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1.
Thorax ; 78(8): 799-807, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36261273

RESUMO

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is rare, poorly understood, with heterogeneous characteristics resulting in difficult diagnosis. We aimed to systematically review evidence of soluble markers in peripheral blood or bronchoalveolar lavage fluid (BALF) as biomarkers in SSc-ILD. METHOD: Five databases were screened for observational or interventional, peer-reviewed studies in adults published between January 2000 and September 2021 that assessed levels of biomarkers in peripheral blood or BALF of SSc-ILD patients compared with healthy controls. Qualitative assessment was performed using Critical Appraisal Skills Programme (CASP) checklists. Standardised mean difference (SMD) in biomarkers were combined in random-effects meta-analyses where multiple independent studies reported quantitative data. RESULTS: 768 published studies were identified; 38 articles were included in the qualitative synthesis. Thirteen studies were included in the meta-analyses representing three biomarkers: KL6, SP-D and IL-8. Greater IL-8 levels were associated with SSc-ILD in both peripheral blood and BALF, overall SMD 0.88 (95% CI 0.61 to 1.15; I2=1%). Greater levels of SP-D and KL-6 were both estimated in SSc-ILD peripheral blood compared with healthy controls, at an SMD of 1.78 (95% CI 1.50 to 2.17; I2=8%) and 1.66 (95% CI 1.17 to 2.14; I2=76%), respectively. CONCLUSION: We provide robust evidence that KL-6, SP-D and IL-8 have the potential to serve as reliable biomarkers in blood/BALF for supporting the diagnosis of SSc-ILD. However, while several other biomarkers have been proposed, the evidence of their independent value in diagnosis and prognosis is currently lacking and needs further investigation. PROSPERO REGISTRATION NUMBER: CRD42021282452.


Assuntos
Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Adulto , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Interleucina-8 , Proteína D Associada a Surfactante Pulmonar , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Biomarcadores , Pulmão
2.
BMC Health Serv Res ; 20(1): 236, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32192505

RESUMO

BACKGROUND: Surgical site infections (SSIs) are highly prevalent in abdominal surgery despite evidence-based prevention measures. Since guidelines are not self-implementing and SSI-preventive compliance is often insufficient, implementation interventions have been developed to promote compliance. This systematic review aims to identify implementation interventions used in abdominal surgery to prevent SSIs and determine associations with SSI reductions. METHODS: Literature was searched in April 2018 (Medline/PubMed and Web of Science Core Collection). Implementation interventions were classified using the implementation subcategories of the EPOC Taxonomy (Cochrane Review Group Effective Practice and Organisation of Care, EPOC). Additionally, an effectiveness analysis was conducted on the association between the number of implementation interventions, specific compositions thereof, and absolute and relative SSI risk reductions. RESULTS: Forty studies were included. Implementation interventions used most frequently ("top five") were audit and feedback (80% of studies), organizational culture (70%), monitoring the performance of healthcare delivery (65%), reminders (53%), and educational meetings (45%). Twenty-nine studies (72.5%) used a multimodal strategy (≥3 interventions). An effectiveness analysis revealed significant absolute and relative SSI risk reductions. E.g., numerically, the largest absolute risk reduction of 10.8% pertained to thirteen studies using 3-5 interventions (p < .001); however, this was from a higher baseline rate than those with fewer or more interventions. The largest relative risk reduction was 52.4% for studies employing the top five interventions, compared to 43.1% for those not including these. Furthermore, neither the differences in risk reduction between studies with different numbers of implementation interventions (bundle size) nor between studies including the top five interventions (vs. not) were significant. CONCLUSION: In SSI prevention in abdominal surgery, mostly standard bundles of implementation interventions are applied. While an effectiveness analysis of differences in SSI risk reduction by number and type of interventions did not render conclusive results, use of standard interventions such as audit and feedback, organizational culture, monitoring, reminders, and education at least does not seem to represent preventive malpractice. Further research should determine implementation interventions, or bundles thereof, which are most effective in promoting compliance with SSI-preventive measures in abdominal surgery.


Assuntos
Abdome/cirurgia , Controle de Infecções/organização & administração , Infecção da Ferida Cirúrgica/prevenção & controle , Atenção à Saúde , Fidelidade a Diretrizes , Humanos , Cultura Organizacional
3.
Unfallchirurg ; 123(7): 541-546, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31883028

RESUMO

BACKGROUND AND OBJECTIVE: A high level of hand hygiene compliance is the best way to prevent postoperative wound infections and is therefore an important starting point for interventions. Despite different campaigns the hand hygiene compliance of physicians remains to be improved. The aim was to analyze the effect of tailored and innovative interventions on the hand hygiene compliance of physicians. METHODS: At first the hand hygiene compliance of physicians was monitored during their ward rounds at three different wards. Afterwards two different interventions were performed and 6 weeks after each intervention the hand hygiene compliance was monitored again. RESULTS: The hand hygiene compliance of the control group (no intervention) did not change throughout the study. The ward where a small intervention was used showed an increase of hand hygiene compliance. Tailored intervention, however, resulted in a significant improvement of hand hygiene compliance in the ward where it was used. DISCUSSION AND PROSPECTS: Training concerning hand hygiene has to be improved to increase the prevention of infections. Tailored interventions with a high amount of practical relevance are suited to increase the compliance with preventive procedures (e.g. hand hygiene compliance). To improve the infection prevention for physicians in the long term, a firm knowledge about the indications for hand hygiene procedures is needed. This can be ensured by infection control training with a practical focus, small memory aids and permanent support from infection prevention professionals.


Assuntos
Higiene das Mãos , Infecção Hospitalar , Fidelidade a Diretrizes , Desinfecção das Mãos , Humanos , Controle de Infecções
4.
Proc Natl Acad Sci U S A ; 113(26): E3725-34, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27286825

RESUMO

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o-, CFBE41o-) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.


Assuntos
Anti-Inflamatórios/farmacologia , Fibrose Cística/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Lactamas/farmacologia , NF-kappa B/genética , NF-kappa B/imunologia , Quercetina/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Transcriptoma , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia
5.
Med Princ Pract ; 24(4): 301-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25925366

RESUMO

Cystic fibrosis (CF) is a lifelong, inflammatory multi-organ disease and the most common lethal, genetic condition in Caucasian populations, with a median survival rate of 41.5 years. Pulmonary disease, characterized by infective exacerbations, bronchiectasis and increasing airway insufficiency is the most serious manifestation of this disease process, currently responsible for over 80% of CF deaths. Chronic dysregulation of the innate immune and host inflammatory response has been proposed as a mechanism central to this genetic condition, primarily driven by the nuclear factor κB (NF-κB) pathway. Chronic activation of this transcription factor complex leads to the production of pro-inflammatory cytokines and mediators such as IL-6, IL-8 and TNF-α. A20 has been described as a central and inducible negative regulator of NF-κB. This intracellular molecule negatively regulates NF-κB-driven pro-inflammatory signalling upon toll-like receptor activation at the level of TRAF6 activation. Silencing of A20 increases cellular levels of p65 and induces a pro-inflammatory state. We have previously shown that A20 expression positively correlates with lung function (FEV1%) in CF. Despite improvement in survival rates in recent years, advancements in available therapies have been incremental. We demonstrate that the experimental use of naturally occurring plant diterpenes such as gibberellin on lipopolysaccharide-stimulated cell lines reduces IL-8 release in an A20-dependent manner. We discuss how the use of a novel bio-informatics gene expression connectivity-mapping technique to identify small molecule compounds that similarly mimic the action of A20 may lead to the development of new therapeutic approaches capable of reducing chronic airway inflammation in CF.


Assuntos
Fibrose Cística/fisiopatologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Técnicas de Cultura de Células , Mapeamento Cromossômico , Proteínas de Ligação a DNA/metabolismo , Humanos , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fenótipo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/biossíntese
7.
Trends Mol Med ; 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39004548

RESUMO

Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty.

8.
Cells ; 13(14)2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39056787

RESUMO

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts.


Assuntos
Interleucinas , Pele , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Interleucinas/metabolismo , Esclerodermia Difusa/patologia , Esclerodermia Difusa/metabolismo , Esclerodermia Difusa/sangue , Esclerodermia Difusa/genética , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/sangue , Pele/patologia , Pele/metabolismo , Serina-Treonina Quinases TOR/metabolismo
9.
Am J Physiol Lung Cell Mol Physiol ; 304(5): L371-82, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23316065

RESUMO

The innate immune response to bacterial infection is mediated through Toll-like receptors (TLRs), which trigger tightly regulated signaling cascades through transcription factors including NF-κB. LPS activation of TLR4 triggers internalization of the receptor-ligand complex which is directed toward lysosomal degradation or endocytic recycling. Cystic fibrosis (CF) patients display a robust and uncontrolled inflammatory response to bacterial infection, suggesting a defect in regulation. This study examined the intracellular trafficking of TLR4 in CF and non-CF airway epithelial cells following stimulation with LPS. We employed cells lines [16hBE14o-, CFBE41o- (CF), and CFTR-complemented CFBE41o-] and confirmed selected experiments in primary nasal epithelial cells from non-CF controls and CF patients (F508del homozygous). In control cells, TLR4 expression (surface and cytoplasmic) was reduced after LPS stimulation but remained unchanged in CF cells and was accompanied by a heightened inflammatory response 24 h after stimulation. All cells expressed markers of the early (EEA1) and late (Rab7b) endosomes at basal levels. However, only CF cells displayed persistent expression of Rab7b following LPS stimulation. Rab7 variants may directly internalize bacteria to the Golgi for recycling or to the lysosome for degradation. TLR4 colocalized with the lysosomal marker LAMP1 in 16 hBE14o- cells, suggesting that TLR4 is targeted for lysosomal degradation in these cells. However, this colocalization was not observed in CFBE41o- cells, where persistent expression of Rab7 and release of proinflammatory cytokines was detected. Consistent with the apparent inability of CF cells to target TLR4 toward the lysosome for degradation, we observed persistent surface and cytoplasmic expression of this pathogen recognition receptor. This defect may account for the prolonged cycle of chronic inflammation associated with CF.


Assuntos
Brônquios/imunologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Lisossomos/metabolismo , Pseudomonas aeruginosa/imunologia , Mucosa Respiratória/imunologia , Receptor 4 Toll-Like/metabolismo , Brônquios/citologia , Linhagem Celular , Fibrose Cística/patologia , Endossomos/metabolismo , Humanos , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Proteínas de Membrana Lisossomal/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico , Infecções por Pseudomonas/imunologia , Mucosa Respiratória/citologia , Proteínas de Transporte Vesicular/biossíntese , Proteínas rab de Ligação ao GTP/biossíntese , proteínas de unión al GTP Rab7
10.
Eur Respir J ; 41(6): 1315-23, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23018911

RESUMO

A20 is a lipopolysaccharide (LPS)-inducible, cytoplasmic zinc finger protein, which inhibits Toll-like receptor-activated nuclear factor (NF)-κB signalling by deubiquitinating tumour necrosis factor receptor-associated factor (TRAF)-6. The action of A20 is facilitated by complex formation with ring finger protein (RNF)-11, Itch and TAX-1 binding protein-1 (TAX1BP1). This study investigated whether the expression of A20 is altered in the chronically inflamed cystic fibrosis (CF) airway epithelium. Nasal epithelial cells from CF patients (F508del homozygous), non-CF controls and immortalised epithelial cells (16HBE14o- and CFBE41o-) were stimulated with LPS. Cytoplasmic expression of A20 and expression of NF-κB subunits were analysed. Formation of the A20 ubiquitin editing complex was also investigated. In CFBE41o-, peak LPS-induced A20 expression was delayed compared with 16HBE14o- and fell significantly below basal levels 12-24 h after LPS stimulation. This was confirmed in primary CF airway cells. Additionally, a significant inverse relationship between A20 and p65 expression was observed. Inhibitor studies showed that A20 does not undergo proteasomal degradation in CFBE41o-. A20 interacted with TAX1BP1, RNF11 and TRAF6 in 16HBE14o- cells, but these interactions were not observed in CFBE41o-. The expression of A20 is significantly altered in CF, and important interactions with complex members and target proteins are lost, which may contribute to the state of chronic NF-κB-driven inflammation.


Assuntos
Fibrose Cística/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epitélio/metabolismo , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Brônquios/citologia , Linhagem Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Citometria de Fluxo , Humanos , Inflamação , Interleucina-8/metabolismo , Lipopolissacarídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estrutura Terciária de Proteína , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
11.
Unfallchirurgie (Heidelb) ; 126(7): 563-568, 2023 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-35499764

RESUMO

BACKGROUND AND OBJECTIVE OF THE STUDY: In the knowledge that hand hygiene is a key measure in preventing healthcare-associated infections, the WHO recommends direct observation as the gold standard in order to evaluate compliance. High compliance rates when performing surgical hand disinfection imply a high rate of compliance throughout the operating room (OR). Concrete numbers reflecting hand hygiene within the OR are rare, however, which is why our goal was to systematically observe hand hygiene and create tailor-made training solutions in order to improve it. METHODS: A hand hygiene data collection form was used to document compliance observations in the OR in 2017 and 2018. Compliance was monitored in two separate surgical departments. Surgeons and perioperative nurses, as well as anesthesiologists and nurse anesthetists, were observed. In order to test a tailor-made training solution, two separate surgical departments were chosen. To test the effectiveness of the training solution, only one of the two surgical departments received a tailor-made training along with direct feedback from a trained infection control nurse. In the second surgical department, no training intervention took place. RESULTS: More than 1500 indications for hand hygiene were observed in the OR between 2017 and 2018. Overall compliance in the intervention group increased from 40% to 75% during the observation period (p < 0.001). Overall compliance in the control group did not increase significantly (48% to 55%; p = 0.069). DISCUSSION: Given that the compliance rate for surgical hand disinfection is so high, the assumption was that the compliance for routine hand hygiene within the OR would be similar. Within the framework of the feedback talks, it became apparent that the employees were unaware that the "5 moments for hand hygiene" also apply within the OR. The employees were also unaware of what exactly the five indications were.


Assuntos
Infecção Hospitalar , Higiene das Mãos , Humanos , Salas Cirúrgicas , Fidelidade a Diretrizes , Infecção Hospitalar/prevenção & controle , Desinfecção das Mãos
12.
Mol Neurobiol ; 60(7): 3963-3978, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37004607

RESUMO

Post-traumatic stress disorder (PTSD), gaining increasing attention, is a multifaceted psychiatric disorder that occurs following a stressful or traumatic event or series of events. Recently, several studies showed a close relationship between PTSD and neuroinflammation. Neuroinflammation, a defense response of the nervous system, is associated with the activation of neuroimmune cells such as microglia and astrocytes and with changes in inflammatory markers. In this review, we first analyzed the relationship between neuroinflammation and PTSD: the effect of stress-derived activation of the hypothalamic-pituitary-adrenal (HPA) axis on the main immune cells in the brain and the effect of stimulated immune cells in the brain on the HPA axis. We then summarize the alteration of inflammatory markers in brain regions related to PTSD. Astrocytes are neural parenchymal cells that protect neurons by regulating the ionic microenvironment around neurons. Microglia are macrophages of the brain that coordinate the immunological response. Recent studies on these two cell types provided new insight into neuroinflammation in PTSD. These contribute to promoting comprehension of neuroinflammation, which plays a pivotal role in the pathogenesis of PTSD.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/metabolismo , Doenças Neuroinflamatórias , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Encéfalo/metabolismo
13.
Eur Respir J ; 39(6): 1377-84, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22088966

RESUMO

Epidemiological evidence supports a positive relationship between fruit and vegetable (FV) intake, lung function and chronic obstructive pulmonary disease (COPD). Increasing FV intake may attenuate the oxidative stress and inflammation associated with COPD. An exploratory randomised controlled trial to examine the effect of increased consumption of FV on oxidative stress and inflammation in moderate-to-severe COPD was conducted. 81 symptomatically stable patients with a habitually low FV intake (two or fewer portions of FV per day) were randomised to the intervention group (five or more portions of FV per day) or the control group (two or fewer portions of FV per day). Each participant received self-selected weekly home deliveries of FV for 12 weeks. 75 participants completed the intervention. There was a significant between-group change in self-reported FV intake and biomarkers of FV intake (zeaxanthin (p = 0.034) and ß-cryptoxanthin (p = 0.015)), indicating good compliance; post-intervention intakes in intervention and control groups were 6.1 and 1.9 portions of FV per day, respectively. There were no significant changes in biomarkers of airway inflammation (interleukin-8 and myeloperoxidase) and systemic inflammation (C-reactive protein) or airway and systemic oxidative stress (8-isoprostane). This exploratory study demonstrated that patients with moderate-to-severe COPD were able to comply with an intervention to increase FV intake; however, this had no significant effect on airway or systemic oxidative stress and inflammation.


Assuntos
Dieta , Comportamento Alimentar , Frutas , Inflamação/reabilitação , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/reabilitação , Verduras , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Criptoxantinas , Dinoprosta/análogos & derivados , Dinoprosta/urina , Feminino , Humanos , Inflamação/fisiopatologia , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Peroxidase/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Escarro/química , Xantofilas/sangue , Zeaxantinas
14.
Nat Commun ; 13(1): 6358, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289219

RESUMO

In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-ß induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.


Assuntos
Receptores de Adiponectina , Escleroderma Sistêmico , Animais , Camundongos , Bleomicina , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Camundongos Knockout , Receptores de Adiponectina/metabolismo , Escleroderma Sistêmico/metabolismo , Transdução de Sinais/genética , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Ubiquitinas/metabolismo
15.
Am J Respir Cell Mol Biol ; 44(6): 743-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21239605

RESUMO

Persistent activation of NF-κB is central to the pathogenesis of many inflammatory lung disorders, including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in autoimmune and inflammatory disorders, including diabetes and Crohn's disease, but which has received little attention in terms of chronic lung disorders. This review examines the existing body of research on A20 regulation of NF-κB signaling and details the mechanism and regulation of A20 action focusing, where possible, on pulmonary inflammation. A20 and its associated signaling molecules are highlighted as being of potential therapeutic interest for the treatment of inflammatory disorders, and a proposed model of A20 activity in inflammatory lung disease is provided.


Assuntos
Quimiocina CCL20/metabolismo , Regulação da Expressão Gênica , Pneumopatias/metabolismo , NF-kappa B/metabolismo , Animais , Doença Crônica , Células Endoteliais/citologia , Humanos , Inflamação , Pulmão/metabolismo , Pneumopatias/microbiologia , Camundongos , Modelos Biológicos , Estrutura Terciária de Proteína , Transdução de Sinais
16.
J Cyst Fibros ; 20(4): 682-691, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34112603

RESUMO

BACKGROUND: In Cystic Fibrosis (CF) airways, the dehydrated, thick mucus promotes the establishment of persistent polymicrobial infections and drives chronic airways inflammation. This also predisposes the airways to further infections, the vicious, self-perpetuating cycle causing lung damage and progressive lung function decline. The airways are a poly-microbial environment, containing both aerobic and anaerobic bacterial species. Pseudomonas aeruginosa (P. aeruginosa) infections contribute to the excessive inflammatory response in CF, but the role of anaerobic Prevotella spp., frequently found in CF airways, is not known. MATERIALS: We assessed innate immune signalling in CF airway epithelial cells in response to clinical strains of P. histicola, P. nigresens and P. aeruginosa. CFBE41o- cells were infected with P. aeruginosa (MOI 100, 2h) followed by infection with P. histicola or P. nigrescens (MOI 100, 2h). Cells were incubated under anaerobic conditions for the duration of the experiments. RESULTS: Our study shows that P. histicola and P. nigresens can reduce the growth of P. aeruginosa and dampen the inflammatory response in airway epithelial cells. We specifically illustrate that the presence of the investigated Prevotella spp. reduces Toll-like-receptor (TLR)-4, MAPK, NF-κB(p65) signalling and cytokine release (Interleukin (IL)-6, IL-8) in mixed infections. CONCLUSION: Our work, for the first time, strongly indicates a relationship between P. aeruginosa and anaerobic Prevotella spp.. The observed modified NF-κB and MAPK signalling indicates some mechanisms underlying this interaction that could offer a novel therapeutic approach to combat chronic P. aeruginosa infection in people with CF.


Assuntos
Brônquios/citologia , Brônquios/microbiologia , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Células Epiteliais/imunologia , Inflamação/etiologia , Inflamação/microbiologia , Prevotella/fisiologia , Infecções por Pseudomonas/etiologia , Pseudomonas aeruginosa/fisiologia , Mucosa Respiratória/citologia , Mucosa Respiratória/microbiologia , Células Cultivadas , Fibrose Cística/imunologia , Humanos
17.
GMS Hyg Infect Control ; 16: Doc08, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796436

RESUMO

Aim: The basic assumption of this study was that the use of medical non-sterile gloves represents a barrier to correct hand hygiene behaviour. The aim of this study was to examine this assumption and detect reasons for possible incorrect behaviour. Accordingly, the hypothesis is that peri-glove compliance is lower than hand-disinfection compliance. Methods: The study involved the direct observation of the use of non-sterile, single-use medical gloves in three different wards of a university hospital. Nursing staff and physicians were observed. After the observation period, the observed persons received a custom-designed questionnaire in order to test their self-assessment, knowledge as well as structural conditions relating to the use of gloves. The results were evaluated and compared with the observation data. Results: All employees disinfected their hands in 18.6% of cases before and in 65% of cases after the use of non-sterile gloves. Gloves were changed in the event of the indication for hand disinfection/change of gloves in 27.5% of cases. When changing gloves, the employees disinfected their hands in 47.2% of cases. The respondents assessed themselves as being significantly better than the observations revealed. The respondents are aware of the rules about hand disinfection before and after the use of gloves. However, it was less commonly known that gloves are not an absolute barrier to the transmission of bacteria. Conclusion: Non-sterile single-use gloves seem to be a barrier to hand disinfection. Solutions must be found in order to improve peri-glove compliance, in particular with regard to hand disinfection before and during the wearing of gloves. Alongside the mere transfer of knowledge, the use of non-sterile gloves with regard to the current structural conditions in everyday clinical practice should be critically scrutinised, questioned, tested and developed for the users through precise instructions.

18.
Access Microbiol ; 3(10): 000278, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34816094

RESUMO

The in vitro antimicrobial potential of physiologically active diterpenoid plant-derived gibberellins (gibberellic acids; GAs) was tested on microbial pathogens of significance to plant and human health. The racemic enantiomer GA3 produced varying inhibitory effects against a wide range of plant host disease causal agents (phytopathogens) comprising fungi, oomycetes and bacteria. The results showed that GA3 effected either strong growth arrest of phytopathogenic fungi or holistic biocidal effects on oomycete and phytopathogenic fungi at higher concentration (>10-50 mM) and increased hyphal extension growth when the concentration of GA3 was lowered (<10-0.1 mM). When human clinical pathogenic bacteria cohorts were challenged with gibberellin enantiomers, viz GA1, GA4, GA5, GA7, GA9 and GA13 (50 mM), employing Kirby-Bauer disc bioassay methods for assessment of their efficacies, no inhibitory effect was seen with gibberellin enantiomers, viz GA1, GA3, GA5 and GA13, while GA4 inhibited all human clinical bacterial organisms examined, with GA7 and GA9 showing limited activity. The antibiotic effects of enantiomeric diterpenoid phytohormones evinced in our preliminary study raise prospects for further studies to fully examine their potential therapeutic value for human healthcare and their compliance with cytotoxicity and other ethical considerations in the future.

19.
Genes Dis ; 8(3): 287-297, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33997176

RESUMO

The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex molecular interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases associated with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.

20.
Antimicrob Resist Infect Control ; 10(1): 67, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827692

RESUMO

BACKGROUND: Prevention of surgical site infections (SSIs), which due to their long-term consequences are especially critical in orthopedic surgery, entails compliance with over 20 individual measures. However, little is known about the psychosocial determinants of such compliance among orthopedic physicians, which impedes efforts to tailor implementation interventions to improve compliance. Thus, for this professional group, this pilot survey examined psychosocial determinants of self-reported compliance, which have been theoretically derived from the COM-B (Capability, Opportunity, Motivation and Behavior) model. METHODS: In 2019, a cross-sectional survey was conducted in a tertiary care university orthopedic clinic in Hannover, Germany, as a pilot for the WACH-trial ("Wundinfektionen und Antibiotikaverbrauch in der Chirurgie" [Wound Infections and Antibiotics Consumption in Surgery]). Fifty-two physicians participated (38 surgeons, 14 anesthesiologists; response rate: 73.2%). The questionnaire assessed self-reported compliance with 26 SSI preventive measures, and its psychosocial determinants (COM-B). Statistical analyses included descriptive, correlational, and linear multiple regression modeling. RESULTS: Self-reported compliance rates for individual measures varied from 53.8 to 100%, with overall compliance (defined for every participant as the mean of his or her self-reported rates for each individual measure) averaging at 88.9% (surgeons: 90%, anesthesiologists: 85.9%; p = 0.097). Of the components identified in factor analyses of the COM-B items, planning, i.e., self-formulated conditional plans to comply, was the least pronounced (mean = 4.3 on the 7-point Likert scale), while motivation was reported to be the strongest (mean = 6.3). Bi-variately, the overall compliance index co-varied with all four COM-B-components, i.e., capabilities (r = 0.512, p < 0.001), opportunities (r = 0.421, p = 0.002), planning (r = 0.378, p = 0.007), and motivation (r = 0.272, p = 0.051). After mutual adjustment and adjustment for type of physician and the number of measures respondents felt responsible for, the final backward regression model included capabilities (ß = 0.35, p = 0.015) and planning (ß = 0.29, p = 0.041) as COM-B-correlates. CONCLUSION: Though based on a small sample of orthopedic physicians in a single hospital (albeit in conjunction with a high survey response rate), this study found initial evidence for positive correlations between capabilities and planning skills with self-reported SSI preventive compliance in German orthopedic physicians. Analyses of the WACH-trial will further address the role of these factors in promoting SSI preventive compliance in orthopedic surgery. TRIAL REGISTRATION: This survey was conducted as part of the research project WACH ("Wundinfektionen und Antibiotikaverbrauch in der Chirurgie" [Wound Infections and Antibiotic Consumption in Surgery]), which has been registered in the German Clinical Trial Registry ( https://www.drks.de/ ; ID: DRKS00015502).


Assuntos
Fidelidade a Diretrizes/estatística & dados numéricos , Autorrelato , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Anestesiologistas , Estudos Transversais , Feminino , Alemanha , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Cirurgiões Ortopédicos , Médicos , Projetos Piloto , Inquéritos e Questionários , Adulto Jovem
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