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Nitrous oxide abuse direct measurement for diagnosis and follow-up: update on kinetics and impact on metabolic pathways.
Lucas, A, Noyce, AJ, Gernez, E, El Khoury, JM, Garcon, G, Cavalier, E, Antherieu, S, Grzych, G
Clinical chemistry and laboratory medicine. 2024
Abstract
Recreational use of nitrous oxide (N2O) has become a major health issue worldwide, with a high number of clinical events, especially in neurology and cardiology. It is essential to be able to detect and monitor N2O abuse to provide effective care and follow-up to these patients. Current recommendations for detecting N2O in cases of recreational misuse and consumption markers are lacking. We aimed to update current knowledge through a review of the literature on N2O measurement and kinetics. We reviewed the outcomes of experiments, whether in preclinical models (in vitro or in vivo), or in humans, with the aim to identify biomarkers of intoxication as well as biomarkers of clinical severity, for laboratory use. Because N2O is eliminated 5 min after inhalation, measuring it in exhaled air is of no value. Many studies have found that urine and blood matrices concentrations are connected to ambient concentrations, but there is no similar data for direct exposure. There have been no studies on N2O measurement in direct consumers. Currently, patients actively abusing N2O are monitored using effect biomarkers (biomarkers related to the effects of N2O on metabolism), such as vitamin B12, homocysteine and methylmalonic acid.
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Mid-Term Evolution of the Serum Acylcarnitine Profile in Critically Ill Survivors: A Metabolic Insight into Survivorship.
Rousseau, AF, Ngongan, A, Colson, C, Minguet, P, Neis-Gilson, S, Cavalier, E, Minguet, G, Misset, B, Boemer, F
Nutrients. 2023;(16)
Abstract
It is unknown if the abnormal acylcarnitine (AC) profile observed early after discharge of a prolonged stay in an intensive care unit (ICU) would persist over time. This prospective observational study aimed to describe the mid-term AC profile evolution in survivors of a prolonged ICU stay (≥7 days). Adults enrolled in our post-ICU follow-up program and who attended the consultation 3 months (M3) after discharge were included. Serum AC concentrations were assessed within 7 days following ICU discharge (T0) and at M3. A total of 64 survivors were analyzed after an ICU stay of 15 (9-24) days. Free carnitine (C0) concentration decreased from 45.89 (35.80-127.5) to 28.73 (20.31-38.93) µmol/L (p < 0.001). C0 deficiency was not observed at T0 but in 7/64 (11%) survivors at M3. The total AC/C0 ratio (normal ≤ 0.4) was 0.33 (0.24-0.39) at T0 and reached 0.39 (0.30-0.56) at M3 (p = 0.001). A ratio >0.4 was observed in 16/64 (25%) at T0 and in 32/64 (50%) at M3 (p = 0.006). The short-chain ACs decreased from 1.310 (0.927-1.829) at T0 to 0.945 (0.709-1.127) µmol/L at M3 (p < 0.001). In parallel, the urea/creatinine ratio and the Sarcopenic Index, respectively, decreased and increased between T0 and M3. This AC profile is suspected to signal a mitochondrial dysfunction and was, especially for short-chain ACs, a marker of protein catabolism.
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Alkaline Phosphatases: Biochemistry, Functions, and Measurement.
Makris, K, Mousa, C, Cavalier, E
Calcified tissue international. 2023;(2):233-242
Abstract
Alkaline phosphatases (ALPs) are a group of isoenzymes, situated on the external layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are significant co-factors for the biological activity of these enzymes. Although ALPs are available in various body tissues and have distinct physiochemical properties, they are true isoenzymes since they catalyze a similar reaction. In the liver, ALP is cytosolic and present in the canalicular membrane of the hepatocytes. ALPs are available in placenta, ileal mucosa, kidney, bone, and liver. However, most of the ALPs in serum (over 80%) are delivered from liver and bone and in more modest quantities from the intestines. Despite the fact that alkaline phosphatases are found in numerous tissues all through the body, their exact physiological function remains largely unknown.
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Determination of parathyroid hormone: from radioimmunoassay to LCMS/MS.
Cavalier, E
Clinical chemistry and laboratory medicine. 2023;(5):946-953
Abstract
Parathyroid hormone (PTH) determination is of paramount importance for the exploration of diseases related with calcium metabolism and for the follow-up of patients suffering from bone and mineral disorders associated with chronic kidney diseases (CKD-MBD). Unfortunately, the biologically active form of PTH, i.e. 1-84 PTH, circulates in the blood stream with many fragments and post-translationally modified forms, which decreases the specificity of immunoassays. The assays used to measure PTH, either from 2nd or 3rd generation, are not standardised, which may lead to interpretation errors and clinical consequences. Reference ranges for PTH have neither been always correctly established and the stability of the peptide is also a matter of concern. Fortunately, these last years, newer techniques using mass spectrometry (either high resolution or triple quadripole) coupled with liquid chromatography have been developed, which will help to standardise the different assays. Indeed, PTH assays standardisation is one of the task of the IFCC Committee for Bone Metabolism. Such standardisation will allow a better consistency in the interpretation of the results and will promote studies aiming at the establishment of correct reference ranges.
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Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor - substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial.
David, K, Devos, G, Narinx, N, Antonio, L, Devlies, W, Deboel, L, Schollaert, D, Eisenhauer, A, Cavalier, E, Vanderschueren, D, et al
EBioMedicine. 2023;:104817
Abstract
BACKGROUND Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest. METHODS Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix) + androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix + matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers. FINDINGS Of the 89 randomised patients, 43 in the degarelix + apalutamide and 44 patients in the degarelix + placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference +0.04 mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups. INTERPRETATION This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT. FUNDING Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.
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The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations.
Heijboer, AC, Cavalier, E
Calcified tissue international. 2023;(2):258-270
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Abstract
Two decades after the discovery of the hormone FGF23, we know more about phosphate homeostasis as it turned out that FGF23 is the central hormone that regulates this. Hereditary hypophosphatemic rickets and tumor-induced osteomalacia could by then be explained, by autonomous FGF23 production, and the nephrology field was excited by this new marker as it turned out to be independently associated with mortality in people treated by hemodialysis. This led to the development of several immunoassays to be able to measure FGF23 in blood. In the past years we learned that FGF23 is a rather stable peptide, the precision of the assays is acceptable but assays are not standardized and therefore not comparable. This means that reference values and cutoff values need to be assay specific. For several assays reference values have been established and gender and age did not seem of high importance. The phosphate content of the diet, which can be culturally dependent, however, should be taken into account when interpreting results, but to what extent is not totally clear. Currently, clinical application of the immunoassays is established in the diagnosis of hereditary hypophosphatemic rickets and diagnosis and follow-up of tumor-induced osteomalacia. Definite conclusions on the usefulness of the FGF23 measurement in people with CKD either as a marker for risk prediction or a as target for treatment remains to be determined. The latter applications would require dedicated prospective clinical trials, which may take years, before providing answers. To improve the standardization of the FGF23 assays and to shed light on the biological functions that fragments might have we might aim for an LC-MS/MS-based method to quantify both intact and fragmented FGF23. In this literature review we will summarize the current knowledge on the physiological role of FGF23, its quantification, and the clinical usefulness of its determination.
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Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.
Ladang, A, Beaudart, C, Reginster, JY, Al-Daghri, N, Bruyère, O, Burlet, N, Cesari, M, Cherubini, A, da Silva, MC, Cooper, C, et al
Calcified tissue international. 2023;(2):197-217
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Abstract
In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations.
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Correction: Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.
Ladang, A, Beaudart, C, Reginster, JY, Al-Daghri, N, Bruyère, O, Burlet, N, Cesari, M, Cherubini, A, da Silva, MC, Cooper, C, et al
Calcified tissue international. 2023;(3):357-358
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Vitamin D: marker, measurand & measurement.
Dirks, NF, Cavalier, E, Heijboer, AC
Endocrine connections. 2023;(4)
Abstract
The measurement of vitamin D metabolites aids in assessing vitamin D status and in diagnosing disorders of calcium homeostasis. Most laboratories measure total 25-hydroxyvitamin D (25(OH)D), while others have taken the extra effort to measure 25(OH)D2 and 25(OH)D3 separately and additional metabolites such as 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. The aim of this review is to provide an updated overview of the main markers of vitamin D metabolism, define the intended measurands, and discuss the advantages and disadvantages of the two most widely used assays, automated assays and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Whether using the easy and fast automated assays or the more complex LC-MS/MS, one should know the pitfalls of the used technique in order to interpret the measurements. In conclusion, automated assays are unable to accurately measure 25(OH)D in all patient groups, including persons using D2. In these cases, an LC-MS/MS method, when appropriately developed and standardized, produces a more reliable measurement.
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Adequacy of Nutritional Intakes during the Year after Critical Illness: An Observational Study in a Post-ICU Follow-Up Clinic.
Rousseau, AF, Lucania, S, Fadeur, M, Verbrugge, AM, Cavalier, E, Colson, C, Misset, B
Nutrients. 2022;(18)
Abstract
Whether nutritional intakes in critically ill survivors after hospital discharge are adequate is unknown. The aims of this observational study were to describe the energy and protein intakes in ICU survivors attending a follow-up clinic compared to empirical targets and to explore differences in outcomes according to intake adequacy. All adult survivors who attended the follow-up clinic at 1, 3 and 12 months (M1, M3, M12) after a stay in our intensive care unit (ICU) ≥ 7 days were recruited. Average energy and protein intakes over the 7 days before the face-to-face consultation were quantified by a dietician using food anamnesis. Self-reported intakes were compared empirically to targets for healthy people (FAO/WHO/UNU equations), for critically ill patients (25 kcal/kg/day and 1.3 g protein/kg/day). They were also compared to targets that are supposed to fit post-ICU patients (35 kcal/kg/day and 1.5 g protein/kg/day). Blood prealbumin level and handgrip strength were also measured at each timepoint. A total of 206 patients were analyzed (49, 97 and 60 at the M1, M3 and M12, respectively). At M1, M3 and M12, energy intakes were 73.2 [63.3-86.3]%, 79.3 [69.3-89.3]% and 82.7 [70.6-93.7]% of healthy targets (p = 0.074), respectively. Protein intakes were below 0.8 g/kg/day in 18/49 (36.7%), 25/97 (25.8%) and 8/60 (13.3%) of the patients at M1, M3 and M12, respectively (p = 0.018), and the protein intakes were 67.9 [46.5-95.8]%, 68.5 [48.8-99.3]% and 71.7 [44.9-95.1]% of the post-ICU targets (p = 0.138), respectively. Prealbumin concentrations and handgrip strength were similar in patients with either inadequate energy intakes or inadequate protein intakes, respectively. In our post-ICU cohort, up to one year after discharge, energy and protein intakes were below the targets that are supposed to fit ICU survivors in recovery phase.