Distinct Modulation of Wild-Type and Selective Gene Mutated Vitamin D Receptor by Essential Polyunsaturated Fatty Acids.

Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor's (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence reports that selective long chain polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We, therefore, hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective of the deficiency of vitamin-D. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.

Possible role of rivoglitazone thiazolidine class of drug as dual-target therapeutic agent for bacterial infections: An in silico study.

Infections due to resistant bacteria are the life-threatening and leading cause of mortality worldwide. The current therapy for bacterial infections includes treatment with various drugs and antibiotics. The misuse and over usage of these antibiotics leads to bacterial resistance. There are several mechanisms by which bacteria exhibit resistance to some antibiotics. These include drug inactivation or modification, elimination of antibiotics through efflux pumps, drug target alteration, and modification of metabolic pathway. However, it is difficult to treat infections caused by resistant bacteria by conventional existing therapy. In the present study binding affinities of some glitazones against ParE and MurE bacterial enzymes are investigated by in silico methods. As evident by extra-precision docking and binding free energy calculation (MM-GBSA) results, rivoglitazone exhibited higher binding affinity against both ParE and MurE enzymes compared to all other selected compounds. Further molecular dynamic (MD) simulations were performed to validate the stability of rivoglitazone/4MOT and rivoglitazone/4C13 complexes and to get insight into the binding mode of inhibitor. Thus, we hypothesize that structural modifications of the rivoglitazone scaffold can be useful for the development of an effective antibacterial agent.

An explorative study on Staphylococcus aureus MurE inhibitor: induced fit docking, binding free energy calculation, and molecular dynamics.

Staphylococcus aureus MurE enzyme catalyzes the addition of l-lysine as third residue of the peptidoglycan peptide moiety. Due to the high substrate specificity and its ubiquitous nature among bacteria, MurE enzyme is considered as one of the potential target for the development of new therapeutic agents. In the present work, induced fit docking (IFD), binding free energy calculation, and molecular dynamics (MD) simulation were carried out to elucidate the inhibition potential of 2-thioxothiazolidin-4-one based inhibitor 1 against S. aureus MurE enzyme. The inhibitor 1 formed majority of hydrogen bonds with the central domain residues Asn151, Thr152, Ser180, Arg187, and Lys219. Binding free-energy calculation by MM-GBSA approach showed that van der Waals (ΔGvdW, -57.30 kcal/mol) and electrostatic solvation (ΔGsolv, -36.86 kcal/mol) energy terms are major contributors for the inhibitor binding. Further, 30-ns MD simulation was performed to validate the stability of ligand-protein complex and also to get structural insight into mode of binding. Based on the IFD and MD simulation results, we designed four new compounds D1-D4 with promising binding affinity for the S. aureus MurE enzyme. The designed compounds were subjected to the extra-precision docking and binding free energy was calculated for complexes. Further, a 30-ns MD simulation was performed for D1/4C13 complex.

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit.

IMPORTANCE: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population. BACKGROUND: We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population. DESIGN: Retrospective audit, tertiary centre hospitals and private practices. PARTICIPANTS: All individuals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011. METHODS: An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality. MAIN OUTCOME MEASURES: Five-, seven- and nine-year survival rates. RESULTS: The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008). CONCLUSIONS AND RELEVANCE: Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.

Visual outcomes following vitrectomy for diabetic retinopathy amongst Indigenous and non-Indigenous Australians in South Australia and the Northern Territory.

IMPORTANCE: Visual outcomes following diabetic vitrectomy have not previously been studied in an Australian population. BACKGROUND: This analysis aimed to determine the rate of, and factors associated with visual success following diabetic vitrectomy performed for Indigenous and non-Indigenous Australians, and investigate factors predisposing to early progression to diabetic retinopathy (DR) requiring vitrectomy. DESIGN: Retrospective, population-based audit. PARTICIPANTS: All patients undergoing vitrectomy for the complications of DR in South Australia (SA) and the Northern Territory (NT) between 2007 and 2011. METHODS: Medical records were audited and data collected, including demographics, diabetic history, past treatment for DR, indication for vitrectomy and visual acuity pre and postoperatively. MAIN OUTCOME MEASURES: Visual success (gain of ≥15 ETDRS letters) at 6 and 12 months, postoperatively. RESULTS: A total of 495 diabetic vitrectomies, for 404 eyes of 335 patients were performed in SA and NT between 2007 and 2011. 77 (23%) patients requiring diabetic vitrectomy were Indigenous Australians. 87% of patients undergoing diabetic vitrectomy had stable or improved vision at 1 year, postoperatively. There was no significant difference between indigenous and non-indigenous eyes achieving visual success (P = 0.929). Timely preoperative laser treatment (P = 0.03) and preoperative visual acuity (P = 0.01) were the predominant factors associated with visual success. CONCLUSIONS AND RELEVANCE: Indigenous patients are just as likely to have improved vision following diabetic vitrectomy as non-Indigenous Australians. However, the small subset of indigenous patients with blind eyes prior to vitrectomy are significantly less likely to improve from surgery. The underlying factors associated with poor outcomes in this group requires further exploration.

Image guidance in prostate cancer - can offline corrections be an effective substitute for daily online imaging?

PURPOSE: This aim of this study was to determine if a less resource-intensive and established offline correction protocol - the No Action Level (NAL) protocol was as effective as daily online corrections of setup deviations in curative high-dose radiotherapy of prostate cancer. MATERIALS AND METHODS: A total of 683 daily megavoltage CT (MVCT) or kilovoltage CT (kvCBCT) images of 30 patients with localized prostate cancer treated with intensity modulated radiotherapy were evaluated. Daily image-guidance was performed and setup errors in three translational axes recorded. The NAL protocol was simulated by using the mean shift calculated from the first five fractions and implemented on all subsequent treatments. Using the imaging data from the remaining fractions, the daily residual error (RE) was determined. The proportion of fractions where the RE was greater than 3,5 and 7 mm was calculated, and also the actual PTV margin that would be required if the offline protocol was followed. RESULTS: Using the NAL protocol reduced the systematic but not the random errors. Corrections made using the NAL protocol resulted in small and acceptable RE in the mediolateral (ML) and superoinferior (SI) directions with 46/533 (8.1%) and 48/533 (5%) residual shifts above 5 mm. However; residual errors greater than 5mm in the anteroposterior (AP) direction remained in 181/533 (34%) of fractions. The PTV margins calculated based on residual errors were 5mm, 5mm and 13 mm in the ML, SI and AP directions respectively. CONCLUSION: Offline correction using the NAL protocol resulted in unacceptably high residual errors in the AP direction, due to random uncertainties of rectal and bladder filling. Daily online imaging and corrections remain the standard image guidance policy for highly conformal radiotherapy of prostate cancer.

Neuroretinitis following bull ant sting.

Cat scratch disease causes the majority of cases of neuroretinitis. Neuroretinitis is characterised by clinical features of papillitis, macular oedema and macular star. We report a case study of infection with Bartonella henselae most likely transmitted by a bull ant sting. The patient presented with blurred vision and reduced visual acuity after being stung by an ant in her garden some 7 days earlier. Further testing revealed positive serology to B henselae and the patient improved with appropriate treatment.

Topical ocular anaesthetic abuse in a contact lens wearer: a case of microbial keratitis.

We describe the abuse of a topical ocular anaesthetic in a contact lens wearer who developed microbial keratitis.

Early imaging of a macular hole following vitrectomy with primary silicone oil tamponade.

BACKGROUND: To describe the morphology of a macular hole in the early postoperative period following vitrectomy with primary silicone oil tamponade. METHODS: A case report with optical coherence tomography (OCT) scans prior to surgery, at 20 minutes postoperatively and then at 17 hours postoperatively. RESULTS: OCT images of a 73-year-old woman with a stage 3 macular hole were obtained. At 20 minutes postoperatively, there was a reduction in intraretinal cysts and a reduction in macular hole size with elevated-open configuration. At 17 hours postoperatively, complete macular hole closure was noted. CONCLUSION: OCT Images of a macular hole in the early postoperative period have been successfully obtained. Macular holes can close within 24 hours postoperatively and show morphological changes that may be predictive of closure within 20 minutes postoperatively.

The management of "coats' response" in a patient with x-linked retinitis pigmentosa-a case report.

The management of exudative retinal detachment in Coats disease can be very difficult with variable results. A case is presented of a 12 year old boy who was diagnosed with X-linked retinitis pigmentosa with an associated "Coat's Response". The patient had a marked reduction in his left visual acuity due to intragel and subhyaloid haemorrhage as well as exudative retinal detachment. This was managed successfully with vitrectomy and endolaser, resulting in clearance of the haemorrhage and flattening of the retina. In our experience endolaser should be considered as viable therapeutic option in the management of this condition.