Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Cognitive-behavioral treatment for depression in smoking cessation.

Cigarette smokers with past major depressive disorder (MDD) received 8 group sessions of standard, cognitive-behavioral smoking cessation treatment (ST; n = 93) or standard, cognitive-behavioral smokiig cessation treatment plus cognitive-behavioral treatment for depression (CBT-D; n = 86). Although abstinence rates were high in both conditions (ST, 24.7%; CBT-D, 32.5%, at 1 year) for these nonpharmacological treatments, no main effect of treatment was found. However, secondary analyses revealed significant interactions between treatment condition and both recurrent depression history and heavy smoking ( > or =25 cigarettes a day) at baseline. Smokers with recurrent MDD and heavy smokers who received CBT-D were significantly more likely to be abstinent than those receiving ST (odds ratios = 2.3 and 2.6, respectively). Results suggest that CBT-D provides specific benefits for some, but not all, smokers with a history of MDD.

Effects of motivational interviewing on smoking cessation in adolescents with psychiatric disorders.

OBJECTIVE: To test the hypothesis that among adolescent smokers hospitalised for psychiatric and substance use disorders, motivational interviewing (MI) would lead to more and longer quit attempts, reduced smoking, and more abstinence from smoking over a 12 month follow up. DESIGN: Randomised control trial of MI versus brief advice (BA) for smoking cessation, with pre- and post-intervention assessment of self efficacy and intentions to change, and smoking outcome variables assessed at one, three, six, nine, and 12 month follow ups. SETTING: A private, university affiliated psychiatric hospital in Providence, Rhode Island, USA. PATIENTS OR OTHER PARTICIPANTS: Consecutive sample (n = 191) of 13-17 year olds, admitted for psychiatric hospitalisation, who smoked at least one cigarette per week for the past four weeks, had access to a telephone, and did not meet DSM-IV criteria for current psychotic disorder. INTERVENTIONS: MI versus BA. MI consisted of two, 45 minute individual sessions, while BA consisted of 5-10 minutes of advice and information on how to quit smoking. Eligible participants in both conditions were offered an eight week regimen of transdermal nicotine patch upon hospital discharge. MAIN OUTCOME MEASURES: Point prevalence abstinence, quit attempts, changes in smoking rate and longest quit attempt. Proximal outcomes included intent to change smoking behaviour (upon hospital discharge), and self efficacy for smoking cessation. RESULTS: MI did not lead to better smoking outcomes compared to BA. MI was more effective than BA for increasing self efficacy regarding ability to quit smoking. A significant interaction of treatment with baseline intention to quit smoking was also found. MI was more effective than BA for adolescents with little or no intention to change their smoking, but was actually less effective for adolescents with pre-existing intention to cut down or quit smoking. However, the effects on these variables were relatively modest and only moderately related to outcome. Adolescents with comorbid substance use disorders smoked more during follow up while those with anxiety disorders smoked less and were more likely to be abstinent. CONCLUSIONS: The positive effect of MI on self efficacy for quitting and the increase in intention to change in those with initially low levels of intentions suggest the benefits of such an intervention. However, the effects on these variables were relatively modest and only moderately related to outcome. The lack of overall effect of MI on smoking cessation outcomes suggests the need to further enhance and intensify this type of treatment approach for adolescent smokers with psychiatric comorbidity.

Exercise attitudes and behaviors among persons in treatment for alcohol use disorders.

The present study investigated self-reported exercise behaviors and exercise-related attitudes in a sample (N = 105) of adults in treatment for alcohol use disorders (AUD) (abuse or dependence). Slightly less than half (47%) of participants reported engaging in regular physical exercise (3 times per week or more). Level of alcohol dependence was not significantly associated with level of physical exercise activity. Level of nicotine dependence was significantly and negatively associated with physical activity level. Nicotine dependence and level of depressive symptoms were both significantly negatively associated with self-efficacy for physical exercise (SPE). Exercise self-efficacy mediated the relationship between nicotine dependence and physical activity level. Tension and stress reduction were among the most strongly endorsed of the perceived benefits of physical activity. Other perceived benefits included more positive outlook and increased self-esteem. Financial costs associated with exercise, lack of motivation, and time constraints were among the most common perceived barriers to exercise in this sample. Together, these preliminary data indicate that exercise-based interventions are may be well-received by those early in recovery from AUDs.

Alcohol expectancies as a mediator of the relationship between injury and readiness to change drinking behavior.

There is a well-established relationship between alcohol expectancies and drinking behavior. The purpose of the present study was to extend the literature by examining the role of alcohol expectancies in determining readiness to change drinking behavior among injured emergency department patients who screened positive for hazardous drinking. Negative expectancies were found to partially mediate the relationships of alcohol-related injuries and injury aversiveness to readiness to change drinking behavior. Results suggest that negative alcohol expectancies are a potential means of increasing patients' readiness to change drinking behavior.

P300 from men with a family history of alcoholism under different incentive conditions.

OBJECTIVE: Males with a family history of alcoholism (Family History Positive [FHP]) have frequently been reported to show an attenuated amplitude of the P300 component of the EEG event-related potential (ERP). The purpose of the present study was to explore the influence of incentives on the amplitude of the P300 to Target stimuli in FHP and FHN (Family History Negative) men. METHOD: The ERPs of 20 FHP and 20 FHN men were recorded in a visual discrimination task under two conditions: a no incentive (Neutral) and a reward/loss of reward (Incentive) conditions. ERPs following Target, Non-Target and Novel stimuli were examined. RESULTS: The FHP subjects displayed the expected attenuation of P300 amplitude, regardless of the stimulus type (Target, Non-Target or Novel), compared to the FHN subjects. The FHN subjects showed the predicted effect of a significantly increased P300 amplitude following Target stimuli in the Incentive condition whereas the FHP subjects did not display significantly greater P300 amplitudes in response to the incentive. CONCLUSIONS: These results may reflect a deficit in the motivational-cognitive system of FHP subjects. Analyses suggest that changes in P300 amplitude in response to the incentive can be predicted by subjects' scores on self-report measures of sensation seeking and behavioral undercontrol. However, such measures could not explain subjects' absolute P300 amplitude to Target stimuli.

Frontal EEG response to threat, aggressive traits and a family history of alcoholism: a preliminary study.

OBJECTIVE: This study investigated the association between frontal EEG response to threat, a family history of alcoholism (positive history = FHP, negative = FHN), aggressive - antisocial traits and negative affect. METHOD: EEG in 17 FHP men and 17 FHN men was recorded while resting and while awaiting an electric shock. RESULTS: Compared with FHNs, FHPs showed significantly greater threat-induced decreases in frontal alpha, but no change in frontal beta power. FHNs had significant threat-induced increases in frontal beta power. A measure of aggressive traits, the Buss-Durkee Hostility Assault scale, was also significantly associated with greater threat-induced decreases in frontal alpha power and low reactivity to threat on frontal beta power. CONCLUSIONS: The data suggest that familial risk for alcoholism and aggressive traits may be associated with a paradoxical pattern of both increased reactivity (more alpha suppression) and decreased reactivity (no increase in beta power) to threat in frontal cortical regions. However, these results are preliminary and tentative due to limitations arising from the small sample size and the exploratory nature of this study.

Anxiety sensitivity: relationship to negative affect smoking and smoking cessation in smokers with past major depressive disorder.

The present study evaluated whether anxiety sensitivity (AS) was related to negative reinforcement smoking motives and increased risk of relapse during the early stages of a quit attempt. Specifically, the role of AS was evaluated in 60 smokers with past major depressive disorder (MDD) during smoking cessation. Consistent with expectations, AS scores, as indexed by the 16-item Anxiety Sensitivity Index (ASI) [Behaviour Research and Therapy 24 (1986) 1], were positively correlated with smoking to reduce negative affect but were not significantly correlated with smoking for other reasons. Higher ASI scores also were associated with increased risk of lapsing during the first 7 days after quit day. Results suggest that smokers with heightened levels of AS may smoke more often to manage negative moods and may be less able to tolerate early withdrawal symptoms, specifically during early stages of a quit attempt.

Psychosocial correlates of cigarette smoking abstinence, experimentation, persistence and frequency during adolescence.

The purpose of this cross-sectional study was to examine and to compare the psychosocial characteristics associated with four dimensions of smoking: abstinence (never vs. ever), experimentation, frequency (daily vs. non-daily), and persistence (former vs. current). Persistent smokers (1 or more years) were contrasted with those who had been able to stop smoking for 1 year or more. From a sample of high school students who were assessed on two occasions (n = 1507), six smoking groups were defined: never smokers (n = 862), experimenters (n = 235), former non-daily (n = 80), current non-daily (n = 73), former daily (n = 71), and current daily (n = 110). The association between the four smoking dimensions and demographic, psychopathology, and psychosocial variables were examined. Differences between the never smokers and the experimenters were relatively small; albeit even minimal use of cigarettes is associated with some level of problems. As found in previous studies, smokers compared to never-smokers had substantially higher scores on most indices of dysfunction. Both frequent and persistent smoking was associated with higher lifetime prevalence of drug abuse/dependence and having more friends who smoke. Smoking persistence was uniquely related to greater conflict with parents and more problematic academic behavior. Smoking frequency was uniquely associated with higher impulsiveness. Gender did not significantly moderate the associations between smoking status and the psychosocial functioning. To the extent that there were differences between the characteristics associated with frequency and persistence, the results have implications for the design of interventions aimed at these dimensions.

Knee magnetic resonance imaging in childhood chronic monarthritis.

OBJECTIVE: To describe the usefulness of magnetic resonance imaging (MRI) of the knee in the evaluation of chronic monarthritis of uncertain cause in childhood. METHODS: We retrospectively reviewed 21 children referred to our clinic with a putative diagnosis of chronic inflammatory monarthritis of the knee who had MRI performed between May 1993 and June 1997. The median age was 13 years (range 2-17) and 11 were girls. RESULTS: The clinical diagnosis prior to MRI assessment was inflammatory arthritis in 16 patients, and a primary noninflammatory cause in 5. MRI was done in the patients with presumptive inflammatory arthritis when there were atypical symptoms, signs, or radiographs (n = 14), or when they failed to respond to therapy (n = 2). In the patients with a presumptive noninflammatory diagnosis, MRI was performed to clarify the diagnosis. Twelve children (57%) had MRI evidence of a noninflammatory diagnosis. In 4 children (19%) the MRI study indicated the presence of arthritis, and in 5 children (24%) the MRI studies were normal. The noninflammatory diagnoses included: lipoma arborescens (n = 1), vascular malformation [intraarticular (n = 1), extraarticular (n = 1)], synovial chondromatosis (n = 2), partial anterior cruciate ligament tear (n = 2), traumatic bone contusion (n = 2), possible meniscal tear (n = 1), osteochondritis dissecans (n = 1), and a soft tissue mass of uncertain significance in the suprapatellar pouch (n = 1). CONCLUSION: Inflammatory arthritis is usually diagnosed by clinical assessment alone. Uncommonly, when a single joint is involved, and atypical features are identified by a pediatric rheumatologist, other causes of chronic pain and swelling need to be excluded. In this selected patient population, MRI is a useful tool either to confirm the presence of inflammatory arthritis or to investigate a wide range of pathology that can mimic knee joint arthritis.

Comparison of criteria for the classification of childhood arthritis.

OBJECTIVE: To evaluate the applicability of the ILAR criteria for classification of childhood arthritis in an outpatient pediatric rheumatology clinic population, and to determine the proportion of children who met standard classification criteria, but failed to meet ILAR criteria for specific arthritides, and therefore became unclassifiable. METHODS: We reviewed the charts of 70 consecutive patients who had arthritis for at least 6 months, and attended the clinic between September and November 1997. Sixty-nine patients were categorized according to one of the traditional classifications [ACR for juvenile rheumatoid arthritis (JRA), European Spondylarthropathy Study Group (ESSG) for spondyloarthropathy, Vancouver Criteria for juvenile psoriatic arthritis (JPsA)], and the ILAR classification system. RESULTS: Sixty-one patients (88.4%) were classifiable by the ILAR system; 8 others failed to fulfill ILAR criteria for any specific category, and were assigned to the "other arthritis" category. Of the 29 patients with oligoarticular onset JRA, 6 were unclassified, 5 because of exclusions, and one because he fulfilled criteria for 2 categories. Presence of a family history of psoriasis accounted for most of the exclusions in the oligoarthritis and enthesitis related arthritis categories. All patients with polyarticular onset or systemic onset JRA were classified in the corresponding category in the ILAR system. One 9-year-old patient with spondyloarthropathy was reclassified as "other arthritis" because of exclusions. All 6 children with definite JPsA met ILAR criteria for PsA. Of 4 patients with probable JPsA, only 2 met ILAR criteria for PsA, a third was classified as rheumatoid factor negative polyarthritis, and the fourth was classified as "other arthritis" because of exclusions. CONCLUSION: The ILAR classification criteria applied to a group of children with chronic arthritis classified by traditional criteria results in reassignment of 11.6% of the patients, predominantly in the oligoarticular group. It will be important to determine the role of the presence of a family history of psoriasis in classifying these patients.