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Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
Defective insulin-stimulated glycogen storage has been found in NIDDM,117 so the enzymes involved in glycogen synthesis are possible candidates for defects in NIDDM. Glycogen synthase catalyzes the addition of uridine diphosphate glucose (UDP glucose) to glycogen, an important step in the nonoxidative pathway of glucose metabolism. The glycogen synthase gene is found on chromosome 19.118,119 A restriction fragment length polymorphism, called Xbal RFLP A2, in the glycogen synthase gene was found to be associated with NIDDM in a Finnish population.118 The patients with this polymorphism had a higher likelihood of hypertension than NIDDM patients without the polymorphism.118 The association of this polymorphism and NIDDM was not found in a French population,120 a Japanese population,121 or a Swedish population.122 However, an association with the alternative allele, Xbal RFLP A1 allele, was found in the French subjects.120 Additionally, a simple tandem repeat polymorphism in the synthase gene was associated with NIDDM in a different group of Japanese NIDDM patients.123 The glycogen synthase locus was not linked to MODY in a study of 15 MODY families.82 Further studies are needed, but it appears there may be a real association with the glycogen synthase gene and NIDDM.
Liver Function Tests in the Differential Diagnosis of Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Hepatic biopsy allows for a multitude of analyses of specific enzyme activities that may relate to hepatobiliary disorders. A few selected examples are (1) relating the levels of both uridine diphosphate glucuronyl transferase and its substrate, UDPGA, to altered hepatic bilirubin conjugation and clinical jaundice (Trotman et al., 1983; Portman et al., 1984); (2) correlating heme oxygenase (HO) activities to bilirubin production rates and jaundice following therapy with HO inhibitors (Simionatto et al., 1985); and (3) relating hyperammonemia with hepatic levels of arginosuccinate synthetase deficiency rather than to portasystemic shunts or cirrhosis (Strombeck et al., 1975).
Alcohol
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Hepatic microsomes are responsible for a large number of metabolic functions. On theoretical grounds one can postulate that several of these functions (which have not as yet been extensively studied) will be found to be affected by either acute or chronic ethanol consumption. One can now anticipate a number of reports, such as the prevention of hyperbilirubinemia of the newborn by ethanol,147 attributed to induction of microsomal uridine - diphosphate-glucuronyl transferase.148 The possible role of microsomal changes (induced by ethanol consumption) in the development of ethanol dependence is particularly intriguing, as discussed subsequently.
A simplified HPLC-based method for measuring unconjugated bilirubin, bilirubin-monoglucuronide, bilirubin-diglucuronide, and delta-bilirubin in plasma with increased conjugated bilirubin
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2023
Morten Hjuler Nielsen, Morten Mørk, Poul Madsen, Axel Brock
In accordance with [14] and other authors [2,4,15], bilirubin is separated into unconjugated bilirubin, mono-conjugated bilirubin, di-conjugated bilirubin, and delta-bilirubin. The chromatogram shows the first bilirubin fraction, delta-bilirubin (Figure 1(A), peak 2), to be eluted together with the albumin fraction (Figure 1(B), peak 2) which accords with [14]. In agreement with the delayed expression of uridine diphosphate (UDP)-glucuronosyltransferase the chromatograms obtained from icteric newborns show the fractions of mono- and di-conjugated bilirubin (Figure 1(C), peaks 3 and 4) to be low compared to that of unconjugated (peak 5). Applied on a commercially available quality control material (Conjugated Bilirubin, Labquality Oy, Helsinki, Finland, Product number: LQ750519011-012US, total bilirubin 185 μmol/L) the chromatogram shows two fractions of conjugated bilirubin corresponding to peak 3 and peak 4 (Figure 1(A,C)), and a fraction of unconjugated bilirubin corresponding to peak 5 (Figure 1(A,C)) which is indistinguishable from that obtained by bilirubin powder (Sigma-Aldrich, St. Louis, MO, USA) (data not shown).
Recent molecules in the treatment of severe infections caused by ESBL-producing bacteria
Published in Expert Review of Anti-infective Therapy, 2021
Alessandro Russo, Marco Berruti, Daniele Roberto Giacobbe, Antonio Vena, Matteo Bassetti
Of interest, new compounds with peculiar mechanisms of action are actually under development. Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) were recently evaluated: in vitro data highlighted the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains, including Enterobacterales and non-fermentative Gram-negative bacilli [80]. Peptide deformylase inhibitors were also evaluated in in vitro studies on Enterobacterales [81]. However, no sufficient clinical data are available for these molecules. In conclusion, these data point out the high mortality associated with severe infections due to ESBL strains, especially in patients who developed severe sepsis or septic shock [82], together with the importance of some clinical characteristics, like source of infection and indicators of severity [83–85], as determinants of the patient’s outcome in this setting, requiring an early escalation of antibiotic therapy [86]. The use of ceftolozane–tazobactam or ceftazidime–avibactam could be considered a first-line therapy in severe infections; however, the definitive role of the new drugs should be definitively assessed considering that, to date, there are not enough data and clinical experiences to recommend these agents as a carbapenem-sparing option [5–8]; moreover, the use of these new antibiotics, without a rational approach, may lead to an increase of resistance among CRE organisms [87–89]. Finally, the availability of these agents and costs are an additional barriers to their use.
Do histone deacytelase inhibitors and azacitidine combination hold potential as an effective treatment for high/very-high risk myelodysplastic syndromes?
Published in Expert Opinion on Investigational Drugs, 2021
Azacitidine can be administered intravenously or subcutaneously. Subcutaneous AZA at a dose of 75 mg/m2 has a bioavailability of 89%; it is rapidly absorbed with mean peak plasma concentration attained in ≤30 min[17]. The bioavailability of subcutaneous AZA (89%) is comparable to intravenous administration (range, 70–112%)[17]. Dose-proportional pharmacokinetics was observed following the administration of azacitidine. In vitro data suggest that azacitidine is not metabolized by cytochrome P450 enzyme, uridine diphosphate or glutathione transferase. Azacitidine is metabolized through spontaneous hydrolysis and cytidine deaminase-mediated deamination. The drug is primarily excreted by the kidneys. Following intravenous and subcutaneous administration of radiolabeled azacitidine, 85 and 50% of radioactivity was recovered in the urine, respectively, with minimal fecal excretion (<1%)[14]. The data is limited regarding the use of AZA in patients with renal or hepatic impairment; however, studies demonstrated similar pharmacokinetics in patients with renal impairment (creatinine clearance < 30 mL/min) compared to those with normal kidney functions[18]. In vitro, studies did not suggest to have inhibition or induction of cytochrome P450 (CYP) enzymes by AZA[19].