPA-EM, 44 EGPA-ICM) and 75 control. Among EGPA-control, EGPA-ICM and EGPA-EM, eosinophil increased (6.12/8.71/10.42 × 109/l, p< 0.01), ANCA positivity decreased (41.33/31.82/14.86%, p< 0.01), and lung involvement reduced (73.33/72.73/43.24%, p= 0.02). In EGPA-EM, cardiac troponin further elevated (0.27 vs 6.00 ng/ml, p< 0.01), ejection fractions decreased (57.79 vs 33.20%, p< 0.01), while more ST-T abnormality was observed (41.89 vs 20.45%, p= 0.02). The prognosis of EGPA-EM was significantly worse, with 14.86% death rate, and 2-year event-free survival rate below 50%. Further, we proposed a LATE-EAST diagnostic score (7 items, 9 points) to discriminate EGPA-EM from EGPA-ICM using 4 points as threshold [AUC 0.85 (95%CI 0.78-0.92), sensitivity 0.78, specificity 0.86]. CONCLUSIONS: We first proposed different subtypes of cardiac involvement in EGPA. Identification and treatment of EGPA-EM needs improvement. LATE-EAST score could recognize the high-risk EGPA-EM effectively. Multi-disciplinary treatment is warranted, immunosuppressive therapy should be given timely and anti-IL-5 antibodies be tested in trials.
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OBJECTIVES: The predominant determinant of an unfavorable prognosis among Systemic Lupus Erythematosus (SLE) patients resides in the irreversible organ damage. This prospective cohort study aimed to identify the additional value of anti-nucleosome antibodies on organ damage accumulation in SLE patients. METHODS: Based on the Chinese SLE Treatment and Research group (CSTAR) registry, demographic characteristics, autoantibodies profiles, and clinical manifestations were collected at baseline. Follow-up data were collected by reviewing clinical records. RESULTS: Of 2481 SLE patients with full follow-up data, 663 (26.7%) were anti-nucleosome antibodies positive and 1668 (68.0%) were anti-dsDNA antibodies positive. 764 (30.8%) patients developed new organ damage during a mean follow-up of 4.31 ± 2.60 years. At baseline, patients with positive anti-nucleosome antibodies have a higher rate of lupus nephritis (50.7% vs 36.2%, p < .001). According to the multivariable Cox regression analysis, both anti-nucleosome (HR = 1.30, 95% CI, 1.09-1.54, p < .001) and anti-dsDNA antibodies (HR=1.68, 95% CI, 1.38-2.05, p < .001) were associated with organ damage accumulation. Anti-nucleosome (HR = 2.51, 95% CI, 1.81-3.46, p < .001) and anti-dsDNA antibodies (HR = 1.69, 95% CI, 1.39-2.06, p < .001) were independent predictors for renal damage. Furthermore, the combination of the two antibodies can provide more accurate information about renal damage in overall SLE patients (HR = 3.19, 95% CI, 2.49-4.10, p < .001) and patients with lupus nephritis at baseline (HR = 2.86, 95% CI, 2.29-3.57, p < .001). CONCLUSION: Besides anti-dsDNA antibodies, anti-nucleosome antibodies can also provide information about organ damage accrual during follow-up. The ability of co-positivity of anti-nucleosome and anti-dsDNA antibodies in predicting renal damage may lead to additional benefits in the follow-up of these patients.
Assuntos
Anticorpos Antinucleares , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Nucleossomos , Humanos , Feminino , Masculino , Adulto , Nucleossomos/imunologia , Estudos Prospectivos , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/sangue , Nefrite Lúpica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem , Autoanticorpos/sangue , Autoanticorpos/imunologia , Sistema de Registros , China , Rim/imunologia , Rim/patologia , Análise Multivariada , SeguimentosRESUMO
OBJECTIVE: To analyze the prevalence of burnout among radiology residents. METHOD: Five databases (PubMed, Web of Science, Embase, PsycINFO, and Scopus) were searched for studies reporting burnout in radiology residents for the period up to November 7, 2022. RESULTS: A total of 423 studies were identified, and eventually, 16 studies were selected for the qualitative analysis, of which 11 studies were used in the meta-analysis. There was a total of 2164 radiology residents. Six studies reported the prevalence of burnout but the data could not be pooled due to their inconsistent definitions of burnout. The mean scores of three burnout subscales indicated a moderate to high degree of severity: emotional exhaustion = 25.2 (95% CI, 22.1-28.3; I2 = 94.4%), depersonalization = 10.2 (95% CI, 8.5-11.9; I2 = 93.0%), and low perception of personal accomplishment = 32.9 (95% CI, 30.5-35.4; I2 = 94.4%). The pooled prevalence of high-degree emotional exhaustion was 49.9% (95% CI, 43.6-56.1%; I2 = 55.7%), high-degree depersonalization was 45.1% (95% CI, 38.3-52.0%; I2 = 63.2%), and high-degree diminished personal accomplishment was 58.2% (95% CI, 36.0-77.6%; I2 = 84.9%). The impact of the COVID-19 pandemic on radiology residents was not investigated. In addition, there are inconsistent findings on the effects of female sex, seniority, and social support on burnout. CONCLUSIONS: About half of the radiology residents showed at least one of the three burnout manifestations (emotional exhaustion, depersonalization, and personal accomplishment), with a moderate to high degree of severity. CLINICAL RELEVANCE STATEMENT: Such a high prevalence and severity of burnout among radiology residents warrant the attention of residency program directors. KEY POINTS: ⢠Burnout, not uncommon among radiology residents, has not been effectively analyzed. ⢠Nearly half of the radiology residents experience at least one of the three manifestations of burnout to a moderate to high degree. ⢠The high prevalence and severe degree of burnout among radiology residents warrant the attention of residency program directors.
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Esgotamento Profissional , Internato e Residência , Radiologia , Humanos , Feminino , Pandemias , Inquéritos e Questionários , Radiologia/educação , Esgotamento Psicológico , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/psicologia , Exaustão Emocional , PrevalênciaRESUMO
BACKGROUND: Diet management is an effective way to retard the progression of chronic kidney disease (CKD). However, very few studies investigated the influence of carbohydrate intake on CKD patients. In this prospective cohort study, the associations between carbohydrate intake and all-cause mortality were investigated in US adult CKD patients. METHODS: Multivariable Cox proportional hazard models and iso-caloric replacement analysis were used to investigate the associations between the macronutrients and the all-cause mortality risk. Total 3683 US adult CKD patients 20 years or older from the National Health and Nutrition Examination Survey (NHANES, 2003-2014) were analyzed (mean age ± SD, 62.4 ± 17.1; 56.5% female), of which 1082 participants with CKD died with a median follow-up time of 67 (IQR 36-99) months. RESULTS: Most macronutrients were non-linearly associated with all-cause mortality risk, including carbohydrates and sugar. Participants with CKD had lower mortality risk when consuming 30-45% energy from carbohydrates (average HR 0.76, 95%CI 0.62-0.93, compared with 60%), 5-20% energy from sugar (average HR 0.75, 95% CI 0.59-0.96 compared with 40%). Replacing the energy intake from carbohydrates with protein (up to 30%) and/or replacing the sugar with non-sugar carbohydrates (up to 55%) reduced the all-cause mortality risk, while the total energy intake remained constant. CONCLUSIONS: Diet advice should be given according to the current diet status, and constituents of carbohydrates should also be taken into consideration.
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Insuficiência Renal Crônica , Adulto , Humanos , Feminino , Masculino , Inquéritos Nutricionais , Estudos Prospectivos , Modelos de Riscos Proporcionais , CarboidratosRESUMO
Monoclonal gammopathy (MG) is common in autoimmune diseases (AID), but its progression to hematological neoplasm (HN) and the predictors for the progression are unclear. Patients diagnosed with AID and MG in our hospital from January 2010 to June 2017 were reviewed and followed. Cox proportional hazard regression analysis was applied. Of 160 patients with AID and MG, the most common AID was primary SjÓ§gren's syndrome (37, 23.1%). Thirty-nine (24.4%) patients developed HN during follow-up (median: 3.7 years, IQR: 0.3-5.5 years). The cumulative probability of HN progression was 21.8% at one year and 29.3% at six years after the finding of MG. High levels of monoclonal protein (> 14.35% of total serum protein) (HR 11.71, 95%CI: 5.37-25.54), significant weight loss (HR 6.24, 95%CI: 2.87-13.59), and reduction of other types of immunoglobulins (HR 3.02, 95%CI: 1.40-6.48) are independent risk indicators for HN whose presence warrants vigorous follow-up and monitoring.
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Doenças Autoimunes/complicações , Neoplasias Hematológicas/etiologia , Paraproteinemias/complicações , Adulto , Idoso , Doenças Autoimunes/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/análise , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Atenção Terciária à SaúdeRESUMO
In March 2020, when coronavirus disease 2019 (COVID-19) was just beginning to spread around the world, we presented the potential benefits and controversies of anti-inflammatory therapy in COVID-19 patients based on the limited experience and proposed some types of anti-inflammatory drugs with potential therapeutic value, while without evidence-based data. In the past one more year, many clinical trials or real-world studies have been performed, either confirm or deny the efficacy of certain anti-inflammatory drugs in the treatment of COVID-19. In this review we summarize the progress of anti-inflammatory and immune therapy in COVID-19, including glucocorticoids, IL-6 antagonist, IL-1 inhibitor, kinase inhibitors, non-steroidal anti-inflammatory drugs and chloroquine/hydroxychloroquine.
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Tratamento Farmacológico da COVID-19 , Anti-Inflamatórios/uso terapêutico , Cloroquina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , SARS-CoV-2RESUMO
Human spinal cord injury (SCI) is characterized by permanent loss of damaged axons, resulting in chronic disability. In contrast, zebrafish can regenerate axonal projections following central nervous system injury and re-establish synaptic contacts with distant targets; elucidation of the underlying molecular events is an important goal with translational potential for improving outcomes in SCI patients. We generated transgenic zebrafish with GFP-labeled axons and transected their spinal cords at 10 days post-fertilization. Intravital confocal microscopy revealed robust axonal regeneration following the procedure, with abundant axons bridging the transection site by 48 h post-injury. In order to analyze neurological function in this model, we developed and validated new open-source software to measure zebrafish lateral trunk curvature during propulsive and turning movements at high temporal resolution. Immediately following spinal cord transection, axial movements were dramatically decreased caudal to the lesion site, but preserved rostral to the injury, suggesting the induction of motor paralysis below the transection level. Over the subsequent 96 h, the magnitude of movements caudal to the lesion recovered to baseline, but the rate of change of truncal curvature did not fully recover, suggesting incomplete restoration of caudal strength over this time course. Quantification of both morphological and functional recovery following SCI will be important for the analysis of axonal regeneration and downstream events necessary for restoration of motor function. An extensive array of genetic and pharmacological interventions can be deployed in the larval zebrafish model to investigate the underlying molecular mechanisms.
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Traumatismos da Medula Espinal , Peixe-Zebra , Animais , Axônios/patologia , Humanos , Larva , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologiaRESUMO
BACKGROUND: Acute kidney injury (AKI), a rare adverse event, cannot be ignored as millions of doses of coronavirus disease 2019 (COVID-19) vaccinations. We aimed to investigate the occurrence of post-vaccine AKI reported to the Vaccine Adverse Event Reporting System (VAERS). METHODS: After data mapping from December 2020 to June 2021, we summarized demographic and clinical features and outcomes of reported cases from three vaccines (Pfizer-BNT, MODERNA, and JANSSEN). The Bayesian and nonproportional analyses explored the correlations between COVID-19 vaccines and AKI. RESULTS: We identified 1133 AKI cases. Pfizer-BNT appeared to have a stronger AKI correlation than MODERNA and JANSSEN, based on the highest reporting odds ratio (ROR = 2.15, 95% confidence interval = 1.97, 2.36). We observed the differences in ages, comorbidities, current illnesses, post-vaccine AKI causes, and time to AKI onset (all pï¼.05) among three vaccines. Most patients are elderly, with the highest age in MODERNA (68.41 years) and lowest in JANSSEN (59.75 years). Comorbidities were noticed in 58.83% of the cases and active infections in over 20% of cases. The leading cause of post-vaccine AKI was volume depletion (40.78%), followed by sepsis (11.74%). Patients in Pfizer-BNT had the worst outcome with 19.78% deaths, following 17.78% in MODERNA and 12.36% in JANSSEN (p = .217). The proportion of patients on dialysis was higher in JANSSEN than in Pfizer-BNT and MODERNA (14.61% vs. 6.54%, 10.62%, p = .008). CONCLUSION: AKI could occur after the COVID-19 vaccines, predominantly in elderly patients. However, the causality needs further identification.
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Injúria Renal Aguda , COVID-19 , Vacinas , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Idoso , Teorema de Bayes , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Vacinas/efeitos adversosRESUMO
Pneumocystis jirovecii pneumonia (PCP) is a life-threatening opportunistic infection in idiopathic membranous nephropathy (IMN) patients, who are treated with immunosuppressive drugs. However, the risk factors of infection and their prognosis are rarely investigated. We aimed to characterize the clinical manifestations of PCP in patients with IMN, and to understand their risk factors, so that we can provide early warnings to patients with high risk and potential poor prognosis. We conducted a retrospective observational study of IMN patients in a referral center in China, from Jan 2012 to Dec 2018. Clinical and laboratory data were collected separately at the time of IMN and PCP diagnosis. Patients with PCP were matched to those without by gender and age at a ratio of 1:4. The risk factors and prognostic factors were determined by univariate and multivariate logistic regression analysis. A total of 879 patients with IMN were included, with a median follow-up of 267 (interquartile range (IQR) 64,842) days. In total, 26 (2.96%) of them were diagnosed with PCP. The infection rate increased to 3.87% among patients who received corticosteroids, and it further increased to 5.49% in those received over 0.5mg/kg prednisone. Univariate analysis indicated that initial usage of corticosteroids, use of cyclophosphamide, reduced estimated glomerular filtration rate (eGFR), and higher 24-h proteinuria were related to the PCP susceptibility. Multivariate analysis revealed that corticosteroid treatment and reduced eGFR increased the risk of the Pneumocystis jirovecii infection. The case fatality rate of the PCP patients was 23.08%, and increased to 75% among patients requiring invasive ventilation. Univariate analysis indicated that pulmonary insufficiency, invasive ventilation, decreased eGFR, and increased lactate dehydrogenase at presentation were linked to poor prognosis. PCP is not rare in patients with IMN, especially those on corticosteroids, and presented with decreased eGFR. Considering the high case fatality rate, further studies are in need for prevention and management of these patients.
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Glomerulonefrite Membranosa/complicações , Pneumonia por Pneumocystis/etiologia , Corticosteroides/administração & dosagem , Adulto , Anti-Inflamatórios/administração & dosagem , China/epidemiologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii/genética , Pneumocystis carinii/fisiologia , Pneumonia por Pneumocystis/epidemiologia , Pneumonia por Pneumocystis/microbiologia , Pneumonia por Pneumocystis/fisiopatologia , Prednisona/administração & dosagem , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Kidney involvement of visceral Leishmaniasis is previously reported, but knowledge is limited. Hypergammaglobulinemia is common in visceral leishmaniasis patients. Whether hypergammaglobulinemia after leishmaniasis depletion can cause kidney injury is not well reported yet. CASE PRESENTATION: We reported a patient who recovered from visceral Leishmaniasis but showed persistent hypergammaglobulinemia and elevated urinary protein. Kidney biopsy showed glomerular hypertrophy with mild segmental mesangial proliferation without tubulointerstitial involvement in light microscopy. No immune complex deposit was found in the mesangial area by neither immunofluorescent staining nor electronic microscope. Increased lysosomes were observed in proximal tubules by electronic microscope. Valsartan was administered to decrease urinary protein, and no immune-suppressive therapy was added. The urinary protein and serum IgG level gradually dropped, and serum creatinine level remained stable during three- month follow up. CONCLUSIONS: Hypergammaglobulinemia is unlikely to cause renal structural or functional damage in the short term. Angiotensin blockade significantly reduced urine protein, with a minor effect on IgG elimination.
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Hipergamaglobulinemia/etiologia , Leishmaniose Visceral/complicações , Proteinúria/etiologia , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Humanos , Hipergamaglobulinemia/tratamento farmacológico , Hipergamaglobulinemia/patologia , Rim/patologia , Masculino , Proteinúria/tratamento farmacológico , Proteinúria/patologia , Resultado do Tratamento , Valsartana/uso terapêuticoRESUMO
BACKGROUND: The incidence, severity, and outcomes of AKI in COVID-19 varied in different reports. In patients critically ill with COVID-19, the clinicopathologic characteristics of AKI have not been described in detail. METHODS: This is a retrospective cohort study of 81 patients critically ill with COVID-19 in an intensive care unit. The incidence, etiologies, and outcomes of AKI were analyzed. Pathologic studies were performed in kidney tissues from ten deceased patients with AKI. RESULTS: A total of 41 (50.6%) patients experienced AKI in this study. The median time from illness to AKI was 21.0 (IQR, 9.5-26.0) days. The proportion of Kidney Disease Improving Global Outcomes (KDIGO) stage 1, stage 2, and stage 3 AKI were 26.8%, 31.7%, and 41.5%, respectively. The leading causes of AKI included septic shock (25 of 41, 61.0%), volume insufficiency (eight of 41, 19.5%), and adverse drug effects (five of 41, 12.2%). The risk factors for AKI included age (per 10 years) (HR, 1.83; 95% CI, 1.24 to 2.69; P=0.002) and serum IL-6 level (HR, 1.83; 95% CI, 1.23 to 2.73; P=0.003). KDIGO stage 3 AKI predicted death. Other potential risk factors for death included male sex, elevated D-dimer, serum IL-6 level, and higher Sequential Organ Failure Assessment score. The predominant pathologic finding was acute tubular injury. Nucleic acid tests and immunohistochemistry failed to detect the virus in kidney tissues. CONCLUSIONS: AKI was a common and multifactorial complication in patients critically ill with COVID-19 at the late stage of the disease course. The predominant pathologic finding was acute tubular injury. Older age and higher serum IL-6 level were risk factors of AKI, and KDIGO stage 3 AKI independently predicted death.
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Injúria Renal Aguda/patologia , Betacoronavirus , Infecções por Coronavirus/complicações , Rim/patologia , Pneumonia Viral/complicações , Injúria Renal Aguda/etiologia , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Infecções por Coronavirus/patologia , Creatinina/sangue , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Interleucina-6/sangue , Rim/ultraestrutura , Rim/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.
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Linfócitos B/imunologia , Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Ativação Linfocitária/genética , MicroRNAs/genética , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , PTEN Fosfo-Hidrolase/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The coronavirus disease-19 (COVID-19) has spread over many countries and regions since the end of 2019, becoming the most severe public health event at present. Most of the critical cases developed multiple organ dysfunction, including acute kidney injury (AKI). Cytokine storm syndrome (CSS) may complicate the process of severe COVID-19 patients. This manuscript reviews the different aspects of blood purification in critically ill patients with AKI and increased inflammatory factors, and examines its potential role in severe COVID-19 treatment. Continuous renal replacement therapy (CRRT) has been practiced in many sepsis patients with AKI. Still, the timing and dosing need further robust evidence. In addition to the traditional CRRT, the high-throughput membrane with adsorption function and cytokine adsorption column are two representatives of recently emerging novel membrane technologies. Their potential in removing inflammatory factors and other toxins prospects for the treatment of severe COVID-19.
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Betacoronavirus , Calcinose/terapia , Infecções por Coronavirus/terapia , Citocinas , Doenças das Valvas Cardíacas/terapia , Hipotricose/terapia , Pneumonia Viral/terapia , Terapia de Substituição Renal , Dermatopatias Genéticas/terapia , COVID-19 , Calcinose/etiologia , Infecções por Coronavirus/complicações , Estado Terminal , Doenças das Valvas Cardíacas/etiologia , Humanos , Hipotricose/etiologia , Pandemias , Pneumonia Viral/complicações , SARS-CoV-2 , Dermatopatias Genéticas/etiologiaRESUMO
BACKGROUND: Patients with chronic kidney disease (CKD) require specialized management. However, the current situation of CKD management is unclear during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to investigate the influence of the COVID-19 on kidney patients' follow-ups. METHODS: In April 2020, we included patients who underwent kidney biopsy from January 2017 to December 2019 in a referral center of China, and then initiated a survey via telephone on different aspects of follow-up during the COVID-19 pandemic. We collected and analyzed demographic data, diagnoses, follow-up conditions, and telemedicine experience. RESULTS: We reached 1190 CKD patients with confirmed kidney biopsies, and included 1164 patients for analysis after excluding those on dialysis. None of our patients have had COVID-19, although more than 50% of them were complicated with other comorbidities, and over 40% were currently using immunosuppressive treatments. Face-to-face clinic visits were interrupted in 836 (71.82%) participants. Medicine adjustments and routine laboratory examinations were delayed or made irregular in about 60% of patients. To continue their follow-ups, 255 (21.90%) patients utilized telemedicine, and about 80% of them were satisfied with the experience. The proportion of telemedicine users was significantly higher in patients with immunosuppressive treatments than those without (31.88% vs. 17.12%, p < 0.001). CONCLUSION: The risk of COVID-19 was mitigated in patients with CKD and other co-existing risk factors when proper protection was utilized. The routine medical care was disrupted during the pandemic, and telemedicine could be a reasonable alternative method.
Assuntos
Doenças Transmissíveis Emergentes/epidemiologia , Infecções por Coronavirus/epidemiologia , Controle de Infecções/métodos , Pandemias/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/patologia , Adulto , Biópsia por Agulha , COVID-19 , China/epidemiologia , Comorbidade , Infecções por Coronavirus/diagnóstico , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Incidência , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Inquéritos e QuestionáriosRESUMO
PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10â8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10â3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10â7), while intraspinal anomalies were uncommon (P = 7.0 × 10â7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10â15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.
Assuntos
Dosagem de Genes , Padrões de Herança , Escoliose/congênito , Escoliose/genética , Proteínas com Domínio T/genética , Animais , Estudos de Coortes , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Genéticos , Escoliose/classificação , Escoliose/patologia , Coluna Vertebral/patologiaRESUMO
OBJECTIVES: To evaluate the clinical efficacy of bisphosphonates treatment for spinal bone marrow oedema (BME) in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: SAPHO syndrome patients presenting to Peking Union Medical College Hospital from 2015 to 2016 were recruited. Patients were administered pamidronate disodium 1 mg/kg/d intravenously, for 3 days, at baseline and 3 months later. The symptoms were evaluated using the Visual Analog Score (VAS) for pain, and other clinical measures including, spinal BME scores, ß-crosslaps, osteocalcin, and inflammatory factors, were collected. RESULTS: A total of 30 patients (20 women and 10 men) with a median age of 47.2 (interquartile range 8.8) years were recruited. In a short time, the patients showed a significant decrease in VAS (before vs. after; first treatment: 5.70±1.62 vs. 2.30±1.29 cm, second treatment: 4.03±1.88 vs. 2.17±1.23 cm) and ß-crosslaps (first treatment: 0.4441±0.1923 vs. 0.0859±0.0374 pg/ml, second treatment: 0.2891±0.1983 vs. 0.0962±0.0324 pg/ml) (all p<0.05). At 12-month follow-up, compared with the baseline, we noticed a significant drop in the VAS (5.70±1.62 vs. 2.43±1.25 cm), erythrocyte sedimentation rate (28.87±25.26 vs. 18.00±18.65 mm/h), high-sensitivity C-reactive protein level (11.76±10.19 vs. 5.84±5.88 mg/L), osteocalcin (2.30±1.27 vs. 1.65±0.80 ng/ml), and BME (30.50±24.09 vs. 22.13±27.79) (all p<0.05). No one had serious adverse events. CONCLUSIONS: Bisphosphonates can significantly and rapidly relieve symptoms in patients with SAPHO syndrome and have a long-term effect on inflammation and spinal BME. We suggest that bisphosphonates could be used as the first-line therapeutic drug for SAPHO syndrome, especially in patients with spinal BME.
Assuntos
Síndrome de Hiperostose Adquirida , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Acne Vulgar , Síndrome de Hiperostose Adquirida/tratamento farmacológico , Feminino , Humanos , Hiperostose , Masculino , Pessoa de Meia-Idade , Osteíte , Estudos Prospectivos , Sinovite , Resultado do TratamentoRESUMO
Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to 'cellular process', molecular function 'structural molecule activity' and cellular component 'extracellular region'. IPA analysis revealed 'LXR/RXR activation' was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency-caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.
Assuntos
Haploinsuficiência/genética , Metabolismo dos Lipídeos/genética , Proteoma/metabolismo , Escoliose/sangue , Escoliose/congênito , Proteínas com Domínio T/metabolismo , Estudos de Casos e Controles , Análise por Conglomerados , Ontologia Genética , Humanos , Escoliose/genéticaRESUMO
With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.