An improved functional assay in blood spot to diagnose Barth syndrome using the monolysocardiolipin/cardiolipin ratio.

Barth syndrome is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and neutropenia, caused by deleterious variants in TAFAZZIN. This gene encodes a phospholipid-lysophospholipid transacylase that is required for the remodeling of the mitochondrial phospholipid cardiolipin (CL). Biochemically, individuals with Barth syndrome have a deficiency of mature CL and accumulation of the remodeling intermediate monolysocardiolipin (MLCL).

The effect of intrauterine resuscitation by maternal hyperoxygenation on perinatal and maternal outcome: a randomized controlled trial.

Background: Maternal hyperoxygenation is widely used during labor as an intrauterine resuscitation technique. However, robust evidence regarding its beneficial effect and potential side effects is scarce, and previous studies show conflicting results.

Objective: To assess the effect of maternal hyperoxygenation upon suspected fetal distress during the second stage of term labor on fetal heart rate, neonatal outcome, maternal side effects, and mode of delivery.

Comparison of the Diagnostic Performance of C26:0-Lysophosphatidylcholine and Very Long-Chain Fatty Acids Analysis for Peroxisomal Disorders.

Peroxisomes are subcellular organelles that are involved in various important physiological processes such as the oxidation of fatty acids and the biosynthesis of bile acids and plasmalogens. The gold standard in the diagnostic work-up for patients with peroxisomal disorders is the analysis of very long-chain fatty acid (VLCFA) levels in plasma. Alternatively, C26:0-lysophosphatidylcholine (C26:0-LPC) can be measured in dried blood spots (DBS) using liquid chromatography tandem mass spectrometry (LC-MS/MS); a fast and easy method but not yet widely used.

Ex vivo innate responses to particulate matter from livestock farms in asthma patients and healthy individuals.

Background: Asthma patients suffer from periodic acute worsening of symptoms (i.e. loss of asthma control or exacerbations), triggered by a variety of exogenous stimuli.

Corticosteroid Withdrawal-Induced Loss of Control in Mild to Moderate Asthma Is Independent of Classic Granulocyte Activation.

Background: Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated.

Methods: Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control.

Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure.

Pyrimidine nucleotides are essential for a vast number of cellular processes and dysregulation of pyrimidine metabolism has been associated with a variety of clinical abnormalities. Inborn errors of pyrimidine metabolism affecting enzymes in the pyrimidine de novo and degradation pathway have been identified but no patients have been described with a deficiency in proteins affecting the cellular import of ribonucleosides. In this manuscript, we report the elucidation of the genetic basis of the observed uridine-cytidineuria in a patient presenting with fever, hepatosplenomegaly, persistent lactate acidosis, severely disturbed liver enzymes and ultimately multi-organ failure.

Duodenal-jejunal lining increases postprandial unconjugated bile acid responses and disrupts the bile acid-FXR-FGF19 axis in humans.

Background And Aims: Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement.

Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.

Background: In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders.

Material And Methods: A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74).

Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders.

Introduction: Zellweger spectrum disorders (ZSD) are a group of genetic metabolic disorders caused by a defect in peroxisome biogenesis. This results in multiple metabolic abnormalities, including elevated very long-chain fatty acid (VLCFA) levels. Elevated levels of C26:0-lysophosphatidylcholine (C26:0-lysoPC) have been shown in dried blood spots (DBS) from ZSD patients.

Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition.

Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming.

A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios.

Cerebrotendinous xanthomatosis (CTX) is a treatable neurodegenerative metabolic disorder of bile acid synthesis in which symptoms can be prevented if treatment with chenodeoxycholic acid supplementation is initiated early in life, making CTX an excellent candidate for newborn screening. We developed a new dried blood spot (DBS) screening assay for this disorder on the basis of different ratios between the accumulating cholestanetetrol glucuronide (tetrol) and specific bile acids/bile acid intermediates, without the need for derivatization. A quarter-inch DBS punch was extracted with methanol, internal standards were added, and after concentration the extract was injected into the tandem mass spectrometer using a 2 min flow injection analysis for which specific transitions were measured for cholestanetetrol glucuronide, taurochenodeoxycholic acid (t-CDCA), and taurotrihydroxycholestanoic acid (t-THCA).

Non-polar lipids accumulate during storage of transfusion products and do not contribute to the onset of transfusion-related acute lung injury.

Background And Objectives: The accumulation of non-polar lipids arachidonic acid, 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE and 15-HETE during storage of transfusion products may play a role in the onset of transfusion-related acute lung injury (TRALI), a syndrome of respiratory distress after transfusion.

Materials And Methods: We investigated non-polar lipid accumulation in red blood cells (RBCs) stored for 42 days, plasma stored for 7 days at either 4 or 20°C and platelet (PLT) transfusion products stored for 7 days. Furthermore, we investigated whether transfusion of RBCs with increased levels of non-polar lipids induces TRALI in a 'two-hit' human volunteer model.

Role of peer support workers in improving patient experience in Tower Hamlets Specialist Addiction Unit.

The aim of the project was to improve patient experience for people in Tower Hamlets Specialist Addictions Unit in order to increase satisfaction by 25% in 12 months starting in August 2014. The team used the model for improvement as part of ELFT's quality improvement programme to support iterative cycles of testing and learning. This involved support from the Trust's quality improvement team.

RodZ and PgsA Play Intertwined Roles in Membrane Homeostasis of and Resistance to Weak Organic Acid Stress.

Weak organic acids like sorbic and acetic acid are widely used to prevent growth of spoilage organisms such as Bacilli. To identify genes involved in weak acid stress tolerance we screened a transposon mutant library of for sorbic acid sensitivity. Mutants of the () gene were found to be hypersensitive to the lipophilic weak organic acid.

Effects of acute dietary weight loss on postprandial plasma bile acid responses in obese insulin resistant subjects.

Background & Aims: Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity.

A novel UPLC-MS/MS based method to determine the activity of N-acetylglutamate synthase in liver tissue.

Background: N-acetylglutamate synthase (NAGS) plays a key role in the removal of ammonia via the urea cycle by catalyzing the synthesis of N-acetylglutamate (NAG), the obligatory cofactor in the carbamyl phosphate synthetase 1 reaction. Enzymatic analysis of NAGS in liver homogenates has remained insensitive and inaccurate, which prompted the development of a novel method.

Methods: UPLC-MS/MS was used in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d acid) dilution for the quantitative detection of NAG produced by the NAGS enzyme.

Pivotal role of glutamine synthetase in ammonia detoxification.

Unlabelled: Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle.

Polyunsaturated fatty acid status in treated isovaleric acidemia patients.

Background/objectives: Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with isovaleric acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications.

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes.

Context: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism.

Objective: To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls.

Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid.

Background: The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study.

Methods: In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples.

C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man.

X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD).

Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers.

Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context.

Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes.