Amelia J. McFarland

Bio: Amelia J. McFarland is an academic researcher from Griffith University. The author has contributed to research in topics: Pyocyanin & Statin. The author has an hindex of 12, co-authored 21 publications receiving 554 citations. Previous affiliations of Amelia J. McFarland include University of Texas at Dallas.

Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa.

Abstract: Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species. The limitations of studies are, to date, focused on the localized effect of the release of pyocyanin (PCN). It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect. This review highlights the possible manifestations of PCN exposure; however, most studies to date are in vitro. Further high quality in vivo studies are needed to fully assess the physiological manifestations of PCN exposure on the various body systems.

Molecular mechanisms underlying the effects of statins in the central nervous system

Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins' effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins' effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins' possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed.

Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions

Abstract: KEY POINTS Animal preparations have revealed that moderate synaptic release of serotonin (5-HT) onto motoneurones enhances motor activity via activation of 5-HT2 receptors, whereas intense release of 5-HT causes spillover of 5-HT to extrasynaptic 5-HT1A receptors on the axon initial segment to reduce motoneurone activity. We explored if increasing extracellular concentrations of endogenously released 5-HT (via the selective serotonin reuptake inhibitor paroxetine) influences the ability to perform unfatigued and fatigued maximal voluntary contractions in humans. Following the ingestion of paroxetine, voluntary muscle activation and torque generation increased during brief unfatigued maximal contractions. In contrast, the ability to generate maximal torque with increased 5-HT availability was compromised under fatigued conditions, which was consistent with paroxetine-induced reductions in motoneurone excitability and voluntary muscle activation. This is the first in vivo human study to provide evidence that 5-HT released onto the motoneurones could play a role in central fatigue. ABSTRACT Brief stimulation of the raphe-spinal pathway in the turtle spinal cord releases serotonin (5-HT) onto motoneurones to enhance excitability. However, intense release of 5-HT via prolonged stimulation results in 5-HT spillover to the motoneurone axon initial segment to activate inhibitory 5-HT1A receptors, thus providing a potential spinal mechanism for exercise-induced central fatigue. We examined how increased extracellular concentrations of 5-HT affect the ability to perform brief, as well as sustained, maximal voluntary contractions (MVCs) in humans. Paroxetine was used to enhance 5-HT concentrations by reuptake inhibition, and three studies were performed. Study 1 (n = 14) revealed that 5-HT reuptake inhibition caused an ∼4% increase in elbow flexion MVC. However, when maximal contractions were sustained, time-to-task failure was reduced and self-perceived fatigue was higher with enhanced availability of 5-HT. Study 2 (n = 11) used twitch interpolation to reveal that 5-HT-based changes in motor performance had a neural basis. Enhanced 5-HT availability increased voluntary activation for the unfatigued biceps brachii and decreased voluntary activation of the biceps brachii by 2-5% following repeated maximal elbow flexions. The final study (n = 8) investigated whether altered motoneurone excitability may contribute to 5-HT changes in voluntary activation. F-waves of the abductor digiti minimi (ADM) were unaffected by paroxetine for unfatigued muscle and marginally affected following a brief 2-s MVC. However, F-wave area and persistence were significantly decreased following a prolonged 60-s MVC of the ADM. Overall, high serotonergic drive provides a spinal mechanism by which higher concentrations of 5-HT may contribute to central fatigue.

Inhibition of autophagy by 3-methyladenine protects 1321N1 astrocytoma cells against pyocyanin- and 1-hydroxyphenazine-induced toxicity

Abstract: Central nervous system (CNS) infections due to Pseudomonas aeruginosa are difficult to treat and have a high mortality rate. Pyocyanin, a virulence factor produced by P. aeruginosa, has been shown to be responsible for the majority of P. aeruginosa’s pathogenicity in mammalian cells. Several lines of evidence in respiratory cells suggest that this damage is primarily mediated by pyocyanin’s ability to generate ROS and deplete host antioxidant defense mechanisms. However, it has yet to be established whether pyocyanin or 1-hydroxyphenazine have potential toxicity to the CNS. Therefore, the aim of this study was to compare the CNS toxicity of pyocyanin and 1-hydroxyphenazine in vitro and to provide insight into mechanisms that underlie this toxicity using 1321N1 astrocytoma cells. To achieve this, we investigated the contribution of oxidative stress and other mediators of cell death including autophagy, senescence and apoptosis. We show that oxidative stress is not a primary mediator of pyocyanin (0–100 μM) and 1-hydroxyphenazine (0–100 μM) induced toxicity in 1321N1 cells. Instead, our results suggest that autophagy may play a central role. The autophagy inhibitor 3-methyladenine (5 mM) protected 1321N1 astrocytoma cells against both pyocyanin and 1-hydroxyphenazine-induced cell injury and increased accumulation of acidic vesicular organelles, a hallmark of autophagy. Furthermore, apoptosis and senescence events may be secondary to autophagy in pyocyanin and 1-hydroxyphenazine-mediated cell injury. In conclusion, this study provides the first evidence on mechanisms underlying the toxicity of both pyocyanin and 1-hydroxyphenazine to astrocytoma cells and provides novel evidence suggesting that this toxicity may be mediated by the formation of acidic vesicular organelles, a hallmark of autophagic cell death.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence.

Abstract: Pseudomonas aeruginosa is an opportunistic pathogen affecting immunocompromised patients. It is known as the leading cause of morbidity and mortality in cystic fibrosis (CF) patients and as one of the leading causes of nosocomial infections. Due to a range of mechanisms for adaptation, survival and resistance to multiple classes of antibiotics, infections by P. aeruginosa strains can be life-threatening and it is emerging worldwide as public health threat. This review highlights the diversity of mechanisms by which P. aeruginosa promotes its survival and persistence in various environments and particularly at different stages of pathogenesis. We will review the importance and complexity of regulatory networks and genotypic-phenotypic variations known as adaptive radiation by which P. aeruginosa adjusts physiological processes for adaptation and survival in response to environmental cues and stresses. Accordingly, we will review the central regulatory role of quorum sensing and signaling systems by nucleotide-based second messengers resulting in different lifestyles of P. aeruginosa. Furthermore, various regulatory proteins will be discussed which form a plethora of controlling systems acting at transcriptional level for timely expression of genes enabling rapid responses to external stimuli and unfavorable conditions. Antibiotic resistance is a natural trait for P. aeruginosa and multiple mechanisms underlying different forms of antibiotic resistance will be discussed here. The importance of each mechanism in conferring resistance to various antipseudomonal antibiotics and their prevalence in clinical strains will be described. The underlying principles for acquiring resistance leading pan-drug resistant strains will be summarized. A future outlook emphasizes the need for collaborative international multidisciplinary efforts to translate current knowledge into strategies to prevent and treat P. aeruginosa infections while reducing the rate of antibiotic resistance and avoiding the spreading of resistant strains.

Statins for the prevention of dementia

Abstract: Background This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of dementia due to Alzheimer's disease and of vascular dementia. Some observational studies have suggested an association between statin use and lowered incidence of dementia. Objectives To evaluate the efficacy and safety of statins for the prevention of dementia in people at risk of dementia due to their age and to determine whether the efficacy and safety of statins for this purpose depends on cholesterol level, apolipoprotein E (ApoE) genotype or cognitive level. Search methods We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 11 November 2015. Selection criteria We included double-blind, randomised, placebo-controlled trials in which statins were administered for at least 12 months to people at risk of dementia. Data collection and analysis We used standard methodological procedures expected by Cochrane. Main results We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05). Authors' conclusions There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.