Serum Osteoprotegerin Is an Independent Marker of Left Ventricular Hypertrophy,Systolic and Diastolic Dysfunction of the Left Ventricle and the Presence of Pericardial Fluid in Chronic Kidney Disease Patients

Background: Osteoprotegerin (OPG) is a molecule which belongs to the tumor necrosis factor receptor superfamily. OPG concentration is elevated in patients with left ventricle hypertrophy, heart failure and acute myocardial infarction. OPG concentrations rise in chronic kidney disease (CKD). The aim of this study was to investigate the association between OPG concentrations and cardiovascular complications, such as left ventricle hypertrophy, systolic and diastolic dysfunction of left ventricle and dysfunction of right ventricle in chronic kidney disease patients not treated with dialysis. The relation between OPG and the amount of pericardial fluid was also examined. Methods: One hundred and one men with CKD stage 3–5 not treated with dialysis were included in the study. Overhydration, body fat mass and lean body mass were measured using bioimpedance spectroscopy (BIS). Echocardiography was performed to evaluate the amount of pericardial fluid and to measure the thickness of the interventricular septum (IVS), systolic and diastolic function of left ventricle, as well as systolic function of right ventricle. Results: We observed a significant positive association between OPG and the thickness of the interventricular septum, the size of the left atrium (LA) and the presence of pericardial fluid. A negative relationship was observed between OPG and ejection fraction (EF). Conclusions: Our results suggest that OPG can be an independent marker of left ventricular hypertrophy, systolic and diastolic dysfunction of left ventricle and the presence of pericardial fluid in chronic kidney disease patients.     

Monocyte activity after stimulation by serum of women with endometriosis

OBJECTIVES: Impairments of immune system play an important role in the development and pathogenesis of endometriosis. In affected women peritoneal macrophages are excessively activated, which is visible in an increased synthesis and release of macrophage-derived cytokines and growth factors. Monocytes are precursors of those cells in peripheral blood. The aim of the study was to evaluate the activity of monocyte from a healthy person, after stimulation by serum of women with endometriosis in cell culture conditions. The indicator of monocyte activity was the concentration of neopterin (NPT), produced by those cells. MATERIAL AND METHODS: Twenty nine women with endometriosis (mean age: 28.7+/-4.5 years) were included into this study. Among them were 18 women with moderate endometriosis (I and II stages according to AFS) and 11 women with advanced stages of the disease (III and IV stages according to AFS). Reference group consisted of fifteen healthy women (mean age: 27.4+/-5.3 years), with excluded endometriosis and other pathological disorders within the pelvis. Monocytes used in the study were isolated from peripheral blood of a healthy male and serum of women with endometriosis and control group. Monocytes were cultured in attendance of 15% and 30% serum of studied women. The concentration of NPT in the supernatants of culture was measured by enzyme-linked immunosorbent ELISA assay. RESULTS: The serum of women with endometriosis causes an increased concentration of NPT in supernatants, when comparing with serum of healthy women (p<0. 0001). The highest concentration was observed after stimulation by serum of women with advanced endometriosis. CONCLUSIONS: Serum of women with endometriosis can have an effect on monocyte activity, which is displayed in the increased synthesis and secreted of NPT.     

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik−Fields Reaction

We reported a new method dealing with the synthesis of novel pharmacologically relevant α-aminophosphonate derivatives via a lipase-catalyzed Kabachnik−Fields reaction with yields of up to 93%. The advantages of this protocol are excellent yields, mild reaction conditions, low costs, and sustainability. The developed protocol is applicable to a range of H-phosphites and organic amines, providing a wide substrate scope. A new class of α-aminophosphonate analogues possessing P-chiral centers was also synthesized. The synthesized compounds were characterized on the basis of their antimicrobial activities against E. coli. The impact of the various alkoxy groups on antimicrobial activity was demonstrated. The crucial role of the substituents, located at the aromatic rings in the phenylethyloxy and benzyloxy groups, on the inhibitory action against selected pathogenic E. coli strains was revealed. The observed results are especially important because of increasing resistance of bacteria to various drugs and antibiotics.     

Branched-Chain Fatty Acids Alter the Expression of Genes Responsible for Lipid Synthesis and Inflammation in Human Adipose Cells

Recently, we have demonstrated a decreased level of iso-branched-chain fatty acids (iso-BCFAs) in patients with excessive weight. However, it is still unclear whether BCFAs may influence lipid metabolism and inflammation in lipogenic tissues. To verify this, human visceral adipocytes were cultured with three different concentrations of selected iso-BCFA (14-methylpentadecanoic acid) and anteiso-BCFA (12-methyltetradecanoic acid), and then the expression of genes associated with lipid metabolism (FASN—fatty acid synthase; SREBP1—sterol regulatory element-binding protein 1; SCD1—stearoyl-CoA desaturase; ELOVL4—fatty acid elongase 4; ELOVL6—fatty acid elongase 6; FADS2—fatty acid desaturase 2; FADS1–fatty acid desaturase 1) and inflammation (COX-2—cyclooxygenase 2; ALOX-15—lipoxygenase 15; IL-6—interleukin 6) were determined. This study demonstrates for the first time that incubation with iso-BCFA decreases the expression of adipocyte genes that are associated with lipid metabolism (except FASN) and inflammation. These findings suggest that changes in the iso-BCFA profile in obese patients may contribute to adipose inflammation and dyslipidemia. Further studies should evaluate whether iso-BCFA supplementation in obese patients would be beneficial.     

CO Oxidation over Pd Catalyst Supported on Porous TiO2 Prepared by Plasma Electrolytic Oxidation (PEO) of a Ti Metallic Carrier

A porous TiO₂ layer was prepared with the plasma electrolytic oxidation (PEO) of Ti. In a further step, Pd was deposited on the TiO₂ surface layer using the adsorption method. The activity of the Pd/TiO₂/Ti catalyst was investigated during the oxidation of CO to CO₂ in a mixture of air with 5% CO. The structure of the catalytic active layer was studied using a scanning electron microscope equipped with an energy dispersive spectrometer (SEM-EDS), time-of-flight secondary ion mass spectrometry (TOF-SIMS), inductively coupled plasma mass spectrometry (ICP-MS), and X-ray diffraction (XRD). The PEO process provided a porous TiO₂ layer with a uniform thickness in the range of 5–10 µm, which is desirable for the production of Pd-supported catalysts. A TOF-SIMS analysis showed the formation of Pd nanoparticles after the adsorption treatment. The conversion of CO to CO₂ in all samples was achieved at 150–280 °C, depending on the concentration of Pd. The composition of Pd/ TiO₂/Ti was determined using ICP-MS. The optimum concentration of Pd on the surface of the catalyst was approximately 0.14% wt. This concentration was obtained when a 0.4% PdCl₂ solution was used in the adsorption process. Increasing the concentration of PdCl₂ did not lead to a further improvement in the activity of Pd/ TiO₂/Ti.     

Pharmacometabonomic association of cyclophosphamide 4‐hydroxylation in hematopoietic cell transplant recipients

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

We report the first pharmacometabonomic study of the association of plasma EMCs with cyclophosphamide pharmacokinetics, specifically the ratio of 4HCY/CY AUC.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question regarding if EMCs in the plasma before PT‐CY administration are associated with the ratio of 4HCY/CY AUC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study adds to our knowledge that longitudinal collection of plasma EMC samples is feasible in HCT patients receiving PT‐CY. In addition, the plasma EMC changes over the ~21‐day time period that starts pre‐HCT to 24‐hr after the first PT‐CY dose.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrates the possibility of pharmacometabolomic research to evaluate the pharmacokinetics of a drug – in this case, cyclophosphamide – with a complex pharmacokinetic disposition.     

Interactions between Tacrolimus and Metronidazole in a renal transplant patient

We present a case which reports the occurrence of a potential elevation of Tacrolimus (Tac) plasma levels to toxic values in a renal transplant recipient after adding Metronidazole (Met) to the medication regimen. A 30-year old female, status post living-related renal transplant, who was stabilized on Tac 4.5 mg, twice daily, for 4 months, presented to the clinic with diarrhea. We used Microparticle Enzyme Immunoassay (MEIA) to determine Tac trough concentration (trough concentrations 5–10 ng/ml). After 6 days of Met therapy on 1.5 g/d, Tac trough concentration and serum creatinine (sCr) increased to 20.2 ng/ml and 7.8 mg/dl respectively. Met therapy was discontinued, also one dose of Tac was withheld, while daily dose was decreased to 2 mg/d. Four days after Met discontinuation, Tac concentration dropped to 8.7 ng/ml, sCr to 2.1 mg/dl, warranting Tac dose increase to 3 mg/d. Co-administration of Tac with Met may result in elevated Tac concentrations, possibly leading to tacrolimus nephrotoxicity. Clinicians should be aware of this potential interaction and closely monitor Tac concentration and renal function.     

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease

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