Search

Chest X-rays play a significant role in diagnosing pneumonia due to the technology's cost-effectiveness and rapid development times. Detecting pneumonia in chest Xrays is a challenging process that relies heavily upon the availability of trained radiologists and high-quality imagery. Training qualified interpreters require significant resources, while medical imaging remains prone to a wide variety of deficiencies. Therefore, an automated system for pneumonia diagnosis consisting of three phases is proposed. An initial sorting phase consisting of a trained ResNet-18 convolutional neural network separates the dataset according to the interpretive quality of the images, creating a high and low-quality class. The unique image translation capabilities of the CycleGAN network are leveraged in the enhancement phase to translate low-quality images into improved versions. A final ResNet-18 network serves to classify pneumonia in the diagnosis phase. The enhancement system improved mixed quality diagnosis accuracy by 12.1% to 86.7%, with training sets composed of enhanced images achieving an accuracy 15.8% higher than their low-quality counterparts. The system's generalized method for image augmentation successfully mitigates the deficiencies of low-quality data, allowing for a higher accuracy diagnosis than otherwise possible.

The most common mutation in cystic fibrosis (CF) patients is deletion of F508 (ΔF508) in the first nucleotide binding domain (NBD1) of the CF transmembrane conductance regulator (CFTR). ΔF508 causes a decrease in the trafficking of CFTR to the cell surface and reduces the thermal stability of isolated NBD1; it is well established that both of these effects can be rescued by additional revertant mutations in NBD1. The current paradigm in CF small molecule drug discovery is that, like revertant mutations, a path may exist to ΔF508 CFTR correction through a small molecule chaperone binding to NBD1. We, therefore, set out to find small molecule binders of NBD1 and test whether it is possible to develop these molecules into potent binders that increase CFTR trafficking in CF-patient-derived human bronchial epithelial cells. Several fragments were identified that bind NBD1 at either the CFFT-001 site or the BIA site. However, repeated attempts to improve the affinity of these fragments resulted in only modest gains. Although these results cannot prove that there is no possibility of finding a high-affinity small molecule binder of NBD1, they are discouraging and lead us to hypothesize that the nature of these two binding sites, and isolated NBD1 itself, may not contain the features needed to build high-affinity interactions. Future work in this area may, therefore, require constructs including other domains of CFTR in addition to NBD1, if high-affinity small molecule binding is to be achieved.

Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Mutations associated with CF cause loss-of-function in CFTR leading to salt imbalance in epithelial tissues. Kalydeco (also called VX-770 or ivacaftor) was approved for CF treatment in 2012 but little is known regarding the compound’s interactions with CFTR including the site of binding or mechanisms of action. In this study we use hydrogen/deuterium exchange (HDX) coupled with mass spectrometry to assess the conformational dynamics of a thermostabilized form of CFTR in apo and ligand-bound states. We observe HDX protection at a known binding site for AMPPNP and significant protection for several regions of CFTR in the presence of Kalydeco. The ligand-induced changes of CFTR in the presence of Kalydeco suggest a potential binding site.

Extracellular vesicles (EVs) present an attractive delivery vehicle for therapeutic proteins. They intrinsically contain many proteins which can provide information to other cells. Advantages include reduced immune reactivity, especially if derived from the same host, stability in biologic fluids and ability to target uptake. Those from mesenchymal stem cells appear to be intrinsically therapeutic, while those from cancer cells promote tumor progression. Therapeutic proteins can be loaded into vesicles by overexpression in the donor cell, with oligomerization and membrane sequences increasing their loading. Examples of protein delivery for therapeutic benefit in pre-clinical models include delivery of: catalase for Parkinson’s disease to reduce oxidative stress and thus help neurons to survive; prodrug activating enzymes which can convert a prodrug which crosses the blood-brain barrier (BBB) into a toxic chemotherapeutic drug for schwannomas and gliomas; and the apoptosis-inducing enzyme, caspase-1 (ICE) under a Schwann cell specific promoter for schwannoma. This therapeutic delivery strategy is novel and being explored for a number of diseases.

Extracellular stimulation of the B cell receptor or mast cell FcεRI receptor activates a cascade of protein kinases, ultimately leading to antigenic or inflammation immune responses, respectively. Syk is a soluble kinase responsible for transmission of the receptor activation signal from the membrane to cytosolic targets. Control of Syk function is, therefore, critical to the human antigenic and inflammation immune response, and an inhibitor of Syk could provide therapy for autoimmune or inflammation diseases. We report here a novel allosteric Syk inhibitor, X1, that is noncompetitive against ATP (K(i) 4 ± 1 μM) and substrate peptide (K(i) 5 ± 1 μM), and competitive against activation of Syk by its upstream regulatory kinase LynB (K(i) 4 ± 1 μM). The inhibition mechanism was interrogated using a combination of structural, biophysical, and kinetic methods, which suggest the compound inhibits Syk by reinforcing the natural regulatory interactions between the SH2 and kinase domains. This novel mode of inhibition provides a new opportunity to improve the selectivity profile of Syk inhibitors for the development of safer drug candidates.

Essentials of clinical examination handbook / , Essentials of clinical examination handbook / , کتابخانه دیجیتال جندی شاپور اهواز

Although autogenous bone graft remains the gold standard graft material, it is associated with an unacceptably high incidence of morbidity. Furthermore, operative time, blood loss, and length of hospitalization are often increased. In order for a graft substitute to replicate the optimal bone healing properties of autogenous graft, 3 essential elements must be present: scaffolding for osteoconduction, growth factors for osteoinduction, and progenitor cells for osteogenesis. A composite graft that combines a synthetic scaffold with osteoprogenitor cells from bone marrow aspirate (BMA) may potentially deliver the advantages of autogenous bone grafts without the procurement morbidity. Sixty consecutive patients with cavitary bone defects were treated with a composite of b-tricalcium phosphate (beta-TCP), Vitoss (Orthovita, Malvern, Pennsylvania), and BMA. The cavitary defects were measured on orthogonal views by experienced musculoskeletal radiologists. Radiographically, resorption and trabeculation increased steadily with time. This differential was slightly more noticeable in large defects with a central trabeculation occurring in advance of the peripheral region. The majority of patients progressed to unrestricted activities by 6 weeks and had returned to their usual activities by 12 weeks. No significant difference in graft incorporation rate was noted based on age, size of defect, or use of adjuvant local treatment. The use of a composite graft (ultraporous beta-TCP+BMA) in the treatment of cavitary lesions appears to be safe and effective.