Correction: Genomic Counter-Stress Changes Induced by the Relaxation Response.

[This corrects the article DOI: 10.1371/journal.pone.0002576.].

Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: In nonhypertensive individuals, lower levels of 25-hydroxyvitamin D (25[OH]D) have been associated with an increased risk of hypertension, and vitamin D deficiency has been associated with endothelial dysfunction in such individuals. However, the effect of vitamin D supplementation on endothelial dysfunction in nonhypertensive individuals has not been examined in a rigorous fashion. METHODS: In this randomized, double-blind, placebo-controlled trial of nonhypertensive, nondiabetic overweight, or obese individuals with vitamin D deficiency (body mass index ≥25 and 25[OH]D ≤ 20 ng/ml), we assigned subjects to receive either ergocalciferol (50,000 units) or matching placebo, once a week for 8 weeks. Our primary outcome was endothelial-dependent vasodilation (EDV) measured by brachial artery ultrasound at baseline and 8 weeks postrandomization. RESULTS: By the end of the trial, 46 and 47 participants were allocated to receive ergocalciferol and placebo, respectively. Mean 25(OH)D levels increased from 14.9 to 30.3 in the vitamin D group and 14.4 to 17.4 in the placebo. EDV did not change significantly with either vitamin D repletion (from 6.3 ± 3.6% at baseline to 6.1 ± 4.6% at 8 weeks; P value = 0.78) or placebo (7.9 ± 4.7% to 6.8 ± 4.7%; P = 0.17). The treatment effect P value (comparing the 8-week change with ergocalciferol to the change with placebo) was 0.35. CONCLUSIONS: In this randomized, double-blind, placebo-controlled trial, there was no improvement in endothelial function (measured as EDV) after repletion of vitamin D in overweight/obese nonhypertensive individuals.

Effect of Uric Acid-Lowering Agents on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial.

Higher levels of serum uric acid are independently associated with endothelial dysfunction, a mechanism for incident hypertension. Overweight/obese individuals are more prone to endothelial dysfunction than their lean counterparts. However, the effect of lowering serum uric acid on endothelial dysfunction in these individuals has not been examined thoroughly. In this randomized, double-blind, placebo-controlled trial of nonhypertensive, overweight, or obese individuals with higher serum uric acid (body mass index ≥25 kg/m2 and serum uric acid ≥5.0 mg/dL), we assigned subjects to probenecid (500-1000 mg/d), allopurinol (300-600 mg/d), or matching placebo. The primary outcome was endothelium-dependent vasodilation measured by brachial artery ultrasound at baseline and 8 weeks. By the end of the trial, 47, 49, and 53 participants had been allocated to receive probenecid, allopurinol, and placebo, respectively. Mean serum uric acid levels significantly decreased in the probenecid (from 6.1 to 3.5 mg/dL) and allopurinol groups (from 6.1 to 2.9 mg/dL) but not in the placebo group (6.1 to 5.6 mg/dL). None of the interventions produced any significant change in endothelium-dependent vasodilation (probenecid, 7.4±5.1% at baseline and 8.3±5.1% at 8 weeks; allopurinol, 7.6±6.0% at baseline and 6.2±4.8% at 8 weeks; and placebo, 6.5±3.8% at baseline and 7.1±4.9% at 8 weeks). In this randomized, double-blind, placebo-controlled trial, uric acid lowering did not affect endothelial function in overweight or obese nonhypertensive individuals. These data do not support the hypothesis that uric acid is causally related to endothelial dysfunction, a potential mechanism for development of hypertension.

Genomic counter-stress changes induced by the relaxation response.

BACKGROUND: Mind-body practices that elicit the relaxation response (RR) have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion. METHODS/PRINCIPAL FINDINGS: We assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M), 19 healthy controls (group N(1)), and 20 N(1) individuals who completed 8 weeks of RR training (group N(2)). 2209 genes were differentially expressed in group M relative to group N(1) (p<0.05) and 1561 genes in group N(2) compared to group N(1) (p<0.05). Importantly, 433 (p<10(-10)) of 2209 and 1561 differentially expressed genes were shared among long-term (M) and short-term practitioners (N(2)). Gene ontology and gene set enrichment analyses revealed significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N(1) controls, 5 N(2) short-term and 6 M long-term practitioners. CONCLUSIONS/SIGNIFICANCE: This study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring RR and stress related responses in multiple disease settings.

Stress management versus lifestyle modification on systolic hypertension and medication elimination: a randomized trial.

Isolated systolic hypertension is common in the elderly, but decreasing systolic blood pressure (SBP) without lowering diastolic blood pressure (DBP) remains a therapeutic challenge. Although stress management training, in particular eliciting the relaxation response, reduces essential hypertension its efficacy in treating isolated systolic hypertension has not been evaluated. We conducted a double-blind, randomized trial comparing 8 weeks of stress management, specifically relaxation response training (61 patients), versus lifestyle modification (control, 61 patients). Inclusion criteria were >or=55 years, SBP 140-159 mm Hg, DBP <90 mm Hg, and at least two antihypertensive medications. The primary outcome measure was change in SBP after 8 weeks. Patients who achieved SBP <140 mm Hg and >or=5 mm Hg reduction in SBP were eligible for 8 additional weeks of training with supervised medication elimination. SBP decreased 9.4 (standard deviation [SD] 11.4) and 8.8 (SD 13.0) mm Hg in relaxation response and control groups, respectively (both ps <0.0001) without group difference (p=0.75). DBP decreased 1.5 (SD 6.2) and 2.4 (SD 6.9) mm Hg (p=0.05 and 0.01, respectively) without group difference (p=0.48). Forty-four (44) in the relaxation response group and 36 in the control group were eligible for supervised antihypertensive medication elimination. After controlling for differences in characteristics at the start of medication elimination, patients in the relaxation response group were more likely to successfully eliminate an antihypertensive medication (odds ratio 4.3, 95% confidence interval 1.2-15.9, p=0.03). Although both groups had similar reductions in SBP, significantly more participants in the relaxation response group eliminated an antihypertensive medication while maintaining adequate blood pressure control.

Association between oxygen consumption and nitric oxide production during the relaxation response.

BACKGROUND: Mind/body practices that elicit the relaxation response (RR) are currently practiced by over 30% of American adults. RR elicitation reduces volumetric oxygen consumption (VO(2)) from rest and counteracts the effects of stress, although the mechanisms mediating the RR remain unknown. This study was designed to investigate whether RR elicitation is mediated by nitric oxide (NO). We developed a method to quantify depth of RR using change in VO(2) (slope) during RR elicitation. We evaluated whether depth of RR elicitation was correlated with changes in NO, as measured by percentage changes in fractional exhaled nitric oxide (F(E)NO). MATERIAL/METHODS: We conducted a randomized, controlled trial, in which 46 subjects were randomized to either 8-weeks of RR training using audiotapes (n=34) or 8-weeks of exposure to a control condition--receiving health-education by audiotapes (n=12). Prior to randomization, VO(2) and F(E)NO were measured while subjects listened to a control audiotape. Eight weeks later, VO(2) and F(E)NO were measured while the RR group listened to a RR-eliciting audiotape and the control group listened to a control audiotape. RESULTS: Prior to receiving any training, there was no association between VO(2) slope and F(E)NO. After training, there was an inverse correlation between VO(2) slope and F(E)NO in the RR group (r = -0.41, P=0.037, n=26), but not in the control group (r=0.12, P=0.78, n=8). CONCLUSIONS: Depth of RR elicitation was associated with increased concentrations of F(E)NO after RR training. The RR may be mediated by NO helping to explain its clinical effects in stress-related disorders.

Activation and inactivation of signal transducers and activators of transcription by ciliary neurotrophic factor in neuroblastoma cells.

Neurons in vivo are exposed to a variety of different growth factors and cytokines. A principal signalling pathway for ciliary neurotrophic factor (CNTF)-like cytokines is the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) system of kinases and transcription factors. In the human cell line (SH-SY5Y), STAT1 and STAT3 activation by CNTF-like cytokines showed tyrosine phosphorylation peaking at 0.5 h and inactivating within 2 h. Tyrosine phosphorylation of the receptor-associated tyrosine kinases Jak1 and Jak2 showed a similar time course of activation and inactivation in response to CNTF. The STAT1 response to the non-CNTF-like cytokine, interferon-gamma (IFN-gamma) did not inactivate. Inactivation to CNTF was not due to a decrease in CNTF receptor subunit gp130 or in levels of Jak1 or Jak2. STAT inactivation was inhibited by the protein kinase blocker H7 and a tyrosine phosphatase blocker, but not by inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) kinase, mTOR-P70/S6 kinase or phosphatidyl inositol-3-kinase (PI-3 kinase). Surprisingly, CNTF caused only a minor increase in levels of suppressors of cytokine signalling, SOCS-1 and SOCS-3. CNTF pretreatment desensitized the cells to the CNTF-like cytokines, leukemia inhibitory factor and oncostatin-M but not to IFN-gamma. These results reveal a complex level of regulation of shared signalling pathways for cytokines that is dependent on both the type of cell and cytokine.