Adaptations of an Effective Evidence-Based Pediatric Weight Management Intervention.

Current childhood obesity treatment programs do not address medically underserved populations or settings where all members of an interdisciplinary team may not exist-either within one organization or within the community. In this paper, we describe the use of a community-academic partnership to iteratively adapt Epstein's Traffic Light Diet (TLD), into Building Healthy Families (BHF), a community-placed evidence-based pediatric weight management intervention (PWMI) and evaluate its effectiveness in reducing BMI z scores. Nine cohorts of families completed BHF. Participants included children aged 6-12 years with obesity (M = 9.46, SD = 1.74). The Framework for Reporting Adaptations and Modifications-Expanded guided our classification of modifications across BHF cohorts. Using the FRAME reporting structure, the changes that were documented were (1) planned and occurred pre-implementation, (2) based on decisions from local stakeholders (e.g., school administrator, members of the implementation team), and (3) specific to changes in content and context-with a focus on implementation and potential for local scale-up. The nature of the adaptations included adding elements (whole of family approach), removing elements (calorie counting), and substituting elements (steps for minutes of physical activity). Across 9 cohorts, 84 families initiated the BHF program, 69 families successfully completed the 12-week program, and 45 families returned for 6-month follow-up assessments. Results indicated that the BMI z score in children was reduced by 0.31 ± 0.17 at 6 months across all cohorts. Reduction in BMI z score ranged from 0.41 in cohort 4 to 0.13 in cohort 5. Iterative adaptations to BHF were completed to improve the fit of BHF to the setting and participants and have contributed to a sustained community PWMI that adheres to the underlying principles and core elements of other evidence-based PWMIs. Monitoring adaptations and related changes to outcomes can play a role in long-term sustainability and effectiveness.

The impact of health literacy on rural adults' satisfaction with a multi-component intervention to reduce sugar-sweetened beverage intake.

SIPsmartER is a 6-month behavioral intervention designed using a health literacy universal precautions approach that has been found effective at reducing sugary beverage intake in rural, low socioeconomic adults. The purpose of this mixed-methods study is to determine if health literacy status influenced participants' satisfaction and perceptions of each intervention component: small group classes, interactive-voice response (IVR) calls, personal action plans and self-monitoring logs. Of the 155 participants enrolled in SIPsmartER, 105 (68%) completed an interview-administered summative evaluation including 68 high and 37 low health literate participants. The quantitative findings show participant satisfaction with each intervention component was high (i.e. classes = 9.6, IVR calls = 8.1, action plans = 8.9-9.1, logs = 8.7 on a 10-point scale) and similar across both health literacy groups. The majority of qualitative responses were positive (81.8%) and code counts were comparable between literacy groups with a few exceptions. As compared with high health literacy respondents, low health literacy respondents more frequently mentioned liking the content and length of IVR calls, liking the motivational aspects of the personal action plans, and identified numeracy issues with the self-monitoring logs. Overall, applying a health literacy universal precautions approach is an effective and acceptable strategy for both high and low health literacy groups.

Peromyscus: effect of early pairing on reproduction.

Sibling mating in prairie deer mice (Peromyscus maniculatus bairdi) results in poor reproductive performance. Siblings experimentally paired before puberty exhibit delayed reproduction when adult. A behavioral mechanism is involved in this reproductive delay, since prepubertal familiarity also delays reproduction in nonsibling pairs. Such a reproductive delay may act to reduce inbreeding depression and regulate population growth.

Does worksite social capital enhance retention into a worksite weight-loss programme?

OBJECTIVE: To determine if worksite social capital predicted retention in a worksite-based weight-loss programme using structural equation modelling. A secondary aim was to determine if worksite social capital was related to changes in weight at 6 months. METHODS: Overweight or obese employees from 28 worksites enrolled in a larger 12-month worksite weight-loss trial. Workplace social capital was assessed using an eight-item scale specific to the workplace. Weight was measured using a HealthSpottm, and change in weight was computed from weigh-ins at baseline and 6 months and reported as pounds (lbs) lost. Retention was defined as those employees who completed a weigh-in at 6 months. RESULTS: Across the trial, N = 1,790; age = 46.6 ± 11; 73% women; 73% White overweight or obese employees participated. The odds of participant attrition were 1.12 times greater with each unit decrease in social capital score at baseline (p < 0.05), and while the model testing the direct effect of social capital at baseline on weight loss at 6 months demonstrated acceptable fit, social capital was not a significant predictor of weight loss (p > 0.05). CONCLUSIONS: Increased worksite social capital was predictive of retention in a worksite weight-loss programme. To maximize return on investments for employee wellness and weight-loss programmes, employers may benefit from understanding the facets of the 'social' environment such as social capital that may increase the likelihood of sustained participation.

Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation.

Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5' noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal-prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC-mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior.

Anxiety and cerebral blood flow during behavioral challenge. Dissociation of central from peripheral and subjective measures.

To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.

Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment.

Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.

Hyperresponsivity to the serotonin agonist m-chlorophenylpiperazine in Alzheimer's disease. A controlled study.

The serotonin agonist m-chlorophenylpiperazine (mCPP) was administered intravenously to 12 patients with Alzheimer's disease and ten age-matched controls. It produced distinct behavioral effects in both treatment groups; however, significantly greater responsivity to mCPP was found in patients with Alzheimer's disease than in controls in measures of psychomotor activation, restlessness, and perceptual abnormalities. Significant and similar increases in plasma prolactin and cortisol levels were found in both patients with Alzheimer's disease and controls following the administration of mCPP vs placebo. Furthermore, blood pressure and pulse changes following mCPP were not significantly different between the groups. Elderly controls, however, did show a significantly greater temperature response following mCPP than did patients with Alzheimer's disease. The overall cognitive effects of mCPP were minimal; however, mCPP produced significantly greater worsening in recent memory and knowledge memory in patients with Alzheimer's disease than in controls. These findings could not be explained by pharmacokinetic differences across populations, because plasma concentrations of mCPP were similar in patients with Alzheimer's disease and controls. The increased behavioral responsivity but unchanged neuroendocrine or other physiologic responsivity to mCPP may be related to damaged brain serotonin neurons or other neuronal systems that interact with serotonin neurons that have been found in postmortem and biopsy studies of patients with Alzheimer's disease.

Clomipramine in obsessive-compulsive disorder. Further evidence for a serotonergic mechanism of action.

Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.

Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results.

Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, double-blind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatment with at least partial benefit were crossed over to fluoxetine treatment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symptoms that were comparable with precrossover ratings completed during clomipramine treatment. A significant exacerbation in obsessive-compulsive disorder and depression ratings as well as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder. Platelet 5-HT concentrations were reduced 95% during both clomipramine and fluoxetine treatment periods. These results suggest that fluoxetine may represent a viable alternative to clomipramine in the treatment of obsessive-compulsive disorder, although further studies with larger sample sizes are needed.

Corticotropin-releasing factor: a marked circadian rhythm in primate cerebrospinal fluid peaks in the evening and is inversely related to the cortisol circadian rhythm.

Continuous sampling of cerebrospinal fluid (CSF) over 24-h periods in 10 rhesus monkeys revealed a 2-fold, highly reproducible circadian rhythm in CRF concentrations. Peak CRF values of 77.9 +/- 6.4 pg/ml occurred in the evening at 1930 h, while the CRF nadir (38.4 +/- 4.2 pg/ml) occurred at 0745 h. Simultaneously sampled CSF cortisol peaked at 0913 h, with a nadir at 2226 h. Both CRF and cortisol rhythms closely fit sinusoidal circadian models, with r2 values of 0.94 and 0.92, respectively. While hypothalamic CRF is regarded as a major physiological regulator of pituitary ACTH secretion and, thereby, of the circadian and stress-related release of cortisol from the adrenal gland, CRF and CRF receptors are also widely distributed in other brain areas of primates and rodents. The marked difference in the circadian rhythm of CRF vs. that of cortisol suggests that CRF in CSF reflects or mediates some nonhypophysiotropic brain functions of this peptide.

Seasonal variation in behavioral responses to m-CPP in patients with seasonal affective disorder and controls.

This paper reports the behavioral responses to m-chlorophenylpiperazine (m-CPP), a serotonin agonist, in patients with seasonal affective disorder (SAD) and controls during the summer. Results are compared with the responses of SAD patients and controls given m-CPP in the winter. Results of the winter study were reported earlier by our group. Baseline Hamilton depression ratings in SAD patients were significantly lower in the summer than in winter (p < 0.05). Additionally, in both SAD patients and controls, there were seasonal differences on the National Institute of Mental Health (NIMH) self-rating scale items: "depressed affect," "dysphoria," and "functional deficit" at baseline. The behavioral responses to m-CPP across seasons differentiated patients from normals only in the "activation/euphoria" item, on which a far greater response was seen in patients than in controls during the winter. This behavioral response may be a state marker for winter depression, as it was significantly reduced after light treatment of these patients in the winter, and in the summer. SAD patients responded differently from controls on "altered self-awareness" and "dysphoria" independently of seasons, and these responses may be considered as possible trait markers for this condition. These results provide further evidence of a possible deficiency in serotonergic transmission in seasonal affective disorder.

Autonomic dysfunction in patients with dementia of the Alzheimer type.

Abnormalities of the noradrenergic system have been documented in the central nervous system of patients with dementia of the Alzheimer's type (DAT). To evaluate the autonomic sympathetic system in DAT, we measured lying and standing blood pressure (BP), pulse, and plasma epinephrine (E) and norepinephrine (NE) in 60 DAT patients (mean age +/- SD = 65 +/- 8 years), and 20 normal elderly controls. DAT patients had normal baseline findings (BP, pulse, NE, and E). Upon standing, plasma NE and E significantly increased in both DAT patients and controls, without group differences. However, the systolic BP response to standing was reduced in DAT patients compared with the normal controls (repeated measures ANOVA, p < 0.01). This impaired response of the systolic BP on standing was particularly evident in DAT patients with symptoms of depression. Severely impaired DAT patients did not differ in E, NE, BP, pulse, or in orthostatic changes from mild-to-moderately impaired patients. These results suggest that the sympathetic response to the stress of standing is functionally impaired in DAT. This deficit was especially evident when DAT was accompanied by depression, consistent with prior studies in non-demented depressed patients.

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder.

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPP's behavioral effects in humans remains controversial. To further study m-CPP's actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPP's ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergoline's ability to block m-CPP's effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPP's effects, including its elicitation of OCD symptoms.

Serum antibody for somatostatin-14 and prodynorphin 209-240 in patients with obsessive-compulsive disorder, schizophrenia, Alzheimer's disease, multiple sclerosis, and advanced HIV infection.

Patients with obsessive-compulsive disorder (OCD) demonstrated significant levels of antibody for somatostatin-28, its C-terminal fragment somatostatin-14, and prodynorphin. In contrast there were lower levels of reactivity for somatostatin-28(1-14) (the N-terminal fragment of somatostatin-28) and negligible reactivity for several other peptides including beta-endorphin and corticotropin. Healthy volunteers and disease controls [schizophrenia, Alzheimer's disease, multiple sclerosis, and subjects with advanced human immunodeficiency virus (HIV) infection] exhibited negligible reactivity. These data raise the consideration of an autoimmune mechanism for some OCD.

A preliminary study of the effects of intravenous m-chlorophenylpiperazine, a serotonin agonist, in elderly subjects.

m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, is currently being investigated as a probe of serotonergic responsivity in various neuropsychiatric disorders. The safety of m-CPP in elderly populations and its potential usefulness in exploring possible serotonergic dysfunction in Alzheimer's disease and normal aging were assessed by examining the behavioral, neuroendocrine, and physiological effects of this agent in 15 elderly subjects (mean age 69 +/- 2 years): 9 Alzheimer patients and 6 healthy normal volunteers. Intravenous m-CPP (0.08 mg/kg) was well tolerated in all subjects and produced no serious adverse effects. The behavioral effects were modest; in particular, minimal anxiety was observed, a finding that contrasted to results from an earlier study reporting that intravenous m-CPP at a slightly higher dose induced marked anxiety and panic attacks in younger subjects. m-CPP produced significant increases in plasma cortisol and prolactin, and significant changes in blood pressure and temperature in these elderly subjects. The results of this preliminary study suggest that intravenous m-CPP is safe and well-tolerated in elderly subjects. Future studies at higher doses can now proceed to study more definitively the question of possible age- and disorder-related reductions in central nervous system (CNS) serotonergic responsivity.

The TRH stimulation test in Alzheimer's disease and major depression: relationship to clinical and CSF measures.

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimer's disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels (delta maxTSH) (p less than 0.02) and higher (though still within normal limits) mean thyroxine (T4) levels (p less than 0.05) than the AD patients or controls. AD patients with a blunted TSH response had a significantly higher mean free T4 (FT4) level (p less than 0.03) and tended to be more severely demented (p less than 0.01) than those with a nonblunted response.

A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to i.v. mCPP.

In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.

Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder.

Eighteen outpatients with obsessive-compulsive disorder were treated with either buspirone, a partial serotonin agonist, or clomipramine, a serotonin uptake inhibitor, in a double-blind, random-assignment study. Both drugs led to statistically significant and similar improvements in scores on the Yale-Brown Obsessive-Compulsive Rating Scale and other obsessive-compulsive and depression scales. This preliminary result warrants further exploration with a larger sample and other serotonergic agents.