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1.
PLoS One ; 15(2): e0229325, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084207

RESUMO

BACKGROUND: Postoperative anaemia is a frequent surgical complication and in contrast to preoperative anaemia has not been validated in relation to mortality, morbidity and its associated health economic effect. Postoperative anaemia can predispose postoperative delirium through impairment of cerebral oxygenation. The aim of this secondary analysis is to investigate the association of postoperative anaemia in accordance with the sex specific World Health Organization definition of anaemia to postoperative delirium and its impact on the duration of hospital stay. METHODS: A secondary analysis of the prospective multicentric observational CESARO-study was conducted. 800 adult patients undergoing elective surgery were enrolled from various operative disciplines across seven hospitals ranging from university hospitals, district general hospitals to specialist clinics of minimally invasive surgery in Germany. Patients were classified as anaemic according to the World Health Organization parameters, setting the haemoglobin level cut off below 12g/dl for females and below 13g/dl for males. Focus of the investigation were patients with acute anaemia. Patients with present preoperative anaemia or missing haemoglobin measurement were excluded from the sample set. Delirium screening was established postoperatively for at least 24 hours and up to three days, applying the validated Nursing Delirium Screening Scale. RESULTS: The initial sample set contained 800 patients of which 183 were suitable for analysis in the study. Ninety out of 183 (49.2%) suffered from postoperative anaemia. Ten out of 93 (10.9%) patients without postoperative anaemia developed a postoperative delirium. In the group with postoperative anaemia, 28 (38.4%) out of 90 patients suffered from postoperative delirium (odds ratio 3.949, 95% confidence interval, (1.358-11.480)) after adjustment for NYHA-stadium, severity of surgery, cutting/suture time, duration of anaesthesia, transfusion of packed red cells and sedation status with Richmond Agitation Scale after surgery. Additionally, patients who suffered from postoperative anaemia showed a significantly longer duration of hospitalisation (7.75 vs. 12.42 days, odds ratio = 1.186, 95% confidence interval, 1.083-1.299, after adjustments). CONCLUSION: The study results reveal that postoperative anaemia is not only a frequent postsurgical complication with an incidence probability of almost 50%, but could also be associated with a postoperative delirium and a prolonged hospitalisation.

2.
J Clin Anesth ; 61: 109632, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31668693

RESUMO

BACKGROUND: Postoperative delirium (POD) is a common complication after surgery. OBJECTIVE: We sought to determine the association between preoperative anticholinergic load calculated using the anticholinergic drug scale (ADS) and POD in cancer patients over 65 years of age. DESIGN: A retrospective sub-investigation of a randomised controlled interventional trial. SETTING: Two tertiary university hospitals. PATIENTS: Overall, patients aged 65 years and older scheduled for surgical treatment of gastrointestinary, genitourinary or gynaecological cancers. MAIN OUTCOME MEASURES: The primary outcome was the interaction between anticholinergic drug scale and occurrence of postoperative delirium. Patient clinical parameters and ADS scores were assessed preoperatively. POD screening was conducted for a total of 7 days following surgery using validated measures. Independent associations between ADS and POD were assessed using multivariate logistical regression analyses. RESULTS: A total of 651 patients (mean age, 71.8 years; 68.5% males) were included. Of those, 66 patients (10.1%) developed POD. The ADS score was independently associated with the occurrence of POD (higher ADS per point OR 1.496; 95% CI 1.09-2.05; p = 0.01). Additionally, age (per year OR 1.06; CI 95% CI 1.01-1.11; p = 0.03) and ASA state (OR 2.16; 95% CI 1.22-3.83; p = 0.01), as well as stay on ICU (yes vs. no OR 2.8; 95% CI 1.57-4.998; p < 0.01), were independently associated with POD. CONCLUSIONS: ADS assessment according to chronic medication use is a cost-effective, non-invasive method of identifying elderly cancer patients at risk for POD. TRIAL REGISTRY: www.clinicaltrials.gov. Identifier NCT01278537. Ethics: IRB of Charité University-Medicine Berlin, Germany; EA2/241/08.

3.
Acta Anaesthesiol Scand ; 64(4): 494-500, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31883373

RESUMO

BACKGROUND: Postoperative delirium (POD) is a severe brain dysfunction. Although data indicate a high relevance, no survey has investigated the routine practice to monitor delirium outside the ICU setting after surgery. Prior to publishing of the new European Society of Anaesthesiology (ESA) guidelines on POD, an international survey was conducted to assess current practice. METHODS: European Society of Anaesthesiology-endorsed online survey; Trial Registration: NCT-identifier: 02513537. RESULTS: In total, 566 respondents from 62 countries accessed, and 564 (99.6%) completed the survey (completion rate). Overall, 385 (68%) of the respondents reported that delirium is either "very relevant" or "relevant" for their daily clinical practice. In all, 38 (7%) of the respondents routinely monitor for delirium in >50% of all patients. Asked on the monitoring time point, more than half (n = 308, 55%) indicated to screen before or at recovery room discharge, 235 (42%) up to the first postoperative day, 143 (25%) up to 3 days, and 77 (14%) up to 5 postoperative days. Although there is a lack of long-term monitoring, nearly all respondents (n = 530, 94%) reported to treat delirium. Availability of EEG/EMG-based monitoring to assess the depth of anaesthesia was high in the study group (n = 547, 97%) and was used by more than one-third of the respondents to reduce risk of burst suppression (n = 189, 34%). CONCLUSION: Although delirium is perceived as a relevant condition among anaesthesiologists, there is a high demand for implementing monitoring strategies after publishing of the POD Guideline. The survey shows that tools necessary for POD Guideline implementation are available in the centres represented by the respondents.

4.
Crit Care Med ; 47(11): e911-e918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31567350

RESUMO

OBJECTIVES: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. DESIGN: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. SETTING: Research laboratory. SUBJECTS: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. INTERVENTION: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. MEASUREMENTS AND MAIN RESULTS: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated CONCLUSIONS:: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

5.
Ann Intensive Care ; 9(1): 100, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31486927

RESUMO

BACKGROUND: Serum potassium concentrations are commonly between 3.5 and 5.0 mmol/l. Standardised protocols for potassium range and supplementation in the ICU are lacking. The purpose of this retrospective analysis of ICU patients was to investigate potassium concentrations, variability and supplementation, and their association with in-hospital mortality. METHODS: ICU patients ≥ 18 years, with ≥ 2 serum potassium values, treated at the Charité - Universitätsmedizin Berlin between 2006 and 2018 were eligible for inclusion. We categorised into groups of mean potassium concentrations: < 3.0, 3.0-3.5, > 3.5-4.0, > 4.0-4.5, > 4.5-5.0, > 5.0-5.5, > 5.5 mmol/l and potassium variability: 1st, 2nd and ≥ 3rd standard deviation (SD). We analysed the association between the particular groups and in-hospital mortality and performed binary logistic regression analysis. Survival curves were performed according to Kaplan-Meier and tested by Log-Rank. In a subanalysis, the association between potassium supplementation and in-hospital mortality was investigated. RESULTS: In 53,248 ICU patients with 1,337,742 potassium values, the lowest mortality (3.7%) was observed in patients with mean potassium concentrations between > 3.5 and 4.0 mmol/l and a low potassium variability within the 1st SD. Binary logistic regression confirmed these results. In a subanalysis of 22,406 ICU patients (ICU admission: 2013-2018), 12,892 (57.5%) received oral and/or intravenous potassium supplementation. Potassium supplementation was associated with an increase in in-hospital mortality in potassium categories from > 3.5 to 4.5 mmol/l and in the 1st, 2nd and ≥ 3rd SD (p < 0.001 each). CONCLUSIONS: ICU patients may benefit from a target range between 3.5 and 4.0 mmol/l and a minimal potassium variability. Clear potassium target ranges have to be determined. Criteria for widely applied potassium supplementation should be critically discussed. Trial registration German Clinical Trials Register, DRKS00016411. Retrospectively registered 11 January 2019, http://www.drks.de/DRKS00016411.

6.
Sci Rep ; 9(1): 11343, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383903

RESUMO

Frailty is a common syndrome in older individuals that is associated with poor cognitive outcome. The underlying brain correlates of frailty are unclear. The aim of this study was to investigate the association between frailty and MRI features of cerebral small vessel disease in a group of non-demented older individuals. We included 170 participants who were classified as frail (n = 30), pre-frail (n = 85) or non-frail (n = 55). The association of frailty and white matter hyperintensity volume and shape features, lacunar infarcts and cerebral perfusion was investigated by regression analyses adjusted for age and sex. Frail and pre-frail participants were older, more often female and showed higher white matter hyperintensity volume (0.69 [95%-CI 0.08 to 1.31], p = 0.03 respectively 0.43 [95%-CI: 0.04 to 0.82], p = 0.03) compared to non-frail participants. Frail participants showed a non-significant trend, and pre-frail participants showed a more complex shape of white matter hyperintensities (concavity index: 0.04 [95%-CI: 0.03 to 0.08], p = 0.03; fractal dimensions: 0.07 [95%-CI: 0.00 to 0.15], p = 0.05) compared to non-frail participants. No between group differences were found in gray matter perfusion or in the presence of lacunar infarcts. In conclusion, increased white matter hyperintensity volume and a more complex white matter hyperintensity shape may be structural brain correlates of the frailty phenotype.

7.
Eur J Anaesthesiol ; 36(9): 683-687, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306183

RESUMO

BACKGROUND: Recent guidelines on postoperative delirium (POD) recommend POD screening in all patients, using a validated tool, starting in the recovery room. An operationalisation of the Confusion Assessment Method (CAM) criteria, the 3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM), has been developed for use in general medical units. OBJECTIVES: The aim of this study was to evaluate 3D-CAM performance in an adult patient population to detect POD in the recovery room. DESIGN: A prospective diagnostic study. SETTING: Recovery room of a tertiary care university hospital in Berlin, Germany, in 2017. PATIENTS: Patients at least 18 years of age undergoing elective surgery. MAIN OUTCOME MEASURES: Patients were subjected to evaluation by blinded investigators using the 3D-CAM and the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5, reference standard). Sensitivity, specificity and positive predictive value (PPV) and negative predictive value (NPV) were analysed for 3D-CAM, in addition to test-retest and inter-rater reliability analyses. RESULTS: Sixteen out of 176 patients (9.1%) developed POD. The 3D-CAM demonstrated strong test performance (specificity 0.88, sensitivity 1.0, area under the curve 0.94, PPV 0.44 and NPV 1.0), with a test-retest reliability of 90% (n = 10) and inter-rater reliability of 80% (n = 10). CONCLUSION: In this diagnostic study, 3D-CAM showed strong performance for detection of POD in the recovery room. Due to the low training requirements, fast application and high sensitivity, it might be particularly appropriate for clinical staff with limited experience in the assessment of POD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02992717.

9.
J Cachexia Sarcopenia Muscle ; 10(4): 734-747, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31016887

RESUMO

BACKGROUND: Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)-cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high-risk ICU-acquired weakness cohort. METHODS: Fifty patients with a SOFA score ≥9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole-body vibration in addition to early protocol-based physiotherapy (intervention) or early protocol-based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow-up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol-based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU-acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier. RESULTS: ICU-acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median [IQR]: CPP 3.3 [3.0-4.3]; control 3.0 [2.7-3.4]; intervention 3.0 [2.1-3.8]; P > 0.05 for all), ICU discharge (MRC median [IQR]: CPP 3.8 [3.4-4.4]; control 3.9 [3.3-4.0]; intervention 3.6 [2.8-4.0]; P > 0.05 for all), and 12 month follow-up (MRC median [IQR]: control 5.0 [4.3-5.0]; intervention 4.8 [4.3-5.0]; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross-sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up-regulated gene expression for myosin heavy chains (fold change median [IQR]: MYH1 2.3 [1.1-2.7]; MYH2 0.7 [0.2-1.8]; MYH4 5.1 [2.2-15.3]) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32. CONCLUSIONS: In our patients with sepsis syndrome at high risk for ICU-acquired weakness muscle activating measures in addition to early protocol-based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow-up. Yet it prevented muscle atrophy.

10.
Minerva Anestesiol ; 85(6): 617-624, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30665281

RESUMO

BACKGROUND: Emergence delirium (ED) is an important postanesthetic complication in children. Although it has been thoroughly studied, data on frequency, predictive factors, and therapy of this phenomenon are inconclusive. In this study, we seek to obtain a better understanding of the frequency of ED and different therapeutic approaches, making use of the large amount of patients in our university hospital. METHODS: After approval by the local ethics committee, patients aged zero to 13 years, who were treated in the post anesthesia care of our hospital, were investigated in this observational study. ED was diagnosed on basis of a clinical evaluation as well as with the Pediatric Anesthesia Emergence Delirium (PAED) Scale. RESULTS: In 86 of 821 patients a PAED-Score≥10 and therefore an ED was detected (10.5%). Based on clinical assessment by the PACU staff only 5.7% experienced an ED. Age

11.
Eur J Anaesthesiol ; 36(2): 114-122, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30431498

RESUMO

BACKGROUND: The cholinergic system is considered to play a key role in the development of postoperative delirium (POD), which is a common complication after surgery. OBJECTIVES: To determine whether peri-operative acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are associated with the development of POD in in-hospital surgical patients, and raise hypotheses on cholinergic regulatory mechanisms in POD. DESIGN: A prospective multicentre observational study by the Peripheral Cholinesterase-activity on Neurocognitive Dysfunctions in Surgical Patients (CESARO) study group. SETTING: Nine German hospitals. PATIENTS: Patients of at least 18 years of age scheduled for inpatient elective surgery for a variety of surgical procedures. A total of 650 patients (mean age 61.5 years, 52.8% male) were included. METHODS: Clinical variables, and peripheral AChE and BuChE activities, were assessed throughout the peri-operative period using bedside point-of-care measurements (one pre-operative and two postoperative measurements). POD screening was conducted postoperatively for at least 24 h and up to the third postoperative day using a validated screening tool (nursing delirium screening scale). RESULTS: In all, 179 patients (27.5%) developed POD within the early postoperative phase. There was a lower BuChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.07, P = 0.091), on postoperative day 1 (Cohen's r = 0.12, P = 0.003) and on postoperative day 2 (Cohen's r = 0.12, P = 0.002). In contrast, there was a significantly higher AChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.10, P = 0.012), on postoperative day 1 (Cohen's r = 0.11, P = 0.004) and on postoperative day 2 (Cohen's r = 0.13, P = 0.002). After adjusting for covariates in multiple logistic regression, a significant association between both BuChE and AChE activities and POD was not found. However, in the multivariable analysis using the Generalized Estimating Equation, cholinesterase activities showed that a decrease of BuChE activity by 100 U L increased the risk of a delirium by approximately 2.1% (95% CI 1.6 to 2.8%) and for each 1 U g of haemoglobin increase in AChE activity, there was a 1.4% (95% CI 0.6 to 2.2%) increased risk of POD. CONCLUSION: Peri-operative peripheral cholinesterase activities may be related to the development of POD, but the clinical implications remain unclear. Further studies, in homogeneous patient groups with a strict protocol for measurement time points, are needed to investigate the relationship between cholinesterase activities and POD. TRIAL REGISTRATION: www.clinicaltrials.gov. Identifier NCT01964274.


Assuntos
Acetilcolinesterase/sangue , Butirilcolinesterase/sangue , Delírio/sangue , Complicações Pós-Operatórias/sangue , Biomarcadores/sangue , Estudos de Coortes , Delírio/diagnóstico , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Estudos Prospectivos , Fatores de Risco
12.
Eur J Anaesthesiol ; 35(12): 929-936, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30113351

RESUMO

BACKGROUND: Epileptiform discharges frequently occur in children during induction of anaesthesia. However, studies analysing the impact of epileptiform discharges on postoperative emergence delirium in children are still scarce. The aim of this study is to correlate the incidence of epileptiform activity during anaesthesia induction with the occurrence of emergence delirium during stay in the recovery room. OBJECTIVES: Prospective, observational cohort study in children 0.5 to 8 years old undergoing planned surgery. Bifrontal electroencephalogram electrodes were placed before induction of anaesthesia. Visual electroencephalogram analysis was performed from start of anaesthetic agent administration until intubation with regard to epileptiform patterns: rhythmic polyspikes; periodic epileptiform discharges; delta with spikes; and suppression with spikes. Emergence delirium was assessed during stay in the recovery room using the Pediatric Assessment of Emergence Delirium Score. DESIGN: Prospective, observational cohort study. SETTING: University hospital - Germany/Berlin. Children were included between September 2015 and February 2017. PATIENTS: A total of 62 Children, aged 0.5 to 8 years old undergoing planned surgery were included. MAIN OUTCOME MEASURES: Primary outcome was emergence delirium. Secondary outcomes, peri-operative Electroencephalography (EEG) data analysis. The presented study analysed an association between emergence delirium and the occurrence of epileptiform discharges during anaesthesia induction. RESULTS: A total of 43.5% of the children developed emergence delirium and 56.5% did not. Epileptiform discharges were observed more often in children developing emergence delirium (63%) compared with children not developing emergence delirium (43%). But only the occurrence of interictal spike events - such as rhythmic polyspikes; periodic epileptiform discharges and delta with spikes - were significantly related to emergence delirium (emergence delirium-group 48% vs. nonemergence delirium-group 14%, OR = 5.6 [95% CI: 1.7 to 18.7]; P = 0.004). CONCLUSION: Emergence delirium in children is significantly related to interictal spike events occurring during induction of anaesthesia. CLINICAL TRIAL: NCT02481999.


Assuntos
Anestesia Geral/tendências , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Eletroencefalografia/tendências , Delírio do Despertar/fisiopatologia , Epilepsia/fisiopatologia , Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/efeitos dos fármacos , Delírio do Despertar/induzido quimicamente , Delírio do Despertar/diagnóstico , Epilepsia/induzido quimicamente , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
13.
Int J Behav Med ; 25(6): 658-668, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30105602

RESUMO

PURPOSE: The interrelated associations of social relationship factors, depression, and outcomes of surgical patients are yet unexplored. The purpose of this study was to investigate whether depression mediates effects of general social support, loneliness, and living alone on hospital length of stay (LOS) of 2487 patients from diverse surgical fields. METHOD: Social relationship factors and depression were assessed prior to surgery. The PROCESS macro for SPSS was used to conduct three simple mediation models that tested the indirect effects of social relationship factors on LOS mediated through depression. The models were adjusted for age, gender, preoperative physical health, surgical field, severity of medical comorbidity, and extent of surgical procedure. RESULTS: Social support and loneliness had significant indirect effects on LOS that were statistically mediated by preoperative depression. Lower social support and the feeling of loneliness were considerably related to higher depression which predicted longer LOS. While social support and loneliness had no direct effects on LOS, there was a small significant direct association of living alone with shorter LOS. CONCLUSION: Data suggest that social support and loneliness are indirectly related with surgical outcomes by an association with depression which in turn is related to worse outcomes. TRIAL REGISTRATION: NCT01357694.


Assuntos
Depressão/epidemiologia , Solidão/psicologia , Apoio Social , Adulto , Comorbidade , Feminino , Hospitais , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
14.
Int J Med Sci ; 15(7): 682-688, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910672

RESUMO

Background: Chronic alcohol consumption is a major cause of liver injury. However, the molecular mechanisms by which alcohol impairs hepatocellular function and induces cell death remain unclear. Macroautophagy (hereafter called 'autophagy') is a degradation pathway involved in the survival or death of cells during conditions of cellular stress. This study examines the effect of chronic alcohol consumption on hepatocellular autophagy in an animal model. Methods: During a 12-week period male Wistar rats were fed a Lieber-DeCarli diet containing 5% alcohol (EtOH group; n=10), or an isocaloric diet (control group; n=10). Hepatic expression of key regulatory autophagy proteins (e.g. Beclin-1, ATG-3, ATG-5, p62/SQSTM1 and LC3) were detected by real-time polymerase chain reaction and Western blot analysis. Markers of cellular stress and apoptotic cell death (e.g. HO-1, caspase-3, PARP-1 and Bcl-2) were determined, and levels of reduced and oxidized glutathione were measured. Results: Chronic alcohol consumption caused cellular and oxidative stress in the liver. Transcriptional and translational expression of Beclin-1 and ATG-5 was significantly impaired. The protein expression of LC3-I and LC3-II was significantly increased, while the ratio of LC3I/II remained unchanged in the EtOH group compared with controls. Hepatocellular expression of p62/SQSTM1 and markers of apoptotic cell death (such as cleaved caspase-3 and cleaved PARP-1) were significantly increased in the EtOH group indicating a disrupted autophagic flux and increased rate of apoptosis in the liver. Conclusions: In this model, chronic alcohol consumption impaired hepatocellular autophagy and induced apoptotic cell death. It appears that changes in autophagy might contribute to alcohol-induced structural and functional hepatocellular injury.


Assuntos
Alcoolismo/fisiopatologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Alemanha , Fígado/patologia , Masculino , Ratos , Ratos Wistar
15.
J Neuroimmune Pharmacol ; 13(3): 383-395, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29790105

RESUMO

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.


Assuntos
Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Lipopolissacarídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fisostigmina/farmacologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/biossíntese , Proteína Beclina-1/metabolismo , Inflamação/genética , Inflamação/patologia , Inflamação/psicologia , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Peptídeo Sintases/biossíntese , Período Pós-Operatório , Ratos , Ratos Wistar , Proteína Sequestossoma-1/biossíntese
16.
J Inflamm Res ; 11: 169-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29750051

RESUMO

Purpose: Although the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1ß, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema. Conclusion: In this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange.

17.
BMC Psychiatry ; 17(1): 417, 2017 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-29284443

RESUMO

BACKGROUND: Readiness to change is a pivotal construct for psychotherapy research and a major target of motivational interventions. Our primary objective was to examine whether pre-treatment readiness to change moderated therapy effects of Bridging Intervention in Anesthesiology (BRIA), an innovative psychotherapy approach for surgical patients. This stepped care program aims at motivating and supporting surgical patients with mental disorders to engage in psychosocial mental health care. METHODS: The major steps of BRIA are two motivational interventions with different intensity. The first step of the program consists of preoperative computer-assisted psychosocial self-assessment including screening for psychological distress and automatically composed computerized brief written advice (BWA). In the second step, patients participate in postoperative psychotherapy sessions combining motivational interviewing with cognitive behavioural therapy (BRIA psychotherapy sessions). We performed regression-based moderator analyses on data from a recent randomized controlled trial published by our research group. The sample comprised 220 surgical patients with diverse comorbid mental disorders according to ICD-10. The most frequent disorders were mood, anxiety, substance use and adjustment disorders. The patients had a mean age of 43.31 years, and 60.90% were women. In a regression model adjusted for pre-treatment psychological distress, we investigated whether readiness to change moderated outcome differences between (1) the BRIA psychotherapy sessions and (2) no psychotherapy / BWA only. RESULTS: Multiple regression analyses showed that readiness to change moderated treatment effects regarding the primary outcomes "Participation in psychosocial mental health care options at month 6" (p = 0.03) and "Having approached psychosocial mental health care options at month 6" (p = 0.048) but not regarding the secondary outcome "Change of general psychological distress between baseline assessment and month 6" (p = 0.329). Probing the moderation effect with the Johnson-Neyman technique revealed that BRIA psychotherapy sessions were superior to BWA in patients with low to moderate readiness, but not in those with high readiness. CONCLUSIONS: Readiness to change may act as moderator of the efficacy of psychosocial therapy. Combinations of motivational interviewing and cognitive behavioural therapy may be effective particularly in patients with a variety of mental disorders and low readiness to change. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01357694.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtornos Mentais/terapia , Entrevista Motivacional/métodos , Cuidados Pré-Operatórios/métodos , Psicoterapia Breve/métodos , Adulto , Feminino , Humanos , Masculino , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Motivação , Análise de Regressão , Procedimentos Cirúrgicos Operatórios/psicologia , Resultado do Tratamento
18.
Lancet ; 390(10110): 2345-2346, 2017 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-29185431
20.
Int J Mol Sci ; 18(9)2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28832497

RESUMO

During surgery or infection, peripheral inflammation can lead to neuroinflammation, which is associated with cognitive impairment, neurodegeneration, and several neurodegenerative diseases. Dexmedetomidine, an α-2-adrenoceptor agonist, is known to exert anti-inflammatory and neuroprotective properties and reduces the incidence of postoperative cognitive impairments. However, on the whole the molecular mechanisms are poorly understood. This study aims to explore whether dexmedetomidine influences microRNAs (miRNAs) in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Adult Wistar rats were injected with 1 mg/kg LPS intraperitoneal (i.p.) in the presence or absence of 5 µg/kg dexmedetomidine. After 6 h, 24 h, and 7 days, gene expressions of interleukin 1-ß (IL1-ß), tumor necrosis factor-α (TNF-α), and microRNA expressions of miR 124, 132, 134, and 155 were measured in the hippocampus, cortex, and plasma. Dexmedetomidine decreased the LPS-induced neuroinflammation in the hippocampus and cortex via significant reduction of the IL1-ß and TNF-α gene expressions after 24 h. Moreover, the LPS-mediated increased expressions of miR 124, 132, 134, and 155 were significantly decreased after dexmedetomidine treatment in both brain regions. In plasma, dexmedetomidine significantly reduced LPS-induced miR 155 after 6 h. Furthermore, there is evidence that miR 132 and 134 may be suitable as potential biomarkers for the detection of neuroinflammation.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anti-Inflamatórios/farmacologia , Encéfalo/metabolismo , Dexmedetomidina/farmacologia , MicroRNAs/genética , Animais , Encéfalo/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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