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We investigated whether pretreatment characteristics and measures of outcome differed for alcohol-, cocaine-, and multisubstance-dependent patients receiving outpatient substance abuse treatment. One hundred and forty substance dependent individuals (32 alcohol, 76 cocaine, and 32 multisubstance) enrolled in a 12-week outpatient treatment program were compared across measures of addiction severity, personality, and treatment-readiness at admission. In-treatment, endoftreatment and 9-month follow-up assessments of treatment outcome were then compared across the three groups. Outcome measures included reduction in problem severity, abstinence, retention, number of sessions attended, dropout, and counselor and patient ratings of treatment benefit. At admission, the multisubstance group had a higher proportion of positive urines, reported more severe drug, alcohol and psychiatric problems, and displayed higher impulsivity and anxiety scores than one or both of the other groups. However, multisubstance patients were more treatment ready in terms of adopting a total abstinence orientation than alcohol or cocaine patients. While a significant reduction in symptoms occurred for the total sample during treatment as well as at follow-up, comparisons of outcomes did not consistently favor any particular group. The three groups had equivalent improvements in eleven of fourteen during-treatment and five of seven follow-up measures. Despite pretreatment differences, in severity and treatment-readiness, outcomes were more similar than different for alcohol-, cocaine-, and multisubstancedependent patients. Clinicians should be cautious about forecasting treatment-outcomes for addicted patients based on their primary substances of abuse. [ABSTRACT FROM AUTHOR]

We investigated whether platelet tritiated paroxetine binding, a measure of serotonin uptake sites differed between cocainedependent subjects and controls, and whether paroxetine binding was related to treatment-outcome for cocaine patients. One hundred twenty-five African-American cocaine-dependent individuals receiving outpatient treatment and 44 controls were studied. Tritiated paroxetine binding sites on platelets were assayed and standardized assessments of behavior were performed. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates and number of treatment sessions attended. Cocaine patients had significantly lower Bmax values of paroxetine binding compared to controls. Furthermore, Bmax values showed a significant positive correlation with days in treatment and negative urines. A combination of Bmax and Addiction Severity Index (ASI) employment scores improved the prediction of days in treatment and a combination of Bmax and ASI drug scores enhanced the prediction of negative urines. The findings indicate that serotonergic mechanisms may be involved in cocaine dependence and may influence treatment-outcome among cocaine patients. [ABSTRACT FROM AUTHOR]

In this study, we aimed to examine the diagnostic yield of pericardial fluid biochemistry and cytology and their prognostic significance in patients with percutaneously drained pericardial effusions, with and without malignancy. This is a single-center, retrospective study of patients who underwent pericardiocentesis between 2010 and 2020. Data were extracted from electronic patient records, including procedural information, underlying diagnosis, and laboratory results. Patients were grouped into those with and without underlying malignancy. A Cox proportional hazards model was used to analyze the association of variables with mortality. The study included 179 patients; 50% had an underlying malignancy. There were no significant differences in pericardial fluid protein and lactate dehydrogenase between the 2 groups. Diagnostic yield from pericardial fluid analysis was greater in the malignant group (32% vs 11%, p = 0.002); 72% of newly diagnosed malignancies had positive fluid cytology. The 1-year survival was 86% and 33% in nonmalignant and malignant groups, respectively (p <0.001). Of 17 patients who died within the nonmalignant group, idiopathic effusions were the largest group (n = 6). In malignancy, lower pericardial fluid protein and higher serum C-reactive protein were associated with increased risk of mortality. In conclusion, pericardial fluid biochemistry has limited value in determining the etiology of pericardial effusions; fluid cytology is the most important diagnostic test. Mortality in malignant pericardial effusions may be associated with lower pericardial fluid protein levels and a higher serum C-reactive protein. Nonmalignant pericardial effusions do not have a benign prognosis and close follow-up is required., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα (Thr172) and CREB-1 (Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65 (Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.

Angiogenesis is an essential physiological process and an important factor in disease pathogenesis. However, its exploitation as a clinical target has achieved limited success and novel molecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascular endothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanisms involved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1 depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation. The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negatively affected directional migration of EC towards VEGF; a phenotype reversed by HO-1 over-expression. EC from Hmox1(-/-) mice behaved similarly. Microarray analysis of HO-1-depleted and control EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2 activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by Ad-HO-1. Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1 depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencing attenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGF-activated HO-1-dependent targets important for VEGF-driven angiogenesis.

Aims: Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes., Methods/results: In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKα(Thr172), and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)(Ser133) phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKα(Thr172) phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression., Conclusions: These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aims: Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosclerosis prevention. The observation that activity of either protein kinase C epsilon (PKCε) or haem oxygenase-1 (HO-1) enhances endothelial cell (EC) resistance to inflammation and apoptosis led us to test the hypothesis that HO-1 is a downstream target of PKCε., Methods and Results: Expression of constitutively active PKCε in human EC significantly increased HO-1 mRNA and protein, whereas conversely aortas or cardiac EC from PKCε-deficient mice exhibited reduced HO-1 when compared with wild-type littermates. Angiotensin II activated PKCε and induced HO-1 via a PKCε-dependent pathway. PKCε activation significantly attenuated TNFα-induced intercellular adhesion molecule-1, and increased resistance to serum starvation-induced apoptosis. These responses were reversed by the HO antagonist zinc protoporphyrin IX. Phosphokinase antibody array analysis identified CREB1((Ser133)) phosphorylation as a PKCε signalling intermediary, and cAMP response element-binding protein 1 (CREB1) siRNA abrogated PKCε-induced HO-1 up-regulation. Likewise, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was identified as a PKCε target using nuclear translocation and DNA-binding assays, and Nrf2 siRNA prevented PKCε-mediated HO-1 induction. Moreover, depletion of CREB1 inhibited PKCε-induced Nrf2 DNA binding, suggestive of transcriptional co-operation between CREB1 and Nrf2., Conclusions: PKCε activity in the vascular endothelium regulates HO-1 via a pathway requiring CREB1 and Nrf2. Given the potent protective actions of HO-1, we propose that this mechanism is an important contributor to the emerging role of PKCε in the maintenance of endothelial homeostasis and resistance to injury., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.

We investigated whether platelet-tritiated paroxetine binding, a measure of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity, and aggression--though not craving--among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.

We studied whether pretreatment levels of learned helplessness (LH) were related to outcomes for substance-dependent individuals receiving high-structure, behaviorally oriented (HSB) or low-structure, facilitative (LSF) treatment. The subjects were 120 substance-dependent patients randomly assigned to the HSB or the LSF treatment style for up to 12 weeks of weekly individual counseling. The two groups were compared across pretreatment characteristics as well as in-treatment, end-of- treatment, and 9-month postadmission follow-up outcome measures. Outcomes reflected reduction in problem severity, abstinence, retention, dropout rate, and ratings of treatment benefit. Significant and comparable reductions in symptoms occurred for the HSB and LSF patients both during treatment and at follow-up. Comparisons of other outcomes also did not consistently favor either treatment style. However, significant and consistent interactions were observed between LH and treatment styles with respect to several outcome measures, and these effects were independent of pretreatment levels of depression, addiction severity, and readiness for treatment. Specifically, the more "helpless" patients did significantly better in HSB treatment, whereas the less "helpless" patients had better outcomes in LSF treatment. A matching approach that assigns patients to high- and low-structure treatments based on pretreatment levels of LH might improve treatment outcomes for substance-dependent patients.

Despite a close association between tobacco and cocaine use, few studies have systematically examined whether smoking predicts an adverse outcome for cocaine-dependent patients. We investigated whether severity of nicotine dependence was related to treatment outcome for cocaine-dependent individuals. Standardized assessments of nicotine dependence (Fagerström Test for Nicotine Dependence; FTND), cocaine use, and personality were obtained for 105 African American cocaine-dependent outpatients. Outcome measures included negative urine drug screens, days in treatment, dropout, and number of treatment sessions attended. The sample was stratified into cocaine-positive and cocaine-negative groups based on admission urine drug screens, and relationships between nicotine dependence and outcome measures were examined in each group. In the cocaine-negative group, higher FTND scores were negatively correlated with number of negative urine drug screens during treatment even after controlling for other predictors, whereas FTND scores were not correlated to outcome in the cocaine-positive group. It seems that severity of tobacco use predicts poor outcome for cocaine-dependent patients who are cocaine free at the time of admission into outpatient treatment.

Genetic research of cocaine abuse has been relatively limited among the African-American population. Since the serotonin transporter (5HTT) may be involved in modulating effects of cocaine, we investigated whether allelic variants of the 5HTT gene may confer susceptibility to cocaine dependence among African-American individuals. One hundred and fifty-six cocaine-dependent subjects and 82 controls were studied. Polymerase chain reaction-based genotyping of a variable-number-tandem-repeat (VNTR) marker yielded three alleles designated 12, 10 and 9. Genotype and allele frequencies were compared using chi-square analyses. We found no differences between subjects and controls with respect to genotype distribution (cocaine: 12/12 = 50%, 10/12 = 35.3%, 10/10 = 13.5%, 9/12 = 1.3%; controls: 12/12 = 42.7%, 10/12 = 39.0%, 10/10 = 17.1%, 9/12 = 1.2%). Similarly, allele frequencies of the VNTR marker did not differ between the two groups (cocaine: 12 = 68.3%, 10 = 31.1%, 9 = 0.6%; controls: 12 = 62.8%, 10 = 36.6%, 9 = 0.6%). Our findings do not seem to support a relationship between VNTR polymorphisms and cocaine dependence among African-American patients. Further studies involving larger samples are required to confirm our results., (Copyright 2002 Lippincott Williams & Wilkins)

We investigated whether urine drug screens (UDS) at admission and platelet paroxetine binding, a measure of serotonin transporter sites, were related to outcome measures for cocaine patients in treatment. Tritiated paroxetine binding sites on platelets were assayed and UDS were obtained for 105 African American cocaine-dependent outpatients. Outcome measures included number of negative urines, days in treatment, dropouts, and number of treatment sessions attended. A significant association was found between cocaine-positive UDS at admission and negative urines, treatment retention, dropouts, and treatment sessions; while Bmax values of paroxetine binding (density of serotonin transporter sites) were significantly associated with treatment retention and negative urines. Moreover, UDS and paroxetine binding combined to enhance prediction of retention and abstinence. Although both admission UDS and paroxetine binding seem to contribute individually in predicting outcome of cocaine patients, a combination of the two variables seems to have a stronger effect in terms of predicting treatment-outcome.

Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (5HTT), may mediate central effects of cocaine and may also be involved in impulsive and aggressive behavior. We investigated whether polymorphisms in the 5HTT gene were related to traits of impulsivity, sensation seeking, and aggression among cocaine abusers. Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls. Two polymorphisms of the 5HTT gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among cocaine patients. No significant relationships were observed between polymorphic variants of the 5HTTLPR and VNTR regions and scores on any of the trait measures. Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among cocaine patients. As expected, cocaine patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls. The findings do not seem to support an association between these polymorphisms in the 5HTT gene and impulsive-aggressive traits among cocaine-dependent African-American individuals.

In this study, a mixed group of 60 substance-dependent patients were randomly assigned to 12 weeks of treatment in either a high-structure, behaviorally oriented (HSB) or a low-structure, facilitative (LSF) individual counseling style. We tested the hypothesis that patients with a more severe pretreatment drug problem will realize greater treatment benefit in HSB counseling, while those with a less severe problem will benefit more in the LSF approach. Six counselors provided the treatments in a counterbalanced design that controlled for possible differences in counselor effectiveness. Treatment benefit comparisons with respect to the counselors' posttreatment ratings, the number of counseling sessions attended, reduction in problem severity, and substance use during treatment were consistently in the hypothesized direction. These findings provide at least partial support for the notion that treatment benefit for substance abuse patients can be improved through appropriate patient-treatment matching on the basis of addiction severity.

In this paper we report preliminary treatment outcome findings for the first 16 substance abuse patients who volunteered and qualified for a 12-week research-treatment program. Eight patients were exposed to a high-structure, behaviorally-oriented (HSB) individual counseling style, while the remaining eight were exposed to a low-structure, facilitative (LSF) style. 'Counselor effects' were controlled by having each of four counselors conduct both styles (two patients each) in serial but counterbalanced order; under these conditions treatment outcomes did not differ for patients randomly assigned to the different counselors. Outcomes also did not differ for the HSB and LSF clients with regard to retention, drug and alcohol use during treatment or for reported symptom reduction during the program as measured by the Addiction Severity Index. Though the LSF clients reported receiving more treatment benefits than did the HSB patients in their post-session ratings, this was not confirmed in the counselors' post-treatment ratings or in the other treatment response measures. Finally, with a few exceptions, patients scoring higher versus lower on four measures of coping, including conceptual and developmental levels of functioning, field independence and social independence, did not differ in their treatment outcomes.

Despite differences in samples and designs, follow-up studies of alcoholic patients by the Rand Corporation, the state of Oklahoma, and the Veterans Administration (VA) revealed more similarities than differences in outcome and relapse. In the VA study at 6, 12, and 24 months' follow-up, it was found that drinking status and psychosocial adjustment were significantly correlated, the percentage of patients drinking moderately varied from 33% to 47% and did not decrease over time, and the percentage of patients in remission remained constant at 55% over the 2-year period. These data appear to support the inclusion of moderate drinking in the definition of remission.

An index of developmental level of functioning, derived from the Rorschach, was compared with several other prognostic measures to predict treatment outcome.

The hypothesis that normal subjects can express emotions more accurately than schizophrenics was tested by having judges match photographs of five posed affects with five emotion words for each of 16 normal and 16 schizophrenic male expressors. Discrimination accuracy was high, but the hypothesis was not confirmed. The results of a second study, in which separate measures of appropriate (intended) and "background" affect (eg, the rated intensity of anger displayed in a subject's nonangry poses) were provided, supported our expectation that discrimination accuracy is a function of both appropriate and background affect. The normal men tended to display more appropriate affect generally, and displayed more background happiness, while the schizophrenics expressed more background anger, sadness, and fear. Both intended and background affect, therefore, must be carefully considered in studies of emotional expressions.

Alcoholic patients who remained abstinent during a Fixed Interval Drinking Decision treatment program had fewer alcohol-related problems at a 6-month follow-up than those who drank during treatment. Pretreatment encouragement to remain abstinent may also have favorably affected the results.

During the first 6 months after their discharge from a Fixed Interval Drinking Decisions Program patients who had been compelled to abstain did significantly better than the drinkers but significantly more poorly than those who had voluntarily abstained during the program.