Insights into the Mode of Action of the Sactibiotic Thuricin CD

peer-reviewedThuricin CD is a two-component bacteriocin, consisting of the peptides Trnα and Trnβ, and belongs to the newly designated sactibiotic subclass of bacteriocins. While it is clear from studies conducted thus far that it is a narrow-spectrum bacteriocin, requiring the synergistic activity of the two peptides, the precise mechanism of action of thuricin CD has not been elucidated. This study used a combination of flow cytometry and traditional culture-dependent assays to ascertain the effects of the thuricin CD peptides on the morphology, physiology and viability of sensitive Bacillus firmus DPC6349 cells. We show that both Trnα and Trnβ are membrane-acting and cause a collapse of the membrane potential, which could not be reversed even under membrane-repolarizing conditions. Furthermore, the depolarizing action of thuricin CD is accompanied by reductions in cell size and granularity, producing a pattern of physiological alterations in DPC6349 cells similar to those triggered by the pore-forming single-component bacteriocin Nisin A, and two-component lacticin 3147. Taken together, these results lead us to postulate that the lytic activity of thuricin CD involves the insertion of thuricin CD peptides into the membrane of target cells leading to permeabilization due to pore formation and consequent flux of ions across the membrane, resulting in membrane depolarization and eventual cell death.HM is a researcher in Teagasc Food Research Centre and the Alimentary Pharmabiotic Centre Microbiome Institute, funded by the Science Foundation of Ireland (SFI)-funded Centre for Science, Engineering and Technology and the Alimentary Pharmabiotic Centre Microbiome Institute (APC) Grant Number SFI/12/RC/2273. Research in PC, CH, MR, VF, and RR laboratories is supported by the Science Foundation of Ireland (SFI)-funded Centre for Science, Engineering and Technology and the APC Microbiome Institute

Current molecular and clinical insights into uveal melanoma (Review)

Uveal melanoma (UM) represents the most prominent primary eye cancer in adults. With an incidence of approximately 5 cases per million individuals annually in the United States, UM could be considered a relatively rare cancer. The 90.95% of UM cases arise from the choroid. Diagnosis is based mainly on a clinical examination and ancillary tests, with ocular ultrasonography being of greatest value. Differential diagnosis can prove challenging in the case of indeterminate choroidal lesions and, sometimes, monitoring for documented growth may be the proper approach. Fine needle aspiration biopsy tends to be performed with a prognostic purpose, often in combination with radiotherapy. Gene expression profiling has allowed for the grading of UMs into two classes, which feature different metastatic risks. Patients with UM require a specialized multidisciplinary management. Primary tumor treatment can be either enucleation or globe preserving. Usually, enucleation is reserved for larger tumors, while radiotherapy is preferred for small/medium melanomas. The prognosis is unfavorable due to the high mortality rate and high tendency to metastasize. Following the development of metastatic disease, the mortality rate increases to 80% within one year, due to both the absence of an effective treatment and the aggressiveness of the condition. Novel molecular studies have allowed for a better understanding of the genetic and epigenetic mechanisms involved in UM biological activity, which differs compared to skin melanomas. The most commonly mutated genes are GNAQ, GNA11 and BAP1. Research in this field could help to identify effective diagnostic and prognostic biomarkers, as well as novel therapeutic targets

Efficacy of Three Different Prophylactic Treatments for Postoperative Nausea and Vomiting after Vitrectomy: A Randomized Clinical Trial

Postoperative nausea and vomiting (PONV) after vitreoretinal surgery may potentially be associated with severe complications, such as suprachoroidal hemorrhage. The purpose of the present multicenter clinical trial (NCT02386059) was to assess the efficacy of three different prophylactic treatments for PONV after vitrectomy under local anesthesia. Patients undergoing primary vitrectomy were randomized to the control arm or to one of the treatment arms (4 mg ondansetron, 4 mg dexamethasone, combination of the two drugs). The primary outcome measure was the proportion of complete response (no nausea, no vomiting, no retching, and no use of antiemetic rescue medication) during 24 h after vitrectomy. Secondary outcomes included the severity standardized score of PONV, postoperative pain standardized score, and rate of ocular and non-ocular adverse events. Baseline demographics of the 1287 patients were comparable between the four arms. The combined therapy group showed a statistically significant lower incidence of PONV compared to the placebo and monotherapy (p < 0.001). PONV severity was also reduced in the combination group compared to the others (p < 0.001). Postoperative pain scores and adverse events were comparable among the four groups. Combined therapy with dexamethasone and ondansetron was the most effective treatment for reducing the incidence and severity of PONV in patients undergoing vitrectomy under local anesthesia

Modified Vitrectomy Technique for Phakic Rhegmatogenous Retinal Detachment with Intermediate Break

Purpose. To evaluate the effects of a modification of the traditional 25-gauge pars plana vitrectomy technique in the treatment of uncomplicated macula-on rhegmatogenous retinal detachment (RRD) with intermediate retinal break(s) and marked vitreous traction in the phakic eye. Methods. Prospective, noncomparative, and interventional case series. All consecutive phakic eyes with primary uncomplicated macula-on RRD with intermediate retinal break(s) and marked vitreous traction, with at least 1 year of postoperative follow-up, were enrolled. In all eyes, “localized 25-gauge vitrectomy” under air infusion with localized removal of the vitreous surrounding the retinal break(s), in association with laser photocoagulation and air tamponade, was performed. The primary end point was the rate of primary retinal attachment. Secondary end points were cataract progression and assessed by digital Scheimpflug lens photography (mean change of nuclear density units) and the rate of complications. Results. Thirty-two phakic eyes were included in the final analysis. At 12 months, the primary outcome of anatomical success was achieved in 94% of eyes. The mean nuclear density units did not change significantly at any time point during the follow-up. After localized vitrectomy, one eye developed an epiretinal membrane, and one eye developed cystoid macular edema; no other significant complications were reported. Conclusions. “Localized vitrectomy” has a high anatomical success rate in phakic eyes with primary uncomplicated macula-on RRD with intermediate retinal break(s) and marked vitreous traction, without causing progression of cataract

Primary vitrectomy for degenerative and tractional lamellar macular holes: A systematic review and meta-analysis

Purpose To assess the efficacy of vitrectomy in degenerative and tractional lamellar macular holes (LMHs) by meta-analysis of published studies. Methods PubMed, Medline and Embase databases were searched up to May 2020. Included cohorts were divided into three groups: degenerative LMH group, lamellar hole associated epiretinal proliferation (LHEP) group and tractional LMH group. LHEP is likely to be associated with degenerative LMHs, but less commonly could be associated with mixed LMHs. To reduce risk of possible misclassification bias, eyes with LHEP which could not have been precisely classified by the authors, were included into the LHEP group. The primary outcome was to investigate the visual change following primary vitrectomy in the degenerative LMH and LHEP group versus the tractional LMH group. A sensitivity analysis excluding the LHEP group was also performed on the primary outcome. Mean difference (MD) in best corrected visual acuity between baseline and post-treatment was calculated, along with 95% confidence interval (CI). Rate of incidence of post-operative full-thickness macular hole (FTMH) was assessed as secondary outcome. Results Thirteen studies were included. Pooled analyses including all groups showed a significant visual improvement following vitrectomy (pre-post MD = -0.17;95%CI = -0.22,-0.12; p<0.001), with no difference in visual improvement between the degenerative LMH and LHEP group and the tractional LMH group. The sensitivity analysis excluding LHEP group confirmed no difference in visual change between the degenerative LMH group (pre-post MD = -0.18;95%CI = -0.24,-0.12;p<0.001) and the tractional LMH group (MD = -0.16;95%CI = -0.26,-0.07;p<0.001). The incidence rate of post-operative FTMH was higher in the degenerative LMH and LHEP group than in the tractional LMH group (p = 0.002). Conclusion Primary vitrectomy for LMH ensured a favorable visual outcome, with no difference in visual gain between degenerative and tractional LMHs. However, a higher incidence of post-operative FTMHs was found in eyes with the degenerative LMH subtype

Anti-vascular endothelial growth factor monotherapy or combined with verteporfin photodynamic therapy for retinal angiomatous proliferation: a systematic review with meta-analysis

Purpose: To assess functional and anatomical outcomes of intravitreal anti-Vascular Endothelial Growth Factor (anti-VEGF) monotherapy versus combined with verteporfin Photodynamic Therapy (PDT) for Retinal Angiomatous Proliferation (RAP). Methods: Studies reporting outcomes of intravitreal anti-VEGF monotherapy and/or in combination with verteporfin PDT in RAP eyes with a follow-up ≥ 12 months were searched. The primary outcome was the mean change in best corrected visual acuity (BCVA) at 12 months. Mean change in central macular thickness (CMT) and mean number of injections were considered as secondary outcomes. The mean difference (MD) between pre- and post-treatment values was calculated along with 95% Confidence Interval (95% CI). Meta-regressions were performed to assess the influence of anti-VEGF number of injections on BCVA and CMT outcomes. Results: Thirty-four studies were included. A mean gain of 5.16 letters (95% CI = 3.30-7.01) and 10.38 letters (95% CI = 8.02-12.75) was shown in the anti-VEGF group and combined group, respectively (anti-VEGF group vs. combined group, p < 0.01). A mean CMT reduction of 132.45 µm (95% CI = from -154.99 to -109.90) and 213.93 µm (95% CI = from -280.04 to -147.83) was shown in the anti-VEGF group and combined group, respectively (anti-VEGF group vs. combined group, p < 0.02). A mean of 4.9 injections (95% CI = 4.2-5.6) and 2.8 injections (95% CI = 1.3-4.4) were administered over a 12-month period in the anti-VEGF group and combined group, respectively. Meta-regression analyses showed no influence of injection number on visual and CMT outcomes. High heterogeneity was found across studies for both functional and anatomical outcomes. Conclusion: A combined approach with anti-VEGF and PDT could provide better functional and anatomical outcomes in RAP eyes compared with anti-VEGF monotherapy