Martin Sauer - Academia.edu (original) (raw)

Papers by Martin Sauer

Trials, Apr 15, 2023

Background Sepsis is as a life-threatening organ dysfunction caused by a dysregulated host respon... more Background Sepsis is as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. The mortality of sepsis and particular of septic shock is very high. Treatment mostly focuses on infection control but a specific intervention that targets the underlying pathological host response is lacking to the present time. The investigators hypothesize that early therapeutic plasma exchange (TPE) will dampen the maladaptive host response by removing injurious mediators thereby limiting organ dysfunction and improving survival in patients with septic shock. Although small prospective studies demonstrated rapid hemodynamic stabilization under TPE, no adequately powered randomized clinical trial has investigated hard outcomes. Methods This is a randomized, prospective, multicenter, open-label, controlled, parallel-group interventional trial to test the adjunctive effect of TPE in patients with early septic shock. Patients with a refractory (defined as norepinephrine (NE) ≥ 0.4 μg/kg/min ≥ 30 min OR NE 0.3 μg/kg/min + vasopressin) and early (shock onset < 24 h) septic shock will be included. The intervention is a standard TPE with donor fresh frozen plasma (1.2 × individual plasma volume) performed within 6 h after randomization and will be compared to a standard of care (SOC) control arm. The primary endpoint is 28 days mortality for which the power analysis revealed a group size of 137 / arm (n = 274) to demonstrate a benefit of 15%. The key secondary objective will be to compare the extent of organ failure indicated by mean SOFA over the first 7 days as well as organ support-free days until day 28 following randomization. Besides numerous biological secondary, safety endpoints such as incidence of bleeding, allergic reactions, transfusion associated lung injury, severe thrombocytopenia, and other severe adverse events will be assessed during the first 7 days. For exploratory scientific analyses, biomaterial will be acquired longitudinally and multiple predefined scientific subprojects are planned. This study is an investigator-initiated trial supported by the German Research Foundation (DFG, DA 1209/7-1), in which 26 different centers in Germany, Switzerland, and Austria will participate over a duration of 33 months. Discussion This trial has substantial clinical relevance as it evaluates a promising adjunctive treatment option in refractory septic shock patients suffering from an extraordinary high mortality. A positive trial result could change the

Intensive Care Medicine Experimental, Jun 16, 2022

Background: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. T... more Background: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. The transfusion of healthy donor immune cells, i.e., granulocyte concentrates (GC) potentially induces tissue damage via local effects of neutrophils. Initial clinical trials using standard donor GC in a strictly extracorporeal bioreactor system for treatment of septic shock patients already provided evidence for beneficial effects with fewer side effects, by separating patient and donor immune cells using plasma filters. In this ex vivo study, we demonstrate the functional characteristics of a simplified extracorporeal therapy system using purified granulocyte preparations. Methods: Purified GC were used in an immune cell perfusion model prefilled with human donor plasma simulating a 6-h treatment. The extracorporeal circuit consisted of a blood circuit and a plasma circuit with 3 plasma filters (PF). PF1 is separating the plasma from the patient's blood. Plasma is then perfused through PF2 containing donor immune cells and used in a dead-end mode. The filtrated plasma is finally retransfused to the blood circuit. PF3 is included in the plasma backflow as a redundant safety measure. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Phagocytosis activity, oxidative burst and cell viability as well as cytokine release and metabolic parameters of purified GCs were assessed. Results: Cells were viable throughout the study period and exhibited well-preserved functionality and efficient metabolic activity. Course of lactate dehydrogenase and free hemoglobin concentration yielded no indication of cell impairment. The capability of the cells to secret various cytokines was preserved. Of particular interest is equivalence in performance of the cells on day 1 and day 3, demonstrating the sustained shelf life and performance of the immune cells in the purified GCs. Conclusion: Results demonstrate the suitability of a simplified extracorporeal system. Furthermore, granulocytes remain viable and highly active during a 6-h treatment even after storage for 3 days supporting the treatment of septic patients with this system in advanced clinical trials.

Frontiers in Medical Technology

Sepsis-associated encephalopathy (SAE) is a common organ dysfunction in patients with severe seps... more Sepsis-associated encephalopathy (SAE) is a common organ dysfunction in patients with severe sepsis or septic shock and leads to higher mortality and longer hospital stay. The diagnosis remains an exclusion process; none of the available measurements are specific for SAE. The aim of the presented prospective and controlled clinical study was to evaluate the possible role of molecular acoustics in determining acute brain injury in septic patients using an acoustocerebrography (ACG) system. ACG is a multifrequency, transcranial ultrasound method that measures the attenuation and time of flight to detect changes in the brain tissue. After approval from the local research ethics committee (of the University Hospital of Rostock: Reg. No.: A 2016-0026), 20 patients were included in two study groups: septic shock group (SG) and control group (CG; postoperative nonseptic patients). All patients were screened several times with the ACG on different days. Blood parameters of organ function, s...

Neuroscience Letters, 2018

NT-proCNP as a new indicator of asthenozoospermia.

Current Issues in Molecular Biology

(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are... more (1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.

The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in r... more The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release sy...

Albumin is the most abundant plasma protein and functions as a transport molecule that continuous... more Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery to target cells. Understanding the immediate effects of albumin on cells is however limited. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We demonstrated that serum starvation causes HepG2/C3A cell numbers to stagnate, whereas inclusion of albumin allows an increase in cell numbers. Cell cycle ...

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques

ABSTRACT: Background: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer ou... more ABSTRACT: Background: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer outcome of critically ill patients. Microcirculatory changes and altered vascular permeability of skeletal muscles might contribute to the pathogenesis of ICU-AW. Muscular ultrasound (MUS) displays increased muscle echogenicity, although its pathogenesis is uncertain. Objective: We investigated the combined measurement of serum and ultrasound markers to assess ICU-AW and clinical patient outcome. Methods: Fifteen patients and five healthy controls were longitudinally assessed for signs of ICU-AW at study days 3 and 10 using a muscle strength sum score. The definition of ICU-AW was based on decreased muscle strength assessed by the muscular research council-sum score. Ultrasound echogenicity of extremity muscles was assessed using a standardized protocol. Serum markers of inflammation and endothelial damage were measured. The 3-month outcome was assessed on the modified Rankin scale. Result...

PLOS ONE

Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of ... more Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of sepsis patients. Neurofilament (Nf) light (NfL) and heavy (NfH) chain levels as biomarkers for neuroaxonal injury were not evaluated in cerebrospinal fluid (CSF) and plasma of patients with sepsis-associated encephalopathy (SAE) before. We conducted a prospective, pilot observational study including 20 patients with septic shock and five patients without sepsis serving as controls. The assessment of SAE comprised a neuropsychiatric examination, electroencephalography (EEG), magnetic resonance imaging (MRI) and delirium screening methods including the confusion assessment method for the ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC). CSF Nf measurements in sepsis patients and longitudinal plasma Nf measurements in all participants were performed on days 1, 3 and 7 after study inclusion. Plasma NfL levels increased in sepsis patients over time (p = 0.0063) and remained stable in patients without sepsis. Plasma NfL values were significantly higher in patients with SAE (p = 0.011), significantly correlated with the severity of SAE represented by ICDSC values (R = 0.534, p = 0.022) and correlated with a poorer functional outcome after 100 days (R =-0.535, p = 0.0003). High levels of CSF Nf were measured in SAE patients. CSF NfL levels were higher in non-survivors (p = 0.012) compared with survivors and correlated with days until death (R =-0.932, p<0.0001) and

International Journal of Molecular Sciences

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in ... more In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stres...

Frontiers in Immunology

Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patie... more Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patients. In patients with severe sepsis or septic shock, LD occurred in nearly 19% of patients. An early diagnosis of LD at time of initial damage of the liver can lead to a better prognosis of these patients because an early start of therapy is possible. We performed a second prospective study with septic patients to test a new cell-based cytotoxicity device (biosensor) to evaluate clinical relevance for early diagnosis of LD and prognostic capacity. In the clinical study, 99 intensive care unit patients were included in two groups. From the patients of the septic group (n = 51, SG), and the control (non-septic) group [n = 49, control group (CG)] were drawn 20 ml blood at inclusion, after 3, and 7 days for testing with the biosensor. Patients' data were recorded for hospital survival, organ function, and demographic data, illness severity [acute physiology and chronic health evaluation (APACHE) II-, sepsis-related organ failure assessment (SOFA) scores], cytokines, circulating-free deoxyribonucleic acid/neutrophil-derived extracellular traps (cf-DNA/NETs), microbiological results, and pre-morbidity. For the developed cytotoxicity test, the human liver cell line HepG2/C3A was used. Patients' plasma was incubated in a microtiter plate assay with the test cells and after 6 days incubation the viability (trypan blue staining, XTT-test) and functionality (synthesis of albumin, cytochrome 1A2 activity) was analyzed. An impairment of viability and functionality of test cells was only seen in the SG compared with the CG. The plasma of non-survivors in the SG led to a more pronounced impairment of test cells than the plasma of survivors at inclusion. In addition, the levels of cf-DNA/NETs were significantly higher in the SG at inclusion, after 3, and after 7 days compared with the CG. The SG showed an in-hospital mortality of 24% and the values of bilirubin, APACHE II-, and SOFA scores were markedly higher at inclusion than in the CG. Hepatotoxicity of septic plasma was already detected with the liver cell-based biosensor at inclusion and also in the course of disease. The biosensor may be a tool for early diagnosis of LD in septic patients and may have prognostic relevance.

PLOS ONE

In Fig 3, the headings above the graph are incorrectly swapped. The left heading should be "No Br... more In Fig 3, the headings above the graph are incorrectly swapped. The left heading should be "No Brain Dysfunction" and the right heading should be "Brain Dysfunction." The authors have provided a corrected version here.

Critical care (London, England), Oct 23, 2017

Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated en... more Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis. We conducted a longitudinal, prospective translational study involving (1) experimental sepsis in an animal model; (2) postmortem studies of brain from patients with sepsis; and (3) a prospective, longitudinal human sepsis cohort study at university laboratory and intensive care units (ICUs). Thirteen ICU patients with septic shock, five ICU patients who died as a result of sepsis, fourteen fluid-resuscitated Wistar rats with fecal peritonitis, eleven sham-operated rats, and three human and four rat control subjects were included. Immunohistologic and protein biomarker analysis were performed on rat brain tissue at baseline and 24, 48, and 72 h after sepsis induction and in sham-treated rats. Immunohist...

International Journal of Molecular Sciences

Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS)... more Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

Journal of International Medical Research

The overall intubation conditions after tracheal intubation with remifentanil, propofol, and sevo... more The overall intubation conditions after tracheal intubation with remifentanil, propofol, and sevoflurane at 1.0 minimum alveolar concentration (MAC) are worse than with rocuronium at 0.45 mg/kg. Therefore, we compared the intubation conditions and laryngeal morbidity (vocal cord injuries, hoarseness, and sore throat) with sevoflurane at 1.2 and 1.4 MAC versus 1.0 MAC. Methods: In this prospective clinical trial, 90 patients were randomized to 3 groups: the sevoflurane 1.0, 1.2, and 1.4 MAC groups. At 3 min, tracheal intubation was performed and the patients' intubation conditions were assessed. The vocal cords were examined for injury by videolaryngoscopy. Additionally, the incidence and severity of laryngeal morbidity were compared between women and men. Results: Acceptable intubation conditions were seen in 72% of the patients without significant differences between the groups. Overall, vocal cord injuries (oedema) occurred in three (4%) patients. Women reported sore throat more often than men (51% vs. 21%, respectively). Conclusions: Intubation conditions were not improved with higher sevoflurane concentrations. The incidence and severity of sore throat were greater in women than men. Trial registration: ClinicalTrials.Gov: NCT 01896245

BioMed Research International

Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious ... more Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious clinical problem; antimycotics are involved in approximately 3% of all DILI cases. The hepatotoxicity of many drugs, including the antimycotics, is poorly screened in human models. Methods. In a standardized assay the cytotoxicity on hepatocytes of different concentrations (Cmax, 5x Cmax, and 10x Cmax) of the antimycotics used for systemic infections was tested. Anidulafungin (ANI), liposomal amphotericerin B (L-AmB), caspofungin (CASPO), fluconazole (FLUCO), and voriconazole (VORI) were incubated with HepG2/C3A cells. After incubation, the viability of cells (XTT test, LDH release, trypan blue staining), the synthesis of albumin, the cytochrome 1A2 activity, and the cell death (DNA fragmentation) were determined. Kruskal-Wallis and Mann–Whitney tests were used for statistical analyses. Results. L-AmB, ANI, and CASPO showed a mild hepatotoxicity in the Cmax concentrations. Higher concent...

BioMed research international, 2017

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outc... more Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01-50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as l...

BioMed research international, 2016

Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A gr... more Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A granulocyte bioreactor for the extracorporeal treatment of sepsis was tested in a prospective clinical study focusing on the dosage of norepinephrine in patients and influence on dynamic and cell based liver tests during extracorporeal therapies. Methods and Patients. Ten patients with severe sepsis were treated twice within 72 h with the system containing granulocytes from healthy donors. Survival, physiologic parameters, extended hemodynamic measurement, and the indocyanine green plasma disappearance rate (PDR) were monitored. Plasma of patients before and after extracorporeal treatments were tested with a cell based biosensor for analysis of hepatotoxicity. Results. The observed mortality rate was 50% during stay in hospital. During the treatments, the norepinephrine-dosage could be significantly reduced while mean arterial pressure was stable. In the cell based analysis of hepatotoxici...

BioMed Research International, 2016

Severe hepatosplenic injury of mansonian schistosomiasis is caused by Th2 mediated granulomatous ... more Severe hepatosplenic injury of mansonian schistosomiasis is caused by Th2 mediated granulomatous response against parasite eggs entrapped within the periportal tissue. Subsequent fibrotic scarring and deformation/sclerosing of intrahepatic portal veins lead to portal hypertension, ascites, and oesophageal varices. The murine model ofSchistosoma mansoni(S. mansoni) infection is suitable to establish the severe hepatosplenic injury of disease within a reasonable time scale for the development of novel antifibrotic or anti-infective strategies againstS. mansoniinfection. The drawback of the murine model is that the material prepared for complex analysis of egg burden, granuloma size, hepatic inflammation, and fibrosis is limited due to small amounts of liver tissue and blood samples. The objective of our study was the implementation of a macroscopic scoring system for mice livers to determine infection-related organ alterations ofS. mansoniinfection. In addition, anin vitrobiosensor sy...

Trials, Apr 15, 2023

Background Sepsis is as a life-threatening organ dysfunction caused by a dysregulated host respon... more Background Sepsis is as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. The mortality of sepsis and particular of septic shock is very high. Treatment mostly focuses on infection control but a specific intervention that targets the underlying pathological host response is lacking to the present time. The investigators hypothesize that early therapeutic plasma exchange (TPE) will dampen the maladaptive host response by removing injurious mediators thereby limiting organ dysfunction and improving survival in patients with septic shock. Although small prospective studies demonstrated rapid hemodynamic stabilization under TPE, no adequately powered randomized clinical trial has investigated hard outcomes. Methods This is a randomized, prospective, multicenter, open-label, controlled, parallel-group interventional trial to test the adjunctive effect of TPE in patients with early septic shock. Patients with a refractory (defined as norepinephrine (NE) ≥ 0.4 μg/kg/min ≥ 30 min OR NE 0.3 μg/kg/min + vasopressin) and early (shock onset < 24 h) septic shock will be included. The intervention is a standard TPE with donor fresh frozen plasma (1.2 × individual plasma volume) performed within 6 h after randomization and will be compared to a standard of care (SOC) control arm. The primary endpoint is 28 days mortality for which the power analysis revealed a group size of 137 / arm (n = 274) to demonstrate a benefit of 15%. The key secondary objective will be to compare the extent of organ failure indicated by mean SOFA over the first 7 days as well as organ support-free days until day 28 following randomization. Besides numerous biological secondary, safety endpoints such as incidence of bleeding, allergic reactions, transfusion associated lung injury, severe thrombocytopenia, and other severe adverse events will be assessed during the first 7 days. For exploratory scientific analyses, biomaterial will be acquired longitudinally and multiple predefined scientific subprojects are planned. This study is an investigator-initiated trial supported by the German Research Foundation (DFG, DA 1209/7-1), in which 26 different centers in Germany, Switzerland, and Austria will participate over a duration of 33 months. Discussion This trial has substantial clinical relevance as it evaluates a promising adjunctive treatment option in refractory septic shock patients suffering from an extraordinary high mortality. A positive trial result could change the

Intensive Care Medicine Experimental, Jun 16, 2022

Background: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. T... more Background: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. The transfusion of healthy donor immune cells, i.e., granulocyte concentrates (GC) potentially induces tissue damage via local effects of neutrophils. Initial clinical trials using standard donor GC in a strictly extracorporeal bioreactor system for treatment of septic shock patients already provided evidence for beneficial effects with fewer side effects, by separating patient and donor immune cells using plasma filters. In this ex vivo study, we demonstrate the functional characteristics of a simplified extracorporeal therapy system using purified granulocyte preparations. Methods: Purified GC were used in an immune cell perfusion model prefilled with human donor plasma simulating a 6-h treatment. The extracorporeal circuit consisted of a blood circuit and a plasma circuit with 3 plasma filters (PF). PF1 is separating the plasma from the patient's blood. Plasma is then perfused through PF2 containing donor immune cells and used in a dead-end mode. The filtrated plasma is finally retransfused to the blood circuit. PF3 is included in the plasma backflow as a redundant safety measure. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Phagocytosis activity, oxidative burst and cell viability as well as cytokine release and metabolic parameters of purified GCs were assessed. Results: Cells were viable throughout the study period and exhibited well-preserved functionality and efficient metabolic activity. Course of lactate dehydrogenase and free hemoglobin concentration yielded no indication of cell impairment. The capability of the cells to secret various cytokines was preserved. Of particular interest is equivalence in performance of the cells on day 1 and day 3, demonstrating the sustained shelf life and performance of the immune cells in the purified GCs. Conclusion: Results demonstrate the suitability of a simplified extracorporeal system. Furthermore, granulocytes remain viable and highly active during a 6-h treatment even after storage for 3 days supporting the treatment of septic patients with this system in advanced clinical trials.

Frontiers in Medical Technology

Sepsis-associated encephalopathy (SAE) is a common organ dysfunction in patients with severe seps... more Sepsis-associated encephalopathy (SAE) is a common organ dysfunction in patients with severe sepsis or septic shock and leads to higher mortality and longer hospital stay. The diagnosis remains an exclusion process; none of the available measurements are specific for SAE. The aim of the presented prospective and controlled clinical study was to evaluate the possible role of molecular acoustics in determining acute brain injury in septic patients using an acoustocerebrography (ACG) system. ACG is a multifrequency, transcranial ultrasound method that measures the attenuation and time of flight to detect changes in the brain tissue. After approval from the local research ethics committee (of the University Hospital of Rostock: Reg. No.: A 2016-0026), 20 patients were included in two study groups: septic shock group (SG) and control group (CG; postoperative nonseptic patients). All patients were screened several times with the ACG on different days. Blood parameters of organ function, s...

Neuroscience Letters, 2018

NT-proCNP as a new indicator of asthenozoospermia.

Current Issues in Molecular Biology

(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are... more (1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.

The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in r... more The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release sy...

Albumin is the most abundant plasma protein and functions as a transport molecule that continuous... more Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery to target cells. Understanding the immediate effects of albumin on cells is however limited. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We demonstrated that serum starvation causes HepG2/C3A cell numbers to stagnate, whereas inclusion of albumin allows an increase in cell numbers. Cell cycle ...

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques

ABSTRACT: Background: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer ou... more ABSTRACT: Background: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer outcome of critically ill patients. Microcirculatory changes and altered vascular permeability of skeletal muscles might contribute to the pathogenesis of ICU-AW. Muscular ultrasound (MUS) displays increased muscle echogenicity, although its pathogenesis is uncertain. Objective: We investigated the combined measurement of serum and ultrasound markers to assess ICU-AW and clinical patient outcome. Methods: Fifteen patients and five healthy controls were longitudinally assessed for signs of ICU-AW at study days 3 and 10 using a muscle strength sum score. The definition of ICU-AW was based on decreased muscle strength assessed by the muscular research council-sum score. Ultrasound echogenicity of extremity muscles was assessed using a standardized protocol. Serum markers of inflammation and endothelial damage were measured. The 3-month outcome was assessed on the modified Rankin scale. Result...

PLOS ONE

Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of ... more Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of sepsis patients. Neurofilament (Nf) light (NfL) and heavy (NfH) chain levels as biomarkers for neuroaxonal injury were not evaluated in cerebrospinal fluid (CSF) and plasma of patients with sepsis-associated encephalopathy (SAE) before. We conducted a prospective, pilot observational study including 20 patients with septic shock and five patients without sepsis serving as controls. The assessment of SAE comprised a neuropsychiatric examination, electroencephalography (EEG), magnetic resonance imaging (MRI) and delirium screening methods including the confusion assessment method for the ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC). CSF Nf measurements in sepsis patients and longitudinal plasma Nf measurements in all participants were performed on days 1, 3 and 7 after study inclusion. Plasma NfL levels increased in sepsis patients over time (p = 0.0063) and remained stable in patients without sepsis. Plasma NfL values were significantly higher in patients with SAE (p = 0.011), significantly correlated with the severity of SAE represented by ICDSC values (R = 0.534, p = 0.022) and correlated with a poorer functional outcome after 100 days (R =-0.535, p = 0.0003). High levels of CSF Nf were measured in SAE patients. CSF NfL levels were higher in non-survivors (p = 0.012) compared with survivors and correlated with days until death (R =-0.932, p<0.0001) and

International Journal of Molecular Sciences

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in ... more In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stres...

Frontiers in Immunology

Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patie... more Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patients. In patients with severe sepsis or septic shock, LD occurred in nearly 19% of patients. An early diagnosis of LD at time of initial damage of the liver can lead to a better prognosis of these patients because an early start of therapy is possible. We performed a second prospective study with septic patients to test a new cell-based cytotoxicity device (biosensor) to evaluate clinical relevance for early diagnosis of LD and prognostic capacity. In the clinical study, 99 intensive care unit patients were included in two groups. From the patients of the septic group (n = 51, SG), and the control (non-septic) group [n = 49, control group (CG)] were drawn 20 ml blood at inclusion, after 3, and 7 days for testing with the biosensor. Patients' data were recorded for hospital survival, organ function, and demographic data, illness severity [acute physiology and chronic health evaluation (APACHE) II-, sepsis-related organ failure assessment (SOFA) scores], cytokines, circulating-free deoxyribonucleic acid/neutrophil-derived extracellular traps (cf-DNA/NETs), microbiological results, and pre-morbidity. For the developed cytotoxicity test, the human liver cell line HepG2/C3A was used. Patients' plasma was incubated in a microtiter plate assay with the test cells and after 6 days incubation the viability (trypan blue staining, XTT-test) and functionality (synthesis of albumin, cytochrome 1A2 activity) was analyzed. An impairment of viability and functionality of test cells was only seen in the SG compared with the CG. The plasma of non-survivors in the SG led to a more pronounced impairment of test cells than the plasma of survivors at inclusion. In addition, the levels of cf-DNA/NETs were significantly higher in the SG at inclusion, after 3, and after 7 days compared with the CG. The SG showed an in-hospital mortality of 24% and the values of bilirubin, APACHE II-, and SOFA scores were markedly higher at inclusion than in the CG. Hepatotoxicity of septic plasma was already detected with the liver cell-based biosensor at inclusion and also in the course of disease. The biosensor may be a tool for early diagnosis of LD in septic patients and may have prognostic relevance.

PLOS ONE

In Fig 3, the headings above the graph are incorrectly swapped. The left heading should be "No Br... more In Fig 3, the headings above the graph are incorrectly swapped. The left heading should be "No Brain Dysfunction" and the right heading should be "Brain Dysfunction." The authors have provided a corrected version here.

Critical care (London, England), Oct 23, 2017

Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated en... more Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis. We conducted a longitudinal, prospective translational study involving (1) experimental sepsis in an animal model; (2) postmortem studies of brain from patients with sepsis; and (3) a prospective, longitudinal human sepsis cohort study at university laboratory and intensive care units (ICUs). Thirteen ICU patients with septic shock, five ICU patients who died as a result of sepsis, fourteen fluid-resuscitated Wistar rats with fecal peritonitis, eleven sham-operated rats, and three human and four rat control subjects were included. Immunohistologic and protein biomarker analysis were performed on rat brain tissue at baseline and 24, 48, and 72 h after sepsis induction and in sham-treated rats. Immunohist...

International Journal of Molecular Sciences

Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS)... more Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

Journal of International Medical Research

The overall intubation conditions after tracheal intubation with remifentanil, propofol, and sevo... more The overall intubation conditions after tracheal intubation with remifentanil, propofol, and sevoflurane at 1.0 minimum alveolar concentration (MAC) are worse than with rocuronium at 0.45 mg/kg. Therefore, we compared the intubation conditions and laryngeal morbidity (vocal cord injuries, hoarseness, and sore throat) with sevoflurane at 1.2 and 1.4 MAC versus 1.0 MAC. Methods: In this prospective clinical trial, 90 patients were randomized to 3 groups: the sevoflurane 1.0, 1.2, and 1.4 MAC groups. At 3 min, tracheal intubation was performed and the patients' intubation conditions were assessed. The vocal cords were examined for injury by videolaryngoscopy. Additionally, the incidence and severity of laryngeal morbidity were compared between women and men. Results: Acceptable intubation conditions were seen in 72% of the patients without significant differences between the groups. Overall, vocal cord injuries (oedema) occurred in three (4%) patients. Women reported sore throat more often than men (51% vs. 21%, respectively). Conclusions: Intubation conditions were not improved with higher sevoflurane concentrations. The incidence and severity of sore throat were greater in women than men. Trial registration: ClinicalTrials.Gov: NCT 01896245

BioMed Research International

Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious ... more Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious clinical problem; antimycotics are involved in approximately 3% of all DILI cases. The hepatotoxicity of many drugs, including the antimycotics, is poorly screened in human models. Methods. In a standardized assay the cytotoxicity on hepatocytes of different concentrations (Cmax, 5x Cmax, and 10x Cmax) of the antimycotics used for systemic infections was tested. Anidulafungin (ANI), liposomal amphotericerin B (L-AmB), caspofungin (CASPO), fluconazole (FLUCO), and voriconazole (VORI) were incubated with HepG2/C3A cells. After incubation, the viability of cells (XTT test, LDH release, trypan blue staining), the synthesis of albumin, the cytochrome 1A2 activity, and the cell death (DNA fragmentation) were determined. Kruskal-Wallis and Mann–Whitney tests were used for statistical analyses. Results. L-AmB, ANI, and CASPO showed a mild hepatotoxicity in the Cmax concentrations. Higher concent...

BioMed research international, 2017

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outc... more Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01-50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as l...

BioMed research international, 2016

Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A gr... more Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A granulocyte bioreactor for the extracorporeal treatment of sepsis was tested in a prospective clinical study focusing on the dosage of norepinephrine in patients and influence on dynamic and cell based liver tests during extracorporeal therapies. Methods and Patients. Ten patients with severe sepsis were treated twice within 72 h with the system containing granulocytes from healthy donors. Survival, physiologic parameters, extended hemodynamic measurement, and the indocyanine green plasma disappearance rate (PDR) were monitored. Plasma of patients before and after extracorporeal treatments were tested with a cell based biosensor for analysis of hepatotoxicity. Results. The observed mortality rate was 50% during stay in hospital. During the treatments, the norepinephrine-dosage could be significantly reduced while mean arterial pressure was stable. In the cell based analysis of hepatotoxici...

BioMed Research International, 2016

Severe hepatosplenic injury of mansonian schistosomiasis is caused by Th2 mediated granulomatous ... more Severe hepatosplenic injury of mansonian schistosomiasis is caused by Th2 mediated granulomatous response against parasite eggs entrapped within the periportal tissue. Subsequent fibrotic scarring and deformation/sclerosing of intrahepatic portal veins lead to portal hypertension, ascites, and oesophageal varices. The murine model ofSchistosoma mansoni(S. mansoni) infection is suitable to establish the severe hepatosplenic injury of disease within a reasonable time scale for the development of novel antifibrotic or anti-infective strategies againstS. mansoniinfection. The drawback of the murine model is that the material prepared for complex analysis of egg burden, granuloma size, hepatic inflammation, and fibrosis is limited due to small amounts of liver tissue and blood samples. The objective of our study was the implementation of a macroscopic scoring system for mice livers to determine infection-related organ alterations ofS. mansoniinfection. In addition, anin vitrobiosensor sy...