Single-Cell Analysis of the Periodontal Immune Niche in Type 2 Diabetes.

Periodontitis (PD) is a common source of uncontrolled inflammation in obesity-associated type 2 diabetes (T2D). PD apparently fuels the inflammation of T2D and associates with poor glycemic control and increased T2D morbidity. New therapeutics are critically needed to counter the sources of periodontal infection and inflammation that are accelerated in people with T2D. The precise mechanisms underlying the relationship between PD and T2D remain poorly understood. Every major immune cell subset has been implicated in the unresolved inflammation of PD, regardless of host metabolic health. However, analyses of inflammatory cells in PD with human periodontal tissue have generally focused on mRNA quantification and immunohistochemical analyses, both of which provide limited information on immune cell function. We used a combination of flow cytometry for cell surface markers and enzyme-linked immunospot methods to assess the subset distribution and function of immune cells isolated from gingiva of people who had PD and were systemically healthy, had PD and T2D (PD/T2D), or, for flow cytometry, were systemically and orally healthy. T-cell subsets dominated the cellular immune compartment in gingiva from all groups, and B cells were relatively rare. Although immune cell frequencies were similar among groups, a higher proportion of CD11b+ or CD4+ cells secreted IFNγ/IL-10 or IL-8, respectively, in cells from PD/T2D samples as compared with PD-alone samples. Our data indicate that fundamental differences in gingival immune cell function between PD and T2D-potentiated PD may account for the increased risk and severity of PD in subjects with T2D. Such differences may suggest unexpected therapeutic targets for alleviating periodontal inflammation in people with T2D.

The effect of smoking cessation counselling in pregnant women: a meta-analysis of randomised controlled trials.

BACKGROUND: Pregnant smokers are often prescribed counselling as part of multicomponent cessation interventions. However, the isolated effect of counselling in this population remains unclear, and individual randomised controlled trials (RCTs) are inconclusive. OBJECTIVE: To conduct a meta-analysis of RCTs examining counselling in pregnant smokers. SEARCH STRATEGY: We searched the CDC Tobacco Information and Prevention, Cochrane Library, EMBASE, Medline and PsycINFO databases for RCTs evaluating smoking cessation counselling. SELECTION CRITERIA: We included RCTs conducted in pregnant women in which the effect of counselling could be isolated and those that reported biochemically validated abstinence at 6 or 12 months after the target quit date. DATA COLLECTION AND ANALYSIS: Overall estimates were derived using random effects meta-analysis models. MAIN RESULTS: Our search identified eight RCTs (n = 3290 women), all of which examined abstinence at 6 months. The proportion of women that remained abstinent at the end of follow up was modest, ranging from 4 to 24% among those randomised to counselling and from 2 to 21% among control women. The absolute difference in abstinence reached a maximum of only 4%. Summary estimates are inconclusive because of wide confidence intervals, albeit with little evidence to suggest that counselling is efficacious at promoting abstinence (odds ratio 1.08, 95% confidence interval 0.84-1.40). There was no evidence to suggest that efficacy differed by counselling type. CONCLUSIONS: Available data from RCTs examining the isolated effect of smoking cessation counselling in pregnant women are limited but sufficient to rule out large treatment effects. Future RCTs should examine pharmacological therapies in this population.

Effects of alcohol on cardiovascular reactivity and the mediation of aggressive behaviour in adult men and women.

AIMS: Recent models have proposed several pharmacological means by which alcohol may produce heightened aggression, among them that alcohol may both hyper-arouse the reward system and diminish the threat detection system. The current study examined these hypotheses employing heart rate and blood pressure as physiological indices of arousal, examining whether arousal differed by alcohol group, and if this related to level of aggression. METHODS: Participants were 32 males and 32 females, aged 18-30 years, screened for physical and psychological disorder, who competed on the Taylor aggression paradigm. The gender groups were further split into half sober, half intoxicated. Arousal was measured at baseline, post-beverage consumption, and post-aggression paradigm. RESULTS: Participants in the alcohol condition initially demonstrated slight heart rate elevations and blood pressure decreases, but showed little arousal in response to the aggression paradigm, whereas sober participants demonstrated considerable arousal on both indices. Intoxicated participants were more aggressive than sober controls; men and women did not differ significantly. Regression analyses demonstrated that change in systolic blood pressure from post-beverage consumption to post-aggression paradigm acts as a mediating variable in the alcohol-aggression relationship. CONCLUSIONS: These results lend support to the stress-response dampening model of the alcohol-aggression relationship, and moreover suggest that the magnitude of intoxicated aggression is related to the magnitude of that dampening.

Reliability and validity of alcohol-induced heart rate increase as a measure of sensitivity to the stimulant properties of alcohol.

RATIONALE: Alcohol-induced heart rate (HR) stimulation during the rising limb of the blood alcohol curve reliably discriminates between individuals at differential risk for alcoholism, and appears to be a potential psychophysiological index of psychomotor stimulation from alcohol. OBJECTIVES: Three studies are presented which explore the reliability and convergent and discriminant validity of this alcohol response index. METHODS: Young men with and without a multigenerational family history of alcoholism were administered a 1.0 ml/kg dose of 95% USP alcohol. Resting baseline cardiac and subjective measures were assessed before and after alcohol consumption. RESULTS: Study 1 demonstrated that alcohol-induced HR stimulation was significantly and positively related to alcohol-induced changes in mood. Study 2 demonstrated that alcohol-induced HR stimulation was reliable across two alcohol administration sessions (r=0.33-0.66, P<0.01). Study 3 explored the relationship between the proposed index and measures of sensitivity to alcohol previously linked to genetic predisposition to alcoholism. Multiple regression analysis indicated that alcohol-induced HR increase and reduced subjective intoxication (measured using the Subjective High Assessment Scale) were both positively associated with alcohol-induced changes in mood states that have previously been shown to be sensitive to the effects of stimulant drugs and the reinforcing effects of alcohol. CONCLUSIONS: Sensitivity to alcohol-induced heart-rate stimulation during the ascending limb of the blood alcohol curve may be a useful and informative marker for understanding susceptibility to alcoholism.

Psychometric evaluation of the short form inventory of drinking situations (IDS-42) in a community-recruited sample of substance-abusing women.

PURPOSE: We investigated the psychometric properties (factor structure, internal consistency reliability, concurrent validity) of the Short Form Inventory of Drinking Situations (IDS-42) in women substance abusers. METHODS: A sample of 297 substance-abusing women was recruited from the community. The women completed the IDS-42 and the three-factor Drinking Motives Questionnaire (DMQ). RESULTS: Confirmatory factor analyses of IDS-42 items suggested a hierarchical structure for the scale. Eight factors (corresponding to Marlatt and Gordon's eight heavy drinking situations) provided the best model fit at the lower-order level, and three factors (i.e., Negatively Reinforcing vs. Positively Reinforcing vs. Temptation Situations) provided the best model fit at the higher-order level. Lower- and higher-order IDS-42 subscales were shown to possess adequate-to-high levels of internal consistency. The eight lower-order IDS-42 factors demonstrated excellent concurrent validity with conceptually similar DMQ subscale scores. Across the entire sample of female substance abusers, a higher frequency of heavy drinking was reported in Positively Reinforcing Situations and Unpleasant Emotions Situations, as compared to other heavy drinking situations. IMPLICATIONS: Results support the IDS-42's good psychometric properties and demonstrate its utility as a tool in identifying situation-specific antecedents to heavy drinking among women substance abusers.

The effects of alcohol intoxication on aggressive responses in men and women.

A considerable literature, clinical and experimental, has demonstrated the aggression-eliciting effects of alcohol intoxication. However, the focus of the experimental literature has been primarily on men and the studies on women have been inconclusive. This study was conducted to test for possible gender differences in the manifestation of alcohol-induced aggression. Participants were 54 males and 60 females, aged 18-30 years, who competed in a competitive aggression paradigm either sober or intoxicated. As expected, intoxicated men were more aggressive than their sober peers. However, under high provocation, both sober and intoxicated, women manifested aggression comparable to the intoxicated men. This study suggests that women can be as aggressive as men, and that alcohol intoxication does not seem to be as important a determining factor.

Efficacy of brief coping skills interventions that match different personality profiles of female substance abusers.

Female substance abusers recruited from the community were randomly assigned to receive 1 of 3 brief interventions that differentially targeted their personality and reasons for drug use. The 90-min interventions were: (a) a motivation-matched intervention involving personality-specific motivational and coping skills training, (b) a motivational control intervention involving a motivational film and a supportive discussion with a therapist, and (c) a motivation-mismatched intervention targeting a theoretically different personality profile. Assessment 6 months later (N = 198) indicated that only the matched intervention proved to be more effective than the motivational control intervention in reducing frequency and severity of problematic alcohol and drug use and preventing use of multiple medical services. These findings indicate promise for a client-treatment matching strategy that focuses on personality-specific motives for substance abuse.

Validation of a system of classifying female substance abusers on the basis of personality and motivational risk factors for substance abuse.

This study explored the validity of classifying a community-recruited sample of substance-abusing women (N = 293) according to 4 personality risk factors for substance abuse (anxiety sensitivity, introversion-hopelessness, sensation seeking, and impulsivity). Cluster analyses reliably identified 5 subtypes of women who demonstrated differential lifetime risk for various addictive and nonaddictive disorders. An anxiety-sensitive subtype demonstrated greater lifetime risk for anxiolytic dependence, somatization disorder, and simple phobia, whereas an introverted-hopeless subtype evidenced a greater lifetime risk for opioid dependence, social phobia, and panic and depressive disorders. Sensation seeking was associated with exclusive alcohol dependence, and impulsivity was associated with higher rates of antisocial personality disorder and cocaine and alcohol dependence. Finally, a low personality risk subtype demonstrated lower lifetime rates of substance dependence and psychopathology.

Acute tyrosine depletion and alcohol ingestion in healthy women.

BACKGROUND: Recently we reported that, in vervet monkeys, ingestion of an amino acid mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, produced a decrease in alcohol self-administration. We now report the results of a similar study in humans. METHODS: Three groups of healthy female social drinkers were administered a nutritionally balanced amino acid mixture (B, n = 13), a mixture deficient in the serotonin precursor, tryptophan (Trp-free, n = 14), or a phenylalanine/tyrosine deficient mixture (Phe/Tyr-free, n = 12). Six hours after administration of the amino acid mixture, alcohol ingestion was measured during a free-choice "Taste Test." RESULTS: Compared to the B mixture, Phe/Tyr-free, but not Trp-free, significantly decreased the ingestion of alcohol [p < 0.02]. Neither Phe/Tyr-free nor Trp-free significantly decreased orange juice ingestion or the self-reported "Liking" of either substance. Some subjects experienced transient nausea and/or regurgitated the amino acid mixtures, but excluding these subjects did not change the results. CONCLUSIONS: The results suggest that (a) Phe/Tyr-free may be a suitable method for investigating the role of catecholamines in the self-administration and subjective effects of alcohol, (b) acutely decreased catecholamine neurotransmission might disrupt mechanisms mediating alcohol self-administration, and (c) acutely decreased serotonin neurotransmission seems not to alter alcohol self-administration.

Effects on mood of acute phenylalanine/tyrosine depletion in healthy women.

Catecholamines have been implicated in the etiology and pathophysiology of mood and anxiety disorders. In the present study, we investigated the effects of experimentally reducing catecholamine neurotransmission by means of acute phenylalanine/tyrosine depletion (APTD). Healthy female volunteers ingested: (1) a nutritionally balanced amino acid (AA) mixture (n = 14); (2) a mixture deficient in the serotonin precursor, tryptophan (n = 15); or (3) one deficient in the catecholamine precursors, phenylalanine and tyrosine (n = 12). Mood was measured at three times: at baseline and both immediately before and after an aversive psychological challenge (public speaking and mental arithmetic) conducted 5 hours after AA mixture ingestion. Acute tryptophan depletion (ATD) lowered mood and energy and increased irritability scores. These effects were statistically significant only after the psychological challenge. The effect of APTD on mood was similar to that of ATD. APTD did not attenuate the anxiety caused by the psychological challenge. These findings suggest that, in healthy women, reduced serotonin and/or catecholamine neurotransmission increases vulnerability to lowered mood, especially following exposure to aversive psychological events.

Executive functions and physical aggression after controlling for attention deficit hyperactivity disorder, general memory, and IQ.

This study examined the role of ADHD in the association between physical aggression and two types of executive functions. Boys received a cognitive-neuropsychological test battery over the ages of 13, 14, and 15 years. Diagnostic Interview Schedule for Children (DISC 2.25) data were collected from the boys and one parent between ages 14 and 16, and an IQ estimate was obtained at age 15. Three groups, differing in stability and level of physical aggression since kindergarten, were formed: Stable Aggressive, Unstable Aggressive, and Non-aggressive. Composite scores of validated executive function tests of working memory representing subjective ordering and conditional association learning were formed. A MANCOVA (N = 149) using ADHD status, teacher-rated negative emotionality, general memory abilities, and IQ as covariates was performed on the two composite scores. ADHD and teacher-rated emotionality did not provide significant adjustment to the dependent variables. Number of ADHD symptoms was negatively associated only with general memory and IQ. General memory contributed significantly to adjusting for conditional association test scores. Group differences indicated lower conditional association scores for Unstable Aggressive boys relative to the other groups. Both IQ and general memory abilities interacted with subjective ordering within the groups. Specifically, Stable Aggressive boys performed poorly on this measure and did not benefit from increases in IQ whereas Nonaggressive boys performed best and were not disadvantaged by lower general memory abilities. This suggests a relationship exists between aspects of working memory and a history of physical aggression regardless of ADHD and IQ.

Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism.

OBJECTIVE: A deficit in serotonergic neurotransmission has been linked to impulsive behavior, as well as to disorders characterized by disinhibition. The present study tested the hypothesis that young men at high risk for alcoholism demonstrate greater behavioral disinhibition after acute dietary depletion of tryptophan, the amino acid precursor of serotonin. METHOD: A double-blind, placebo-comparison, between-subjects study design was used. Nonalcoholic young men with a multigenerational paternal family history of alcoholism (N = 13) or with no family history of alcoholism (N = 15) in two previous generations were administered mixtures of tryptophan-deficient amino acid to achieve plasma tryptophan depletion. Comparison subjects with a multigenerational paternal family history of alcoholism (N = 1) and comparison subjects with no family history of alcoholism (N = 18) were given a balanced mixture. Five hours after this, all were tested on a modified Taylor task and a go/ no-go task measuring aggressive response and disinhibition, respectively. RESULTS: Plasma tryptophan levels were reduced by 89% in both groups. Tryptophan depletion had no effect on aggressive response. In contrast, tryptophan-depleted individuals with a family history of alcoholism made more commission errors (responses to stimuli associated with punishment or loss of reward) than did tryptophan-depleted individuals with no family history of alcoholism and those receiving the balanced (comparison) mixture of amino acid in either group. CONCLUSIONS: Low serotonin levels may be implicated in the high disinhibition or impulsivity observed in some individuals with a genetic vulnerability to alcohol abuse or dependence.

Motivational effects of alcohol on memory consolidation and heart rate in social drinkers.

Several studies have documented the retrograde facilitation of memory by alcohol, but the mechanisms responsible for this curious effect are unknown. In an experiment designed to complement previous studies on incidental learning, social drinkers (men aged 18 to 30; n = 44) took part in an experiment examining the effects of alcohol on intentional learning of emotionally salient verbal stimuli. Learning occurred when participants were sober. Alcohol or placebo (1.0 vs. 0.1 ml/kg) was consumed after learning, and memory was tested, sober, 24 hr later. Compared with placebo, alcohol modestly enhanced recall of positive but not negative stimuli. Furthermore, results suggest that the reinforcing effects on memory for positive (relative to negative) stimuli occurred in association with acute psychomotor stimulant effects during the ascending limb of the blood alcohol curve. The present finding that alcohol appeared to enhance intentional learning in association with its incentive effects contrasts results from previous studies, demonstrating that alcohol appears to enhance incidental learning by memory mechanisms independent of its incentive effects. These findings support a theory of alcoholism that is based on motivational systems.

Alcohol and retrograde memory effects: role of individual differences.

OBJECTIVE: When alcohol is consumed following learning, the effect on delayed, sober memory can vary from person to person. We examined a range of individual differences to look for predictors of this variability. METHOD: Male social drinkers (N = 65; average age 23.3 years) were exposed to emotionally charged verbal stimulus materials while sober. Participants consumed 1.0 ml/kg alcohol immediately afterward and remained in an environment designed to minimize retrograde interference. Stimulus recall and recognition were tested 24 hours later, when participants had breath-alcohol concentrations of zero. Relationship between memory scores and individual differences (in age, education, alcohol consumption, vocabulary, verbal learning, emotionality, mood state 24 hours after learning, response to alcohol, personality and alcohol expectancies) were determined. RESULTS: Only age and vocabulary were significantly associated with memory score following drinking, probably because they constrained initial understanding of the statements and mediated the effects of alcohol on memory consolidation. CONCLUSIONS: The effects of a given dose of alcohol on emotionally charged verbal memory are similar for men of equal age and verbal skill, but independent of other individual differences. It is most likely that alcohol affects incidental memory by nonspecific enhancement or interference processes.

A comparison of the effects of acute tryptophan depletion and acute phenylalanine/tyrosine depletion in healthy women.

Acute tryptophan depletion (ATD), which is thought to lower serotonin levels, can result in a lowering of mood. In the present study we compared the effect of ATD with acute phenylalanine/tyrosine depletion (APTD) in healthy women. Although considerable evidence relates catecholamines to the regulation of anxiety, there was no difference in anxiety responses in the ATD and APTD groups when the women underwent a mildly stressful psychological challenge. Both ATD and APTD caused a similar lowering of mood. Both depletions also increased heart rate. These results suggest that APTD is a useful method for studying the effect of low catecholamine levels in humans, and that catecholamines are involved in the regulation of mood.

Functional associations among trauma, PTSD, and substance-related disorders.

This review article presents several potential functional pathways which may explain the frequent co-occurrence of PTSD and substance abuse disorders in traumatized individuals. Emerging empirical studies which have examined these potential pathways are reviewed, including studies on relative order of onset, PTSD patients' perceptions of various drug effects, comparisons of PTSD patients with and without comorbid substance use disorders, and correlational studies examining the relations between severity of specific PTSD symptom clusters and substance disorder symptoms. Research on the acute and chronic effects of alcohol and other drugs on cognitive and physiological variables relevant to PTSD intrusion and arousal symptoms is reviewed to highlight ways in which these two sets of PTSD symptoms might be functionally interrelated with substance abuse. Finally, based on these findings, recommendations are made for the treatment of individuals with comorbid PTSD-substance use disorders.

Current directions in research on understanding and preventing intoxicated aggression.

The present paper describes promising research directions that emerged from a recent international conference on intoxication and aggression and from the scientific literature generally. In this overview, intoxicated aggression is seen as arising from an interactional process involving multiple contributing factors or causes. This model helps to define research directions that can further understanding and prevention. First, the societal/cultural framing of intoxication and aggression exerts a powerful influence on drinking behaviour and needs to be better understood. Another important area for research is the moderating role on alcohol-related aggression of personal factors such as predisposition to aggression and individual differences in expectations about alcohol and aggression. Research on the role of basic pharmacological effects of alcohol in increasing the likelihood of aggressive behaviour is also a critical aspect of understanding intoxicated aggression. Drinking contexts and environments play a considerable role in the relationship between intoxication and aggressive behaviour and need to be better understood. Another critical direction for future research is the study of intoxicated aggression as a process involving the interaction of the person, the situation and the effects of alcohol in natural and experimental settings. Finally, the paper highlights promising directions for research on interventions to prevent intoxicated aggression and violence.

Cognitive functioning and the inhibition of alcohol-induced aggression.

OBJECTIVE: A highly replicable research finding is that alcohol intoxication tends to induce aggressive responding. Recent research investigating the role of cognitive function in this relationship has shown that individuals who perform poorly on certain cognitive tasks have difficulty responding to contingencies to inhibit aggression, while high performers do not. High performers, however, do show increased aggression while intoxicated. This study investigated whether subjects with above average cognitive functioning would, when intoxicated, inhibit aggression in order to attain monetary reward. METHOD: Men (N = 43), aged 18-30, selected on the basis of high performance on a neuropsychological test putatively assessing function of dorsolateral prefrontal cortex, the spatial conditional associative learning task, participated in a modified version of the Taylor Aggression Task. Half the subjects were acutely alcohol intoxicated, the other half were sober. Furthermore, half the subjects in each of these groups received contingent monetary reward for choosing lower shocks. Aggression was defined as shock intensity delivered to a sham opponent. RESULTS: Contrary to the hypothesis, intoxicated subjects, even though significantly impaired cognitively relative to their nonintoxicated peers (F = 4.29, 1/41 df, p < .05), appeared to have no difficulty inhibiting their aggression in order to gain monetary reward. That is, there was no difference between intoxicated and nonintoxicated subjects on the dependent variable, shock intensity, when contingent money was available (F = .01, 1/20 df, p = .935). CONCLUSION: This finding provides further evidence that alcohol-induced aggression is not a uniform phenomenon, and it suggests a neuropsychological mechanism that may mediate the relationship. It may be that individuals with above average cognitive abilities retain sufficient residual functioning to inhibit aggressive responding, even when acutely alcohol intoxicated.

Tryptophan depletion, executive functions, and disinhibition in aggressive, adolescent males.

Low serotonin has been associated with aggressive behavior and impulsivity. Executive functions (cognitive abilities involved in the initiation/maintenance of goal attainment) have also been related to aggression. We tested whether dietary depletion of tryptophan, the amino acid precursor of serotonin, would increase disinhibition (impulsivity) in aggressive male adolescents. Cognitive-neuropsychological variables predictive of disinhibition were explored. Stable aggressive and nonaggressive adolescent men received balanced and tryptophan-depleted, amino acid mixtures separately (counterbalanced, double-blind). Commission errors on a go/no-go learning task (i.e., failures to inhibit responding to stimuli associated with punishment/nonreward) measured disinhibition. Aggressive adolescent males made more commission errors as compared to nonaggressives. Lower executive functioning was significantly related to commission errors over and above conventional memory abilities. Tryptophan depletion had no effect on commission errors in the aggressive adolescents, possibly because of a ceiling effect.

Paternal alcoholism, paternal absence and the development of problem behaviors in boys from age six to twelve years.

OBJECTIVE: The purpose of this study was to examine the association between paternal alcoholism, paternal absence, and the development and stability of behavioral problems in boys, from kindergarten to the end of elementary school. METHOD: A sample of 642 boys originating from low socioeconomic status (SES) families was used. Paternal alcoholism was established using the Short Michigan Alcohol Screening Test. Behavioral problems (opposition, hyperactivity, inattention, physical aggression and anxiety) were assessed by teachers' reports when the boys were 6 and 12 years old. Four groups of boys were created on the basis of paternal alcoholism (nonalcoholic, alcoholic) and family structure (intact families, nonintact/father-absent families). RESULTS: Consistent with personality theories of alcoholism, results showed that a propensity for physical aggression and low anxiety best distinguished sons of male alcoholics (SOMAs) from non-SOMAs at both ages (6 and 12 years), even when SES was controlled. In addition, SOMAs were more oppositional and hyperactive than non-SOMAs at both ages. No significant effects were observed for family structure or age, or an interaction between these factors and paternal alcoholism in the multivariate analysis. CONCLUSIONS: The results suggest that problem behaviors in SOMAs begin early and persist over time, and that paternal alcoholism and family structure are not associated with changes in boys' behaviors between kindergarten and the end of elementary school in this population, at least in the sample used.