Proline at the P2 position in protein C is important for calcium- mediated regulation of protein C activation and secretion

Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)- dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell.     

The Incidence and Outcomes of Ischemic Hepatitis: A Systematic Review with Meta-analysis

Background

Ischemic hepatitis is a devastating cause of acute liver injury. Data are limited regarding its incidence and outcomes.

Methods

Systematic review and meta-analysis of studies from PubMed, EMBASE, and Web of Science with specific search terms. Inclusion criteria included case series with >10 patients and clear case definition (especially liver enzyme levels >10 times the upper limit of normal).

Results

Twenty-four papers met inclusion criteria. A total of 1782 cases were identified in these papers (mean 78 per paper, range 12-322). The pooled average age of the included patients was 64.2 years, and their mean peak aspartate aminotransferase level, alanine aminotransferase level, and total bilirubin were 2423 IU/L, 1893 IU/L, and 2.55 mg/dL, respectively. Ischemic hepatitis was present in 2 of every 1000 admissions; including 2.5 of every 100 intensive care unit admissions and 4 of 10 admissions associated with an aminotransferase level >10 times the upper limit of normal. The pooled proportions of patients with ischemic hepatitis who had a predisposing acute cardiac event or sepsis were 78.2% and 23.4%, respectively. The proportion of patients with a documented hypotensive event of any duration was 52.9%. Overall, the pooled rate of survival to discharge was 51% (range 23.1%-85.7%).

Conclusions

Ischemic hepatitis is a common cause of severe acute liver injury and is associated with a significant risk of in-hospital death. A major opportunity in the management of ischemic hepatitis is recognition of the condition without documented hypotension.     

Characterisation of microsatellite markers for the granite endemic Kunzea pulchella (Lindl.) A. S. George (Myrtaceae) identified using next generation sequencing

A set of 11 polymorphic microsatellite loci were developed for Kunzea pulchella, a plant species endemic to granite outcrops in Western Australia. Genomic sequences were obtained from next generation (454) sequencing. A total of 20 microsatellite markers were then chosen for amplification and genotyping trials in individuals across the species range. Eleven of these loci were selected for analysis based on amplification and genotyping success. All were polymorphic with 4–10 alleles per locus (mean = 5.9). Expected and observed heterozygosity ranged from 0.29 to 0.92 averaging 0.606 and 0.690 respectively. Loci were in Hardy–Weinberg equilibrium (P < 0.05) except for two which showed evidence for null alleles. Linkage disequilibrium was evident in three loci pair combinations. These polymorphic microsatellite markers will be valuable for analysis of population genetic structure and connectivity in K. pulchella.     

Isolation and characterisation of ten microsatellite markers for the tetraploid Stypandra glauca R.Br. (Hemerocallidaceae) identified using next generation sequencing

Ten polymorphic microsatellite loci were developed for the tetraploid plant species Stypandra glauca which is common on granite outcrops in Western Australia. Amplification and genotyping trials were conducted on 48 individuals from two sampling localities. All 10 loci revealed multi-banding patterns with up to 4 bands visible in individuals consistent with tetraploidy. The number of alleles per locus ranged from 6 to 32 (mean = 12.5). The proportion of observed heterozygotes at each locus ranged from 0.32 to 0.98 (mean = 0.73). These polymorphic microsatellite markers will facilitate further analysis of population genetic structure and connectivity in Stypandra glauca.     

Influence of Bariatric Surgery on the Use and Pharmacokinetics of Some Major Drug Classes

The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.