Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5–15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.     

Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure.

OBJECTIVES: This study sought to assess the potential utility of impedance cardiography (ICG) in predicting clinical deterioration in ambulatory patients with heart failure (HF). BACKGROUND: Impedance cardiography uses changes in thoracic electrical impedance to estimate hemodynamic variables, but its ability to predict clinical events has not been evaluated. METHODS: We prospectively evaluated 212 stable patients with HF and a recent episode of clinical decompensation who underwent serial clinical evaluation and blinded ICG testing every 2 weeks for 26 weeks and were followed up for the occurrence of death or worsening HF requiring hospitalization or emergent care. RESULTS: During the study, 59 patients experienced 104 episodes of decompensated HF (16 deaths, 78 hospitalizations, and 10 emergency visits). Multivariate analysis identified 6 clinical and ICG variables that independently predicted an event within 14 days of assessment. These included three clinical variables (visual analog score, New York Heart Association functional class, and systolic blood pressure) and three ICG parameters (velocity index, thoracic fluid content index, and left ventricular ejection time). The three ICG parameters combined into a composite score was a powerful predictor of an event during the next 14 days (p = 0.0002). Visits with a high-risk composite score had 2.5 times greater likelihood and those with a low-risk score had a 70% lower likelihood of a near-term event compared with visits at intermediate risk. CONCLUSIONS: These results suggest that when performed at regular intervals in stable patients with HF with a recent episode of clinical decompensation, ICG can identify patients at increased near-term risk of recurrent decompensation.     

Molecular Evolution of Peste des Petits Ruminants Virus

Despite safe and efficacious vaccines against peste des petits ruminants virus (PPRV), this virus has emerged as the cause of a highly contagious disease with serious economic consequences for small ruminant agriculture across Asia, the Middle East, and Africa. We used complete and partial genome sequences of all 4 lineages of the virus to investigate evolutionary and epidemiologic dynamics of PPRV. A Bayesian phylogenetic analysis of all PPRV lineages mapped the time to most recent common ancestor and initial divergence of PPRV to a lineage III isolate at the beginning of 20th century. A phylogeographic approach estimated the probability for root location of an ancestral PPRV and individual lineages as being Nigeria for PPRV, Senegal for lineage I, Nigeria/Ghana for lineage II, Sudan for lineage III, and India for lineage IV. Substitution rates are critical parameters for understanding virus evolution because restrictions in genetic variation can lead to lower adaptability and pathogenicity.     

Hydroxyapatite nanorods loaded with parathyroid hormone (PTH) synergistically enhance the net formative effect of PTH anabolic therapy

Parathyroid hormone (PTH) has been a major contributor to the anabolic therapy for osteoporosis, but its delivery to bone without losing activity and avoiding adverse local effects remain a challenge. Being the natural component of bone, use of hydroxyapatite for this purpose brings a major breakthrough in synergistic anabolism. This study focuses on synthesis, characterization and evaluation of in vitro and in vivo efficacy of PTH (1-34) adsorbed hydroxyapatite nanocarrier for synergistic enhancement in the anabolic activity of PTH for bone regeneration. The negative zeta potential of this nanocarrier facilitated its affinity to the Ca²⁺ rich bone tissue and solubilization at low pH enhanced specific delivery of PTH to the resorption pits in osteoporotic bone. In this process, PTH retained its anabolic effect and at the same time an increase in bone mineral content indicated enhancement of the net formative effect of the PTH anabolic therapy.     

Desmethyl Macrolides: Synthesis and Evaluation of 4-Desmethyl Telithromycin

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Pre-clinical pharmacokinetic and pharmacodynamic modelling study of 4-hydroxyisoleucine using validated ultra-performance liquid chromatography-tandem mass spectrometry

A reliable and sensitive ultra-performance liquid chromatography-tandem mass spectrometry-based method has been developed for the estimation of 4-hydroxyisoleucine (4-HI), a potent insulinotropic and hypolipidemic agent. The extraction of 4-HI from plasma was accomplished by the protein precipitation technique using l-isoleucine as an internal standard. The separation of analytes was achieved with a mobile phase consisting of acetonitrile and 0.1% formic acid in an isocratic flow system on a BEH Shield RP-18 column (150 mm × 2.1 mm, 1.7 μm). 4-HI and l-isoleucine were detected using an electrospray ionization (ESI) ion source, using multiple reaction monitoring (MRM) in positive ion mode. The precursor to product ion transitions of 4-HI and l-isoleucine were found at m/z values of 148.19 > 74.02 and 132.17 > 69.04, respectively. As per the guidelines for bioanalytical methods, all validation parameter results were within the acceptable range. The method exhibited a robust and reproducible linearity range of 1–5000 ng mL⁻¹ with a coefficient of regression of 0.9999. The method was successfully applied for the estimation of pharmacokinetic parameters after oral administration of 4-HI (10 mg kg⁻¹) in Wistar rats, by using Thoth Pro (version: 4.3) software. Herein, the two-compartment model was statistically fitted based on AIC and SBC values for evaluation of the pharmacokinetic parameters of 4-HI. Pharmacodynamic studies were also performed by measuring the levels of triglyceride and total cholesterol, and showed that the pharmacokinetic and pharmacodynamic data of 4-HI correlated with each other.

A reliable and sensitive UPLC-MS/MS based method has been developed for the estimation of 4-hydroxyisoleucine, a potent insulinotropic and hypolipidemic agent.