What Has Dual Energy CT Taught Us About Gout?

PURPOSE OF THE REVIEW: Dual energy computed tomography (DECT) scan has emerged as a useful diagnostic tool in the diagnosis of gout over recent years. Here, we review the role of DECT in the context of typical and atypical gout, including its role in identifying extra-articular monosodium urate (MSU) deposition. RECENT FINDINGS: DECT has been found to be more accurate than ultrasound in detecting extra-articular MSU deposition in soft tissue. It has the ability to identify axial MSU deposition in gout patients with non-specific back pain. For individuals with no other clear etiology, this potentially implicates MSU as the cause of the pain. DECT also has the ability to detect vascular MSU deposition. This correlates with high coronary calcium scores and elevated Framingham cardiovascular risk. DECT continues to aid our understanding of articular and extra-articular MSU deposition, including the role of vascular MSU deposition on cardiovascular health. Not only does it allow quantification of urate burden but it can also potentially avoid invasive diagnostic procedures. The limitations and advantages of DECT are further explored in this article.

Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation.

OBJECTIVE: von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically different from the endothelial cell-derived VWF (EC-VWF). However, little is known about relative contribution of different pools of VWF in stroke. APPROACH AND RESULTS: Using bone marrow transplantation, we generated chimeric Plt-VWF mice, Plt-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13(-/-)), and EC-VWF mice to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size and postischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, interleukin-1ß, and tumor necrosis factor-α levels) within lesions were comparable between EC-VWF and wild-type mice. Infarct size and postischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13(-/-) mice, but decreased compared with EC-VWF and wild-type mice (P<0.05) and increased compared with Vwf(-/-) mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between wild-type and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13(-/-) mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13(-/-) mice compared with Vwf(-/-) mice (P<0.05), but decreased compared with wild-type or EC-VWF mice. CONCLUSIONS: Plt-VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and postischemic thrombo-inflammation after stroke. EC-VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting postischemic thrombo-inflammation.

A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture.

BACKGROUND: Dengue has emerged as the most significant of arboviral diseases in the 21st century. It is endemic to >100 tropical and sub-tropical countries around the world placing an estimated 3.6 billion people at risk. It is caused by four genetically similar but antigenically distinct, serotypes of dengue viruses. There is neither a vaccine to prevent nor a drug to treat dengue infections, at the present time. The major objective of this work was to explore the possibility of identifying a small molecule inhibitor of the dengue virus protease and assessing its ability to suppress viral replication in cultured cells. METHODS: We cloned, expressed and purified recombinant dengue virus type 2 protease. Using an optimized and validated fluorogenic peptide substrate cleavage assay to monitor the activity of this cloned dengue protease we randomly screened ~1000 small molecules from an 'in-house' library to identify potential dengue protease inhibitors. RESULTS: A benzimidazole derivative, named MB21, was found to be the most potent in inhibiting the cloned protease (IC50 = 5.95 µM). In silico docking analysis indicated that MB21 binds to the protease in the vicinity of the active site. Analysis of kinetic parameters of the enzyme reaction suggested that MB21 presumably functions as a mixed type inhibitor. Significantly, this molecule identified as an inhibitor of dengue type 2 protease was also effective in inhibiting each one of the four serotypes of dengue viruses in infected cells in culture, based on analysis of viral antigen synthesis and infectious virus production. Interestingly, MB21 did not manifest any discernible cytotoxicity. CONCLUSIONS: This work strengthens the notion that a single drug molecule can be effective against all four dengue virus serotypes. The molecule MB21 could be a potential candidate for 'hit-to-lead' optimization, and may pave the way towards developing a pan-dengue virus antiviral drug.

Effects of unilateral robotic limb loading on gait characteristics in subjects with chronic stroke.

BACKGROUND: Hemiparesis after stroke often leads to impaired ankle motor control that impacts gait function. In recent studies, robotic devices have been developed to address this impairment. While capable of imparting forces to assist during training and gait, these devices add mass to the paretic leg which might encumber patients' gait pattern. The purpose of this study was to assess the effects of the added mass of one of these robots, the MIT's Anklebot, while unpowered, on gait of chronic stroke survivors during overground and treadmill walking. METHODS: Nine chronic stroke survivors walked overground and on a treadmill with and without the anklebot mounted on the paretic leg. Gait parameters, interlimb symmetry, and joint kinematics were collected for the four conditions. Repeated-measures analysis of variance (ANOVA) tests were conducted to examine for possible differences across four conditions for the paretic and nonparetic leg. RESULTS: The added inertia and friction of the unpowered anklebot had no statistically significant effect on spatio-temporal parameters of gait, including paretic and nonparetic step time and stance percentage, in both overground and treadmill conditions. Noteworthy, interlimb symmetry as characterized by relative stance duration was greater on the treadmill than overground regardless of loading conditions. The presence of the unpowered robot loading reduced the nonparetic knee peak flexion on the treadmill and paretic peak dorsiflexion overground (p < 0.05). CONCLUSIONS: Our results suggest that for these subjects the added inertia and friction of this backdriveable robot did not significantly alter their gait pattern.

Use of FDA-Approved Medications: Biologics for Psoriatic Arthritis in Patients at an Urban Outpatient Rheumatology Clinic.

OBJECTIVE: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis that manifests as peripheral arthritis, dactylitis, enthesitis, and spondylitis. Biologics, particularly tumor necrosis factor inhibitors (TNFis) and some interleukin 17 (IL-17) and interleukin 23 (IL-23) inhibitors, are the only US Food and Drug Administration (FDA)-approved treatments shown to limit joint damage in clinical trials for PsA. Conventional synthetic disease-modifying antirheumatic drugs have also been adapted to PsA treatment. Current 2018 American College of Rheumatology (ACR) guidelines regard TNFis as first-line therapy in treatment-naïve patients. The aim of this project is to review the prescribing practices for patients with PsA at an urban rheumatology office, with a focus on biologic prescribing. METHODS: A retrospective chart review was performed to search for patients seen from June 1, 2017, to June 1, 2018, using International Classification of Diseases, 10th Revision codes for PsA. A log of prescribing practices listed the use of biologics versus oral small molecules (OSMs) (methotrexate, sulfasalazine, leflunomide, and apremilast) across different ages, sex, and disease severity. RESULTS: This study included a total of 97 patients (40 women and 57 men), and 66% were on biologics (60% of women and 70% of men). There was no sex bias in biologic prescribing (P = 0.59). Use of biologics was highest in the 38 to 57 years age group and lowest in the 78 to 97 years age group, although, statistically, there was no age bias in biologic prescribing (P = 0.22). Biologics provided superior disease control (84.37%) compared with nonbiologics (66.6%) (P = 0.0016). OSMs provided slightly better control (69.5%) over apremilast monotherapy (61.5%) (P = 0.016). CONCLUSION: There is no age or sex bias in prescribing practices for PsA. In accordance with the ACR, patients with controlled symptoms on OSMs are being appropriately maintained. Although apremilast is allocated as an add-on therapy, 13.4% of patients were on apremilast monotherapy. This quality improvement project reveals that in most instances, biologics are being appropriately initiated as the primary mode of therapy for patients with PsA at our outpatient practice; however, treatment modifications can be made regarding patients who are managed with apremilast alone.

Evaluation of a pan-serotype point-of-care rapid diagnostic assay for accurate detection of acute dengue infection.

The catastrophic rise in dengue infections in India and globally has created a need for an accurate, validated low-cost rapid diagnostic test (RDT) for dengue. We prospectively evaluated the diagnostic performance of NS1/IgM RDT (dengue day 1) using 211 samples from a pediatric dengue cohort representing all 4 serotypes in southern India. The dengue-positive panel consisted of 179 dengue real-time polymerase chain reaction (RT-PCR) positive samples from symptomatic children. The dengue-negative panel consisted of 32 samples from dengue-negative febrile children and asymptomatic individuals that were negative for dengue RT-PCR/NS1 enzyme-linked immunosorbent assay/IgM/IgG. NS1/IgM RDT sensitivity was 89.4% and specificity was 93.8%. The NS1/IgM RDT showed high sensitivity throughout the acute phase of illness, in primary and secondary infections, in different severity groups, and detected all 4 dengue serotypes, including coinfections. This NS1/IgM RDT is a useful point-of-care assay for rapid and reliable diagnosis of acute dengue and an excellent surveillance tool in our battle against dengue.

Dengue Fever: Causes, Complications, and Vaccine Strategies.

Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals.