Montelukast and cefoperazone act as antiquorum sensing and antibiofilm agents against Pseudomonas aeruginosa.

AIMS: Drug repurposing is an attractive strategy to control biofilm-related infectious diseases. In this study, two drugs (montelukast and cefoperazone) with well-established therapeutic applications were tested on Pseudomonas aeruginosa quorum sensing (QS) inhibition and biofilm control. METHODS AND RESULTS: The activity of montelukast and cefoperazone was evaluated for Pqs signal inhibition, pyocyanin synthesis, and prevention and eradication of Ps. aeruginosa biofilms. Cefoperazone inhibited the Pqs system by hindering the production of the autoinducer molecules 2-heptyl-4-hydroxyquinoline (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (the Pseudomonas quinolone signal or PQS), corroborating in silico results. Pseudomonas aeruginosa pyocyanin production was reduced by 50%. The combination of the antibiotics cefoperazone and ciprofloxacin was synergistic for Ps. aeruginosa biofilm control. On the other hand, montelukast had no relevant effects on the inhibition of the Pqs system and against Ps. aeruginosa biofilm. CONCLUSION: This study provides for the first time strong evidence that cefoperazone interacts with the Pqs system, hindering the formation of the autoinducer molecules HHQ and PQS, reducing Ps. aeruginosa pathogenicity and virulence. Cefoperazone demonstrated a potential to be used in combination with less effective antibiotics (e.g. ciprofloxacin) to potentiate the biofilm control action.

Dual action of benzaldehydes: Inhibiting quorum sensing and enhancing antibiotic efficacy for controlling Pseudomonas aeruginosa biofilms.

Quorum sensing (QS) has a central role in biofilm lifestyle and antimicrobial resistance, and disrupting these signaling pathways is a promising strategy to control bacterial pathogenicity and virulence. In this study, the efficacy of three structurally related benzaldehydes (4-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxy-3,5-dimethoxybenzaldehyde (syringaldehyde)) in disrupting the las and pqs systems of Pseudomonas aeruginosa was investigated using bioreporter strains and computational simulations. Additionally, these benzaldehydes were combined with tobramycin and ciprofloxacin antibiotics to evaluate their ability to increase antibiotic efficacy in preventing and eradicating P. aeruginosa biofilms. To this end, the total biomass, metabolic activity and culturability of the biofilm cells were determined. In vitro assays results indicated that the aromatic aldehydes have potential to inhibit the las and pqs systems by > 80 %. Molecular docking studies supported these findings, revealing the aldehydes binding in the same pocket as the natural ligands or receptor proteins (LasR, PQSA, PQSE, PQSR). Benzaldehydes were shown to act as virulence factor attenuators, with vanillin achieving a 48 % reduction in pyocyanin production. The benzaldehyde-tobramycin combination led not only to a 60 % reduction in biomass production but also to a 90 % reduction in the metabolic activity of established biofilms. A similar result was observed when benzaldehydes were combined with ciprofloxacin. 4-Hydroxybenzaldehyde demonstrated relevant action in increasing biofilm susceptibility to ciprofloxacin, resulting in a 65 % reduction in biomass. This study discloses, for the first time, that the benzaldehydes studied are potent QS inhibitors and also enhancers of antibiotics antibiofilm activity against P. aeruginosa.

Isolated corneal involvement by Lichen Planus - multi-modal evaluation.

PURPOSE: To describe a case of ocular Lichen Planus, successfully managed using a multimodal evaulation, including Anterior Segment OCT (AS-OCT). OBSERVATIONS: A female patient in her forties with a history of cutaneous Lichen Planus presents with blurred vision and burning eye sensation. Anterior segment evaluation revealed bilateral punctate keratitis, stromal haze and subepithelial pigmented dots. AS-OCT was pivotal for diagnosis, showing anterior stromal hyperreflective dots. A diagnosis of ocular Lichen Planus was estabilished and the patient was treated with topical hydrocortisone, with complete subsidence of the complaints. CONCLUSIONS AND IMPORTANCE: Ocular Lichen Planus can present as isolated corneal involvement independent from severe cicatrizing conjunctivitis. Appropriate and timely treatment can prevent irreversible ocular surface disease. Ophthalmologists should be aware of Lichenoid Tissue Reaction (LTR) disorders, especially in patients with relentless blepharitis and/or ocular surface disease.

Myelin oligodendrocyte glycoprotein antibody disorder (MOGAD) optic perineuritis following severe COVID19 infection.

Purpose: To describe the case of bilateral myelin oligodendrocyte glycoprotein antibody disorder (MOGAD) perineuritis following severe COVID19 pneumonia. Observations: A 56-year-old man presents with bilateral vision loss (BCVA OU of counting fingers) following severe COVID19 infection. Neuroimaging revealed bilateral perineuritis, with MOG-IgG antibody positive (1:20), confirmed by cell-based assay, elevated ESR and CRP (42 mm/h and 8.2 mg/dL, respectively). The patient was started on IV methylprednisolone with significant improvement in visual field testing bilaterally, followed by slow steroid taper. After 6 months, repeat MOG-IgG antibody was negative (seronegative conversion) and inflammatory parameters (ESR and CRP) were within normal limits. Conclusions and importance: COVID-19 has been previously associated with MOGAD optic perineuritis, mostly with higher antibody titers. This case suggests a new pathophysiological hypothesis in which concomitant cytokine storm in severe COVID-19 disrupts the blood-brain-barrier, leading to the entry of even lower MOG-IgG titers to the central nervous system (CNS) and exacerbate severe visual loss. Clinicians should be aware of the association of COVID-19 and MOGAD.

The action of phytochemicals in biofilm control.

Covering: 2009 to 2021Antimicrobial resistance is now rising to dangerously high levels in all parts of the world, threatening the treatment of an ever-increasing range of infectious diseases. This has becoming a serious public health problem, especially due to the emergence of multidrug-resistance among clinically important bacterial species and their ability to form biofilms. In addition, current anti-infective therapies have low efficacy in the treatment of biofilm-related infections, leading to recurrence, chronicity, and increased morbidity and mortality. Therefore, it is necessary to search for innovative strategies/antibacterial agents capable of overcoming the limitations of conventional antibiotics. Natural compounds, in particular those obtained from plants, have been exhibiting promising properties in this field. Plant secondary metabolites (phytochemicals) can act as antibiofilm agents through different mechanisms of action from the available antibiotics (inhibition of quorum-sensing, motility, adhesion, and reactive oxygen species production, among others). The combination of different phytochemicals and antibiotics have revealed synergistic or additive effects in biofilm control. This review aims to bring together the most relevant reports on the antibiofilm properties of phytochemicals, as well as insights into their structure and mechanistic action against bacterial pathogens, spanning December 2008 to December 2021.

Deep Capillary Plexus Features in Acute Macular Neuroretinopathy: Novel Insights Based on the Anatomy of Henle Fiber Layer.

Purpose: The purpose of this study was to identify a precise location of deep capillary plexus (DCP) injury in acute macular neuroretinopathy (AMN) lesions using multimodal imaging. Methods: En face structural optical coherence tomography (OCT) images were manually segmented to delineate outer retinal AMN lesions involving the ellipsoid zone and interdigitation zone. AMN lesion centroid was calculated, and image distortion was applied to correct for Henle fiber layer (HFL) length and orientation. The resulting image was registered with the corresponding en face OCT angiography (OCTA) image segmented at the DCP and structural OCT volume before grading for vascular and structural features, respectively. Results: Thirty-nine AMN lesions from 16 eyes (11 female patients, mean age 34 ± 4 years) were analyzed. After correcting for HFL anatomy, in 62% of AMN lesions, the centroid co-localized with a capillary vortex (pattern 1); flow defects were detected in 33% of lesions (pattern 2); and in 5% of lesions no specific pattern could be identified (pattern 3). The detection of a specific pattern increased after correcting the projection of AMN lesion for HFL anatomy (28% vs. 5%, P = 0.04). Outer nuclear layer thickness was lower in the centroid area in 10 (29%) AMN lesions from 6 patients, all corresponding to lesions fitting pattern 2 (r = 0.78, P < 0.001). Conclusions: AMN lesions might be a result of DCP impairment at the level of the capillary vortex or draining venule. In eyes with AMN, the location of outer retinal changes associated with DCP ischemia appears to be influenced by the length and orientation of HFL.

Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review.

The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.

Prototypic Heptamethine Cyanine Incorporating Nanomaterials for Cancer Phototheragnostic.

Developing technologies that allow the simultaneous diagnosis and treatment of cancer (theragnostic) has been the quest of numerous interdisciplinary research teams. In this context, nanomaterials incorporating prototypic near infrared (NIR)-light responsive heptamethine cyanines have been showing very promising results for cancer theragnostic. The precisely engineered features of these nanomaterials endow them with the ability to achieve a high tumor accumulation, enabling a tumor's visualization by NIR fluorescence and photoacoustic imaging modalities. Upon interaction with NIR light, the tumor-homed heptamethine cyanine-incorporating nanomaterials can also produce a photothermal/photodynamic effect with a high spatio-temporal resolution and minimal side effects, leading to an improved therapeutic outcome. This progress report analyses the application of nanomaterials incorporating prototypic NIR-light responsive heptamethine cyanines (IR775, IR780, IR783, IR797, IR806, IR808, IR820, IR825, IRDye 800CW, and Cypate) for cancer photothermal therapy, photodynamic therapy, and imaging. Overall, the continuous development of nanomaterials incorporating the prototypic NIR absorbing heptamethine cyanines will cement their phototheragnostic capabilities.

Sulfobetaine methacrylate-functionalized graphene oxide-IR780 nanohybrids aimed at improving breast cancer phototherapy.

The application of Graphene Oxide (GO) in cancer photothermal therapy is hindered by its lack of colloidal stability in biologically relevant media and modest Near Infrared (NIR) absorption. In this regard, the colloidal stability of GO has been improved by functionalizing its surface with poly(ethylene glycol) (PEG), which may not be optimal due to the recent reports on PEG immunogenicity. On the other hand, the chemical reduction of GO using hydrazine hydrate has been applied to enhance its photothermal capacity, despite decreasing its cytocompatibility. In this work GO was functionalized with an amphiphilic polymer containing [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) brushes and was loaded with IR780, for the first time, aiming to improve its colloidal stability and phototherapeutic capacity. The attained results revealed that the SBMA-functionalized GO displays a suitable size distribution, neutral surface charge and adequate cytocompatibility. Furthermore, the SBMA-functionalized GO exhibited an improved colloidal stability in biologically relevant media, while its non-SBMA functionalized equivalent promptly precipitated under the same conditions. By loading IR780 into the SBMA-functionalized GO, its NIR absorption increased by 2.7-fold, leading to a 1.2 times higher photothermal heating. In in vitro cell studies, the combination of SBMA-functionalized GO with NIR light only reduced breast cancer cells' viability to 73%. In stark contrast, by combining IR780 loaded SBMA-functionalized GO and NIR radiation, the cancer cells' viability decreased to 20%, hence confirming the potential of this nanomaterial for cancer photothermal therapy.

Driver's behavioral adaptation to adaptive cruise control (ACC): the case of speed and time headway.

PROBLEM: The Adaptive Cruise Control is an Advanced Driver Assistance System (ADAS) that allows maintaining given headway and speed, according to settings pre-defined by the users. Despite the potential benefits associated to the utilization of ACC, previous studies warned against negative behavioral adaptations that might occur while driving with the system activated. Unfortunately, up to now, there are no unanimous results about the effects induced by the usage of ACC on speed and time headway to the vehicle in front. Also, few studies were performed including actual users of ACC among the subjects. OBJECTIVES: This research aimed to investigate the effect of the experience gained with ACC on speed and time headway for a group of users of the system. In addition, it explored the impact of ACC usage on speed and time headway for ACC users and regular drivers. METHOD: A matched sample driving simulator study was planned as a two-way (2×2) repeated measures mixed design, with the experience with ACC as between-subjects factor and the driving condition (with ACC and manually) as within-subjects factor. RESULTS: The results show that the usage of ACC brought a small but not significant reduction of speed and, especially, the maintenance of safer time headways, being the latter result greater for ACC users, probably as a consequence of their experience in using the system. SUMMARY: The usage of ACC did not cause any negative behavioral adaptations to the system regarding speed and time headway. PRACTICAL APPLICATIONS: Based on this research work, the Adaptive Cruise Control showed the potential to improve road safety for what concerns the speed and the time headway maintained by the drivers. The speed of the surrounding traffic and the minimum time headway settable through the ACC seem to have an important effect on the road safety improvement achievable with the system.

A method to investigate drivers' acceptance of Blind Spot Detection System®.

Lately, with the goal of improving road safety, car makers developed and commercialised some Advanced Driver Assistance Systems (ADAS) which, through the detection of blind spot areas on the vehicle's sides, could help the drivers during the overtaking and the change lane task. Despite the possible benefits to reduce lateral crashes, the overall impact on road safety of such systems have not been deeply studied yet; notably, despite some researches have been carried out, there is a lack of studies regarding the long-term usage and drivers' acceptance of those systems. In order to fill the research gap, a methodology, based on the combination of focus groups interviews, questionnaires and a small-scale field operational test (FOT), has been designed in this study; such a methodology aims at evaluating drivers' acceptance of Blind Spot Information System® and at proposing some ideas to improve the usability and user-friendliness of this (or similar) device in their future development.

Assessing driver's mental representation of Adaptive Cruise Control (ACC) and its possible effects on behavioural adaptations.

The introduction of Adaptive Cruise Control (ACC) could be very helpful for making the longitudinal driving task more comfortable for the drivers and, as a consequence, it could have a global beneficial effect on road safety. However, before or during the usage of the device, due to several reasons, drivers might generate in their mind incomplete or flawed mental representations about the fundamental operation principles of ACC; hence, the resulting usage of the device might be improper, negatively affecting the human-machine interaction and cooperation and, in some cases, leading to negative behavioural adaptations to the system that might neutralise the desirable positive effects on road safety. Within this context, this paper will introduce the methodology which has been developed in order to analyse in detail the topic and foresee, in the future, adequate actions for the recovery of inaccurate mental representations of the system.