Atypical Presentation of Ankylosing Spondylitis

Radiographic axial spondyloarthritis axSpA ) or typical ankylosing spondyloarthritis (AS) is a classification of axial spondyloarthritis with the classic radiographic features of sacroiliitis. Axial spondyloarthritis is a disabling spondyloarthropathy of the spine that presents with chronic back pain usually before the age of 45. It may be associated with extraspinal features including dactylitis , synovitis, and enthesitis in addition to other nonarticular signs. Chronic back pain is one of the most common presenting symptoms for AS , but frequently there is a 5-7 year delay between the onset of symptoms and diagnosis of the disease . A standard AP plain radiograph demonstrating changes to the sacroiliac joint including erosions, ankylosis or sclerosis along with the patient’s complaints of chronic back pain are strong indicators for AS. We present a case of an atypical presentation of AS in a patient with recently diagnosed asthma and no other past medical history who had a 40 pound rapid (4 month) weight loss and polyarticular joint pain. Our case is unusual due to the short time course between presenting symptoms and time to diagnosis

Characterization and assembly of the Pseudomonas aeruginosa aspartate transcarbamoylase-pseudo dihydroorotase complex

Pseudomonas aeruginosa is a virulent pathogen that has become more threatening with the emergence of multidrug resistance. The aspartate transcarbamoylase (ATCase) of this organism is a dodecamer comprised of six 37 kDa catalytic chains and six 45 kDa chains homologous to dihydroorotase (pDHO). The pDHO chain is inactive but is necessary for ATCase activity. A stoichiometric mixture of the subunits associates into a dodecamer with full ATCase activity. Unlike other known ATCases, the P. aeruginosa catalytic chain does not spontaneously assemble into a trimer. Chemical-crosslinking and size-exclusion chro- matography showed that P. aeruginosa ATCase is monomeric which accounts for its lack of catalytic activity since the active site is a composite comprised of residues from adjacent monomers in the trimer. Circular dichroism spectroscopy indicated that the ATCase chain adopts a structure that contains secondary structure elements although neither the ATCase nor the pDHO subunits are very stable as determined by a thermal shift assay. Formation of the complex increases the melting temperature by about 30 ̊C. The ATCase is strongly inhibited by all nucleotide di- and triphosphates and exhibits extreme cooperativity. Previous studies suggested that the regulatory site is located in an 11-residue extension of the amino end of the catalytic chain. However, deletion of the extensions did not affect catalytic activity, nucleotide inhibition or the assembly of the dodecamer. Nucleotides destabilized the dode- camer which probably accounts for the inhibition and apparent cooperativity of the substrate saturation curves. Contrary to previous interpretations, these results suggest that P. aerugi- nosa ATCase is not allosterically regulated by nucleotides

Efficacy and safety of ascending dosages of albendazole against Trichuris trichiura in preschool-aged children, school-aged children and adults: a multi-cohort randomized controlled trial

The efficacy of the widely used albendazole against the soil-transmitted helminth; Trichuris trichiura; is limited; yet optimal doses, which may provide increased efficacy, have not been thoroughly investigated to date.; A randomized-controlled trial was conducted in Côte d'Ivoire with preschool-aged children (PSAC), school-aged children (SAC), and adults infected with; T. trichiura; . Participants were randomly assigned (1:1:1:1) using computer-generated randomization. PSAC were randomized to 200 mg, 400 mg, 600 mg of albendazole or placebo. SAC and adults were randomized to 400 mg, 600 mg, 800 mg of albendazole or placebo. The primary outcome was cure rates (CRs) against trichuriasis. Secondary outcomes were; T. trichiura; egg reduction rates (ERRs), safety, CRs and ERRs against other soil-transmitted helminths. Outcome assessors and the trial statistician were blinded. Trial registration at ClinicalTrial.gov: NCT03527745.; 111 PSAC, 180 SAC, and 42 adults were randomized and 86, 172, and 35 provided follow-up stool samples, respectively. The highest observed CR among PSAC was 27·8% (95% CI: 9·7%-53·5%) in the 600 mg albendazole treatment arm. The most efficacious arm for SAC was 600 mg of albendazole showing a CR of 25·6% (95% CI: 13·5%-41·2%), and for adults it was 400 mg of albendazole with a CR of 55·6% (95% CI: 21·2%-86·3%). CRs and ERRs did not differ significantly among treatment arms and flat dose-responses were observed. 17·9% and 0·4% of participants reported any adverse event at 3 and 24 h follow-up, respectively.; Albendazole shows low efficacy against; T. trichiura; in all populations and doses studied, though findings for PSAC and adults should be carefully interpreted as recruitment targets were not met. New drugs, treatment regimens, and combinations are needed in the management of; T. trichiura; infections.; Bill and Melinda Gates Foundation

Orthopaedic aspect of anatomy and radiology of proximal femur

Femoral pathology is common in relation to the orthopedic. There is complex anatomy of the proximal femur and hip joint. So, its knowledge regarding anatomy and radiological correlation is necessary to the well-known fact for the orthopedics for the routine day to day practice. This review article briefly illustrates important anatomical and radiological aspect of the proximal femur

Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity

N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development