A Novel Hemiarthroplasty Design for Treatment of Post-traumatic Elbow Ankylosis and Distal Humerus Nonunion: A Case Report.

Case: A 26 year old man sustained a blast injury to the right elbow, resulting in chronic distal humerus nonunion and post-traumatic ankylosis. After debridement and flap coverage, a custom distal humerus hemiarthroplasty construct with extramedullary orthogonal plating was used. Satisfaction and functional outcomes were maintained through 6 years of follow-up.

Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs.

Purpose: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood-brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.

Experimental Design: We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple and BBB preclinical models.

First Radiolabeling of a Ganglioside with a Positron Emitting Radionuclide: PET Demonstrates Low Exposure of Radiofluorinated GM1 in Non-human Primate Brain.

Gangliosides are biologically important glycolipids widely distributed in vertebrate cells. An important member of the ganglioside family is the monosialylganglioside GM1, which has been suggested as a potential therapeutic for Parkinson's disease. In the current study, a late-stage radiofluorination protocol was developed, in which fluorine-18 was introduced by substitution of a terminal tosyl group in the fatty acid backbone of GM1.

Bronchoperitoneal and Enterocutaneous Fistula Development Following a Colorectal Anastomosis Leak.

Bronchoperitoneal fistulas are rare but serious pathologies that pose numerous treatment challenges to physicians. There is usually a delay in diagnosis, and treatment recommendations are mainly derived from case reports. Here, we present an interesting case of a patient who developed a left bronchoperitoneal fistula and two subsequent enterocutaneous fistulas resulting from a massive intra-abdominal phlegmon eroding through the left diaphragm.

as an Infection Model for Sterne.

Understanding bacterial virulence provides insight into the molecular basis behind infection and could identify new drug targets. However, assessing potential virulence determinants relies on testing in an animal model. The mouse is a well-validated model but it is constrained by the ethical and logistical challenges of using vertebrate animals.

Transcriptional profiling of the clpX mutant in Bacillus anthracis reveals regulatory connection with the lrgAB operon.

ClpX functions as either an independent chaperone or a component of the ClpXP protease, a conserved intracellular protease that acts as a global regulator in the bacterial cell by degrading regulatory proteins, stress response proteins and rate-limiting enzymes. Previously, we found that loss of clpX in Bacillus anthracis Sterne leads to increased susceptibility to antimicrobial agents that target the cell envelope. The aim of this study was to identify genes within the regulatory network of clpX that contribute to antimicrobial resistance.

Enhancing the fathead minnow fish embryo toxicity test: Optimizing embryo production and assessing the utility of additional test endpoints.

The fathead minnow fish embryo toxicity (FET) test has been identified as a potential alternative to toxicity test methods that utilize older fish. However, several challenges have been identified with the fathead minnow FET test, including: 1) difficulties in obtaining appropriately-staged embryos for FET test initiation, 2) a paucity of data comparing fathead minnow FET test performance to the fathead minnow larval growth and survival (LGS) test and 3) a lack of sublethal endpoints that could be used to estimate chronic toxicity and/or predict adverse effects. These challenges were addressed through three study objectives.

Development of [ Carbonyl-C]AZ13198083, a Novel Histamine Type-3 Receptor Radioligand with Favorable Kinetics.

The histamine subtype-3 receptor (HR) is implicated in a range of central nervous system disorders, and several radioligands have been developed for HR positron emission tomography imaging. However, a limitation of currently used PET radioligands for HR is the slow binding kinetics in high density brain regions. To address this, we herein report the development of three novel candidate HR radioligands, namely, [ carbonyl-C]AZ13153556 ([ carbonyl-C]4), [ carbonyl-C]AZD5213([ carbonyl-C]5), and [ carbonyl-C]AZ13198083 ([ carbonyl-C]6), and their subsequent preclinical evaluation in nonhuman primates (NHP).

Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain.

Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system is the muscarinic receptor antagonist N-[1-C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [C]PPB, we designed and synthesized four structurally related analogues of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (3.

Shining dead bone-cause for cautious interpretation of [F]NaF PET scans.

Background and purpose - [F]Fluoride ([F]NaF) PET scan is frequently used for estimation of bone healing rate and extent in cases of bone allografting and fracture healing. Some authors claim that [F]NaF uptake is a measure of osteoblastic activity, calcium metabolism, or bone turnover. Based on the known affinity of fluoride to hydroxyapatite, we challenged this view.

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.

Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases.

Discovery and Preclinical Validation of [(11)C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor.

Unlabelled: The histamine type 3 receptor (H3) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H3 receptor, 4-(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]-N-methyl-benzamide (5), and its comparison with one of the frontrunner radioligands for H3 imaging, namely, GSK189254 (1). Compounds 1 and 5 were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments.

Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing.

Introduction: The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for (11)C-labeling of AZD3241 was developed.

Vertical bone augmentation using recombinant bone morphogenetic protein, mineralized bone allograft, and titanium mesh: a retrospective cone beam computed tomography study.

Purpose: This retrospective study evaluated the use of a composite graft of recombinant human bone morphogenetic protein-2 (rhBMP-2) and particulate mineralized bone allograft protected by a titanium mesh for vertical bone augmentation.

Materials And Methods: A review of data on patients from four oral and maxillofacial surgery practices in the United States who required vertical augmentation prior to implant treatment was conducted. Vertical augmentation was accomplished with rhBMP-2 in an absorbable collagen sponge (ACS) carrier and particulate allograft.

Imaging agent of a TRPA1 inhibitor.

A method for the preparation of [3'-(3) H]-4-(2'-chloro-6'-hydroxyphenyl)-2-thioxo-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5(2H)-one (1), a TRPA1 inhibitor, was developed for the evaluation of imaging properties of a class of TRPA1 inhibitors. 1 was prepared via tritiation of a protected benzaldehyde followed by a tetrachlorosilane catalyzed multicomponent one-step fusion and was obtained at a specific activity of 0.9 TBq/mmol.

Biotransformation of two β-secretase inhibitors including ring opening and contraction of a pyrimidine ring.

Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of β-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings.

Effect of solvents on the time-dependent inhibition of CYP3A4 and the biotransformation of AZD3839 in human liver microsomes and hepatocytes.

Time-dependent inhibition (TDI) of the cytochrome P450 (P450) family of enzymes is usually studied in human liver microsomes (HLM) by investigating whether the inhibitory potency is increased with increased incubation times. The presented work was initiated after a discrepancy was observed for the TDI of an important P450 enzyme, CYP3A4, during early studies of the investigational drug compound AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate]; TDI was detected using a regulatory method but not with an early screening method. We show here that the different solvents present in the respective studies, dimethyl sulfoxide (DMSO, screening method) versus methanol or water (regulatory method), were responsible for the different TDI results.

Complications in oral and maxillofacial surgery: management of hemostasis and bleeding disorders in surgical procedures.

Oral and maxillofacial surgeons perform a wide variety of surgical procedures. One of the major complications of these various surgical techniques is uncontrolled bleeding. The best management of perioperative hemorrhage is prevention.

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [3H]-MNPA, [3H]-(+)-PHNO, and [3H]-raclopride.

Positron emission tomography (PET) antagonist ligands such as [(11)C]-raclopride are commonly used to study dopamine D2 receptor (D2) binding of antipsychotics. It has been suggested that agonist radioligands bind preferentially to the high-affinity state of D2 receptor and may provide a more relevant means of assessing D2 occupancy. The main objective of this study was to determine if D2 receptor occupancy (RO) could be differentiated with agonist and antagonist radioligands in vivo.

Hemostasis of oral surgery wounds with the HemCon Dental Dressing.

Purpose: This study evaluated the efficacy of the HemCon Dental Dressing (HDD; HemCon Medical Technologies, Inc, Beaverton, OR) hemostatic oral wound dressing derived from the US military HemCon Bandage combat wound dressing and whether early hemostasis affects postoperative care and surgical healing outcomes following oral surgical procedures.

Patients And Methods: All patients aged 18 to 90, except those allergic to seafood, who consented to participate were eligible for enrollment into this study regardless of other medical history findings. All patients were required to have 2 or more surgical sites so they would have internal surgical control sites.

CCN5 Expression in mammals. II. Adult rodent tissues.

CCN5 is a secreted heparin- and estrogen-regulated matricellular protein that inhibits vertebrate smooth muscle cell proliferation and motility. CCN5 is expressed throughout murine embryonic development in most organs and tissues. However, after embryonic development is complete, we hypothesized that CCN5 distribution would be largely restricted to small set of tissues, including smooth muscle cells of the arteries, uterus, airway, and digestive tract.

Extracellular transglutaminase 2 activates beta-catenin signaling in calcifying vascular smooth muscle cells.

Accumulation of transglutaminase 2 (TG2) is often associated with mineral deposits in vasculature. Here, we demonstrate that purified TG2 stimulated a 3-fold increase in matrix mineralization and up-regulation of osteoblastic markers in cultured primary vascular smooth muscle cells (VSMCs). Extracellular TG2 interacts with the low density lipoprotein related-protein 5 receptor and activates beta-catenin signaling in VSMCs.

Regulation of in vitro vascular calcification by BMP4, VEGF and Wnt3a.

Vascular calcification is a common clinical complication of cardiovascular disease, diabetes and end-stage renal failure, associated with significant morbidity and mortality. In this study we demonstrate that factors secreted by the hypertrophic chondrocytes induce matrix mineralization and osteoblastic transformation in cultured mouse vascular smooth muscle cells (VSMCs). In addition, these factors render VSMCs responsive to BMP4 and Wnt3a ligands.