Nevertheless, our findings are limited by relatively small sample size. Furthermore, as prior studies have reported ethnic differences in frequencies of alleles and effects of genes involved in blood pressure traits, the novel loci we found may not be generalized to other population groups and await further replication. Pharmaceutical heparin is largely obtained from porcine intestinal mucosa by a multi-step extraction process that involves proteolysis, anion exchange chromatography or quaternary ammonium complexes, ethanol precipitation and bleaching. Throughout this process other naturally occurring GAGs, such as chondroitin, dermatan and heparan sulfates, as well as proteins and small molecules accompany heparin and, additionally, heparin may be modified. The removal of these additional compounds incurs loss, which on an industrial scale is an undesirable outcome. Since this process is quite complex, it requires carefully executed procedures and effective quality control monitoring to avoid the co-purification of Penfluridol impurities and contaminating species. Owing to the complex isolation and purification required, the issue of heparin impurities has long been recognized and was first brought up in 1955 when traces of phosphate were found in commercial heparins. Ethylenediaminetetraacetic acid and histamine have also been identified in commercial heparin, and the presence of EDTA has been associated with increased bleeding effects. In 1989, nuclear magnetic resonance spectroscopy was used to identify the presence of other GAGs in pharmaceutical heparins. Dermatan sulfate was found to be the most common impurity comprising up to 10�C15 percent of the polymer mixture. Again, in 2001, DS, sodium acetate and ethanol were identified as frequent impurities in heparin preparations. Additionally, in early 1990��s the outbreak of bovine spongiform encephalopathy resulted in the exclusion of materials originating from ruminants for the production of heparin. Barlerin Several methods involving molecular biology and immunochemical approaches were used to check the raw materials used by heparin manufacturers. However, none of these issues led to any reported adverse clinical responses, or resulted in significant number of deaths. In 2008, significant numbers of adverse clinical responses associated with heparin use were first reported, leading to at least 149 deaths in the United States. Once again, using NMR and other analytical methods, the major contaminant present in heparin batches related to adverse clinical events was identified as an oversulfated chondroitin sulfate. Several papers were then published regarding analytical approaches to assess heparin purity. However, many of these methods are expensive, time consuming and/or require access to sophisticated and costly instrumentation and facilities, making them difficult to use for producers and regulatory authorities in many locations.