Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.

Extracellular Vesicles as Markers of Liver Function: Optimized Workflow for Biomarker Identification in Liver Disease.

Liver diseases represent a significant global health burden, necessitating the development of reliable biomarkers for early detection, prognosis, and therapeutic monitoring. Extracellular vesicles (EVs) have emerged as promising candidates for liver disease biomarkers due to their unique cargo composition, stability, and accessibility in various biological fluids. In this study, we present an optimized workflow for the identification of EVs-based biomarkers in liver disease, encompassing EVs isolation, characterization, cargo analysis, and biomarker validation. Here we show that the levels of microRNAs miR-10a, miR-21, miR-142-3p, miR-150, and miR-223 were different among EVs isolated from patients with nonalcoholic fatty liver disease and autoimmune hepatitis. In addition, IL2, IL8, and interferon-gamma were found to be increased in EVs isolated from patients with cholangiocarcinoma compared with healthy controls. By implementing this optimized workflow, researchers and clinicians can improve the identification and utilization of EVs-based biomarkers, ultimately enhancing liver disease diagnosis, prognosis, and personalized treatment strategies.

Changes in Therapy and Outcome of Patients Requiring Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) is related with poor outcome, especially in Germany. We aimed to analyze whether changes in vv-ECMO therapy during the pandemic were observed and lead to changes in the outcome of vv-ECMO patients. METHODS: All patients undergoing vv-ECMO support for COVID-19 between 2020 and 2021 in a single center (n = 75) were retrospectively analyzed. Weaning from vv-ECMO and in-hospital mortality were defined as primary and peri-interventional adverse events as secondary endpoints of the study. RESULTS: During the study period, four infective waves were observed in Germany. Patients were assigned correspondingly to four study groups: ECMO implantation between March 2020 and September 2020: first wave (n = 11); October 2020 to February 2021: second wave (n = 23); March 2021 to July 2021: third wave (n = 25); and August 2021 to December 2021: fourth wave (n = 20). Preferred cannulation technique changed within the second wave from femoro-femoral to femoro-jugular access (p < 0.01) and awake ECMO was implemented. Mean ECMO run time increased by more than 300% from 10.9 ± 9.6 (first wave) to 44.9 ± 47.0 days (fourth wave). Weaning of patients was achieved in less than 20% in the first wave but increased to approximately 40% since the second one. Furthermore, we observed a continuous numerically decrease of in-hospital mortality from 81.8 to 57.9% (p = 0.61). CONCLUSION: Preference for femoro-jugular cannulation and awake ECMO combined with preexisting expertise and patient selection are considered to be associated with increased duration of ECMO support and numerically improved ECMO weaning and in-hospital mortality.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model.

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10-15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

Specialist Palliative Care Consultations in COVID-19 Patients in the ICU-A Retrospective Analysis of Patient Characteristics and Symptoms at a German University Hospital.

COVID-19 patients who may require invasive therapeutic procedures such as extracorporeal membrane oxygenation (ECMO) have high symptom burden and in-hospital mortality. In addition, awake patients on ECMO are new in the intensive care unit (ICU) setting. Inpatient specialist palliative care (sPC) provides support such as symptom control on a physical, psychosocial and spiritual level. The field of sPC in COVID-19 patients is still new and important to investigate. We aim to analyze sPC of COVID-19 patients in the ICU with regard to patient characteristics and symptoms from a palliative care perspective. We conducted a retrospective analysis (03/2020-04/2021) and identified 51 ICU patients receiving sPC. The statistical analysis included descriptive statistics and comparisons of symptoms. The first sPC contact of patients (mean age 69.5 years, 62.7% male) was around 14 days after COVID-19 confirmation, and 43% were treated with ECMO therapy. The baseline symptom burden was high with a focus on weakness (100%), tiredness (98%), dyspnea (96%) and family burden (92%). The symptom intensity significantly decreased during the time period of sPC and COVID-19 treatment (t(99) = 3.119, p = 0.003, d = 0.437). These results help intensivists and sPC clinicians to identify symptoms and the need for sPC in COVID-19 patients. However, studies with prospective and controlled designs need to follow.

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study.

BACKGROUND: A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. METHODS: In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. RESULTS: Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). CONCLUSIONS: Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

[Venovenous extracorporeal membrane oxygenation for COVID-19]. / Venovenöse extrakorporale Membranoxygenierung bei COVID-19: Erkenntnisse eines Zentrums aus 96 konsekutiven Fällen.

Background: Since the beginning of the COVID-19 pandemic global health systems are confronted with a large number of unknown problems. Venovenous (vv) extracorporeal membrane oxygenation (ECMO) in cases of therapy refractive ARDS often represents a last resort treatment. To improve the health care it is necessary to identify possible influencing factors. Objective: This analysis presents the findings of an ECMO centre and aims to identify potential factors with an impact on vv-ECMO therapy in cases of COVID-19. Material and methods: Between 03/2020 and 01/2022 n = 96 patients were treated with vv-ECMO in cases of a COVID-19 infection in our center. A retrospective analysis of demographic and health-specific data took place. The patients with fatal treatment outcome (L-group, n = 62) were compared to the surviving patients (Ü-group, n = 34). Results: Overall n = 34 (35%) of the patients survived the hospital stay. The patients with a fatal treatment outcome had an average age of 56.7 ± 9.5 years compared to the average age of the surviving patients of 47.9 ± 12.9 years. There were n = 72 (75%) males and n = 24 (25%) females among the treated patients, n = 51 (82.3%) of the deceased patients were male and n = 11 (17.7%) were female. The prevalence of pre-existing illnesses like COPD, diabetes mellitus, cardiovascular diseases and chronic renal insufficiency had shown no significant difference between both groups. Also, in relation to the presence of arterial hypertension and obesity we could not prove a negative influence on the treatment outcome. A nicotine abuse in the patient history showed a negative tendency. The most common reasons for the death of patients were respiratory failure, neurological injury, multiorgan failure and sepsis. Conclusion: The use of vv-ECMO in cases of therapy resistant ARDS in COVID-19 still correlates with a high mortality and as such should only be considered as a last resort of intensive care treatment.According to our expectations we could notice better therapy results for younger patients as well as for women in our patient database. In addition, for most comorbidities we could not prove any negative influence on the therapy outcome. This knowledge could help to identify future high-risk patients.

[ECMO cannulation for COVID-19]. / ECMO-Kanülierung bei COVID-19: Venovenöse extrakorporale Membranoxygenierung bei COVID-19: Einfluss der Kanülierungsstrategie auf das Therapieergebnis.

Background: The novel coronavirus disease 2019 (COVID-19) can cause a severe and therapy-refractory acute respiratory distress syndrome. Temporary mechanical assistance by veno-venous extracorporeal membrane oxygenation (v.v.-EMCO) is a well-established supportive therapy, but is still associated with a high mortality. Objective: This work aimed to identify potential effects of the ECMO cannulation strategy on the outcome in COVID-19 patients. Material and methods: All patients who were treated in a single center between March 2020 and November 2021 for COVID-19-related ARDS (n = 75) were prospectively entered into an institutional database. The patients were assigned into two groups with respect to the ECMO cannulation (femorofemoral: n = 20, femorojugular: n = 55) and the outcome was retrospectively analyzed. Results: We observed severe therapy-related adverse events in both groups in more than 70% of patients with sepsis being the most common (> 50% each). The outcome (successful ECMO weaning, in-hospital death, 6­month survival) was comparable in both groups. In-hospital mortality was about 70% each; however, the duration of event-free ECMO support seemed to be prolonged in the femorojugular group. Conclusion: Regardless of the support duration, v.v.-ECMO therapy for COVID-19 is associated with high mortality rates. The cannulation strategy did not impact on the outcome; however, femorojugular cannulation might prolong the event-free support duration and facilitate the mobilization of the patients during ECMO support.

Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129.

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.

Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany.

BACKGROUND: Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants. METHODS: After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration. FINDINGS: After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution - known to confer immune escape - was detected at the time of viral rebound but not before bamlanivimab treatment. INTERPRETATION: Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies. FUNDING: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.

Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.

This case of secondary sclerosing cholangitis (SSC-CIP) emphasizes the need to provide follow-up care for patients that have recovered from COVID-19 in order to understand the complexity of SARS-CoV-2 associated sequela.

Prevalence of SARS-COV-2 positivity in 516 German intensive care and emergency physicians studied by seroprevalence of antibodies National Covid Survey Germany (NAT-COV-SURV).

Healthcare personnel are at risk to aquire the corona virus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the prevalence of SARS-CoV-2 antibodies and positive nasopharyngeal reverse transcriptase polymerase-chain reaction (RT-PCR) tests in German intensive care and emergency physicians. Physicians attending intensive care and emergency medicine training courses between June 16th and July 2nd 2020 answered a questionnaire and were screened for SARS-CoV-2 antibodies via automated electrochemiluminiscence immunoassay. We recruited 516 physicans from all parts of Germany, 445/516 (86%) worked in high risk areas, and 379/516 (73%) had treated patients with COVID-19. The overall positive rate was 18/516 (3.5%), 16/18 (89%) had antibodies against SARS-COV-2, another 2 reported previous positive RT-PCR results although antibody testing was negative. Of those positive, 7/18 (39%) were unaware of their infection. A stay abroad was stated by 173/498 (35%), mostly in Europe. 87/516 (17%) reported a febrile respiratory infection after January 1st 2020 which was related to SARS-CoV-2 in 4/87 (4.6%). Contact to COVID-19 positive relatives at home was stated by 22/502 (4.4%). This was the only significant risk factor for Covid-19 infection (Fisher´s exact test, p = 0.0005). N95 masks and eye protection devices were available for 87% and 73%, respectively. A total of 254/502 (51%) had been vaccinated against seasonal influenza. The overall SARS-CoV-2 infection rate of german physicians from intensive care and emergency medicine was low compared to reports from other countries and settings. This finding may be explained by the fact that the German health care system was not overwhelmed by the first wave of the SARS-CoV-2 pandemic.

Remote ischemic preconditioning does not induce activation of Akt and STAT5 in the rat heart.

Remote ischemic preconditioning (RIPC) is hypothesized to be a promising cardioprotective strategy to protect hearts against ischemia and reperfusion (I/R) injury; however, the current understanding of the underlying signal transduction pathways involved remains unclear. It has been previously demonstrated that protein kinase B/AKT, which is a crucial protein of the reperfusion injury salvage kinases pathway, and STAT5, which is a member of the survivor activating factor enhancement pathway, serve a pivotal role in cardioprotection. However, whether and at what time-points (TPs) RIPC leads to the activation of AKT and STAT5 in a rat model of RIPC and I/R injury remains to be determined. The present study hypothesized that RIPC may induce the phosphorylation of AKT and/or STAT5 immediately following RIPC and/or at a later TP with or without subsequent I/R. In the first set of experiments (part A), male Wistar rats were randomized into 2 groups (n=6 per group): The first group underwent RIPC via a hind limb tourniquet (4x5 min I/R episodes), while the second group received the respective sham treatment. In the second set of experiments (part B), the rats were randomized into 4 groups (n=6 per group) that either underwent RIPC or sham treatment prior to 35 min of ischemia by occlusion of the left anterior descending coronary artery followed by 120 min reperfusion or a respective sham treatment. At the end of the experiments, the heart tissue was isolated in order to analyze the phosphorylation levels of AKT and STAT5. The results revealed that RIPC did not induce the immediate or late phosphorylation of AKT or STAT5. In addition, following I/R, the activation of AKT and STAT5 was not modulated by RIPC. In conclusion, the findings of the present study suggested that RIPC-induced cardioprotection may not be mediated by the activation of AKT or STAT5 at the investigated TPs.

[Acute Kidney Injury: Epidemiology, Pathophysiology, Repair Mechanisms]. / Akute Nierenschädigung: Epidemiologie, Pathophysiologie, Reparaturmechanismen.

Acute kidney injury (AKI) is a major complication in critically ill patients and affects up to 50% of those admitted to intensive care units. Causes of AKI include patient specific factors (susceptibility: e.g. age, pre-existing chronic kidney disease, chronic heart failure, diabetes) and patient unspecific factors (exposure: e.g. sepsis, hypovolemia, cardiac surgery, nephrotoxin application). Mortality of severe AKI is in the range of 40 - 50%.AKI is accompanied by volume overload, electrolyte disorders, acidosis, and uremia. The diagnosis of AKI is based on an increase of creatinine levels and/or a decrease in urine output within 7 days after an insult. These 2 markers are late und unspecific, especially with regard to early identification of patients at risk of AKI. New AKI markers have been investigated within the last decade including NGAL (neutrophil gelatinase-associated lipocalin), the product of IGFBP-7 (insulin like growth factor binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2), KIM-1 (kidney injury molecule 1) and the cysteine-protease-inhibitor cystatin C. New markers or a panel of new markers might improve the diagnosis of patients at risk of AKI in the future.There are currently no specific therapeutics in the treatment of AKI. Therefore, the prevention of AKI is of an utmost importance. The recommended preventive measures include optimization of hemodynamics and volume status, close monitoring of creatinine levels and urine output, avoidance or discontinuation of nephrotoxic drugs, normoglycemia and the application of alternatives to radiocontrast agents if possible.As the long term prognosis of AKI highly depends on renal recovery, the 2 major goals for the future will be 1) the early identification of patients at AKI risk and 2) the support of renal recovery of AKI patients.

Dexmedetomidine Provides Cardioprotection During Early or Late Reperfusion Mediated by Different Mitochondrial K+-Channels.

BACKGROUND: Cardioprotective interventions-such as pharmacological postconditioning-are a promising strategy to reduce deleterious consequences of ischemia and reperfusion injury (I/RI) in the heart, especially as timing and onset of myocardial infarction are unpredictable. Pharmacological postconditioning by treatment with dexmedetomidine (Dex), an α2-adrenoreceptor agonist, during reperfusion protects hearts from I/RI, independently of time point and duration of application during the reperfusion phase. The mitochondrial ATP-sensitive K (mKATP) and mitochondrial large-conductance calcium-sensitive potassium channel (mBKCa) play a pivotal role in mediating this cardioprotective effect. Therefore, we investigated whether Dex-induced cardioprotection during early or late reperfusion is mediated variously by these mitochondrial K-channels. METHODS: Hearts of male Wistar rats were randomized into 8 groups and underwent a protocol of 15 minutes adaption, 33 minutes ischemia, and 60 minutes reperfusion in an in vitro Langendorff-system. A 10-minute treatment phase was started directly (first subgroup, early reperfusion) or 30 minutes (second subgroup, late reperfusion) after the onset of reperfusion. Control (Con) hearts received vehicle only. In the first subgroup, hearts were treated with 3 nM Dex, 100 µM mKATP-channel blocker 5-hydroxydecanoate (5HD) or 1 µM mBKCa-channel blocker Paxilline (Pax) alone or with respective combinations (5HD + Dex, Pax + Dex). Hearts of the second subgroup received Dex alone (Dex30') or in combination with the respective blockers (5HD + Dex30', Pax + Dex30'). Infarct size was determined with triphenyltetrazoliumchloride staining. Hemodynamic variables were recorded during the whole experiment. RESULTS: During early reperfusion (first subgroup), the infarct size reducing effect of Dex (Con: 57% ± 9%, Dex: 31% ± 7%; P< .0001 versus Con) was completely abolished by 5HD and Pax (52% ± 6%; Pax + Dex: 53% ± 4%; each P< .0001 versus Dex), while both blockers alone had no effect on infarct size (5HD: 54% ± 8%, Pax: 53% ± 11%). During late reperfusion (second subgroup) the protective effect of Dex (Dex30': 33% ± 10%, P< .0001 versus Con) was fully abrogated by Pax (Pax + Dex30': 58% ± 7%, P < .0001 versus Dex30'), whereas 5HD did not block cardioprotection (5HD + Dex30': 36% ± 7%). Between groups and within each group throughout reperfusion no significant differences in hemodynamic variables were detected. CONCLUSIONS: Cardioprotection by treatment with Dex during early reperfusion seems to be mediated by both mitochondrial K-channels, whereas during late reperfusion only mBKCa-channels are involved.