Leukocyte Gene Expression in Patients with Medication Refractory Depression before and after Treatment with ECT or Isoflurane Anesthesia: A Pilot Study.

Objective. To evaluate leukocyte gene expression for 9 selected genes (mRNAs) as biological markers in patients with medication refractory depression before and after treatment with ECT or isoflurane anesthesia (ISO). Methods. In a substudy of a nonrandomized open-label trial comparing effects of ECT to ISO therapy, blood samples were obtained before and after treatment from 22 patients with refractory depression, and leukocyte mRNA was assessed by quantitative PCR. Patients' mRNAs were also compared to 17 healthy controls. Results. Relative to controls, patients before treatment showed significantly higher IL10 and DBI and lower ADRA2A and ASIC3 mRNA (P < 0.025). Both ECT and ISO induced significant decreases after treatment in 4 genes: IL10, NR3C1, DRD4, and Sult1A1. After treatment, patients' DBI, ASIC3, and ADRA2A mRNA remained dysregulated. Conclusion. Significant differences from controls and/or significant changes after ECT or ISO treatment were observed for 7 of the 9 mRNAs studied. Decreased expression of 4 genes after effective treatment with either ECT or ISO suggests possible overlap of underlying mechanisms. Three genes showing dysregulation before and after treatment may be trait-like biomarkers of medication refractory depression. Gene expression for these patients has the potential to facilitate diagnosis, clarify pathophysiology, and identify potential biomarkers for treatment effects.

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.

OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Comparative effects of caffeine and albuterol on the bronchoconstrictor response to exercise in asthmatic athletes.

The main aim of this study was to evaluate the comparative and additive effects of caffeine and albuterol (short-acting beta (2)-agonist) on the severity of EIB. Ten asthmatic subjects with EIB (exercise-induced bronchoconstriction) participated in a randomized, double-blind, double-dummy crossover study. One hour before an exercise challenge, each subject was given 0, 3, 6, or 9 mg/kg of caffeine or placebo mixed in a flavored sugar drink. Fifteen minutes before the exercise bout, an inhaler containing either albuterol (180 microg) or placebo was administered to each subject. Pulmonary function tests were conducted pre- and post-exercise. Caffeine at a dose of 6 and 9 mg/kg significantly reduced (p<0.05) the mean maximum % fall in post-exercise FEV (1) to -9.0+/-9.2% and -6.8+/-6.5% respectively compared to the double-placebo (-14.3+/-11.1%) and baseline (-18.4+/-7.2%). There was no significant difference (p>0.05) in the post-exercise % fall in FEV (1) between albuterol ( PLUS CAFFEINE PLACEBO) (-4.0+/-5.2%) and the 9 mg/kg dose of caffeine (-6.8+/-6.5%). Interestingly, there was no significant difference (p>0.05) in the post-exercise % fall in FEV (1) between albuterol ( PLUS CAFFEINE PLACEBO) (-4.0+/-5.2%) and albuterol with 3, 6 or 9 mg/kg of caffeine (-4.4+/-3.8, -6.8+/-5.6, -4.4+/-6.0% respectively). Similar changes were observed for the post-exercise % fall in FVC, FEF (25-75%) and PEF. These data indicate that moderate (6 mg/kg) to high doses (9 mg/kg) of caffeine provide a significant protective effect against EIB. It is feasible that the negative effects of daily use of short-acting beta (2)-agonists by asthmatic athletes could be reduced simply by increasing caffeine consumption prior to exercise.