Publications by authors named "Martin Hersberger"

101 Publications

Cerebral perfusion in depression: Relationship to sex, dehydroepiandrosterone sulfate and depression severity.

Neuroimage Clin 2021 Sep 28;32:102840. Epub 2021 Sep 28.

Unit of Psychiatry Research, University of Fribourg, Chemin du Cardinal-Journet 3, 1752 Villars-sur-Glâne, Fribourg, Switzerland.

Background: Major depressive disorder (MDD) is a leading cause of disease burden and shows a marked sexual dimorphism. Previous studies reported changes in cerebral perfusion in MDD, an association between perfusion and dehydroepiandrosterone sulfate (DHEAS) levels, and large sex differences in perfusion. This study examines whether perfusion and DHEAS might mediate the link between sex and depressive symptoms in a large, unmedicated community sample.

Methods: The sample included 203 healthy volunteers and 79 individuals with past or current MDD. Depression severity was assessed with the Hamilton Depression Scale (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS). 3 T MRI perfusion data were collected with a pseudocontinuous arterial spin labelling sequence and DHEAS was measured in serum by LC-MS/MS.

Results: Large sex differences in perfusion were observed (p < 0.001). Perfusion was negatively correlated with DHEAS (r = -0.23, p < 0.01, n = 250) and with depression severity (HAM-D: r = -0.17, p = 0.01, n = 242; partial Spearman correlation, controlling for age and sex), but not with anxiety. A significant sex*perfusion interaction on depression severity was observed. In women, perfusion showed more pronounced negative correlations with depressive symptoms, with absent or, in the case of the MADRS, opposite effects observed in men. A mediation analysis identified DHEAS and perfusion as mediating variables influencing the link between sex and the HAM-D score.

Conclusion: Perfusion was linked to depression severity, with the strongest effects observed in women. Perfusion and the neurosteroid DHEAS appear to mediate the link between sex and HAM-D scores, suggesting that inter-individual differences in perfusion and DHEAS levels may contribute to the sexual dimorphism in depression.
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http://dx.doi.org/10.1016/j.nicl.2021.102840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515484PMC
September 2021

Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS.

Clin Chem Lab Med 2021 Oct 12;59(11):1811-1823. Epub 2021 Jul 12.

Division of Clinical Chemistry and Biochemistry, Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objectives: Lipid mediators are bioactive lipids which help regulate inflammation. We aimed to develop an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify 58 pro-inflammatory and pro-resolving lipid mediators in plasma, determine preliminary reference ranges for adolescents, and investigate how total parenteral nutrition (TPN) containing omega-3 polyunsaturated fatty acid (n-3 PUFA) or n-6 PUFA based lipid emulsions influence lipid mediator concentrations in plasma.

Methods: Lipid mediators were extracted from plasma using SPE and measured using UHPLC-MS/MS. EDTA plasma was collected from healthy adolescents between 13 and 17 years of age to determine preliminary reference ranges and from mice given intravenous TPN for seven days containing either an n-3 PUFA or n-6 PUFA based lipid emulsion.

Results: We successfully quantified 43 lipid mediators in human plasma with good precision and recovery including several leukotrienes, prostaglandins, resolvins, protectins, maresins, and lipoxins. We found that the addition of methanol to human plasma after blood separation reduces post blood draw increases in 12-hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE), 12S-hydroxyeicosatrienoic acid (12S-HETrE), 14-hydroxydocosahexaenoic acid (14-HDHA) and thromboxane B2 (TXB2). Compared to the n-6 PUFA based TPN, the n-3 PUFA based TPN increased specialized pro-resolving mediators such as maresin 1 (MaR1), MaR2, protectin D1 (PD1), PDX, and resolvin D5 (RvD5), and decreased inflammatory lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2).

Conclusions: Our method provides an accurate and sensitive quantification of 58 lipid mediators from plasma samples, which we used to establish a preliminary reference range for lipid mediators in plasma samples of adolescents; and to show that n-3 PUFA, compared to n-6 PUFA rich TPN, leads to a less inflammatory lipid mediator profile in mice.
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http://dx.doi.org/10.1515/cclm-2021-0644DOI Listing
October 2021

Omics Profiling of S2P Mutant Fibroblasts as a Mean to Unravel the Pathomechanism and Molecular Signatures of X-Linked Osteogenesis Imperfecta.

Front Genet 2021 21;12:662751. Epub 2021 May 21.

Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by low bone density, bone fragility and recurrent fractures. The characterization of its heterogeneous genetic basis has allowed the identification of novel players in bone development. In 2016, we described the first X-linked recessive form of OI caused by hemizygous missense variants resulting in moderate to severe phenotypes. encodes site-2 protease (S2P), which activates transcription factors involved in bone (OASIS) and cartilage development (BBF2H7), ER stress response (ATF6) and lipid metabolism (SREBP) via regulated intramembrane proteolysis. In times of ER stress or sterol deficiency, the aforementioned transcription factors are sequentially cleaved by site-1 protease (S1P) and S2P. Their N-terminal fragments shuttle to the nucleus to activate gene transcription. Intriguingly, missense mutations at other positions of cause the dermatological spectrum condition Ichthyosis Follicularis, Atrichia and Photophobia (IFAP) and Keratosis Follicularis Spinulosa Decalvans (KFSD) without clinical overlap with OI despite the proximity of some of the pathogenic variants. To understand how single amino acid substitutions in S2P can lead to non-overlapping phenotypes, we aimed to compare the molecular features of -OI and -IFAP/KFSD, with the ultimate goal to unravel the pathomechanisms underlying -OI. RNA-sequencing-based transcriptome profiling of primary skin fibroblasts from healthy controls ( = 4), -OI ( = 3), and IFAP/KFSD ( = 2) patients was performed to identify genes that are differentially expressed in -OI and IFAP/KFSD individuals compared to controls. We observed that SREBP-dependent genes are more downregulated in OI than in IFAP/KFSD. This is coupled to alterations in the relative abundance of fatty acids in -OI fibroblasts , while no consistent alterations in the sterol profile were observed. Few OASIS-dependent genes are suppressed in -OI, while BBF2H7- and ATF6-dependent genes are comparable between OI and IFAP/KFSD patients and control fibroblasts. Importantly, we identified genes involved in cartilage physiology that are differentially expressed in OI but not in -IFAP/KFSD fibroblasts. In conclusion, our data provide clues to how pathogenic mutations cause skeletal deformities via altered fatty acid metabolism or cartilage development that may affect bone development, mineralization and endochondral ossification.
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http://dx.doi.org/10.3389/fgene.2021.662751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176293PMC
May 2021

Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

Child and Adolescent Psychiatry Research Centre, Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital, University of Zurich, CH-8032 Zurich, Switzerland.

Major depressive disorders (MDDs) are often associated with a deficiency in long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs), as well as signs of low-grade inflammation. Epidemiological and dietary studies suggest that a high intake of fish, the major source of ω-3 PUFAs, is associated with lower rates of MDDs. Meta-analyses of randomized placebo-controlled ω-3 PUFAs intervention-trials suggest that primarily eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), is responsible for the proposed antidepressant effect. In this review, we dissect the current biological knowledge on EPA and DHA and their bioactive lipid metabolites to search for a pharmacological explanation of this, to date, unexplained clinical observation. Through enzymatic conversion by cyclooxygenase (COX), lipoxygenase (ALOX), and cytochrome P-450 monooxygenase (CYP), EPA and DHA are metabolized to major anti-inflammatory and pro-resolving lipid mediators. In addition, both ω-3 PUFAs are precursors for endocannabinoids, with known effects on immunomodulation, neuroinflammation, food intake and mood. Finally, both ω-3 PUFAs are crucial for the structure and organization of membranes and lipid rafts. While most biological effects are shared by these two ω-3 PUFAs, some distinct features could be identified: (1) The preferential CYP monooxygenase pathway for EPA and EPA derived eicosanoids; (2) The high CB2 receptor affinities of EPA-derived EPEA and its epoxy-metabolite 17,18-EEQ-EA, while the DHA-derived endocannabinoids lack such receptor affinities; (3) The competition of EPA but not DHA with arachidonic acid (AA) for particular glycerophospholipids. EPA and AA are preferentially incorporated into phosphatidylinositols, while DHA is mainly incorporated into phosphatidyl-ethanolamine, -serine and -choline. We propose that these distinct features may explain the superior antidepressant activity of EPA rich ω-3 PUFAs and that these are potential novel targets for future antidepressant drugs.
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http://dx.doi.org/10.3390/ijms22094393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122828PMC
April 2021

Advanced Imaging and New Cardiac Biomarkers in Long-term Follow-up After Childhood Cancer.

J Pediatr Hematol Oncol 2021 Apr 6. Epub 2021 Apr 6.

Department of Paediatric Cardiology, Heart Center Division of Clinical Chemistry and Biochemistry Department of Paediatric Oncology, University Children's Hospital, Zurich, Switzerland.

Objectives: Pathologic ejection fraction (EF), shortening fraction (FS), and standard heart failure biomarkers (high sensitive troponin T and N-terminal brain natriuretic peptide) during follow-up after childhood cancer have been associated with irreversible cardiac damage. We aimed to evaluate strain imaging values by echocardiography and new biomarkers for heart failure with preserved ejection fraction (HFpEF) as potential more sensitive parameters for cardiac deterioration in childhood cancer survivors (CCS).

Materials And Methods: Prospective study with 50 CCS (median 16.2 y) at a median follow-up of 13 years. In addition to standard echo and laboratory parameters for heart failure, strain measurements and new biomarkers, including myocardial inflammation (interleukin 6), extracellular matrix (ECM) remodeling (C-telopeptide for type I collagen, intact N-terminal propeptide of type III procollagen), and other heart failure biomarkers (galectin 3, solutable ST2, growth differentiation factor 15), were obtained and compared with 50 healthy controls.

Results: No significant differences in EF, FS, high sensitive troponin T, N-terminal brain natriuretic peptide, interleukin 6, solutable ST2, and galectin 3 were found between study and control groups. In contrast, strain imaging showed significant differences between both groups (global longitudinal strainGLS -16.1% vs. -20.4%, P<0.0001; global circumferential strain -14.3 vs. -21.4%, P<0.0001), detecting 66% (global longitudinal strain) and 76% (global circumferential strain) of patients with pathologic values in contrast to 6% (EF) and 16% (FS) for standard parameters. Markers for disturbances of ECM remodeling (C-telopeptide for type I collagen, intact N-terminal propeptide of type III procollagen, each P<0.0001) and growth differentiation factor 15 (P<0.0001) were significantly different between the groups.

Conclusion: Strain imaging and new cardiac biomarkers used in HFpEF focusing on ECM remodeling appear to be more sensitive in detecting early remodeling processes in CCS than standard echo and laboratory parameters.
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http://dx.doi.org/10.1097/MPH.0000000000002156DOI Listing
April 2021

Diet and Inflammatory Bowel Disease: What Quality Standards Should Be Applied in Clinical and Laboratory Studies?

Mol Nutr Food Res 2021 03 22;65(5):e2000514. Epub 2021 Feb 22.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, 27599-7080, USA.

Many patients suffering from inflammatory bowel disease (IBD) follow restrictive diets, as many respective recommendations circulate. Efforts are made to evaluate and summarize the published information, for example, in a recent consensus manuscript by the International Organization for the Study of IBD (IOIBD). However, the standards that should be applied to make claims about dietary effects are poorly defined. In this manuscript, the scientific basis of recommendations for nutritional interventions in IBD is analyzed. Epidemiological evidence on diet in IBD is always biased by numerous factors, and the number of robust dietary intervention studies is limited due to methodological difficulties. Therefore, animal models are used to test hypotheses with respect to dietary factors and intestinal inflammation. Naturally, animal models have limitations, and knowledge of key characteristics of colitis animal models is crucial to understand their advantages and disadvantages. In recent years the important role of the microbiota for IBD and dietary factors has been discovered. Microbiota data are added to many publications on IBD and nutrition. The quality of those data varies largely. Subsequently, quality standards for microbiota analyses also are discussed. Finally, quality requirements to be applied on recommendations for dietary changes in patients with IBD are suggested.
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http://dx.doi.org/10.1002/mnfr.202000514DOI Listing
March 2021

Verbal Memory Performance in Depressed Children and Adolescents: Associations with EPA but Not DHA and Depression Severity.

Nutrients 2020 Nov 25;12(12). Epub 2020 Nov 25.

Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, 8032 Zurich, Switzerland.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been described as positively associated with cognitive functioning. Current meta-analyses have identified eicosapentaenoic acid (EPA) as potentially more effective than docosahexaenoic acid (DHA). An especially vulnerable subgroup that might benefit from these beneficial effects are depressed youths. In this study, we examined associations between red blood cell (RBC) DHA and EPA levels and depression severity and verbal memory performance in a sample of 107 moderately ( = 63) and severely ( = 44) depressed youths. The findings showed that youths with high RBC EPA levels had steeper learning curves compared to those with moderate or low RBC EPA levels (Pillai's Trace = 0.195, = 0.027, η = 0.097). No associations between RBC DHA levels or depression severity and verbal memory performance were observed. Our results further confirm previous findings indicating a more important role of EPA compared to DHA in relation to cognitive functioning. Future research should further investigate the differential role of EPA and DHA concerning cognitive functioning in depressed youths. Evidence supporting beneficial supplementation effects could potentially establish a recommendation for a natural and easily accessible intervention for cognitive improvement or remission.
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http://dx.doi.org/10.3390/nu12123630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761519PMC
November 2020

Efficacy of intramuscular hydroxocobalamin supplementation in cats with cobalamin deficiency and gastrointestinal disease.

J Vet Intern Med 2020 Sep 20;34(5):1872-1878. Epub 2020 Aug 20.

Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland.

Background: In humans, absorption and tissue retention rates of intramuscularly administered hydroxocobalamin (OH-Cbl) are superior compared to cyanocobalamin (CN-Cbl). Supplementation with OH-Cbl has not been described in cats.

Objectives: To evaluate effects of parenteral OH-Cbl supplementation on clinical signs, serum Cbl and methylmalonic acid (MMA) concentrations in hypocobalaminemic cats with gastrointestinal disease.

Animals: Twenty-three client-owned cats.

Methods: Prospective study. Serum Cbl and MMA concentrations were determined at enrollment (t0), immediately before the 4th OH-Cbl IM injection (300 μg, given q2 weeks) (t1), and 4 weeks after the 4th injection (t2). Severity of clinical signs (activity, appetite, vomiting, diarrhea, body weight) was graded at each time point and expressed as clinical disease activity score.

Results: Median clinical disease activity score decreased significantly from t0 (6; range, 2-10) to t1 (1; range, 0-6) and t2 (1; range, 0-9). Median serum Cbl concentration increased significantly from 111 pmol/L (range, 111-218; reference range, 225-1451 pmol/L) at t0 to 1612 pmol/L (range, 526-14 756) (P < .001) at t1, and decreased again significantly to 712 pmol/L (range, 205-4265) (P < .01) at t2. Median baseline serum MMA concentration at t0 (802 nmol/L; range, 238-151 000; reference range, 120-420 nmol/L) decreased significantly (P < .001) to 199 nmol/L (range, 29-478) at t1, and was 205 nmol/L (range, 88-734) at t2. Serum MMA concentrations normalized in 22/23 cats at t1, and were not significantly higher at t2 compared to t1.

Conclusions And Clinical Importance: The herein described OH-Cbl injection scheme appears efficacious for normalization of cellular Cbl deficiency in cats with gastrointestinal disease.
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http://dx.doi.org/10.1111/jvim.15865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517839PMC
September 2020

Nutritional Lipids and Mucosal Inflammation.

Mol Nutr Food Res 2021 03 26;65(5):e1901269. Epub 2020 Aug 26.

Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, 8032, Switzerland.

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation in the intestine. Given their role in regulation of inflammation, long-chain n-3 polyunsaturated fatty acids (PUFAs) represent a potential supplementary therapeutic approach to current drug regimens used for IBD. Mechanistically, there is ample evidence for an anti-inflammatory and pro-resolution effect of long-chain n-3 PUFAs after they incorporate into cell membrane phospholipids. They disrupt membrane rafts and when released from the membrane suppress inflammatory signaling by activating PPAR-γ and free fatty acid receptor 4; furthermore, they shift the lipid mediator profile from pro-inflammatory eicosanoids to specialized pro-resolving mediators. The allocation of long-chain n-3 PUFAs also leads to a higher microbiome diversity in the gut, increases short-chain fatty acid-producing bacteria, and improves intestinal barrier function by sealing epithelial tight junctions. In line with these mechanistic studies, most epidemiological studies support a beneficial effect of long-chain n-3 PUFAs intake on reducing the incidence of IBD. However, the results from intervention trials on the prevention of relapse in IBD patients show no or only a marginal effect of long-chain n-3 PUFAs supplementation. In light of the current literature, international recommendations are supported that adequate diet-derived n-3 PUFAs might be beneficial in maintaining remission in IBD patients.
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http://dx.doi.org/10.1002/mnfr.201901269DOI Listing
March 2021

Choice of Lipid Emulsion Determines Inflammation of the Gut-Liver Axis, Incretin Profile, and Insulin Signaling in a Murine Model of Total Parenteral Nutrition.

Mol Nutr Food Res 2021 03 13;65(5):e2000412. Epub 2020 Aug 13.

Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada.

Scope: The aim of this study is to test whether the choice of the lipid emulsion in total parenteral nutrition (TPN), that is, n-3 fatty acid-based Omegaven versus n-6 fatty acid-based Intralipid, determines inflammation in the liver, the incretin profile, and insulin resistance.

Methods And Results: Jugular vein catheters (JVC) are placed in C57BL/6 mice and used for TPN for 7 days. Mice are randomized into a saline group (saline infusion with oral chow), an Intralipid group (IL-TPN, no chow), an Omegaven group (OV-TPN, no chow), or a chow only group (without JVC). Both TPN elicite higher abundance of lipopolysaccharide binding protein in the liver, but only IL-TPN increases interleukin-6 and interferon-γ, while OV-TPN reduces interleukin-4, monocyte chemoattractant protein-1, and interleukin-1α. Insulin plasma concentrations are higher in both TPN, while glucagon and glucagon-like peptide-1 (GLP-1) were higher in IL-TPN. Gluconeogenesis is increased in IL-TPN and the nuclear profile of key metabolic transcription factors shows a liver-protective phenotype in OV-TPN. OV-TPN increases insulin sensitivity in the liver and skeletal muscle.

Conclusion: OV-TPN as opposed to IL-TPN mitigates inflammation in the liver and reduces the negative metabolic effects of hyperinsulinemia and hyperglucagonemia by "re-sensitizing" the liver and skeletal muscle to insulin.
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http://dx.doi.org/10.1002/mnfr.202000412DOI Listing
March 2021

Diabetic Rat Hearts Show More Favorable Metabolic Adaptation to Omegaven Containing High Amounts of n3 Fatty Acids Than Intralipid Containing n6 Fatty Acids.

Anesth Analg 2020 09;131(3):943-954

Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background: While Omegaven, an omega-3 (n3) fatty acid-based lipid emulsion, fosters insulin signaling in healthy hearts, it is unknown whether beneficial metabolic effects occur in insulin-resistant diabetic hearts.

Methods: Diabetic hearts from fructose-fed Sprague-Dawley rats were perfused in the working mode for 90 minutes in the presence of 11 mM glucose and 1.2 mM palmitate bound to albumin, the first 30 minutes without insulin followed by 60 minutes with insulin (50 mU/L). Hearts were randomly allocated to Intralipid (25 and 100 µM), Omegaven (25 and 100 µM), or no emulsion (insulin alone) for 60 minutes. Glycolysis, glycogen synthesis, and glucose oxidation were measured with the radioactive tracers [5-H]glucose and [U-C]glucose. Central carbon metabolites, acyl-coenzyme A species (acyl-CoAs), ketoacids, purines, phosphocreatine, acylcarnitines, and acyl composition of phospholipids were measured with mass spectrometry.

Results: Diabetic hearts showed no response to insulin with regard to glycolytic flux, consistent with insulin resistance. Addition of either lipid emulsion did not alter this response but unexpectedly increased glucose oxidation (ratio of treatment/baseline, ie, fold change): no insulin 1.3 (0.3) [mean (standard deviation)], insulin alone 1.4 (0.4), insulin + 25 µM Intralipid 1.8 (0.5), insulin + 100 µM Intralipid 2.2 (0.4), P < .001; no insulin 1.3 (0.3), insulin alone 1.4 (0.4), insulin + 25 µM Omegaven 2.3 (0.5) insulin + 100 µM Omegaven 1.9 (0.4), P < .001. Intralipid treatment led to accumulation of acylcarnitines as a result of the released linoleic acid (C18:2-n6) and enhanced its integration into phospholipids, consistent with incomplete or impaired β-oxidation necessitating a compensatory increase in glucose oxidation. Accumulation of acylcarnitines was also associated with a higher nicotinamide adenine dinucleotide reduced/oxidized (NADH/NAD) ratio, which inhibited pyruvate dehydrogenase (PDH), and resulted in excess lactate production. In contrast, Omegaven-treated hearts showed no acylcarnitine accumulation, low malonyl-CoA concentrations consistent with activated β-oxidation, and elevated PDH activity and glucose oxidation, together indicative of a higher metabolic rate possibly by substrate cycling.

Conclusions: Omegaven is the preferred lipid emulsion for insulin-resistant diabetic hearts.
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http://dx.doi.org/10.1213/ANE.0000000000004838DOI Listing
September 2020

Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes.

Mol Nutr Food Res 2021 03 25;65(5):e1901270. Epub 2020 May 25.

Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada.

Total parenteral nutrition (TPN) is a life-saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN-associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut-originating incretins as well as the potentially toxicity of phytosterols and pro-inflammatory fatty acids mainly released from soybean oil-based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti-inflammatory n-3 to pro-inflammatory n-6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN-associated adverse effects.
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http://dx.doi.org/10.1002/mnfr.201901270DOI Listing
March 2021

LC-MS/MS method for the differential diagnosis of treatable early onset inherited metabolic epilepsies.

J Inherit Metab Dis 2020 09 16;43(5):1102-1111. Epub 2020 May 16.

Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.

Rapid diagnosis and early specific treatment of metabolic epilepsies due to inborn errors of metabolism (IEMs) is crucial to avoid irreversible sequalae. Nowadays, besides the profile analysis of amino- and organic acids, a range of additional targeted assays is used for the selective screening of those diseases. This strategy can lead to long turn-around times, repeated sampling and diagnostic delays. To replace those individual targeted assays, we developed a new liquid chromatography mass spectrometry method (LC-MS/MS) for the differential diagnosis of inherited metabolic epilepsies that are potentially treatable. The method was developed to simultaneously quantify 12 metabolites (sulfocysteine, guanidinoacetate, creatine, pipecolic acid, Δ -piperideine-6-carboxylate (P6C), proline, Δ -pyrroline-5-carboxylate (P5C), and the B -vitamers) enabling the diagnosis of nine different treatable IEMs presenting primarily with early-onset epilepsy. Plasma and urine samples were mixed with internal standards, precipitated and the supernatants were analyzed by LC-MS/MS. In comparison with previous assays, no derivatization of the metabolites is necessary for analysis. This LC-MS method was validated for quantitative results for all metabolites except P6C and P5C for which semiquantitative results were obtained due to the absence of commercially available standards. Coefficients of variation for all analytes were below 15% and recovery rates range between 80% and 120%. Analysis of patient samples with known IEMs demonstrated the diagnostic value of the method. The presented assay covers a selected panel of biochemical markers, improves the efficiency in the laboratory, and potentially leads to faster diagnoses and earlier treatment avoiding irreversible damage in patients affected with IEMs.
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http://dx.doi.org/10.1002/jimd.12244DOI Listing
September 2020

Polymorphisms of SOCS-1 Are Associated With a Rapid HIV Progression Rate.

J Acquir Immune Defic Syndr 2020 06;84(2):189-195

Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.

Objectives: Immune activation, among others driven by interferon (IFN)-α and IFN-γ activation, is a main feature of progressive HIV infection. Suppressor of cytokine signaling (SOCS) 1 and 3 are negative feedback regulators of the IFN-α and IFN-γ axis. Here, we analyzed the role of 9 single-nucleotide polymorphisms (SNPs) within SOCS-1 and SOCS-3 genes for their association with an HIV progression rate in a cohort of 318 rapid vs 376 slow progressors from the Swiss HIV Cohort Study.

Design And Methods: We analyzed 9 SNPs, which we have identified in Swiss blood donors, in a cohort of HIV-infected patients (n = 1144), which have been categorized according to the decline in CD4 T-cell counts. In all the conducted analyses, we focused on the comparison between rapid and slow progressors with regard to SNPs in SOCS-1 and SOCS-3 and with regard to haplotypes using multivariate logistic regression models.

Results: Three SOCS-1 SNPs (rs193779, rs33989964, and rs4780355) are associated with a risk reduction for rapid progression. Two of these SNPs, rs33989964 and rs4780355, are in strong linkage disequilibrium, forming a frequent haplotype. Homozygous carriers of this haplotype are also associated with a risk reduction for rapid progression. By contrast, the minor TT genotype of rs33977706 is associated with twice the risk for rapid progression. No associations have been observed for the 4 SOCS-3 SNPs or the major SOCS-3 haplotypes.

Conclusions: Our data suggest that SNPs in SOCS-1 are associated with HIV disease progression and speak in favor that immune activation is causal for the progressive immunodeficiency.
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http://dx.doi.org/10.1097/QAI.0000000000002319DOI Listing
June 2020

Validation of a Food Frequency Questionnaire to Assess Intake of Polyunsaturated Fatty Acids in Switzerland.

Nutrients 2019 Aug 10;11(8). Epub 2019 Aug 10.

Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, 8032 Zurich, Switzerland.

Population-based data suggest that high intake of omega-3 ( polyunsaturated fatty acids (PUFA) may be beneficial in a variety of health conditions. It is likely that mainly those patients with preexisting deficiency are those that benefit most from fatty acid supplementation. Therefore, for targeted interventions, a fast and reliable screening tool for PUFA intake is necessary. Thus, the aim of this project was to adapt and validate a food frequency questionnaire (FFQ) for PUFA intake in Switzerland while using as references the following: (1) 7-day food records (FR), and (2) fatty acid composition of red blood cells (RBC). We recruited 46 healthy adults for the first part of the study and 152 for the second. We used the dietary software EBISpro for the analysis of PUFA intake. RBC fatty acid composition was determined by gas chromatography mass spectrometry (GC-MS). Using correlation analysis, we found a moderate significant association between FFQ and FR for α-linolenic acid (ALA), eicosapentanoic acid (EPA), docosahexanoic acid (DHA), and total fatty acids (all between 0.523 and 0.586, all < 0.001). Bland Altman analysis further showed good agreement between the two methods and no proportional bias. Correlations between FFQ and RBC fatty acid composition were also moderate for EPA and DHA ( = 0.430 and = 0.605, < 0.001), but weaker for ALA and total ( = 0.314 and = 0.211, < 0.01). The efficacy of the FFQ to classify individuals into the same or adjacent quartile of RBC PUFA content ranged between 70% and 87% for the different fatty acids. In conclusion, we showed that the Swiss PUFA FFQ is a valid tool to assess dietary PUFA intake, especially DHA and EPA, to determine population groups at risk for low intake.
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http://dx.doi.org/10.3390/nu11081863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722517PMC
August 2019

Lipid Emulsion Containing High Amounts of n3 Fatty Acids (Omegaven) as Opposed to n6 Fatty Acids (Intralipid) Preserves Insulin Signaling and Glucose Uptake in Perfused Rat Hearts.

Anesth Analg 2020 01;130(1):37-48

Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background: It is currently unknown whether acute exposure to n3 fatty acid-containing fish oil-based lipid emulsion Omegaven as opposed to the n6 fatty acid-containing soybean oil-based lipid emulsion Intralipid is more favorable in terms of insulin signaling and glucose uptake in the intact beating heart.

Methods: Sprague-Dawley rat hearts were perfused in the working mode for 90 minutes in the presence of 11 mM glucose and 1.2 mM palmitate bound to albumin, the first 30 minutes without insulin followed by 60 minutes with insulin (50 mU/L). Hearts were randomly allocated to 100 µM Intralipid, 100 µM Omegaven, or no emulsion (insulin treatment alone) for 60 minutes. Glycolysis and glycogen synthesis were measured with the radioactive tracer [5-H]glucose, and glucose uptake was calculated. Phosphorylation of protein phosphatase 2A (PP2A), protein kinase Akt, and phosphofructokinase (PFK)-2 was measured by immunoblotting. Glycolytic metabolites were determined by enzymatic assays. Mass spectrometry was used to establish acylcarnitine profiles. Nuclear factor κB (NFκB) nuclear translocation served as reactive oxygen species (ROS) biosensor.

Results: Insulin-mediated glucose uptake was decreased by Intralipid (4.9 ± 0.4 vs 3.7 ± 0.3 μmol/gram dry heart weight [gdw]·min; P = .047) due to both reduced glycolysis and glycogen synthesis. In contrast, Omegaven treatment did not affect insulin-mediated glycolysis or glycogen synthesis and thus preserved glucose uptake (5.1 ± 0.3 vs 4.9 ± 0.4 μmol/gdw·min; P = .94). While Intralipid did not affect PP2A phosphorylation status, Omegaven resulted in significantly enhanced tyrosine phosphorylation and inhibition of PP2A. This was accompanied by increased selective threonine phosphorylation of Akt and the downstream target PFK-2 at S483. PFK-1 activity was increased when compared with Intralipid as measured by the ratio of fructose 1,6-bisphosphate to fructose 6-phosphate (Omegaven 0.60 ± 0.11 versus Intralipid 0.47 ± 0.09; P = .023), consistent with increased formation of fructose 2,6-bisphosphate by PFK2, its main allosteric activator. Omegaven lead to accumulation of acylcarnitines and fostered a prooxidant response as evidenced by NFκB nuclear translocation and activation.

Conclusions: Omegaven as opposed to Intralipid preserves glucose uptake via the PP2A-Akt-PFK pathway in intact beating hearts. n3 fatty acids decelerate β-oxidation causing accumulation of acylcarnitine species and a prooxidant response, which likely inhibits redox-sensitive PP2A and thus preserves insulin signaling and glucose uptake.
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http://dx.doi.org/10.1213/ANE.0000000000004295DOI Listing
January 2020

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.

Mucosal Immunol 2019 05 11;12(3):733-745. Epub 2019 Feb 11.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2 mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2 mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.
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http://dx.doi.org/10.1038/s41385-019-0140-xDOI Listing
May 2019

Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.

J Vet Intern Med 2019 Mar 15;33(2):751-757. Epub 2018 Dec 15.

Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland.

Background: Efficacy of PO cobalamin (Cbl) supplementation in dogs with hereditary Cbl malabsorption (Imerslund-Gräsbeck syndrome, IGS) is unknown.

Objectives: To evaluate PO Cbl supplementation in Beagles with IGS previously treated parenterally. We hypothesized that 1 mg cyano-Cbl daily PO would maintain clinical and metabolic remission.

Animals: Three client-owned Beagles with IGS and 48 healthy control dogs.

Methods: Prospective study. Daily PO cyanocobalamin (cyano-Cbl; 1 mg) supplementation was monitored for 13 (2 dogs) and 8 months (1 dog). Health status was assessed by owner observations. Methylmalonic acid (MMA)-to-creatinine concentrations were measured using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-TMS) method on urine samples collected monthly. Concurrent measurements of serum MMA concentration (n = 7; UPLC-TMS) were available for 1 dog.

Results: All dogs remained in excellent health during PO supplementation. Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2-9; healthy dogs [n = 30], median, 2.9 mmol/mol creatinine; range, 1.3-76.5). Urine MMA ranged from 38.9-84.9 mmol/mol creatinine during the first 6 months in 1 dog already known to excrete comparable amounts when supplemented parenterally. Brief antibiotic treatment for an unrelated condition after 6 months resulted in low urine MMA (median, 2.8 mmol/mol creatinine; range, 1.9-4.8) for the next 7 months. All concurrent serum MMA concentrations (median, 651 nmol/L; range, 399-919) before and after month 6 were within the established reference interval (393-1476 nmol/L; n = 48).

Conclusions And Clinical Importance: One milligram of cyano-Cbl daily PO appears efficacious for maintaining normal clinical status and normal cellular markers of Cbl metabolism in Beagles with IGS.
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http://dx.doi.org/10.1111/jvim.15380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430909PMC
March 2019

Risk factor analysis for a complicated postoperative course after neonatal arterial switch operation: The role of troponin T.

Congenit Heart Dis 2018 Jul 17;13(4):594-601. Epub 2018 Jul 17.

Pediatric Cardiology, University Children's Hospital, Zurich, Switzerland.

Objective: To find risk factors for a complicated early postoperative course after arterial switch operation (ASO) in neonates with d-transposition of the great arteries (dTGA). In addition to anatomical and surgical parameters, the predictive value of early postoperative troponin T (TnT) values in correlation to the early postoperative course after ASO is analyzed.

Methods: Seventy-nine neonates (57 (72%) male) with simple dTGA treated by ASO between 2009 and 2016 were included in the analysis. A complicated early postoperative course (30 days) was defined by one of the following criteria: (A) moderate to severe cardiac dysfunction without rhythm disturbances, (B) rhythm disturbances causing hemodynamic instability with the need for medical treatment, (C) signs for ischemia in ECG, (D) need for surgical or catheter interventional reinterventions other than diagnostic, or (E) other reasons.

Results: Forty of 79 patients (51%) showed a complicated early postoperative course after ASO, with 2 patients dying after 13 and 16 days. Patients with a complicated early postoperative course had a longer PICU stay (P < .001), needed longer mechanical ventilator support (P = .001) and longer inotropic support (P = .03), and more reinterventions (surgical or catheter interventional) were necessary (P = .001). Only the presence of a VSD (P = .001) and longer surgery duration (P = .026) were associated to a complicated postoperative course. TnT values only showed a trend toward higher values in patients with a complicated postoperative course (P = .06). A secondary rise in TnT was seen in 10 patients, ranging from 11.6% to 410.2%, of whom 7 could be classified in the complicated postoperative group.

Conclusions: The postoperative course after ASO in dTGA neonates is influenced by other cardiac comorbidities like a VSD with the need for surgical treatment, influencing surgery duration. Postoperative higher TnT values reflect a longer and more vulnerable intraoperative course with limited predictive value on the early postoperative course.
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http://dx.doi.org/10.1111/chd.12615DOI Listing
July 2018

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats.

Physiol Rep 2017 Aug;5(16)

Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

Despite the fact that skeletal muscle insulin resistance is the hallmark of type-2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose-induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type-2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased -hydroxyacyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase activities, despite reduced mitochondrial mass. Long-chain acyl-CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long-chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type-2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.
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http://dx.doi.org/10.14814/phy2.13388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582268PMC
August 2017

The value of plasma vitamin B6 profiles in early onset epileptic encephalopathies.

J Inherit Metab Dis 2016 09 24;39(5):733-741. Epub 2016 Jun 24.

Division of Child Neurology, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.

Background: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients.

Methods: We evaluated the vitamin B6 vitamers pyridoxal 5'-phosphate (PLP), pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN) and the catabolite pyridoxic acid (PA) in the so far largest patient cohort: reference (n = 50); pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency (n = 6); antiquitin (ATQ) deficiency (n = 21); tissue non-specific alkaline phosphatase (TNSALP) deficiency (n = 2) and epileptic encephalopathy (EE) of unknown etiology tested negative for ATQ and PNPO deficiency (n = 64).

Results: High plasma PM concentration was found in all patients with PNPO deficiency irrespective of vitamin B6 supplementation. Their PM concentration and the PM/PA ratio was significantly higher (p < 0.0001), compared to any other patients analysed. One patient with TNSALP deficiency and sampling prior to PN supplementation had markedly elevated plasma PLP concentration. On PN supplementation, patients with TNSALP deficiency, ATQ deficiency and patients of the EE cohort had similar plasma vitamin B6 profiles that merely reflect the intake of supra-physiological doses of vitamin B6. The interval of sampling to the last PN intake strongly affected the plasma concentrations of PN, PL and PA.

Conclusions: PM concentrations and the PM/PA ratio clearly separated PNPO-deficient patients from the other cohorts. The plasma PM/PA ratio thus represents a robust biomarker for the selective screening of PNPO deficiency.
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http://dx.doi.org/10.1007/s10545-016-9955-8DOI Listing
September 2016

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.

J Inherit Metab Dis 2016 05 1;39(3):331-340. Epub 2016 Apr 1.

Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.

Background: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.
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http://dx.doi.org/10.1007/s10545-016-9928-yDOI Listing
May 2016

Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32.

J Immunol 2016 Apr 11;196(8):3429-37. Epub 2016 Mar 11.

Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland

Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-β and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1β and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-β, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans.
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http://dx.doi.org/10.4049/jimmunol.1501701DOI Listing
April 2016

Laughing Gas in a Pediatric Emergency Department-Fun for All Participants: Vitamin B12 Status Among Medical Staff Working With Nitrous Oxide.

Pediatr Emerg Care 2016 Dec;32(12):827-829

From the *Department of Emergency Care, †Divisions of Metabolism, ‡Clinical Chemistry and Biochemistry, University Children's Hospital and Children's Research Center, Zurich, Switzerland.

The efficiency of nitrous oxide in an equimolar mixture with oxygen or in concentrations up to 70% is approved for short painful procedures. Evaluation of the vitamin B12 levels in anesthetic staff applying nitrous oxide showed reduced vitamin B12 plasma levels. This study examines the vitamin B12 status of medical staff working with nitrous oxide in a pediatric emergency department (ED). Medical staff of the ED at the University Children's Hospital Zurich participated. The vitamin B12 status was evaluated by measuring homocysteine, methylmalonic acid, vitamin B12, blood count, and the MTHFR C677T genotype. As a control group, medical personnel working in the "nitrous oxide-free" pediatric intensive care unit were recruited.

Results: The parameters for the vitamin B12 status of all participants were in the reference range, and there were no significant differences for the 2 groups. By trend, the ED staff showed higher vitamin B12 levels. The ED staff members were slightly older (P = 0.07) and had higher hemoglobin levels (P < 0.04) compared with the pediatric intensive care unit staff.

Conclusions: The use of nitrous oxide (50%-70%) with a demand valve is safe for the vitamin B12 status of medical personnel in the ED.
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http://dx.doi.org/10.1097/PEC.0000000000000582DOI Listing
December 2016

Effects of Steroid Hormones on Sex Differences in Cerebral Perfusion.

PLoS One 2015 10;10(9):e0135827. Epub 2015 Sep 10.

Center for MR-Research, University Children's Hospital Zurich, Zürich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland.

Sex differences in the brain appear to play an important role in the prevalence and progression of various neuropsychiatric disorders, but to date little is known about the cerebral mechanisms underlying these differences. One widely reported finding is that women demonstrate higher cerebral perfusion than men, but the underlying cause of this difference in perfusion is not known. This study investigated the putative role of steroid hormones such as oestradiol, testosterone, and dehydroepiandrosterone sulphate (DHEAS) as underlying factors influencing cerebral perfusion. We acquired arterial spin labelling perfusion images of 36 healthy adult subjects (16 men, 20 women). Analyses on average whole brain perfusion levels included a multiple regression analysis to test for the relative impact of each hormone on the global perfusion. Additionally, voxel-based analyses were performed to investigate the sex difference in regional perfusion as well as the correlations between local perfusion and serum oestradiol, testosterone, and DHEAS concentrations. Our results replicated the known sex difference in perfusion, with women showing significantly higher global and regional perfusion. For the global perfusion, DHEAS was the only significant predictor amongst the steroid hormones, showing a strong negative correlation with cerebral perfusion. The voxel-based analyses revealed modest sex-dependent correlations between local perfusion and testosterone, in addition to a strong modulatory effect of DHEAS in cortical, subcortical, and cerebellar regions. We conclude that DHEAS in particular may play an important role as an underlying factor driving the difference in cerebral perfusion between men and women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565711PMC
May 2016

Diagnostic performance of S100B protein serum measurement in detecting intracranial injury in children with mild head trauma.

Emerg Med J 2016 Jan 17;33(1):42-6. Epub 2015 Aug 17.

Pediatric Emergency Department, University Children's Hospital, Zurich, Switzerland.

Objective: To assess the accuracy of S100B serum level to detect intracranial injury in children with mild traumatic brain injury.

Methods: A multicenter prospective cohort study was carried out in the paediatric emergency departments of three tertiary hospitals in Switzerland between January 2009 and December 2011. Participants included children aged <16 years with a mild traumatic brain injury (GCS ≥13) for whom a head CT was requested by the attending physician. Venous blood was obtained within 6 h of the trauma in all children for S100B measurement before a head CT was performed. As the S100B value was not available during the acute care period, the patient's management was not altered. The main measures were protein S100B value and the CT result.

Results: 20/73 (27.4%) included children had an intracranial injury detected on CT. S100B receiver operating characteristics area under the curve was 0.73 (95% CI 0.60 to 0.86). With a 0.14 µg/L cut-off point, S100B reached an excellent sensitivity of 95% (95% CI 77% to 100%) and 100% (95% CI 81% to 100%) in all children and in children aged >2 years, respectively. The specificity, however, was 34% (95% CI 27% to 36%) and 37% (95% CI 30% to 37%), respectively.

Conclusions: S100B has an excellent sensitivity but poor specificity. It is therefore an accurate tool to help rule out an intracranial injury but cannot be used as the sole marker owing to its specificity. Used with clinical decision rules, S100B may help to reduce the number of unnecessary CT scans.
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http://dx.doi.org/10.1136/emermed-2014-204513DOI Listing
January 2016

LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.

Clin Biochem 2015 Jun 25;48(9):596-602. Epub 2015 Mar 25.

Division of Clinical Chemistry and Biochemistry, Children's Research Center, University Children's Hospital Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address:

Background: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking.

Methods: We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them.

Results: The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%±23% for C-triol and 52%±29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients.

Conclusions: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.03.007DOI Listing
June 2015

ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages.

J Immunol 2015 Mar 30;194(5):2330-7. Epub 2015 Jan 30.

Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland

ChemR23 is a G protein-coupled receptor that is triggered by two ligands, the peptide chemerin and the eicosapentaenoic acid-derived lipid mediator resolvin E1 (RvE1). Chemerin acts as a chemoattractant for monocytes and macrophages, whereas RvE1 promotes resolution of inflammation-inducing macrophage phagocytosis of apoptotic neutrophils. Although ChemR23-mediated signaling plays a role in mononuclear cell migration to inflamed tissue, as well as in the resolution of inflammation, its regulation in different polarization states of macrophages is largely unknown. We analyzed the expression and function of ChemR23 in monocytes and differently activated human primary macrophages. Using 5' RACE, we identified three transcription start sites and several splice variants of ChemR23 in both monocytes and macrophages. Although the promoters P1 and P3 are used equally in unpolarized macrophages, stimulation with LPS or IFN-γ leads to increased transcription from P3 in inflammatory M1 macrophages. Such ChemR23-expressing M1 macrophages are chemotactic to chemerin, whereas M2 macrophages not expressing ChemR23 surface receptor are not. Repolarization of ChemR23-expressing M1 macrophages with 10 nM RvE1 increases IL-10 transcription and phagocytosis of microbial particles, leading to a resolution-type macrophage distinct from the M2 phenotype. These results show that ChemR23 is tightly regulated in response to inflammatory and anti-inflammatory stimuli. The restricted expression of ChemR23 in naive and M1 macrophages supports the role of ChemR23 in the attraction of macrophages to inflamed tissue by chemerin and in the initiation of resolution of inflammation through RvE1-mediated repolarization of human M1 macrophages toward resolution-type macrophages.
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http://dx.doi.org/10.4049/jimmunol.1402166DOI Listing
March 2015

Genetic associations with coronary heart disease: meta-analyses of 12 candidate genetic variants.

Gene 2015 Mar 13;558(2):299. Epub 2015 Jan 13.

Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.gene.2015.01.017DOI Listing
March 2015

Propofol (Diprivan®) and Intralipid® exacerbate insulin resistance in type-2 diabetic hearts by impairing GLUT4 trafficking.

Anesth Analg 2015 Feb;120(2):329-40

From the *Department of Anesthesiology and Pain Medicine and Department of Pharmacology, University of Alberta, Edmonton, Canada; †Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada; ‡Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland; §Department of Pharmacology, University of Alberta, Edmonton, Canada; and ‖Department of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.

Background: The IV anesthetic, propofol, when administered as fat emulsion-based formulation (Diprivan) promotes insulin resistance, but the direct effects of propofol and its solvent, Intralipid, on cardiac insulin resistance are unknown.

Methods: Hearts of healthy and type-2 diabetic rats (generated by fructose feeding) were aerobically perfused for 60 minutes with 10 μM propofol in the formulation of Diprivan or an equivalent concentration of its solvent Intralipid (25 μM) ± insulin (100 mU•L). Glucose uptake, glycolysis, and glycogen metabolism were measured using [H]glucose. Activation of Akt, GSK3β, AMPK, ERK1/2, p38MAPK, S6K1, JNK, protein kinase Cθ (PKCθ), and protein kinase CCβII (PKCβII) was determined using immunoblotting. GLUT4 trafficking and phosphorylations of insulin receptor substrate-1 (IRS-1) at Ser307(h312), Ser1100(h1101), and Tyr608(hTyr612) were measured. Mass spectrometry was used to determine acylcarnitines, phospholipids, and sphingolipids.

Results: Diprivan and Intralipid reduced insulin-induced glucose uptake and redirected glucose to glycogen stores in diabetic hearts. Reduced glucose uptake was accompanied by lower GLUT4 trafficking to the sarcolemma. Diprivan and Intralipid inactivated GSK3β but activated AMPK and ERK1/2 in diabetic hearts. Only Diprivan increased phosphorylation of Akt(Ser473/Thr308) and translocated PKCθ and PKCβII to the sarcolemma in healthy hearts, whereas it activated S6K1 and p38MAPK and translocated PKCβII in diabetic hearts. Furthermore, only Diprivan phosphorylated IRS-1 at Ser1100(h1101) in healthy and diabetic hearts. JNK expression, phosphorylation of Ser307(h312) of IRS-1, and PKCθ expression and translocation were increased, whereas GLUT4 expression was reduced in insulin-treated diabetic hearts. Phosphatidylglycerol, phosphatidylethanolamine, and C18-sphingolipids accumulated in Diprivan-perfused and Intralipid-perfused diabetic hearts.

Conclusions: Propofol and Intralipid promote insulin resistance predominantly in type-2 diabetic hearts.
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http://dx.doi.org/10.1213/ANE.0000000000000558DOI Listing
February 2015
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