Lack of longitudinal changes in cognition in individuals with methamphetamine use disorder during the first 6 weeks after commencing treatment.

Background: Methamphetamine use disorder (MUD) associates with cognitive impulsivity deficits. However, few studies have examined longitudinal changes in cognition, and it remains unclear if deficits resolve during early recovery.Objectives: To compare: (1) cognitive function of individuals with MUD at treatment onset and six-weeks later with controls tested over the same period; (2) cognitive changes in MUD-individuals who remained abstinent versus relapsed.Method: We recruited 108 participants meeting DSM-IV-TR criteria for methamphetamine dependence (81 males) and 50 demographically matched controls (38 males); 77 methamphetamine- dependent participants (59 males) and 48 controls (36 males) were retained at follow-up. We administered response inhibition, delay discounting and uncertainty-based decision-making tests at both endpoints. Relapse was defined as methamphetamine concentrations >0.4 ng/mg at follow-up in hair toxicology.Results: We found a significant time-by-group interaction on uncertainty-based decision-making (effect size: η2 = .05), although post-hoc tests to disentangle this interaction yielded inconclusive results (p-range = .14-.40; BF10-range = 0.43-1.67). There were no significant time-by-group interactions on response inhibition or delay discounting, with the former likely a null effect (η2-interaction = .003 and .02; BFincl = 0.23 and 0.71). There were no significant differences in cognitive recovery between individuals who maintained abstinence (n = 12) versus relapsed (n = 65) (η2-range = .003-.04), although evidence was inconclusive toward whether findings reflected true null effects (BFincl-range = 0.33-0.75).Conclusion: We did not find evidence that MUD-related cognitive impulsivity deficits improve beyond practice effects over 6 weeks. Findings do not support previous, albeit conflicting, evidence of early recovery of cognitive deficits in MUD.

Working memory predicts methamphetamine hair concentration over the course of treatment: moderating effect of impulsivity and implications for dual-systems model.

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.

Size and conformation limits to secretion of disulfide-bonded loops in autotransporter proteins.

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.

Cognitive deficits in methamphetamine addiction: Independent contributions of dependence and intelligence.

BACKGROUND: Methamphetamine's effects on brain function have been associated with cognitive deficits, which have a negative impact on clinical outcomes. However, it remains unclear if cognitive deficits relate to methamphetamine dependence (potentially amenable to abstinence and retraining) or background characteristics, mental health and other drug use. We tested the association between methamphetamine dependence and cognitive performance, while factoring in the impact of background characteristics, depressive symptoms and tobacco, alcohol and cannabis use. METHOD: The sample comprised 108 treatment-seeking participants who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV TR) criteria for methamphetamine dependence and 50 socio-demographically matched controls. We administered a comprehensive neuropsychological test battery (delay discounting, decision making, disinhibition, episodic and working memory) and examined cognitive deficits in methamphetamine users after taking into account socio-demographic characteristics, tobacco, alcohol and cannabis use, and depressive symptoms. RESULTS: Hierarchical multiple regression analyses showed that methamphetamine dependence was associated with poorer performance in decision-making and disinhibition over and above other predictors, while IQ better explained performance in episodic and working memory. Although duration of methamphetamine use was linked to disinhibition, other patterns of methamphetamine use (including dose and frequency) were not consistently related to performance. CONCLUSIONS: Methamphetamine dependence impacts inhibitory control and decision-making, whereas lower IQ associates with memory/working memory deficits among methamphetamine users. Findings suggest the need to target disinhibition and impulsive decision-making as part of methamphetamine dependence treatment, while buffering the impact of IQ on memory systems.

Emotion Recognition and Impulsive Choice in Relation to Methamphetamine Use and Psychosis Symptoms.

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.

Sustained attention but not effort-based decision-making predicts treatment motivation change in people with methamphetamine dependence.

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 (ß = -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.

Impulsivity predicts poorer improvement in quality of life during early treatment for people with methamphetamine dependence.

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 (ß = -0.54, P = 0.013), cognitive impulsivity (ß = -0.46, P = 0.029) and impulsive choice (ß = -0.26, P = 0.019). Change in the psychological domain was predicted significantly by motor impulsivity (ß = -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.

The gingipains: scissors and glue of the periodontal pathogen, Porphyromonas gingivalis.

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.

High molecular weight gingipains from Porphyromonas gingivalis induce cytokine responses from human macrophage-like cells via a nonproteolytic mechanism.

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-1beta, granulocyte-macrophage colony stimulatory factor and interferon-gamma 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-1beta 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.