From Self-Esteem to Selflessness: An Evidence (Gap) Map of Self-Related Processes as Mechanisms of Mindfulness-Based Interventions.

Self-related processes (SRPs) have been theorized as key mechanisms of mindfulness-based interventions (MBIs), but the evidence supporting these theories is currently unclear. This evidence map introduces a comprehensive framework for different types of SRPs, and how they are theorized to function as mechanisms of MBIs (target identification). The evidence map then assesses SRP target engagement by mindfulness training and the relationship between target engagement and outcomes (target validation).

Emotion-related constructs engaged by mindfulness-based interventions: A systematic review and meta-analysis.

Objectives: Mindfulness-based interventions (MBIs) have been widely implemented to improve self-regulation behaviors, often by targeting emotion-related constructs to facilitate change. Yet the degree to which MBIs engage specific measures of emotion-related constructs has not been systematically examined.

Methods: Using advanced meta-analytic techniques, this review examines construct and measurement engagement in trials of adults that used standardized applications of the two most established MBIs: Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Cognitive Therapy (MBCT), or modified variations of these interventions that met defined criteria.

Dismantling Mindfulness-Based Cognitive Therapy: Creation and validation of 8-week focused attention and open monitoring interventions within a 3-armed randomized controlled trial.

Background: While mindfulness-based interventions (MBIs) employ two distinct practices, focused attention (FA) and open monitoring (OM), the integrated delivery of these practices in MBIs precludes understanding of their practice-specific effects or mechanisms of action. The purpose of this study is to isolate hypothesized active ingredients and practice-specific mechanistic target engagement by creating structurally equivalent interventions that differ only by the active ingredient (meditation practice) offered and to test whether the hypothesized components differentially engage the mechanistic targets that they are purported to engage.

Methods: Participants were intended to be representative of American meditators and had mild to severe affective disturbances.

Investigations of a new field in gas chromatography: capillary columns with a super-thick layer of stationary liquid phase.

Basic characteristics (efficiency, selectivity, non-equilibrium) of capillary columns with a super-thick layer of stationary liquid phase are investigated. In contrast to traditionally used capillary columns with standard stationary phase thickness of 0.1-0.

Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines.

Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity.

Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.

Mean corpuscular volume may correlate with erythrocyte 6-thioguanine nucleotide concentrations in patients treated with azathioprine and 6-mercaptourine. We conducted a study of 166 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentrations, disease activity as measured by the Inflammatory Bowel Disease Questionnaire (active disease <170, remission >170), and leukopenia. Blood was submitted for mean corpuscular volume, whole blood 6-thioguanine nucleotide concentration, and leukocyte count.

Chemical modifications to study mutations that affect the ability of the general base (E268) to function in human liver mitochondrial aldehyde dehydrogenase.

The action of a general base is needed in two possible steps during the aldehyde dehydrogenase catalyzed oxidation of an aldehyde to an acid. The base is glutamate at position 268 in the cytosolic and mitochondrial class 1 and 2 enzyme. A chemical modification approach was undertaken to determine if the base were necessary in the initial attack of the nucleophilic cysteine (302) on the aldehyde as well as the attack by water on the acyl intermediate formed after the aldehyde is oxidized.

Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration.

Peptide nucleic acids (PNAs) are DNA analogs that hybridize to complementary nucleic sequences with high affinity and stability. In our previous work, we showed that a PNA complementary to a 12-base pair (bp) sequence of the coding region of the rat neurotensin receptor (rNTR1) mRNA is effective in significantly blocking a rat's central responses to neurotensin (NT), even when the PNA is injected intraperitoneally (i.p.

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.

Background: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine.

Methods: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count.

Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.

Aim: We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine.

Methods: Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day.

Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood.

The conversion of the cytotoxic and immunosuppressive 6-mercaptopurine (6MP) to the active 6-thioguanine nucleotides (6TGN) is necessary for clinical efficacy of 6MP and its prodrug azathioprine. Another metabolite, 6-methylmercaptopurine nucleotide (6MMPN), is formed via a competing pathway by thiopurine methyl transferase. The concentrations of 6TGN and 6MMPN are measured in washed erythrocytes as a surrogate to the intracellular levels of these metabolites in the target tissues.

In vivo inhibition of aldehyde dehydrogenase by disulfiram.

Disulfiram (DSF) has found extensive use in the aversion therapy treatment of recovering alcoholics. Although it is known to irreversibly inhibit hepatic aldehyde dehydrogenase (ALDH), the specific mechanism of in vivo inhibition of the enzyme by the drug has not yet been determined. In this report, we demonstrate a novel, but simple and rapid method for structurally characterizing in vivo derived protein-drug adducts by linking on-line sample processing to HPLC-electrospray ionization mass spectrometry (HPLC-MS) and HPLC-tandem mass spectrometry (HPLC-MS/MS).

Overview--in vitro inhibition of aldehyde dehydrogenase by disulfiram and metabolites.

Disulfiram (DSF) has found extensive use in the aversion therapy treatment of recovering alcoholics. It is known that DSF or a metabolite irreversibly inhibits aldehyde dehydrogenase (ALDH). However, the actual mechanism of inhibition is still not known.

Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase.

Extensive use for disulfiram (DSF) has been found in the aversion therapy treatment of recovering alcoholics. Although it is known to irreversibly inhibit hepatic aldehyde dehydrogenase (ALDH), the specific mechanism of in vivo inhibition of the enzyme by the drug has not been determined yet. We have demonstrated in this report a novel, but simple and rapid method for structurally characterizing in vivo derived protein-drug adducts by linking on-line sample processing to HPLC-electrospray ionization mass spectrometry (HPLC-MS) and HPLC-tandem mass spectrometry (HPLC-MS/MS).

Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes.

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol deterrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-diethylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Several isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) metabolize MeDDC in the liver. The human kidney contains FMO1 and several isoforms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subfamilies.

Intravenous azathioprine in severe ulcerative colitis: a pilot study.

Objective: Azathioprine use in acute ulcerative colitis has been limited by its perceived long onset of action. The aim of this study was to determine the safety and clinical effect of an i.v.

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease.

Introduction: This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease.

Methods: Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score.

Effect of enzyme inhibitors on protein quaternary structure determined by on-line size exclusion chromatography-microelectrospray ionization mass spectrometry.

Aldehyde dehydrogenases (ALDH) are a family of enzymes primarily involved in the oxidation of various aldehydes. Most ALDH enzymes derived from mammalian sources have been shown to exist as homotetramers, consisting of four identical subunits of approximately 54 kDa. The presence of the homotetramer appears to be necessary for enzyme activity.

Rat liver constitutive and phenobarbital-inducible cytosolic aldehyde dehydrogenases are highly homologous proteins that function as distinct isozymes.

Rat liver contains two class 1 aldehyde dehydrogenases (ALDHs): a constitutive isozyme (ALDH1) and a phenobarbital-inducible isozyme (ALDH-PB). Defining characteristics of mammalian class 1 ALDHs include a homotetrameric structure, high expression in liver, sensitivity to the inhibitor disulfiram, and high activity for the oxidation of retinal. It is often presumed that ALDH-PB is the rat ortholog of mammalian ALDH1, and the identity of rat ALDH-PB is commonly interchanged with ALDH1.

Drug-grapefruit juice interactions.

Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Role of disulfiram in the in vitro inhibition of rat liver mitochondrial aldehyde dehydrogenase.

The alcohol aversion therapy drug disulfiram has been shown to inhibit hepatic aldehyde dehydrogenase (ALDH), one of the key enzymes involved in ethanol metabolism. It is believed by some that disulfiram could be one of the active inhibitors in vivo. However, the actual interaction between disulfiram and ALDH remains ambiguous.

Methylphenidate: its pharmacology and uses.

Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attention-deficit/hyperactivity disorder and narcolepsy.

Identification of the protein-drug adduct formed between aldehyde dehydrogenase and S-methyl-N,N-diethylthiocarbamoyl sulfoxide by on-line proteolytic digestion high performance liquid chromatography electrospray ionization mass spectrometry.

Disulfiram has been used clinically as an aversion therapy treatment for recovering alcoholics. One of its metabolites, S-methyl-N, N-diethylthiocarbamoyl sulfoxide (MeDTC-SO), is currently believed by some to be the active metabolite in vivo. We demonstrate in this report that MeDTC-SO is a potent irreversible inhibitor of recombinant rat liver mitochondrial aldehyde dehydrogenase (rlmALDH), the enzyme responsible for oxidizing acetaldehyde formed during ethanol metabolism.

Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction.

An abridged five-item version of the 15-item International Index of Erectile Function (IIEF) was developed (IIEF-5) to diagnose the presence and severity of erectile dysfunction (ED). The five items selected were based on ability to identify the presence or absence of ED and on adherence to the National Institute of Health's definition of ED. These items focused on erectile function and intercourse satisfaction.

A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis.

Background And Aims: The optimum initial dose of methotrexate for steroid-requiring inflammatory bowel disease is not known.

Aim: To compare directly the efficacy and toxicity of methotrexate 15 and 25 mg/week, and to explore the value of methotrexate blood levels as predictors of outcome.

Methods: A 16-week randomized single-blind comparison of subcutaneous methotrexate 15 or 25 mg/week was performed in 32 patients with steroid-requiring Crohn's disease or ulcerative colitis.