Impact of micronutrient deficiency & malnutrition in systemic sclerosis: Cohort study and literature review.

OBJECTIVES: The purpose of our study was to determine the prevalence and risk factors associated with malnutrition, and selenium (Se) and vitamin C (vitC) deficiencies in systemic sclerosis (SSc) patients. METHODS: We included adult SSc patients fulfilling the 2013 ACR/EULAR criteria from the Toulouse University Hospital cohort who underwent a micronutrient workup (including vitC, Se or thiamine levels) between 2011 and 2016. RESULTS: 82 patients were included, mostly women (76%), with a median age of 60 years. SSc was limited in 76% of the cases, with Scl-70 and centromere antibodies in 32% and 44%, respectively. Median disease duration was 7.4 years. Cardiac involvement was noticed in 19% and gastrointestinal tract in and 95%; 9% had pulmonary artery hypertension (PAH) and 63% had interstitial lung disease. Overt malnutrition was present in 14 (17%) patients. Micronutrient deficiencies included Se (35%), vitC (31%) and/or thiamine (6%). Malnourished patients had significantly a higher summed Medsger disease severity scales (7.5 vs. 5, P = .003), lower hemoglobin (10.6 vs. 12.9 g/dL, P < .0001) and vitC levels (3.6 vs. 10.6 mg/L, P = .003). Cardiac involvement was significantly associated with Se deficiency (OR 6.2, IC 95%[1.48-32.70], P = .05). The factors associated with vitC deficiency were malnutrition (OR 8.57, IC 95%[2.16-43.39], P = .003), modified Rodnan skin score ≤ 14 (OR 0.33, IC95[0.11-1], P = .05), PAH (27% in deficient vs. none in non-deficient patients, P = .0006) and esophagitis or Barrett's mucosa (OR 4.05, IC95[1.27-13.54], P = .02). CONCLUSIONS: Se testing should be considered as soon as cardiac involvement is suspected. VitC testing should be considered in malnourished SSc patients, especially if skin involvement is extensive.

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

To date, therapeutic drug monitoring (TDM) is carried out with antiretrovirals and is usually based on total concentrations (Ct ). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (Cu ) is the pharmacological active form, the aim of the study was to evaluate the value of Cu and the unbound fraction (fu , fu = Cu /Ct ) for the TDM of ATV. The variability of Cu and the corresponding fu of ATV was explored in 43 patients treated with ATV for an average of 13.5 months. Cu was determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein (AAG), the correlation between fu and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough Cu and Ct were 37.9 µg/L (Interquartile range (IQR) 20.6-94.9 µg/L) and 628.6 µg/L (IQR 362.7-1078.1 µg/L), respectively. fu , Cu and Ct showed high variability, but the fu variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (P = 0.21 and P = 0.65 for Cu and fu , respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for Cu ). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than Ct .

Annexin II-dependent actin remodelling evoked by hydrogen peroxide requires the metalloproteinase/sphingolipid pathway.

Actin remodeling is a dynamic process associated with cell shape modification occurring during cell cycle and proliferation. Oxidative stress plays a role in actin reorganization via various systems including p38MAPK. Beside, the mitogenic response evoked by hydrogen peroxide (H2O2) in fibroblasts and smooth muscle cells (SMC) involves the metalloproteinase (MMPs)/sphingomyelinase 2 (nSMase2) signaling pathway. The aim of this work was to investigate whether this system plays a role in actin remodeling induced by H2O2. Low H2O2 dose (5µM) rapidly triggered a signaling cascade leading to nSMase2 activation, src and annexin 2 (AnxA2) phosphorylation, and actin remodeling, in fibroblasts and SMC. These events were blocked by pharmacological inhibitors of MMPs (Ro28-2653) and p38MAPK (SB203580), and were lacking in MMP2(-/-) and in nSMase2-mutant (fro) fibroblasts. Likewise, H2O2 was unable to induce actin remodeling in fro and MMP2(-/-) fibroblasts or in cells pretreated with p38MAPK, or MMP inhibitors. Finally we show that nSMase2 activation by H2O2, depends on MMP2 and p38MAPK, and is required for the src-dependent phosphorylation of AnxA2, and actin remodeling. Taken together, these findings indicate for the first time that AnxA2 phosphorylation and actin remodeling evoked by oxidative stress depend on the sphingolipid pathway, via MMP2 and p38MAPK.

Alteration of plasma phospholipid fatty acid profile in patients with septic shock.

In septic shock patients, alterations of plasma phospholipid fatty acid profile have never been described. The purpose of this monocentric, non-interventional, observational prospective study was to describe this fatty acid profile in the early phase of septic shock in intensive care unit. Thirty-seven adult patients with septic shock were included after the first day of stay in intensive care unit, before any form of artificial nutritional support. Plasma phospholipid fatty acid composition was determined by gas chromatography. All biological data from patients with septic shock were compared with laboratory reference values. Patients presented hypocholesterolemia and hypertriglyceridemia. They had low concentrations of phospholipid fatty acids specifically n-6 and n-3 polyunsaturated fatty acids (PUFAs) with a high n-6/n-3 ratio. Plasma phospholipid PUFA concentrations were strongly correlated with cholesterolemia. PUFAs/SFAs (saturated fatty acids) and PUFAs/MUFAs (monounsaturated fatty acids) ratios were low because of low percentage of n-6 and n-3 PUFAs and high percentage of SFAs and MUFAs. Low levels of plasma long chain PUFAs (≥20 carbons) were significantly associated with mortality at 28th day. In conclusion, plasma phospholipid FA profile of septic patients is very characteristic, close to that of acute respiratory distress syndrome and mortality is associated with long chain PUFA decrease. This profile could be explained by numerous non-exclusive physio-pathological processes 1) an activation of hepatic de novo lipogenesis that could contribute to hepatic steatosis, 2) an elevated adipose tissue lipolysis, 3) an increased free radical attack of FA by oxidative stress, 4) an over-production of inflammatory lipid mediators.

A signaling cascade mediated by ceramide, src and PDGFRß coordinates the activation of the redox-sensitive neutral sphingomyelinase-2 and sphingosine kinase-1.

Stress-inducing agents, including oxidative stress, generate the sphingolipid mediators ceramide (Cer) and sphingosine-1-phosphate (S1P) that are involved in stress-induced cellular responses. The two redox-sensitive neutral sphingomyelinase-2 (nSMase2) and sphingosine kinase-1 (SK1) participate in transducing stress signaling to ceramide and S1P, respectively; however, whether these key enzymes are coordinately regulated is not known. We investigated whether a signaling link coordinates nSMase2 and SK1 activation by H2O2. In mesenchymal cells, H2O2 elicits a dose-dependent biphasic effect, mitogenic at low concentration (5µM), and anti-proliferative and toxic at high concentration (100µM). Low H2O2 concentration triggered activation of nSMase2 and SK1 through a nSMase2/Cer-dependent signaling pathway that acted upstream of activation of SK1. Further results implicated src and the trans-activation of PDGFRß, as supported by the blocking effect of specific siRNAs, pharmacological inhibitors, and genetically deficient cells for nSMase2, src and SK1. The H2O2-induced src/PDGFRß/SK1 signaling cascade was impaired in nSMase2-deficient fro/fro cells and was rescued by exogenous C2Cer that activated src/PDGFRß/SK1. Thus, the results define a nSMase2/SK1 signaling pathway implicated in the mitogenic response to low oxidative stress. On the other hand, high oxidative stress induced inhibition of SK1. The results also showed that the toxicity of high H2O2 concentration was comparable in control and nSMase2-deficient cells. Taken together the results identify a tightly coordinated nSMase2/SK1 pathway that mediates the mitogenic effects of H2O2 and may sense the degree of oxidative stress.

Copeptin improves the diagnostic performance of sensitive troponin I-Ultra but cannot rapidly rule out non-ST-elevation myocardial infarction at presentation to an emergency department.

STUDY OBJECTIVE: We assess the performance of a single multimarker strategy, using a combination of sensitive troponin I-Ultra and copeptin assays to rule out non-ST-elevation myocardial infarction (NSTEMI) at presentation to an emergency department (ED). METHODS: A secondary analysis was carried out on 587 consecutive patients with chest pain who presented to the ED without ST elevation on ECG and were included in a single-site, prospective observational study. Samples for copeptin and combination of sensitive troponin I-Ultra assays were collected at presentation. The performance of the combination of copeptin and combination of sensitive troponin I-Ultra for NSTEMI was calculated in the whole cohort and after stratification by thrombosis in myocardial infarction (TIMI) risk score. RESULTS: NSTEMI was diagnosed in 87 patients (14.8%). The sensitivity and the negative predictive value of the combination of copeptin and combination of sensitive troponin I-Ultra were 96.6% (95% confidence interval [CI] 90.3% to 99.3%) and 99.1% (95% CI 97.4% to 99.8%), respectively, for a cutoff level of copeptin less than 12 pmol/L. Among the 243 patients with a low TIMI score, all 8 who had an NSTEMI were detected with the combination (sensitivity 100%; 95% CI 63.1% to 100%), and 158 were a combination of sensitive troponin I-Ultra and copeptin negative and had no NSTEMI (negative predictive value 100%; 95% CI 97.7% to 100%). CONCLUSION: In this study, the combination of sensitive troponin and copeptin measurements had a high sensitivity and negative predictive value for NSTEMI diagnosis, especially among subjects with a low TIMI risk score. However, the sensitivity was too low to rule out NSTEMI with a single-draw strategy at ED presentation. Future studies are needed on the low-risk TIMI group to further investigate this preliminary finding.