Does P-Cresylglucuronide Have the Same Impact on Mortality as Other Protein-Bound Uremic Toxins?

Background

Uremic toxins are emerging as important, non-traditional cardiovascular risk factors in chronic kidney disease (CKD). P-cresol has been defined as a prototype protein-bound uremic toxin. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter’s association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality.

Methodology/Principal Findings

We studied 139 patients (mean ± SD age: 67±12; males: 60%) at different CKD stages (34.5% at CKD stages 2–3, 33.5% at stage 4–5 and 32% at stage 5D). A recently developed high-performance liquid chromatography method was used to assay PCG concentrations. Total and free PCG levels increased with the severity of CKD. During the study period (mean duration: 779±185 days), 38 patients died. High free and total PCG levels were correlated with overall and cardiovascular mortality independently of well-known predictors of survival, such as age, vascular calcification, anemia, inflammation and (in predialysis patients) the estimated glomerular filtration rate. In the same cohort, free PCS levels and free IS levels were both correlated with mortality. Furthermore, the respective predictive powers of three Cox multivariate models (free PCS+other risk factors, free IS+other risk factors and free PCS+other risk factors) were quite similar - suggesting that an elevated PCG concentration has much the same impact on mortality as other uremic toxins (such as PCS or IS) do.

Conclusions

Although PCG is the minor metabolite of p-cresol, our study is the first to reveal its association with mortality. Furthermore, the free fraction of PCG appears to have much the same predictive power for mortality as PCS and IS do.     

InDiaMed: A Comprehensive Database of Indian Medicinal plants for Diabetes

According to International Diabetes Federation (IDF), India has 62.4 million people with diabetes and by 2030 it is predicted that the number will rise to 100 million. Studies claim that there are around 410 experimentally proven Indian medicinal plants which have anti-diabetic activity, of which the mechanism of action of 109 plants has been elucidated or reported. So, the need of the hour is to explore the claims of Indian medicinal flora and open up the facets of many Indian plants which are being examined for their beneficial role in diabetes. So, we created a database (InDiaMed) of Indian medicinal plants that captures their role in anti-diabetic activity. InDiaMed''s features include chemical, pharmacological, biochemical and geographical information of the medicinal plant, scientifically relevant information of the plant, and the coherent research done on it in the field of diabetes. The database also includes the list of poly-herbal formulations which are used for treatment of diabetes in India.

Availability

http://www.indiamed.info     

Large-scale exploration of growth inhibition caused by overexpression of genomic fragments in Saccharomyces cerevisiae

We have screened the genome of Saccharomyces cerevisiae for fragments that confer a growth-retardation phenotype when overexpressed in a multicopy plasmid with a tetracycline-regulatable (Tet-off) promoter. We selected 714 such fragments with a mean size of 700 base-pairs out of around 84,000 clones tested. These include 493 in-frame open reading frame fragments corresponding to 454 distinct genes (of which 91 are of unknown function), and 162 out-of-frame, antisense and intergenic genomic fragments, representing the largest collection of toxic inserts published so far in yeast.     

Phylogenetic classification of transporters and other membrane proteins from Saccharomyces cerevisiae

On the basis of functional and phylogenetic criteria, we have identified a total of 229 subfamilies and 111 singletons predicted to carry out transport or other membrane functions in Saccharomyces cerevisiae. We have extended the Transporter Classification (TC) and created a Membrane Classification (MC) for non-transporter membrane proteins. Using the preliminary phylogenetic digits X, Y, Z (for new families, subfamilies, and clusters, respectively), we allocated a five-digit number to 850 proteins predicted to contain more than two transmembrane domains. Compared with a previous TC of the yeast genome, we classified an additional set of 538 membrane proteins (transporters and non-transporters) and identified 111 novel phylogenetic subfamilies. Electronic Publication     

Computer literacy enhancement in the Teaching Hospital Olomouc. Part I: project management techniques. Short communication

Information explosion and globalization make great demands on keeping pace with the new trends in the healthcare sector. The contemporary level of computer and information literacy among most health care professionals in the Teaching Hospital Olomouc (Czech Republic) is not satisfactory for efficient exploitation of modern information technology in diagnostics, therapy and nursing. The present contribution describes the application of two basic problem solving techniques (brainstorming, SWOT analysis) to develop a project aimed at information literacy enhancement.     

Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease

Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease.     

New inflammation-related biomarkers during malaria infection

Malaria is one of the most prevalent infectious diseases worldwide with more than 250 million cases and one million deaths each year. One of the well-characterized malarial-related molecules is hemozoin (HZ), which is a dark-brown crystal formed by the parasite and released into the host during the burst of infected red blood cells. HZ has a stimulatory effect on the host immune system such as its ability to induce pro-inflammatory mediators responsible for some of the malaria related clinical symptoms such as fever. However, the host serum proteins interacting with malarial HZ as well as how this interaction modifies its recognition by phagocytes remained elusive. In the actual study, using proteomic liquid chromatographic mass spectrometry (LC-MS/MS) and immunochemical approaches, we compared the serum protein profiles of malaria patients and healthy individuals. Particularly, we utilized the malarial HZ itself to capture serum proteins capable to bind to HZ, enabling us to identify several proteins such as apolipoprotein E (ApoE), serum amyloid A (SAA), gelsolin, complement factor H and fibrinogen that were found to differ among healthy and malaria individual. Of particular interest is LPS binding protein (LBP), which is reported herein for the first time in the context of malaria. LBP is usually produced during innate inflammatory response to gram-negative bacterial infections. The exact role of these biomarkers and acute phase responses in malaria in general and HZ in particular remains to be investigated. The identification of these inflammation-related biomarkers in malaria paves the way to potentially utilize them as diagnostic and therapeutic targets.