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Cardiovascular diseases (CVDs) are the leading cause of death globally, and accurately estimating an individual's risk of developing CVD is crucial for appropriate management. Current prediction models for cardiovascular risk have limitations, particularly in individuals with socioeconomic disadvantage. Focusing on the antiatherogenic functions of high-density lipoprotein (HDL) rather than just the cholesterol concentration in HDL particles shows promise for improving cardiovascular risk stratification. Assays such as cholesterol efflux capacity (CEC) and HDL anti-inflammatory capacity have been shown to predict cardiovascular outcomes, but they are not suitable for clinical laboratories. However, recent advancements have been made in developing cell-free assays, such as cholesterol uptake capacity (CUC) and HDL-specific phospholipid efflux (HDL-SPE), which offer the potential for routine use in clinical practice. These assays have shown associations with prevalent coronary artery disease (CAD) and incident ASCVD events, independently of HDL cholesterol levels and other risk factors. While these cell-free assays have shown promise, further research is needed to determine their clinical value and how they compare to other risk assessment methods. [Extracted from the article]

In patients with diabetes, peripheral arterial disease, particularly below the knee, is associated with medial arterial calcification. This is a frequent and potentially serious complication, affecting all types of diabetes. In recent years, our understanding of the pathophysiology and clinical significance of medial arterial calcification has improved considerably. Here, we offer a short narrative review of the epidemiology, clinical consequences, and pathophysiology of this complication. Now that medial arterial calcification of the lower limbs is better understood, we also focus on the prospect of treatments targeting arterial calcification., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Recent advances in pharmaceutical technology, aimed at overcoming poor drug permeation across the intestinal-epithelial membrane and the challenges posed by the acidic gastrointestinal environment, have led to the development of orally administered somatostatin receptor ligands (SRLs). This development represents a promising step forward in the management of acromegaly, offering an alternative to the limitations associated with injectable SRLs. Several key clinical findings have emerged in the past two years, notably including the results from the extension phase of the MPOWERED trial, which evaluated oral octreotide capsules (OOCs), and the placebo-controlled PATHFNDR-1 trial using paltusotine. This prompted us to conduct a systematic review of the literature focusing on the efficacy of oral SRLs in controlling acromegaly, based on biochemical response. Of the 136 reports identified through our search on Medline and ClinicalTrials.gov, twelve were included, encompassing data from five interventional trials. Both OOCs and paltusotine demonstrated the ability to maintain biochemical control in patients previously controlled with injectable SRLs. While long-term maintenance was confirmed for OOCs, no data are yet available for paltusotine. Several gaps remain, such as the need for head-to-head comparisons between OOCs and paltusotine, and clinical trials in patients who have not received prior injectable SRL treatment.

ApolipoproteinC1 (apoC1) is the main physiological inhibitor of the cholesterol ester transfer protein (CETP). Increased CETP activity is associated with macrovascular complications in patients with type 1 diabetes (T1D). ApoC1 has lost its ability to inhibit CETP in patients with T1D, and in vitro glycation of apoC1 increases CETP activity, suggesting that hyperglycemia could be a factor implicated in the loss of the inhibitory effect of apoC1 on CETP. Thus, we aimed to see whether improvement of glycemic control might restore apoC1 inhibitory effect on CETP. We studied 98 patients with T1D and HbA1c > 9% at baseline and 3 months after improvement of glycemic control by a medical intervention (insulin introduction or changes in multi-injection therapy or pump therapy introduction/therapeutic education for all patients). CETP activity was assessed by a radioactive method and plasma apoC1 levels were measured by ELISA. The different isoforms of apoC1 were determined by mass spectrometry. CETP activity was not significantly modified after improvement of glycemic control, despite a significant reduction in mean HbA1c (8.7 ± 1.7 vs. 10.8 ± 2, p < 0.0001). No association between plasma apoC1 and CETP activity was observed in patients with T1D at baseline, nor at 3 months, even in the subgroup of patients with optimal control (3-month HbA1c < 7%). We did not find any glycated form of apoC1 using mass spectrometry in people with T1D. Hyperglycemia in vivo does not seem to be a major factor implicated in the loss of apoC1 ability to inhibit CETP activity observed in T1D. Other factors, such as qualitative abnormalities of lipoproteins, could be involved. Our data emphasize the fact that hyperglycemia is not the only factor involved in lipid abnormalities and macrovascular complications in T1D. Clinical trial reg. no. NCT02816099 ClinicalTrials.gov.

Aim: New tools are required to better assess cardiovascular risk in individuals with type 2 diabetes mellitus (T2DM). Plasma ceramides emerge as promising candidates, given their substantial influence on the pathogenesis of both T2DM and atherosclerosis. The current study aimed to investigate whether plasma ceramides in patients with T2DM are a predictive factor for carotid intima-media thickness (CIMT), a well-established noninvasive marker for atherosclerosis that predicts adverse cardiovascular outcomes., Methods: A lipidomic analysis was carried out on the circulating ceramides of a large cohort consisting of 246 patients with T2DM who underwent a high-resolution real-time B ultrasonography to measure CIMT., Results: Both plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with CIMT, even after adjustment for traditional cardiovascular risk factors [standardized β ± standard error: 0.168 ± 0.072 (P = 0.020) and 0.180 ± 0.068 (P = 0.009), respectively]. Similar independent associations were found with respect to the prediction of CIMT ≥ 0.80 mm [β = 8.07 ± 3.90 (P = 0.038) and 16.5 ± 7.0 (P = 0.019), respectively]. The goodness-of-fit for multivariate models in predicting CIMT was 5.7 and 7.6 times higher when plasma 16:0 ceramide or the 16:0/24:0 ceramide ratio were included in combination with traditional cardiovascular risk factors (P = 0.020 and 0.015, respectively). This reached a 3.1 and 10.0-fold increase regarding the ability to predict CIMT ≥ 0.80 mm (P = 0.039 and 0.008, respectively)., Conclusions: Our findings suggest that 16:0 ceramide and the 16:0/24:0 ceramide ratio may serve as plasma biomarkers to improve cardiovascular risk assessment in individuals with T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Aim: The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D., Methods: An in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1- 13 C]leucine followed by a 16-hour constant infusion., Results: Liraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m 2 , P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386)., Conclusion: Six months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The recreational use of nitrous oxide (N2O) is an emerging public health issue. Chronic N2O abuse may result in various clinical symptoms, encompassing neurological, psychiatric and cardiovascular outcomes. Despite the difficulties for the laboratory investigation of N2O intoxication, there is currently no guidelines in France to help both clinicians and biologists use appropriate biomarkers for the diagnosis and monitoring of patients with clinical symptoms potentially related to N2O intoxication. A multi-disciplinary Working Group, carried out under the auspices of the French Society of Clinical Biology (SFBC) and in collaboration with the French Societies of Emergency Medicine (SFMU), Analytical Toxicology (SFTA), Hemostasis and Thrombosis (SFTH), Vitamins and Biofactors (SFVB), and the French Federation of Neurology (FFN), was recently implemented to elaborate practical guidelines. The methodology of the Working Group is based on the critical analysis of the literature, and raising concerns and objectives are grouped into five working packages. The present manuscript primarily aims to expound upon the methodology and objectives of the ongoing SFBC Working Group on N2O.

Background: Studies have demonstrated that coronary artery calcification on one hand and non-alcoholic fatty liver disease (NAFLD) on the other hand are strongly associated with cardiovascular events. However, it remains unclear whether NAFLD biomarkers could help estimate cardiovascular risk in individuals with type 2 diabetes (T2D). The primary objective of the present study was to investigate whether the biomarkers of NAFLD included in the FibroMax® panels are associated with the degree of coronary artery calcification in patients with T2D., Methods: A total of 157 and 460 patients with T2D were included from the DIACART and ACCoDiab cohorts, respectively. The coronary artery calcium score (CACS) was measured in both cohorts using computed tomography. FibroMax® panels (i.e., SteatoTest®, FibroTest®, NashTest®, and ActiTest®) were determined from blood samples as scores and stages in the DIACART cohort and as stages in the ACCoDiab cohort., Results: CACS significantly increased with the FibroTest® stages in both the DIACART and ACCoDiab cohorts (p-value for trend = 0.0009 and 0.0001, respectively). In DIACART, the FibroTest® score was positively correlated with CACS in univariate analysis (r = 0.293, p = 0.0002) and remained associated with CACS independently of the traditional cardiovascular risk factors included in the SCORE2-Diabetes model [β = 941 ± 425 (estimate ± standard error), p = 0.028]. In the ACCoDiab cohort, the FibroTest® F3-F4 stage was positively correlated with CACS in point-biserial analysis (r pbi  = 0.104, p = 0.024) and remained associated with CACS after adjustment for the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (β = 234 ± 97, p = 0.016). Finally, the prediction of CACS was improved by adding FibroTest® to the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (goodness-of-fit of prediction models multiplied by 4.1 and 6.7 in the DIACART and ACCoDiab cohorts, respectively). In contrast, no significant relationship was found between FibroMax® panels other than FibroTest® and CACS in either cohort., Conclusions: FibroTest® is independently and positively associated with the degree of coronary artery calcification in patients with T2D, suggesting that FibroTest® could be a relevant biomarker of coronary calcification and cardiovascular risk., Trial Registration: ClinicalTrials.gov identifiers NCT02431234 and NCT03920683., (© 2024. The Author(s).)

(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.

Background: There is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events. However, the relationship between plasma ceramide levels and NAFLD severity in type 2 diabetes remains unclear. The main purpose of the present study was to investigate whether circulating levels of ceramides in patients with type 2 diabetes are associated with liver steatosis assessed by the highly accurate magnetic resonance imaging proton density fat fraction (MRI-PDFF). The secondary objective was to assess the relationship between plasma ceramides and noninvasive scores of liver fibrosis., Methods: In this cross-sectional single-center study, plasma concentrations of 7 ceramides were measured by liquid chromatography-mass spectrometry in 255 patients with type 2 diabetes (GEPSAD cohort). Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis (i.e. Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest® and Fibrotic NASH Index) were calculated. A validation cohort of 80 patients with type 2 diabetes was also studied (LIRA-NAFLD cohort)., Results: Liver steatosis, defined as a liver fat content > 5.56%, was found in 62.4 and 82.5% of individuals with type 2 diabetes in the GEPSAD and LIRA-NAFLD cohorts, respectively. In GEPSAD, MRI-PDFF-measured liver fat content was positively associated with plasma levels of total ceramides (r = 0.232, p = 0.0002), and 18:0, 20:0, 22:0 and 24:0 ceramides in univariate analysis (p ≤ 0.0003 for all). In multivariate analysis, liver fat content remained significantly associated with total ceramides (p = 0.001), 18:0 (p = 0.006), 22:0 (p = 0.0009) and 24:0 ceramides (p = 0.0001) in GEPSAD, independently of age, diabetes duration, body mass index and dyslipidemia. Overall, similar relationship between plasma ceramides and liver fat content was observed in the LIRA-NAFLD validation cohort. No significant association was found between plasma ceramides and noninvasive scores of fibrosis after adjustment for age in both cohorts., Conclusions: Plasma ceramide levels are associated with liver steatosis in patients with type 2 diabetes, independently of traditional risk factors for NAFLD. The independent association between plasma ceramides and liver steatosis adds new insights regarding the relationship between ceramides and NAFLD in type 2 diabetes., (© 2023. The Author(s).)

The recreational use of nitrous oxide (N 2 O) as "laughing gas" is a growing problem. The chronic toxicity of N 2 O is mainly due to its ability to oxidize vitamin B12, making it dysfunctional as a cofactor in metabolic pathways. This mechanism plays a major role in the development of neurological disorders in N 2 O users. The assessment of vitamin B12 status in N 2 O users is important but challenging due to the lack of decrease in total vitamin B12 in most cases despite genuine vitamin B12 functional deficiency. Other biomarkers, such as holotranscobalamin (holoTC), homocysteine (tHcy) and methylmalonic acid (MMA), are interesting candidates to properly assess vitamin B12 status. Here, we conducted a systematic review of case series in order to assess the prevalence of abnormal values of total vitamin B12, holoTC, tHcy and MMA in recreational N 2 O users, which is an important prerequisite for determining the best screening strategy in future guidelines. We included 23 case series (574 N 2 O users) from the PubMed database. Total circulating vitamin B12 concentration was low in 42.2% (95% confidence interval 37.8-46.6%, n = 486) of N 2 O users, while 28.6% (7.5-49.6%, n = 21) of N 2 O users had low circulating concentrations of holoTC. tHcy levels were elevated in 79.7% (75.9-83.5%, n = 429) of N 2 O users, while 79.6% (71.5-87.7%, n = 98) of N 2 O users had increased concentrations of MMA. In summary, the increases in tHcy and MMA were the most prevalent abnormalities, and should be measured alone or in combination in symptomatic N 2 O users rather than total vitamin B12 or holoTC.

Background: Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis., Methods: Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy., Results: Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05)., Conclusions: Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888., (© 2023. The Author(s).)

The link between vitamin D and multiple sclerosis (MS) has been suggested in epidemiological, genetic, immunological, and clinical studies. The aim of the present systematic review of the literature was to assess the effects of vitamin D supplementation on clinical and imaging outcomes in patients with MS. The outcomes we assessed included relapse events, disability progression, and magnetic resonance imaging (MRI) lesions. The search was conducted using PubMed, ClinicalTrials.gov, and EudraCT databases, and it included records published up until 28 February 2023. The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Nineteen independent clinical studies (corresponding to 24 records) were included in the systematic review. The risk of bias in randomized controlled trials (RCTs) was analyzed using the Cochrane risk-of-bias tool. Fifteen trials investigated relapse events, and most of them reported no significant effect of vitamin D supplementation. Eight of 13 RCTs found that vitamin D supplementation had no effect on disability [assessed by Expanded Disability Status Scale (EDSS) scores] compared to controls. Interestingly, recent RCTs reported a significant reduction in new MRI lesions in the central nervous system of MS patients during supplementation with vitamin D3.

Diabetic dyslipidemia is characterized by quantitative and qualitative abnor-malities in lipoproteins. In addition to glycation and oxidation, carbamylation is also a post-translational modification affecting lipoproteins in diabetes. Patients with type 2 diabetes (T2D) exhibit higher levels of carbamylated low-density lipoproteins (cLDL) and high-density lipoproteins (cHDL). Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes. cLDL levels have been shown to predict cardiovascular events and all-cause mortality. cLDL facilitates immune cell recruitment in the vascular wall, promotes accumulation of lipids in macrophages, and contributes to endothelial dysf-unction, endothelial nitric oxide-synthase (eNOS) inactivation and endothelial repair defects. Lastly, cLDL induces thrombus formation and platelet aggregation. On the other hand, recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients. This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation. Thus, cHDL loses the ability to remove cholesterol from macrophages, to inhibit monocyte adhesion and recruitment, to induce eNOS activation and to inhibit apoptosis. Taken together, it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes., Competing Interests: Conflict-of-interest statement: The author reports no relevant conflicts of interest for this review., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Alterations affecting high-density lipoproteins (HDLs) are one of the various abnormalities observed in dyslipidemia in type 2 diabetes mellitus (T2DM) and obesity. Kinetic studies have demonstrated that the catabolism of HDL particles is accelerated. Both the size and the lipidome and proteome of HDL particles are significantly modified, which likely contributes to some of the functional defects of HDLs. Studies on cholesterol efflux capacity have yielded heterogeneous results, ranging from a defect to an improvement. Several studies indicate that HDLs are less able to inhibit the nuclear factor kappa-B (NF-κB) proinflammatory pathway, and subsequently, the adhesion of monocytes on endothelium and their recruitment into the subendothelial space. In addition, the antioxidative function of HDL particles is diminished, thus facilitating the deleterious effects of oxidized low-density lipoproteins on vasculature. Lastly, the HDL-induced activation of endothelial nitric oxide synthase is less effective in T2DM and metabolic syndrome, contributing to several HDL functional defects, such as an impaired capacity to promote vasodilatation and endothelium repair, and difficulty counteracting the production of reactive oxygen species and inflammation.

Objective: To assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities., Design and Methods: This is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs)., Results: The cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ± 4.3 vs 35.5 ± 2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ± 16.5 vs -63.5 ± 18.7%, P = 0.14; and -62.1 ± 13.2 vs -54.7 ± 17.7%, P = 0.16, respectively)., Conclusion: Despite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Reduced cholesterol efflux capacity (CEC) of HDLs is likely to increase cardiovascular risk in type 1 diabetes (T1D). We aimed to assess whether improvement of glycemic control in T1D patients is associated with changes in CEC in relation with changes in carbamylation of HDLs., Methods: In this open-label trial, 27 uncontrolled T1D patients were given a three-month standard medical intervention to improve glycemic control. HDL fraction was isolated from plasma, and CEC was measured on THP-1 macrophages. Carbamylation of HDLs was evaluated by an immunoassay. Control HDLs from healthy subjects were carbamylated in vitro with potassium cyanate., Results: HbA 1c decreased from 11.4% [10.2-12.9] (median [1st-3rd quartiles]) at baseline to 8.1% [6.6-9.0] after the three-month intervention (P < 0.00001). The CEC of HDLs increased after intervention in 19 (70%) patients (P = 0.038). At the same time, the carbamylation of HDLs decreased in 22 (82%) patients after intervention (P = 0.014). The increase in CEC significantly correlated with the decrease in carbamylated HDLs (r = -0.411, P = 0.034), even after adjustment for the change in HbA 1c (β = -0.527, P = 0.003). In vitro carbamylation of control HDLs decreased CEC by 13% (P = 0.041) and 23% (P = 0.021) using 1 and 10 mmol/L of potassium cyanate, respectively., Conclusions: The improvement of CEC in relation to a decrease in the carbamylation of HDLs may likely contribute to the beneficial cardiovascular effect of glycemic control in T1D patients., Trial Registration: NCT02816099 ClinicalTrials.gov., (© 2022. The Author(s).)

Objective: Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC., Design: Prospective, observational study., Methods: Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice., Results: In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively)., Conclusions: We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.

Background: In septic shock, both systemic vasodilatation and glomerular arteriole dilatation are responsible for the drop in glomerular filtration observed in early acute kidney injury. Angiotensin II has been shown to act on both mechanisms. Our objective was to evaluate the impact of renin angiotensin system activation, on hemodynamic deficiency and renal outcome in patient with septic shock and to assess whether urinary sodium could be a reliable test for high plasma renin concentration screening., Methods: This was a prospective and observational study. Inclusion criteria were early septic shock (first episode), dose of norepinephrine ≥ 0.25 μg/kg/min, before the start of substitutive corticosteroids. Plasma renin concentration, plasma aldosterone concentration, and urinary sodium were measured at inclusion. Renal outcome, organ deficiency, and 28-day survival were followed., Results: Plasma renin concentration was associated with worse hemodynamic deficiency and adverse renal outcome. Natriuresis was associated with shock severity but was not associated with renal outcome. Low natriuresis (< 20 mM) was associated with higher renin concentration. Those two variables were only weakly correlated., Conclusion: Plasma renin concentration is associated with adverse renal outcome, probably through shock severity and insufficient glomerular efferent arterioles vasoconstriction. An association was observed between low natriuresis and high plasma renin concentration.

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome, and type 2 diabetes. NAFLD is also seen in patients with endocrinopathies. However, the relationship between endocrine diseases and the development of NAFLD is not well known. In this study, we set out to determine whether liver fat content (LFC) was associated with IGF1 levels in people with pituitary diseases (PD). Eighty-nine patients with pituitary diseases and 74 healthy controls were included in this study. LFC was measured using MRI. Hepatic steatosis was defined as LFC>5.5%. Patients with PD were older, and had a higher BMI than healthy controls. LFC was significantly higher in people with PD than in controls (6.5% vs. 3.2%; p<0.001). LFC was negatively associated with the IGF1 level. The prevalence of steatosis was higher in PD patients than in controls (36.3% vs. 14.8%; p=0.002). In multivariate analysis, which included patients and controls, the predictive variables for steatosis were age, BMI and IGF1 levels, whereas the presence of pituitary diseases and gender were not associated with steatosis. Our data showed that LFC was strongly associated with IGF1 levels. These results suggest that steatosis associated with PD is probably a consequence of a low IGF1 level in these patients., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: 25-hydroxyvitamin D [25(OH)D] is the most reliable biomarker of vitamin D status, but until now 25(OH)D assays have suffered from inter-laboratory and inter-assay discrepancies. In the setting of the international Vitamin D Standardization Program, Immunodiagnostic Systems (IDS) recently reformulated and restandardized the 25(OH)D immunoassay available on the automated iSYS platform. In the present study, we evaluated this new generation of the 25(OH)D immunoassay (IS-2500)., Methods: Repeatability and within-laboratory imprecision were verified according to the Clinical and Laboratory Standards Institute EP15-A3. Results from the sera of 63 patients were compared with those obtained with the previous iSYS method (IS-2700S) using Passing-Bablok and Bland-Altman analysis. The prevalence and bias-adjusted kappa (PABAK) coefficient was calculated to assess the agreement of vitamin D status provided by the two iSYS immunoassays. Fourteen Vitamin D External Quality Assessment Scheme (DEQAS) samples were used to evaluate inaccuracy., Results: Using the EP15-A3 protocol, repeatability and within-laboratory imprecision obtained with the new iSYS method were lower than 6% and 8%, respectively. These results are consistent with the manufacturer's claims. In more adverse conditions (50 measurements over 15days with multiple calibrations), the within-laboratory imprecision was 14.8% (39nmol/L) and 7.7% (155nmol/L). 25(OH)D concentrations measured with the new assay showed a strong correlation with those provided by the previous version (r=0.969, p<0.0001). The Passing-Bablok regression equation was as follows: new assay=1.079 x (previous assay) - 3.6nmol/L. The PABAK coefficient of 0.810 reflected almost perfect agreement between the two immunoassays to classify patients according to their vitamin D status (85.7% of agreement). Using DEQAS samples, the mean inaccuracy bias was lower than 5% when the new iSYS method was compared with LC-MS/MS methods and the NIST reference measurement procedure., Conclusion: The new generation of the iSYS immunoassay evaluated in this study meets requirements for routinely measuring 25(OH)D levels in clinical laboratories., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The biological diagnosis of primary aldosteronism (PA) is a real challenge in clinical laboratories. First, PA is a major cause of secondary hypertension, and more widespread screening is currently recommended. In addition, the recent development of automated and mass spectrometry tests has made it necessary to determine the most appropriate cutoff values in clinical studies. New French and international guidelines will play an important role in the standardization of PA diagnosis. The first diagnostic step is to measure the aldosterone to renin ratio (ARR), which is widely considered the best screening test. The preanalytical phase is crucial to properly interpret the ARR, and rigorous testing conditions must be observed to improve the diagnostic efficiency. The choice of the most appropriate cutoff value for ARR is a real concern in laboratories due to variability between methods. The second step of PA diagnosis aims to rule out false-positive ARRs using one or more dynamic confirmatory tests based on aldosterone suppression. Finally, the third step involves adrenal venous sampling to distinguish between unilateral and bilateral disease.

Objective: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS)., Approach and Results: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides ( P <0.01) and 15% poorer in sphingosine-1-phosphate ( P <0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[ 3 H]arginine to L-[ 3 H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls ( P <0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% ( P <0.001) and 39% ( P <0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity ( P <0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 ( P <0.05) and in Akt phosphorylation at Ser473 ( P =0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity ( P =0.90) and phosphorylation at Ser1177 ( P =0.87)., Conclusions: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients., (© 2017 American Heart Association, Inc.)

Background: Nonalcoholic fatty liver disease is very frequent in type 2 diabetes, with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce., Objective: To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC., Design, Setting, Participants: LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus., Intervention: Liraglutide 1.2 mg/d., Outcome Measure: Change in LFC., Results: Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C, and a marked relative reduction in LFC of 31% (P < 0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and body weight were highly correlated (r = 0.490; P < 0.0001). In multivariate analysis, the reduction in LFC was independently associated with baseline LFC (P < 0.0001), age (P = 0.010), and reduction in body weight (P < 0.0001), triglycerides (P = 0.019), and HbA1c (P = 0.034). In the patients who had no significant decrease in body weight, no significant reduction in LFC was observed., Conclusions: Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction. Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression., (Copyright © 2017 by the Endocrine Society)

Background: Recent studies revealed that obesity is associated with decreased serum but at the same time increased red blood cell (RBC) folate concentrations compared with lean subjects, thus casting doubt upon the agreement between serum and RBC folate measurements for assessing folate status. This work aimed to determine whether these two metrics lead to the same classification of folate status in obese patients., Methods: RBC and serum folate concentrations were measured with a chemiluminescent immunoassay in 263 adults with body mass index ≥30 kg/m 2 and without previous bariatric surgery. Among them, 68.1 % were eligible for bariatric surgery. Each serum and RBC folate result was classified as deficient or not according to thresholds recommended by the kit manufacturer (model A) or by the World Health Organization (model B). The agreement between serum and RBC folate results was evaluated using the proportion of overall agreement and the prevalence-adjusted bias-adjusted kappa (PABAK) statistics., Results: The overall percentage agreements between serum and RBC measurements were 91.6 % (95 % CI 87.6-94.7 %) and 92.4 % (95 % CI 88.5-95.3 %) with PABAK coefficients of 0.87 (95 % CI 0.82-0.93) and 0.88 (95 % CI 0.83-0.94) in the models A and B, respectively, corresponding to almost perfect agreement. The same was true in the subgroup of patients eligible for bariatric surgery. Gender, age, and BMI did not influence the quality of agreement between the two parameters., Conclusions: The present study showed that folate measurements in serum and in RBC display similar performances to assess folate status in obese patients.

Background and Aims: Diabetic patients are at high risk of stroke and coronary artery disease. Recent data suggest that arachidonic acid metabolism is altered in diabetic conditions and that these alterations contribute to accelerated atherosclerosis. Little is known about how these alterations affect the metabolism and the proportions of different lipid species within the atherosclerotic plaque. The aim of our study was to perform a targeted lipidomic analysis of human atherosclerotic lesions, with a specific focus on PUFA-containing lipid species, to reveal differences in the fatty-acid composition of plaque in diabetic patients compared with non-diabetic controls., Methods: Carotid atheroma plaque samples were obtained from 31 diabetic and 48 non-diabetic patients undergoing carotid endarterectomy. Targeted lipidomic analysis was then performed to determine the fatty acid composition of major glycerophospholipids and cholesteryl ester species by liquid chromatography-tandem mass spectrometry., Results: Atheroma plaques from diabetic patients were significantly enriched with 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) (2.3 ± 0.8% Vs. 1.8 ± 0.6% p = 0.0002). Multivariable logistic regression showed that an increased 2-AA-LPC level was independently associated with diabetes. Finally, a positive relationship was found between 2-AA-LPC and HbA1c levels. Interestingly, endothelial lipase and calcium independent PLA2 gamma which could account for the production of 2-AA-LPC were detected in carotid plaques by immunohistochemistry., Conclusions: 2-AA-LPC stands at the crossroads of major metabolic pathways that lead to the synthesis of bioactive molecules such as AA-derived eicosanoids, 2-AA-lysophosphatidic acid and 2-AA-glycerol. 2-AA-LPC therefore appears to be a promising molecule to investigate in the context of diabetes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: 25-Hydroxyvitamin D (25(OH)D) deficiency is a frequent condition in patients who suffer a stroke, and several studies suggested that it may be associated with a poorer prognosis. The aim of this study was to investigate specifically the association between 25(OH)D levels and functional outcome at 3 months in ischemic stroke patients treated with intravenous thrombolysis., Methods: Consecutive ischemic stroke patients who received intravenous thrombolysis were enrolled between 2010 and 2013. Baseline characteristics were collected, and serum concentrations of 25(OH)D were measured within the first 24 hours after admission and were analyzed according to the quartiles of their distribution (<25 nmol/L versus ≥ 25 nmol/L). Multivariable ordinal logistic regression was used to evaluate the association between 25(OH)D and 3-month functional outcome assessed by the modified Rankin score., Results: Three hundred fifty-two patients were included (mean age 68.6 ± 15.8, 50.7% women, mean 25(OH)D level 45 ± 25 nmol/L). The characteristics of the patients only differed with regard to higher premorbid functional impairment in patients with low 25(OH)D. In univariate analysis, the risk of functional impairment in patients with low 25(OH)D levels was greater than that in patients with higher 25(OH)D levels (odds ratio [OR] 2.10, 95% confidence interval [CI]: 1.35-3.27, P = .001). This association was still observed after adjustment for confounding variables (OR 1.70, 95% CI: 1.06-2.71, P = .027)., Conclusion: A low serum 25(OH)D level is associated with worse functional outcome in patients with acute ischemic stroke treated with intravenous thrombolysis. Further investigations are required to understand the underlying mechanisms of this association., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: Phospholipids and sphingolipids play a critical role in the protective effects of HDL against atherosclerosis. These properties are impaired in patients with metabolic syndrome, before the development of diabetes. We thus investigated whether HDL from patients with metabolic syndrome but normal fasting glycaemia present abnormalities in their sphingophospholipid profile., Methods: Using liquid chromatography/tandem mass spectrometry, we quantified the different species of the main phospholipids and sphingolipids in the HDL2 and HDL3 from 26 obese patients with metabolic syndrome but normal fasting glycaemia and 50 controls., Results: Phosphatidylcholines, when expressed as the relative amount compared with total phospholipids and sphingolipids, were similar in both HDL2 and HDL3 in the two groups. Lysophosphatidylcholines were 41% (p = 0.0002) and 86% (p < 0.0001) higher in HDL2 and HDL3, respectively, from patients with metabolic syndrome than in those from controls. Phosphatidylinositols were also higher in HDL2 and HDL3 (respectively, +60 and + 103% (p < 0.0001)). In contrast, both HDL2 and HDL3 from patients with metabolic syndrome showed lower proportions of phosphatidylethanolamine-based plasmalogens (respectively -78 and -73%, p < 0.0001), phosphatidylcholine-based plasmalogens (respectively -44 and -53%, p < 0.0001), d18:1-sphingosine-1-phosphate (respectively -52 and -38%, p < 0.0001) and sphingomyelins (respectively -19% (p < 0.0001) and -24% (p = 0.0006)), than did controls. Moreover, we observed a decrease in C18:2 fatty acid-containing phospholipids and an increase in C20:4 fatty acid-containing phospholipids., Conclusion: The sphingophospholipidome of HDL from normoglycaemic obese patients with metabolic syndrome is profoundly modified, before the dysregulation of glycaemia. Most of the changes observed have pejorative effect in terms of vascular protection., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Major hyperferritinemia is a rare feature in clinical laboratories associated with a wide variety of disorders, including hemophagocytic lymphohistiocytosis (HLH). The diagnosis of HLH is based on clinical and biological criteria, such as those proposed by the Histiocyte Society. However, several of these criteria are not relevant in the specific setting of hematologic malignancies., Materials and Methods: A 69-year-old male was treated for an acute myeloid leukaemia. On day 15 after the start of chemotherapy, he developed severe sepsis with high fever, low blood pressure and hepatosplenomegaly., Results: Blood tests were marked by extreme hyperferritinemia (191,000 µg/L, reference range: 26-388 µg/L) with increased C-reactive protein (87.0 mg/L) and procalcitonin (1.94 µg/L) and aspartate aminotransferase (499 U/L 37 °C) in the setting of chemotherapy-induced aplasia. This unusual extreme ferritinemia led to suspect HLH triggered by an invasive infection. Under intensive treatment, the clinical status improved and ferritin levels significantly decreased., Conclusions: The diagnosis of HLH is usually based on clinical and biological criteria, mainly fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis and hyperferritinemia. In this patient, the diagnosis of HLH was challenging because several criteria, such as hypertriglyceridemia, hemophagocytosis and hypofibrinogenemia, were absent. In addition, some criteria of HLH are not relevant in the setting of hematologic malignancy, in which fever, splenomegaly, cytopenias and elevated lactate dehydrogenase are commonly observed independently of HLH. This unusual case of extremely high ferritinemia emphasizes the important weight of the ferritin level for the diagnosis of HLH in adult patients in the setting of hematologic malignancies.

Objective: Phospholipids and sphingolipids are major components of HDL. They play a critical role in HDL functionality and protective effects against atherosclerosis. As HDL are dysfunctional in type 1 diabetic patients, we ascertained whether they presented abnormalities in their phospholipid and sphingolipid profile, despite normal HDL cholesterol concentration., Methods: Using liquid chromatography-tandem mass spectrometry, we quantified the main species of phosphatidylcholines, sphingomyelins, lysophophatidylcholines, phosphatidylethanolamines, phosphatidylinositols, ceramides, plasmalogens and sphingosines 1-phosphate in the HDL2 and HDL3 from 54 type 1 diabetic patients and 50 controls., Results: Serum HDL cholesterol was similar in the 2 groups of subjects. When data were expressed relative to the total amount of phospholipids and sphingolipids, sphingosines-1-phosphate (S1P) were 11.7% (NS) and 14.4% (p = 0.0062) lower in HDL2 and HDL3, respectively, from type 1 diabetic patients than from controls. Ceramides were 23% (p = 0.005) and 24% (borderline significance) lower in HDL2 and HDL3, respectively. The concentration of apolipoprotein M, the carrier of S1P, was similar in patients and controls. In type 1 diabetic patients compared to controls, the concentration of d18:1-S1P, the main S1P species, was decreased in total plasma (-17.0%, p < 0.0001), HDL fraction (-21.9%, p < 0.0001) and non-HDL fraction (-13.7%, p = 0.012). The concentration of ceramides was decreased in total plasma (-24.4%, p < 0.0001), HDL fraction (-27.9%, p = 0.0006) and non-HDL fraction (-22.0%, p = 0.0087)., Conclusion: Despite normal HDL cholesterol level, the phospholipid + sphingolipid profile is impaired in HDL from type 1 diabetic patients. These abnormalities, especially the decrease in S1P, could contribute to the impaired HDL functionality observed in these patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Several recent studies have shown some discrepancies between 25-hydroxyvitamin D [25(OH)D] assay methods, despite some improvement in the past few years. The accuracy of 25(OH)D assay methods is still a real challenge for clinical laboratories. The aim of this study was to assess the agreement between a large panel of routine assays and a two-dimensional liquid chromatography/tandem mass spectrometry (2D LC-MS/MS) method, selected as the reference method., Methods: Forty-nine human plasma samples with only endogenous 25(OH)D₃ were analyzed with 11 different methods, especially with three LC-UV methods that differed in the extraction step. Seven routine immunoassays were also tested: two manual (RIA and EIA from IDS) and five fully-automated methods. The results of the 25(OH)D₃ assays were compared with those of the 2D LC-MS/MS method using weighted Deming regression analysis, Bland-Altman plots and concordance correlation coefficient (CCC). The ability of these methods to properly classify patients was evaluated by sorting results depending on vitamin D status., Results: The CCC was >0.90 for the three LC-UV methods and for most of the automated IA, meaning substantial agreement with 2D LC-MS/MS results. The ability to properly classify patients according to their vitamin D status was overall satisfactory for most of the methods tested (concordance >90%)., Conclusions: The immunoassays available on Liaison, Isys, Architect and Elecsys, together with our in-house LC-UV method preceded by an SLE step met the minimum requirements for the assessment of vitamin D status in clinical laboratories.

According to the current paradigm, lymphocyte homing to the small intestine requires the expression of two tissue-specific homing receptors, the integrin α4β7 and the CCL25 receptor CCR9. In this study, we investigated the organ distribution and the homing molecule expression of IgA Ab-secreting cells (ASCs) induced by intrarectal immunization with a particulate Ag, in comparison with other mucosal immunization routes. Intrarectal immunization induces gut-homing IgA ASCs that localize not only in the colon but also in the small intestine, although they are not responsive to CCL25, unlike IgA ASCs induced by oral immunization. The mucosal epithelial chemokine CCL28, known to attract all IgA ASCs, does not compensate for the lack of CCL25 responsiveness, because the number of Ag-specific cells is not decreased in the gut of CCR10-deficient mice immunized by the intrarectal route. However, Ag-specific IgA ASCs induced by intrarectal immunization express the integrin α4β7, and their number is considerably decreased in the gut of β7-deficient mice immunized by the intrarectal route, indicating that α4β7 enables these cells to migrate into the small intestine, even without CCL25 responsiveness. In contrast, IgA ASCs induced by intranasal immunization express low α4β7 levels and are usually excluded from the gut. Paradoxically, after intranasal immunization, Ag-specific IgA ASCs are significantly increased in the small intestine of β7-deficient mice, demonstrating that lymphocyte homing is a competitive process and that integrin α4β7 determines not only the intestinal tropism of IgA ASCs elicited in GALTs but also the intestinal exclusion of lymphocytes primed in other inductive sites.

Multiple myeloma diagnosis and follow-up are based on monoclonal protein measurement. The estimation of monoclonal immunoglobulin production requires serum protein electrophoresis, immunoelectrophoresis and free light chain assay. However these classical assays have some limitations. Hevylite™ IgA (Binding Site) is a new nephelometric/turbidimetric assay allowing the IgA κ and IgA λ measurement. The aim of this study was to determine the performance of this assay, for the diagnosis and follow-up of myeloma patients at different stages. Sixty seven frozen sera from 26 patients were assayed. Total IgA, IgA κ, IgA λ concentrations, serum protein electrophoresis and serum immunofixation were performed at diagnosis and during follow-up. All myeloma patients had an abnormal IgA κ/IgA λ ratio at diagnosis. During disease monitoring, the IgA κ or IgA λ concentrations correlated well with the electrophoretic estimation of the monoclonal spike and the values of total IgA. Hevylite™ test was more sensitive than serum protein electrophoresis and provided numerical and reproductible assessment of the monoclonal and non-monoclonal isotype. The IgA κ/IgA λ ratio allowed early prediction of disease relapse. Hevylite™ is an interesting assay especially when the monoclonal IgA comigrates on electrophoresis with normal proteins making impossible a reliable densitometric estimation. Hevylite™ might become an important assay in the biological exploration of gammopathies.