Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation

Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in?vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in?vitro in comparison to controls. in?vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.     

Tomato bushy stunt virus (TBSV), a versatile platform for polyvalent display of antigenic epitopes and vaccine design

Viruses-like particles (VLPs) are frequently being used as platforms for polyvalent display of foreign epitopes of interest on their capsid surface to improve their presentation enhancing the antigenicity and host immune response. In the present study, we used the VLPs of Tomato bushy stunt virus (TBSV), an icosahedral plant virus, as a platform to display 180 copies of 16 amino acid epitopes of ricin toxin fused to the C-terminal end of a modified TBSV capsid protein (NΔ52). Expression of the chimeric recombinant protein in insect cells resulted in spontaneous assembly of VLPs displaying the ricin epitope. Cryo-electron microscopy and image reconstruction of the chimeric VLPs at 22 Å resolution revealed the locations and orientation of the ricin epitope exposed on the TBSV capsid surface. Furthermore, injection of chimeric VLPs into mice generated antisera that detected the native ricin toxin. The ease of fusing of short peptides of 15-20 residues and their ability to form two kinds (T = 1, T = 3) of bio-nanoparticles that result in the display of 60 or 180 copies of less constrained and highly exposed antigenic epitopes makes TBSV an attractive and versatile display platform for vaccine design.     

Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: A pilot study

ObjectiveThis study compared the efficacy and safety of oxcarbazepine and divalproex sodium in acute mania patients.Subjects and methodsIn this 12 week, randomized, double-blind pilot study, 60 patients diagnosed with acute mania (DSM-IV) and a baseline Young Mania Rating Scale (YMRS) score of 20 or more received flexibly dosed oxcarbazepine (1000–2400 mg/day) or divalproex (750–2000 mg/day). The mean decrease in the YMRS score from baseline was used as the main outcome measure of response to treatment. A priori protocol-defined threshold scores were ≤12 for remission and ≥15 for relapse. Number of patients showing adequate response and the time taken to achieve improvement was compared. Adverse events were systematically recorded throughout the study.ResultsOver 12 weeks, mean improvement in YMRS scores was comparable for both the groups including the mean total scores as well as percentage fall from baseline. There were no significant differences between treatments in the rates of symptomatic mania remission (90% in divalproex and 80% in oxcarbazepine group) and subsequent relapse. Median time taken to symptomatic remission was 56 days in divalproex group while it was 70 days in the oxcarbazepine group (p = 0.123). A significantly greater number of patients in divalproex group experienced one or more adverse drug events as compared to patients in the oxcarbazepine group (66.7% versus 30%, p < 0.01).ConclusionOxcarbazepine demonstrated comparable efficacy to divalproex sodium in the management of acute mania. Also the overall adverse event profile was found to be superior for oxcarbazepine.     

How to...mechanically erupt a palatal canine

Management of ectopic permanent maxillary canines represents one of the greatest challenges to orthodontists. This paper outlines a variety of techniques and mechanics which may facilitate expedient, predictable and safe eruption of palatal canines. While each method may be useful in isolation, the varying presentations of palatal canines ensure that the ability to apply an array of techniques is essential if successful outcomes are to be consistently achieved.     

Focal lesions in acute mild traumatic brain injury and neurocognitive outcome: CT versus 3T MRI

Abstract Mild traumatic brain injury (mTBI) is associated with long-term cognitive deficits. This study compared the detection rate of acute post-traumatic focal lesions on computed tomography (CT) and 3T (Tesla) magnetic resonance (MR) imaging with neurocognitive outcomes. Adults (n = 36; age range, 19-52 years) with a single episode of mTBI (Glasgow Coma Scale 13-15, as well as loss of consciousness and post-traumatic amnesia) were prospectively enrolled and had CT within 24 h of injury and 3T MR within 2 weeks of injury. The CT and MR scans were reviewed by two neuroradiologists who were blinded to clinical information. Twenty-eight of these mTBI subjects and 18 matched healthy volunteers also underwent serial neurocognitive testing. Of the 36 mTBI cases, intraparenchymal lesions were detected in 18 CT and 27 acute MR exams, consisting of hemorrhagic traumatic axonal injury (TAI) (eight CT, 17 MR), non-hemorrhagic TAI (zero CT, four MR), and cerebral contusions (13 CT, 21 MR). Mild TBI patients had significantly worse performance on working memory tasks than matched controls at the acute time point (<2 weeks), and at 1 month and at 1 year post-injury; yet there was no significant correlation of imaging findings with working memory impairment. In conclusion, 3T MR detected parenchymal lesions in 75% of this mTBI cohort with loss of consciousness and post-traumatic amnesia, a much higher rate than CT. However, the CT and 3T MR imaging findings did not account for cognitive impairment, suggesting that newer imaging techniques such as diffusion tensor imaging are needed to provide biomarkers for neurocognitive and functional outcome in mTBI.     

Implementation,reliability testing,and compliance monitoring of the Confusion Assessment Method for the Intensive Care Unit in trauma patients

OBJECTIVE: To implement delirium monitoring, test reliability, and monitor compliance of performing the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in trauma patients. DESIGN AND SETTING: Prospective, observational study in a level 1 trauma unit of a tertiary care, university-based medical center. PATIENTS: Acutely injured patients admitted to the trauma unit between 1 February 2006 and 16 April 2006. MEASUREMENTS AND RESULTS: Following web-based teaching modules and group in-services, bedside nurses evaluated patients daily for depth of sedation with the Richmond Agitation-Sedation Scale (RASS) and for the presence of delirium with the CAM-ICU. On randomly assigned days over a 10-week period, evaluations by nursing staff were followed by evaluations by an expert evaluator of the RASS and the CAM-ICU to assess compliance and reliability of the CAM-ICU in trauma patients. Following the audit period the nurses completed a postimplementation survey. The expert evaluator performed 1,011 random CAM-ICU assessments within 1[Symbol: see text]h of the bedside nurse's assessments. Nurses completed the CAM-ICU assessments in 84% of evaluations. Overall agreement (kappa) between nurses and expert evaluator was 0.77 (0.721-0.822; p[Symbol: see text]<[Symbol: see text]0.0001), in TBI patients 0.75 (0.667-0.829; p[Symbol: see text]<[Symbol: see text]0.0001) and in mechanically ventilated patients 0.62 (0.534-0.704; p[Symbol: see text]<[Symbol: see text]0.0001). The survey revealed that nurses were confident in performing the CAM-ICU, realized the importance of delirium, and were satisfied with the training that they received. It also acknowledged obstacles to implementation including nursing time and failure of physicians/surgeons to address treatment approaches for delirium. CONCLUSIONS: The CAM-ICU can be successfully implemented in a university-based trauma unit with high compliance and reliability. Quality improvement projects seeking to implement delirium monitoring would be wise to address potential pitfalls including time complaints and the negative impact of physician indifference regarding this form of organ dysfunction.     

Characterization of protein rheology and delivery forces for combination products

Characterization of a protein–device combination product over a wide range of operating parameters defined by end-user requirements is critical for developing a product presentation that is convenient for patient use. In addition to the device components, several product attributes, such as product rheology and product–container interactions, govern the functionality of a delivery system. This article presents results from a characterization study conducted for a high-concentration antibody product in a prefilled syringe. Analytical models are used to study the rheological behavior and to estimate delivery forces over a broad design space comprising temperature, concentration, and shear stress. Data suggest that high-viscosity products may exhibit significant shear thinning under the shear rates encountered under desired injection times.