Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap.

We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ketone using a combination of electronic and steric effects.

Direct-to-Consumer Testing 2.0: Emerging Models of Direct-to-Consumer Genetic Testing.

Direct-to-consumer (DTC) genetic testing emerged in the early 2000s as a means of allowing consumers to access information on their genetics without the involvement of a physician. Although early models of DTC were popular with consumers, they were controversial in medical and regulatory circles. In this article, we trace the history of DTC genetic testing, discuss its regulatory implications, and describe the emergence of a new hybrid model we call DTC 2.0.

Vascular lesions of the skull base: endovascular prospective for the otolaryngologist.

With continual advances being made in endovascular equipment and techniques, the role that these image-guided, minimally invasive therapies play in the multidisciplinary management of vascular lesions of the skull base will probably continue to expand. The introduction of emerging technologies, including the development and implementation of implantable bioactive devices such as drug-eluting stents, bioactive embolic coils, and bioactive particulate embolic materials, will provide an increasing array of options for these patients. This article has reviewed the basic concepts of embolization and revascularization for vascular lesions of the skull base encountered by the practicing otolaryngologist. These concepts can provide a framework for collaboration between the otolaryngologist and neuroendovascular operator in a cooperative approach to these patients. The importance of detailed knowledge of the vascular anatomy of the skull base when dealing with these lesions, the concept of dangerous anastomoses, several clinically useful classification schemes for these lesions, and basic endovascular techniques of embolization and revascularization have been highlighted.

Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A(2) based on a 1,3-disubstituted propan-2-one skeleton.

Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).

Delayed thromboembolic events 9 weeks after endovascular treatment of an anterior communicating artery aneurysm: case report.

We present a case of delayed thromboembolic events that occurred 9 weeks after endovascular treatment of an anterior communicating artery aneurysm with GDC.

Dual modality drainage for symptomatic walled-off pancreatic necrosis reduces length of hospitalization, radiological procedures, and number of endoscopies compared to standard percutaneous drainage.

BACKGROUND: Symptomatic walled-off pancreatic necrosis (WOPN) treated with dual modality endoscopic and percutaneous drainage (DMD) has been shown to decrease length of hospitalization (LOH) and use of radiological resources in comparison to standard percutaneous drainage (SPD). AIM: The aim of this study is to demonstrate that as the cohort of DMD and SPD patients expand, the original conclusions are durable. METHODS: The database of patients receiving treatment for WOPN between January 2006 and April 2011 was analyzed retrospectively. PATIENTS: One hundred two patients with symptomatic WOPN who had no previous drainage procedures were evaluated: 49 with DMD and 46 with SPD; 7 were excluded due to a salvage procedure. RESULTS: Patient characteristics including age, sex, etiology of pancreatitis, and severity of disease based on computed tomographic severity index were indistinguishable between the two cohorts. The DMD cohort had shorter LOH, time until removal of percutaneous drains, fewer CT scans, drain studies, and endoscopic retrograde cholangiopancreatography (ERCPs; p < 0.05 for all). There were 12 identifiable complications during DMD, which were successfully treated without the need for surgery. The 30-day mortality in DMD was 4% (one multi-system organ failure and one out of the hospital with congestive heart failure). Three patients receiving SPD had surgery, and three (7%) died in the hospital. CONCLUSION: DMD for symptomatic WOPN reduces LOH, radiological procedures, and number of ERCPs compared to SPD.

Percutaneous embolization of the pancreatic duct with cyanoacrylate tissue adhesive in disconnected duct syndrome.

Traditionally, patients with chronic end-pancreatic fistulas caused by pancreatic necrosis have been treated with long-term percutaneous catheter drainage and/or surgical procedures such as resection or open drainage. With surgical treatment, the endocrine and exocrine functions of the removed pancreatic segment are sacrificed. Surgery in this patient population presents additional risks because of the inflammatory changes of pancreatitis and associated venous thromboses. The authors devised a method of percutaneous embolization of the pancreatic duct in a patient with catheter-dependent pancreatic fistula who wished to avoid surgery. The procedure was performed under fluoroscopic guidance with use of a microcatheter and wire system to access the duct, which was embolized with opacified n-butyl cyanoacrylate tissue adhesive. After 1 year of surveillance, the patient remains symptom-free. There has been no need for replacement of the drainage catheter and no further intervention has been performed.

Synthesis and evaluation of substrate-mimicking cytosolic phospholipase A2 inhibitors--reducing the lipophilicity of the arachidonyl chain isostere.

The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has been reduced by the modification of a decyloxyphenyl chain designed to mimic the arachidonyl group of the natural substrate. These changes have resulted in an improvement in the whole cell potency of the inhibitors.