Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC).

An and efficacy evaluation of gene therapy candidate SBT101 in mouse models of adrenomyeloneuropathy and in NHPs.

Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human [h]), aims to ameliorate pathology by delivering functional copies of h to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect.

Age-Specific Reference Intervals for Thyroid-Stimulating Hormones and Free Thyroxine to Optimize Diagnosis of Thyroid Disease.

Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults.

Lipidomic biomarkers in plasma correlate with disease severity in adrenoleukodystrophy.

Background: X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by pathogenic variants in ABCD1 resulting very long-chain fatty acids (VLCFA) accumulation in plasma and tissues. Males can present with various clinical manifestations, including adrenal insufficiency, spinal cord disease, and leukodystrophy. Female patients typically develop spinal cord disease and peripheral neuropathy.

Evaluation of structural problems in the application of strict criteria for sperm morphology assessment.

Background: The WHO manual for basic semen analysis and ISO 23162 describe sperm morphology assessment as a standard part of semen analysis. Older studies showed a correlation between morphology results and (artificial) conception. In more recent studies this relationship was less apparent and there is more emphasis on sperm morphology as a marker for healthy spermatogenesis (and general male health).

Cohort profile of BIGPROMISE: a perioperative biobank of a high-risk surgical population.

Purpose: Postoperative complications increase mortality, disability and costs. Advanced understanding of the risk factors for postoperative complications is needed to improve surgical outcomes. This paper discusses the rationale and profile of the BIGPROMISE (biomarkers to guide perioperative management and improve outcome in high-risk surgery) cohort, that aims to investigate risk factors, pathophysiology and outcomes related to postoperative complications.

Four-dimensional lipidomics profiling in X-linked adrenoleukodystrophy using trapped ion mobility mass spectrometry.

Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility spectrometry and MS has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions-retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra-providing a heightened level of confidence in lipid annotation.

Sex differences in thermophysiological responses of elderly to low-intensity exercise during uncompensable heat strain.

Purpose: The rising frequency of extreme heat events poses an escalating threat of heat-related illnesses and fatalities, placing an additional strain on global healthcare systems. Whether the risk of heat-related issues is sex specific, particularly among the elderly, remains uncertain.

Methods: 16 men and 15 women of similar age (69 ± 5 years) were exposed to an air temperature of 39.

Should we depend on reference intervals from manufacturer package inserts? Comparing TSH and FT4 reference intervals from four manufacturers with results from modern indirect methods and the direct method.

Objectives: Correct interpretation of thyroid function tests relies on correct reference intervals (RIs) for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). ISO15189 mandates periodic verification of RIs, but laboratories struggle with cost-effective approaches. We investigated whether indirect methods (utilizing historical laboratory data) could replace the direct approach (utilizing healthy reference individuals) and compared results with manufacturer-provided RIs for TSH and FT4.

Clarifying how social epidemiological research constructs the category of low socioeconomic status: A response to Kamphuis et al.

In our previous article, published in this journal, we argued that epidemiology has a constructive role with regard to socioeconomic health inequalities. We concluded that, as long as the construction of LSES remains unquestioned, social epidemiology might continue to (re)produce what it examines: LSES populations 'known to be unhealthy'. Recently, in this journal, Kamphuis et al.

Sex-specific newborn screening for X-linked adrenoleukodystrophy.

Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very long-chain fatty acids (VLCFA), including C26:0-lysophosphatidylcholine (C26:0-LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives.

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the Gene.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in .

'Known to be unhealthy': Exploring how social epidemiological research constructs the category of low socioeconomic status.

We examine how the category of low socioeconomic status (LSES) was constructed in European social epidemiological research and policy advice from 1977 to 2019. We analysed 22 empirical social epidemiological research publications on LSES and health, as well as six scientific advisory reports that offered government officials an overview of scientific evidence on health inequalities. We show the construction and reification of LSES as a problematic group in dominant thought, which consists of the following components: 1) the proliferation of SES concepts, indicators and groups labelled LSES; 2) generalisation through which LSES is constructed as a single population; 3) problematisation through which LSES is constructed as an inherently unhealthy population; and 4) individualisation by which a LSES personality is presented as an explanation of health differences.

Associations Between Preoperative Biomarkers and Cardiac Surgery-Associated Acute Kidney Injury in Elderly Patients: A Cohort Study.

Background: Acute kidney injury (AKI) is associated with mortality after cardiac surgery. Novel risk factors may improve identification of patients at risk for renal injury. The authors evaluated the association between preoperative biomarkers that reflect cardiac, inflammatory, renal, and metabolic disorders and cardiac surgery-associated AKI (CSA-AKI) in elderly patients.

The effect of remote ischaemic preconditioning on postoperative cardiac and inflammatory biomarkers in pancreatic surgery: a randomized controlled trial.

Background: Cardiac and inflammatory biomarkers have been associated with adverse outcome after major abdominal surgery. This study investigated the effect of remote ischaemic preconditioning (RIPC) on perioperative concentrations of high-sensitive cardiac troponin (hs-cTn) T and interleukin (IL) 6.

Methods: Adult patients scheduled for elective pancreatic surgery between March 2017 and February 2019 were randomized to either three cycles of upper-limb ischaemia and reperfusion (each 5 min) or a sham procedure before surgery.

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit.

Corrigendum: Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor.

[This corrects the article DOI: 10.3389/fcell.2020.

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.

Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor.

X-linked adrenoleukodystrophy (ALD) is a devastating metabolic disorder affecting the adrenal glands, brain and spinal cord. Males with ALD are at high risk for developing adrenal insufficiency or progressive cerebral white matter lesions (cerebral ALD) at an early age. If untreated, cerebral ALD is often fatal.

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy.

Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter () cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity.

Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy with a birth incidence of 1:14,700 live births. The disease is caused by mutations in ABCD1 and characterized by very long-chain fatty acids (VLCFA) accumulation. In childhood, male patients are at high-risk to develop adrenal insufficiency and/or cerebral demyelination.

Are graduated intensivists prepared for practice? A case study from The Netherlands.

Purpose: An evaluation of the alignment between intensive care medicine (ICM) training and practice provides valuable information for the development of ICM training. Therefore this study examines how well recently licensed intensivists feel prepared for practice and whether intensivists from different background specialties attain comparable preparedness rates.

Methods: An inventory was developed to cover the tasks that constitute ICM practice.

Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene and characterized by elevated levels of very long-chain fatty acids (VLCFA) in plasma and tissues, with the most pronounced increase in the central nervous system. Virtually all male patients develop adrenal insufficiency and myelopathy (adrenomyeloneuropathy), but a subset develops a fatal cerebral demyelinating disease (known as cerebral ALD). Female patients may also develop myelopathy, but adrenal insufficiency or leukodystrophy are very rare.

Method for Measurement of Peroxisomal Very Long-Chain Fatty Acid Beta-Oxidation and De Novo C26:0 Synthesis Activity in Living Cells Using Stable-Isotope Labeled Docosanoic Acid.

Peroxisomes are present in virtually every eukaryotic cell type with the exception of the mature erythrocyte. In higher eukaryotes, one of the main functions of peroxisomes is lipid metabolism by means of beta-oxidation of very long-chain fatty acids (VLCFA; ≥22 carbon atoms). A dysfunction in peroxisomal VLCFA beta-oxidation results in elevated VLCFA levels in cells, tissue, and plasma.