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Anemia Ferropriva , Ferro , Humanos , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/terapia , Anemia Ferropriva/etiologia , Ferro/administração & dosagem , Ferro/uso terapêutico , Feminino , Gravidez , Masculino , Consenso , Adulto , Criança , HungriaRESUMO
Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-ß, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.
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Injúria Renal Aguda , Modelos Animais de Doenças , Rim , Ratos Wistar , Traumatismo por Reperfusão , Animais , Masculino , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Rim/patologia , Rim/metabolismo , Fibrose , Asfixia Neonatal/metabolismo , Asfixia Neonatal/complicações , Asfixia Neonatal/patologia , Animais Recém-Nascidos , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Citocinas/metabolismo , Fatores Etários , Mediadores da Inflamação/metabolismoRESUMO
BACKGROUND: Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine, ornithine and arginine. Infants with LPI typically present with recurrent vomiting, poor growth, interstitial lung disease or renal impairment. The early onset of pulmonary alveolar proteinosis (PAP) has been reported to be associated with a severe form of LPI. Treatment of PAP most commonly consists of whole-lung lavage (WLL) and in autoimmune PAP, granulocyte-macrophage colony stimulating factor (GM-CSF) administration. Nevertheless, GM-CSF therapy in LPI-associated PAP has not been scientifically justified. CASE PRESENTATION: We describe the case of an 8-month-old infant presenting with respiratory failure due to LPI associated with PAP, who was twice treated with WLL; firstly, while on veno-venous ECMO assistance and then by the use of a selective bronchial blocker. After the two treatments with WLL, she was weaned from daytime respiratory support while on initially subcutaneous, then on inhaled GM-CSF therapy. CONCLUSIONS: This case supports the notion that GM-CSF therapy might be of benefit in patients with LPI-associated PAP. Further studies are needed to clarify the exact mechanism of GM-CSF in patients with LPI-associated PAP.
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Erros Inatos do Metabolismo dos Aminoácidos , Lavagem Broncoalveolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Proteinose Alveolar Pulmonar , Humanos , Proteinose Alveolar Pulmonar/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Lactente , Feminino , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Erros Inatos do Metabolismo dos Aminoácidos/complicaçõesRESUMO
Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.
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Toxoplasma , Toxoplasmose , Humanos , Feminino , Adulto , Masculino , Inflamassomos , Interleucina-18 , Imunoglobulina GRESUMO
Background: Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), are associated with higher thrombotic risk and enhanced thrombin generation (TG) in adults. Despite encouraging data reporting vaccine safety and low IBD flare rates in adults with IBD, vaccine hesitancy was demonstrated to be high in families of children with IBD. We aimed to find out whether TG is increased in children with IBD as compared to healthy controls and whether TG parameters show significant changes following SARS-CoV-2 mRNA vaccination. Patients and methods: In this observational case-control study, 38 children with IBD (CD:18, UC: 20) aged 12-18 years and 62 healthy age-and sex-matched children were enrolled. Blood was collected before the first dose and 2-6 weeks after the second dose of BNT162b2 (Pfizer-BioNTech) mRNA vaccine dose. Blood cell counts, fibrinogen, inflammatory markers (hsCRP, ferritin), anti-SARS-CoV-2 antibody levels were investigated, TG assay was carried-out using platelet-poor plasma. Detailed clinical parameters including disease activity scores (PUCAI, PCDAI) were registered pre-and post- vaccination. A guided questionnaire was used to collect data on adverse reactions (AEs) post- vaccination. Results: Baseline TG parameters did not differ between patients and controls. Endogenous thrombin potential showed a significant positive correlation with markers of inflammation and with PCDAI. Inflammatory parameters and TG did not increase in patients and controls post-vaccination. Vaccination significantly increased antibody levels in all three investigated groups, but post-vaccination anti-SARS-CoV-2 S IgG/IgM levels were below the 5th percentile value of healthy children in more than one third of patients. Those receiving TNFα inhibitor therapy presented significantly lower SARS-CoV-2 S IgG/IgM levels as compared to patients on other immunosuppressive regimens. Systemic AEs did not differ between patients and controls while lower rate of local symptoms was found post-vaccination in children with IBD. Only 2 IBD flares were detected 2-6 weeks after the second dose of vaccination. Conclusion: Our study is the first to support the safety and efficacy of anti-SARS-CoV-2 BNT162b2 vaccination in children with IBD with detailed pre-and post-vaccination laboratory data including TG. Results of this study may further increase confidence and reduce vaccine hesitancy in caretakers of pediatric IBD patients.
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COVID-19 , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Criança , Humanos , Anticorpos Antivirais , Vacina BNT162 , Estudos de Casos e Controles , COVID-19/prevenção & controle , Imunoglobulina G , Imunoglobulina M , RNA Mensageiro , SARS-CoV-2 , TrombinaRESUMO
Next to the skin, the peritoneum is the largest human organ, essentially involved in abdominal health and disease states, but information on peritoneal paracellular tight junctions and transcellular channels and transporters relative to peritoneal transmembrane transport is scant. We studied their peritoneal localization and quantity by immunohistochemistry and confocal microscopy in health, in chronic kidney disease (CKD) and on peritoneal dialysis (PD), with the latter allowing for functional characterizations, in a total of 93 individuals (0-75 years). Claudin-1 to -5, and -15, zonula occludens-1, occludin and tricellulin, SGLT1, PiT1/SLC20A1 and ENaC were consistently detected in mesothelial and arteriolar endothelial cells, with age dependent differences for mesothelial claudin-1 and arteriolar claudin-2/3. In CKD mesothelial claudin-1 and arteriolar claudin-2 and -3 were more abundant. Peritonea from PD patients exhibited increased mesothelial and arteriolar claudin-1 and mesothelial claudin-2 abundance and reduced mesothelial and arteriolar claudin-3 and arteriolar ENaC. Transperitoneal creatinine and glucose transport correlated with pore forming arteriolar claudin-2 and mesothelial claudin-4/-15, and creatinine transport with mesothelial sodium/phosphate cotransporter PiT1/SLC20A1. In multivariable analysis, claudin-2 independently predicted the peritoneal transport rates. In conclusion, tight junction, transcellular transporter and channel proteins are consistently expressed in peritoneal mesothelial and endothelial cells with minor variations across age groups, specific modifications by CKD and PD and distinct associations with transperitoneal creatinine and glucose transport rates. The latter deserve experimental studies to demonstrate mechanistic links.Clinical Trial registration: The study was performed according to the Declaration of Helsinki and is registered at www.clinicaltrials.gov (NCT01893710).
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Insuficiência Renal Crônica , Insuficiência Renal , Humanos , Peritônio/metabolismo , Junções Íntimas/metabolismo , Claudina-1/metabolismo , Células Endoteliais/metabolismo , Claudina-2/metabolismo , Creatinina/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal/metabolismo , Glucose/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismoRESUMO
The aim of this study is to evaluate the strategy of the cystic fibrosis newborn screening (CFNBS) programme in Hungary based on the results of the first year of screening. A combined immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) CFNBS protocol (IRT/IRT×PAP/IRT) was applied with an IRT-dependent safety net (SN). Out of 88,400 newborns, 256 were tested screen-positive. Fourteen cystic fibrosis (CF) and two cystic fibrosis-positive inconclusive diagnosis (CFSPID) cases were confirmed from the screen-positive cases, and two false-negative cases were diagnosed later. Based on the obtained results, a sensitivity of 88% and a positive predictive value (PPV) of 5.9% were calculated. Following the recognition of false-negative cases, the calculation method of the age-dependent cut-off was changed. In purely biochemical CFNBS protocols, a small protocol change, even after a short period, can have a significant positive impact on the performance. CFNBS should be monitored continuously in order to fine-tune the screening strategy and define the best local practices.
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BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.
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Transtorno Bipolar , Transtornos Mentais , Transtornos Psicóticos , Humanos , Estudos Transversais , Transtornos Mentais/tratamento farmacológico , Comportamento Impulsivo , Transtorno Bipolar/tratamento farmacológico , LítioRESUMO
Rapidly evolving clinical data suggest that the novel coronavirus (SARS-CoV-2) and vaccination against COVID-19 might be associated with thyroid disturbances. However, studies remain limited among the pediatric population. Our aim was to assess the prevalence and permanence of thyroid autoimmunity (TA) and dysfunction in children after an acute infection and its potential association with vaccination. A prospective, multicenter registry analysis was performed among 458 children (mean age: 12.4 ± 3,8 years, 45.4% male) with preceding COVID-19. Patient inclusion lasted from 24th March, 2021 to 23rd March, 2022 at three pediatric outpatient facilities at Semmelweis University, Budapest. Primary outcomes were the rate of thyroid disturbances assessed by laboratory parameters (thyroid function tests, antithyroglobulin [ATG] and anti-thyroid peroxidase [ATPO] antibodies) and thyroid ultrasound. TA rate among vaccinated and unvaccinated children was determined. Children with newly diagnosed thyroid alterations were followed up for 12.7 ± 4.3 months. Six children had previous thyroid disease. Out of 452 children, 30 cases (6.6%) of newly diagnosed TA (six of them had abnormal thyroid-stimulating hormone [TSH] levels) and eight cases (1.8%) of isolated TSH elevation were observed. Ultrasound-proven autoimmune thyroiditis (AIT) was 4.0%. No association was found between COVID-19 vaccination and thyroid autoimmunity (χ2(1,N = 452) = 0.138, p = 0.815). Among children with TA, 73.3% had long-lasting alterations. Conclusion: Vaccination had no effect on the prevalence of TA. Until further controlled studies state otherwise, children with preceding COVID-19 might benefit from thyroid screening. What is Known: ⢠Numerous case reports implicate that coronavirus disease-2019 (COVID-19) and vaccination against SARS-CoV-2 can be responsible for thyroid disturbances. ⢠Thyroid alterations discovered during acute COVID-19 tend to cease by time and only incidental thyroid autoimmunity (TA) is diagnosed after COVID-19. In adults, no increase in vaccine-related hyper- or hypothyroidism was found. What is New: ⢠TA rate after COVID-19 vaccination among children was not increased. TA had no role in long COVID syndrome. ⢠We discovered a considerable rate of TA (6.6%) and ultrasound-proven autoimmune thyroiditis (AIT) (4.0%) after SARS-CoV-2 infection, and the majority of these alterations remained positive after 6 months.
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COVID-19 , Tireoidite Autoimune , Adulto , Criança , Humanos , Masculino , Feminino , Tireoidite Autoimune/complicações , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/epidemiologia , Síndrome de COVID-19 Pós-Aguda , Estudos Prospectivos , Vacinas contra COVID-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/complicações , SARS-CoV-2 , Vacinação/efeitos adversos , TireotropinaRESUMO
Rationale: Psilocybin is a serotonergic psychedelic that has gained prominent attention recently as a potential therapeutic for neuropsychiatric disorders including Major Depressive Disorder. Pre-clinical and initial studies in humans suggest that serotonin 2A receptor agonists, including serotonergic psychedelics, have anti-inflammatory effects. This may contribute to its therapeutic effects as previous studies indicate a link between neuropsychiatric disorders and inflammatory processes. However, the effect of psilocybin on biomarkers of inflammation has not been evaluated in humans. Objectives: Investigate the effect of a single dose of psilocybin on peripheral biomarkers of inflammation in healthy humans. Methods: Blood samples were collected from 16 healthy participants before and one day after the administration of a single oral dose of psilocybin (mean dose: 0.22 mg/kg) and subsequently analyzed for concentrations of high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR). Change in inflammatory markers was evaluated using a paired t-test where p < 0.05 was considered statistically significant. Results: We did not observe statistically significant changes in any of the above biomarkers of inflammation (all Cohen's d ≤ 0.31; all p ≥ 0.23). Conclusions: Our data do not support that a single dose of psilocybin reduces biomarkers of inflammation in healthy individuals one day after administration. Nevertheless, we suggest that future studies consider additional markers of inflammation, including markers of neuroinflammation, and evaluate potential anti-inflammatory effects of psilocybin therapy in clinical cohorts where more prominent effects may be observable.
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Given the wide diversity of causes of hematuria, ranging from simple urinary tract infections with rapid recovery to severe glomerulonephritis with fast decline in kidney function, it is essential to recognize the underlying disease. The first objective of the assessment is to determine whether the cause of the hematuria is medically significant. The combination of hematuria with proteinuria, the presence of hypertension, or worsening kidney function can represent signs of progressive kidney disease. Differentiating the various causes of hematuria is often simple and obvious based on the clinical signs and gross appearance of the urine. However, in some instances, additional non-invasive investigations, such as ultrasound imaging, urinary red cell morphology, measurement of calcium and other solutes in the urine, evaluation of kidney function, and protein excretion, are needed to elucidate the nature of the hematuria. Taking a detailed family history can help in establishing the underlying cause in cases of familial hematuria. On the other hand, the decision to perform a kidney biopsy in children with asymptomatic hematuria remains a challenging issue for clinicians. Ultimately, the frequency of diagnosis of glomerular involvement causing hematuria may depend on the threshold for performing a kidney biopsy. The following review will focus on the diagnostics of hematuria, starting with difficulties regarding its definition, followed by various means to differentiate between urinary, glomerular, and other causes, and finally reviewing the most common diseases that, due to their frequency or their effect on kidney function, present a diagnostic challenge in everyday practice.
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Glomerulonefrite , Nefropatias , Criança , Humanos , Hematúria/diagnóstico , Hematúria/etiologia , Hematúria/urina , Rim/diagnóstico por imagem , Rim/patologia , Nefropatias/diagnóstico , Glomerulonefrite/complicações , Glomerulonefrite/diagnóstico , Glomerulonefrite/terapia , Glomérulos Renais/patologiaRESUMO
Background: Treatment of the coronavirus disease (COVID-19) is still challenging due to the lack of evidence-based treatment protocols and continuously changing epidemiological situations and vaccinations. Remdesivir (RDV) is among the few antiviral medications with confirmed efficacy for specific patient groups. However, real-world data on long-term outcomes for a short treatment course are scarce. Methods: This retrospective observational cohort study included real-life data collected during the second and third wave of the COVID-19 pandemic in Hungary (September 1, 2020-April 30, 2021) from inpatients at a University Center (n = 947). Participants consisted of two propensity score-matched cohorts (370/370 cases): Group RDV including patients receiving RDV and supplementary oxygen and Group standard of care (SOC) as control. The primary outcome was the effect of 5-day RDV treatment on 30- and 60-day all-cause mortality. Multivariate analyses were performed to assess the effect of RDV by different covariates. Results: Group RDV included significantly more patients from the alpha variant wave, with greater frequency of comorbidities diabetes and anemia, and larger degree of parenchymal involvement. All-cause mortality at 30- and 60-day were significantly lower in Group RDV compared to Group SOC. Significant risk reduction of 60-day all-cause mortality was observed for RDV treatment in men and patients with COPD or multiple comorbidities. Conclusions: Hospitalized COVID-19 patients with 5-day RDV treatment had significantly lower 30- and 60-day all-cause mortality, despite their more severe clinical condition. Men and patients with multiple comorbidities, including COPD, profited the most from RDV treatment in the long term. Due to the ongoing COVID-19 pandemic, effective treatment regimens are needed for hospitalized patients.
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Tratamento Farmacológico da COVID-19 , Infecções por Coronavirus , Coronavirus , Doença Pulmonar Obstrutiva Crônica , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Humanos , Masculino , Pandemias , Estudos Retrospectivos , SARS-CoV-2RESUMO
Cystinosis is a rare lysosomal storage disease affecting amino acid metabolism, characterized by the accumulation and crystallization of cystine in various tissues, primarily in the eye and kidney. The major ophthalmic symptom is photophobia, which is related to the corneal deposition of cystine crystals. The light sensitivity significantly impairs the quality of life of the affected patients, thus, effective ophthalmic treatment to reduce the crystal density is very importance. In the current case report, we present the characteristic ocular clinical appearance and treatment options of cystinosis by reviewing the literature. A simple aqueous solution of cysteamine, which aids in the dissolution of crystals, has been widely used in topical treatment in the past, however, its therapeutic efficacy is debatable. Recently, a new viscous formulation of cysteamine has been proposed for ophthalmic treatment. For the treatment of corneal cystine crystals in our patient, the new viscous format of cysteamine has been applied, and therapeutic effects were recorded for a year. Applying the viscous cysteamine formulation, a marked and gradual decrease in photophobia was observed in our patient in the first year of the treatment. Anterior-segment optical coherence tomography and in vivo confocal microscopy represented a continuous decrease in the density of corneal crystals even from the first month of the treatment period. The aim of our case report is to present the ophthalmic symptoms of cystinosis and the results of the first clinical application of viscous formulation of cysteamin eye drops in Hungary in a cystinosis patient.
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Doenças da Córnea , Cistinose , Córnea/metabolismo , Doenças da Córnea/diagnóstico , Doenças da Córnea/tratamento farmacológico , Doenças da Córnea/etiologia , Cisteamina/metabolismo , Cisteamina/uso terapêutico , Cistina/química , Cistina/metabolismo , Cistina/uso terapêutico , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Humanos , Fotofobia/etiologia , Qualidade de Vida , Acuidade VisualRESUMO
OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (ß = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (ß = 0.06, t = 1.27, p = 0.20), IL-18 (ß = 0.05, t = 1.25, p = 0.21), IL-18R1 (ß = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.
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Interleucina-18 , Transtornos Psicóticos , Biomarcadores , Humanos , Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1 , Subunidade alfa de Receptor de Interleucina-18RESUMO
Fibroblasts play a central role in diseases associated with excessive deposition of extracellular matrix (ECM), including idiopathic pulmonary fibrosis. Investigation of different properties of fibroblasts, such as migration, proliferation, and collagen-rich ECM production is unavoidable both in basic research and in the development of antifibrotic drugs. In the present study we developed a cost-effective, 96-well plate-based method to examine the migration of fibroblasts, as an alternative approach to the gold standard scratch assay, which has numerous limitations. This article presents a detailed description of our transient agarose spot (TAS) assay, with instructions for its routine application. Advantages of combined use of different functional assays for fibroblast activation in drug development are also discussed by examining the effect of nintedanib-an FDA approved drug against IPF-on lung fibroblasts.
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Bioensaio/métodos , Movimento Celular/fisiologia , Sefarose/química , Células A549 , Animais , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Matriz Extracelular/fisiologia , Fibroblastos/fisiologia , Células HT29 , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiologia , Pulmão/fisiopatologia , RatosRESUMO
Respiratory transmission of SARS-CoV-2 from one older patient to another by airborne mechanisms in hospital and nursing home settings represents an important health challenge during the COVID-19 pandemic. However, the factors that influence the concentration of respiratory droplets and aerosols that potentially contribute to hospital- and nursing care-associated transmission of SARS-CoV-2 are not well understood. To assess the effect of health care professional (HCP) and patient activity on size and concentration of airborne particles, an optical particle counter was placed (for 24 h) in the head position of an empty bed in the hospital room of a patient admitted from the nursing home with confirmed COVID-19. The type and duration of the activity, as well as the number of HCPs providing patient care, were recorded. Concentration changes associated with specific activities were determined, and airway deposition modeling was performed using these data. Thirty-one activities were recorded, and six representative ones were selected for deposition modeling, including patient's activities (coughing, movements, etc.), diagnostic and therapeutic interventions (e.g., diagnostic tests and drug administration), as well as nursing patient care (e.g., bedding and hygiene). The increase in particle concentration of all sizes was sensitive to the type of activity. Increases in supermicron particle concentration were associated with the number of HCPs (r = 0.66; p < 0.05) and the duration of activity (r = 0.82; p < 0.05), while submicron particles increased with all activities, mainly during the daytime. Based on simulations, the number of particles deposited in unit time was the highest in the acinar region, while deposition density rate (number/cm2/min) was the highest in the upper airways. In conclusion, even short periods of HCP-patient interaction and minimal patient activity in a hospital room or nursing home bedroom may significantly increase the concentration of submicron particles mainly depositing in the acinar regions, while mainly nursing activities increase the concentration of supermicron particles depositing in larger airways of the adjacent bed patient. Our data emphasize the need for effective interventions to limit hospital- and nursing care-associated transmission of SARS-CoV-2 and other respiratory pathogens (including viral pathogens, such as rhinoviruses, respiratory syncytial virus, influenza virus, parainfluenza virus and adenoviruses, and bacterial and fungal pathogens).
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COVID-19 , SARS-CoV-2 , Aerossóis , Hospitais , Humanos , PandemiasRESUMO
BACKGROUND: In atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known. CASE-DIAGNOSIS/TREATMENT: We present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn's disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses. CONCLUSION: In aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Doença de Crohn , Enteropatias , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Criança , Proteínas do Sistema Complemento , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Humanos , RecidivaRESUMO
Recently the role of Parkinson's disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)-compound increasing PARK7 activity-treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn's disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-ß treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.
Assuntos
Colite/metabolismo , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Proteína Desglicase DJ-1/fisiologia , Adolescente , Animais , Criança , Pré-Escolar , Colite/induzido quimicamente , Colite/imunologia , Colo/metabolismo , Colo/patologia , Citocinas/imunologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Células HT29 , Humanos , Peróxido de Hidrogênio , Lactente , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PermeabilidadeRESUMO
Összefoglaló. A gyulladásos bélbetegség (inflammatory bowel disease, IBD) incidenciája folyamatosan no, etiológiája egyelore ismeretlen. Kezelésében gyakran alkalmazunk immunszuppresszív, illetve immunmoduláns szereket. Egyes esetekben azonban szolidszerv-transzplantációt követoen, folyamatos immunszuppresszív kezelés mellett is megfigyelheto de novo IBD kialakulása. Célunk az volt, hogy Klinikánk beteganyagából összesítsük azon eseteket, amelyekben szolid szerv (máj, vese, tüdo) transzplantációját követoen de novo IBD alakult ki. A transzplantációt megelozoen szklerotizáló cholangitis miatt gondozott betegeket kizártuk. A Klinikánkon gondozott, szolid szerv transzplantációján (179 máj, 197 vese, 29 tüdo) átesett betegek közül 4 (2 máj- és 2 vesetranszplantált) gyermeknél alakult ki de novo IBD. A transzplantációhoz vezeto alapbetegségek biliaris atresia, polycystás vese és Denys-Drash-szindróma voltak. A transzplantációt követo immunszuppresszív terápia mind a 4 esetben tartalmazott szisztémásszteroid- és takrolimuszkezelést, emellett 3 esetben mikofenolát-mofetil (MMF)-terápiát is. A kivizsgálást indikáló fobb tünetek a haematochesia, hasmenés, fáradékonyság és fogyás voltak. A családi anamnézis 1 esetben volt pozitív. A de novo IBD diagnózisának felállítását követoen mind a 4 betegnél az addigi immunszuppressziós terápia módosításra került. Összességében elmondható, hogy a szolidszerv-transzplantációt követo de novo IBD kialakulása ritka, etiológiája tisztázatlan. Az irodalom felveti az alkalmazott immunszuppresszív szerek (takrolimusz és MMF), illetve infekciók etiológiai szerepét, de az is felmerül, hogy a de novo IBD olyan önálló entitás, mely elkülönül a klasszikus IBD kategóriáitól. Klinikai szempontból fontos a tünetek hátterében álló betegség tisztázása, hiszen a prezentációs tüneteknek megfelelo, a differenciáldiagnosztika során felmerülo egyéb betegségek terápiája meroben eltér. A megfelelo terápia hozzájárulhat a transzplantált betegek morbiditásának és mortalitásának csökkentéséhez. Orv Hetil. 2021; 162(18): 720-726. Summary. The incidence of inflammatory bowel disease (IBD) is increasing, however, the aetiology is still unknown. The therapy consists of immunosuppressants and immunomodulators. In some cases, despite the continuous immunosuppressant therapy, de novo IBD develops. Our aim was to evaluate patients diagnosed with de novo IBD after solid organ (liver, kidney, or lung) transplantation. Patients treated with sclerosing cholangitis prior to liver transplantation were excluded. 4 patients (two kidney and two liver transplants) were diagnosed with de novo IBD. The underlying diseases leading to transplantation were biliary atresia, polycystic kidney, and Denys-Drash syndrome. All patients received systemic steroid and tacrolimus treatment, and 3 patients (2 kidney and 1 liver transplant) also received mycophenolate mofetil (MMF). The main symptoms indicative of de novo IBD were haematochezia, diarrhoea, fatigue, and weight loss. Family history for IBD was positive in 1 case. Following the diagnosis of IBD, immunosuppressive therapy was modified. Overall, the development of de novo IBD following solid organ transplantation is quite rare, and its aetiology is unknown. According to the literature, immunosuppressants (tacrolimus and MMF) and infections play a role in the pathomechanism, but it seems that de novo IBD is a separate entity from the classical IBD categories. From a clinical point of view, it is important to elucidate the underlying disease of the symptoms, as the treatment of other diseases that arise during differential diagnosis according to the presentation symptoms is very different. Appropriate therapy can help reduce morbidity and mortality in transplant patients. Orv Hetil. 2021; 162(18): 720-726.
Assuntos
Doenças Inflamatórias Intestinais , Transplante de Órgãos , Criança , Humanos , Transplante de Órgãos/efeitos adversosRESUMO
Despite the high heritability of schizophrenia (SCZ), details of its pathophysiology and etiology are still unknown. Recent findings suggest that aberrant inflammatory regulation and microRNAs (miRNAs) are involved. Here we performed a comparative analysis of the global miRNome of human induced pluripotent stem cell (iPSC)-astrocytes, derived from SCZ patients and healthy controls (CTRLs), at baseline and following inflammatory modulation using IL-1ß. We identified four differentially expressed miRNAs (miR-337-3p, miR-127-5p, miR-206, miR-1185-1-3p) in SCZ astrocytes that exhibited significantly lower baseline expression relative to CTRLs. Group-specific differential expression (DE) analyses exploring possible distinctions in the modulatory capacity of IL-1ß on miRNA expression in SCZ versus CTRL astroglia revealed trends toward altered miRNA expressions. In addition, we analyzed peripheral blood samples from a large cohort of SCZ patients (n = 484) and CTRLs (n = 496) screening for the expression of specific gene targets of the four DE miRNAs that were identified in our baseline astrocyte setup. Three of these genes, LAMTOR4, IL23R, and ERBB3, had a significantly lower expression in the blood of SCZ patients compared to CTRLs after multiple testing correction. We also found nominally significant differences for ERBB2 and IRAK1, which similarly displayed lower expressions in SCZ versus CTRL. Furthermore, we found matching patterns between the expressions of identified miRNAs and their target genes when comparing our in vitro and in vivo results. The current results further our understanding of the pathobiological basis of SCZ.