Rationally Designed Macrocyclic Peptides as Synergistic Agonists of LPS-Induced Inflammatory Response.

Toll-like receptor 4 (TLR4) plays an important role in the regulation of the innate and adaptive immune response. Both agonists and antagonists of TLR4 are of considerable interest as drug leads for various disease indications. We herein report the rational design of two myeloid differentiation factor 2 (MD2)-derived macrocyclic peptides as TLR4 modulators, using the software.

Accuracy and early outcomes in medial unicompartmental knee arthroplasty performed using patient specific instrumentation.

Unicompartmental knee arthroplasty (UKA) is a technically demanding procedure and poor implant positioning has been identified as a factor in early failure. The aim of this study was to evaluate the accuracy and clinical outcomes of the patient specific instrumentation implementation technique with a fixed bearing UKA. We carried out a prospective study of 41 patients (44 procedures) between December 2011 and April 2013.

Leukemia presenting as serous retinal detachment.

Background: To describe a patient who presented with bilateral serous retinal detachments without the other retinal vascular or ocular inflammatory signs, and who was ultimately diagnosed with acute leukemia.

Methods: Case report and review of the literature.

Results: This patient presented with isolated bilateral serous retinal detachments as the initial manifestation of hematologic malignancy.

Covalent docking of large libraries for the discovery of chemical probes.

Chemical probes that form a covalent bond with a protein target often show enhanced selectivity, potency and utility for biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Here we describe a general method (DOCKovalent) for screening large virtual libraries of electrophilic small molecules.

Signalling dynamics in the spindle checkpoint response.

The spindle checkpoint ensures proper chromosome segregation during cell division. Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation. New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin.

Effect of topical aqueous suppression on intraocular gas duration after pure perfluoropropane injection in nonvitrectomized eyes with retinal detachment.

Purpose: To determine whether topical aqueous suppressants affect the duration of pure expansile intraocular gas in nonvitrectomized eyes.

Methods: A prospective randomized controlled trial was performed on nonvitrectomized patients undergoing retinal detachment repair with scleral buckle or pneumatic retinopexy using 0.3 mL of 100% perfluoropropane (C3F8) gas tamponade.

Pars plana vitrectomy and scleral buckle versus pars plana vitrectomy alone for patients with rhegmatogenous retinal detachment at high risk for proliferative vitreoretinopathy.

Purpose: To compare using pars plana vitrectomy (PPV) combined with a scleral buckle versus primary vitrectomy alone in patients with rhegmatogenous retinal detachment at high risk for postoperative proliferative vitreoretinopathy (PVR).

Methods: Six hundred and seventy-eight patients were identified from billing data as having rhegmatogenous retinal detachment between April 1, 2010 and August 1, 2012. Patients were considered at high risk for PVR if they presented with retinal detachment in 2 or more quadrants, retinal tears >1 clock hour, preoperative PVR, or vitreous hemorrhage.

Prediction of substrates for glutathione transferases by covalent docking.

Enzymes in the glutathione transferase (GST) superfamily catalyze the conjugation of glutathione (GSH) to electrophilic substrates. As a consequence they are involved in a number of key biological processes, including protection of cells against chemical damage, steroid and prostaglandin biosynthesis, tyrosine catabolism, and cell apoptosis. Although virtual screening has been used widely to discover substrates by docking potential noncovalent ligands into active site clefts of enzymes, docking has been rarely constrained by a covalent bond between the enzyme and ligand.

Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint.

The spindle checkpoint is a conserved signaling pathway that ensures genomic integrity by preventing cell division when chromosomes are not correctly attached to the spindle. Checkpoint activation depends on the hierarchical recruitment of checkpoint proteins to generate a catalytic platform at the kinetochore. Although Mad1 kinetochore localization is the key regulatory downstream event in this cascade, its receptor and mechanism of recruitment have not been conclusively identified.

The role of vascular endothelial growth factor and vascular stability in diseases of the ear.

Objectives/hypothesis: Vascular endothelial growth factor (VEGF) is a critical mediator of vascular permeability and angiogenesis and likely plays an important role in cochlear function and hearing. This review highlights the role of VEGF in hearing loss associated with vestibular schwannomas, otitis media with effusion, and sensorineural hearing loss.

Study Design: PubMed literature review.

Druggable protein-protein interactions--from hot spots to hot segments.

Protein-Protein Interactions (PPIs) mediate numerous biological functions. As such, the inhibition of specific PPIs has tremendous therapeutic value. The notion that these interactions are 'undruggable' has petered out with the emergence of more and more successful examples of PPI inhibitors, expanding considerably the scope of potential drug targets.

Peptide docking and structure-based characterization of peptide binding: from knowledge to know-how.

Peptide-mediated interactions are gaining increased attention due to their predominant roles in the many regulatory processes that involve dynamic interactions between proteins. The structures of such interactions provide an excellent starting point for their characterization and manipulation, and can provide leads for targeted inhibitor design. The relatively few experimentally determined structures of peptide-protein complexes can be complemented with an outburst of modeling approaches that have been introduced in recent years, with increasing accuracy and applicability to ever more systems.

Drug-induced uveitis.

Purpose Of Review: Although more than 50% of all uveitis cases have no identifiable cause, certain medications can cause ocular inflammation and are often overlooked. Drug-induced ocular inflammation has increased in frequency with the advent of new bisphosphonates, antitumor necrosis factor biologic agents, and intravitreal triamcinolone and antivascular endothelial growth factor medications. Identification of these inciting drugs will simplify work-up and management of patients with uveitis and improve visual outcomes.

Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.

Objectives: There have been concerns that performing carotid endarterectomy (CEA) in the hyperacute period after onset of a transient ischaemic attack (TIA) or stroke may be associated with a significant increase in the procedural risk that could offset any long-term benefit to the patient. The aim of this audit was to determine the 30-day risk of stroke/death after CEA in symptomatic patients, stratified for delay from the most recent neurological event, mode of presentation, and age.

Methods: Retrospective audit in 475 recently symptomatic patients between October 1, 2008, and April 24, 2013.

Role of secondary intention healing.

Secondary intention wound healing is a simple, yet powerful tool in facial reconstruction. Considered as the most elementary form of wound reconstruction, it is often unused because of concern about the predictability of the result and the desire for immediate reconstruction. Secondary intention wound healing can successfully be used for reconstruction of defects for patients who may not be candidates for involved surgical procedures and should be considered an ideal form of reconstruction for certain defects.

Closing the loop: a 21-year audit of strategies for preventing stroke and death following carotid endarterectomy.

The objective of this review was to identify causes of stroke/death after carotid endarterectomy (CEA) and to develop transferable strategies for preventing stroke/death after CEA, via an overview of a 21-year series of themed research and audit projects. Three preventive strategies were identified: (i) intra-operative transcranial Doppler (TCD) ultrasound and completion angioscopy which virtually abolished intra-operative stroke, primarily through the removal of residual luminal thrombus prior to restoration of flow; (ii) dual antiplatelet therapy with a single 75-mg dose of clopidogrel the night before surgery in addition to regular 75 mg aspirin which virtually abolished post-operative thromboembolic stroke and may also have contributed towards a decline in stroke/death following major cardiac events; and (iii) the provision of written guidance for managing post-CEA hypertension which was associated with virtual abolition of intracranial haemorrhage and stroke as a result of hyperperfusion syndrome. The pathophysiology of peri-operative stroke is multifactorial and no single monitoring or therapeutic strategy will reduce its prevalence.

Midterm Outcomes and Predictors of Clinical Success With the KineSpring Knee Implant System.

The purpose of this study was to (1) evaluate joint pain and function in knee osteoarthritis (OA) patients treated with a joint-sparing, extracapsular implant and (2) identify patient characteristics that influenced clinical outcomes. This study included 99 patients with symptomatic medial knee OA refractory to conservative care who were treated with the KineSpring Knee Implant System and followed for a mean of 17 months (range, 1.5 to 48 months).

Tympanoplasty with intact canal wall mastoidectomy for cholesteatoma: long-term hearing outcomes.

Objectives/hypothesis: To review long-term hearing results after intact canal wall mastoidectomy with tympanoplasty for treatment of cholesteatoma and to identify factors associated with improved hearing outcomes.

Study Design: A retrospective analysis of all cases of cholesteatoma treated with intact canal wall mastoidectomy at a single institution by the senior author over a period of 9 years, for which at least 2 years of follow-up data exist.

Methods: Patient and disease information was collected retrospectively and analyzed.

An accurate binding interaction model in de novo computational protein design of interactions: if you build it, they will bind.

Computational protein design efforts aim to create novel proteins and functions in an automated manner and, in the process, these efforts shed light on the factors shaping natural proteins. The focus of these efforts has progressed from the interior of proteins to their surface and the design of functions, such as binding or catalysis. Here we examine progress in the development of robust methods for the computational design of non-natural interactions between proteins and molecular targets such as other proteins or small molecules.

Drug-induced uveitis.

A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates.

Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability.

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response.

Relacin, a novel antibacterial agent targeting the Stringent Response.

Finding bacterial cellular targets for developing novel antibiotics has become a major challenge in fighting resistant pathogenic bacteria. We present a novel compound, Relacin, designed to inhibit (p)ppGpp production by the ubiquitous bacterial enzyme RelA that triggers the Stringent Response. Relacin inhibits RelA in vitro and reduces (p)ppGpp production in vivo.

In silico and in vitro elucidation of BH3 binding specificity toward Bcl-2.

Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide-receptor complexes.