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Adropin is a peptide that was suggested to have a role in cirrhosis. The present study aimed to determine the ability to use serum adropin levels to improve their prediction accuracy as an adjunct to the current scores. In a single-center, proof-of-concept study, serum adropin levels were determined in thirty-three cirrhotic patients. The data were analyzed in correlation with Child-Pugh and MELD-Na scores, laboratory parameters, and mortality. Adropin levels were higher among cirrhotic patients that died within 180 days (1,325.7 ng/dL vs. 870.3 ng/dL, p = 0.024) and inversely correlated to the time until death (r 2 = 0.74). The correlation of adropin serum levels with mortality was better than MELD or Child-Pough scores (r 2 = 0.32 and 0.38, respectively). Higher adropin levels correlated with creatinine (r 2 = 0.79. p < 0.01). Patients with diabetes mellitus and cardiovascular diseases had elevated adropin levels. Integrating adropin levels with the Child-Pugh and MELD scores improved their correlation with the time of death (correlation coefficient: 0.91 vs. 0.38 and 0.67 vs. 0.32). The data of this feasibility study suggest that combining serum adropin with the Child-Pugh score and MELD-Na score improves the prediction of mortality in cirrhosis and can serve as a measure for assessing kidney dysfunction in these patients.
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Peptídeos e Proteínas de Sinalização Intercelular , Cirrose Hepática , Humanos , Prognóstico , Índice de Gravidade de Doença , Peptídeos e Proteínas de Sinalização Intercelular/sangueRESUMO
Biological adjuvants that target the gut immune system are being developed for modulating the immune system. Hyperimmune bovine colostrum (HBC), produced by harvesting the bovine colostrum of dairy cows immunized to exogenous antigens, has been shown to modulate the immune responses and alleviate immune-mediated organ damages. The aim of the present study was to determine the ability of HBC to promote antiviral interferonγ (IFNγ) T cell responses. In a preclinical study, mice were orally administered with HBC for 5 days and tested for the number of T cell clones secreting IFNγ in response to viral antigens of the swine flu, New Caledonia influenza, and cytomegalovirus. In a phase I/IIa clinical trial, five healthy volunteers were treated for 5 days with HBC followed by testing the anti-coronavirus disease (COVID-19) immunity. In the preclinical study, oral administration of HBC augmented the number of T cell clones secreting IFNγ in response to viral antigens. In the clinical trial, oral administration of HBC to healthy males significantly increased the number of anti-COVID-19 spike protein IFNγ positive T cell clones. Oral administration of HBC provides a novel method for augmenting antiviral responses. Its high-safety profile makes it ideal for all disease stages and for pre-emptive therapy among medical personnel and other workers who are at a high risk of exposure to infections. The relatively low cost of HBC is expected to minimize care provider burdens, costs, and enable its global application.
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COVID-19 , Colostro , Administração Oral , Animais , Antígenos Virais , Antivirais/farmacologia , Antivirais/uso terapêutico , Bovinos , Feminino , Humanos , Fatores Imunológicos , Interferon gama , Masculino , Camundongos , Gravidez , Linfócitos TRESUMO
Severe acute respiratory syndrome coronavirus 2 infected patients, receiving background anti-CD20 therapy, were treated with convalescent plasma or plasma-based products. Eight patients were included in the study, presenting with prolonged disease course and delayed viral clearance. CP/plasma-based products were offered as an add-on therapy to standard medical treatment. All patients showed remarkable clinical and laboratory improvement. In addition, polymerase chain reaction from nasopharyngeal swabs rapidly converted to negative following plasma administration. This study emphasizes the therapeutic efficacy of convalescent plasma and plasma-based products in a subgroup of immunocompromised patients with iatrogenic B-cell depletion.
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Linfócitos B/imunologia , Tratamento Farmacológico da COVID-19 , COVID-19/imunologia , COVID-19/terapia , Hospedeiro Imunocomprometido/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Anticorpos Antivirais/sangue , Antineoplásicos Imunológicos/administração & dosagem , COVID-19/fisiopatologia , Feminino , Humanos , Imunização Passiva/métodos , Masculino , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Resultado do Tratamento , Soroterapia para COVID-19RESUMO
Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.
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Sistema Nervoso Autônomo/fisiologia , Ritmo Circadiano , Encefalopatia Hepática/tratamento farmacológico , Fígado/metabolismo , Animais , Fármacos Gastrointestinais/uso terapêutico , Encefalopatia Hepática/metabolismo , Humanos , Fígado/fisiologia , Fígado/fisiopatologiaRESUMO
OBJECTIVES: To evaluate the incidence of hospitalization for coronavirus disease 2019 (COVID-19) in patients with FMF, as compared with the general population, and to compare the disease course between FMF inpatients, and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. METHODS: We used electronic medical records to obtain data about the total number of the insured population and the number of FMF patients in the two largest health management organizations in Jerusalem, Clalit and Meuhedet. The total number of COVID-19 inpatients at the Hadassah Medical Center, including those with FMF, for the period between 1 February 2020 and 10March 2021, was retrieved from the electronic medical records of Hadassah. COVID-19 course was compared between the FMF inpatient group and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. Each FMF inpatient was matched with two non-FMF controls. RESULTS: We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population (0.46% vs 0.41%, P = 0.73). Furthermore, we found similar disease severity and therapeutic approach in FMF COVID-19 inpatients and matched non-FMF COVID-19 inpatients. CONCLUSIONS: Neither FMF nor baseline colchicine therapy, appear to affect the incidence of hospitalization for COVID-19 or the disease course, in terms of severity and therapeutic approach.
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COVID-19/epidemiologia , Febre Familiar do Mediterrâneo/virologia , Hospitalização/estatística & dados numéricos , SARS-CoV-2 , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , COVID-19/genética , Estudos de Casos e Controles , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Incidência , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Antiphospholipid syndrome and cold agglutinin-mediated autoimmune hemolytic anemia are 2 distinct immune-mediated hematologic disorders. While no clear association exists between these 2 entities, complement activation is known to occur in both of them. Herein, we report a unique case of cold agglutinin hemolytic anemia in a patient with a known primary antiphospholipid syndrome.
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Anemia Hemolítica Autoimune/diagnóstico , Síndrome Antifosfolipídica/diagnóstico , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/metabolismo , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/metabolismo , Ativação do Complemento , Crioglobulinas/efeitos adversos , Eletroforese , Feminino , Humanos , Imunoglobulina M/efeitos adversos , Imunoglobulina M/análise , Pessoa de Meia-IdadeRESUMO
Sphingolipids (SL) are a family of bioactive lipids and a major cellular membrane structural component. SLs include three main compounds: ceramide (Cer), sphingosine (Sp), and sphingosine-1-phosphate (S-1P), all of which have emerging roles in biological functions in cells, especially in the liver. They are under investigation in various liver diseases, including cirrhosis and end-stage liver disease. In this review, we provide an overview on the role of SLs in liver pathobiology and focus on their potential role in the development of hepatic fibrosis. We describe recent evidence and suggest SLs are a promising potential therapeutic target for the treatment of liver disease and fibrosis.
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Cirrose Hepática/metabolismo , Fígado/metabolismo , Esfingolipídeos/metabolismo , Animais , Proliferação de Células , Inibidores Enzimáticos/uso terapêutico , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Fetal complete atrioventricular block (CAVB) is usually autoimmune mediated. The risk of developing CAVB is 2% to 3% in anti-Ro/SS-A seropositive pregnancies and it increases 10 times after previous CAVB in siblings. Despite being a rare complication, CAVB carries a 20% mortality rate and substantial morbidity, as about 65% of newborns will eventually need life-long pacing. Once found, fetal CAVB is almost always irreversible, despite aggressive immunotherapy. This poor outcome prompted some research groups to address this situation. All groups followed anti-Ro/SS-A seropositive pregnancies on a weekly basis during the second trimester of pregnancy and tried to detect first degree atrioventricular block (AVB) using accurate echocardiographic tools, assuming they may characterize the initiation of the immune damage to the A-V conduction system, at which point the process might still be reversible. Some of the groups treated fetuses with first degree AVB with maternal oral fluorinated steroids. We summarized the results of all groups, including our group. We describe a case of a fetus that developed CAVB 6 days after normal sinus rhythm (NSR), who under aggressive dexamethasone therapy gradually reverted to NSR. This fetus had a previous sibling with CAVB. We assumed the immune damage to the conduction system in this small group of fetuses with a previous CAVB sibling may have occurred more quickly than usual. We therefore recommend a twice-weekly follow-up with these fetuses.
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Bloqueio Atrioventricular/tratamento farmacológico , Dexametasona/administração & dosagem , Doenças Fetais/tratamento farmacológico , Adulto , Bloqueio Atrioventricular/diagnóstico , Bloqueio Atrioventricular/imunologia , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/imunologia , Glucocorticoides/administração & dosagem , Humanos , Recém-Nascido , Gravidez , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal/métodos , Resultado do TratamentoRESUMO
Both patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid ß-glucocerebrosidase (GCase) activity. This observation, together with other clinical systemic observations raises the possibility that extra-cellular GC actually has beneficial, anti-inflammatory, properties. Based on this hypothesis, we suggest here that the administration of supplementary oral GC to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death. Such a treatment may act synergistically in GBA carriers once given in combination with an agent that prevent the primary pathologic process that leads to cell death. Ambroxol hydrochloride, a pharmacological chaperone, which reduces endoplasmic reticulum (ER) stress induced by accumulation of mutant misfolded GCase could serve as such an agent. The efficacy of this combined therapy, derived from clinical observations, in vivo and in vitro studies, should be evaluated in clinical trials.
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Ambroxol/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Expectorantes/uso terapêutico , Doença de Gaucher/complicações , Doença de Gaucher/tratamento farmacológico , Glucosilceramidas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Animais , Descoberta de Drogas , Doença de Gaucher/genética , Doença de Gaucher/patologia , Glucosilceramidase/genética , Humanos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/patologiaAssuntos
Úlceras Orais , Trombose , Uveíte , Humanos , Úlceras Orais/diagnóstico , Úlceras Orais/etiologia , Uveíte/diagnóstico , Uveíte/etiologiaRESUMO
Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson's disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients' medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments.
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Background and Aims: Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. Methods: This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment. Results: No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm. Conclusion: The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).
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Background: SARS-CoV-2 vaccine responses that could harbor potential risks to chronic liver diseased patients. Aims: To assess immune response following Pfizer's SARS-CoV-2 vaccine in patients with different liver fibrosis severities of nonalcoholic fatty liver disease (NAFLD). Methods: Clinical and histological (NAS-score and fibrosis stage) characteristics of NAFLD patients before vaccine were correlated with serologic vaccine responses of two doses of the BNT162b2. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed on day seven following immunization (Liaison assay). Results: The mean-age of patients (n = 157) was 56.9 ± 13.2 years (46.5 % males). 94.8 % had a positive response (anti-S levels ≥ 19 AU/ml). The anti-S cutoff of 200 AU/ml used to separate strong vs. weak responses. A strong response (anti-S titers ≥ 200 AU/ml) was observed in 93/157 (59.2 %) patients with a mean-age of 53.1 ± 13.8 years (45.2 % males). A weak response (anti-S titers < 200 AU/ml) was observed in 64/157 (40.8 %) cases with a mean-age of 62.3 ± 10.2 years (p < 0.0001). The strong response subgroup had lower metabolic comorbidities, including glucose hemostasis, hypertension, and dyslipidemia (p < 0.04). Moreover, the strong response subgroup had fibrosis stages F0-F2 (75.3 % vs. 56.3 %) and lower rates of advanced stages F3-F4 (24.7 % vs. 43.8 %). The F0-F2 subgroups had significantly higher rates of strong responses than the F3-F4 stages. The anti-S ≥ 200 and anti-S ≥ 400 AU/ml response achieved in 66 % and 36.8 % of the F0-F2 population was significantly higher than the 45.1 % (p = 0.006) and 23.5 % (p = 0.05) in the F3-F4 population, respectively. The Fib-4 calculations and Fibroscan evaluations were consistent with histologic fibrosis assessment. Conclusion: Advanced liver fibrosis (assessed by histology, Fib-4, or Fibroscan) is a risk factor for lower response to Pfizer's BNT162b2 vaccine, and patients should be prioritized for the vaccine booster against SARS-CoV-2.
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The association between infectious diseases and autoimmunity has long been reported. Specifically, during the coronavirus disease 2019 (COVID-19) pandemic, this relation was further emphasized. The interplay between the two disease processes remains interesting, yet incompletely defined. Herein, we report a case series of six patients presenting with autoimmune phenomena first developed or exacerbated following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We describe the disease course and discuss the possible mechanisms underlying the association between autoimmunity and COVID-19.
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We report a case of Staphylococcus warneri native valve endocarditis in an immunocompetent healthy adult, without known risk factors for infective endocarditis, two months following COVID-19 infection, who recovered with conservative treatment. Additionally, we reviewed previous cases of native valve endocarditis caused by Staphylococcus warneri and summarized the main clinical implications.
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COVID-19 , Endocardite Bacteriana , Endocardite , Infecções Estafilocócicas , Adulto , Valva Aórtica , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/tratamento farmacológico , Humanos , Infecções Estafilocócicas/tratamento farmacológico , StaphylococcusRESUMO
We report the case of a 29-year-old adult presenting with severe IgA vasculitis, with cutaneous, urologic, and renal manifestations. The late appearance of severe gastrointestinal bleeding dominated the clinical picture, necessitating the administration of tens of units of packed cells and the augmentation of the immunosuppressive protocol. It was not until therapy with intravenous immunoglobulin (IVIG) was introduced that the massive bleeding was controlled. We herein discuss the patient's presentation, the gastrointestinal manifestations of IgA vasculitis, the recommended treatments, and the existent evidence about IVIG therapy.
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Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
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Anti-Inflamatórios/uso terapêutico , Hepatite Animal/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/imunologia , Animais , Anti-Inflamatórios/farmacologia , Hepatite Animal/sangue , Hepatite Animal/imunologia , Hepatite Animal/patologia , Interferon gama/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Transdução de Sinais , Esfingosina/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologiaRESUMO
Coronavirus disease 2019 (COVID-19), which is a respiratory illness associated with high mortality, has been classified as a pandemic. The major obstacles for the clinicians to contain the disease are limited information availability, difficulty in disease diagnosis, predicting disease prognosis, and lack of disease monitoring tools. Additionally, the lack of valid therapies has further contributed to the difficulties in containing the pandemic. Recent studies have reported that the dysregulation of the immune system leads to an ineffective antiviral response and promotes pathological immune response, which manifests as ARDS, myocarditis, and hepatitis. In this study, a novel platform has been described for disseminating information to physicians for the diagnosis and monitoring of patients with COVID-19. An adjuvant approach using compounds that can potentiate antiviral immune response and mitigate COVID-19-induced immune-mediated target organ damage has been presented. A prolonged beneficial effect is achieved by implementing algorithm-based individualized variability measures in the treatment regimen.
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Antivirais/imunologia , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/diagnóstico , Quimioterapia Adjuvante/métodos , Informática Médica/métodos , Algoritmos , COVID-19/imunologia , Gerenciamento Clínico , Progressão da Doença , Trato Gastrointestinal/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Índice de Gravidade de DoençaRESUMO
Vaccines represent an attractive possible solution to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Widespread vaccine distribution has yet to occur in most countries, partially due to public concerns regarding possible side effects. While studies indicate the vaccine is exceptionally safe, rare systemic side effects remain possible. In Israel, where a large percentage of the population has been rapidly vaccinated, such adverse events may be more apparent. We report a series of patients presenting with de-novo or flares of existing autoimmune conditions associated with the Pfizer BNT162b2 mRNA SARS-CoV-2 vaccine. All patients were assessed in our tertiary care center in Israel and had no history of previous SARS-COV-2 infection. We observed that while immune phenomena may occur following vaccination, they usually follow a mild course and require modest therapy. We briefly expound on the theoretical background of vaccine related autoimmunity and explore future research prospects.