Effect of charge on microvascular permeability in early experimental sepsis in the rat

A key feature of sepsis is hypovolemia due to increased microvascular permeability. It has been suggested that the negative charge of albumin and of the endothelial glycocalyx is important for maintenance of the normally low permeability for albumin. Here we tested the hypothesis that charge effects contribute to the increased permeability in sepsis. Transcapillary escape rate (TER) and initial distribution volume for ¹²⁵I-labeled bovine serum albumin (BSA, isoelectric point pH 4.6) and for ¹³¹I-labeled charge modified BSA (cBSA, average isoelectric point, pH 7.1) was measured 3 h after sepsis was induced by cecal ligation and incision (CLI) (n = 11) and in control animals (n = 12). The importance of charge for permeability in sepsis was estimated by comparing the ratio between TER for cBSA and TER for BSA during control conditions to that after CLI. Plasma concentration of the glycocalyx component glycosaminoglycans (GAGs) was measured in separate control and CLI animals. The initial distribution volume for BSA and cBSA in control animals was 38 ± 3 ml/kg and 47 ± 4 mL/kg and decreased by 17% and 19%, respectively, following CLI. TER for BSA increased from 16.7 ± 4.1% in the controls to 20.1 ± 1.9% following CLI. Corresponding values for cBSA were 26.7 ± 5.6% and 29.8 ± 3.5%, respectively. The ratio between TER for cBSA and TER for BSA was 1.62 ± 0.1 in the control group and 1.49 ± 0.1 following CLI (p < 0.05). Plasma GAG concentrations were higher in CLI animals than in the control group. We conclude that CLI induce hypovolemia secondary to increased microvascular permeability. Negative charge contributes to the normally low permeability of albumin and the importance of charge is decreased in early experimental sepsis. The observed charge effects are associated with CLI-induced breakdown of the glycocalyx.     

HIF1a Inhibitor Rescues Acute-on-Chronic Liver Failure

Introduction and ObjectivesHypoxia-inducible factor-1α is critically involved in the pathogenesis of liver diseases. Its inhibitor genistein attenuated D-galactosamine (D-GalN)-induced liver damage. However, the role of genistein in acute-on-chronic liver failure (ACLF) is unclear. The influence of genistein on reactive oxygen species (ROS) and hepatocyte functions were evaluated in a rat model of ACLF.Material and methodsGenistein [20 mg/ (kg. day)]/coenzyme Q10 [10 mg/ (kg. day)]/lipoic acid [20 mg/ (kg. day)] was administered via the intra-gastric route daily for 6 weeks as co-treatment to the rats in the experimental groups. Then, 100 μg/kg LPS combined with 0.5 g/kg D-GalN was injected intraperitoneally to attack the rats.ResultsGenistein significantly attenuated LPS/D-GalN-induced ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, reduced AST level in serum, whereas increased levels of ATP, ADP/O, and respiratory control ratio (RCR) in mitochondria. Genistein suppressed necrosis and ROS production.ConclusionThese results suggested that genistein could protect against ACLF through inhibiting cellular ROS production and necrosis, improving RCR, and decreasing permeability transition pores in mitochondrial, which was similar as mitochondrial protective agent coenzyme Q10.     

Anti-TNF-α antibodies improve intestinal barrier function in Crohn's disease

Background and aimsIntestinal barrier function in Crohn's disease patients and their first degree healthy relatives is impaired. The increased intestinal permeability may result in an enhanced mucosal immune response and thereby aggravate intestinal inflammation. Humanised anti-TNF-α antibodies have been shown to be effective in the treatment of active Crohn's disease and in the treatment of entero-cutaneous fistula.The aim of the present study was to investigate the influence of anti-TNF-α antibody (infliximab) treatment on the intestinal barrier function of patients with active Crohn's disease.MethodsThe differential intestinal uptake of lactulose and mannitol was measured to quantify intestinal permeability in patients with long standing active Crohn's disease (n = 17) directly before and seven days after treatment with infliximab (5 mg/kg bodyweight). In parallel, intestinal permeability was studied in a healthy control group (n = 20). Serum samples were analysed with pulsed amperometric detection after separation on an anion exchange column.ResultsIntestinal permeability was significantly increased in all patients with Crohn's disease (L/M ratio 0.24 ± 0.17) prior to infliximab treatment compared to the control group (L/M ratio 0.01 ± 0.02; p-value < 1 × 10^− 7). Treatment of patients with infliximab resulted in a marked decrease of intestinal permeability as measured by L/M ratio from 0.24 ± 0.17 before to 0.02 ± 0.02 (p-value < 1 × 10^− 7) seven days after infliximab application.ConclusionsTreatment with anti-TNF-α antibodies improved impaired intestinal barrier function in patients with Crohn's disease. This effect may correlate to the well documented anti-inflammatory effect of TNF-α blockade in this intestinal disease.     

High C-reactive protein in Crohn's disease patients predicts nonresponse to infliximab treatment

BackgroundInfliximab (IFX) is effective in treating Crohn's disease (CD) and C-reactive protein (CRP) is a useful biomarker in assessing inflammatory activity.AimCorrelate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment.MethodsRetrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug.ResultsBaseline CRP levels were higher in PNR compared with SR (26.2 mg/L vs 9.6 mg/L, p = 0.015) and RTA (26.2 mg/L vs 7.6 mg/L, p = 0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1 mg/L vs 7.6 mg/L p = 0.019) and PNR (3.1 mg/L vs 9.1 mg/L; p = 0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2 mg/L vs 0.6 mg/L p = 0.027).ConclusionCRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response.     

Modification of liver fibrosis,glucose and lipid profile after hepatitis C virus clearance with direct-acting antiviral agents

IntroductionThere is little information on whether direct-acting antiviral (DAA) treatment can improve liver fibrosis or change glucose and lipid profile in patients with chronic hepatitis C (CHC). We aimed to evaluate the impact of sustained virologic response (SVR) on liver stiffness, glucose and lipid levels.Methods445 monoinfected CHC patients started treatment with interferon-free DAA therapy from January 2015 to February 2017. Transient elastography (TE), fibrosis scores, glucose and lipid levels were analyzed at baseline and 48 weeks post-treatment (SVR48).ResultsThe SVR rate was 97.7%. Finally, we evaluated 369 patients who achieved SVR and had reliable TE measurements. Median liver stiffness significantly decreased from 9.3 (IQR 7.3–14.3) kPa at baseline to 6.4 (IQR 4.9–8.9) at SVR48 (p < 0.0001). 54.7% of the cohort presented fibrosis regression. Median FIB4 score regressed from 2.0 (IQR 1.1–3.3) to 1.3 (IQR 0.9–2.0) (p < 0.0001). Median APRI and Forns values significantly decreased from 0.9 (IQR 0.5–1.7) to 0.3 (IQR 0.2–0.4) and from 6.2 (5.0–7.5) to 4.9 (IQR 3.8–5.9) (p < 0.001), respectively. Mean levels of total cholesterol and LDL-C increased from 172 mg/dL and 101.5 mg/dL to 191 mg/dL and 117.5 mg/dL (p < 0.0001), respectively. In the sub-group of patients with pre-diabetes or diabetes, mean glucose levels decreased from 142.7 mg/dL at baseline to 127.2 mg/dL at SVR48 (p < 0.001).DiscussionSVR reduces liver stiffness based on TE and fibrosis scores, in patients treated with DAA. Our results show elevated total cholesterol and LDL-C and decreased glucose levels at SVR48.     

Exercise Capacity and Activities of Daily Living are Related in Patients With Chronic Obstructive Pulmonary Disease

IntroductionThe knowledge of the relationship between exercise capacity and activities of daily living (ADLs) is important to minimize the negative outcomes in ADLs resulting from reduced exercise capacity in patients with chronic obstructive pulmonary disease (COPD). There is a limited study about the association between exercise capacity and ADLs in patients with COPD. This study aimed to investigate the relationship between maximal exercise capacity and ADLs in patients with GOLD stage II–III COPD.MethodsTwenty-seven clinically stable GOLD stage II–III COPD patients were included (mean age = 58.59 ± 9.63 years and mean FEV₁ = 50.6 ± 13.7%) in this cross-sectional study. Maximal and submaximal exercise capacity were evaluated using an incremental shuttle walk test (ISWT) and 6-min walk test (6MWT), respectively. Activities of daily living were assessed using Glittre-ADL test.ResultsThe ISWT distance was significantly correlated with Glittre-ADL test time (r = −0.517, p = 0.006). There was also a negative correlation between 6MWT distance and Glittre-ADL test time (r = −0.506, p = 0.007).ConclusionA moderate relationship was found between maximal exercise capacity and general activities of daily living performance. The reduction in exercise capacity increases the negative influences in ADLs and strengthens our beliefs that exercise interventions in pulmonary rehabilitation could influence activities of daily living positively.     

Progression of incidence and estimate of net survival from papillary thyroid cancers diagnosed between 2008 and 2016 in France

BackgroundAfter several decades of increasing incidence of papillary thyroid cancer (PTC), a change in this trend has been recently observed, particularly in the United States. This is attributed to the impact of new guidelines for the management of thyroid disease. The objective of this study was to describe the recent situation in France in terms of incidence and survival, taking account of tumor size.MethodsData from the FRANCIM network cancer registries, covering around 25% of the French metropolitan population, were analyzed. Distribution according to tumor size was determined in terms of frequency, trends in incidence and spatial distribution for the period 2008–2016. Analysis of net survival considered gender, age and tumor size.ResultsCancers of size ≤ 5 mm were predominant in patients diagnosed between 55 and 74 years of age. Incidence of ≤ 5 mm tumors in women and of 5–10 mm tumors in men began declining in the early 2010s. Incidence of 10–20 mm and 20–40 mm tumors in men increased significantly throughout the period 2008–2016. For both men and women, the incidence of the largest tumors (> 40 mm) also increased, but not significantly. The spatial distribution of incidence showed great heterogeneity. Net survival was generally high, although decreasing with age and tumor size.ConclusionThe recent epidemiological situation in France is consistent with the hypothesis of recent progress in medical management of thyroid pathologies. Variations in incidence should be monitored for both small (< 10 mm) and larger tumors, and notably > 40 mm tumors. Net survival is generally high, although decreasing with age and tumor size.     

Increased intestinal permeability,measured by serum zonulin,is associated with metabolic risk markers in overweight pregnant women

BackgroundIncreased intestinal permeability with subsequent metabolic endotoxemia, i.e., elevated circulating levels of bacterial lipopolysaccharide, LPS, has been introduced as a novel initiator of obesity related metabolic disturbances in non-pregnant individuals. The objective was to investigate the extent to which intestinal permeability, measured by serum zonulin concentration, is related to metabolic endotoxemia and metabolic risk markers in overweight pregnant women.MethodsThis was a cross-sectional study including 100 pregnant overweight women in early pregnancy. Serum zonulin was analyzed using ELISA, and markers for metabolic endotoxemia (LPS), inflammation (high-sensitive C-reactive protein and glycoprotein acetylation GlyA), glucose metabolism (fasting glucose and insulin), and lipid metabolism were measured.ResultsHigher serum zonulin concentration associated positively with LPS (P = 0.02), inflammatory markers (P < 0.001), insulin (P < 0.001), insulin resistance (P < 0.001), and triglycerides (P = 0.001), and negatively with insulin sensitivity (P = 0.001) (ANOVA with Tukey's corrections or Kruskal–Wallis nonparametric test with Bonferroni correction for zonulin quartiles). All the observed associations were confirmed (P < 0.015) in a linear regression model adjusted with potential confounding factors. Both LPS and GlycA showed positive relationship with insulin resistance, serum insulin, triglycerides, total and LDL-cholesterol and negative relationship with insulin sensitivity (P ≤ 0.03) in the univariate linear regression. Positive relationship was also found between LPS and HDL-cholesterol (P = 0.03).ConclusionsOur findings suggest that increased serum zonulin concentration, i.e., increased intestinal permeability, contributes to metabolic endotoxemia, systemic inflammation, and insulin resistance in overweight pregnant women. By reinforcing intestinal barrier, it may be possible to manipulate maternal metabolism during pregnancy with subsequent health benefits.     

Effects of vitamin C supplementation on oxidative stress and serum paraoxonase/arylesterase activities in patients on long-term hemodialysis

BackgroundOxidative stress increases oxidizability of apolipoprotein-B containing lipoproteins and decreases paraoxonase (PON) activity in hemodialysis (HD) patients and plays an important part in the development of atherosclerotic cardiovascular diseases. In HD patients, plasma ascorbic acid (AA) levels are decreased either due to the loss by hemodialysis membranes or due to malnutrition and contribute to the imbalance of antioxidant defense mechanisms. We hypothesized that long-term ascorbic acid (AA) supplementation recovers oxidizability of lipoproteins in HD patients by reinforcing PON activity.MethodsTwenty-nine adult patients were treated with 100 mg and 500 mg AA at the end of each HD session thrice a week for two consecutive 16 weeks-periods, respectively. Blood samples were obtained before the first HD session and prior to the first HD sessions following the 100 mg AA-supplemented and the 500 mg AA-supplemented periods.ResultsPON activities were significantly increased after 100 mg (p < 0.05) and 500 mg AA (p < 0.001) supplementation periods compared to the basal level. Apo-B lipoprotein oxidizability (Δ-MDA) was significantly decreased after 500 mg AA supplementation compared to both basal (p < 0.05) and 100 mg AA supplementation periods (p < 0.05). Plasma AA concentrations were negatively correlated with Δ-MDA levels (R = −0.327; p < 0.01).ConclusionOur results suggest that long-term parenteral 500 mg AA supplementation improves PON activity alleviating apo B-containing lipoproteins oxidizability in HD patients.     

Intestinal permeability is increased in children with non-alcoholic fatty liver disease,and correlates with liver disease severity

BackgroundIncreased intestinal permeability seems to play a major role in non-alcoholic liver disease development and progression.AimTo investigate the prevalence of altered intestinal permeability in children with non-alcoholic fatty liver disease, and to study its potential association with the stage of liver disease.MethodsWe performed a case–control study examining intestinal permeability in children using the lactulose–mannitol bowel permeability test.ResultsOverall, 39 consecutive patients (30 males, median age 12 years) and 21 controls (14 males, median age 11.8 years) were included. The lactulose/mannitol ratio resulted impaired in 12/39 patients (31%) and none of the controls. Intestinal permeability was higher in children with non-alcoholic fatty liver disease (lactulose/mannitol ratios: 0.038 ± 0.037 vs. 0.008 ± 0.007, p < 0.05). Within the non-alcoholic fatty liver disease group, intestinal permeability was increased in children with steatohepatitis compared to those with steatosis only (0.05 ± 0.04 vs. 0.03 vs. 0.03, p < 0.05). Pathological lactulose/mannitol ratio correlated with portal inflammation (p = 0.02), fibrosis (p = 0.0002), and ballooning of hepatocytes (p = 0.003). Blood lipopolysaccharides levels were higher in children with steatohepatitis (2.27 ± 0.68 vs. 2.80 ± 0.35, p < 0.05).ConclusionsIntestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with the severity of the disease.     

Association between fibromyalgia syndrome clinical severity and body composition. A principal component analysis

IntroductionThe type of body composition modulates the severity of some musculoskeletal conditions, in fibromyalgia syndrome (FMS), this type of association remains relatively unexplored.ObjectiveTo analyze the association between the type of body composition and FMS using Principal Component Analysis (PCA). The FMS clinical outcome measures were: Symptom Severity Scale (SSS), Widespread Pain Index (WPI; and Fibromyalgia Impact Questionnaire (FIQ).MethodsForty-three women with FMS (ACR 2010 criteria) were clinically and anthropometrically evaluated. The anthropometric data were integrated into two indicators using a PCA methodology (PCA-Fat and PCA-muscle). Additionally, the patients were classified into high and low categories for each clinical indicator, which were used as dependent variables in binomial logistic regression (BLR) models.ResultsWe found a positive correlation between PCA-Fat with WPI (r = 0.326, P = .043) and FIQ (r = 0.325, P = .044), and negative correlation (r = ?0.384, P = .013) between PCA-muscle and SSS. In the BLR analysis, PCA-Fat was a significant predictor for high WPI (OR = 2.477, P = .038); while for high SSS, PCA-muscle (OR = 0.303, P = .009) was an inversely significant predictor.ConclusionsThe results suggest that the volume of fat mass can negatively modulate the severity of FMS. We propose that the evaluation of body composition should be a basic element for the clinical approach of patients with FMS.     

Permeability of rat IgE across rat aortic endothelial cell is enhanced by histamine

BackgroundIt is a well-known fact that IgE is a key substance that induces an allergic reaction in extravascular tissue. However, it remains to be elucidated how IgE in the circulating blood transfers to the site of the allergic reaction in the extravascular tissue. In the present paper, rat IgE passage through cultured rat aortic endothelial cells (RAEC) was first examined using a dual-chamber system. Second, we examined the effects of histamine, which is thought to affect endothelial permeability, on IgE passage through the RAEC in comparison with the effects of albumin and IgG2a.MethodsThe permeability constant (PC) was used to evaluate the degree of IgE passage through the RAEC.ResultsThe value of the PC for rat IgE (0.58 ± 0.11 x 10^− 5cm/s) was lower than that for IgG2a and albumin (0.88 ± 0.28 x 10^− 5 and 0.93 ± 0.26 x 10^− 5 cm/s, respectively) under conditions of non-exposure to histamine. In contrast, the PC of rat IgE was significantly increased by exposure to histamine (10^− 10 mol/L) at 12 h after exposure. However, the PC for IgG2a and albumin were not significantly increased following exposure to histamine. The enhancement by histamine of IgE passage through the RAEC was not inhibited by diphenhydramine, a histamine H receptor antagonist, but were inhibited by cimetidine, a histamine H₂ receptor antagonist.ConclusionsOn the basis of results from the present study, histamine, acting via H₂ receptors, enhances the permeability of rat IgE across the RAEC monolayer. The increased permeability of endothelial cells induced by histamine may contribute greatly to the transfer of IgE from circulating blood to extravascular tissue.     

SGLT2 inhibition increases serum copeptin in young adults with type 1 diabetes

AimsCopeptin, a surrogate of vasopressin, is elevated in type 1 diabetes (T1D) and predicts kidney disease and cardiovascular mortality. Given the cardiorenal protective effects of SGLT2 inhibition (SGLT2i), our aim was to examine: 1) the relationship between serum copeptin, metabolic, renal and systemic hemodynamic parameters in adults with T1D; and 2) serum copeptin after SGLT2i with empagliflozin.Materials and methodsIn this post-hoc, exploratory analysis, serum copeptin, glomerular filtration rate (GFR_Inulin), effective renal plasma flow (ERPF_PAH), plasma renin angiotensin aldosterone system markers, HbA_1c, 24-hour urine volume and sodium excretion were measured in 40 participants with T1D (24.3 ± 5.1 years) during eu- and hyperglycaemia before and after 8 weeks of 25 mg of daily empagliflozin.ResultsHigher baseline copeptin correlated with higher HbA_1c, lower 24-hour urine volume and sodium excretion, after correcting for age, sex, systolic blood pressure, and HbA_1c. Copeptin concentrations increased in response to empagliflozin under euglycaemia (4.1 ± 2.1 to 5.1 ± 2.8 pmol/L, P = 0.0053) and hyperglycaemia (3.3 ± 1.4 to 5.6 ± 2.8 pmol/L, P < 0.0001). The rise in copeptin in response to empagliflozin correlated with change in 24-hour urine volume, but was independent of changes in fractional excretion of sodium and haematocrit.ConclusionsElevated serum copeptin was associated with worse glycaemic control and lower diuresis and natriuresis. SGLT2i increased serum copeptin in adults with T1D, and the rise correlated with change in diuresis, but not natriuresis and hemo-concentration. Further work is required to evaluate the clinical implications of elevated copeptin with SGLT2i, including whether it is simply a marker of diuresis or may contribute to cardiorenal disease long-term.     

Comparative prognostic value of low-density lipoprotein cholesterol and C-reactive protein in patients with stable coronary artery disease treated with percutaneous coronary intervention and chronic statin therapy

BackgroundThe comparative prognostic value of low density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI) and statin therapy is poorly investigated.MethodsThe study included 7595 patients with stable CAD treated with PCI. Based on a cut-off of 100 mg/dl for LDL-C and 3 mg/L for CRP, patients were divided into 4 groups: patients with LDL-C ≤ 100 mg/dl and CRP ≤ 3 mg/L (n = 2795); patients with LDL-C > 100 mg/dl and CRP ≤ 3 mg/L (n = 2091); patients with LDL-C ≤ 100 mg/dl and CRP > 3 mg/L (n = 1296); and patients with LDL-C > 100 mg/dl and CRP > 3 mg/L (n = 1413). Statins at discharge were prescribed in all patients. The primary outcome was 1-year all-cause mortality.ResultsOne-year mortality was 2.1% (160 deaths): 1.2% (33 deaths) among patients with LDL-C ≤ 100 mg/dl and CRP ≤ 3 mg/L, 1.4% (28 deaths) among patients with LDL-C > 100 mg/dl and CRP ≤ 3 mg/L, 4.8% (60 deaths) among patients with LDL-C ≤ 100 mg/dl and CRP > 3 mg/L and 2.9% (39 deaths) among patients with LDL-C > 100 mg/dl and CRP > 3 mg/L (P < 0.001). After adjustment, CRP (hazard ratio [HR] = 1.64, 95% confidence interval [CI] 1.33–2.02, for 1 standard deviation increase in the logarithmic scale) but not LDL-C (HR = 1.03 [0.90–1.17], for 30 mg/dl increase) showed an independent association with 1-year mortality. CRP (P = 0.045) but not LDL-C (P = 0.294) increased the discriminatory power of multivariable model for prediction of mortality.ConclusionIn patients with stable CAD treated with PCI and statin therapy, CRP but not LDL-C was independently associated with increased risk of 1-year mortality.     

Accuracy assessment of online glucose monitoring by a subcutaneous enzymatic glucose sensor during exercise in patients with type 1 diabetes treated by continuous subcutaneous insulin infusion

AimOnline continuous glucose monitoring (CGM) during physical exercise would be highly useful in patients with insulin-treated diabetes. For this reason, this study assessed whether such a goal could be reached with a subcutaneous ‘needle-type’ enzymatic sensor.MethodsTen patients (five women/five men), aged 51 ± 12 years, with type 1 diabetes for 24 ± 11 years treated by continuous subcutaneous insulin infusion (CSII) for more than 1 year (HbA_1c: 7.5 ± 0.8%) performed a 30-min bout of exercise at a constant high-intensity load (15% above their individual ventilatory threshold) on a cycle ergometer. All patients wore a subcutaneous ‘needle-type’ enzymatic glucose sensor linked to a portable monitor (Guardian^® RT, Medtronic-MiniMed, Northridge, CA, USA) that had been inserted the previous evening. Sensor calibration was performed against capillary blood glucose immediately before the exercise. CGM values were recorded every 5 min from T_–10 to T₊₃₀, then every 10 min during the recovery period from T₊₃₀ to T₊₉₀. These recorded values were compared with blood glucose assays performed on simultaneously collected venous samples.ResultsSensor functioning and tolerability raised no problems except for one sensor that could not be adequately calibrated. Data from this patient were excluded from the data analysis. An average blood glucose decrease of 63 ± 63 mg/dL (3.5 ± 3.5 mmol/L) (median decrease: 58 mg/dL [3.22 mmol/L]; range: –3 mg/dL [0.16 mmol/L] to 178 mg/dL [9.8 mmol/L]) occurred during exercise bouts, while CGM values decreased by 38 ± 49 mg/dL (2.11 ± 2.72 mmol/L) (median: 32 mg/dL [1.7 mmmol/L]; range: –15 mg/dL [0.83 mmol/L] to 58 mg/dL [3.22 mmol/L]). Cumulative paired glucose values (n = 135) could be analyzed. The correlation factor between CGM and blood glucose values was 0.957 with an intercept of 0.275. The mean difference between paired values according to Bland–Altman analysis was 10 ± 31 mg/dL (0.56 ± 1.72 mmol/L). Clarke error grid analysis showed 91% of paired points in A and B zones, while 0%, 9% and 0% of paired points were in the C, D and E zones, respectively.ConclusionBlood glucose changes during intensive physical-exercise bouts performed by CSII-treated type 1 diabetes patients can be estimated with acceptable clinical accuracy by online CGM.     

Factors predictive of macrosomia in pregnancies with a positive oral glucose challenge test: Importance of fasting plasma glucose

AimThe study aimed to determine the factors associated with fetal macrosomia following a positive oral glucose challenge test (OGCT).MethodsIn this retrospective single-centre study of 1268 pregnancies with positive 50-g OGCTs (plasma glucose ≥ 130 mg/dL, or 7.2 mmol/L), gestational diabetes mellitus (GDM) was defined as fasting plasma glucose (FPG) ≥ 95 mg/dL (5.3 mmol/L) and/or postprandial glucose (PPG) ≥ 120 mg/dL (6.7 mmol/L).ResultsIn GDM pregnancies, the odds ratios adjusted for confounders (age, BMI, ethnicity, parity and weight gain) were 2.02 for macrosomia (Z score ≥ 1.28) and 2.62 for severe macrosomia (Z score ≥ 1.88). For each 10-mg/dL increase in FPG, the mean birth–weight increase was 60 g. Macrosomia risk did not differ between GDM patients with normal FPG (< 95 mg/dL, or 5.3 mmol/L) and non-diabetics, but increased significantly in cases of FPG ≥ 95 mg/dL and regardless of the level of PPG.ConclusionIn our study population, birth–weight and macrosomia risk were strongly correlated with FPG, suggesting that it is a simple and efficient marker for the risk of macrosomia.     

Are oral cefuroxime axetil,cefixime and cefditoren pivoxil adequate to treat uncomplicated acute pyelonephritis after switching from intravenous therapy? A pharmacokinetic/pharmacodynamic perspective

ObjectivesThe goal of this study is to assess, by means of pharmacokinetic/pharmacodynamic (PK/PD) analysis using the Monte Carlo simulation, the adequacy of oral cephalosporins cefuroxime axetil, cefixime and cefditoren at different dosing regimens as switch therapy after intravenous cephalosporin treatment in uncomplicated acute pyelonephritis.MethodsThe methodology included: (i) dosing regimen selection and acquisition of pharmacokinetic data; (ii) microbiological data acquisition; and (iii) Monte Carlo simulation to estimate the PTA (probability of PK/PD target attainment) and CFR (cumulative fraction of response), as indicators of treatment success.ResultsAt the current susceptibility breakpoints defined by EUCAST and CLSI for either cefuroxime axetil or cefixime, the probability of bactericidal target attainment is zero for the dosage regimens simulated. Considering the bactericidal target %fT_>MIC > 70%, the likelihood of the cefuroxime 500-mg q8h regimen or the cefixime 200-mg q12h regimen producing this exposure or achieving this target is only above 90% for organisms yielding MICs ≤ 0.5 mg/l and MICs ≤ 0.25 mg/l, respectively. Cefditoren pivoxil 400 mg q12h provided probabilities of bactericidal target attainment of 80% or higher for MICs ≤ 0.03 mg/l, and ≤0.25 mg/l if considering total instead of free drug concentrations.ConclusionsThe results of the PK/PD target attainment analysis reveal that the likelihood of treatment success based upon the current breakpoints proposed by either EUCAST or CLSI is low. Of the three cephalosporins, cefixime 400 mg q12h prove to be the best option in oral APN treatment, although this regimen is currently off label.     

C-reactive protein and prognosis in women and men with coronary artery disease after percutaneous coronary intervention

BackgroundSex-based differences in the association between C-reactive protein (CRP) and cardiovascular events in patients with coronary artery disease (CAD) are incompletely investigated. We investigated whether there are gender differences in the association between CRP and outcome in patients with CAD after percutaneous coronary intervention (PCI).MethodsThis study included 13,170 consecutive patients with CAD: 10,098 men and 3072 women. CRP was measured on admission in all patients. The primary outcome was 1-year mortality.ResultsCRP level (median [25th–75th percentiles]) was higher in women than in men (3.08 [1.30–8.37] mg/L vs 2.30 [0.92–6.47] mg/L; P < 0.001). CRP was > 3 mg/L in 4250 men (42.1%) and 1554 women (50.6%; P < 0.001). One-year mortality was 4.9% (n = 641 deaths). Deaths occurred in 318 men with CRP > 3 mg/L and 122 men with CRP ≤ 3 mg/L (mortality estimates 7.7% and 2.1%, P < 0.001) and in 154 women with CRP > 3 mg/L and 47 women with CRP ≤ 3 mg/L (mortality estimates 10.1% and 3.2%, P < 0.001). After adjustment in the Cox model, CRP was associated with increased risk of mortality in women (adjusted hazard ratio [HR] = 1.03, 95% confidence interval [CI] 1.01–1.04, P < 0.001 for each 5 mg/L increase) and in men (adjusted HR = 1.02 [1.01–1.03], P < 0.001, for each 5 mg/L increase). CRP predicted mortality with an area under the receiver-operating characteristic curve = 0.721, [0.683–0.760] in women and 0.732, [0.707–0.757] in men (P = 0.659).ConclusionsElevated CRP levels provide similar prognostic information in men and women with CAD after PCI which is independent and supplementary to that provided by conventional cardiovascular risk factors.     

Efficacy and safety of recombinant growth hormone treatment in children with growth retardation related to long-term glucocorticosteroid therapy

ObjectiveTo evaluate safety and efficacy of recombinant human growth hormone treatment in children on long-term glucocorticoid therapy.MethodsA 5-year prospective open-label study included children on glucocorticoid therapy with either standard deviation score (SDS) < −2 for height for chronological age (CA) if naïve to growth hormone treatment, or annual growth rate ≥ 0 SDS for CA if currently receiving growth hormone.ResultsNinety-eight patients began treatment, 63 discontinued; 59 were analyzed for safety and 58 for efficacy. There was male predominance (78.0%). Median age was 13.0 years. Median height screening was 136.0 cm (range, 95.1–159.7 cm). Mean SDS for height for CA in the efficacy analysis set was −2.91 ± 1.19 (range, −7.49 to −0.96). Mean growth hormone dose was 0.4, 0.4, 0.4 and 0.3 mg/kg/week at month 0, M12, M24, and M36, respectively. Primary analysis of change in SDS for height for CA from baseline to M36 showed a significant increase of 0.80 ± 1.03. Twenty patients in the safety analysis set had ≥ 1 treatment-emergent adverse event (TEAE) related to study treatment. Two patients experienced serious treatment-related TEAEs: 1 case of poor compliance, and 1 of mild hyperglycemia, both already observed under growth hormone treatment.ConclusionThis study suggests that growth hormone treatment could be effective in increasing height in children on long-term glucocorticoid treatment with a safety profile comparable to that in approved rhGH treatment indications.Clinical trial registrationNCT00163189.     

Age — a significant independent factor of A1C levels. Evidence from the National Health and Nutrition Examination Survey 1999–2014

AimThe aim of our study is to examine the association between age and A1C levels in nondiabetic subjects and develop the age-adjusted A1C levels for screening and diagnosis of prediabetes and diabetes.MethodsParticipants from National Health and Nutrition Examination Survey (NHANES) -1999–2014 with age over 12 years were examined. Individuals with previous diagnosed diabetes, baseline anemia, established hemoglobinopathies, known liver or chronic kidney disease, and abnormal liver function tests or creatinine levels were excluded. Total 16949 subjects consisting of 8651 female subjects and 8298 male subjects were included in the analyses. Linear regression and multivariate regression analyses were performed to assess the relationship between A1C levels and age. Age adjusted A1C levels were determined.ResultsSignificant positive correlation between A1C and age was found in both female and male subjects in the fasting plasma glucose (FPG) interval between 4.4–7 mmol/L (80–126 mg/dL) (P < 0.0001). There was a linear correlation between A1C levels and age. Linear regression analysis suggested A1C levels rose by 0.009% (about 0.09 mmol/mol) in female and by 0.008% (about 0.08 mmol/mol) in male per year in subjects without abnormality in glucose homeostasis (p < 0.0001).ConclusionsOur study concluded that age is a significant independent factor of A1C levels.