Publications by authors named "Uta Merle"

89 Publications

Coronataxi Brings Outpatient Care to COVID-19 Patients.

Ann Emerg Med 2020 12 5;76(6):811-812. Epub 2020 Jun 5.

Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.annemergmed.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274638PMC
December 2020

Hypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID-19 Patients.

Hemasphere 2020 Dec 10;4(6):e492. Epub 2020 Nov 10.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6 μmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with hepcidin. We conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury.
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http://dx.doi.org/10.1097/HS9.0000000000000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665253PMC
December 2020

[Retrospective cross-sectional study based on nationwide data of drug prescriptions and contractional data of outpatient offices regarding Morbus Wilson's disease].

Z Gastroenterol 2020 Nov 16;58(11):1054-1064. Epub 2020 Nov 16.

Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Chirurgische Universitätsklinik Heidelberg, Heidelberg, Germany.

Introduction:  In this article, the prevalence of the Morbus Wilson disease in Germany is determined. This is based on nationwide data of drug prescriptions and contractional data of outpatient offices. The prevalence is set in ratio to the found prevalence of prescriptions in Germany.

Method:  The descriptive evaluation is based on the database of the Central Research Institute of Ambulatory Health Care (Zi) in Germany. Additionally, data of the Federal Office of Statistics regarding inpatient treatment are available.

Results:  It can be seen that there is a notable difference between the prevalence of patients undergoing therapy and the patients with verified diagnoses. In total, prevalence is increasing. The incidence on hand and the given dynamic of the patient population could indicate that, possibly, there is an increased rate of misdiagnosis in the first year of diagnosis. According to data, the hepatic form is the more often diagnosed form. The human genetic diagnostic increases, on average, are most distinct.

Attributes:  Wilson Disease, Prevalence, Incidence, Trientine, Trientintetrahydrochlorid, D-Penicillamin, Zinc acetat, Zinc.
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http://dx.doi.org/10.1055/a-1246-3190DOI Listing
November 2020

Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset.

Clin Genet 2021 03 25;99(3):376-383. Epub 2020 Nov 25.

Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.

Failure to thrive (FTT) causes significant morbidity, often without clear etiologies. Six individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Standard diagnostic work up did not ascertain an etiology. Autozygosity mapping and whole exome sequencing identified homozygosity for a novel genetic variant of the long chain fatty acyl-CoA synthetase 5 (ACSL5) shared among the affected individuals (NM_203379.1:c.1358C>A:p.(Thr453Lys)). Autosomal recessive genotype-phenotype segregation was confirmed by Sanger sequencing. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss-of-function mutation without any remaining activity. ACSL5 belongs to an essential enzyme family required for lipid metabolism and is known to contribute the major activity in the mouse intestine. Based on the function of ACSL5 in intestinal long chain fatty acid metabolism and the gastroenterological symptoms, affected individuals were treated with total parenteral nutrition or medium-chain triglyceride-based formula restricted in long-chain triglycerides. The patients responded well and follow up suggests that treatment is only required during early life.
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http://dx.doi.org/10.1111/cge.13883DOI Listing
March 2021

The arrhythmogenic face of COVID-19: Brugada ECG pattern during acute infection.

Eur Heart J Case Rep 2020 Oct 30;4(FI1):1-2. Epub 2020 Jul 30.

Department of Cardiology, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1093/ehjcr/ytaa230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454489PMC
October 2020

A Randomized Open label Phase-II Clinical Trial with or without Infusion of Plasma from Subjects after Convalescence of SARS-CoV-2 Infection in High-Risk Patients with Confirmed Severe SARS-CoV-2 Disease (RECOVER): A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Oct 6;21(1):828. Epub 2020 Oct 6.

Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.

Objectives: Primary objectives • To assess the time from randomisation until an improvement within 84 days defined as two points on a seven point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of SARS-CoV-2 infection or standard of care. Secondary objectives • To assess overall survival, and the overall survival rate at 28 56 and 84 days. • To assess SARS-CoV-2 viral clearance and load as well as antibody titres. • To assess the percentage of patients that required mechanical ventilation. • To assess time from randomisation until discharge.

Trial Design: Randomised, open-label, multicenter phase II trial, designed to assess the clinical outcome of SARS-CoV-2 disease in high-risk patients (group 1 to group 4) following treatment with anti-SARS-CoV-2 convalescent plasma or standard of care.

Participants: High-risk patients >18 years of age hospitalized with SARS-CoV-2 infection in 10-15 university medical centres will be included. High-risk is defined as SARS-CoV-2 positive infection with Oxygen saturation at ≤ 94% at ambient air with additional risk features as categorised in 4 groups: • Group 1, pre-existing or concurrent hematological malignancy and/or active cancer therapy (incl. chemotherapy, radiotherapy, surgery) within the last 24 months or less. • Group 2, chronic immunosuppression not meeting the criteria of group 1. • Group 3, age ≥ 50 - 75 years meeting neither the criteria of group 1 nor group 2 and at least one of these criteria: Lymphopenia < 0.8 x G/l and/or D-dimer > 1μg/mL. • Group 4, age ≥ 75 years meeting neither the criteria of group 1 nor group 2. Observation time for all patients is expected to be at least 3 months after entry into the study. Patients receive convalescent plasma for two days (day 1 and day 2) or standard of care. For patients in the standard arm, cross over is allowed from day 10 in case of not improving or worsening clinical condition. Nose/throat swabs for determination of viral load are collected at day 0 and day 1 (before first CP administration) and subsequently at day 2, 3, 5, 7, 10, 14, 28 or until discharge. Serum for SARS-Cov-2 diagnostic is collected at baseline and subsequently at day 3, 7, 14 and once during the follow-up period (between day 35 and day 84). There is a regular follow-up of 3 months. All discharged patients are followed by regular phone calls. All visits, time points and study assessments are summarized in the Trial Schedule (see full protocol Table 1). All participating trial sites will be supplied with study specific visit worksheets that list all assessments and procedures to be completed at each visit. All findings including clinical and laboratory data are documented by the investigator or an authorized member of the study team in the patient's medical record and in the electronic case report forms (eCRFs).

Intervention And Comparator: This trial will analyze the effects of convalescent plasma from recovered subjects with SARS-CoV-2 antibodies in high-risk patients with SARS-CoV-2 infection. Patients at high risk for a poor outcome due to underlying disease, age or condition as listed above are eligible for enrollment. In addition, eligible patients have a confirmed SARS-CoV-2 infection and O saturation ≤ 94% while breathing ambient air. Patients are randomised to receive (experimental arm) or not receive (standard arm) convalescent plasma in two bags (238 - 337 ml plasma each) from different donors (day 1, day 2). A cross over from the standard arm into the experimental arm is possible after day 10 in case of not improving or worsening clinical condition.

Main Outcomes: Primary endpoints: The main purpose of the study is to assess the time from randomisation until an improvement within 84 days defined as two points on a seven-point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of a SARS-CoV-2 infection or standard of care. Secondary endpoints: • Overall survival, defined as the time from randomisation until death from any cause 28-day, 56-day and 84-day overall survival rates. • SARS-CoV-2 viral clearance and load as well as antibody titres. • Requirement mechanical ventilation at any time during hospital stay (yes/no). • Time until discharge from randomisation. • Viral load, changes in antibody titers and cytokine profiles are analysed in an exploratory manner using paired non-parametric tests (before - after treatment).

Randomisation: Upon confirmation of eligibility (patients must meet all inclusion criteria and must not meet exclusion criteria described in section 5.3 and 5.4 of the full protocol), the clinical site must contact a centralized internet randomization system ( https://randomizer.at/ ). Patients are randomized using block randomisation to one of the two arms, experimental arm or standard arm, in a 1:1 ratio considering a stratification according to the 4 risk groups (see Participants).

Blinding (masking): The study is open-label, no blinding will be performed.

Numbers To Be Randomised (sample Size): A total number of 174 patients is required for the entire trial, n=87 per group.

Trial Status: Protocol version 1.2 dated 09/07/2020. A recruitment period of approximately 9 months and an overall study duration of approximately 12 months is anticipated. Recruitment of patients starts in the third quarter of 2020. The study duration of an individual patient is planned to be 3 months. After finishing all study-relevant procedures, therapy, and follow-up period, the patient is followed in terms of routine care and treated if necessary. Total trial duration: 18 months Duration of the clinical phase: 12 months First patient first visit (FPFV): 3 Quarter 2020 Last patient first visit (LPFV): 2 Quarter 2021 Last patient last visit (LPLV): 3 Quarter 2021 Trial Report completed: 4 Quarter 2021 TRIAL REGISTRATION: EudraCT Number: 2020-001632-10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE , registered on 04/04/2020.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). The eCRF is attached (Additional file 3).
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http://dx.doi.org/10.1186/s13063-020-04735-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538058PMC
October 2020

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

Infection 2021 Feb 1;49(1):63-73. Epub 2020 Oct 1.

Department I for Internal Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.

Purpose: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19.

Methods: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models.

Results: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis.

Conclusion: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.
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http://dx.doi.org/10.1007/s15010-020-01499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527665PMC
February 2021

Methionine- and Choline-Deficient Diet Enhances Adipose Lipolysis and Leptin Release in aP2-Cre Fatp4-Knockout Mice.

Mol Nutr Food Res 2020 11 12;64(22):e2000361. Epub 2020 Oct 12.

Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Scope: Inadequate intake of choline commonly leads to liver diseases. Methionine- and choline-deficient diets (MCDD) induce fatty liver in mice which is partly mediated by triglyceride (TG) lipolysis in white adipose tissues (WATs). Because Fatp4 knockdown has been shown to increase adipocyte lipolysis in vitro, here, the effects of MCDD on WAT lipolysis in aP2-Cre Fatp4-knockout (Fatp4 ) mice are determined.

Methods And Results: Isolated WATs of Fatp4 mice exposed to MCD medium show an increase in lipolysis, and the strongest effect is noted on glycerol release from subcutaneous fat. Fatp4 mice fed with MCDD for 4 weeks show an increase in serum glycerol, TG, and leptin levels associated with the activation of hormone-sensitive lipase in subcutaneous fat. Chow-fed Fatp4 mice also show an increase in serum leptin and very-low-density lipoproteins as well as liver phosphatidylcholine and sphingomyelin levels. Both chow- and MCDD-fed Fatp4 mice show a decrease in serum ketone and WAT sphingomyelin levels which supports a metabolic shift to TG for subsequent WAT lipolysis CONCLUSIONS: Adipose Fatp4 deficiency leads to TG lipolysis and leptin release, which are exaggerated by MCDD. The data imply hyperlipidemia risk by a low dietary choline intake and gene mutations that increase adipose TG levels.
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http://dx.doi.org/10.1002/mnfr.202000361DOI Listing
November 2020

Accurate Measurement of Copper Overload in an Experimental Model of Wilson Disease by Laser Ablation Inductively Coupled Plasma Mass Spectrometry.

Biomedicines 2020 Sep 16;8(9). Epub 2020 Sep 16.

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany.

Wilson disease is a rare inherited autosomal recessive disorder. As a consequence of genetic alterations in the gene, copper begins to accumulate in the body, particularly in the liver and brain. Affected persons are prone to develop liver cancer and severe psychiatric and neurological symptoms. Clinically, the development of corneal Kayser-Fleischer rings and low ceruloplasmin concentrations (<20 mg/dL) are indicative of Wilson disease. However, the detection of elevated hepatic copper content (>250 µg/g dry weight) alone is still considered as the best but not exclusive diagnostic test for Wilson disease. Presently, specific copper stains (e.g., rhodanine) or indirect staining for copper-associated proteins (e.g., orcein) are widely used to histochemically visualize hepatic copper deposits. However, these procedures only detect lysosomal copper, while cytosolic copper is not detectable. Similarly, elemental analysis in scanning electron microscope with energy dispersive X-ray analysis (EDX) often leads to false negative results and inconsistencies. Here, we tested the diagnostic potential of laser ablation inductively-coupled mass spectrometry (LA-ICP-MS) that allows quantitative analysis of multiple elements. Comparative studies were performed in wild type and the null mouse model. We propose LA-ICP-MS as a versatile and powerful method for the accurate determination of hepatic copper in people with Wilson disease with high spatial resolution.
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http://dx.doi.org/10.3390/biomedicines8090356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555421PMC
September 2020

Vitamin D Deficiency and Outcome of COVID-19 Patients.

Nutrients 2020 Sep 10;12(9). Epub 2020 Sep 10.

Department of Internal Medicine IV, University of Heidelberg, 69121 Heidelberg, Germany.

Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses an enormous challenge to health care systems throughout the world. Without causal treatment, identification of modifiable prognostic factors may help to improve outcomes. To explore possible associations of vitamin D (VitD) status with disease severity and survival, we studied 185 patients diagnosed with coronavirus disease 2019 (COVID-19) and treated at our center. VitD status at first presentation was assessed retrospectively using accredited laboratory methods. VitD deficiency was defined as serum total 25-hydroxyvitamin D level < 12 ng/mL (<30 nM). Primary endpoint was severe course of disease (i.e., need for invasive mechanical ventilation and/or death, IMV/D). Within a median observation period of 66 days (range 2-92), 23 patients required IMV. A total of 28 patients had IMV/D, including 16 deaths. Ninety-three (50%) patients required hospitalization (inpatient subgroup). A total of 41 (22%) patients were VitD deficient. When adjusted for age, gender, and comorbidities, VitD deficiency was associated with higher risk of IMV/D and death (HR 6.12, 95% CI 2.79-13.42, < 0.001 and HR 14.73, 95% CI 4.16-52.19, < 0.001, respectively). Similar correlations were observed in the inpatient subgroup. Our study demonstrates an association between VitD deficiency and severity/mortality of COVID-19, highlighting the need for interventional studies on VitD supplementation in SARS-CoV-2 infected individuals.
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http://dx.doi.org/10.3390/nu12092757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551780PMC
September 2020

The Pathology of Severe COVID-19-Related Lung Damage.

Dtsch Arztebl Int 2020 07;117(29-30):500-506

Institute of Pathology, University Hospital Heidelberg; Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University Hospital Heidelberg; Department of Gastroenterology and Hepatology, University Hospital Heidelberg; Institute of Pathology, Hannover Medical School; Biomedical Research in Endstage and Obstructive Lung Dis ease Hannover (BREATH), Center for Lung Research (DZL), Hannover Medical School; TI Biobank; German Center for Infection Research (DZIF), - University Hospital Heidelberg.

Background: The histomorphological changes of lung damage in severe coronavirus disease 2019 (COVID-19) have not yet been adequately characterized. In this article, we describe the sequence of pathological changes in COVID-19 and discuss the implications for approaches to treatment.

Methods: Standardized autopsies were performed on thirteen patients who had died of COVID-19. The findings were analyzed together with clinical data from the patients' medical records.

Results: Most (77%) of the deceased patients were men. Their median age at death was 78 years (range, 41-90). Most of them had major pre-existing chronic diseases, most commonly arterial hypertension. The autopsies revealed characteristic COVID-19-induced pathological changes in the lungs, which were regarded as the cause of death in most patients. The main histological finding was sequential alveolar damage, apparently due in large measure to focal capillary microthrombus formation. Alveolar damage leads to the death of the patient either directly or by the induction of pulmonary parenchymal fibrosis. Diffuse lung damage was seen exclusively in invasively ventilated patients.

Conclusion: Autopsies are crucial for the systematic assessment of new diseases such as COVID-19: they provide a basis for further investigations of disease mechanisms and for the devising of potentially effective modes of treatment. The autopsy findings suggest that focal damage of the microvascular pulmonary circulation is a main mechanism of lethal lung disease due to the SARS-CoV-2 virus. It may also be a cause of persistent lung damage in patients who recover from severe COVID-19.
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http://dx.doi.org/10.3238/arztebl.2020.0500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588618PMC
July 2020

Rotational thrombelastometry (ROTEM) improves hemostasis assessment compared to conventional coagulation test in ACLF and Non-ACLF patients.

BMC Gastroenterol 2020 Aug 17;20(1):271. Epub 2020 Aug 17.

Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Background: Patients with liver cirrhosis typically exhibit abnormal coagulation parameters in conventional coagulation tests (CCTs). Rotational thromboelastometry (ROTEM) is a holistic blood coagulation assay. This method provides an insight into the global hemostatic capabilities and has been suggested to provide a better overview of the coagulation system in liver cirrhosis.

Methods: The goal of this study was to examine hemostasis in patients with stable liver cirrhosis (Non-ACLF) and in acute-on-chronic liver failure (ACLF) by CCT and ROTEM including agreement of both tests and the prospective assessment of test performance based on clinical outcomes in ACLF patients. Therefore, ACLF patients were additionally subgrouped by bleeding events. Fifty-five Non-ACLF patients and twenty-two patients with ACLF were analysed in this prospective cohort study.

Results: Coagulation parameters analysed by CCT were outside the normal range in Non-ACLF and ACLF patients, but were significantly more aberrant in ACLF patients. Non-ACLF patients analysed by ROTEM revealed parameters largely within the normal limits, while significantly more ROTEM parameters in ACLF patients were affected. Maximum clot firmness (MCF) was significantly divergent between both patient groups and correlated well with levels of fibrinogen and platelet count. Using Cohen's Kappa coefficient κ, the strength of agreement between CCT and ROTEM analyses was determined to be fair for Non-ACLF patients and moderate for ACLF patients. Bleeding events occurred significantly more often in ACLF group with significantly reduced A10 and MCF.

Conclusions: For assessing hemostasis in Non-ACLF and ACLF patients the underlying dataset shows advantages of ROTEM over CCT. A10 and MCF represent suitable prognostic parameters in predicting bleeding events in ACLF group.
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http://dx.doi.org/10.1186/s12876-020-01413-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433140PMC
August 2020

Plasma exchange in critically ill COVID-19 patients.

Crit Care 2020 08 4;24(1):481. Epub 2020 Aug 4.

Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany.

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http://dx.doi.org/10.1186/s13054-020-03171-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399583PMC
August 2020

Plasma Lipidome, PNPLA3 polymorphism and hepatic steatosis in hereditary hemochromatosis.

BMC Gastroenterol 2020 Jul 17;20(1):230. Epub 2020 Jul 17.

Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Background: Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH.

Methods: We conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination.

Results: HH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis.

Conclusion: Our study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.
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http://dx.doi.org/10.1186/s12876-020-01282-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368730PMC
July 2020

Assessment of rotational thrombelastometry (ROTEM) parameters in hepatocellular carcinoma.

Thromb Res 2020 11 6;195:55-57. Epub 2020 Jul 6.

Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.07.006DOI Listing
November 2020

Evaluation of the COVID-19 pandemic using an algorithm based on the Bateman function: Prediction of disease progression using observational data for the city of Heidelberg, Germany
.

Int J Clin Pharmacol Ther 2020 Jul;58(7):366-374

The COVID-19 pandemic has been evaluated using an algorithm based on the Bateman function in a modified SIR/SIZ-Model. Prediction of the number of persons carrying the live COVID-19 coronavirus (I) in a susceptible population (S) was achieved using two rate constants describing the rate of increase and decrease in the number of infectious persons on a daily basis. The model was verified using observational data for the city of Heidelberg, Germany. Three hypothetical scenarios, having their counterparts in practice were considered, namely Scenario A - No restrictions on the population; Scenario B - Assumption of a 10-fold higher number of infections than observed; Scenario C - Protective measures introduced only for elderly persons. It could be demonstrated using the model that the lockdown measures introduced prevented a major medical emergency and possibly a near catastrophe in the region. It was further demonstrated that the prospective application of the model can facilitate realtime decisions on pandemic management strategy for the population. This is achieved by curve-fitting for the rate constants, determinants for the number of infectious persons. The calculated maximum numbers of infected and infectious persons daily increased in proportion to the number of persons initially susceptible to the infection. After appearance of the first two infections in Heidelberg, the calculated maximum number of persons carrying live virus was 2,291 at Day 102 (Scenario B), 18,936 infectious persons at Day 139 (Scenario C) and 22,535 infectious at Day 142 (Scenario A). In Scenario A, high values would have persisted for 6 months during which a total of 124,301 persons would have been infected in Heidelberg. The model predicted that the virus would have disappeared within 1 year after being first detected. A disease catastrophe of this magnitude would not be expected provided the rate constant (α) for the rate of increase in the number of infectious persons remained lower than the rate constant (β) for the fall in number of infectious persons.
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http://dx.doi.org/10.5414/CP203824DOI Listing
July 2020

Severe Multiorgan Failure Following Yellow Fever Vaccination.

Vaccines (Basel) 2020 May 26;8(2). Epub 2020 May 26.

Center for Infectious Diseases, Virology, University Hospital of Heidelberg, 69120 Heidelberg, Germany.

Background: The yellow fever (YF) vaccination is recommended by the WHO for people traveling or living in endemic areas at risk for yellow fever infections in Africa and South America. Although the live attenuated yellow fever vaccine is a safe and efficient vaccine, rare serious adverse events after vaccination have been reported.

Case Presentation: We present the case of a 74-year-old male with multiorgan failure after yellow fever vaccination for a trip to Brazil. The patient required admission to the intensive care unit with a prolonged stay due to severe organ dysfunction. Five days after the YF vaccination, the patient experienced nausea, vomiting, diarrhea, and general illness. Three days later he sought medical attention and was transferred to the University Hospital Heidelberg with beginning multiorgan failure and severe septic shock, including hypotonia, tachypnea, thrombopenia, and acute renal failure the same day. Within one week after vaccination, antibodies against YF virus were already detectable and progressively increased over the next two weeks. Viral RNA was detected in serum on the day of admission, with a viral load of 1.0 × 10 copies/mL. The YF virus (YFV) RNA was also present in tracheal secretions for several weeks and could be detected in urine samples up to 20 weeks after vaccination, with a peak viral load of 1.3 × 10 copies/mL. After 20 weeks in the ICU with nine weeks of mechanical ventilation, the patient was transferred to another hospital for further recovery.

Conclusions: The risk for severe adverse events due to the YF vaccination should be balanced against the risk of acquiring a severe YF infection, especially in elderly travelers.
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http://dx.doi.org/10.3390/vaccines8020249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349955PMC
May 2020

Applicability of scoring systems predicting outcome of transarterial chemoembolization for hepatocellular carcinoma.

J Cancer Res Clin Oncol 2020 Apr 27;146(4):1033-1050. Epub 2020 Feb 27.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany.

Purpose: Several scoring systems have been proposed to predict the outcome of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). However, the application of these scores to a bridging to transplant setting is poorly validated. Evaluation of the applicability of prognostic scores for patients undergoing TACE in palliative intention vs. bridging therapy to liver transplantation (LT) is necessary.

Methods: Between 2008 and 2017, 148 patients with HCC received 492 completed TACE procedures (158 for bridging to transplant; 334 TACE procedures in palliative treatment intention at our center and were analyzed retrospectively. Scores (ART, CLIP, ALBI, APRI, SNACOR, HAP, STATE score, Child-Pugh, MELD, Okuda and BCLC) were calculated and evaluated for prediction of overall survival. ROC analysis was performed to assess prediction of 3-year survival and treatment discontinuation.

Results: In patients receiving TACE in palliative intention most scores predicted OS in univariate analysis but only mSNACOR score (p = 0.006), State score (p < 0.001) and Child-Pugh score (p < 0.001) revealed statistical significance in the multivariate analysis. In the bridging to LT cohort only the BCLC score revealed statistical significance (p = 0.002).

Conclusions: Clinical usability of suggested scoring systems for TACE might be limited depending on the individual patient cohorts and the indication. Especially in patients receiving TACE as bridging to LT none of the scores showed sufficiently applicability. In our study Child-Pugh score, STATE score and mSNACOR score showed the best performance assessing OS in patients with TACE as palliative therapy.
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http://dx.doi.org/10.1007/s00432-020-03135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085483PMC
April 2020

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

J Clin Invest 2020 05;130(5):2364-2376

Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.

BACKGROUNDPreclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODSIn this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day -2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTSMIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSIONMIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATIONEudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220.FUNDINGFederal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
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http://dx.doi.org/10.1172/JCI133595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190926PMC
May 2020

Cell Cycle Biomarkers and Soluble Urokinase-Type Plasminogen Activator Receptor for the Prediction of Sepsis-Induced Acute Kidney Injury Requiring Renal Replacement Therapy: A Prospective, Exploratory Study.

Crit Care Med 2019 12;47(12):e999-e1007

Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy.

Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long's tests, and logistic regression models were calculated.

Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018.

Patients: One-hundred critically ill patients with positive Sepsis-3 criteria.

Interventions: None.

Measurement And Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80-0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75-0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86-1.00]).

Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.
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http://dx.doi.org/10.1097/CCM.0000000000004042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867703PMC
December 2019

Urinary cell cycle arrest biomarker [TIMP-2]·[IGFBP7] in patients with hepatorenal syndrome.

Biomarkers 2019 Nov 22;24(7):692-699. Epub 2019 Aug 22.

Department of Gastroenterology, University Hospital Heidelberg , Heidelberg , Germany.

Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients' outcome. Nevertheless diagnosis of HRS remains difficult. First-line therapy terlipressin is often associated with severe complications. Biomarkers become more on focus for an early diagnosis. The aim of this study was to test the diagnostic accuracy of urinary [TIMP-2]·[IGFBP7] for HRS patients and prognostic value for therapy responding patients. NephroCheck measures urinary concentrations of TIMP-2 and IGFBP-7, both indicating stress of renal cells and associated with induction of cell cycle arrest. 22 HRS patients and 30 patients with normal kidney function were included. [TIMP-2]·[IGFBP7] was measured using NephroCheck. HRS patients receiving terlipressin were also examined. [TIMP-2]·[IGFBP7] values did not differ significantly (1.3 ± 2.09 vs. 1.03 ± 1.03;  = 0.55). Furthermore, there was no significant difference of [TIMP-2]·[IGFBP7] regarding response of terlipressin (1.32 ± 2.39 vs. 0.81 ± 1.05;  = 0.56). Low [TIMP-2]·[IGFBP7] values were significantly associated with higher mortality ( = 0.01). The results of this study suggest that [TIMP-2]·[IGFBP7] is not suitable for diagnostic of HRS and prediction of therapy response, but there might be evidence for prognostic value of [TIMP-2]·[IGFBP7] in regard to mortality of liver cirrhosis patients.
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http://dx.doi.org/10.1080/1354750X.2019.1652347DOI Listing
November 2019

An ultra-sensitive UHPLC-MS/MS assay for the quantification of orally administered vancomycin in plasma.

J Pharm Biomed Anal 2019 Sep 27;174:633-638. Epub 2019 Jun 27.

Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Though marketed for over half a century, little is known about the pharmacokinetics of oral vancomycin except that its bioavailability is low, thus making accurate determination of plasma concentrations difficult. To quantify plasma concentrations of vancomycin after oral administration, we developed an ultra-sensitive UHPLC-MS/MS assay and validated it according to FDA´s and EMA´s pertinent guidelines. A fast and simple protein precipitation method followed by short UHPLC chromatography was developed for extraction and separation of vancomycin from plasma. Quantification was performed via heated positive electrospray tandem mass spectrometry with multiple reaction monitoring using deuterated internal standard. The assay was linear in the calibrated concentration range of 0.05-100 ng/mL showing correlation coefficients >0.997. Intraday and interday accuracy showed coefficients of variation <12% at the lower limit of quantification (LLOQ) of 0.05 ng/mL and <6% in the calibrated range while corresponding values for precision were <13% and <8%, respectively. With its high sensitivity, the assay allows for the accurate quantification of therapeutic plasma concentrations in the therapeutic range (up to 100 μg/mL) in 1000-fold diluted samples with a sample volume decreased down to 1 μL. The UHPLC-MS/MS assay was successfully used for the determination of trough plasma concentrations of two patients with Clostridium difficile infection receiving oral vancomycin therapy and its performance was compared to a commercial immunoassay for concentrations close to its LLOQ.
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http://dx.doi.org/10.1016/j.jpba.2019.06.015DOI Listing
September 2019

Clinical features of Wilson disease.

Ann Transl Med 2019 Apr;7(Suppl 2):S61

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH-University Hospital, Aachen, Germany.

Wilson disease (WD) presents often as a chameleon with a plethora of mild and discrete symptoms. As disease of young aged people, the clinical diagnosis is extremely difficult and misdiagnoses are frequent. Tremor, dysarthria and hepatomegaly sometimes suggest alcoholic liver disease which is a disaster for the patients. Due to the only moderate abnormality of liver function tests the disease is underestimated in its severity with a fatal prognosis when not adequately treated. Therefore, it is the challenge to consider WD as diagnosis, particularly in young patients with unclear liver disease, neuropsychiatric disorders or hemolysis.
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http://dx.doi.org/10.21037/atm.2019.01.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531660PMC
April 2019

Metallothionein is elevated in liver and duodenum of Atp7b mice.

Biometals 2018 08 7;31(4):617-625. Epub 2018 May 7.

Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.

Different mutations in the copper transporter gene Atp7b are identified as the primary cause of Wilson's disease. These changes result in high copper concentrations especially in the liver and brain, and consequently lead to a dysfunction of these organs. The Atp7 mouse is an established animal model for Wilson's disease and characterized by an abnormal copper accumulation, a low serum oxidase activity and an increased copper excretion in urine. Metallothionein (MT) proteins are low molecular weight metal-binding proteins and essential for the zinc homeostasis but also play a role for the regulation of other metals, e.g. copper. However the molecular mechanisms of MT in regard to Atp7b remain still elusive. In this study we investigate the expression of MT in the liver and duodenum of Atp7b mice and wildtype mice. Hepatic and duodenal expression of MT was measured by real-time reverse transcription-polymerase chain reaction and post-translational expression was analyzed by immunoblot and immunofluorescence. Expression of MT in liver und duodenum was significantly higher in Atp7b mice than in controls. Hepatic and duodenal copper, iron and zinc content were also studied. Compared to control hepatic copper and iron content was significantly higher while hepatic zinc content was significantly lower in Atp7b mice. In the duodenum copper and zinc content of Atp7b mice was significantly lower than in controls. Duodenal iron content was also lower in Atp7b mice, but did not reach statistical significance. The results of our study suggest that metallothionein is elevated in the liver and duodenum of Atp7b mice.
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http://dx.doi.org/10.1007/s10534-018-0110-xDOI Listing
August 2018

Hemophagocytic lymphohistiocytosis in an adult kidney transplant recipient successfully treated by plasmapheresis: A case report and review of the literature.

Medicine (Baltimore) 2017 Dec;96(50):e9283

Department of Nephrology Department of Anesthesiology Departement of Gastroenterology, Heidelberg University Hospital, Germany.

Rationale: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease entity primarily described in children, but not less relevant in adults. It is characterized by a misdirected activation of the immune system, resulting in an uncontrolled cytokine release from macrophages and cytotoxic T-cells (CTLs). Primary HLH relies on a genetic predisposition, whereas secondary HLH develops in the context of infections, malignancies or autoimmune diseases. However, the awareness and therapeutic knowledge for HLH in adulthood is limited. Most therapy protocols are almost exclusively validated in pediatric cohorts and for primary HLH. Their transferability to adult individuals with mostly secondary HLH is doubtful. Especially the high liver and bone marrow toxicity of applied etoposide-based protocols is discussed controversially and connected to overwhelming infections and death.

Patient Concern: A 51-year old, male, kidney transplant recipient was admitted to our center suffering from diarrhea, fever, nausea, hyponatremia, kidney graft failure, disorientation, progressive hemodynamic instability, and multiorgan failure.

Diagnoses: Clinical and laboratory findings resembled those of a septic shock. Ferritin and soluble interleukin-2 receptor (sCD25) levels were disproportionally elevated. Only a mild hepatosplenomegaly was diagnosed in a CT scan. A T2-weighted, fluid-attenuated inversion recovery MRI showed marked, bilateral and periventricular white matter hyperintensities. The cerebrospinal fluid (CSF) analysis showed a moderately elevated protein content and cell count. There was no evidence of any bacterial, viral, or parasitic infection. The diagnosis of HLH was made.

Interventions & Outcomes: The patient was successfully treated by a combined approach consisting of plasma exchange (PE), corticosteroids, anakinra, and cyclosporine (CsA).

Lessons: HLH is an important differential diagnosis in critically ill patients. Its unspecific clinical picture complicates an early diagnosis and may be misclassified as sepsis. A combination of plasma exchange (PE), corticosteroids, anakinra, and cyclosporine (CsA) may be a promising and less toxic approach for HLH therapy in adults.
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http://dx.doi.org/10.1097/MD.0000000000009283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815798PMC
December 2017

Hypercalcemia, necrotizing pancreatitis and bone lesions: a benign cause.

Clin Cases Miner Bone Metab 2017 May-Aug;14(2):245-246. Epub 2017 Oct 25.

Department of Gastroenterology and Hepatology, University Hospital, Heidelberg, Germany.

Primary Hyperparathyroidism is asymptomatic in most patients (PHPT). We report a case of PHPT in a young male patient. He presented with severe pancreatitis due to hypercalcemia and multiple bone lesions resulting in pathological fractures. The patients recovered rapidly after parathyroidectomy.
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http://dx.doi.org/10.11138/ccmbm/2017.14.2.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726219PMC
October 2017

Slow ventricular tachycardia presenting with acute liver failure.

SAGE Open Med Case Rep 2017 12;5:2050313X17718100. Epub 2017 Jul 12.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

Objectives: Cardiac hepatopathy is an important differential diagnosis of acute liver failure. Slow ventricular tachycardia (slow VT) is a ventricular tachycardia (VT), in which heart rate is below the typical frequency of VT. We here report a case of acute liver failure in a patient with slow VT.

Methods: The 64-year old male patient with history of cardiac pacemaker implantation for complete atrioventricular block was referred to our intensive care unit because of acute liver failure.

Results: Workup identified cardiac failure as cause of hepatopathy; however, reason for cardiac failure remained unknown even after left heart catheterization with coronary angiography. Finally, the analysis of cardiac pacemaker recordings led to the diagnosis of slow VT. This could not be terminated with either electric cardioversion or pharmacological treatment, and the patient died of cardiac failure.

Conclusion: Diagnosis of VT can be challenging if occurring at unexpected slow heart rates. Analysis of pacemaker recordings could help to make the diagnosis of slow VT.
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http://dx.doi.org/10.1177/2050313X17718100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528920PMC
July 2017

Pseudobacteremia outbreak of biofilm-forming Achromobacter xylosoxidans - environmental transmission.

BMC Infect Dis 2016 10 19;16(1):584. Epub 2016 Oct 19.

Department of Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 324, D-69120, Heidelberg, Germany.

Background: Achromobacter xylosoxidans (AX) is known for intrinsic resistance to disinfectants. Our laboratory routine surveillance system detected an unexpected rise in AX bloodstream infections in a 2200-bed hospital. An epidemiological investigation was conducted to find the source and disrupt further transmission.

Methods: Outbreak cases were defined as patients with at least one positive blood culture positive for AX from May 2014 to May 2015. Medical records were reviewed, affected wards, as well as the microbiology laboratory were audited. Additionally, microbiologic culture and biofilm staining for suspected antiseptic reusable tissue dispensers were performed, and isolated AX strains were typed using RAPD PCR and PFGE.

Results: During the outbreak period, AX were isolated from blood cultures from 26 patients. The retrospective cohort study did not reveal common risk factors. The clinical features of the case patients suggested a pseudobacteremia. The reusable tissue dispensers containing Incidin® Plus solution product were found to be contaminated with biofilm-forming AX. Typing of the isolates revealed that blood culture isolates were identical with the strains found in the dispensers.

Conclusions: After changing the usage of the product to single-use and educating staff, the outbreak was terminated. Contamination of dispensers occurred due to insufficient reprocessing, since biofilm disrupting steps were not included in the process.
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http://dx.doi.org/10.1186/s12879-016-1909-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070352PMC
October 2016

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

J Clin Invest 2016 07 20;126(7):2721-35. Epub 2016 Jun 20.

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.
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http://dx.doi.org/10.1172/JCI85226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922707PMC
July 2016

Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice.

Hepatology 2016 06 22;63(6):1828-41. Epub 2016 Feb 22.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Unlabelled: Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper-transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b(-/-) mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b(-/-) mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b(-/-) mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved.

Conclusions: The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828-1841).
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http://dx.doi.org/10.1002/hep.28406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874878PMC
June 2016
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