Validation of the Body Scan®, a new device to detect small fiber neuropathy by assessment of the sudomotor function: agreement with the Sudoscan®

BackgroundSudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (μS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting.MethodsIn patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 μS and > 50 μS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 μS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland–Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices.ResultsA total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [−5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®.ConclusionThe ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice.Clinical trial registrationClinicalTrials.gov, identifier NCT05178459

Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits

OBJECTIVE A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice. RESEARCH DESIGN AND METHODS The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients. RESULTS Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). CONCLUSIONS HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages

Objective Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response. Methods Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. Results We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo. Conclusion In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation

Prévalence de l'ischémie myocardique silencieuse détectée par échocardiographie de stress à la dobutamine chez des patients asymptomatiques avec dyslipidémie infectés par le VIH

PARIS5-BU Méd.Cochin (751142101) / SudocPARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Etude prospective sur la prise en charge des malaises hypoglycémiques par le SAMU 91

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mécanismes moléculaires de la programmation fœtale de la masse et de la fonction des cellules b pancréatiques par les glucocorticoïdes (implication de PGC-1a et de la sérotonine)

Le diabète de type 2 peut être programmée au cours de la vie fœtale par l intermédiaire d une atteinte des cellules b. Nos travaux précédents ont identifié les glucocorticoïdes (GCs) comme acteurs de cette programmation. Pour mieux comprendre le mode d'action des GCs, mon travail de thèse s est centré sur 2 aspects de leur signalisation :1) le rôle d un co-régulateur transcriptionnel du récepteur au GCs (GR), PGC-1a et 2) les conséquences de l invalidation chez la souris du GR dans les cellules pancréatiques précurseurs (GRPdxCre). Nous avons montré qu un partenaire du GR, PGC-1a, était stimulé par les GCs dans les cellules b, sa surexpression inhibait l expression de certains gènes clés dont Pdx1 en se liant avec le GR sur son promoteur. Dans des souris surexprimant PGC-1a dans les cellules b, ce co-régulateur altérait la masse et la fonction des cellules b, entrainant une intolérance au glucose. La surexpression uniquement fœtale de PGC-1a suffisait à induire une dysfonction des cellules b. Nous avons ensuite exploré les souris souris GRPdxCre. Elles possédaient un doublement de la masse et une dysfonction des cellules b. Le transcriptôme des îlots de ces souris a révélé la surexpression des gènes codant Tph1 et 2 (Tryptophane hydroxylase), enzymes de synthèse de la sérotonine, dont le contenu était augmenté dans les îlots des souris GRPdxCre. A l inverse, l activation de la voie des GCs dans des cellules b in vitro diminuait l expression des gènes Tph1 et Tph2 et la synthèse de sérotonine.En conclusion, nos travaux suggèrent que PGC-1a et la sérotonine participent aux effets délétères des GCs sur les cellules b, notamment lors de la programmation fœtale.The etiology of type 2 diabetes is complex. This disease may be programmed during fetal life through an impairment of b cells. We previously identified glucocorticoids (GCs) as actors of this fetal programming since we showed that these hormones inhibit b-cell development. Our work has focused on two aspects of GCs signaling: 1) the role of a GCs receptor (GR) transcriptional co-regulator, PGC-1a and 2) the consequences of the GR invalidation in pancreatic precursor cells. We first showed that the GR co-regulator, PGC-1a was stimulated by GCs in the b cells, that its overexpression represses crucia genes for b-cell development and function, including Pdx1, a transcription factor of insulin through binding of a GR/PGC-1a complex to the Pdx1 promoter. Mice overexpressing PGC-1a in b cells exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion and decreased b-cell mass. PGC-1a expression in fetal life only was sufficient to impair adult b-cell function. Then, we explored mice with conditional invalidation of GR in pancreatic precursors (GRPdxCre) that present a phenotype characterized by a doubled b-cell mass and b-cell dysfunction. Transcriptome analysis of the islets of these mice showed overexpression of genes encoding TPH1 and 2 (tryptophan hydroxylase), enzymes involved in serotonin synthesis, whose content was increased in the islets of mice GRPdxCre. In contrast, activation of the GCs pathway in b cells in vitro decreased TPH1 and 2 expression and serotonin synthesis. In conclusion, our findings suggest that PGC-1a and serotonin contribute to the deleterious effects of GCs on the b cells, especially during fetal programming.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

PAX4 gene variations predispose to ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes

Early short-course corticosteroids and furosemide combination to treat non-critically ill COVID-19 patients: An observational cohort study

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