Publications by authors named "Christian Lange"

199 Publications

Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity.

Front Immunol 2020 14;11:581352. Epub 2021 Jan 14.

Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
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http://dx.doi.org/10.3389/fimmu.2020.581352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874116PMC
January 2021

Editorial: Metabolic Regulation of Stem Cells and Tissue Growth.

Front Mol Neurosci 2020 28;13:625606. Epub 2021 Jan 28.

Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

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http://dx.doi.org/10.3389/fnmol.2020.625606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876400PMC
January 2021

Dysregulated Adaptive Immunity Is an Early Event in Liver Cirrhosis Preceding Acute-on-Chronic Liver Failure.

Front Immunol 2020 26;11:534731. Epub 2021 Jan 26.

Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.

Introduction: Acute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF.

Conclusion: Impaired innate and-in particular-adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.
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http://dx.doi.org/10.3389/fimmu.2020.534731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870861PMC
January 2021

[Ga]Ga-PSMA-11 PET/CT improves tumor detection and impacts management in patients with hepatocellular carcinoma (HCC).

J Nucl Med 2021 Jan 28. Epub 2021 Jan 28.

Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Germany.

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. A growing number of local and systemic therapies are available, and accurate staging is critical for management decisions. We assessed the impact of neovasculature imaging by Ga-Ga-PSMA-11 PET/CT on disease staging, prognostic groups and management of patients with HCC compared to staging with computed tomography (CT). Forty patients who received imaging with Ga-Ga-PSMA-11 PET/CT for HCC staging between September 2018 and September 2019 were retrospectively included. Management pre- and post-PET scan was assessed by standardized surveys. Presence of HCC was evaluated by three blinded readers on a per-patient and per-region basis for PET/CT (PET criteria) and multi-phase contrast-enhanced CT (CT criteria) in separate sessions. Lesions were validated by follow-up imaging or histopathology, and progression-free survival (PFS) was recorded. Endpoints were detection rate and positive predictive value (PPV) for Ga-Ga-PSMA-11 PET vs. CT, inter-reader reproducibility, and changes in stage, prognostic groups and management plans. Median age was 65 years (range, 37-81), median Child-Pugh score was 5 (range, 5-9). Most patients were treatment naïve (27 of 40, 67.5%). The sensitivity of PET vs. CT to identify liver lesions for patients with lesion validation was 31/32 (97%) for both modalities, while it was 6/6 (100%) vs. 4/6 (67%) for extra-hepatic lesions. PET and CT each had a PPV of 100% at the liver level. PET vs. CT stage was congruent in 30/40 (75%) patients; upstaging was seen in 8/40 patients (20%), while 2/40 (5%) had downstaging by PET. Intended management changed in 19/40 patients (47.5%); 9/19 of these patients were found to have detectable distant metastases (47.4%) and assigned stage 4 disease, the majority of whom were shifted to systemic therapy (8 of 9, 89%). Two patients underwent Lu-Lu-PSMA-617 radioligand therapy. Median PFS was 5.2 months for the entire cohort; 5.3 months for PET M0, and 4.7 months for PET M1 patients, respectively. Ga-Ga-PSMA-11 PET demonstrated higher accuracy than CT in the detection of HCC metastases and was associated with management change in about half of the patient cohort.
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http://dx.doi.org/10.2967/jnumed.120.257915DOI Listing
January 2021

Progression of aural plaques to squamous cell carcinoma in a horse.

Vet Dermatol 2020 Oct 28;31(5):397-400. Epub 2020 Jul 28.

Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, 382 West Street Rd., Kennett Square, PA, 19348, USA.

Background: Aural plaques are associated with and thought to be caused by one or more Equus caballus papillomaviruses (EcPV). Aural plaques have not previously been reported to be associated with squamous cell carcinoma (SCC).

Hypothesis/objectives: To describe a horse with aural plaques and squamous cell carcinoma (SCC) on the right pinna.

Animals: A 28-year-old thoroughbred gelding presented for multiple plaques and a mass on the right pinna.

Methods And Materials: Pinnal resection, histopathological investigation, multiple conventional PCRs for papillomavirus DNA and Sanger sequencing were performed.

Results: Multiple, raised, pale tan, fronded plaques covered 60% of the concave surface of the right pinna. Focally these plaques coalesced into an exophytic ulcerated mass near the base of the pinna. Multiple aural plaques and a SCC were diagnosed histopathologically. EcPV4 was detected via PCR in a sample of the SCC.

Conclusions And Clinical Importance: This report demonstrates the possibility of malignant transformation from aural plaques to SCC on the pinna of a horse. To the best of the authors' knowledge, this is the first report of EcPV4 associated with SCC.
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http://dx.doi.org/10.1111/vde.12870DOI Listing
October 2020

Hypopituitarism in Wilson's disease resolved after copper-chelating therapy.

Endocrinol Diabetes Metab Case Rep 2021 Jan 11;2021. Epub 2021 Jan 11.

Medical Department 1, University Hospital of the Goethe-University Frankfurt, Frankfurt am Main, Germany.

Summary: Wilson's disease (WD) is a rare disorder of copper metabolism usually presenting with variable liver damage and neuropsychiatric symptoms. Here we report a 39-year-old Taiwanese female with late manifestation of WD presenting with gonadotroph, thyreotroph and corticotroph hypopituitarism. Molecular genetic testing revealed compound heterozygosity for two mutations in exons 12 and 14 (c.2828G>A and c.3140A>T). Copper-chelating therapy with D-penicillamine and zinc was initiated along with supplementation of hydrocortisone and L-thyroxine. Hypopituitarism resolved when urinary copper excretion returned to normal levels under copper chelation. This case should raise awareness of pituitary function in WD patients.

Learning Points: Hypopituitarism can complicate Wilson's disease (WD) and endocrinologists should be aware of it when caring for hypopituitary patients. Hepatologists should consider endocrinologic testing for hypopituitarism when WD patients present with symptoms of adrenal insufficiency, thyroid or gonadal dysfunction. Copper-chelating treatment is mandatory and may lead to the recovery of pituitary function in such patients.
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http://dx.doi.org/10.1530/EDM-20-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849456PMC
January 2021

A switch in pdgfrb cell-derived ECM composition prevents inhibitory scarring and promotes axon regeneration in the zebrafish spinal cord.

Dev Cell 2021 Feb 6;56(4):509-524.e9. Epub 2021 Jan 6.

Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, 01307 Dresden, Germany; Max Planck Institute for the Science of Light, 91058 Erlangen, Germany; Max-Planck-Zentrum für Physik und Medizin, 91058 Erlangen, Germany. Electronic address:

In mammals, perivascular cell-derived scarring after spinal cord injury impedes axonal regrowth. In contrast, the extracellular matrix (ECM) in the spinal lesion site of zebrafish is permissive and required for axon regeneration. However, the cellular mechanisms underlying this interspecies difference have not been investigated. Here, we show that an injury to the zebrafish spinal cord triggers recruitment of pdgfrb myoseptal and perivascular cells in a PDGFR signaling-dependent manner. Interference with pdgfrb cell recruitment or depletion of pdgfrb cells inhibits axonal regrowth and recovery of locomotor function. Transcriptional profiling and functional experiments reveal that pdgfrb cells upregulate expression of axon growth-promoting ECM genes (cthrc1a and col12a1a/b) and concomitantly reduce synthesis of matrix molecules that are detrimental to regeneration (lum and mfap2). Our data demonstrate that a switch in ECM composition is critical for axon regeneration after spinal cord injury and identify the cellular source and components of the growth-promoting lesion ECM.
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http://dx.doi.org/10.1016/j.devcel.2020.12.009DOI Listing
February 2021

Stool and sputum microbiome during quinolone prophylaxis of spontaneous bacterial peritonitis: an exploratory study.

Gut Pathog 2020 Oct 30;12(1):51. Epub 2020 Oct 30.

Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized.

Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome.

Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis.

Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.
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http://dx.doi.org/10.1186/s13099-020-00389-yDOI Listing
October 2020

Redistribution of Monocyte Subsets in Obstructive Sleep Apnea Syndrome Patients Leads to an Imbalanced PD-1/PD-L1 Cross-Talk with CD4/CD8 T Cells.

J Immunol 2021 Jan 2;206(1):51-58. Epub 2020 Dec 2.

Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany

Obstructive sleep apnea syndrome (OSAS) represents a substantial disease of recurrent sleep fragmentation, leading to intermittent hypoxia and subsequent diseases such as cardiovascular, metabolic, or cognitive dysfunctions. In addition, OSAS is considered as low-grade systemic inflammation, which is associated with a higher incidence of cancer, severity of infections, and an overall immune dysregulation. This research project aims to comprehensively investigate the interplay of wholesome sleep and the immune functions of circulating monocytes and T cells in OSAS patients, which are known to be affected by oxidative stress. We studied the distribution of the CD14/CD16 characterized monocyte subsets in peripheral blood as well as their PD-L1 expression and complex formation with T cells. Furthermore, a detailed analysis of T cell subsets with regard to their PD-1 and PD-L1 expression was performed. Data revealed a decrease of classical monocytes accompanied by an increase of both CD16 monocyte subsets in OSAS patients that was positively correlated with the body mass index. OSAS patients revealed an increased PD-1 and PD-L1 expression in T cells and monocytes, respectively, which was linked to the severity of monocyte subset alterations. The complex formation of monocytes and T cells was also elevated in OSAS patients, which indicates a deregulated PD-1/PD-L1 cross-talk between these cells. Our data show for the first time, to our knowledge, massive alterations of peripheral monocyte subsets in response to OSAS and its accompanying phenomena.
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http://dx.doi.org/10.4049/jimmunol.2001047DOI Listing
January 2021

Human Interactions with Bat Populations in Bombali, Sierra Leone.

Ecohealth 2020 09 11;17(3):292-301. Epub 2020 Nov 11.

Metabiota, Inc., 425 California St., Suite 1200, San Francisco, CA, 94104, USA.

Human contact with bats has been epidemiologically linked to several of the most recent Ebola outbreaks, including the 2014 West Africa epidemic and the 2007 Luebo, Democratic Republic of the Congo, outbreak. While fruit bats remain the likely primary reservoir for Ebola virus (Zaire ebolavirus), recent wildlife surveillance efforts have identified a new species of ebolavirus (Bombali ebolavirus) in microchiropteran insect-eating bats in West and East Africa. Given the role of bats as potential Ebola reservoirs and sources of spillover into human populations, it is critically important to understand the circumstances and behaviors that bring human populations into close contact with bats. This study explores two sites in Bombali, Sierra Leone, where human populations have had close contact with microchiropteran bats via household infestations and fruit bats by hunting practices. Through interviews and focus groups, we identify the knowledge, beliefs, perceptions, and behaviors that may potentially protect or expose individuals to zoonotic spillover through direct and indirect contact with bats. We also describe how this research was used to develop a risk reduction and outreach tool for living safely with bats.
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http://dx.doi.org/10.1007/s10393-020-01502-yDOI Listing
September 2020

Reactive oligodendrocyte progenitor cells (re-)myelinate the regenerating zebrafish spinal cord.

Development 2020 12 16;147(24). Epub 2020 Dec 16.

Center for Regenerative Therapies Dresden TU Dresden (CRTD) and Cluster of Excellence, Physics of Life (PoL), TU Dresden, Dresden 01307, Germany

Spinal cord injury (SCI) results in loss of neurons, oligodendrocytes and myelin sheaths, all of which are not efficiently restored. The scarcity of oligodendrocytes in the lesion site impairs re-myelination of spared fibres, which leaves axons denuded, impedes signal transduction and contributes to permanent functional deficits. In contrast to mammals, zebrafish can functionally regenerate the spinal cord. Yet, little is known about oligodendroglial lineage biology and re-myelination capacity after SCI in a regeneration-permissive context. Here, we report that, in adult zebrafish, SCI results in axonal, oligodendrocyte and myelin sheath loss. We find that OPCs, the oligodendrocyte progenitor cells, survive the injury, enter a reactive state, proliferate and differentiate into oligodendrocytes. Concomitantly, the oligodendrocyte population is re-established to pre-injury levels within 2 weeks. Transcriptional profiling revealed that reactive OPCs upregulate the expression of several myelination-related genes. Interestingly, global reduction of axonal tracts and partial re-myelination, relative to pre-injury levels, persist at later stages of regeneration, yet are sufficient for functional recovery. Taken together, these findings imply that, in the zebrafish spinal cord, OPCs replace lost oligodendrocytes and, thus, re-establish myelination during regeneration.
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http://dx.doi.org/10.1242/dev.193946DOI Listing
December 2020

Single-cell transcriptome analysis reveals thyrocyte diversity in the zebrafish thyroid gland.

EMBO Rep 2020 12 3;21(12):e50612. Epub 2020 Nov 3.

IRIBHM, Université Libre de Bruxelles (ULB), Brussels, Belgium.

The thyroid gland regulates growth and metabolism via production of thyroid hormone in follicles composed of thyrocytes. So far, thyrocytes have been assumed to be a homogenous population. To uncover heterogeneity in the thyrocyte population and molecularly characterize the non-thyrocyte cells surrounding the follicle, we developed a single-cell transcriptome atlas of the region containing the zebrafish thyroid gland. The 6249-cell atlas includes profiles of thyrocytes, blood vessels, lymphatic vessels, immune cells, and fibroblasts. Further, the thyrocytes show expression heterogeneity, including bimodal expression of the transcription factor pax2a. To validate thyrocyte heterogeneity, we generated a CRISPR/Cas9-based pax2a knock-in line that monitors pax2a expression in the thyrocytes. A population of pax2a-low mature thyrocytes interspersed in individual follicles can be distinguished. We corroborate heterogeneity within the thyrocyte population using RNA sequencing of pax2a-high and pax2a-low thyrocytes, which demonstrates 20% differential expression in transcriptome between the two subpopulations. Our results identify and validate transcriptional differences within the presumed homogenous thyrocyte population.
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http://dx.doi.org/10.15252/embr.202050612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726803PMC
December 2020

Stool and sputum microbiome during quinolone prophylaxis of spontaneous bacterial peritonitis: an exploratory study.

Gut Pathog 2020 30;12:51. Epub 2020 Oct 30.

Present Address: Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized.

Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome.

Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant ) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis.

Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.
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http://dx.doi.org/10.1186/s13099-020-00389-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596951PMC
October 2020

Response to the Letter: Impact of SARS-CoV-2 Infection on Patients Suffering from Liver Injury.

Dig Dis 2021 9;39(1):68-69. Epub 2020 Oct 9.

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

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http://dx.doi.org/10.1159/000512151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801960PMC
January 2021

Serum Sphingosine-1-Phosphate Is Decreased in Patients With Acute-on-Chronic Liver Failure and Predicts Early Mortality.

Hepatol Commun 2020 Oct 12;4(10):1477-1486. Epub 2020 Aug 12.

Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany.

Sphingosine-1-phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute-on-chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF ( < 0.001). S1P levels further decreased with progression to ACLF grade 3 ( < 0.05), and S1P highly inversely correlated with the Model for End-Stage Liver Disease score ( = -0.508;  < 0.001). In multivariate analysis, S1P remained an independent predictor of 7-day mortality with high diagnostic accuracy (area under the curve, 0.874;  < 0.001). In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.
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http://dx.doi.org/10.1002/hep4.1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527696PMC
October 2020

Efficacy of Norfloxacin Prophylaxis to Prevent Spontaneous Bacterial Peritonitis: A Systematic Review and Meta-Analysis.

Clin Transl Gastroenterol 2020 Aug;11(8):e00223

1Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; 2Liver Unit, Hospital Clinic Barcelona, Catalonia, Spain; 3Department for Gastroenterology and Hepatology, University Hospital Essen and University of Duisburg-Essen, Essen, Germany; 4Institute of Biostatistics and Mathematical Modeling, Goethe University, Frankfurt am Main, Germany.

Introduction: With the emergence of multidrug-resistant organisms, the efficacy of antibiotic prophylaxis to prevent spontaneous bacterial peritonitis (SBP) has been debated. The aim of this study was to assess factors impacting effectiveness of SBP prophylaxis.

Methods: We searched PubMed, Embase, and the Cochrane Registry from inception to May 2019 to identify randomized controlled trials of patients with liver cirrhosis that assessed SBP occurrence/recurrence during antibiotic prophylaxis with the common antibiotic agents. Network meta-analysis was performed, pooling data with regard to incidence rate ratios (IRRs) of SBP, death, or extraperitoneal infections.

Results: Overall, 1,626 patients in 12 randomized controlled trials were included. During primary prophylaxis, the incidence rate of SBP and death in the norfloxacin-treated patients was 0.117 and 0.438 per patient-year, respectively, and IRRs of placebo vs norfloxacin were significantly higher (IRR 5.35, 95% confidence interval 1.99-14.38, P = 0.0009 for SBP and IRR 2.04, 95% confidence interval 1.20-3.44, P = 0.008 for death). The efficacy of norfloxacin to prevent SBP, but not death, decreased over time (annual percent change from 1992 to 2015 8.2%, P = 0.019), The positive treatment effect was lower in studies including patients with increased ascites protein (P = 0.021) or exceedingly high serum bilirubin (P = 0.012) levels. Norfloxacin was not superior to other antibiotics. The incidence rate of SBP was 2.5-fold higher in patients treated with norfloxacin as secondary compared with primary prophylaxis. No significant differences between treatment designs were observed in secondary prophylaxis.

Discussion: Norfloxacin remained superior to placebo in preventing SBP, yet the efficacy to prevent SBP, not death, decreased over time. Further studies to understand this phenomenon are urgently needed.
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http://dx.doi.org/10.14309/ctg.0000000000000223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431273PMC
August 2020

Serology and Behavioral Perspectives on Ebola Virus Disease Among Bushmeat Vendors in Equateur, Democratic Republic of the Congo, After the 2018 Outbreak.

Open Forum Infect Dis 2020 Aug 17;7(8):ofaa295. Epub 2020 Jul 17.

Metabiota Inc, San Francisco, California, USA.

After the 2018 Ebola outbreak in Equateur Province, Democratic Republic of the Congo, we conducted behavioral interviews and collected samples from bushmeat vendors and primates in Mbandaka to test for evidence of Ebola virus exposure. Although participants indicated being aware of Ebola, they did not consider themselves at occupational risk for infection. We found antibodies against Zaire ebolavirus in one participant despite no reported history of disease or contact with infected individuals. Our data underline concerns of possible subclinical or undiagnosed Ebola virus infections and the importance and challenges of risk communication to populations who are occupationally exposed to bushmeat. Following the 2018 Ebola outbreak in Equateur Province, Democratic Republic of the Congo, bushmeat vendors interviewed in Mbandaka indicated being aware of Ebola, but did not consider themselves at occupational risk. Antibodies against Zaire ebolavirus were detected in one participant.
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http://dx.doi.org/10.1093/ofid/ofaa295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443109PMC
August 2020

Mild versus Severe Liver Injury in SARS-CoV-2 Infection.

Dig Dis 2021 10;39(1):52-57. Epub 2020 Aug 10.

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

Background: Abnormal liver function has been reported in patients with COVID-19 infection. The aim of our study was to report on the prevalence of liver injury in our cohort, to evaluate the association of mild versus severe liver injury with mortality in COVID-19 patients and to scrutinize the temporal pattern of viral detection and liver injury.

Methods: We present data from a German cohort of 147 SARS-CoV-2 infected patients. The patients were divided into 3 groups according to their liver status during treatment. The first group included patients without elevated alanine aminotransferase or bilirubin, the third group patients meeting the biochemical criteria of acute liver failure (ALF), and the second group all other patients.

Results: Liver injury was detected in 75 (50.7%) and 93 (63%) patients by admission and during treatment, respectively. ALF was associated with the male sex, younger age, and higher BMI. Mortality was associated with the presence of ALF (OR = 9.423, 95% CI: 2.410-36.858) in contrast to milder liver injury (OR 1.101, 95% CI: 0.435-2.791). In 30% of patients with mild liver injury and in 50% of ALF patients, peak liver injury was observed at a time point when the virus was no longer detectable in the respiratory tract.

Conclusion: Mild liver injury was not associated with worse outcome in our cohort, and the pattern of liver injury did not fit well to the theory of SARS-CoV-2 directly causing liver impairment. Instead, severe liver injury in our cohort was associated multiple-organ failure and acute vascular events.
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http://dx.doi.org/10.1159/000510758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573903PMC
January 2021

Vertebrate brain regeneration - a community effort of fate-restricted precursor cell types.

Curr Opin Genet Dev 2020 10 7;64:101-108. Epub 2020 Aug 7.

Center for Regenerative Therapies Dresden (CRTD), CMCB, Technische Universität Dresden, Fetscherstr. 105, 01307, Dresden, Germany. Electronic address:

The process of regeneration describes the full restoration of tissue after destruction from injury or disease. Most mammals show very limited ability for regeneration of adult organs, while vertebrate models of regeneration such as fish and salamanders, allow to study regeneration mechanism of the brain, heart, limbs, retina, and other organs in adults. The regenerative abilities of teleost fish are well documented, but the cellular sources for regeneration, the specificity of source cells for restored cell types, as well as the extent and fidelity of cell replacement are only beginning to be revealed for many regeneration paradigms. Here, we highlight recent analyses of adult neurogenesis and regeneration after injury in teleost fish that address these issues, and we discuss how such analyses can help to evaluate the role of different cells in tissues in the regeneration process.
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http://dx.doi.org/10.1016/j.gde.2020.06.014DOI Listing
October 2020

Biomonitoring of Polycyclic Aromatic Hydrocarbon Deposition in Greenland Using Historical Moss Herbarium Specimens Shows a Decrease in Pollution During the 20 Century.

Front Plant Sci 2020 15;11:1085. Epub 2020 Jul 15.

Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Although most point sources of persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs), are at lower latitudes, the Arctic region is contaminated. In particular, PAHs now dominate the POP body burden of the region's marine biota at the lower trophic levels. Greenlandic Inuits have the most elevated levels of POPs in their blood compared to any other population, due to their consumption of seal meat and other marine mammals. PAHs, the by-products of the incomplete combustion of petroleum products, are known carcinogens and have been shown to affect the immune system, reproduction, endocrine functions, and the nervous system. With industrial activities and climate change set to increase local PAH emissions, it is paramount to document changes in atmospheric PAH deposition to further investigate PAH exposure in the region and attribute contaminations to their sources. As a measure of atmospheric pollution, we sampled bryophyte herbarium specimens of three common and widespread species collected in Greenland between the 1920s and 1970s after which time new collections were not available. They were analyzed for 19 PAHs using GC-MS (gas chromatography mass spectrometry). The presence of more low-molecular-weight PAHs than high-molecular-weight PAHs is evidence that the PAH contamination in Greenland is due to long-range transport rather than originating from local sources. The results show peaks in PAH atmospheric deposition in the first part of the 19th century followed by a trend of decrease, which mirror global trends in atmospheric pollution known from those periods. PAHs associated with wood and fossil-fuel combustion decrease in the 1970s coinciding with the disappearance of charcoal pits and foundries in Europe and North America, and a shift away from domestic heating with wood during the 19 century. The results highlight the value of bryophytes as bioindicators to measure PAH atmospheric pollution as well as the unrealized potential of herbaria as historical records of environmental change.
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http://dx.doi.org/10.3389/fpls.2020.01085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373755PMC
July 2020

Alox12/15 Deficiency Exacerbates, While Lipoxin A Ameliorates Hepatic Inflammation in Murine Alcoholic Hepatitis.

Front Immunol 2020 14;11:1447. Epub 2020 Jul 14.

Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A (LXA), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15 and Alox12/15 mice, with or without supplementation of LXA. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA significantly lowered transaminase levels only in Alox12/15 mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA injection attenuated selected parameters of disease progression in Alox12/15 mice, its beneficial impact on immunity was also apparent in Alox12/15 mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
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http://dx.doi.org/10.3389/fimmu.2020.01447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371948PMC
July 2020

Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors.

J Biol Chem 2020 10 3;295(40):13862-13874. Epub 2020 Aug 3.

Department of Internal Medicine 1, Goethe University Hospital Frankfurt, Frankfurt, Germany

Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
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http://dx.doi.org/10.1074/jbc.RA120.013898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535904PMC
October 2020

Standard coagulation tests are superior to thromboelastometry in predicting outcome of patients with liver cirrhosis.

PLoS One 2020 28;15(7):e0236528. Epub 2020 Jul 28.

Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background And Aims: Thromboelastometry (TEM) is superior to standard coagulation tests in the management of bleedings / invasive procedures in patients with liver cirrhosis. In contrast, the role of TEM as a prognostic parameter in liver cirrhosis is not well established. We therefore aimed to assess the role of TEM in predicting survival of outpatients with liver cirrhosis.

Methods: TEM was performed in consecutive outpatients with liver cirrhosis admitted in 2018 and 2019 to the University Hospital Essen. Associations with transplant-free survival were assessed in regression models.

Results: A number of 145 outpatients with liver cirrhosis were included, of whom 27 received a liver transplant (N = 7) or died (N = 20) within 6 months of follow-up. None of the TEM values was associated with transplant-free survival in this cohort. However, as expected, the classical coagulation tests INR (OR = 8.69 (95% CI 1.63-46.48), P = 0.01), PTT (OR = 1.15 (95% CI 1.04-1.27), P<0.01), as well as antithrombin (OR = 0.96 (95% CI 0.94-0.99), P<0.01), and protein C (OR = 0.96 (95% CI 0.92-0.99), P<0.01) were significantly associated with transplant-free survival.

Conclusion: In contrast to the superiority of TEM over classical coagulation tests to guide transfusion of blood products in patients with liver cirrhosis, TEM has no relevance in predicting mortality in outpatients with liver cirrhosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236528PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386616PMC
September 2020

A prospective, multicentre study in acute non-cirrhotic, non-malignant portal vein thrombosis: comparison of medical and interventional treatment.

Aliment Pharmacol Ther 2020 07 7;52(2):329-339. Epub 2020 Jun 7.

Freiburg, Germany.

Background: To evaluate medical versus interventional treatment (transjugular thrombus fragmentation, local thrombolysis with or without stent implantation) in patients with acute non-cirrhotic, non-malignant portal vein thrombosis (PVT).

Methods: This prospective, observational study enrolled 65 patients with acute (<28 days since begin of symptoms, no cavernoma) PVT in nine centres. Thirty patients received medical treatment and 35 patients received interventional treatment. PVT was graded into grade 1: short thrombosis and incomplete occlusion of the vessel lumen and grade 2: extended thrombosis or complete occlusion. Treatment response was classified as partial or complete, if thrombosis was reduced by one grade or to <25% of the vessel diameter respectively.

Results: Partial and complete response rates were 7% and 30% in the medical compared to 17% and 54% (P < 0.001) in the interventional treatment group. In the multivariate analysis, interventional treatment showed a strong positive (OR 4.32, P < 0.016) and a myeloproliferative aetiology a negative (OR 0.09, P = 0.006) prediction of complete response. Complications were rare in the medical group and consisted of septicaemia and upper gastrointestinal bleeding of unknown origin in one patient each. Interventional treatment was accompanied by mild and self-limiting bleeding complications in nine patients, moderate intra-abdominal bleeding requiring transfusions (2 units) in one patient and peritoneal bleeding requiring surgical rescue in one patient. Four patients in each group developed intestinal gangrene requiring surgery. One patient died 52 days after unsuccessful interventional treatment.

Conclusions: Compared to medical treatment alone, interventional treatment doubled response rates at the cost of increased bleeding complications.
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http://dx.doi.org/10.1111/apt.15811DOI Listing
July 2020

Coronavirus surveillance of wildlife in the Lao People's Democratic Republic detects viral RNA in rodents.

Arch Virol 2020 Aug 1;165(8):1869-1875. Epub 2020 Jun 1.

Metabiota Inc., Nanaimo, BC, Canada.

Coronaviruses can become zoonotic, as in the case of COVID-19, and hunting, sale, and consumption of wild animals in Southeast Asia increases the risk for such incidents. We sampled and tested rodents (851) and other mammals and found betacoronavirus RNA in 12 rodents. The sequences belong to two separate genetic clusters and are closely related to those of known rodent coronaviruses detected in the region and distantly related to those of human coronaviruses OC43 and HKU1. Considering the close human-wildlife contact with many species in and beyond the region, a better understanding of virus diversity is urgently needed for the mitigation of future risks.
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http://dx.doi.org/10.1007/s00705-020-04683-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265875PMC
August 2020

Anemia and Systemic Inflammation Rather than Arterial Circulatory Dysfunction Predict Decompensation of Liver Cirrhosis.

J Clin Med 2020 Apr 26;9(5). Epub 2020 Apr 26.

Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Background: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation.

Aim: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis.

Methods: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis.

Results: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism ( = 0.002), model of end-stage liver disease (MELD) score ( = 0.00002), serum IL-6 concentration ( = 0.006), heart rate ( = 0.03), low arterial blood pressure ( < 0.05), maximal portal venous flow ( = 0.008), and low hemoglobin concentration ( < 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51-0.78, = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01-1.04, = 0.03)-but not of hemodynamic parameters-with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow ( = -0.362, < 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, < 0.000001) was high.

Conclusion: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.
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http://dx.doi.org/10.3390/jcm9051263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287639PMC
April 2020

Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines.

Nat Commun 2020 03 13;11(1):1393. Epub 2020 Mar 13.

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.

Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.
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http://dx.doi.org/10.1038/s41467-020-15058-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069944PMC
March 2020

DSM-TACE of HCC: Evaluation of Tumor Response in Patients Ineligible for Other Systemic or Loco-Regional Therapies.

Rofo 2020 Sep 4;192(9):862-869. Epub 2020 Mar 4.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Germany.

Purpose:  To analyze tumor response, survival and safety in patients with non-resectable hepatocellular carcinoma (HCC) treated with transarterial hepatic chemoembolization using degradable starch microspheres (DSM-TACE) combined with doxorubicin who had no local interventional or systemic therapy alternative according to an interdisciplinary conference.

Materials And Methods:  In this retrospective study, 28 patients (23 male, 5 female, median age 67 years) with unresectable HCC, serum bilirubin levels < 3 mg/dl and contraindications to Sorafenib, RFA, SIRT or cTACE were included. DSM-TACE was performed using Embocept S (15 ml) and doxorubicin (50 mg/25 ml) three times every 4-6 weeks. Patients were initially staged using the Barcelona Clinic Liver Cancer System (BCLC). Basic liver function was evaluated with the MELD-score. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST).

Results:  DSM-TACE could be technically successfully performed in all 28 patients. At control imaging after three treatments, the overall rates of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were 14.3 %, 25 %, 39.3 % and 21.4 %, respectively, according to mRECIST. With regard to BCLC stages, the results were as follows (CR, PR, PD): BCLC A (n = 8): 7.1 %, 7.1 %, 10.7 %, 1.2 %; BCLC B (n = 12): 0 %, 10.7 %, 17.9 %, 14.3 %; BCLC C (n = 5): 0 %, 3.6 %, 10.7 %, 3.6 %; BCLC D (n = 3): 3.6 %, 3.6 %, 0 %, 3.6 %. According to this, DSM-TACE showed an overall good median survival of 682 days, although the patients' survival was strictly dependent on BCLC stage.

Conclusion:  DSM-TACE is a safe and promising treatment alternative for patients with unresectable HCC who are ineligible for other loco-regional therapies.

Key Points:   · DSM-TACE is a safe treatment alternative for patients ineligible for other local or systemic treatments.. · DSM-TACE did not influence the MELD-score in our study population.. · Patients treated with DSM-TACE showed an overall good median survival of 682 days, strictly dependent on BCLC stage..

Citation Format: · Haubold J, Reinboldt MP, Wetter A et al. DSM-TACE of HCC: Evaluation of Tumor Response in Patients Ineligible for Other Systemic or Loco-Regional Therapies. Fortschr Röntgenstr 2020; 192: 862 - 869.
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http://dx.doi.org/10.1055/a-1111-9955DOI Listing
September 2020

Evidence of Low-Level Dengue Virus Circulation in the South Region of Cameroon in 2018.

Vector Borne Zoonotic Dis 2020 04 14;20(4):314-317. Epub 2020 Jan 14.

Metabiota, Inc., Nanaimo, Canada.

Dengue fever is an understudied disease in many parts of Africa and little is known about its prevalence in Cameroon. We tested blood from 629 individuals from the South Region of Cameroon, collected over the course of one year, for flavivirus RNA using conventional broad range PCR. Flavivirus RNA corresponding to dengue virus (DENV) serotype 1 was identified in two individuals who were also diagnosed with malaria. This finding confirms previous reports that indicate the presence of low-level circulation of DENV in Cameroon and supports the concern that dengue fever may be underdiagnosed due to more prevalent diseases that have similar symptomology and insufficient diagnostic capacity.
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http://dx.doi.org/10.1089/vbz.2019.2531DOI Listing
April 2020