Mesalazine granules are superior to Eudragit-L-coated mesalazine tablets for induction of remission in distal ulcerative colitis - a pooled analysis.

BACKGROUND: Different oral formulations of 'mesalazine (mesalamine)' may have different efficacy in distal ulcerative colitis. AIM: To evaluate the efficacy of mesalazine granules (Salofalk granules) vs. mesalazine tablets (Salofalk tablets) as induction therapy in patients with distinct extensions of ulcerative colitis. METHODS: A pooled analysis of 705 patients from four prospective, randomised, double-blind phase III trials was performed. The efficacy of 8 weeks' induction with 3 g/day mesalazine granules [3 g once daily (o.d.) or 1 g three times daily (t.d.s)] vs. 3 g/day mesalazine tablets (1 g t.d.s.) was compared in terms of clinical remission (CR: CAI ≤ 4) and endoscopic remission (ER: EI ≤ 3) (both according to Rachmilewitz) in subgroups with pancolitis, left-sided colitis, or proctosigmoiditis. RESULTS: Mesalazine granules were equipotent to mesalazine tablets in pancolitis regarding CR (72% vs. 71%, P = 0.909) and ER (58% vs. 49%, P = 0.338). In left-sided colitis, both mesalazine formulations were equipotent regarding CR (66% vs. 67%; P = 0.843) but mesalazine granules were superior regarding ER (56% vs. 37%; P = 0.025). In proctosigmoiditis, mesalazine granules were significantly more effective than mesalazine tablets regarding CR (78% vs. 55% P < 0.001) and ER (67% vs. 43% P < 0.001). Furthermore, o.d. application of mesalazine granules was more effective than t.d.s. dosing in left-sided colitis (CR 73% vs. 62%, P = 0.181; ER 71% vs. 48% P = 0.005) and proctosigmoiditis (CR 86% vs. 73%, P = 0.020; ER 75% vs. 61%, P = 0.021), but not in pancolitis. CONCLUSION: This pooled analysis supports the hypothesis that mesalazine granules are superior to mesalazine tablets in induction of remission in distal colitis and should be taken once daily.

Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-kappaB in adult T-cell leukemia/lymphoma.

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-kappaB (NF-kappaB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Tax-expressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-kappaB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-kappaB p50/p50 alone and p50/c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-kappaB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-kappaB activation and also suggest a Tax-independent mechanism of activation of PTHrP in ATLL.

A low-cost, sustainable intervention for drinking reduction in the HIV primary care setting.

Excess drinking poses multiple substantial health risks to HIV-infected individuals. However, no published intervention studies have focused on drinking reduction as the main outcome in HIV primary care patients. An intervention in this setting must place minimal demands on pressured staff and resources. This pilot study tested such an intervention, which consisted of brief Motivational Interviewing (MI) and HealthCall, an automated daily telephone self-monitoring system based on Interactive Voice Response (IVR), designed to extend and enhance the effects of brief MI. Thirty-one patients entered the study, received a 30-minute MI and were instructed in daily use of the IVR system. They received graphical feedback on their daily drinking from the HealthCall database after 30 days. A statistically significant decrease in drinking was found over time, both as reported in daily IVR calls (beta = - 0.01, se 0.01, p=.03) and in follow-up interviews (beta = - 0.04, se 0.12, p=.02) at 60 days. The proportion of daily calls made supported the feasibility of the intervention. The results indicate that HealthCall is acceptable to a disadvantaged HIV patient population, and preliminary data support the efficacy of this intervention in reducing harmful drinking among HIV primary care patients.

Manual-guided cognitive-behavioral therapy training: a promising method for disseminating empirically supported substance abuse treatments to the practice community.

A gap exists between empirically supported substance abuse treatments and those used in community settings. This study examined the feasibility of training substance abuse counselors to deliver cognitive-behavioral treatment (CBT) using treatment manuals. Participants were 29 counselors. Counselors were randomly assigned to receive CBT training or to a control group. Counselor attitudes were assessed pre- and posttraining. In addition, CBT therapy sessions were videotaped and rated for adherence and skillfulness. CBT counselors reported high levels of satisfaction with the training, intention to use CBT interventions, and confidence in their ability to do so. Ratings indicated that 90% of counselors were judged as having attained at least adequate levels of CBT skillfulness. Findings demonstrate the feasibility of using psychotherapy technology tools as a means of disseminating science-based treatments to the substance abuse practice community.

Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis.

The CED4/Apaf-1 family of proteins functions as critical regulators of apoptosis and NF-kappaB signaling pathways. A novel human member of this family, called CARD12, was identified that induces apoptosis when expressed in cells. CARD12 is most similar in structure to the CED4/Apaf-1 family member CARD4, and is comprised of an N-terminal caspase recruitment domain (CARD), a central nucleotide-binding site (NBS), and a C-terminal domain of leucine-rich repeats (LRR). The CARD domain of CARD12 interacts selectively with the CARD domain of ASC, a recently identified proapoptotic protein. In addition, CARD12 coprecipitates caspase-1, a caspase that participates in both apoptotic signaling and cytokine processing. CARD12 may assemble with proapoptotic CARD proteins to coordinate the activation of downstream apoptotic and inflammatory signaling pathways.

Testing the effectiveness of cognitive-behavioral treatment for substance abuse in a community setting: within treatment and posttreatment findings.

This study evaluated the short-term effectiveness of cognitive-behavioral treatment (CBT) for substance abuse delivered in a community setting. At entry into outpatient community substance abuse treatment, participants (N = 252) were randomly assigned to 3 conditions: high-standardization CBT, low-standardization CBT, and treatment as usual. Treatment consisted of 12 weekly individual therapy sessions. There was a significant decrease in substance use from baseline, with participants reporting being abstinent on 90% of within-treatment days and 85% of days during the 6 months posttreatment. However, there were no significant differences in outcomes across conditions. Findings do not support the hypothesis that disseminating CBT to community settings will improve outcomes and suggest that standard substance abuse counseling may be more effective than previously thought.

Cognitive-behavioral treatment for alcohol dependence: a review of evidence for its hypothesized mechanisms of action.

OBJECTIVE: This review examined support for the hypothesis that cognitive-behavioral treatment (CBT) for alcohol dependence works through increasing cognitive and behavioral coping skills. METHOD: Ten studies were identified that examined the hypothesized mechanisms of action of CBT. These studies involved random assignment (or its near equivalent) of participants to CBT and at least one comparison condition. RESULTS: Although numerous analyses of the possible causal links have been conducted to evaluate whether CBT works through increasing coping, the results indicate little support for the hypothesized mechanisms of action of CBT. CONCLUSIONS: Research has not yet established why CBT is an effective treatment for alcohol dependence. Negative findings may reflect methodological flaws of prior studies. Alternatively, findings may indicate one or more conceptual assumptions underlying CBT require revision.

Identification of leptin-induced transcripts in the mouse hypothalamus.

Long-form leptin receptor (OB-R(L)) is a signal-transducing member of the cytokine receptor superfamily that is essential for mediating the effects of leptin on mammalian body weight homeostasis. At present, the range of transcriptional targets responsive to OB-R(L) activation, and consequently, the likely mediators of leptin action, remain undefined. In this report, we have used cDNA subtractive hybridization to identify transcripts induced by leptin in immortalized hypothalamic neurons expressing OB-R(L). Differential expression of the identified transcripts in these cells was confirmed by both array technology and Northern blotting. In situ hybridization studies indicate that these transcripts are expressed in the mouse central nervous system, including nuclei of the hypothalamus that coexpress OB-R(L). Comparative in situ analysis of slices of hypothalami generated from control and leptin-injected ob/ob mice demonstrates that a subset of the identified transcripts is induced in vivo after leptin injection. The potential role of the proteins encoded by these transcripts in mediating the effects of leptin on body weight and energy homeostasis are discussed.

Effective technology transfer in alcoholism treatment.

Alcoholism treatment services in the United States continue to be characterized by a lack of evidence-based care. Problems establishing effective research-practice knowledge transfer stem, in part, from the strong allegiance of scientists and practitioners to contrasting treatment models. Four underlying assumptions of the Minnesota model that continue to guide the delivery of alcohol services in the United States are identified and related research is reviewed. Findings indicate little support for these assumptions. However, support for superiority of alternative science-based treatments to replace current practices varies. To facilitate effective technology transfer, research practitioner collaboration must be promoted. Research paradigms are needed that possess high salience to practitioners while preserving scientific rigor. Two examples of studies involving research-practitioner collaboration are described.

Effects of executive function impairment on change processes and substance use outcomes in 12-step treatment.

OBJECTIVE: A strong clinical rationale exists to hypothesize that neuropsychological impairment interferes with treatment-initiated change, thereby leading to poor outcome. This study examined the relationship of executive function impairment, change process factors and substance use outcomes in a sample of substance users in intensive 12-step treatment. METHOD: Participants were 118 individuals entering residential or intensive day treatment at two traditional treatment programs. Participants were assessed at entry into treatment, at discharge from treatment, and at 1 and 6 months following treatment. Participants were administered a battery of measures to assess executive function impairment, processes hypothesized to mediate change in 12-step treatment, negative prognostic indicators and substance use outcomes. RESULTS: More than half the sample showed some form of executive function impairment. Executive function impairment did not directly predict worse substance use outcomes nor difficulty acquiring or maintaining change processes. However, impairment significantly moderated the relationship between change processes and outcome. Change processes were strongly related to outcome for unimpaired individuals but weakly related for impaired individuals. CONCLUSIONS: Executive function impairment is not a significant predictor of poor treatment response in 12-step treatment. However, analyses suggest that impaired and unimpaired individuals traverse different pathways in achieving equivalent outcomes.

Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin.

A mutation in the tub gene leads to maturity-onset obesity, insulin resistance, and progressive retinal and cochlear degeneration in mice. tub is a member of a growing family of genes that encode proteins of unknown function that are remarkably conserved across species. The absence of obvious transmembrane domain(s) or signal sequence peptide motif(s) suggests that Tub is an intracellular protein. Additional sequence analysis revealed the presence of putative tyrosine phosphorylation motifs and Src homology 2 (SH2)-binding sites. Here we demonstrate that in CHO-IR cells, transfected Tub is phosphorylated on tyrosine in response to insulin and insulin-like growth factor-1 and that in PC12 cells, insulin but not EGF induced tyrosine phosphorylation of endogenous Tub. In vitro, Tub is phosphorylated by purified insulin receptor kinase as well as by Abl and JAK 2 but not by epidermal growth factor receptor and Src kinases. Furthermore, upon tyrosine phosphorylation, Tub associated selectively with the SH2 domains of Abl, Lck, and the C-terminal SH2 domain of phospholipase Cgamma and insulin enhanced the association of Tub with endogenous phospholipase Cgamma in CHO-IR cells. These data suggest that Tub may function as an adaptor protein linking the insulin receptor, and possibly other protein-tyrosine kinases, to SH2-containing proteins.

Cognitive-behavioral coping-skills therapy for alcohol dependence. Current status and future directions.

Cognitive-behavioral coping-skills training (CBST) is an alcoholism treatment approach aimed at improving the patients' cognitive and behavioral skills for changing their drinking behavior. CBST encompasses a variety of approaches that despite their core similarities differ in duration, modality, content, and treatment setting. Numerous studies and reviews have ranked CBST among the most effective approaches for treating alcoholic patients. Nevertheless, a recent analysis of nine studies failed to identify specific CBST components that could account for the treatment's effectiveness. Furthermore, a similar analysis of 26 studies suggested that CBST's superior effectiveness was limited to specific treatment contexts (i.e., when delivered as part of a comprehensive treatment program) and to specific patient subgroups (e.g., patients with less severe alcohol dependence). Several measures may help broaden CBST's focus and effectiveness, such as incorporating components of other treatment approaches.

Do treatment process factors mediate the relationship between type A-type B and outcome in 12-Step oriented substance abuse treatment?

AIMS: One underutilized strategy for enhancing treatment research is to examine intervening factors that link client characteristics to endpoint outcomes. This study tested the hypothesis that Type B substance abusers would demonstrate difficulties engaging in the treatment process, and that these problems would mediate their poorer outcomes. DESIGN: Longitudinal naturalistic study. SETTING: Two intensive 12-Step substance abuse treatment programs. PARTICIPANTS: A sample of 115 men and women seeking treatment. MEASUREMENT: Empirical clustering techniques were used to divide the sample, and the link between type, process factors, and 12-month outcomes was examined. FINDINGS: Hypotheses were not supported. Type Bs did not demonstrate difficulties with the treatment process, but had greater problems sustaining gains posttreatment. Contrary to prediction, Type Bs were better matched to self-help affiliation than Type As. CONCLUSIONS: Findings argue for a more optimistic perspective on treating Type Bs, and for the utility of Type A-Type B in informing treatment research.

Constitutive and impaired signaling of leptin receptors containing the Gln --> Pro extracellular domain fatty mutation.

Leptin (OB), an adipocyte-secreted circulating hormone, and its receptor (OB-R) are key components of an endocrine loop that regulates mammalian body weight. In this report we have analyzed signal transduction activities of OB-R containing the fatty mutation [OB-R(fa)], a single amino acid substitution at position 269 (Gln --> Pro) in the OB-R extracellular domain that results in the obese phenotype of the fatty rat. We find that this mutant receptor exhibits both ligand-independent transcriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transducer and activator of transcription (STAT) proteins 1 and 3. However, OB-R(fa) is unable to constitutively activate STAT5B and is highly impaired for ligand induced activation of STAT5B compared with OB-R(wt). Introduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa). Constitutive mutant OB-R(fa) receptor signaling is repressed by coexpression of OB-R(wt). The implications of an extracellular domain amino acid substitution generating a cytokine receptor with a partially constitutive phenotype are discussed both in terms of the mechanism of OB-R triggering and the biology of the fatty rat.

Affiliation with Alcoholics Anonymous after treatment: a study of its therapeutic effects and mechanisms of action.

Relatively little is known about how substance abuse treatment facilitates positive outcomes. This study examined the therapeutic effects and mechanisms of action of affiliation with Alcoholics Anonymous (AA) after treatment. Patients (N = 100) in intensive 12-step substance abuse treatment were assessed during treatment and at 1- and 6-month follow-ups. Results indicated that increased affiliation with AA predicted better outcomes. The effects of AA affiliation were mediated by a set of common change factors. Affiliation with AA after treatment was related to maintenance of self-efficacy and motivation, as well as to increased active coping efforts. These processes, in turn, were significant predictors of outcome. Findings help to illustrate the value of embedding a test of explanatory models in an evaluation study.

Physiological alcohol dependence as a "specifier" of risk for medical problems and relapse liability in DSM-IV.

OBJECTIVE: This study tested the ability of DSM-IV physiological alcohol dependence to predict multiple indices of medical problems and relapse behavior. It also tested the ability of three additional variables--DSM-IV nonphysiological dependence, an alternative dichotomous criterion for coding physiological dependence and a dimensional measure of physiological dependence--to predict medical problems and relapse behavior in alcoholism. METHOD: A heterogeneous group of 365 patients was recruited from eight addictions treatment programs in the northeastern United States. A multidimensional assessment battery able to diagnose the presence of physiological dependence according to each of three systems--the criteria of DSM-IV, alternative dichotomous criteria and a dimensional scale-- was administered about 2 weeks after admission, and 241 subjects were reinterviewed 6 months later. The three systems were compared for their ability to predict a variety of external measures of medical complications and relapse liability. RESULTS: Physiological alcohol dependence as diagnosed by DSM-IV bore no relationship to either risk for medical problems or relapse behavior. Further analyses showed that this failure was due to operational problems of physiological dependence in DSM-IV, rather than to a lack of conceptual merit for physiological dependence per se as a course specifier. Use of alternative criteria for coding physiological dependence which are difficult and less internally consistent, and use of a dimensional measure, found improved relationships with the external validators. CONCLUSIONS: Contrary to early reports, physiological dependence can serve as a course specifier for alcohol problems, but must be more sensitively scaled than it was in DSM-IV. Tests of alternative options suggest that a multistage criterion to replace DSM-IV's dichotomous criterion is the best remedy.

The comorbidity of alcoholism and personality disorders in a clinical population: prevalence rates and relation to alcohol typology variables.

This study assessed prevalence rates and overlap among Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised; DSM-III-R; American Psychiatric Association, 1987) personality disorders in a multisite sample of 366 substance abusers in treatment. In addition, the relation of antisocial personality disorder (APD), borderline personality disorder (BPD), and paranoid personality disorder (PPD) to alcohol typology variables was examined. Structured diagnostic interviews and other measures were administered to participants at least 14 days after entry into treatment. Results indicated high prevalence rates for APD and non-APD disorders. There was extensive overlap between Axis I disorders and personality disorders, and among personality disorders themselves. APD, BPD, and PPD were linked to more severe symptomatology of alcoholism and other clinical problems. However, only APD and BPD satisfied subtyping criteria, after controlling for other comorbidity. Implications for classifying alcoholics by comorbid disorders are discussed.

The major dog allergens, Can f 1 and Can f 2, are salivary lipocalin proteins: cloning and immunological characterization of the recombinant forms.

Canis familiaris allergen 1 (Can f 1) and Canis familiaris allergen 2 (Can f 2) are the two major allergens present in dog dander extracts. We now report the isolation of cDNAs encoding both proteins and present their nucleotide and deduced amino acid sequences. Can f 1, produced by tongue epithelial tissue, has homology with the von Ebner's gland (VEG) protein, a salivary protein not previously thought to have allergenic properties. Can f 2, produced by tongue and parotid gland, has homology with mouse urinary protein (MUP), a known allergen. Both VEG protein and MUP are members of the lipocalin family of small ligand-binding proteins. Recombinant forms of Can f 1 and Can f 2 were produced and tested for immunoglobulin E (IgE) reactivity. Among dog-allergic subjects, 45% had IgE directed exclusively to rCan f 1, and 25% had IgE to both rCan f 1 and rCan f 2. In addition, both recombinant proteins were able to cross-link IgE and elicit histamine release from peripheral blood leucocytes in vitro. These findings confirm that Can f 1 and Can f 2 are major and minor dog allergens, respectively, and demonstrate that recombinant forms of dog allergens retain at least some IgE-binding epitopes.

Measuring diagnostic agreement.

Diagnostic agreement tests the reliability and concordance of diagnostic systems. The introduction of measures of agreement with reputations for baserate independence (e.g., Yule's Y and Q), and new studies occasioned by the publication of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) and the International Classification of Diseases--10 (ICD-10; World Health Organization, 1992) make it necessary to study the relationship of illness baserates to measures of agreement. Testing diagnostic concordance for diagnoses of drug dependence from the third edition of the DSM (American Psychiatric Association, 1980) versus DSM-IV diagnoses of drug dependence under 3 baserate conditions, it was found that Yule's Y and Q proved as vulnerable to differences in baserates as kappa or percent agreement and that specificity covaried with baserate rather than being fixed, as most theoretical discussions assume. The uncritical use of Y and Q, therefore, is likely to lead to optimistic interpretations of agreement. Kappa should be preferred for most purposes, although an adjustment to the computational formulas for Y and Q is presented that can diminish their positive bias.