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1.
Toxicol Lett ; 336: 57-67, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33075463

RESUMO

As a leading cause of occupational asthma, toluene diisocyanate (TDI)-induced asthma is an inflammatory disease of the airways with one of the most significant characteristics involving inflammation, in which the receptor of advanced glycation end products (RAGE) plays an extremely important role. However, the mechanism underlying the upregulation of RAGE is still unknown. The aim of the present study was to examine whether JNK mediates ß-catenin stabilization via activation of RAGE in asthma. Herein from the results by analyzing the blood from healthy donors and patients with asthma, it was found that the expression of RAGE and p-JNK is highly correlated and elevated concomitantly with the severity of bronchial asthma. Additionally, upon sensitizing and challenging the mice with TDI, we found that RAGE inhibitor (FPS-ZM1) and JNK inhibitor (SP600125) significantly reduced the TDI-induced asthma inflammation in vivo. Furthermore, SP600125 also considerably restored RAGE and p-JNK expression. Besides, the in vitro results from TDI-HSA treatment of 16HBE cells reveal that therapeutic inhibition of JNK reduced TDI driving RAGE expression and ß-catenin translocation, while treatment with Anisomycin, a JNK agonist, showed the opposite effect. Moreover, genetic knockdown of RAGE does not contribute to JNK phosphorylation, indicating that JNK functions upstream of RAGE. Collectively, these findings highlight a role for JNK signaling in RAGE/ß-catenin regulation and have important therapeutic implications for the treatment of TDI induced asthma.


Assuntos
Antiasmáticos/farmacologia , Asma/enzimologia , Broncoconstrição , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/enzimologia , Pneumonia/enzimologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , beta Catenina/metabolismo , Adulto , Idoso , Animais , Asma/induzido quimicamente , Asma/fisiopatologia , Asma/prevenção & controle , Broncoconstrição/efeitos dos fármacos , Estudos de Casos e Controles , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosforilação , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Pneumonia/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Albumina Sérica Humana , Transdução de Sinais , Tolueno 2,4-Di-Isocianato
2.
Toxicology ; 447: 152634, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33197509

RESUMO

Cadmium (Cd) is one of the most toxic environmental heavy metals to which the general population is exposed mainly via the oral route. Owing to its immunomodulatory potential, orally acquired Cd affects antimicrobial immune defense in several organs, including the lungs. While there are data concerning Cd and viral and bacterial pulmonary infections, effects on fungal infections are not studied yet. In the present study, the effect of the Cd (5 mg/L for 30 days, in drinking water, the average daily Cd intake 0.641 ± 0.089 mg/kg) on the immune response of rats to pulmonary A. fumigatus infection was examined. Data obtained showed that orally acquired cadmium does not affect the elimination of the fungus in immunocompetent rats owing to the preservation of some aspects of innate immune responses (lung leukocyte infiltration and NBT reduction) and an increase in other (increased numbers of mucus-producing goblet cells, MPO release). Cd does not affect an IFN-γ response in lung leukocytes during the infection (despite suppression of cytokine production in cells of lung-draining lymph nodes), while it stimulates IL-17 and suppresses IL-10 response to the fungus. As a result, the elimination of the fungus occurs in a milieu with the prevailing proinflammatory response in Cd-exposed animals that preserved fungal elimination from the lungs, though with more intense injury to the lung tissue. Therefore, the proinflammatory microenvironment in the lungs created by Cd that sustains inflammatory/immune response to the fungus to which humans are exposed for a lifetime, raises a concern of orally acquired Cd as a risk factor for the development of chronic low-grade pulmonary inflammation.


Assuntos
Aspergilose/prevenção & controle , Aspergillus fumigatus/efeitos dos fármacos , Cádmio/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Infecções Oportunistas/prevenção & controle , Pneumonia/induzido quimicamente , Animais , Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Cádmio/toxicidade , Exposição Ambiental , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/imunologia , Masculino , Infecções Oportunistas/imunologia , Pneumonia/imunologia , Pneumonia/prevenção & controle , Ratos
3.
Support Care Cancer ; 29(1): 135-143, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32323001

RESUMO

PURPOSE: This retrospective study investigated the effect of perioperative oral care intervention on postoperative outcomes in patients undergoing lung cancer resection, in terms of the length of postoperative hospital stay and the incidence of postoperative respiratory infections. METHODS: In total, 585 patients underwent lung resection for lung cancer, 397 received perioperative oral care intervention, whereas the remaining 188 did not. This study retrospectively investigated the demographic and clinical characteristics (including postoperative complications and postoperative hospital stay) of each group. To determine whether perioperative oral care intervention was independently associated with either postoperative hospital stay or postoperative respiratory infections, multivariate analysis, multiple regression analysis, and multivariate logistic regression analysis were conducted. RESULTS: Parameters significantly associated with a prolonged postoperative hospital stay in lung cancer surgery patients were older age, postoperative complications, increased intraoperative bleeding, more invasive operative approach (e.g., open surgery), and lack of perioperative oral care intervention (standard partial regression coefficient (ß) = 0.083, p = 0.027). Furthermore, older age and longer operative time were significant independent risk factors for the occurrence of postoperative respiratory infections. Lack of perioperative oral care intervention was a potential risk factor for the occurrence of postoperative respiratory infections, although not statistically significant (odds ratio = 2.448, 95% confidence interval = 0.966-6.204, p = 0.059). CONCLUSION: These results highlight the importance of perioperative oral care intervention prior to lung cancer surgery, in order to shorten postoperative hospital stay and reduce the risk of postoperative respiratory infections.


Assuntos
Cárie Dentária/terapia , Neoplasias Pulmonares/cirurgia , Periodontite/terapia , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/prevenção & controle , Infecções Respiratórias/prevenção & controle , Adulto , Idoso , Cárie Dentária/diagnóstico , Empiema/tratamento farmacológico , Empiema/prevenção & controle , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Pulmão/patologia , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Razão de Chances , Saúde Bucal , Pacientes , Periodontite/diagnóstico , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/microbiologia , Infecções Respiratórias/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco
4.
BMC Infect Dis ; 20(1): 823, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176722

RESUMO

BACKGROUND: The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model. METHODS: MSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1ß, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured. RESULTS: The administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1ß were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups. CONCLUSION: The administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/cirurgia , Virus da Influenza A Subtipo H5N1 , Transplante de Células-Tronco Mesenquimais , Infecções por Orthomyxoviridae/complicações , Pneumonia/etiologia , Pneumonia/cirurgia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Pneumonia/prevenção & controle , Pneumonia/virologia , Resultado do Tratamento
5.
Open Heart ; 7(2)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33132209

RESUMO

OBJECTIVES: The aim of this study was to investigate the impact of acute left ventricular unloading by percutaneous left ventricular assist device on pulmonary congestion and pneumonia in patients with cardiogenic shock (CS). METHODS: In this retrospective study, we analysed patients with CS who received the Impella percutaneous left ventricular assist device (n=50) compared with those who received intra-aortic balloon pump (IABP) support (n=50). Pulmonary congestion was longitudinally assessed while on support by calculating characteristic findings on the chest X-ray using the Halperin score. The rate of pneumonia and early mortality were assessed as a secondary endpoint. RESULTS: The groups (Impella vs IABP) did not differ in terms of age, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology, Chronic Health Evaluation (APACHE) II score or serum lactate levels. Pulmonary congestion decreased in patient treated with Impella at each time point postimplantation. No change in congestion status was observed in patients supported with IABP. Multivariate analysis indicated Impella support as an independent predictor for pulmonary decongestion (OR 4.06, 95% CI 1.15 to 14.35, p=0.030). The rate of early pneumonia was lower in the Impella group compared with the IABP group (54% vs 74%, p=0.037). Failure of pulmonary decongestion during mechanical circulatory support independently predicted early pneumonia (OR 0.28, 95% CI 0.12 to 0.70, p=0.006). CONCLUSION: Pulmonary decongestion may facilitate treatment of pneumonia in patients with CS. Left ventricular unloading by Impella device might support pulmonary decongestion, although a larger prospective trial in this patient population is required.


Assuntos
Coração Auxiliar , Balão Intra-Aórtico , Pneumonia/prevenção & controle , Implantação de Prótese/instrumentação , Edema Pulmonar/prevenção & controle , Choque Cardiogênico/terapia , Função Ventricular Esquerda , Idoso , Feminino , Humanos , Balão Intra-Aórtico/efeitos adversos , Balão Intra-Aórtico/mortalidade , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico , Pneumonia/mortalidade , Pneumonia/fisiopatologia , Implantação de Prótese/efeitos adversos , Implantação de Prótese/mortalidade , Edema Pulmonar/diagnóstico , Edema Pulmonar/mortalidade , Edema Pulmonar/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
6.
Trials ; 21(1): 875, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092632

RESUMO

OBJECTIVES: The primary objective is to demonstrate that COVID-19 convalescent plasma (CCP) prevents progression to severe pneumonia in elderly COVID-19 pneumonia patients with chronic comorbidities. Secondary objectives are to demonstrate that CCP decreases the viral load in nasopharyngeal swabs and increases the anti-SARS-CoV-2 antibody titre in recipients. TRIAL DESIGN: This is a randomized, open-label, parallel group, phase II/III study with a superiority framework. The trial starts with a screening phase II designed with two-tailed alpha=0.2. In case of positive results, the trial will proceed in a formally comparative phase III (alpha=0.05). PARTICIPANTS: Adult patients with confirmed or suspected COVID-19 who are at risk according to CDC definition are eligible. Inclusion criteria are all the following: age ≥ 65; pneumonia at CT scan; PaO2/FiO2 ≥300 mmHg; presence of one or more comorbidities; signed informed consent. Exclusion criteria are one of the following: age < 65; PaO2/FiO2 < 300 mmHg; pending cardiopulmonary arrest; refusal to blood product transfusions; severe IgA deficiency; any life-threatening comorbidity or any other medical condition which, in the opinion of the investigator, makes the patient unsuitable for inclusion. The trial is being conducted at three reference COVID-19 centres in the middle of Italy. INTERVENTION AND COMPARATOR: Intervention: COVID-19 Convalescent Plasma (CCP) in addition to standard therapy. Patients receive three doses (200 ml/day on 3 consecutive days) of ABO matched CCP. Comparator: Standard therapy MAIN OUTCOMES: A. Primary outcome for Phase II: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. B. Primary outcome for Phase III: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. Secondary outcomes for Phase III: Decreased viral load on nasopharyngeal swab at days 6, 9 and 14; Decreased viremia at days 6 and 9; Increased antibody titer against SARS-CoV2 at days 30 and 60; Proportion of patients with negative of SARS-CoV2 nasopharyngeal swab at day 30; Length of hospital stay; Mortality rate at day 28; Total plasma related adverse event (day 60); Total non-plasma related adverse events (day 60); Severe adverse events (SAE) (day 60). RANDOMISATION: Treatment allocation is randomized with a ratio 1:1 in both phase II and phase III. Randomization sequences will be generated at Fondazione Policlinico Gemelli IRCCS through the RedCap web application. Randomized stratification is performed according to age (under/over 80 years), and sex. BLINDING (MASKING): None, this is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Phase II: 114 patients (57 per arm). Phase III: 182 patients (91 per arm) TRIAL STATUS: The trial recruitment started on May 27, 2020. The anticipated date of recruitment completion is April 30, 2021. The protocol version is 2 (May 10, 2020). TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov (May 5, 2020). The Identifier number is NCT04374526 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/genética , Transfusão de Sangue/métodos , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Progressão da Doença , Feminino , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Consentimento Livre e Esclarecido/ética , Itália/epidemiologia , Masculino , Mortalidade/tendências , Pandemias , Pneumonia/diagnóstico por imagem , Pneumonia/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Tomografia Computadorizada por Raios X/métodos , Carga Viral/imunologia , Carga Viral/estatística & dados numéricos
8.
J Stroke Cerebrovasc Dis ; 29(10): 105112, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912565

RESUMO

BACKGROUND: Medical complications often occur, particularly in the acute phase of severe stroke, and lead to poor outcomes. However, it is unclear whether out-of-bed mobilization (OM) reduces such complications or not in the acute phase of severe stroke. Thus, we investigated the association between OM and complications of immobility in the acute phase of severe stroke. METHODS: We enrolled 407 patients diagnosed with ischemic stroke or intracerebral hemorrhage and patients with modified Rankin Scale 5 at discharge in this study. Patients were divided into two groups: OM (303 patients) and bed rest (BR; 104 patients) at discharge based on their medical records. Complications of immobility (such as pneumonia, urinary tract infection, pressure sore, and falls) during hospitalization in each group were recorded. RESULTS: The total complication rate of immobility, incidence of pneumonia, and the incidence of pressure sores were significantly lower in the OM group than in the BR group [60.7% vs. 88.5%, 45.5% vs. 62.5%, and 3.6% vs. 12.5%; odds ratio, 0.20, 0.50, and 0.26; and 95% confidence intervals, 0.11-0.39, 0.32-0.79, and 0.11-0.61, respectively]. Urinary tract infection and falls did not differ significantly between the two groups. CONCLUSIONS: In the acute phase of severe stroke, OM was significantly associated with a lower risk of total complication rate of immobility, incidence of pneumonia, and incidence of pressure sore without increasing falls.


Assuntos
Repouso em Cama/efeitos adversos , Isquemia Encefálica/reabilitação , Deambulação Precoce , Hemorragias Intracranianas/reabilitação , Limitação da Mobilidade , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Acidentes por Quedas/prevenção & controle , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/fisiopatologia , Avaliação da Deficiência , Deambulação Precoce/efeitos adversos , Humanos , Incidência , Hemorragias Intracranianas/diagnóstico , Hemorragias Intracranianas/epidemiologia , Hemorragias Intracranianas/fisiopatologia , Japão/epidemiologia , Alta do Paciente , Pneumonia/epidemiologia , Pneumonia/prevenção & controle , Lesão por Pressão/epidemiologia , Lesão por Pressão/prevenção & controle , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/efeitos adversos , Resultado do Tratamento
9.
PLoS One ; 15(9): e0235818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915807

RESUMO

BACKGROUND: Pneumonia is a leading cause of morbidity and mortality among children under five years of age in developing countries, including Ethiopia. However, data on this serious illness among highly susceptible and vulnerable children living in local peri-urban areas are limited. Establishing the prevalence of pneumonia and identifying the associated factors are important for proper planning and intervention. METHODS: A community-based cross-sectional study was conducted among 560 systematically selected children under the age of five years in peri-urban areas of Dessie City from January through March 2019. Data were collected using a pretested structured questionnaire, physical examination of children and direct observation of housing conditions. Pneumonia was examined using World Health Organization (WHO) guidelines as the presence of the symptoms of fast breathing or indrawn chest with or without fast breathing during the two weeks prior to the study. A principal component analysis was used to construct a household wealth index. Data were analyzed using a binary logistic regression model at 95%CI (confidence interval). The analysis involved estimating the crude odds ratio (COR) using bivariate analysis, and adjusted odds ratio (AOR) using multivariable analysis. From the multivariable analysis, variables at p-value of less than 0.05 were declared statistically significant. MAIN FINDINGS: The prevalence of pneumonia among children under five was 17.1% (95%CI: 13.9%-19.9%). Of the participating children, 113 (21.0%) had a cough, 92 (17.1%) had fast breathing, 76 (14.1%) had fever, and 40 (7.4%) of the children had chest indrawn. Domestic fuel was the most common source of cooking fuel 383 (71.1%). Majority 445 (82.6%) of children were fully vaccinated and 94 (17.4%) were not fully vaccinated. Most (481, 89.2%) of the children were got exclusive breastfeeding. Slightly more than half (284, 52.7%) of the under-five children had acute malnutrition and 27.1% of the children had a childhood history of ARI. The multivariable analysis showed using domestic fuel as the energy source for cooking (adjusted odds ratio [AOR] = 3.95, 95%CI: 1.47-10.62), cooking in the living room (AOR = 6.23; 95%CI: 1.80-21.68), overcrowding (AOR = 3.37, 95%CI: 1.56-7.27), child history of acute respiratory infection (ARI) (AOR = 6.12 95%CI: 2.77-13.53), family history of ARI (AOR = 4.69, 95%CI: 1.67-13.12) and acute malnutrition (AOR = 2.43, 95%CI: 1.18-5.04) were significantly associated with childhood pneumonia. CONCLUSION: In this study, pneumonia remains a leading public health problem among under five children in the study area and higher than national averages. Domestic fuel as the energy source for cooking, cooking in the living room, overcrowding, child history of ARI, family history of ARI and acute malnutrition were predictors of pneumonia. Community-based interventions focusing on improving housing conditions, reduced use of domestic biofuels, adequate and balanced food intake, including exclusive breastfeeding of infants, and early treatment of ARIs.


Assuntos
Pneumonia/epidemiologia , Pré-Escolar , Estudos Transversais , Etiópia/etnologia , Feminino , Habitação , Humanos , Imunização , Lactente , Masculino , Avaliação Nutricional , Pneumonia/prevenção & controle , Saúde Pública , Fatores de Risco , Fatores Socioeconômicos
10.
Sci Rep ; 10(1): 13629, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788581

RESUMO

Host-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB). Previous in vitro studies revealed that the p38 MAP kinase signaling pathway coordinates several inflammatory and stress responses in Mycobacterium tuberculosis (Mtb)-infected host cells. Here we extend these findings and show that in vivo treatment of Mtb-infected C57BL/6 mice with doramapimod, a p38 MAP-kinase inhibitor, results in reduced inflammation, granuloma formation and lung pathology. Moreover, doramapimod, together with standard antibiotic treatment, significantly reduced lung and spleen mycobacterial loads compared to antibiotic treatment alone. Our in vivo data suggest the opportunity to repurpose p38 MAPK inhibitors for adjunct host directed therapies. We also provide first data on safety of p38 MAPK inhibition which is of relevance for future application of these substances in inflammatory diseases and concomitant TB.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pneumonia/prevenção & controle , Tuberculose/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Pneumonia/imunologia , Tuberculose/microbiologia
11.
Am J Respir Cell Mol Biol ; 63(6): 758-766, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32853024

RESUMO

Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against microbial pathogens including respiratory viruses, but the mechanisms remain incompletely understood. The objective of this study was to validate strategies for immune modulation in a preclinical model of viral pneumonia and determine their mechanisms. Mice were challenged with the Sendai paramyxovirus in the presence or absence of Pam2-ODN treatment. Virus burden and host immune responses were assessed to elucidate Pam2-ODN mechanisms of action and to identify additional opportunities for therapeutic intervention. Enhanced survival of Sendai virus pneumonia with Pam2-ODN treatment was associated with reductions in lung virus burden and with virus inactivation before internalization. We noted that mortality in sham-treated mice corresponded with CD8+ T-cell lung inflammation on days 11-12 after virus challenge, after the viral burden had declined. Pam2-ODN blocked this injurious inflammation by minimizing virus burden. As an alternative intervention, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. Stimulation of local innate immunity within the lungs by TLR agonists early in disease or suppression of adaptive immunity by systemic CD8+ T-cell depletion late in disease improves outcomes of viral pneumonia in mice. These data reveal opportunities for targeted immunomodulation to protect susceptible human subjects.


Assuntos
Imunidade Inata/imunologia , Lipopeptídeos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia/prevenção & controle , Infecções por Respirovirus/tratamento farmacológico , Vírus Sendai/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Feminino , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Infecções por Respirovirus/imunologia , Infecções por Respirovirus/virologia , Vírus Sendai/imunologia
12.
J Stroke Cerebrovasc Dis ; 29(9): 104942, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807413

RESUMO

BACKGROUND AND OBJECTIVES: Studies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury. METHODS: Adult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls. RESULTS: Relative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures. CONCLUSIONS: Constitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.


Assuntos
Células Epiteliais Alveolares/enzimologia , Isquemia Encefálica/enzimologia , Encéfalo/metabolismo , Neurônios/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Superóxido Dismutase/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade Inata , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/patologia , Neutrófilos/imunologia , Pneumonia/enzimologia , Pneumonia/genética , Pneumonia/imunologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Transdução de Sinais , Superóxido Dismutase/genética
13.
J Med Internet Res ; 22(8): e21257, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32750008

RESUMO

BACKGROUND: The coronavirus disease (COVID-19) pandemic is an important health crisis worldwide. Several strategies were implemented to combat COVID-19, including wearing masks, hand hygiene, and social distancing. The impact of these strategies on COVID-19 and other viral infections remains largely unclear. OBJECTIVE: We aim to investigate the impact of implemented infectious control strategies on the incidences of influenza, enterovirus infection, and all-cause pneumonia during the COVID-19 pandemic. METHODS: We utilized the electronic database of the Taiwan National Infectious Disease Statistics System and extracted incidences of COVID-19, influenza virus, enterovirus, and all-cause pneumonia. We compared the incidences of these diseases from week 45 of 2016 to week 21 of 2020 and performed linear regression analyses. RESULTS: The first case of COVID-19 in Taiwan was reported in late January 2020 (week 4). Infectious control strategies have been promoted since late January. The influenza virus usually peaks in winter and decreases around week 14. However, a significant decrease in influenza was observed after week 6 of 2020. Regression analyses produced the following results: 2017, R2=0.037; 2018, R2=0.021; 2019, R2=0.046; and 2020, R2=0.599. A dramatic decrease in all-cause pneumonia was also reported (R2 values for 2017-2020 were 0.435, 0.098, 0.352, and 0.82, respectively). Enterovirus had increased by week 18 in 2017-2019, but this was not observed in 2020. CONCLUSIONS: Using this national epidemiological database, we found a significant decrease in cases of influenza, enterovirus, and all-cause pneumonia during the COVID-19 pandemic. Wearing masks, hand hygiene, and social distancing may contribute not only to the prevention of COVID-19 but also to the decline of other respiratory infectious diseases. Further studies are warranted to elucidate the causal relationship.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/prevenção & controle , Coronavirus/patogenicidade , Infecções por Enterovirus/prevenção & controle , Higiene das Mãos/métodos , Controle de Infecções/métodos , Influenza Humana/prevenção & controle , Máscaras/tendências , Pandemias/prevenção & controle , Pneumonia/prevenção & controle , /psicologia , Infecções por Coronavirus/psicologia , Infecções por Enterovirus/epidemiologia , Humanos , Incidência , Influenza Humana/epidemiologia , Pneumonia/epidemiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/psicologia , Estudos Retrospectivos
14.
PLoS One ; 15(8): e0237871, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817720

RESUMO

Streptococcus pneumoniae is a common cause of infectious diseases such as pneumonia and sepsis. Its colonization is thought to be the first step in the development of invasive pneumococcal diseases. This study aimed to investigate pneumococcal colonization patterns in early childhood. A longitudinal birth cohort study was conducted for investigating nasopharyngeal colonized pneumococci at 1, 6, 12, 18, 24, and 36 months of age, particularly focusing on the serotype distribution and antimicrobial susceptibilities. Pneumococcal conjugate vaccine (PCV) effect on nasopharyngeal colonization was also assessed. During 2013-2017, 855 infants were enrolled and a total of 107 isolates were recovered from 95 infants during the first three years of life. In this period, the prevalence of pneumococcal colonization increased, with values ranging from 0.2% (2/834) at 1 month of age to 5.9% (19/323) at 36 months of age. The investigation of serotype revealed that 81.1% (73/90) belonged to the non-PCV13 serotypes-23A, 15A, 15C, and 15B. Moreover, PCV13 serotypes significantly decreased during 2014-2015, when routine PCV13 vaccination was initiated in Taiwan. PCV13 introduction may lead to the reduction in the rates of pneumococcal isolates resistant (R) to penicillin. Under conditional PCV13 vaccination, pneumococcal isolates primarily belonged to non-PCV13 serotypes. This non-PCV13 serotype replacement exhibited lower rates of penicillin R isolates, suggesting that PCV13 administration may reduce the antibiotic-nonsusceptible pneumococcal disease burden and antibiotic use.


Assuntos
Doenças Nasofaríngeas/tratamento farmacológico , Nasofaringe/efeitos dos fármacos , Infecções Pneumocócicas/tratamento farmacológico , Streptococcus pneumoniae/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Doenças Nasofaríngeas/imunologia , Doenças Nasofaríngeas/microbiologia , Doenças Nasofaríngeas/patologia , Nasofaringe/microbiologia , Penicilinas/administração & dosagem , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/microbiologia , Pneumonia/prevenção & controle , Sepse/microbiologia , Sepse/prevenção & controle , Sorogrupo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Taiwan , Vacinas Conjugadas/administração & dosagem
15.
Med Hypotheses ; 143: 110051, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32650197

RESUMO

Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline - might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals - yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium - might also improve therapeutic outcomes in COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Dipiridamol/uso terapêutico , Pandemias , Pentoxifilina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptor A2A de Adenosina/metabolismo , Agonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Suplementos Nutricionais , Fibrinolíticos/uso terapêutico , Humanos , Modelos Biológicos , Pneumonia/etiologia , Pneumonia/prevenção & controle , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trombose/etiologia , Trombose/prevenção & controle , Pesquisa Médica Translacional , Replicação Viral/efeitos dos fármacos
16.
J Dairy Sci ; 103(9): 8130-8142, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32684449

RESUMO

The objective of this study was to determine the effect of partial replacement of whole milk with colostrum on the growth performance and health status of Holstein dairy calves. Neonatal heifer calves (n = 144; 2 d of age; 39.3 ± 0.82 kg of body weight, BW; mean ± SE) were assigned randomly to 3 groups with partial replacement of pasteurized whole milk with pasteurized colostrum at 0 (C0; 0 kg/d of colostrum + 5 kg/d of whole milk), 350 g (C350; 0.350 kg/d of colostrum + 4.650 kg/d of whole milk), or 700 g (C700; 0.700 kg/d of colostrum + 4.300 kg/d of whole milk) for 14 d; there were no refusals of liquid feed. From d 15 onward, the calves were fed with 5 kg/d of pasteurized whole milk, weaned on d 61, and monitored until d 81 of life. Throughout the study, the calves had free access to fresh clean water and calf starter. Partial replacement of whole milk with colostrum increased liquid feed dry matter intake (DMI) but decreased milk DMI; however, intakes of starter DMI, total DMI, metabolizable energy, crude protein, and ether extract were not affected by treatments. Overall, the C700 calves recorded greater weaning weight, final BW, heart girth change, feed efficiency, and average daily gain (ADG). The calves fed milk had a higher chance of having rectal temperature ≥39.4°C and general appearance score ≥2 compared with those receiving colostrum in their milk. Diarrhea was more prevalent in C0 versus C700 calves. The occurrence of pneumonia tended to be higher in milk-fed calves compared with C350 and C700 animals. Colostrum feeding resulted in fewer days with a rectal temperature ≥39.4°C, general appearance ≥2, diarrhea, and pneumonia. We computed Cliff's delta (effect sizes) of the extended colostrum feeding (C350 vs. C0, C700 vs. C0, and C700 vs. C350) on starter and milk DMI, ADG, BW, and feed efficiency. In C350 calves, the effect sizes (Cliff's delta) for milk DMI, ADG, BW, and feed efficiency were positive and small, but negative in C700 calves. Compared with C350 treatment, C700 treatment resulted in greater final BW with moderate effect size. Positive and moderate effects of feeding colostrum (C700 vs. C0) were observed on postweaning ADG and final BW. The findings showed that the inclusion of 700 g of colostrum in 5 kg of milk may be beneficial to the growth and health of dairy calves.


Assuntos
Doenças dos Bovinos/prevenção & controle , Colostro/imunologia , Indústria de Laticínios/métodos , Diarreia/veterinária , Dieta/veterinária , Crescimento/imunologia , Pneumonia/veterinária , Ração Animal/normas , Animais , Animais Recém-Nascidos , Peso Corporal , Bovinos , Diarreia/prevenção & controle , Feminino , Leite , Pasteurização , Pneumonia/prevenção & controle , Gravidez , Distribuição Aleatória , Desmame
17.
Tuberk Toraks ; 68(1): 66-75, 2020 Mar.
Artigo em Turco | MEDLINE | ID: mdl-32718141

RESUMO

Lung cancer remains as the main cause of cancer-related deaths worldwide. Over the last two decades, information about biology and pathogenesis of cancer has increased, immune checkpoint inhibitors (ICIs) have been introduced, and thus a significant period has started in treatment of solid cancers. This review discussed lung cancer in the framework of innovations in treatment, immunotherapy, and multidisciplinary approach to treatment. Non-small cell lung cancer (NSCLC) was the focal point of this article as it is the most frequent lung cancer type and the type of lung cancer which can ideally benefit from ICI treatment due to its characteristics. This review is the first review in Turkish language, which aimed to raise the multidisciplinary awareness about immunotherapy approach in lung cancer treatment in all branches, primarily in chest diseases, and to provide information about its management. Moreover, this review has importance as it presents the remarkable results of recent clinical trials on the use of ICIs in NSCLC treatment. Immunotherapy has initiated a new era in cancer treatment; the specific mechanism of action of ICIs has resulted in a group of some new adverse events, among which pneumonitis is particularly important and when necessary, patients are needed to be consulted with relevant specialties about adverse events. Lung cancer treatment should be planned specific to each patient by considering patient characteristics, histological features, and genetic status and specialty areas of chest diseases, thoracic surgery, medical oncology, radiation oncology, pathology, and radiology should collaborate together for diagnostic evaluation and optimal treatment of a lung cancer patient. Moreover, family physicians may have an important role in early diagnosis of lung cancer and in preventing lung cancer by encouraging their patients regarding tobacco cessation. Moreover, screening studies for lung cancer should be targeted to create awareness in society and for early diagnosis.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia/prevenção & controle
18.
Drug Discov Ther ; 14(3): 151-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669524

RESUMO

Community-acquired pneumonia (CAP) is the third leading contributor to lost disability-adjusted life years worldwide, and this is especially true in the elderly population. In order to reduce the burden of disease, effective management of CAP is crucial to public health in terms of maintaining and promoting the health of the elderly and involves safe drug use, vaccinations, early treatment in the ICU, and health education. Since the long-term mortality of CAP is particularly high in the elderly, biomarkers and a predictive diagnostic model of CAP should be developed in future research.


Assuntos
Antibacterianos/administração & dosagem , Infecções Comunitárias Adquiridas/prevenção & controle , Gerenciamento Clínico , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Atenção , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Humanos , Educação de Pacientes como Assunto/métodos , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia
20.
Int J Infect Dis ; 98: 194-199, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32553718

RESUMO

INTRODUCTION: Community-Acquired Pneumonia (CAP) is one of the most frequent causes of hospital admission in children. Our objective is to measure the impact of the introduction of pneumococcal conjugate vaccines on the hospitalization of previously healthy children due to CAP. METHOD: From 2011 to 2016, a partially retrospective, prospective, and descriptive study was carried out on healthy pediatric patients (3 months-14 years old) with CAP, who required hospital admission. Clinical, epidemiological, and demographic characteristics were collected, and vaccination status was obtained from medical records. RESULTS: A total of 292 cases were included, with a mean age of 33.4 months, 54% males. There was a progressive and significant 42% decrease in the number of admissions each year, without significant changes in the annual percentage of parapneumonic pleural effusion (PPE). Fifty-six percent of patients were immunized with a pneumococcal conjugate vaccine (PCV). The percentage of children who were not vaccinated decreased by 14%, and the coverage with PCV-13 increased by 46%. This revealed a significant increase of PPE in vaccinated patients with PCV-7 (63%) compared with unvaccinated (45%) and with PCV-13 (57%), without association with the presence of severe PPE. Moreover, no significant differences in severity or hospital stay were observed in unvaccinated patients, compared to those who were vaccinated. In >2-year-olds, we observed a significant increase in PPE (59%) compared to 45% in younger children. CONCLUSIONS: The increase in vaccination coverage with PCV-13 resulted in a decrease in hospitalizations due to CAP and PPE. Vaccination with PCV-7 is associated in our sample with an increase in PPE but not with severe PPE nor an increase in the hospital stay. There was an epidemiological shift of severe forms of pneumonia and empyema at later ages (>2 years).


Assuntos
Infecções Comunitárias Adquiridas/terapia , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/terapia , Vacinas Conjugadas/administração & dosagem , Adolescente , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/prevenção & controle , Feminino , Hospitalização , Humanos , Imunização , Lactente , Tempo de Internação , Masculino , Derrame Pleural/microbiologia , Vacinas Pneumocócicas/imunologia , Pneumonia/prevenção & controle , Estudos Prospectivos , Estudos Retrospectivos , Vacinação , Vacinas Conjugadas/imunologia
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