Objective: Troponins are considered as the biomarkers of choice to highlight cardiac injury in em... more Objective: Troponins are considered as the biomarkers of choice to highlight cardiac injury in emergency departments, but are also valuable to detect cardiac injury in a non-emergency setting. In this latter case, transport of blood samples to laboratories often exceeds the manufacturer's recommendations (<2 h between vein puncture and analysis for the Beckman Coulter AccuTnI+3 assay). We aim to evaluate in vitro the stability of troponin Ic (cTnI) at two intervals (<2 h and at 4 h) over a wide range of concentrations using the Beckman Coulter AccuTnI+3 assay. Patients and methods: For each of the 95 patients included in this study, we analyzed the first blood sample with a time of transport <2 h, and the second sample after 4 h from vein puncture. We then calculated the correlation between the two periods of analysis and evaluated the bias by a Bland-Altman test. Results: Taking into account of our analytical reproducibility, we did not observe any significant differences in cTnI values between <2 h and 4 h. Conclusions: The time between vein puncture and analysis of cTnI can be extended to 4 h.
Objectif La toxicite hepatique du paracetamol est liee a la formation d’un metabolite reactif, la... more Objectif La toxicite hepatique du paracetamol est liee a la formation d’un metabolite reactif, la N-acetyl-p-benzoquinone imine (NAPQI), produit par une voie metabolique minoritaire dependante du cytochrome P450 2E1 (CYP2E1). A dose toxique, les capacites de neutralisation du NAPQI par le gluthation sont depassees, entrainant une cytolyse et une necrose hepatocytaire dose-dependante. Les sujets carences en glutathion peuvent egalement presenter des signes de toxicite hepatique apres ingestion de paracetamol a dose therapeutique. La dose de paracetamol consideree comme entrainant un risque d’intoxication grave au paracetamol, et donc justifiant l’administration de N-acetyl cysteine, est variable selon les pays. En France, elle est de 125 mg/kg. Cependant, les repercussions de l’ingestion de telle dose sur le bilan hepatique et sur le risque de cytolyse sont tres variables selon les patients intoxiques. Malgre l’ingestion de doses massives et reiterees, certains patients semblent etre naturellement proteges de la toxicite du paracetamol. Une meilleure connaissance de ces patients et des facteurs qui les protegent permettrait peut-etre d’ameliorer la prise en charge des cas graves. Methode Nous relatons ici le cas d’une patiente depressive et epileptique, multirecidiviste d’intoxications volontaires par le paracetamol (environ 10 intoxications par an depuis 2006 avec ingestion de 8 a 10 grammes de paracetamol en moyenne). Cette patiente suivie en milieu psychiatrique depuis de nombreuses annees presente par ailleurs des antecedents d’alcoolisme chronique donc des facteurs de vulnerabilite concernant le risque de toxicite hepatique et indique lors de certains de ces passages aux urgences, un « besoin » de consommer le paracetamol comme une « drogue ». Resultats Les concentrations plasmatiques mesurees en moyenne 2 a 4 h apres l’ingestion varient de 80 a plus de 200 mg/l et les demi-vies d’elimination estimees grâce a la seconde mesure se situent entre 2 et 3 heures, pour les intoxications les plus anciennes comme pour les plus recentes. Les bilans hepatiques ne sont jamais perturbes avec des variations pour les Gamma GT (gamma-glutamyltranspeptidase), les ASAT (aspartate aminotransferase) et les et ALAT (alanine aminotransferase) se situant toujours dans les valeurs standards et des phosphatases alcalines parfois legerement augmentees. Conclusion L’absence de toxicite aigue et chronique du paracetamol chez cette patiente peut s’expliquer par un possible statut genetique de metaboliseur ultra-lent pour le CYP2E1 ou par une capacite de detoxification accrue du NAPQI par le glutathion [1] . La determination du statut genetique de cette patiente serait probablement tres utile a la comprehension des facteurs pouvant proteger de la toxicite du paracetamol. Ceci d’autant plus que les sujets alcooliques presentent, en principe, une toxicite accrue du paracetamol par une probable potentialisation du metabolisme du paracetamol en un metabolite reactif via le CYP2E1 [2] , ce qui n’est pas le cas ici.
Mitochondrial diseases, characterized by a respiratory chain deficiency, are considered as rare g... more Mitochondrial diseases, characterized by a respiratory chain deficiency, are considered as rare genetic diseases but are the most frequent among inherited metabolic disorders. The complexity of their diagnosis is due to the dual control by the mitochondrial (mtDNA) and the nuclear DNA (nDNA), and to the heterogeneous clinical presentations; illegitimate association of symptoms should prompt the clinician to evoke a mitochondrial disorder. The goals of this review are to provide clinicians a better understanding of mitochondrial diseases in adults. After a brief overview on the mitochondrial origin and functions, especially their role in the energy metabolism, we will describe the genetic bases for mitochondrial diseases, then we will describe the various clinical presentations with the different affected tissues as well as the main symptoms encountered. Even if the new sequencing approaches have profoundly changed the diagnostic process, the brain imaging, the biological, the biochemical, and the histological explorations are still important highlighting the need for a multidisciplinary approach. While for most of the patients with a mitochondrial disease, only supportive and symptomatic therapies are available, recent advances in the understanding of the pathophysiological mechanisms have been made and new therapies are being developed and are evaluated in human clinical trials.
Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic moni... more Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic monitoring in a wide range of diseases. However, the low intrinsic sensitivity of MRI to detect exogenous contrast agents and the lack of biodegradable microprobes have prevented its clinical development. Here, we synthetized a contrast agent for molecular MRI based on a previously unknown mechanism of self-assembly of catechol-coated magnetite nanocrystals into microsized matrix-based particles. The resulting biodegradable microprobes (M3P for microsized matrix-based magnetic particles) carry up to 40,000 times higher amounts of superparamagnetic material than classically used nanoparticles while preserving favorable biocompatibility and excellent water dispersibility. After conjugation to monoclonal antibodies, targeted M3P display high sensitivity and specificity to detect inflammation in vivo in the brain, kidneys, and intestinal mucosa. The high payload of superparamagnetic material, ex...
Background: Peptides derived from cow’s milk proteins have in vitro protective effects on iron-in... more Background: Peptides derived from cow’s milk proteins have in vitro protective effects on iron-induced peroxidation that could be used to prevent the side effects of iron fortification. The aim of the study was to confirm these properties in an in vivo model of gut peroxidation. Methods: Iron bound to the 1–25 phosphopeptide of β-casein [Fe-β-CPP(1–25)] was compared to an encapsulated ferric pyrophosphate (Fe-P) in the Caco-2 model. Ferrous sulfate (FeSO4) was used as control (100 µmol/l iron, n = 6 per group). The concentration of malondialdehyde (MDA), a stable byproduct of lipid peroxidation, was used as the marker of peroxidation. Results: The lowest MDA levels were observed in cells grown with Fe-β-CPP(1–25) and the highest with Fe-P. Iron absorption of Fe-β-CPP(1–25) was higher than in the 2 other forms, due to its high cellular uptake and high basolateral transfer, while iron absorption of Fe-P showed high uptake and high cell retention. Conclusions: The enhancing effect of β-CPP(1–25) on iron absorption was associated with a protective effect against enterocyte peroxidation, perhaps due to its low storage by enterocytes. These observations support a role for specific milk components in food fortification to prevent iron deficiency.
Vemurafenib, an anti-rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival... more Vemurafenib, an anti-rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival among patients with metastatic BRAF-mutated melanoma. Photosensitivity, a frequent cutaneous adverse effect induced by vemurafenib, can lead to cessation of treatment. To investigate photosensitivity mechanisms in patients treated with vemurafenib for metastatic melanoma. In a prospective study of 12 patients, photobiological explorations with measurements of ultraviolet A (UVA) minimal erythema dose (MED) and polychromatic MED were performed over 3 days in all 12 patients. UVA MED and polychromatic MED were also assessed for four patients before treatment. We then performed spectrophotometric analyses of (i) serum and faeces in these four patients, before and after introduction of vemurafenib; (ii) the lyophilized form of vemurafenib without excipient added; and (iii) the lyophilized form of vemurafenib added to serum and faeces before treatment. Photosensitivity was present in 92% of the patients. UVA MED was normal before treatment and decreased after treatment, while polychromatic MED remained normal. The same three peaks (210, 260 and 310 nm) were identified in the spectrum for UVB and UVC but not for UVA on spectrophotometric analyses for each condition (lyophilized vemurafenib; serum and faeces after introduction of vemurafenib; and lyophilized vemurafenib added to serum and faeces before treatment). The peaks were different before treatment. Our study confirms that photosensitivity under vemurafenib treatment was a UVA phototoxicity reaction, and our results suggest that a metabolite of vemurafenib rather than the parent molecule is involved in this phototoxicity.
Glycated hemoglobin A1c (HbA1c) reflects the mean blood glucose over the lifespan of red blood ce... more Glycated hemoglobin A1c (HbA1c) reflects the mean blood glucose over the lifespan of red blood cells and has become a valuable tool both for diagnosis and monitoring of diabetes. Nevertheless, some factors may under-estimate the HbA1c value, compromising its application. The aim of this retrospective study was to evaluate the incidence rate of HbA1c lower than 4% and to identify some clinical and biological factors that can potentially reduce the HbA1c level. Between January 1st 2015 and October 1st 2017, we selected 17 patients with a HbA1c level lower than 4% that were measured in our laboratory of biochemistry at the university medical center of Caen. From the medical records, we identified medical conditions, treatments and biological parameters that could potentially explain a decrease of HbA1c level. Meanwhile the measurement of HbA1c, 8/16 patients had hemoglobin level lower than 100 g/L and 5/6 presented with reticulocytosis (>100 G/L). Ten patients over 17 suffered from hepatopathy (cirrhosis from various etiologies) with abnormal liver blood tests for 12 patients. Two patients showed hemolytic anemia and another one was investigated for hypoglycemia due to congenital hyperinsulinism. Finally, 3 patients were treated with drugs known to lower HbA1c levels. True hypoglycemia periods but also other circumstances which are known to alter erythrocytes lifespan or the glycation process may decrease HbA1c level. Such biological result should be critically interpreted and alternative biological markers should be considered.
Objective: Troponins are considered as the biomarkers of choice to highlight cardiac injury in em... more Objective: Troponins are considered as the biomarkers of choice to highlight cardiac injury in emergency departments, but are also valuable to detect cardiac injury in a non-emergency setting. In this latter case, transport of blood samples to laboratories often exceeds the manufacturer's recommendations (<2 h between vein puncture and analysis for the Beckman Coulter AccuTnI+3 assay). We aim to evaluate in vitro the stability of troponin Ic (cTnI) at two intervals (<2 h and at 4 h) over a wide range of concentrations using the Beckman Coulter AccuTnI+3 assay. Patients and methods: For each of the 95 patients included in this study, we analyzed the first blood sample with a time of transport <2 h, and the second sample after 4 h from vein puncture. We then calculated the correlation between the two periods of analysis and evaluated the bias by a Bland-Altman test. Results: Taking into account of our analytical reproducibility, we did not observe any significant differences in cTnI values between <2 h and 4 h. Conclusions: The time between vein puncture and analysis of cTnI can be extended to 4 h.
Objectif La toxicite hepatique du paracetamol est liee a la formation d’un metabolite reactif, la... more Objectif La toxicite hepatique du paracetamol est liee a la formation d’un metabolite reactif, la N-acetyl-p-benzoquinone imine (NAPQI), produit par une voie metabolique minoritaire dependante du cytochrome P450 2E1 (CYP2E1). A dose toxique, les capacites de neutralisation du NAPQI par le gluthation sont depassees, entrainant une cytolyse et une necrose hepatocytaire dose-dependante. Les sujets carences en glutathion peuvent egalement presenter des signes de toxicite hepatique apres ingestion de paracetamol a dose therapeutique. La dose de paracetamol consideree comme entrainant un risque d’intoxication grave au paracetamol, et donc justifiant l’administration de N-acetyl cysteine, est variable selon les pays. En France, elle est de 125 mg/kg. Cependant, les repercussions de l’ingestion de telle dose sur le bilan hepatique et sur le risque de cytolyse sont tres variables selon les patients intoxiques. Malgre l’ingestion de doses massives et reiterees, certains patients semblent etre naturellement proteges de la toxicite du paracetamol. Une meilleure connaissance de ces patients et des facteurs qui les protegent permettrait peut-etre d’ameliorer la prise en charge des cas graves. Methode Nous relatons ici le cas d’une patiente depressive et epileptique, multirecidiviste d’intoxications volontaires par le paracetamol (environ 10 intoxications par an depuis 2006 avec ingestion de 8 a 10 grammes de paracetamol en moyenne). Cette patiente suivie en milieu psychiatrique depuis de nombreuses annees presente par ailleurs des antecedents d’alcoolisme chronique donc des facteurs de vulnerabilite concernant le risque de toxicite hepatique et indique lors de certains de ces passages aux urgences, un « besoin » de consommer le paracetamol comme une « drogue ». Resultats Les concentrations plasmatiques mesurees en moyenne 2 a 4 h apres l’ingestion varient de 80 a plus de 200 mg/l et les demi-vies d’elimination estimees grâce a la seconde mesure se situent entre 2 et 3 heures, pour les intoxications les plus anciennes comme pour les plus recentes. Les bilans hepatiques ne sont jamais perturbes avec des variations pour les Gamma GT (gamma-glutamyltranspeptidase), les ASAT (aspartate aminotransferase) et les et ALAT (alanine aminotransferase) se situant toujours dans les valeurs standards et des phosphatases alcalines parfois legerement augmentees. Conclusion L’absence de toxicite aigue et chronique du paracetamol chez cette patiente peut s’expliquer par un possible statut genetique de metaboliseur ultra-lent pour le CYP2E1 ou par une capacite de detoxification accrue du NAPQI par le glutathion [1] . La determination du statut genetique de cette patiente serait probablement tres utile a la comprehension des facteurs pouvant proteger de la toxicite du paracetamol. Ceci d’autant plus que les sujets alcooliques presentent, en principe, une toxicite accrue du paracetamol par une probable potentialisation du metabolisme du paracetamol en un metabolite reactif via le CYP2E1 [2] , ce qui n’est pas le cas ici.
Mitochondrial diseases, characterized by a respiratory chain deficiency, are considered as rare g... more Mitochondrial diseases, characterized by a respiratory chain deficiency, are considered as rare genetic diseases but are the most frequent among inherited metabolic disorders. The complexity of their diagnosis is due to the dual control by the mitochondrial (mtDNA) and the nuclear DNA (nDNA), and to the heterogeneous clinical presentations; illegitimate association of symptoms should prompt the clinician to evoke a mitochondrial disorder. The goals of this review are to provide clinicians a better understanding of mitochondrial diseases in adults. After a brief overview on the mitochondrial origin and functions, especially their role in the energy metabolism, we will describe the genetic bases for mitochondrial diseases, then we will describe the various clinical presentations with the different affected tissues as well as the main symptoms encountered. Even if the new sequencing approaches have profoundly changed the diagnostic process, the brain imaging, the biological, the biochemical, and the histological explorations are still important highlighting the need for a multidisciplinary approach. While for most of the patients with a mitochondrial disease, only supportive and symptomatic therapies are available, recent advances in the understanding of the pathophysiological mechanisms have been made and new therapies are being developed and are evaluated in human clinical trials.
Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic moni... more Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic monitoring in a wide range of diseases. However, the low intrinsic sensitivity of MRI to detect exogenous contrast agents and the lack of biodegradable microprobes have prevented its clinical development. Here, we synthetized a contrast agent for molecular MRI based on a previously unknown mechanism of self-assembly of catechol-coated magnetite nanocrystals into microsized matrix-based particles. The resulting biodegradable microprobes (M3P for microsized matrix-based magnetic particles) carry up to 40,000 times higher amounts of superparamagnetic material than classically used nanoparticles while preserving favorable biocompatibility and excellent water dispersibility. After conjugation to monoclonal antibodies, targeted M3P display high sensitivity and specificity to detect inflammation in vivo in the brain, kidneys, and intestinal mucosa. The high payload of superparamagnetic material, ex...
Background: Peptides derived from cow’s milk proteins have in vitro protective effects on iron-in... more Background: Peptides derived from cow’s milk proteins have in vitro protective effects on iron-induced peroxidation that could be used to prevent the side effects of iron fortification. The aim of the study was to confirm these properties in an in vivo model of gut peroxidation. Methods: Iron bound to the 1–25 phosphopeptide of β-casein [Fe-β-CPP(1–25)] was compared to an encapsulated ferric pyrophosphate (Fe-P) in the Caco-2 model. Ferrous sulfate (FeSO4) was used as control (100 µmol/l iron, n = 6 per group). The concentration of malondialdehyde (MDA), a stable byproduct of lipid peroxidation, was used as the marker of peroxidation. Results: The lowest MDA levels were observed in cells grown with Fe-β-CPP(1–25) and the highest with Fe-P. Iron absorption of Fe-β-CPP(1–25) was higher than in the 2 other forms, due to its high cellular uptake and high basolateral transfer, while iron absorption of Fe-P showed high uptake and high cell retention. Conclusions: The enhancing effect of β-CPP(1–25) on iron absorption was associated with a protective effect against enterocyte peroxidation, perhaps due to its low storage by enterocytes. These observations support a role for specific milk components in food fortification to prevent iron deficiency.
Vemurafenib, an anti-rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival... more Vemurafenib, an anti-rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival among patients with metastatic BRAF-mutated melanoma. Photosensitivity, a frequent cutaneous adverse effect induced by vemurafenib, can lead to cessation of treatment. To investigate photosensitivity mechanisms in patients treated with vemurafenib for metastatic melanoma. In a prospective study of 12 patients, photobiological explorations with measurements of ultraviolet A (UVA) minimal erythema dose (MED) and polychromatic MED were performed over 3 days in all 12 patients. UVA MED and polychromatic MED were also assessed for four patients before treatment. We then performed spectrophotometric analyses of (i) serum and faeces in these four patients, before and after introduction of vemurafenib; (ii) the lyophilized form of vemurafenib without excipient added; and (iii) the lyophilized form of vemurafenib added to serum and faeces before treatment. Photosensitivity was present in 92% of the patients. UVA MED was normal before treatment and decreased after treatment, while polychromatic MED remained normal. The same three peaks (210, 260 and 310 nm) were identified in the spectrum for UVB and UVC but not for UVA on spectrophotometric analyses for each condition (lyophilized vemurafenib; serum and faeces after introduction of vemurafenib; and lyophilized vemurafenib added to serum and faeces before treatment). The peaks were different before treatment. Our study confirms that photosensitivity under vemurafenib treatment was a UVA phototoxicity reaction, and our results suggest that a metabolite of vemurafenib rather than the parent molecule is involved in this phototoxicity.
Glycated hemoglobin A1c (HbA1c) reflects the mean blood glucose over the lifespan of red blood ce... more Glycated hemoglobin A1c (HbA1c) reflects the mean blood glucose over the lifespan of red blood cells and has become a valuable tool both for diagnosis and monitoring of diabetes. Nevertheless, some factors may under-estimate the HbA1c value, compromising its application. The aim of this retrospective study was to evaluate the incidence rate of HbA1c lower than 4% and to identify some clinical and biological factors that can potentially reduce the HbA1c level. Between January 1st 2015 and October 1st 2017, we selected 17 patients with a HbA1c level lower than 4% that were measured in our laboratory of biochemistry at the university medical center of Caen. From the medical records, we identified medical conditions, treatments and biological parameters that could potentially explain a decrease of HbA1c level. Meanwhile the measurement of HbA1c, 8/16 patients had hemoglobin level lower than 100 g/L and 5/6 presented with reticulocytosis (>100 G/L). Ten patients over 17 suffered from hepatopathy (cirrhosis from various etiologies) with abnormal liver blood tests for 12 patients. Two patients showed hemolytic anemia and another one was investigated for hypoglycemia due to congenital hyperinsulinism. Finally, 3 patients were treated with drugs known to lower HbA1c levels. True hypoglycemia periods but also other circumstances which are known to alter erythrocytes lifespan or the glycation process may decrease HbA1c level. Such biological result should be critically interpreted and alternative biological markers should be considered.
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