Molecular Medicine Ireland

Introduction: Pseudomonas aeruginosa is a significant pathogen associated with acute and chronic infections, particularly in immunocompromised individuals. Its capacity for biofilm formation, combined with antibiotic resistance, plays a critical role in the persistence of these infections. Peptidyl-arginine deiminases (PADs), including PAD2 and PAD4 isoforms, are involved in neutrophil phagocytic killing of P. aeruginosa. This study aimed to investigate the impact of PAD enzymes on biofilm development and virulence factor production in P. aeruginosa, with focus on the multidrug resistant strain, PGO2330. Methods: Biofilm formation was assessed using crystal violet assays and confocal scanning laser microscopy. Quorum sensing (QS) gene expression and QS-related virulence factor production were quantified using qPCR and virulence factor assays. Results: Exposure to 20 nm of PAD2 or PAD4 reduced PGO2330 surface attachment (p < 0.0001) and biofilm formation to 67.9 ± 5.6% (p < 0.0001) and 68.2 ± 4.2% (p = 0.0004), respectively. Moreover, rPAD2 and rPAD4 citrullinated multiple protein substrates of P. aeruginosa, yet citrullination activity was not required by rPADs to reduce P. aeruginosa biofilm formation. PGO2330 exposed to PAD2 and PAD4 showed reduced lasR, lasI, rhlR, rhlI, and mvfR gene expression and reduced levels of extracellular DNA, rhamnolipids, pyocyanin, and protease activity. Conclusion: These results demonstrate that PADs inhibit P. aeruginosa biofilm formation and decrease the production of QS-related virulence factors, highlighting their potential as novel antimicrobials and supporting further research into the development of PAD-based therapeutics.

There is a wealth of data indicating that the immune system plays an important role in seizure disorders. This includes autoimmune encephalitis, in which an immune response directed against neuronal antigens results in brain inflammation and subsequent seizure activity, as well as autoimmune‐associated epilepsy and neuroinflammatory changes detected in the tissues of patients with epilepsy, in which context it is often difficult to distinguish whether the inflammation is causal or a consequence of the seizures. Here, we summarize the discussion on this topic held during the XVII Workshop on Neurobiology of Epilepsy (WONOEP XVII), organized in 2023 by the Neurobiology Commission of the International League Against Epilepsy on the topic of the extracellular space in epilepsy. This critical appraisal explores the progress, emerging concepts, and discussion on the immunopathogenesis of epilepsy, with a particular focus on the interplay between the immune system and the central nervous system, highlighting the role of autoimmunity, neuroinflammation, and neuroimmunological processes in the etiology of various epileptic disorders and the prospects for new therapies.

Background/Objectives Bacterial infections caused by resistant strains such as Pseudomonas aeruginosa , Staphylococcus aureus , Klebsiella pneumoniae , Enterococcus spp. and Escherichia coli represent a growing threat to human and animal health. In the face of rising resistance, essential oils derived from medicinal plants offer a promising natural alternative. The present study aims to characterize the phytochemical composition and evaluate the antioxidant and antimicrobial activities of the essential oil extracted from the aerial part of Ononis natrix . Methods The phytochemical composition, antioxidant activity and antimicrobial efficacy of the essential oil were assessed using gas chromatography-mass spectrometry (GC-MS), the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and Ferric-Reducing Antioxidant Power (FRAP) assays, as well as the disk diffusion method, supplemented by determining of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), respectively. Results Our findings revealed that Ononis natrix essential oil contains a high level of oxygenated monoterpenes (45.6%) and oxygenated sesquiterpenes (35.35%). The lowest IC 50 value obtained, of the order of 339 μg/mL, was observed with the reducing power test, thus reflecting a reducing capacity of this oil towards the ferric ion Fe 3+ . In addition, the essential oil showed marked antimicrobial effects against the Candida strains and multi-resistant bacteria tested. Conclusion The findings of the current study demonstrated strong antioxidant and antimicrobial properties of O. natrix , which could potentially provide novel treatments, thus, addressing antibiotic resistance issues in the clinical setting.

Providing bereavement support to parents who have experienced a perinatal loss requires knowledge, empathy and sensitivity. Undergraduate opportunities to learn directly from parents with personal experience remain limited. This study assessed medical students' responses to parent-led stories on perinatal loss, evaluating their self-reported changes in knowledge, skills and self-awareness. Final-year medical students in University College Dublin participated in a new educational initiative featuring parent-educators from three perinatal loss advocacy groups. Each session focused on the parents' personal experiences of pregnancy loss and was designed collaboratively with the authors and independently led by the parents. Evaluation used a validated preintervention and postintervention questionnaire-the Perinatal Bereavement Care Confidence Scale (PBCCS). This measures self-reported knowledge, support skills and self-awareness in providing bereavement care. Students also provided free-text comments on confidence promoters, inhibitors and suggestions for improvement. Statistically significant improvements were observed across all three domains of the PBCCS following the educational sessions. Knowledge scores increased 28.2%, from 2.80 to 3.59 (p < 0.01; Cohen's d = 0.39). Skills rose 43.1%, from 2.16 to 3.09 (p < 0.001; d = 0.65). Self-awareness increased 21.6%, from 3.29 to 4.00 (p < 0.001). Thematic content analysis of free-text responses revealed a lack of experience and fear of 'saying the wrong thing' as confidence inhibitors. Postintervention responses highlighted the value of hearing from the bereaved parents, with students calling for continued parent-educator sessions. This pilot educational programme highlights the value of in-person, parent-led education and suggests that integrating the lived experience can better prepare students to provide bereavement care.

Mitochondrial metabolites and their derivatives have been the focus of recent efforts to develop new anti-inflammatory therapeutics. The widely used therapeutic agents dimethyl fumarate (DMF) and metformin have anti-inflammatory properties and have been shown to target metabolism. The mitochondrial metabolites succinate, itaconate, and fumarate have multiple immunomodulatory effects and present interesting therapeutic possibilities for immune and inflammatory diseases. Mitochondrial DNA and double-stranded RNA have also been shown to be highly inflammatory, acting via specific pattern recognition receptors (PRRs) such as cGAS and TLR9 for mitochondrial DNA, RIG-I, MDA5 for mitochondrial double stranded RNA, and TLR7 for mitochondrial single stranded RNA. These recent discoveries are changing our view of mitochondria suggesting that they are at the heart of multiple inflammatory diseases and provide opportunities for the development of new anti-inflammatory therapeutics.

ObjectivesThis study aimed to identify main sex-specific correlates of cardiorespiratory fitness (CRF) in a population-based, urban sample of Swedish adults.DesignCross-sectional.SettingMulti-site study at university hospitals, data from the Gothenburg site.ParticipantsA total of 5308 participants (51% women, aged 50–64 years) with a valid estimated VO2max, from submaximal cycle test, in the Swedish CArdioPulmonary bioImage Study (SCAPIS), were included.Primary and secondary outcomesA wide range of correlates were examined including (a) sociodemographic and lifestyle behaviours, (b) perceived health, anthropometrics and chronic conditions and (c) self-reported as well as accelerometer-derived physical activity and sedentary behaviours. Both continuous levels of estimated VO2max as well as odds ratios (OR) and confidence intervals (CI)s of low VO2max (lowest sex-specific tertile) were reported.ResultsIn multivariable regression analyses, higher age, being born abroad, short education, high waist circumference, poor perceived health, high accelerometer-derived time in sedentary and low in vigorous physical activity, as well as being passive commuter, correlated independently and significantly with low VO2max in both men and women (OR range 1.31–9.58). Additionally in men, financial strain and being an ex-smoker are associated with higher odds for low VO2max (OR 2.15; 95% CI 1.33 to 3.48 and OR 1.40; 95% CI 1.09 to 1.80), while constant stress with lower odds (OR 0.61; 95% CI 0.43 to 0.85). Additionally in women, being a regular smoker is associated with lower odds for low VO2max (OR 0.64; 95% CI 0.45 to 0.92).ConclusionsThe present study provides important reference material on CRF and correlates of CRF in a general middle-aged population, which can be valuable for future research, clinical practice and public health work. If relations are causal, increased knowledge about specific subgroups will aid in the development of appropriate, targeted interventions.

Abstract Background The Sustained Attention to Response Task (SART) is a standard computer-based cognitive test designed to measure the sustained attention, fundamental for completing tasks that require supervision over time (Robertson et al., 1997). However, commonly used average features may result in loss of information and data misinterpretation, leading to inability to detect clinically expected associations (O’Halloran et al., 2014). Methods Here, we present a new method to visualise the full information obtained from the SART test, ordering by age, and categorising in groups based on mobility status in a large population-based study of ageing in Ireland. A new threshold, derived from the visualisation and based on the individual trial number of mistakes, was employed to individuate poorer SART performances, and to predict mobility and cognitive decline after 4 years in binary logistic regression models. Results Raw SART data were available for 4,864 participants aged 50 years and over at baseline. The new variable bad performances, expressing the number of SART trials with at least 4 mistakes, was the most significant predictor of mobility decline, defined as the transition from Timed Up-and-Go (TUG) &amp;lt; 12 to TUG ≥12 seconds (Odds Ratio (OR) = 1.29; 95% Confidence Interval (CI) 1.14–1.46; p &amp;lt; 0.001), and the only significant predictor of new falls (OR = 1.11; 95% CI 1.03–1.21; p = 0.011) compared to traditional SART variables in models adjusted for multiple covariates. No SART-related variables resulted significant predictors of cognitive decline, defined as a decrease of at least 2 points in the Mini-Mental State Examination (MMSE) score. Conclusion This multimodal visualisation and the new threshold approach could help clinicians to easily develop relevant hypotheses, and better identify subjects at higher risk of future mobility decline.