Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation.

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.

Patient-treatment matching in substance abuse. Drug addiction severity.

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.

Treatment structure, client coping methods, and response to brief individual counseling: preliminary findings in a substance dependent sample.

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.

Follow-up of abstinent and nonabstinent alcoholics.

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.

Developmental level and prognosis in alcoholics.

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

Voluntary versus involuntary abstinence in the treatment of alcoholics.

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.

Consequences of social modification of drinking behavior.

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.

Appropriate and background affect in facial displays of emotion. Comparison of normal and schizophrenic males.

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.