1,190 research outputs found
ATYPICAL BILE ACIDS AS CHEMICAL PROBES FOR DIAGNOSIS AND THERAPHY MONITORING OF PROGRESSIVE CHOLESTATIC LIVER DISEASE IN HSD3B7 PATIENTS
No full textInborn errors in bile acid synthesis are a well-recognized category of metabolic liver disease. These autosomal recessive genetic defects manifest as a broad phenotype presenting with an overlapping spectrum of variable degrees of neonatal cholestasis, fat-soluble vitamin malabsorption, and neuropathies. 3b-Hydroxy-D5-C27-steroid oxidoreductase (HSD3B7) deficiency is the most common of the 9 known defects in bile acid biosynthesis and is often the cause of idiopathic forms of late-onset chronic cholestasis in children and adolescents, and even in adult. Early diagnosis of these genetic defects is crucial to prognosis, because if undiagnosed or untreated, the liver disease, which is a progressive form of intrahepatic cholestasis, leads to fibrosis, cirrhosis, and end-stage disease. Treatment options include liver transplantation or preferably oral bile acid therapy with the primary bile acids, cholic or chenodeoxycholic acids. Diagnosis of HSD3B7 deficiency is based on the detection of increased concentrations of atypical 3-hydroxy-D5-bile acids that accumulate in urine because of the lack of enzyme activity caused by mutations in HSDB7 gene. So far, direct and accurate measurement of these conjugated 3b-hydroxy-D5-bile acids has not been possible for the lack of reference standards.
We describe here the synthesis and bio-chemical characterization of a series of D5-cholenoic acid analogs, which are the signature metabolites of the HSD3B7 deficiency in humans. Using these synthesized compounds as tools to gain insights into the mechanism(s) responsible of the cholestasis and liver damage in patients with the HSD3B7 deficiency, we report their cellular hepatocytotoxicity, their affinity towards a subset of bile acid-responsive nuclear receptors and the effects on genes and cytochromes involved in bile acid homeostasis and detoxification. Moreover, the availability of these reference compounds has allowed developing an electrospray ionization (ESI) LC-MS/MS method for the accurate measurement of their concentrations in clinical diagnosis and monitoring of response to therapy in patients with HSD3B7 deficiency
Influence of breast feeding, and adapted and hydrolyzed formulas on biliary bile acids in newborn guinea pigs
No full textBackground: The type of feeding can differently influence bile acid ontogeny during the period of physiologic cholestasis that characterizes early human development. Aim: To investigate the effects of feeding from birth, conventional or partially protein hydrolyzed cow's milk formulas were compared with breast milk regarding bile acid concentration and the composition of gallbladder bile in newborn guinea pigs. Methods: Forty newborn guinea pigs were allocated to one of three different feeding regimens: breast milk (n =14), intact protein formula (n =13) and partially protein hydrolyzed formula (n =13). After 8 days, one third of the pups from each group was sacrificed; another third was sacrificed on the 14th day and the remainder on the 20th day of life. Bile acids in gallbladder bile were analyzed by gas chromatography/mass spectrometry and HPLC. Results: During the first 2 weeks of life, weight gain was significantly higher in breast-fed than in artificially fed pups. An age-related increase in total biliary bile acid concentrations was evident for breast-fed and hydrolyzed formula-fed animals, but not for those fed intact protein formula. Breast-fed animals had the highest total biliary bile acid concentrations on day 20 of life, with significant increases in chenodeoxycholic and 7-oxo-lithocholic acid concentrations, which were absent in the other two groups. Concentrations of 7-oxo-lithocholic acid on day 8 were significantly higher in animals fed intact protein formula compared with breast-fed and partially protein hydrolyzed formula-fed animals. Conclusions: In newborn guinea pigs, breast feeding is associated with a marked increase in biliary bile acid concentrations, which was not observed in artificially fed animals. The higher biliary bile acid concentrations and better weight gain in our breast-fed animals may reflect a greater feed efficiency associated with natural feeding. Biliary bile acid composition on day 8 suggests more rapid intestinal bacterial bile acid biotransformation in animals fed intact protein formula compared to other feeding regimens. Copyright© 2003 S. Karger AG, Basel
Chemical Synthesis of [13C]Daidzein
No full textPharmacokinetic and metabolic studies of phytoestrogens of the isoflavone class have been hampered by the lack of suitable stable-isotope-labeled analogs. A method for preparation of a [13C]-labeled analog of daidzein is described. [2-13C]Daidzein was synthesized by reaction of [13C]diethoxydimethylaminomethane with 2,4-dihydroxybenzoin. The final product was purified to more than 99% by reverse-phase high-performance liquid chromatography and structural analysis confirmed by nuclear magnetic resonance spectroscopy and mass spectrometry. Because [2-13C]daidzein is analytically and metabolically stable, it is a suitable analog for use as an internal standard for quantifying daidzein in biological fluids using isotope dilution mass spectrometry. This nonradioactive tracer is also ideal for investigating the pharmacokinetics of daidzein in humans because it is biologically indistinguishable from the unlabeled form
Tandem Mass Spectrometric Determination of Atypical 3-Hydroxy-Δ5-Bile Acids in Patients with 3-Hydroxy-Δ5-C27-Steroid Oxidoreductase Deficiency: Application to Diagnosis and Monitoring of Bile Acid Therapeutic Response
No full text3Beta-hydroxy-5-C27-steroid oxidoreductase (HSD3B7) deficiency, a progressive cholestatic liver disease, is the most common genetic defect in bile acid synthesis. Early diagnosis is important because patients respond to oral primary bile acid therapy, which targets the negative feedback regulation for bile acid synthesis to reduce the production of hepatotoxic 3beta-hydroxy-5-bile acids. These atypical bile acids are highly labile and difficult to accurately measure, yet a method for accurate determination of 3-hydroxy-5-bile acid sulfates is critical for dose titration and monitoring response to therapy
Rewarding Innovation: Improving Federal Tax Support for Business R&D in Canada
Get PDFBusiness innovation is viewed by many as a solution to Canada’s ailing productivity performance. One of the more troubling aspects of Canada’s innovation track record is that businesses spend relatively little on research and development (R&D) despite having access to some of the world’s most generous R&D tax incentives. Canada’s low levels of business R&D have called into question the effectiveness of Canada’s generous R&D tax incentives, particularly the flagship federal Scientific Research and Experimental Development (SR&ED) program. A deeper analysis, however, reveals that tax incentives are effective in stimulating more R&D – that is, Canada would have lower levels of business R&D in the absence of these inducements. Instead, the root cause of Canada’s business R&D deficit appears to stem from structural aspects of the economy and, more importantly, a lack of demand-related pressure to pursue innovation.Fiscal and Tax Competitiveness, Canada, research and development (R&D) incentives, Scientific Research and Experimental Development (SR&ED) program
How Effective are Fiscal Incentives for R&D? A New Review of the Evidence
Get PDFThis paper surveys the econometric evidence on the effectiveness of fiscal incentives for R&D. We describe the effects of tax systems in OECD countries on the user cost of R&D - the current position, changes over time and across different firms in different countries. We describe and criticize the methodologies used to evaluate the effect of the tax system on R&D behavior and the results from different studies. In the current (imperfect) state of knowledge we conclude that a dollar in tax credit for R&D stimulates a dollar of additional R&D.
The Current State of Research and Development Approach (R&D) in the Saudi Construction Industry
Get PDFabstract: For the past three decades, the Saudi construction industry (SCI) has exhibited poor performance. Many research efforts have tried to identify the problem and the potential causes but there have been few publications identifying ways to mitigate the problem and describing testing to validate the proposed solution. This paper examines the research and development (R&D) approach in the SCI. A literature research was performed identifying the impact that R&D has had on the SCI. A questionnaire was also created for surveying industry professionals and researchers. The results show evidence that the SCI practice and the academic research work exist in separate silos. This study recommends a change of mindset in both the public and private sector on their views on R&D since cooperation is required to create collaboration between the two sectors and improve the competitiveness of the country's economy
The Current State of Research and Development Approach (R&D) in the Saudi Construction Industry
No full textAbstractFor the past three decades, the Saudi construction industry (SCI) has exhibited poor performance. Many research efforts have tried to identify the problem and the potential causes but there have been few publications identifying ways to mitigate the problem and describing testing to validate the proposed solution. This paper examines the research and development (R&D) approach in the SCI. A literature research was performed identifying the impact that R&D has had on the SCI. A questionnaire was also created for surveying industry professionals and researchers. The results show evidence that the SCI practice and the academic research work exist in separate silos. This study recommends a change of mindset in both the public and private sector on their views on R&D since cooperation is required to create collaboration between the two sectors and improve the competitiveness of the country's economy
HUMAN CAPITAL ASSESSMENT INDICATORS AS INFLUENTIAL DETERMINANTS PERTAINING TO THE ADMISSION CRITERIA UTILIZED BY PRE-LICENSURE PROGRAMS FOR NURSING EDUCATION
Get PDFThe attainment of educational credentials contributes to the acquisition of human capital. Academic preparedness is a component therein that allows for the attainment of increased levels of education. Most institutions of higher education utilize measures of academic preparedness, such as grade point averages or standardized tests. Requirements for the levels of academic preparedness are based upon many factors. The requirements most relevant to this study are the selectivity of the institution and the academic preparedness of potential candidates of pre-licensure programs for nursing education.
The pre-licensure education of nurses is enigmatic when compared to other professional disciplines. Pre-licensure education for registered nurses exists in three distinct and differently classified programs: a hospital-based diploma program, an associate degree program, or a baccalaureate program. (There is an additional baccalaureate program, known as accelerated second degree programs, for students possessing a baccalaureate degree in another discipline. These accelerated programs are not included in this discussion.) The National Center for Education Statistics classifies each of the three programs, making clear that the differing program levels of post-secondary education are neither equivalent nor interchangeable.
According to the literature, the academic preparedness of individuals and the level of selectivity of higher education institutions vary greatly depending upon the particular classification of nursing program. What then, is the level of programmatic selectivity, given that all three pre-licensure programs produce candidates for the identical occupational certification while attracting candidates known to have varying levels of academic preparedness? This study aimed to determine the levels of selectivity of the three pre-licensure nursing education programs types so as identify trends and patterns within and across pre-licensure program types. In order to determine these trends and patterns, the author examined the admissions requirements that are transparent to the public on schools’ websites in which these programs are housed, employing the methodology of document analysis. The determination for the level of selectivity was based upon Barron’s Measure of Selectivity (Barron’s Educational Series, 2011)
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