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1.
Am Heart J ; 228: 109-115, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32882569

RESUMO

BACKGROUND: Patients aged ≥80 years are often treated with new-generation drug-eluting stents (DES), but data from randomized studies are scarce owing to underrepresentation in most trials. We assessed 1-year clinical outcome of octogenarians treated with new-generation DES versus younger patients. METHODS: We pooled patient-level data of 9,204 participants in the TWENTE, DUTCH PEERS, BIO-RESORT, and BIONYX (TWENTE I-IV) randomized trials. The main clinical end point was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction (MI), or clinically indicated target vessel revascularization. RESULTS: The 671 octogenarian trial participants had significantly more comorbidities. TVF was higher in octogenarians than in 8,533 patients <80 years (7.3% vs 5.3%, hazard ratio [HR]: 1.36, 95% CI: 1.0-1.83, P = .04). The cardiac death rate was higher in octogenarians (3.9% vs 0.8%, P < .001). There was no significant between-group difference in target vessel MI (2.3% vs 2.3%, P = .88) and repeat target vessel revascularization (1.9% vs 2.8%, P = .16). In multivariate analyses, age ≥ 80 years showed no independent association with TVF (adjusted HR: 1.04, 95% CI: 0.76-1.42), whereas the risk of cardiac death remained higher in octogenarians (adjusted HR: 3.38, 95% CI: 2.07-5.52, P < .001). In 6,002 trial participants, in whom data on major bleeding were recorded, octogenarians (n = 459) showed a higher major bleeding risk (5.9% vs 1.9%; HR: 3.08, 95% CI: 2.01-4.74, P < .001). CONCLUSIONS: Octogenarian participants in 4 large-scale randomized DES trials had more comorbidities and a higher incidence of the main end point TVF. Cardiac mortality was higher in octogenarians, whereas there was no increase in MI or target vessel revascularization rates. Treatment of octogenarian patients with new-generation DES appears to be safe and effective.


Assuntos
Stents Farmacológicos/classificação , Everolimo/farmacologia , Infarto do Miocárdio , Complicações Pós-Operatórias , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Reoperação/métodos , Reoperação/estatística & dados numéricos , Risco Ajustado/métodos , Fatores de Risco , Resultado do Tratamento
2.
PLoS One ; 15(8): e0238062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841308

RESUMO

This retrospective multicenter cohort study investigated the kinetics (ascending and descending phases) of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-DNA in whole blood (WB) and plasma samples collected from adult kidney transplant (KT) recipients. CMV-DNA kinetics according to antiviral therapy were investigated. Three hundred twenty-eight paired samples from 42 episodes of CMV infection and 157 paired samples from 26 episodes of EBV infection were analyzed by a single commercial molecular method approved by regulatory agencies for both matrices. CMV-DNAemia followed different kinetics in WB and plasma. In the descending phase of infection, a slower decay of viral load and a higher percentage of CMV-DNA positive samples were observed in plasma versus WB. In the 72.4% of patients receiving antiviral therapy, monitoring with plasma CMV-DNAemia versus WB CMV-DNAemia could delay treatment interruption by 7-14 days. Discontinuation of therapy based on WB monitoring did not result in relapsed infection in any patients. Highly different EBV-DNA kinetics in WB and plasma were observed due to lower positivity in plasma; EBV positive samples with a quantitative result in both blood compartments were observed in only 11.5% of cases. Our results emphasize the potential role of WB as specimen type for post-KT surveillance of both infections for disease prevention and management.


Assuntos
Citomegalovirus/genética , DNA Viral/sangue , Herpesvirus Humano 4/genética , Transplante de Rim , Adulto , Antivirais/farmacologia , Estudos de Coortes , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/fisiologia , Humanos , Imunossupressores/farmacologia , Cinética , Estudos Retrospectivos
3.
Biochimie ; 177: 50-52, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32805303

RESUMO

Various interferon (IFN)-inducible transmembrane (IFITM) proteins are known to be expressed in human tissues though only IFITM 1-3 are inducible by IFN. Numerous studies have shown that activation of IFITM3 could suppress infection by influenza and coronaviruses such as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In view of the potential application of IFITM proteins' induction to target SARS-CoV-2 infection that causes COVID-19, this article layout insights into the known antiviral mechanisms and therapeutic agents related to IFITM. Blocking viral entry through various mechanisms and the potential application of the FDA approved immunosuppressant agent, mycophenolic acid, as inducer of IFITM3 are among those discussed.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferons/farmacologia , Proteínas de Membrana/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas de Ligação a RNA/efeitos dos fármacos , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Humanos , Imunossupressores/farmacologia , Proteínas de Membrana/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Proteínas de Ligação a RNA/imunologia
4.
Nat Rev Neurol ; 16(9): 493-505, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641860

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is concerning for patients with neuroimmunological diseases who are receiving immunotherapy. Uncertainty remains about whether immunotherapies increase the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or increase the risk of severe disease and death upon infection. National and international societies have developed guidelines and statements, but consensus does not exist in several areas. In this Review, we attempt to clarify where consensus exists and where uncertainty remains to inform management approaches based on the first principles of neuroimmunology. We identified key questions that have been addressed in the literature and collated the recommendations to generate a consensus calculation in a Delphi-like approach to summarize the information. We summarize the international recommendations, discuss them in light of the first available data from patients with COVID-19 receiving immunotherapy and provide an overview of management approaches in the COVID-19 era. We stress the principles of medicine in general and neuroimmunology in particular because, although the risk of viral infection has become more relevant, most of the considerations apply to the general management of neurological immunotherapy. We also give special consideration to immunosuppressive treatment and cell-depleting therapies that might increase susceptibility to SARS-CoV-2 infection but reduce the risk of severe COVID-19.


Assuntos
Betacoronavirus , Consenso , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Imunoterapia/normas , Neuroimunomodulação/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Neuroimunomodulação/efeitos dos fármacos , Pandemias
5.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
6.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32646657

RESUMO

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado , Pandemias , Pneumonia Viral/epidemiologia , Imunidade Adaptativa , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Contraindicações de Medicamentos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Interações Medicamentosas , Everolimo/efeitos adversos , Everolimo/farmacologia , Everolimo/uso terapêutico , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Pneumonia Viral/imunologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
7.
BMJ Open ; 10(6): e039978, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-592392

RESUMO

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus , Imunização Passiva/métodos , Imunossupressores/farmacologia , Pandemias , Plasma/imunologia , Pneumonia Viral , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/estatística & dados numéricos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Estudos Transversais , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema de Registros/estatística & dados numéricos , Terapias em Estudo/métodos , Terapias em Estudo/estatística & dados numéricos
8.
PLoS One ; 15(6): e0234548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542046

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. METHODS: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. RESULTS: Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. CONCLUSIONS: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.


Assuntos
Imunossupressão , Neoplasias Mamárias Experimentais/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Imunossupressores/farmacologia , Ativação Linfocitária/genética , Ativação Linfocitária/fisiologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Atividade Motora/genética , Atividade Motora/fisiologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Células Supressoras Mieloides/patologia , Células Supressoras Mieloides/fisiologia
9.
BMJ Open ; 10(6): e039978, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518212

RESUMO

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus , Imunização Passiva/métodos , Imunossupressores/farmacologia , Pandemias , Plasma/imunologia , Pneumonia Viral , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/estatística & dados numéricos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Estudos Transversais , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema de Registros/estatística & dados numéricos , Terapias em Estudo/métodos , Terapias em Estudo/estatística & dados numéricos
11.
Br J Cancer ; 123(5): 691-693, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546835
12.
Food Chem ; 330: 127257, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32535321

RESUMO

Huangshui (HS), the by-product of Chinese Baijiu, has attracted considerable attention due to its nutrient and microbial composition; however, none of the studies has explored the polysaccharides in HS yet. Here, from HS, we isolated a novel polysaccharide, HSP-3, with an average molecular weight of 26.40 kDa. The structure was elucidated based on monosaccharide composition and methylation analysis, NMR, FT-IR, and AFM analysis. It is mainly composed of mannose (46.6%), galactose (17.3%), arabinose (11.2%), glucose (10.5%), xylose (8.2%), fucose (5.2%), and rhamnose (1.0%). The backbone of HSP-3 was made up of â†’ 2)-ß-d-Manp-(1 â†’ 2,6)-ß-d-Manp-(1 â†’ 6)-ß-d-Galp-(1 â†’ 3,6)-ß-d-Galp-(1 â†’ 4)-α-l-Rhap-(1 â†’ 3,4)-α-l-Rhap-(1 â†’ . Moreover, stimulation of the production of ROS, NO, TNF-α and IL-6, upregulation of the mRNA and protein expression levels of TNF-α and IL-6 in THP-1 cells, and enhanced the pinocytic and phagocytic capacities of THP-1 cells exhibited significant immunomodulatory properties of HSP-3. Altogether, this study suggests that HSP-3 could be used as an active component in functional foods.


Assuntos
Imunossupressores/farmacologia , Interleucina-6/metabolismo , Óxido Nítrico/biossíntese , Polissacarídeos/farmacologia , Rios/química , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Imunossupressores/química , Peso Molecular , Polissacarídeos/química , Células THP-1
13.
Neurology ; 94(22): e2373-e2383, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430312

RESUMO

OBJECTIVE: Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS). METHODS: PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure. RESULTS: Forty-four studies, including 55 distinct MS patient samples, were found eligible for the systematic review. Twenty-five studies were related to platform therapies (mainly ß-interferon [n = 17] and glatiramer acetate [n = 4]), whereas 22 studies were related to escalation therapies (mainly natalizumab [n = 14] and fingolimod [n = 6]). Reported data were mostly confined to the cognitive domain processing speed. A meta-analysis including 41 studies and 7,131 patients revealed a small to moderate positive effect on cognitive test performance of DMTs in general (g = 0.27, 95% confidence interval [CI] = [0.21-0.33]), but no statistically significant differences between platform (g = 0.27, 95% CI = [0.18-0.35]) and escalation therapies (g = 0.28, 95% CI = [0.19-0.37]) or between any single DMT and ß-interferon. CONCLUSIONS: DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/farmacologia , Acetato de Glatiramer/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
14.
Am J Cardiol ; 127: 16-24, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360038

RESUMO

Cigarette smoking is a well-known risk factor for coronary artery disease (CAD). However, the impact of smoking on outcomes after coronary revascularization, especially in patients with left main CAD (LMCAD) is less well understood. The EXCEL trial randomized 1,905 patients with LMCAD and visually assessed low or intermediate anatomical complexity (SYNTAX score ≤32) to PCI with everolimus-eluting stents or CABG. Patients were categorized according to smoking status (current, former, or never), and their outcomes at 5 years were compared by logistic regression with follow-up time included as a log-transformed offset variable. The primary endpoint was a composite of death, myocardial infarction, or stroke. Among 1893 patients with known smoking status at baseline, 416 (22%) were current smokers and 774 (41%) were former smokers. The crude rates of the primary endpoint were 19.5% for never smokers, 20.5% for former smokers (p = 0.61 vs never smokers), and 23.1% for smokers (p = 0.15 vs never smokers). Compared with never smokers, the adjusted risk of the primary endpoint was higher for current smokers (adjOR 1.82, 95% confidence interval [CI] 1.126 to 2.63; p = 0.001), but not for former smokers (adjOR 1.00, 95% CI 0.75 to 1.33, p = 0.10). The relative efficacy of PCI versus CABG for the 5-year primary endpoint was similar irrespective of smoking status (Pinteraction = 0.22). In conclusion, current smokers in the EXCEL trial had a higher adjusted 5-year risk of the primary composite endpoint of death, myocardial infarction, or stroke than never smokers, whereas former smokers were not at increased risk. Active smoking was a risk factor after LMCAD revascularization irrespective of revascularization method.


Assuntos
Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Stents Farmacológicos , Everolimo/farmacologia , Intervenção Coronária Percutânea/métodos , Fumar/efeitos adversos , Idoso , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Vasos Coronários/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
15.
Inflamm Bowel Dis ; 26(6): 797-808, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: covidwho-116826

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.


Assuntos
Regulação da Expressão Gênica , Imunossupressores/farmacologia , Síndrome do Intestino Irritável/fisiopatologia , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Animais , Betacoronavirus/metabolismo , Biópsia , Colo/efeitos dos fármacos , Colo/metabolismo , Biologia Computacional , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Imunossupressores/uso terapêutico , Inflamação/fisiopatologia , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Adulto Jovem
18.
Med Sci Monit ; 26: e921276, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249762

RESUMO

BACKGROUND Cartilage degeneration during osteoarthritis (OA) most adversely affects the quality of life by hindering the movement. The present study investigated the role of verbascoside in the protection of cartilage degeneration induced by osteoarthritis. MATERIAL AND METHODS The enzyme-linked immunosorbent (ELISA) and western blot assays were used for determination of inflammatory cytokine secretion in serum and cartilage tissues, respectively. RESULTS Treatment of the OA rats with verbascoside inhibited overproduction of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1ß in serum as well as cartilage tissues. The expression of P2X7R and matrix metalloproteinase (MMP)-13 was much higher in the rats induced with OA. However, administration of verbascoside reversed the OA-induced upregulation of P2X7R and MMP-13 expression in the cartilage tissues. The OA-mediated increase in substance P (SP) and prostaglandin E2 (PGE2) expression was also reduced in the cartilage tissues by the verbascoside treatment. Western blot assay revealed that verbascoside treatment markedly decreased the activation of IkappaBalpha and NF-kappaB p65 in the OA rats. CONCLUSIONS Thus, verbascoside inhibited inflammatory cytokine secretion in the OA rats by targeting P2X7R expression, production of matrix metalloproteinase, PGE2 and downregulation of NF-kappaB signaling pathway. Therefore, verbascoside may be used as potent agent for osteoarthritis treatment.


Assuntos
Citocinas/metabolismo , Glucosídeos/farmacologia , Imunossupressores/farmacologia , NF-kappa B/metabolismo , Osteoartrite/prevenção & controle , Fenóis/farmacologia , Animais , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Qualidade de Vida , Ratos
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