Plasma Total Levels Research Articles

Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study

ObjectivesTo investigate the relationship between low-density lipoprotein cholesterol (LDL-C) and all-cause mortality among middle-aged and elderly Chinese population.DesignProspective cohort study.SettingThis study used data from the China Health and Retirement Longitudinal...

The particulars of certain drugs' effect on the endogenous coenzyme Q10 plasma level in patients with cardiovascular diseases.

Objectives Coenzyme Q10 (CoQ10) has many vital functions in human body and its endogenous level can be affected either by various diseases or by administrated drugs. This study reveals the effect of atorvastatin, amlodipine and ethoxidol on the endogenous CoQ10 plasma concentration. Methods It was determined the total plasma concentration of endogenous CoQ10 in the plasma of 54 healthy individuals and 62 patients with cardiovascular diseases during treatment with various drugs using high performance liquid chromatography with mass spectrometric detection (HPLC-MS/MS). Results It was found that CoQ10 plasma concentration inpatients is statistically significantly lower (on average-49.0Δ%) than in practically healthy individuals. The total CoQ10 plasma level in patients receiving atorvastatin in the complex therapy is statistically significantly lower (-15.2 Δ%), and in patients taking amlodipine or ethoxidol is statistically significantly higher (+18.2 and+20.2 Δ%, respectively) than in patients of control groups (a group of patients who receive the same drugs, except for the studied one). Conclusions The study showed that in patients with CVDs treated with various drugs the CoQ10 plasma level is statistically significantly lower than in practically healthy individuals. So, to avoid the adverse reactions connected with low CoQ10 plasma levels, it is recommended to adjust the therapy to maintain its constant level.

P1070ONLINE HIGH-VOLUME HEMODIAFILTRATION REDUCES PRE-DIALYSIS LEVELS OF INDOXYL SULFATE COMPARED TO HIGH-FLUX HEMODIALYSIS: RESULTS FROM HDFIT MULTICENTRIC RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims Online High-Volume Hemodiafiltration (OL-HDF) combines convective and diffusive clearances and is associated with better outcomes compared to standard hemodialysis (HD). Although HDF has been shown to improve the clearance and pre-dialysis concentration of middle size uremic toxins, little is known about its effect on concentration of protein-bound uremic toxins (PBUT), particularly in comparison to high-flux HD. Here, we investigated whether high-volume post-dilution OL-HDF impacts pre-dialysis plasma levels of PBUT indoxyl sulfate (IxS), p-cresyl sulfate (pCS) and indole 3-acetic acid (IAA) compared to high-flux HD over time, since accumulation of these PBUT has been associated with increased overall mortality of CKD patients. Method This is post hoc analysis of the multicentric randomized controlled trial (RCT) studying the impact of post-dilution high-volume OL-HDF versus high-flux HD on measured physical activity (HDFit - clinicalTrials.gov: NCT02787161), which included clinically stable HD patients with a vintage >3 to <24 months. Total plasma levels of IxS, pCS and IAA were determined by high performance liquid chromatography (HPLC) with fluorescence detection at baseline, 3 and 6 months. The difference between HDF and HD in respect to changes in the PBUT concentrations during the follow up, analyzed using linear mixed effect models, was compared. Results are presented as mean differences between groups in the change from baseline along with 95% confidence intervals (CI). Results 193 patients (mean age 53 years old, 70% males and 60% white – no differences between groups) were analyzed. There were no differences between HD and OL-HDF groups regarding clinical and biochemical characteristics at the baseline. In the OL-HDF group, 99% of patients achieved a convective volume higher than 22 L and both groups had similar dialysis session duration and blood flows throughout the follow up. The mean differences (95% CI) in concentrations over time for PBUTs among HDF and HD groups are shown in Figure 1. HDF group presented a significantly lower trajectory of IxS levels and a lower trajectory of pCS levels than HD group. Trajectories of IAA levels were not different between groups. Conclusion OL-HDF reduced the pre-dialysis concentration of IxS and pCS through 6 months-period compared to high-flux HD.

Genetic determinants of lipid aberrations in patents with essential hypertension

Aim. To reveal the relationship between apolipoprotein E gene polymorphism and lipid spectrum modification in patients with essential hypertension. Materials and methods. The lipid spectrum components and apolipoprotein E gene polymorphism were analyzed in 310 patients with essential hypertension. Results. The mean plasma levels of total cholesterol, high and low density lipoproteins, triglycerides and the atherogenic index were 5.18 ± 0.08 mmol/l, 1.32 ± 0.03 mmol/l, 3.06 ± 0.07 mmol/l, 1.74 ± 0.05 mmol/l and 3.21 ± 0.08, respectively. In patients with essential hypertension, the genetic polymorphism of apolipoprotein E was characterized by the alleles E2 (13.26 %), E3 (93.87 %) and E4 (30.65 %) presence. Based on single nucleotide polymorphism identification, there were defined the following genotypes: E2/E2 (0.65 %), E2/E3 (10.97 %), E2/E4 (1.61 %), E3/E3 (57.74 %), E3/E4 (25.16 %) and E4/E4 (3.87 %). Individuals with E2/E4 genotype had higher levels of total cholesterol (+17.56 %, P < 0.05) and low density lipoproteins (+25.7 %, P < 0.01), and atherogenic index was increased (+38.18 %, P < 0.05) in E4/E4 carriers in comparison with E2/E3. Hypertonic E4/E4 carriers were found to have elevated plasma triglycerides (+20.23 %, P < 0.05) in comparison with E3/E3, as well as increased triglycerides (+25.3 %, p < 0.05) and very low density lipoproteins (+25.33 %, P < 0.05) in comparison with E3/E4 carriers. E3/E3 and E3/E4 carriers demonstrated decrease in total cholesterol (-12.9 %, P < 0.05) and (-11.04 %, P < 0.05), respectively, as well as low density lipoproteins (-15.69 %, P < 0.001) and (-11.48 %, P < 0.05), respectively, as compared to E2/E4. The plasma content of high density lipoproteins was not dependent on ApoE genotype. Conclusions. In patients with essential hypertension, the most common allele is E3 (93.87 %) and the E3/E3 genotype (57.74 %), while the E3/E4 genotype is 25.16 %. Presence of the E2/E4 genotype is significantly associated with the elevated total cholesterol and low density lipoproteins plasma levels, whereas the E4/E4 genotype is accompanied by the increased triglycerides, low density lipoproteins levels and atherogenic index.

Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children

IntroductionAllogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens. MethodsTwo different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline® and ATG-F (Grafalon®), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded. ResultsrATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 µg/ml for ATG-F and 60.4 µg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells. ConclusionsATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.

Three-weeks moderate aerobic exercise in increasing production of endogenous antioxidant enzyme and lowering oxidative stress level among sedentary men

Background: During exercise, there will be an increase of free radical due to the elevation of oxygen consumption to fulfill the increasing demand for energy. This free radical could produce by muscle and other tissue, especially from the leakage of mitochondria respiratory chain reaction. Moderate exercise training may provide adequate protection against exercise-induced oxidative stress by elevating the antioxidant level and healthier mitochondria that will produce less free radicals. This research will investigate the change of baseline level of MDA and superoxide dismutase (SOD) and also MDA and SOD level after a single bout of moderate exercise before and after three weeks of intervention.Methods: Seven sedentary men with age average 17.2 + 0.2 years recruited for this study. They were meet the criteria of healthy sedentary men. Moderate aerobic exercise of 30 minutes running at 11 – 13 RPE Borg Scale, three times a week for three weeks in a row was applied to the subject. MDA and SOD examination was done by chromatographic assays for total plasma level. The collected data were analyzed using dependent student t-test. Data were normally distributed.Results: The result of this research found a significant elevation of SOD production (p&lt;0.01) after a single bout moderate exercise after three week training (19.98 + 15.52 vs 40.43 +19.64 mg/ml) and significant depression of MDA production (p&gt;0.05) after training program (0.79 + 0.62 vs 1.97 + 0.94 nmol/ml).Conclusion: There is no significant change in post-exercise MDA and SOD level before and after the training program. Initial fitness status, food intake, lifestyle could affect baseline level of MDA and SOD before and after exercise.

The clinical value of total plasma cell-free DNA in hepatitis B virus-related hepatocellular carcinoma.

Circulating cell-free DNA (cfDNA), which is present in the blood, is related to the apoptosis and necrosis of cancer cells; inflammation also influences the total plasma level of cfDNA. However, the total plasma cfDNA level has not been investigated in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) who experience cancer and HBV infection at the same time. The aim of the study was to investigate total plasma cfDNA in patients with HBV-related HCC. HBV-related HCC patients were included from January 2018 to May 2019. All patients underwent hepatectomy and were diagnosed with HCC by histopathology. Peripheral blood samples were obtained preoperatively, and the levels of total plasma cfDNA were quantitated by a fluorometric double-stranded DNA (dsDNA) assay. We examined the correlation between cfDNA and clinical parameters, and recurrence-free survival was evaluated using Kaplan-Meier curves. Forty-eight HBV-related HCC patients were included. The average age in years was 50.90±13.15, and the mean albumin level was 41.63±5.38 g/L. HBV-DNA, Child-Turcotte-Pugh (CTP) class, TNM stage, tumor number and vascular invasion showed a relationship with total plasma cfDNA (P<0.05), and albumin, prothrombin time (PT) and tumor diameter had linear correlation with plasma cfDNA. Based on multivariate analysis, tumor diameter, vascular invasion, and CTP class (P<0.05) were independent risk factors of total plasma cfDNA. Median recurrence times for low-cfDNA and high-cfDNA groups were 14.729±0.712 and 9.264±1.22 months (P=0.026). In addition to tumor diameter and vascular invasion, CTP class can influence total plasma cfDNA in HBV-related HCC patients, and the total plasma cfDNA level can be used as a biomarker to predict early recurrence in HBV-related HCC patients.

Adipokine gene expression in adipocytes isolated from different fat depots of coronary artery disease patients

To compare DPP4, LCN2, NAMPT, ITLN1, APLN mRNA levels in adipocytes isolated from the biopsies of subcutaneous, epicardial and perivascular fat obtained from 25 patients with coronary artery disease. Gene expression signature was determined by RT-qPCR with hydrolysis probes. We found DPP4 and APLN mRNA was higher expressed only in adipocytes isolated from epicardial adipose tissue compared to the subcutaneous fat. The ITLN1 gene was overexpressed in epicardial adipose tissue compared to both subcutaneous and perivascular tissues. APLN mRNA expression was positively correlated with total and LDL cholesterol plasma level, and DPP4 mRNA expression – with VLDL cholesterol concentration. Thus, adipocytes isolated from different adipose depots are characterised by differential gene expression of adipokines. Epicardial adipose tissue is of particular interest in the context of its function, molecular and genetic mechanisms of regulation of the cardiovascular system and as a therapeutic target for correction of adipose tissue-induced effects on health.

Bound, free, and total L-dopa measurement in plasma of Parkinson's disease patients.

Peaks and troughs of levodopa in plasma contribute to pulsatile postsynaptic dopamine receptor stimulation in patients with Parkinson's disease. Measurement of levodopa plasma levels mostly only considers the total levodopa plasma concentration. Objectives were to determine bound, free, and total plasma levodopa and to investigate their correlations to each other. We employed reversed-phase high-performance liquid chromatography combined with electrochemical detection. Bound levodopa was computed as difference between total and free L-dopa values. Close correlations between free and total (R = 0.93, p < 0.0001), bound and total (R = 0.91, p < 0.0001) plasma levodopa appeared. A considerable variability of levodopa concentrations occurred. The ratio between bound and free levodopa did not differ in patients with a higher and lower oral daily levodopa dosing. Free, bound, and total levodopa plasma levels are closely related. Estimation of the total levodopa level only seems to be meaningful.

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Correlation of serum uric acid levels with traditional risk factors and cardiovascular disease in the area of Blida (Algeria)

To investigate the relationship of Serum Uric Acid (SUA) levels with the traditional risk factors and fatal cardiovascular disease (CVD) in the area of Blida (Algeria). We prospectively enrolled 1954 hypertensive patients: 912 men (57.4 ± 8.5 years old) and 1042 women (56.3 ± 8.7 years old) consulting for evaluation in our hypertension clinic. In all subjects; routine blood chemistry, including SUA determination, echocardiographic examination, office and 24 h ambulatory blood pressure (BP) monitoring were obtained along with data regarding lifestyle habits. The risk of fatal cardiovascular disease was evaluated by using the SCORE risk chart for countries with low CVD risk based on the following risk factors: age, sex, smoking, systolic BP and total cholesterol. Spearman analysis showed that the SUA levels were significantly and positively associated with the average 24 hours systolic BP levels (RS = 0.088, P < 0.02 for SBP) but not with diastolic BP levels (RS = 0.051, P > 0.05). Furthermore, the Kruskal Wallis analysis revealed that SUA levels were significantly associated with fatal CVD risk ( P < 0.01). Specifically, patients with SCORE risk < 1%, between 1–5%, risk > 5% had SUA levels of 5.3 ± 1.1 mg/dl, 5.9 ± 1.3 mg/dl and 6.7 ± 1.7 mg/dl respectively (Z:- 6.9 P< 0.001). SUA levels were significantly associated with almost all major risk factors. Specifically SUA levels were significantly higher in males (Mann-Whitney U = 17384.70, P < 0.01), in elder patients (RS = 0.12, P < 0.01), in patients with increased body mass index (RS = 0.381, P < 0.01), with diabetes (U = 17745.70, P < 0.05) and with increased systolic BP levels (RS = 0.087, P < 0.04). In contrast, smoking status was not related with SUA levels ( P = NS). Regarding lipoproteins, only serum HDL levels were significantly associated with SUA levels (RS= – 0.327, P < 0.01) but not total cholesterol and LDL plasma levels (NS). Subjects with lower SUA levels presented lower BP levels as well as SCORE risk for fatal cardiovascular disease. SUA levels were significantly associated with SBP levels. The relative importance of these associations has made it possible to specify the possible role of uric acid in the cardiovascular continuum.

Long-term treatment with α-lipoic acid and myo-inositol positively affects clinical and metabolic features of polycystic ovary syndrome

The aim of this retrospective study was to evaluate the effects of a long-term treatment with α-lipoic acid (ALA) combined with myo-inositol (MI) on clinical and metabolic features of women with polycystic ovary syndrome (PCOS). Fifty-seven women with PCOS and a history of oligoamenorrhea were treated with MI and ALA (800 mg + 2000 mg per day). Forty-four of them had complete clinical charts and were considered eligible for the study. Information about cycle length and body mass index (BMI) was checked after 6, 12, and 24 months. After 12 months ovarian volume, total testosterone plasma levels and changes in hirsutism were also evaluated. The metabolic parameters were evaluated in 16 women after 6 and 18 months of the treatment. Cycle length was significantly reduced at 6 (p < .001), 12, and 24 months of treatment (p < .01). BMI showed a reduction only at 6 months (p < .05), thereafter returning similar to the basal values. No changes of testosterone and ovarian volume were observed. HOMA-IR and fasting insulin were unchanged, but the insulin response to a 3 h OGTT was improved after 6 (p < .01) and 18 months (p < .05) of treatment. No individual suffered from any adverse event. In conclusion, the combination of ALA and MI showed to be useful as long-term therapy in PCOS women, providing a normalization of the menstrual cycle and an amelioration of insulin levels with a high tolerability.

1702-P: Fine-Scale Haplotype Mapping of PPM1K Gene Reveals New Genetic Markers for the Study of Insulin Resistance at Clinical Scale

Branched chain amino acids (BCAA) plasma levels represent potential biomarkers for development of type 2 diabetes (T2D). Mendelian randomization and prospective studies indicated causal relationship between SNPs in PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) gene (Chr 4q22.1) and increased risk of incident T2D while other studies, including ours suggested the contribution of MUT (metylmalonyl-CoA mutase) gene (Chr 6p12.3) in insulin resistance (IR). To define genetic markers we performed fine-scale haplotype mapping of PPM1K in two populations (French and Romanians) with metabolic syndrome (n = 465). SNPs were genotyped with Affymetrix and enriched by imputation at 1000 genome density (BEAGLE 4.1). Haplotype association was performed by sliding window (4 SNPs windowing) and analyzed in HAPLOVIEW and PHASE 2.1. Previous leader SNPs in PPM1K (rs7678928 and rs1440581) were not associated with IR in our population but haplotype mapping revealed two major signals downstream (GGGC) and upstream (ACAG), centered by rs71609524 and rs4423843 with P &amp;lt; 3.76 x 10-3 (OR 1.59, 95% CI [1.13 - 2.23]) and &amp;lt; 4.72x10-3 (OR 1.50, 95% CI [1.12 - 2.01]), respectively. Values were weaker that those from MUT gene (P-value of the most significant haplotype, centered by rs2167284 was &amp;lt; 10-5). Total BCAA plasma levels were associated with PPM1K by several SNPs, including rs7656367 and rs4693955 with P &amp;lt; 5 x 10-3, OR of 0.41 and 3.22, respectively. Interestingly, correlation trend test with leucine, isoleucine and valine were better correlated with SNPs in the MUT gene: rs10948396 was associated with P &amp;lt; 7.91 x 10-5 (Bonferroni 6 x 10-2) and confirmed by correlation with total BCAA levels (P &amp;lt; 1.60 x 10-6, Bonferroni 1.22 x 10-3). These data suggest synergistic effects and indicate that new valuable genetic markers can be defined for clinical trials using fine-scale haplotype mapping, thus revealing complex relationship between genes in the determinism of IR and BCAA metabolism. Disclosure S. Haydar: None. C. Lautier: None. F. Grigorescu: None. Funding MEDIGENE (FP7-279171)

Expression of the receptor of advanced glycation end-products (RAGE) and membranal location in peripheral blood mononuclear cells (PBMC) in obesity and insulin resistance.

Objective(s):The present study aimed to evaluate the receptor of advanced glycation end-products (RAGE), NF-kB, NRF2 gene expression, and RAGE cell distribution in peripheral blood mononuclear cells (PBMC) in subjects with obesity and IR compared with healthy subjects.Materials and Methods:The mRNA expression levels of RAGE, NF-kB, NRF2, and GAPDH were determined in PBMC by qPCR in 20 obese (OB), 17 obese with insulin resistance (OB-IR), and 20 healthy subjects (HS), matched by age and sex. RAGE protein expression and its localization were determined by Western Blot and immunocytochemistry (ICC) analysis, total soluble RAGE (sRAGE) and MCP-1 plasma levels by ELISA. Results: :RAGE, NF-kB, and NRF2 genes mRNA expression in PBMCs did not show variation between groups. RAGE protein was lower in OB and OB-IR groups; RAGE was located predominantly on the cell-surface in the OB-IR group compared to the HS group (22% vs 9.5%, P<0.001). OB-IR group showed lower sRAGE plasma levels, and correlated negatively with HOMA-IR, ALT parameters (r= -0.374, r= -0.429, respectively), and positively with NFE2L2 mRNA (r= 0.540) P<0.05. Conclusion:In this study, OB-IR subjects did not reflect significant differences in gene expression; however, correlations detected between sRAGE, biochemical parameters, and NRF2, besides the predominant RAGE distribution on the cell membrane in PBMC could be evidence of the early phase of the inflammatory cascade and the subsequent damage in specific tissues in subjects with OB-IR.

Effects of cyclical short-term fasting and refeeding on juvenile Lophiosilurus alexandri, a carnivorous Neotropical catfish

The effects of different feeding strategies on the growth rate and hematology of Lophiosilurus alexandri were investigated. An experiment was carried out at the Laboratório de Aquacultura, Universidade Federal Minas Gerais, with nine hundred juvenile L. alexandri (length 4.3 ± 0.3, weight cm 0.9 ± 0.2 g) fed exclusively extruded dry diet and kept in fifteen 30-L cultivation tanks in a recirculating aquaculture system. The design was completely randomized with five replicates of each of three feeding treatments: every day of the week (control), six days of the week (F6:1) and five days of the week (F5:2). The following were calculated at the end of the experiment: survival, daily weight gain (DWG), total length (TL), daily feed intake (DFI), feed conversion rate (FCR), specific growth rate (SGR), final body weight (FBW), condition factor (K), protein efficiency ratio (PER), nitrogen retention (NR) and the hepatosomatic index (HSI). Blood samples were taken after 42 days (prior to feed restriction) and at 45 days (after feed restriction of one or two days), and levels of hematocrit, total plasma, hemoglobin, erythrocytes, leukocytes glucose, cholesterol and triglycerides determined. Data were submitted to ANOVA and means compared by the Tukey test (5%). No significant differences were found for survival, FCR, DWG, TL, FBW, K, and SGR. The highest DFI and HSI values were recorded in the control treatment, while PER and NR were highest in the F5.2 treatment. The highest hematocrit values were observed for the control and F6:1 treatments. In all treatments, the values for hematocrit, total protein, leukocytes and glucose were lower after fasting. The highest values for leukocytes were for the control and F6.1 treatments prior to fasting, while after fasting the control treatment was highest. For the F5:2 treatment, the highest value for erythrocytes was after fasting. The highest values for cholesterol were after fasting for all treatments. In conclusion, L. alexandri exhibits compensatory growth in relation to the two short-term food restriction treatments tested. The species adapted to dietary strategies and maintained hematological and biochemical parameters close to those of the control groups when returned to feeding.

The Association of Childhood Maltreatment With Lipid Peroxidation and DNA Damage in Postpartum Women.

Childhood maltreatment (CM) is associated with an increased risk for the development of psychiatric and somatic disorders in later life. A potential link could be oxidative stress, which is defined as the imbalance between the amount of reactive oxygen species (ROS) and the neutralizing capacity of anti-oxidative defense systems. However, the findings linking CM with oxidative stress have been inconsistent so far. In this study, we aimed to further explore this association by investigating biological markers of DNA and lipid damage due to oxidation in a comprehensive approach over two study cohorts of postpartum women (study cohort I and study cohort II). The severity of CM experiences (maltreatment load) was assessed in both studies using the Childhood Trauma Questionnaire. In study cohort I (N = 30), we investigated whether CM was associated with higher levels of structural DNA damage in peripheral blood mononuclear cells (PBMC) by two methods that are highly sensitive for detecting nuclear DNA strand breaks (comet assay and γH2AX staining). In study cohort II (N = 117), we then assessed in a larger cohort, that was specifically controlled for potential confounders for oxidative stress measurements, two established serum and plasma biomarkers of oxidative stress, one representing oxidative DNA and RNA damage (8-hydroxy-2′-deoxyguanosine and 8-hydroxyguanosine; 8-OH(d)G) and the other representing lipid peroxidation (8-isoprostane). In study cohort I, the analyses revealed no significant main effects of maltreatment load on cellular measures of nuclear DNA damage. The analyses of peripheral oxidative stress biomarkers in study cohort II revealed a significant main effect of maltreatment load on free 8-isoprostane plasma levels, but not on total 8-isprostane plasma levels and 8-OH(d)G serum levels. Taken together, by combining different methods and two study cohorts, we found no indications for higher oxidative DNA damages with higher maltreatment load in postpartum women. Further research is needed to investigate whether this increase in free 8-isoprostane is a marker for oxidative stress or whether it is instead functionally involved in ROS-related signaling pathways that potentially regulate inflammatory processes following a history of CM.

A Semi-physiologically Based Model for Methylphenidate Pharmacokinetics in Adult Humans

To determine if a literature-sourced physiological model for immediate-release (IR) methylphenidate (MPH), with addition of parameters for extended-release (ER) absorption can be adapted for NONMEM analysis to describe extended-release MPH drug products (i.e., Concerta® ER 54 mg tablets and Ritalin-LA® 40 mg capsules) pharmacokinetics (PK) in adults. This semi-physiological model will provide a platform to allow more accurate determination of Cmax in the analysis of methylphenidate plasma data from formulations with complex absorption. Adult reference data for total MPH plasma levels (summation of d- and l- enantiomers) were generated using individual subject parameters from a published NONMEM model for ER MPH (individual subject parameter generated data was used because the true experimental data is proprietary with only the previously-published summary parameters available for public use). The IR physiological model required analysis of both d- and l-MPH enantiomers which were estimated at each time point for the data by calculating the d/l enantiomer ratio from total MPH plasma concentration levels, based upon literature ratio estimates. Absorption was characterized by a fast zero-order and a delayed slow first-order release. Consistent with the literature IR model, two duplicate physiological models were used to describe the d- and l-MPH enantiomers. The mean and variability ratios for the individual subject parameter-generated data/true experimental data were very close to 1.0. The predictive performance of the absorption-modified physiological model and its disposition parameters were demonstrated, as they described both the Concerta® and Ritalin LA® PK and Cmax values very well. The bias was less than 6% for Concerta® peaks while peak 1 for d-Ritalin LA® was 12.9% and peak 2, 7.5%. The IR MPH physiological model, adapted for NONMEM analyses of the ER MPH drug products Concerta® and Ritalin LA® described the individual parameter-generated reference data well for both formulations.

High-sensitivity C-reactive protein and cystatin C independently and jointly predict all-cause mortality among the middle-aged and elderly Chinese population

Studies investigating the relationship between high-sensitivity C-reactive protein (hs-CRP), cystatin C, and all-cause mortality yielded inconsistent results. Moreover, the joint effect of hs-CRP and cystatin C on mortality risk is largely unknown for the general population. In this study, we examined the associations between hs-CRP, cystatin C, and all-cause mortality using data from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and elderly participants with complete data were enrolled for a 4-year follow-up of total mortality and plasma levels of hs-CRP (n = 11,409) and cystatin C (n = 8680). In study population, the highest quartiles of hs-CRP and cystatin C were significantly associated with increased total mortality risk compared with the lowest quartile, and adjusted hazard ratios (95% confidence intervals) were 2.08 (1.49–2.91) and 1.97 (1.33–2.94) for hs-CRP and cystatin C, respectively. Remarkably, the adjusted hazard ratio (95% confidence interval) of the co-occurrence of elevated hs-CRP and increased cystatin C was 4.17 (2.94–5.92), in contrast to each elevation alone: 1.89 (1.45–2.47) for hs-CRP and 2.08 (1.46–2.97) for cystatin C. Moreover, a subgroup analysis by gender yielded similar associations. Lastly, the addition of hs-CRP and cystatin C to conventional factors significantly improved risk prediction of total mortality (net reclassification index 0.3622, P < 0.0001; integrated discrimination improvement 0.0354, P < 0.0001). Taken together, findings suggest that plasma hs-CRP and cystatin C serve as independent predictors of all-cause mortality among the middle-aged and elderly Chinese population. Furthermore, the combination of hs-CRP and cystatin C could predict overall mortality better than each component individually.

Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundaci\xf3 ACE Healthy Brain Initiative (FACEHBI)

BackgroundPeripheral biomarkers that identify individuals at risk of developing Alzheimer’s disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.MethodsThe Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aβ40 and Aβ42 peptides. The association between Aβ40 and Aβ42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aβ levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aβ plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis.ResultsFBB-PET global SUVR correlated weakly but significantly with Aβ42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aβ measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aβ FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aβ measurements (p value for interaction = 0.105).ConclusionBrain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity

Male obesity is known to be associated with hypogonadism, which can be reverted after surgical weight reduction. However, the evidence about how rapidly this effect rises after surgery and what consequences each procedure have on prostate function and prostatic-specific antigen (PSA) concentration is scarce. So, we evaluated total testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone and PSA plasma levels in a group of 29 Caucasian obese men (BMI - 43.4 ± 8.5 kg/m2) before and one month after sleeve gastrectomy. 19 lean healthy male subjects were considered as controls. As expected, obese patients showed a high prevalence of hypogonadism (51.6%) at baseline, with reduced total testosterone compared to lean controls (10.8 ± 3.5 vs 15.7 ± 4.2 nmol/l, p < .01), higher estradiol (124.4 ± 46.5 vs 78.7 ± 39.6 pmol/l, p < .01), lower luteinizing hormone and follicle stimulating hormone (3.6 ± 1.3 and 2.5 ± 0.9 vs 5.2 ± 2.4 and 5.9 ± 3.8 U/L, respectively, p < .05) plasma levels. One month after surgery, patients showed a significant body weight reduction (−17.2 ± 6.7 kg) with increased total testosterone (from 10.8 ± 3.5 to 18.9 ± 4.9 nmol/l, p < .001), reduced estradiol (from 124.4 ± 46.5 to 96.1 ± 34.3 pmol/l, p < .05) and increased PSA (from 0.74 ± 0.38 to 1.0 ± 0.51 μg/l, p < .001). These results confirm that hypogonadism is highly prevalent in obese males, but they also show that it can be early reversed after sleeve gastrectomy, further confirming the strong indication to surgery of hypogonadal patients with severely reduced quality of life. Higher testosterone levels may be responsible for the increase of PSA observed after surgery; however, PSA concentration has to be monitored over time to avoid underrating of potential severe prostate diseases.