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"Wood, Stephen J."
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Pseudomonas aeruginosa: Infections, Animal Modeling, and Therapeutics
Pseudomonas aeruginosa is an important Gram-negative opportunistic pathogen which causes many severe acute and chronic infections with high morbidity, and mortality rates as high as 40%. What makes P. aeruginosa a particularly challenging pathogen is its high intrinsic and acquired resistance to many of the available antibiotics. In this review, we review the important acute and chronic infections caused by this pathogen. We next discuss various animal models which have been developed to evaluate P. aeruginosa pathogenesis and assess therapeutics against this pathogen. Next, we review current treatments (antibiotics and vaccines) and provide an overview of their efficacies and their limitations. Finally, we highlight exciting literature on novel antibiotic-free strategies to control P. aeruginosa infections.
Journal Article
Risk Perception and Risk-Taking Behaviour during Adolescence: The Influence of Personality and Gender
This study investigated the influence of personality characteristics and gender on adolescents' perception of risk and their risk-taking behaviour. Male and female participants (157 females: 116 males, aged 13-20) completed self-report measures on risk perception, risk-taking and personality. Male participants perceived behaviours as less risky, reportedly took more risks, were less sensitive to negative outcomes and less socially anxious than female participants. Path analysis identified a model in which age, behavioural inhibition and impulsiveness directly influenced risk perception, while age, social anxiety, impulsiveness, sensitivity to reward, behavioural inhibition and risk perception itself were directly or indirectly associated with risk-taking behaviour. Age and behavioural inhibition had direct relationships with social anxiety, and reward sensitivity was associated with impulsiveness. The model was representative for the whole sample and male and female groups separately. The observed relationship between age and social anxiety and the influence this may have on risk-taking behaviour could be key for reducing adolescent risk-taking behaviour. Even though adolescents may understand the riskiness of their behaviour and estimate their vulnerability to risk at a similar level to adults, factors such as anxiety regarding social situations, sensitivity to reward and impulsiveness may exert their influence and make these individuals prone to taking risks. If these associations are proven causal, these factors are, and will continue to be, important targets in prevention and intervention efforts.
Journal Article
Heterogeneity in treatment outcomes and incomplete recovery in first episode psychosis: does one size fit all?
The heterogeneity in recovery outcomes for individuals with First Episode Psychosis (FEP) calls for a strong evidence base to inform practice at an individual level. Between 19–89% of young people with FEP have an incomplete recovery despite gold-standard evidence-based treatments, suggesting current service models, which adopt a ‘one-size fits all’ approach, may not be addressing the needs of many young people with psychosis. The lack of consistent terminology to define key concepts such as recovery and treatment resistance, the multidimensional nature of these concepts, and common comorbid symptoms are some of the challenges faced by the field in delineating heterogeneity in recovery outcomes. The lack of robust markers for incomplete recovery also results in potential delay in delivering prompt, and effective treatments to individuals at greatest risk. There is a clear need to adopt a stratified approach to care where interventions are targeted at subgroups of patients, and ultimately at the individual level. Novel machine learning, using large, representative data from a range of modalities, may aid in the parsing of heterogeneity, and provide greater precision and sophistication in identifying those on a pathway to incomplete recovery.
Journal Article
Autism and schizophrenia: One, two or many disorders?
Autism and psychotic disorders such as schizophrenia co-occur more frequently than would be expected by chance alone. Exactly why this should be remains unclear, but a better understanding would have important implications for diagnosis, treatment and for biological explanations of both conditions.
Journal Article
Psychosocial functioning in the balance between autism and psychosis: evidence from three populations
Functional impairment is a core feature of both autism and schizophrenia spectrum disorders. While diagnostically independent, they can co-occur in the same individual at both the trait and diagnostic levels. The effect of such co-occurrence is hypothesized to worsen functional impairment. The diametric model, however, suggests that the disorders are etiologically and phenotypically diametrical, representing the extreme of a unidimensional continuum of cognition and behavior. A central prediction of this model is that functional impairment would be attenuated in individuals with mixed symptom expressions or genetic liability to both disorders. We tested this hypothesis in two clinical populations and one healthy population. In individuals with chronic schizophrenia and in individuals with first episode psychosis we evaluated the combined effect of autistic traits and positive psychotic symptoms on psychosocial functioning. In healthy carriers of alleles of copy number variants (CNVs) that confer risk for both autism and schizophrenia, we also evaluated whether variation in psychosocial functioning depended on the combined risk conferred by each CNV. Relative to individuals with biased symptom/CNV risk profiles, results show that functional impairments are attenuated in individuals with relatively equal levels of positive symptoms and autistic traits—and specifically stereotypic behaviors—, and in carriers of CNVs with relatively equal risks for either disorder. However, the pattern of effects along the “balance axis” varied across the groups, with this attenuation being generally less pronounced in individuals with high-high symptom/risk profile in the schizophrenia and CNV groups, and relatively similar for low-low and high-high individuals in the first episode psychosis group. Lower levels of functional impairments in individuals with “balanced” symptom profile or genetic risks would suggest compensation across mechanisms associated with autism and schizophrenia. CNVs that confer equal risks for both disorders may provide an entry point for investigations into such compensatory mechanisms. The co-assessment of autism and schizophrenia may contribute to personalized prognosis and stratification strategies.
Journal Article
A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance
Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the human pathogen
Streptococcus pneumoniae
responds to 20 antibiotics. We build a genome-wide atlas of drug susceptibility determinants and generated a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide atlas of cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in genes that decrease antibiotic sensitivity and increase tolerance readily evolve and are frequently associated with resistant strains, indicating such mutations could be harbingers for the emergence of antibiotic resistance.
A lack of understanding in the development and emergence of antimicrobial resistance presents as a problem for accurate infection diagnosis and treatment. Here, authors utilize
Streptococcus pneumoniae
and build a genome-wide atlas to understand the genes and interactions that contribute to altered drug susceptibility.
Journal Article
Re-imaging the intentional stance
The commonly used paradigm to investigate Dennet's ‘intentional stance’ compares neural activation when participants compete with a human versus a computer. This paradigm confounds whether the opponent is natural or artificial and whether it is intentional or an automaton. This functional magnetic resonance imaging study is, to our knowledge, the first to investigate the intentional stance by orthogonally varying perceptions of the opponents' intentionality (responding actively or passively according to a script) and embodiment (human or a computer). The mere perception of the opponent (whether human or computer) as intentional activated the mentalizing network: the temporoparietal junction (TPJ) bilaterally, right temporal pole, anterior paracingulate cortex (aPCC) and the precuneus. Interacting with humans versus computers induced activations in a more circumscribed right lateralized subnetwork within the mentalizing network, consisting of the TPJ and the aPCC, possibly reflective of the tendency to spontaneously attribute intentionality to humans. The interaction between intentionality (active versus passive) and opponent (human versus computer) recruited the left frontal pole, possibly in response to violations of the default intentional stance towards humans and computers. Employing an orthogonal design is important to adequately capture Dennett's conception of the intentional stance as a mentalizing strategy that can apply equally well to humans and other intentional agents.
Journal Article
Pseudomonas aeruginosa Cytotoxins: Mechanisms of Cytotoxicity and Impact on Inflammatory Responses
Pseudomonas aeruginosa is one of the most virulent opportunistic Gram-negative bacterial pathogens in humans. It causes many acute and chronic infections with morbidity and mortality rates as high as 40%. P. aeruginosa owes its pathogenic versatility to a large arsenal of cell-associated and secreted virulence factors which enable this pathogen to colonize various niches within hosts and protect it from host innate immune defenses. Induction of cytotoxicity in target host cells is a major virulence strategy for P. aeruginosa during the course of infection. P. aeruginosa has invested heavily in this strategy, as manifested by a plethora of cytotoxins that can induce various forms of cell death in target host cells. In this review, we provide an in-depth review of P. aeruginosa cytotoxins based on their mechanisms of cytotoxicity and the possible consequences of their cytotoxicity on host immune responses.
Journal Article
Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial
The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/; ACTRN12607000608460).
Journal Article