Anti-microbial screening of some sulphonanilide complexes with Tm(III) ion against gram positive cocci & gram negative bacilli

A series of different sulphonanilide complexes with Tm(III) metal ion were prepared and the systems have been screened for anti-microbial activities by Bauer-Kirby discdiffusion technique against bacterial species such as Staphylococcus aureus, Pseudomonas aeruginosa and E.Coli (gram positive and gram negative) and were found to have moderate to significant activity against bacterialspecies

Structural Modeling of a Novel CAPN5 Mutation that Causes Uveitis and Neovascular Retinal Detachment

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants

A cost-utility analysis of mesh prophylaxis in the prevention of incisional hernias following stoma closure surgery

Background: Stoma closure is a widely performed surgical procedure, with 6295 undertaken in England in 2018 alone. This procedure is associated with significant complications; incisional hernias are the most severe, occurring in 30% of patients. Complications place considerable financial burden on the NHS; hernia costs are estimated at GBP 114 million annually. As recent evidence (ROCSS, 2020) found that prophylactic meshes significantly reduce rates of incisional hernias following stoma closure surgery, an evaluation of this intervention vs. standard procedure is essential. Methods: A cost-utility analysis (CUA) was conducted using data from the ROCSS prospective multi-centre trial, which followed 790 patients, randomly assigned to mesh closure (n = 394) and standard closure (n = 396). Quality of life was assessed using mean EQ-5D-3L scores from the trial, and costs in GBP using UK-based sources over a 2-year time horizon. Results: The CUA yielded an incremental cost-effectiveness ratio (ICER) of GBP 128,356.25 per QALY. Additionally, three univariate sensitivity analyses were performed to test the robustness of the model. Conclusion: The results demonstrate an increased benefit with mesh prophylaxis, but at an increased cost. Although the intervention is cost-ineffective and greater than the ICER threshold of GBP 30,000/QALY (NICE), further investigation into mesh prophylaxis for at risk population groups is needed

Study investigating the role of skeletal muscle mass estimation in metastatic spinal cord compression

Background Age-related loss of functional muscle mass is associated with reduced functional ability and life expectancy. In disseminated cancer, age-related muscle loss may be exacerbated by cachexia and poor nutritional intake, increasing functional decline, morbidity and accelerate death. Patients with spinal metastases frequently present for decompressive surgery with decision to operate based upon functional assessment. A subjective assessment of physical performance has, however, been shown to be a poor indicator of life expectancy in these patients. We aimed to develop an objective measure based upon lean muscle mass to aid decision making, in these individuals, by investigating the association between muscle mass and 1-year survival. Methods Muscle mass was calculated as total psoas area (TPA)/ vertebral body area (VBA), by two independent blinded doctors from CT images, acquired within 7 days of spinal metastases surgery, at the mid L3 vertebral level. Outcome at 1 year following surgery was recorded from a prospectively updated metastatic spinal cord compression database. Results 86 patients were followed for 1 year, with an overall mortality of 39.5 %. Mortality rates at 1 year were significantly high among patients in the lowest quartile of muscle mass, compared with those in the highest quartile (57.1 vs 23.8 %, p = 0.02). Conclusion Death within 1 year in individuals with spinal metastases is related to lean muscle mass at presentation. Assessment of lean muscle mass may inform decision to operate in patients with spinal metastases

The Multifunctional Host Defense Peptide SPLUNC1 Is Critical for Homeostasis of the Mammalian Upper Airway

Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear

Functional Characterization of Circulating Tumor Cells with a Prostate-Cancer-Specific Microfluidic Device

Cancer metastasis accounts for the majority of cancer-related deaths owing to poor response to anticancer therapies. Molecular understanding of metastasis-associated drug resistance remains elusive due to the scarcity of available tumor tissue. Isolation of circulating tumor cells (CTCs) from the peripheral blood of patients has emerged as a valid alternative source of tumor tissue that can be subjected to molecular characterization. However, issues with low purity and sensitivity have impeded adoption to clinical practice. Here we report a novel method to capture and molecularly characterize CTCs isolated from castrate-resistant prostate cancer patients (CRPC) receiving taxane chemotherapy. We have developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that combines an anti-prostate specific membrane antigen (PSMA) antibody with a 3D geometry that captures CTCs while minimizing nonspecific leukocyte adhesion. Enumeration of GEDI-captured CTCs (defined as intact, nucleated PSMA+/CD45− cells) revealed a median of 54 cells per ml identified in CRPC patients versus 3 in healthy donors. Direct comparison with the commercially available CellSearch® revealed a 2–400 fold higher sensitivity achieved with the GEDI device. Confocal microscopy of patient-derived GEDI-captured CTCs identified the TMPRSS2:ERG fusion protein, while sequencing identified specific androgen receptor point mutation (T868A) in blood samples spiked with only 50 PC C4-2 cells. On-chip treatment of patient-derived CTCs with docetaxel and paclitaxel allowed monitoring of drug-target engagement by means of microtubule bundling. CTCs isolated from docetaxel-resistant CRPC patients did not show any evidence of drug activity. These measurements constitute the first functional assays of drug-target engagement in living circulating tumor cells and therefore have the potential to enable longitudinal monitoring of target response and inform the development of new anticancer agents

An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection

The airway epithelium secretes proteins that function in innate defense against infection. BPI fold-containing family member A1 (BPIFA1) is secreted into airways and has a protective role during bacterial infections, but it is not known whether it also has an antiviral role. To determine a role in host defense against influenza A virus (IAV) infection and to find the underlying defense mechanism we developed transgenic mouse models that are deficient in BPIFA1 and used these, in combination with in vitro 3D mouse tracheal epithelial cell (mTEC) cultures, to investigate its antiviral properties. We show that BPIFA1 has a significant role in mucosal defense against IAV infection. BPIFA1 secretion was highly modulated after IAV infection. Mice deficient in BPIFA1 lost more weight after infection, supported a higher viral load and virus reached the peripheral lung earlier, indicative of a defect in the control of infection. Further analysis using mTEC cultures showed that BPIFA1-deficient cells bound more virus particles, displayed increased nuclear import of IAV ribonucleoprotein complexes and supported higher levels of viral replication. Our results identify a critical role for BPIFA1 in the initial phase of infection by inhibiting the binding and entry of IAV into airway epithelial cells