Trypanosoma cruzi in the vertebrate and invertebrate hosts, with special reference to the modes of transmission

Abstract not available.<p

A New Class of Small Molecule Inhibitor of BMP Signaling

Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development

The nucleotide and partial amino acid sequences of rat fetuin

Fetuins are among the major plasma proteins, yet their biological role has remained elusive. Here we report the molecular cloning of rat fetuin and the sequence analysis of a full-length clone, RF619 of 1456 bp with an open reading frame of 1056 bp encoding 352 amino acid residues. The coding part of RF619 was identical with the cDNA sequence of the natural inhibitor of the insulin receptor tyrosine kinase from rat (pp63) except for four substitutions and a single base insertion causing divergence of the predicted protein sequences. Partial amino acid sequences of rat plasma fetuin were in agreement with the predictions based on the RF619 cDNA. Purified rat fetuin inhibited the insulin receptor tyrosine kinase in vitro. Therefore, we conclude that RF619 and pp63 cDNA encode the same protein, i.e. authentic rat fetuin which is a functional tyrosine kinase inhibitor

A Systematic Review Of The Types And Causes Of Prescribing Errors Generated From Using Computerized Provider Order Entry Systems in Primary and Secondary Care

Objective To understand the different types and causes of prescribing errors associated with computerized provider order entry (CPOE) systems, and recommend improvements in these systems. Materials and Methods We conducted a systematic review of the literature published between January 2004 and June 2015 using three large databases: the Cumulative Index to Nursing and Allied Health Literature, Embase, and Medline. Studies that reported qualitative data about the types and causes of these errors were included. A narrative synthesis of all eligible studies was undertaken. Results A total of 1185 publications were identified, of which 34 were included in the review. We identified 8 key themes associated with CPOE-related prescribing errors: computer screen display, drop-down menus and auto-population, wording, default settings, nonintuitive or inflexible ordering, repeat prescriptions and automated processes, users’ work processes, and clinical decision support systems. Displaying an incomplete list of a patient’s medications on the computer screen often contributed to prescribing errors. Lack of system flexibility resulted in users employing error-prone workarounds, such as the addition of contradictory free-text comments. Users’ misinterpretations of how text was presented in CPOE systems were also linked with the occurrence of prescribing errors. Discussion and Conclusions Human factors design is important to reduce error rates. Drop-down menus should be designed with safeguards to decrease the likelihood of selection errors. Development of more sophisticated clinical decision support, which can perform checks on free-text, may also prevent errors. Further research is needed to ensure that systems minimize error likelihood and meet users’ workflow expectations