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Background: Methamphetamine use disorder (MUD) associates with cognitive impulsivity deficits. However, few studies have examined longitudinal changes in cognition, and it remains unclear if defici...

Introduction: The cognitive profiles of people with methamphetamine use disorder are characterized by impulsivity and impairment in social cognition. However, previous studies have not fully accounted for the presence and impact of co-occurring mental health problems on these domains. For instance, psychotic symptoms are commonly experienced by people who use methamphetamine and may influence cognitive performance. We aimed to examine decision making and emotion recognition in individuals with methamphetamine use, compared to healthy controls, to map the nature and degree of impairments in relation to the presence of psychotic symptoms. Method: In this naturalistic study, we assessed reward-based decision-making and facial emotion recognition across three groups, methamphetamine-using individuals with (MAP, n = 29) and without psychotic symptoms (MNP, n = 70), and healthy controls (HC, n = 32). Results: In comparison to healthy controls, methamphetamine-using individuals presented with poorer performance on tasks of decision-making and emotion recognition. Emotion recognition was impaired across all methamphetamine-using individuals, with significantly poorer recognition of anger and sadness in those with psychotic symptoms. Conclusion: We found specific impairments in emotion recognition in relation to psychotic symptoms in people who use methamphetamine regularly. This builds on previous evidence on cognitive profiles in methamphetamine use disorder, highlighting the need to assess co-morbid mental health and psychotic symptoms. Our finding that methamphetamine-using individuals with psychotic symptoms present with particular difficulties recognizing anger has implications for frontline clinicians.

Background and aims Methamphetamine dependence is associated with heightened impulsivity and diminished quality of life, but the link between impulsivity and changes in quality of life during treatment has not been examined. We aimed to investigate how different elements of impulsivity predict change in quality of life in the 6 weeks after engaging in treatment. Design Longitudinal, observational cohort study. Setting Public and private detoxification and rehabilitation facilities in metropolitan Melbourne, Australia. Participants One hundred and eight individuals with methamphetamine dependence (81 male) tested within 3 weeks of commencing treatment; 80 (74%) were followed-up at 6 weeks. Measurements The Continuous Performance Test-2 measured impulsive action (cognitive and motor impulsivity); the Delay Discounting Task measured impulsive choice. Quality of life was measured with the World Health Organization Quality of Life Scale-Brief, which includes social, psychological, physical and environment domains. Control variables included age, gender, estimated IQ, depression severity score, methamphetamine dependence severity score, cannabis dependence severity score and treatment modality. Findings We found that all three forms of impulsivity were significant predictors of change in the social domain: motor impulsivity (β = -0.54, P = 0.013), cognitive impulsivity (β = -0.46, P = 0.029) and impulsive choice (β = -0.26, P = 0.019). Change in the psychological domain was predicted significantly by motor impulsivity (β = -0.45, P = 0.046). Control variables of age and depression were associated significantly with changes in the physical domain. Conclusions In Australian methamphetamine-dependent individuals, elevated impulsivity predicts lower improvement of social and psychological quality of life in the first 6-9 weeks of treatment.

Background Early treatment motivation is a meaningful predictor of clinical outcomes in the context of methamphetamine dependence (MD). Cognitive deficits associated with MD can have a significant impact on motivational fluctuations during early treatment. We specifically examined if sustained attention and effort-based decision-making predict early treatment motivation change in individuals with MD. We hypothesised that both variables would be significant predictors of individual differences in treatment motivation change. Methods We conducted a longitudinal, observational, cohort study on individuals with MD (N = 72, Age, M = 31.1, SD = 7.3, 29% female). Participants were assessed with cognitive tests of sustained attention (continuous performance test) and effort-based decision-making (effort expenditure for rewards task) within three weeks of entering treatment and rated their treatment motivation at baseline and at follow up six weeks later (n = 50). Multiple regression was used to examine the predictive value of cognitive variables after controlling for nuisance variables. Results Cognitive measures significantly predicted change in treatment motivation after accounting for nuisance variables, F(5,43) = 2.89, p = .025. Analysis of individual predictors showed that sustained attention, but not decision-making, was a significant negative predictor of improvement in treatment motivation (β = −0.34, p = .015). Conclusions Poorer attentional function was associated with limited improvement in motivation during early treatment. These findings help to characterise cognitive predictors of treatment motivation and suggest directions for tailored treatment programs. Individuals entering treatment with attentional deficits may benefit from adjustments to therapy and/or cognitive remediation.

High impulsivity and poor executive function are characteristic of methamphetamine use disorder. High arousal in the impulsive system has been proposed to compromise the executive system's regulating ability (i.e. the dual-systems model). While interaction between these variables may partly explain poor treatment outcomes associated with methamphetamine use disorder, previous research has tended to examine each factor separately. We investigated whether high impulsivity (measured with an impulsive choice task) and poor executive function (measured with a working memory task) predict methamphetamine use (determined by hair sample) in the 6 weeks following treatment commencement. We also investigated whether impulsive choice moderates the relationship between working memory and methamphetamine use. One hundred and eight individuals with methamphetamine use disorder (75 percent male) were tested within 3 weeks of commencing treatment; 80 (74 percent) were followed up 6 weeks following baseline testing. Cognitive measures significantly predicted drug use after controlling for nuisance variables. Working memory was a significant predictor, while impulsive choice was not. The interaction model included working memory as a predictor and impulsive choice as a moderator. This model was significant, as was the interaction term. Working memory significantly predicted levels of methamphetamine use in early treatment, and impulsive choice moderated this relationship. Those with working memory deficits are particularly vulnerable to using greater amounts of methamphetamine. As working memory increased methamphetamine use decreased among individuals with low/medium delay discounting. Pre-treatment cognitive testing may identify patients at high risk, while remediation of working memory function may be a treatment target for reducing methamphetamine use.

Background and Objective: Porphyromonas gingivalis, an anaerobic bacterium associated with adult periodontal disease, employs a number of pathogenic mechanisms, including protease/adhesin complexes (gingipains), fimbriae and hemagglutinins, to maintain attachment within colonized hosts. Here we examined the binding of gingipains and whole, live P. gingivalis cells to immobilized extracellular matrix proteins in the presence of soluble forms of the same proteins, to investigate whether this may constitute a colonization mechanism in the oral environment. Material and Methods: Binding of purified gingipain molecules and whole bacterial cells to immobilized matrix proteins was examined in the presence and absence of soluble competitors using enzyme-linked immunosorbent assays. Results: Purified gingipains or whole, live bacteria preferentially bound immobilized forms of matrix proteins, even in the presence of soluble forms of the same proteins. Fimbriae appeared to be redundant for adhesion to immobilized proteins in the presence of the gingipains, indicating that the protease/adhesins and hemagglutinins may be more important for adhesion under these conditions. Conclusion: The data presented here provide evidence for a model of adhesion for P. gingivalis within the fluid environment of the oral cavity, where preferential binding of matrix-located proteins over soluble forms facilitates colonization of the host.

Periodontal disease is an oral inflammatory disease affecting the supporting structures of teeth. Porphyromonas gingivalis, a major pathogenic agent for the disease, expresses a number of virulence factors, including cysteine proteases called the gingipains. The arginine- and lysine-specific gingipains, HRgpA and Kgp, respectively, are expressed as high molecular weight forms containing both catalytic and adhesin subunits. We examined the expression pattern of cytokines and their receptors in differentiated macrophages following exposure to active and inactive forms of the gingipains, using a cDNA array, quantitative PCR and ELISA analysis. Amongst other pro-inflammatory cytokines, results from the cDNA array suggested that interleukin-1β, granulocyte-macrophage colony stimulatory factor and interferon-γ were upregulated after exposure of the macrophages to the gingipains. Quantitative PCR analysis substantiated these observations and indicated that active or inactive forms of the high molecular weight gingipains were able to upregulate expression of transcripts for these cytokines. The strongly enhanced production of interleukin-1β and granulocyte-macrophage colony stimulatory factor by differentiated macrophages in response to active or inactive forms of the high molecular weight gingipains was confirmed at the protein level by ELISA analysis. The results indicate that the adhesin subunits of the gingipains mediate strong upregulation of the expression of pro-inflammatory cytokines in macrophages.

Background and Objective: Porphyromonas gingivalis is a major aetiological agent in the development of periodontitis, the major clinical hallmark of which is bone resorption. The cysteine proteases (gingipains) produced by P. gingivalis have a critical role in the pathogenesis of the disease, and previous studies on whole bacteria have implicated these enzymes in osteoclastogenesis, a process which serves to upregulate bone resorption. The effects of the gingipains from P. gingivalis on osteoclast differentiation were investigated here to determine whether the enzymes directly contribute to osteoclastogenesis and thus to bone resorption. Material and Methods: The effects of the gingipains on osteoclast differentiation were investigated in primary mouse bone marrow cultures. The cultures harvested from C57BL6/J mice were incubated in the presence of parathyroid hormone, a known osteoclastogenic factor, or active/inactivated forms of three gingipains. Osteoclast differentiation was quantified by counting the number of multinucleated cells positive for tartrate-resistant acid phosphatase, an enzyme marker for these cells. Results: After 10 days of culture, the gingipains, either active or inactive, failed to stimulate osteoclast differentiation in comparison to the parathyroid hormone. Conclusion: The data presented here demonstrate that the gingipains do not induce osteoclast differentiation in this system, indicating that the bacterium uses other mechanisms to induce bone loss.

Autotransporters are a superfamily of virulence factors typified by a channel-forming C terminus that facilitates translocation of the functional N-terminal passenger domain across the outer membrane of Gram-negative bacteria. This final step in the secretion of autotransporters requires a translocation-competent conformation for the passenger domain that differs markedly from the structure of the fully folded secreted protein. The nature of the translocation-competent conformation remains controversial, in particular whether the passenger domain can adopt secondary structural motifs, such as disulfide-bonded segments, while maintaining a secretion-competent state. Here, we used the endogenous and closely spaced cysteine residues of the plasmid-encoded toxin (Pet) from enteroaggregative Escherichia coli to investigate the effect of disulfide bond-induced folding on translocation of an autotransporter passenger domain. We reveal that rigid structural elements within disulfide-bonded segments are resistant to autotransporter-mediated secretion. We define the size limit of disulfide-bonded segments tolerated by the autotransporter system demonstrating that, when present, cysteine pairs are intrinsically closely spaced to prevent congestion of the translocator pore by large disulfide-bonded regions. These latter data strongly support the hairpin mode of autotransporter biogenesis.

The anaerobic bacterium, Porphyromonas gingivalis, is associated with chronic periodontal disease (periodontitis or gum disease). The disease is not only the leading cause of tooth loss in the developed world, but is associated with a number of systemic diseases, such as cardiovascular disease and diabetes. The most potent virulence factors of this bacterium are the gingipains, three cysteine proteases that bind and cleave a wide range of host proteins. This article summarizes current knowledge of the structure and function of the enzymes, with a particular focus on what remains to be elucidated regarding the structure and function of the nonenzymatic adhesin domains of the high-molecular-weight forms of the proteases.