Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder.

RATIONALE: Chronic alcohol intake down-regulates GABAergic transmission and reduces levels of neuroactive steroids. These changes are associated with greater stress dysregulation and high alcohol craving which in turn increases relapse risk. OBJECTIVES: This study tested whether potentiation of the neurosteroid system with pregnenolone (PREG), a precursor to neuroactive steroids and known to increase GABAergic transmission, will normalize chronic alcohol-related stress adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses and reduce alcohol craving to significantly impact relapse risk. METHODS: Forty-three treatment-seeking individuals with alcohol use disorder (AUD) were randomized to placebo (PBO) or supraphysiologic pregnenolone doses of 300 mg or 500 mg treatment using a parallel-between subject design as part of a larger 8-week pilot clinical trial. In week 2, they participated in a 3-day laboratory experiment where on each day they self-administered the assigned study drug in the laboratory and were then exposed to 5-min personalized guided imagery provocation of stress, alcohol, or neutral/relaxing cues, one condition per day on separate days, in a random, counterbalanced order. Repeated assessments of alcohol craving, anxiety, HPA axis, heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP) and serum pregnenolone levels were made on each day. RESULTS: Pregnenolone levels were significantly increased in the PREG groups versus PBO. PREG treatment decreased stress- and alcohol cue- induced craving and dose-specifically reduced stress-induced anxiety in the 300 mg/day group. Both PREG doses compared to PBO also normalized CORT/ACTH and increased stress-induced HR, stress- and cue-induced SBP, and in the 300 mg PREG group cue-induced DBP responses relative to neutral condition. CONCLUSIONS: Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.

25-OHD response to vitamin D supplementation in children: effect of dose but not GC haplotype.

OBJECTIVE: GC/DBP effects on response to vitamin D supplementation have not been well-studied. Thus we assessed free and total 25-OHD after vitamin D treatment across the six common GC haplotypes. DESIGN: This double-blind, randomized study compared two vitamin D3 doses in healthy, urban-dwelling 6-month to 10-year-old children at-risk for vitamin D deficiency. Randomization was stratified by GC haplotype. METHODS: Children were randomized to receive 2800 or 7000 International Units of vitamin D3 weekly. 25-OHD and 1,25(OH)2D were sampled at baseline and after 1-6 months of supplementation. RESULTS AND CONCLUSIONS: One hundred ninety-two of 225 enrolled subjects completed the study. After one month, total 25-OHD increased with both doses and were higher with 7000 IU/week (85.5 ± 22.8 nmol/L) compared to 2800 IU/week (76.8 ± 18.0 nmol/L), despite equivalent baseline levels. No further significant increase occurred at 6 months (89.8 ± 35.5 and 74.3 ± 18.3 nmol/L, respectively). Free 25-OHD similarly changed. 25-OHD differed among GC groups at baseline. Although no significant effects of individual GC haplotypes on incremental changes were evident, a trend toward an effect of combined 'at risk' GC alleles on response was evident (P = 0.06). Total 1,25(OH)2D showed modest increases, moreso with the larger dose. In urban-dwelling children at-risk for vitamin D deficiency, 1 month of vitamin D3 2800 IU/week increased 25-OHD across all GC haplotype groups, and somewhat enhanced with 7000 IU/week with no further significant increases after 6 months of supplementation. Free 25-OHD measures offer no monitoring advantage over total 25-OHD.

Stress-related suppression of peripheral cytokines predicts future relapse in alcohol-dependent individuals with and without subclinical depression.

Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression. We also examine the potential link between cytokine adaptations in response to stress and prospective alcohol relapse risk. Thirty-three, alcohol-dependent individuals (21 with and 12 without high depressive symptoms) and 37 controls (16 with and 21 without high depressive symptoms) were exposed to two 5-minute personalized guided imagery conditions (stress and neutral) across consecutive days in a randomized and counterbalanced order. Alcohol craving and serum measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were collected prior to and following imagery exposure. Following treatment discharge, follow-up interviews were conducted over 90 days to assess relapse. Dampened IL-1ra and IL-6 in response to stress was observed as a function of alcohol dependence and not moderated by depressive symptoms. Lower levels of IL-6 following stress also predicted greater drinking days following treatment. Conversely, high depressive symptomatology was associated solely with pro-inflammatory adaptations. Stress-related suppression of TNFα predicted drinking severity only in alcohol-dependent individuals with subclinical depression, and suppressed TNFR1 following stress was only seen in individuals with subclinical depression. Stress-induced suppression of pro-inflammatory TNF markers may indicate a risk factor for alcohol-dependent individuals with co-occurring depressive symptoms.

Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia.

Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400 IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27 h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.

Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers.

BACKGROUND: Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. METHODS: Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the "alcohol taste test" (ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. RESULTS: Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. CONCLUSIONS: Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake.

The Effect of a Whey Protein Supplement on Bone Mass in Older Caucasian Adults.

CONTEXT: It has been assumed that the increase in urine calcium (Ca) that accompanies an increase in dietary protein was due to increased bone resorption. However, studies using stable Ca isotopes have found that dietary protein increases Ca absorption without increasing bone resorption. OBJECTIVE: The objective of the study was to investigate the impact of a moderately high protein diet on bone mineral density (BMD). DESIGN: This was a randomized, double-blind, placebo-controlled trial of protein supplementation daily for 18 months. SETTING: The study was conducted at two institutional research centers. PARTICIPANTS: Two hundred eight older women and men with a body mass index between 19 and 32 kg/m(2) and a self-reported protein intake between 0.6 and 1.0 g/kg participated in the study. INTERVENTION: Subjects were asked to incorporate either a 45-g whey protein or isocaloric maltodextrin supplement into their usual diet for 18 months. MAIN OUTCOME MEASURE: BMD by dual-energy x-ray absorptiometry, body composition, and markers of skeletal and mineral metabolism were measured at baseline and at 9 and 18 months. RESULTS: There were no significant differences between groups for changes in L-spine BMD (primary outcome) or the other skeletal sites of interest. Truncal lean mass was significantly higher in the protein group at 18 months (P = .048). C-terminal telopeptide (P = .0414), IGF-1 (P = .0054), and urinary urea (P < .001) were also higher in the protein group at the end of the study period. There was no difference in estimated glomerular filtration rate at 18 months. CONCLUSION: Our data suggest that protein supplementation above the recommended dietary allowance (0.8 g/kg) may preserve fat-free mass without adversely affecting skeletal health or renal function in healthy older adults.

Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study.

CONTEXT: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. OBJECTIVE: The objective of the study was to suppress elevated PTH levels in XLH patients. DESIGN: This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. SETTING: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit. PATIENTS: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less. INTERVENTION: The intervention for this study was the use of paricalcitol or placebo for 1 year. MAIN OUTCOME MEASURES: Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans. RESULTS: PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject. CONCLUSIONS: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.

Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women.

Increasing dietary protein within a physiologic range stimulates intestinal calcium absorption, but it is not known if specific amino acids or dietary protein as a whole are responsible for this effect. Therefore, we selectively supplemented a low-protein (0.7 g/kg) diet with either the calcium-sensing receptor-activating amino acids (CaSR-AAAs) L-tryptophan, L-phenylalanine, and L-histidine, or the dibasic amino acids (DAAs) L-arginine and L-lysine, to achieve intakes comparable to the content of a high-protein diet (2.1 g/kg) and measured intestinal calcium absorption. Fourteen young women took part in a placebo-controlled, double-blind, crossover feeding trial in which each participant ingested a 6-d low-protein diet supplemented with CaSR-AAAs, DAAs, or methylcellulose capsules (control) after an 11-d adjustment period. All participants ingested all 3 diets in random order. Intestinal calcium absorption was measured between days 5 and 6 using dual-stable calcium isotopes ((42)Ca, (43)Ca, and (44)Ca). There was no difference in calcium absorption between the diet supplemented with CaSR-AAAs (22.9 ± 2.0%) and the control diet (22.3 ± 1.4%) (P = 0.64). However, calcium absorption tended to be greater during the DAA supplementation period (25.2 ± 1.4%) compared with the control diet period (22.3 ± 1.4%) (P < 0.10). Larger and longer clinical trials are needed to clarify the possible benefit of arginine and lysine on calcium absorption.

Dietary protein-induced increases in urinary calcium are accompanied by similar increases in urinary nitrogen and urinary urea: a controlled clinical trial.

To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearson's correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3±1.7 g/g (99.6±13.8 mmol/mmol) to 16.8±2.2 g/g (135.5±17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76±1.84 mg (1.19±0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719×(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11×(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials.

Demographic, dietary, and biochemical determinants of vitamin D status in inner-city children.

BACKGROUND: Reports of clinical rickets are particularly evident in minority infants and children, but only limited analyses of vitamin D are available in this demographic group. OBJECTIVE: We sought to characterize circulating 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and their determinants, including circulating parathyroid hormone (PTH), total alkaline phosphatase activity (ALP), calcium, and phosphorus, in minority infants and children. DESIGN: We obtained demographic information and blood samples for measurement of PTH, ALP, 25(OH)D, and 1,25(OH)(2)D in >750 6-mo- to 3-y-old children. Dietary intake data were obtained and analyzed. RESULTS: The mean (±SD) 25(OH)D concentration was 66 ± 22 nmol/L (26.3 ± 8.7 ng/dL). A total of 15% of children had 25(OH)D concentrations less than the recommended target threshold of 50 nmol/L. Combined elevations of PTH and ALP occurred in only 2.5% of children. Determinants of 25(OH)D included vitamin D intake, age (decreasing with age), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), formula use (higher intakes), season (greater concentrations in the summer and fall than in the winter and spring), and, inversely, PTH. The mean 1,25(OH)(2)D concentration was 158 ± 58 pmol/L (60.6 ± 22.5 pg/mL), which was consistent with a reference range of 41-274 pmol/L or 15.7-105.5 pg/mL. Determinants for 1,25(OH)(2)D were age (decreasing with age), sex (greater concentrations in girls than in boys), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), and, inversely, serum calcium and phosphorus. CONCLUSIONS: Although 15% of subjects were vitamin D insufficient, only 2.5% of subjects had elevations of both PTH and ALP. The greater 25(OH)D concentrations observed with formula use confirm that dietary vitamin D fortification is effective in this demographic group. Circulating 1,25(OH)(2)D is higher in infants than in older children and adults and, in contrast to 25(OH)D, is not directly correlated with nutrient intakes.

The experience of being listened to: a human becoming study with music.

The purpose of this research was to discover the structure of the lived experience of being listened to from the perspective of 10 older women receiving in-patient rehabilitation. The Parse research method was used to guide this study where music was used in the dialogical engagement process. The women told their stories and created melodies of being listened to with the researcher using her flute. The findings include three core concepts--an acknowledging engagement, gratifying contentment, and an unburdening respite. Findings extend the theory of human becoming, enhance understanding of the experience of being listened to, and affirm its value.