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.

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.

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.

Assessment of Customer Service in Academic Health Care Libraries (ACSAHL): an instrument for measuring customer service.

OBJECTIVES: In a pilot study, the library had good results using SERVQUAL, a respected and often-used instrument for measuring customer satisfaction. The SERVQUAL instrument itself, however, received some serious and well-founded criticism from the respondents to our survey. The purpose of this study was to test the comparability of the results of SERVQUAL with a revised and shortened instrument modeled on SERVQUAL. The revised instrument, the Assessment of Customer Service in Academic Health Care Libraries (ACSAHL), was designed to better assess customer service in academic health care libraries. METHODS: Surveys were sent to clients who had used the document delivery services at three academic medical libraries in Texas over the previous twelve to eighteen months. ACSAHL surveys were sent exclusively to clients at University of Texas (UT) Southwestern, while the client pools at the two other institutions were randomly divided and provided either SERVQUAL or ACSAHL surveys. RESULTS: Results indicated that more respondents preferred the shorter ACSAHL instrument to the longer and more complex SERVQUAL instrument. Also, comparing the scores from both surveys indicated that ACSAHL elicited comparable results. CONCLUSIONS: ACSAHL appears to measure the same type of data in similar settings, but additional testing is recommended both to confirm the survey's results through data replication and to investigate whether the instrument applies to different service areas.

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers.

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.

Change in diagnosis among orthopedists compared to non-orthopedists in the management of acute knee injuries.

OBJECTIVE: Uncertainty regarding diagnosis is associated with lower patient satisfaction and can lead to delays in definitive treatment and to inappropriate use of resources. We sought to compare change in diagnosis among orthopedists and non-orthopedists caring for a community based cohort of individuals with incident acute knee injuries. METHODS: We conducted a longitudinal investigation of a population based cohort of Olmsted County residents with their first episode of acute knee injury occurring between January 1, 1993, and December 31, 1995. We reviewed the entire (inpatient and outpatient) medical records for these patients and collected extensive clinical data on all diagnoses made (including possible and probable) and the specialty of the attending physician(s) making them. Diagnoses were categorized as: (1) meniscus injury, cruciate injury, or osteochondral fracture; (2) ligament injury, patellar instability, patellar injury; or (3) sprain, strain, injury (unspecified). Diagnostic switches were defined as changes from one diagnostic category to another, or the addition or subtraction of a diagnostic category. We then examined the quality of the documented evidence supporting meniscal, ligamentous, and cruciate diagnoses (at initial evaluation) by comparing the clinical evidence to the recommendations outlined by the American Academy of Orthopaedic Surgeons clinical algorithm on acute knee injury. Analyses were conducted comparing (1) the number of diagnostic switches and (2) the quality of the documented evidence among those cases initially cared for by orthopedists and those cared for by non-orthopedists, using logistic regression analysis adjusting for age, sex, and injury severity. The influence of these variables on costs of care was also examined. RESULTS: There were 664 patients (361 men and 303 women) in our study population, with an average age of 36.0 years (minimum 17, maximum 87). Of these, 324 were excluded because they only had one clinical encounter for their acute knee injury. Of the remaining 340, 59 (17.4%) were initially cared for by an orthopedist and 211 (62.1%) were cared for by an orthopedist at some time during their care. Diagnostic switches were significantly less frequent in the group who were cared for by orthopedists (55% vs 74%, p < 0.001). This result persisted after adjusting for age, sex, and severity (p = 0.003). The proportion of cases whose diagnoses were supported by evidence was significantly higher among the group whose first attending physician was an orthopedist (63.0% vs 37.6%, p = 0.002). Both change in diagnosis (p < 0.001) and physician specialty (p < 0.001) were statistically significant predictors of costs of care. CONCLUSION: Compared to non-orthopedic care, orthopedic care for acute knee injury was associated with fewer changes in diagnosis, and diagnoses made by orthopedists were more likely to be supported by evidence. However, even after adjusting for severity, orthopedic care remained significantly more costly than non-orthopedic care.

Stage-dependent effects of epidermal growth factor on Ca2+ efflux in mouse oocytes.

Epidermal growth factor (EGF) has received much attention recently for its positive effects on mammalian oocyte maturation and embryo development and its potential importance in cytoplasmic maturation of oocytes. Calcium (Ca2+) homeostasis in germinal vesicle stage oocytes has also been suggested to play a role in cytoplasmic maturation. This study examined the effects of EGF on Ca2+ mobilization as measured by its efflux from mouse oocytes at three time periods throughout maturation (0-4 hr, 4-8 hr, and 12 hr). Immature cumulus oocyte complexes (COCs) removed from the ovary for less than 4 hr exhibit oscillations in Ca2+ efflux that initiated 5-30 min following EGF stimulation. This response was not observed in COCs matured for 4-8 hr or 12 hr or in unstimulated 0-4 hr COCs. Denuded oocytes and cumulus cells did not show the same response to EGF (8.2 nM and 16.4 nM). Immunohistochemistry for detection of the EGF receptor along with EGF internalization studies showed that receptors are present both on cumulus cells and the oocyte but EGF appears to be internalized mainly by the cumulus cells. These data demonstrate that EGF induces oscillations in Ca2+ efflux in COCs 0-4 hr old and this response is mediated by the cumulus cells.

Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers.

BACKGROUND: The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug. METHODS: Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. RESULTS: Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. CONCLUSIONS: The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.

Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of pentazocine in non-drug-abusing volunteers and to compare and contrast the effects of pentazocine with those of morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 7.5, 15 or 30 mg/70 kg pentazocine or 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. Pentazocine increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "sweating" and "turning of stomach" and increased visual analog scale ratings of "difficulty concentrating," "drunk" and "having unpleasant bodily sensations." Pentazocine (30 mg) had a greater propensity to increase ratings associated with dysphoria than did 10 mg of morphine. Pentazocine produced impairment on four measures of psychomotor performance. Ten milligrams of morphine produced minimal psychomotor impairment. Both pentazocine and morphine induced miosis, but 10 mg of morphine had a greater magnitude of effect than 30 mg of pentazocine. The results of the present study demonstrate that 7.5 to 30 mg of pentazocine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of pentazocine, 30 mg, produced a greater magnitude of dysphoric subjective effects than did 10 mg of morphine, which is consistent with the literature reporting that pentazocine has a greater likelihood of inducing psychotomimesis than do other opioids.

Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive-compulsive disorder (OCD): behavioral and biological results.

Obsessive-compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT3 receptor antagonist, the present study was undertaken to investigate 5-HT3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP + placebo, m-CPP + ondansetron, ondansetron + placebo and placebo + placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.

Redox-dependent conformational changes are common structural features of cytochrome c from various species.

Discrepant results from X-ray crystallographic and physicochemical studies on the conformations of the two redox states of cytochrome c raise important questions about the nature of redox-dependent conformational changes and whether differences are common structural features of various cytochrome c species. Comparative studies of cytochrome c from 10 species (horse, cow, sheep, pig, dog, rabbit, chicken, pigeon, tuna, and baker's yeast) in aqueous solutions were carried out using Fourier transform infrared (FT-IR) spectroscopy. The second-derivative analysis revealed similar conformational changes in all 10 species upon reduction of the heme iron regardless of the differences in the amino acid sequences. The redox-dependent changes involve the amide I regions ascribed to extended beta-structure, beta-turn, and alpha-helix structures. Three species (cow, sheep, and pig) with identical amino acid sequences displayed nearly identical infrared spectra for the oxidized and reduced states, which rules out the possible contribution of experimental error. These results show unequivocally that redox-dependent conformational changes are common structural feature of various cytochrome c species and demonstrate the usefulness of FT-IR spectroscopy as a quick and inexpensive tool in comparative studies of functionally related conformational changes of proteins.

Effects of culturing bovine oocytes either singly or in groups on development to blastocysts.

In vitro maturation, fertilization and culture (IVM/IVF/IVC) of cattle oocytes from individual cows requires adapting existing culture protocols so that small numbers of oocytes can be cultured. The culture of single oocytes is desirable for correlating the relationship between follicular properties with oocyte developmental competence or for facilitating ovum pick-up procedures. In Experiment 1 we compared group and single culture under cell-free conditions on embryo development; significantly higher (P<0.001) rates of cleavage (66.4 vs 47.6%) and blastocyst formation (7.5 vs 0.5%) were observed in the group cultured oocytes. In Experiment 2 we compared group and single oocyte co-culture with granulosa cells. Although there was no effect of oocyte number on the percentage cleaving (73.1 vs 66.6%), there were significantly higher blastocyst yields (37.4 vs 10.1%) and blastocyst cell numbers (91.6 vs 66.2) in group-cultured oocytes. In Experiment 3 we examined the effect of group size (1, 5, 10, 20 and 40 oocytes) in a co-culture system using granulosa cell monolayers. The results show a difference in cleavage rates between the single cultured oocytes (66.8%) and each group of cultured oocytes, with the highest cleavage rate (81.5%) obtained in the 20-oocyte group. The blastocyst yield from both cleaved and total oocytes showed that group culture of 20 or 40 oocytes resulted in the highest number of blastocysts (32.5%), with smaller group sizes yielding significantly (P<0.05) fewer blastocysts. In Experiment 4 we examined the effects of co-culture on the development of single vs group-cultured oocytes. The results showed no significant difference (P>0.05) in the cleavage rate between single and group culture systems. No blastocysts were formed with single oocytes cultured without monolayers, while the blastocyst formation rate for those co-cultured with granulosa cells was 12.4%. Blastocyst formation was significantly higher (P < 0.006) in group co-culture on monolayers (24.2 vs 8.5%). These data indicate that oocytes cultured in groups are developmentally more competent and suggest that for optimum development oocytes need some undefined paracrine activity that is absent from the culture medium in addition to coculture with granulosa cells, which enhances development to the blastocyst stage of both group and singly cultured oocytes.

Influence of ovine oviducal amino acid concentrations and an ovine oestrus-associated glycoprotein on development and viability of bovine embryos.

This study examined the effects of incorporating an ovine oviducal oestrus-associated glycoprotein (oEGP) and amino acids, at the concentrations present in the ovine oviduct around the time of oestrus, on in vitro production and subsequent viability of bovine embryos. The first experiment compared the influence of ovine oviducal concentrations of amino acids with MEM and BME amino acids. There was no treatment effect on cleavage rate (74.9% vs. 75.5%), but there was a higher (P < 0.05) blastocyst yield (30.4 vs. 25.2) and a shorter time (P < 0.05) to blastocyst formation (7.16 +/- 0.64 vs. 7.27 +/- 0.56 days) following use of oviducal concentrations of amino acids. Experiment 2 examined the influence of oEGP in combination with each of the amino acid treatments. oEGP had no effect on cleavage or blastocyst yield within amino acid treatments. Day of blastocyst formation significantly influenced nuclei numbers (P < 0.001) with higher numbers being obtained on day 7 than on either day 6 or day 8. There was also a significant (P < 0.01) interaction between day of blastocyst formation and amino acid treatment on blastocyst nuclei numbers. The third experiment studied the effects of the amino acid treatments on embryo viability. There was no effect of amino acid treatment of embryos on pregnancy rates (34.5 vs. 44.4%) following transfer of days 6 and 7 blastocysts to synchronized recipients. oEGP did not influence any of the parameters of bovine embryo development that were measured, suggesting that effects of this protein observed on ovine embryos are species specific. It is concluded that ovine oviducal amino acid concentrations are beneficial to blastocyst development in vitro but do not have any further beneficial effect following transfer of blastocysts to recipients.

Behavioral, physiological and neuroendocrine responses in healthy volunteers to m-chlorophenylpiperazine (m-CPP) with and without ondansetron pretreatment.

Several serotonin3 (5-HT3) antagonists have been shown to attenuate the anxiogenic effects of the serotonergic agent, m-chlorophenylpiperazine (m-CPP), in animal models, but little data regarding possible effects of 5-HT3 antagonists on responses to m-CPP are available from studies in humans. Therefore, we studied the behavioral, physiological and neuroendocrine responses of 12 healthy volunteers to i.v. administered placebo and m-CPP (0.08 mg/kg), with and without i.v. pretreatment with the selective 5-HT3 antagonist, ondansetron (0.15 mg/kg). Compared to placebo, m-CPP given alone significantly increased ratings of anxiety and several other behavioral measures. m-CPP also produced statistically significant increases in temperature, systolic and diastolic blood pressure, heart rate, and in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and norepinephrine. Responses to ondansetron given alone were no different from those of placebo. Pretreatment with ondansetron did not affect peak behavioral responses to m-CPP, but was associated with a significantly earlier return to baseline levels of ratings of anxiety and functional deficit as well as a summary measure of overall behavioral effects. Following ondansetron pretreatment, the increases produced by m-CPP in systolic and diastolic blood pressure and heart rate were no longer significantly different from placebo. Ondansetron pretreatment significantly reduced their plasma cortisol response to m-CPP without affecting the other plasma hormone responses. Plasma concentrations of m-CPP were unaffected by ondansetron pretreatment. These findings suggest that in normal human subjects some behavioral, cardiovascular and neuroendocrine effects of m-CPP may be partially modulated by 5-HT3 receptor-mediated mechanisms.

Development of ovine embryos in synthetic oviductal fluid containing amino acids at oviductal fluid concentrations.

The effects of supplementing synthetic oviductal fluid (SOF) with amino acids, at oviductal fluid concentrations, on the development of ovine in vitro-matured/in vitro-fertilized embryos was examined in three experiments. In the first, embryo development in SOF, SOF + 2% human serum (HS), SOF + 20% HS, and SOF + BSA, with and without amino acid supplementation, was examined. Development of zygotes to the blastocyst and hatching blastocyst stages was highest in medium containing 20% HS (64.8% and 54.4%, respectively) irrespective of amino acid supplementation. However, supplementation was significantly beneficial in all other media, with up to 42.1% of zygotes developing into hatching blastocysts. In these media, supplementation also significantly increased the mean number of nuclei per newly formed blastocyst (up to a mean of 70.8) and reduced the time during which blastocysts formed. Experiment 2 was an examination of the effect on embryo development of three amino acid preparations (oviduct amino acid concentrations vs. Eagle's Basal Medium (BME) essential + Minimum Essential Medium (MEM) nonessential vs. MEM essential + MEM nonessential concentrations) and the presence or absence of BSA. Both the amino acid and BSA treatments significantly influenced the percentage of zygotes that developed to the hatching blastocyst stage but not to the blastocyst stage. The preferred medium contained amino acids at oviductal fluid concentrations and BSA (54.5% hatching rate). The amino acid treatments did not significantly influence the mean number of nuclei per newly formed blastocyst, but the addition of BSA had a significant effect (70.7 +/- 1.14 vs. 75.7 +/- 1.13). In experiment 3, embryo development to Day 13 was examined after culture in SOF containing amino acids at oviductal fluid concentrations. Embryos were cultured in the presence of either BSA, polyvinyl alcohol (PVA), or no additional supplement and were transferred to recipient ewes on either Day 0 (after in vitro fertilization), 3, or 5. The addition of BSA or PVA had no significant effect, but significantly more embryos developed to Day 13 following transfer on Day 0 (60.0%) than on either Day 3 or 5 (overall 45.4%). It is concluded that SOF containing oviductal fluid concentrations of amino acids 1) facilitates the development of a high percentage (57.5%) of blastocysts, 2) improves embryo morphology compared with that observed in medium containing HS, 3) significantly improves hatching rates compared with those obtained in SOF containing commercially available preparations of amino acids, and 4) produces embryos with relatively high levels of viability to Day 13 of pregnancy.

Biological and behavioral responses to D-amphetamine, alone and in combination with the serotonin3 receptor antagonist ondansetron, in healthy volunteers.

Evidence that serotonin3 (5-hydroxytryptamine3, 5-HT3) antagonists attenuate behavioral responses to D-amphetamine and cocaine suggests that 5-HT3 receptors modulate brain dopamine in animals. This study examined the potential interactions of the 5-HT3 antagonist ondansetron and D-amphetamine in 10 healthy human volunteers. After the subjects were pretreated with placebo or ondansetron (0.15 mg/kg, i.v.), 5-h challenge tests with oral D-amphetamine (0.5 mg/kg) were performed. As animal studies and early clinical studies with ondansetron have suggested nonlinear dose-response relationships, three subjects also underwent pilot studies with three doses of ondansetron (0.15, 0.05, and 0.015 mg/kg) before they received D-amphetamine. Administration of D-amphetamine increased plasma levels of cortisol, prolactin, growth hormone; elevated blood pressure, pulse, and temperature; and tended to increase self-ratings of activation/euphoria and anxiety. Amphetamine-induced increases in plasma prolactin were significantly reduced by ondansetron pretreatment, but the other neuroendocrine responses were unchanged. Diastolic blood pressure elevations were also significantly attenuated after administration of the lower ondansetron doses, but the other physiologic responses were unchanged. In subjects with minimal or moderate activation/euphoria responses, ondansetron pretreatment only minimally affected these effects of D-amphetamine. Preliminary data, however, indicate that those subjects with robust activation-euphoria responses to D-amphetamine had attenuated responses after ondansetron pretreatment. Taken together, these results suggest that some but not most of D-amphetamine's biological and behavioral effects may be modified by a 5-HT3 antagonist in healthy human volunteers.

Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans.

Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.

Evidence that 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.

The effects of various 5-HT receptor subtype-selective antagonists were studied on phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in Wistar rats, in an attempt to characterize the 5-HT receptor subtype mediating DOI-induced hyperthermia. Intraperitoneal administration of DOI to rats produced hyperthermia with a peak effect at 60 min. Pretreatment with propranolol (beta-adrenoceptor antagonist that also has binding affinity for 5-HT1A, 5-HT1B and 5-HT2C sites), MDL-72222 or ondansetron (5-HT3 antagonists) did not attenuate DOI-induced hyperthermia. In contrast, pretreatment with metergoline (5-HT1/5-HT2 antagonist), ketanserin, LY53857, mesulergine, mianserin and ritanserin (5-HT2C/5-HT2A antagonists), as well as spiperone (5-HT1A/5-HT2A/D2 antagonist), significantly attenuated DOI-induced hyperthermia. Furthermore, daily administration of DOI (2.5 mg/kg per day) for 17 days did not produce either tolerance to its hyperthermic effect or modify m-CPP-induced hyperthermia in rats. These findings suggest that DOI-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.