Short communication: The effect of ruminal administration of 5-hydroxy-l-tryptophan on circulating serotonin concentrations.

The monoamine serotonin has been shown to regulate peripartal calcium homeostasis in multiparous cows and be a possible mitigation tool for hypocalcemia. Increasing circulating serotonin concentrations via prepartum intravenous (IV) administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) increases postpartum calcium concentrations. However, the ability of 5-HTP to be used orally or ruminally to alter circulating serotonin concentrations has not been established. Hence, our objective was to determine if ruminal administration of 5-HTP altered circulating serotonin concentrations. Four ruminally cannulated, nonlactating, nonpregnant multiparous Holstein dairy cows were randomly assigned to 1 of 4 treatments in a 4 × 4 replicated Latin square with 4-d periods separated by a 7-d washout. On d 1 and 2 of each period, cows were dosed with 1 of 4 experimental treatments as follows: (1) 0 mg/kg of body weight (BW) of 5-HTP, (2) 1 mg/kg of BW of intraruminal 5-HTP, (3) 2 mg/kg of BW of intraruminal 5-HTP, or (4) 1 mg/kg of BW of IV 5-HTP. Infusions were administered over a 1-h period, and all groups not receiving 5-HTP IV were infused with an equal volume of IV saline to that of IV 1 mg/kg of BW of 5-HTP treatment. Continuous serial blood samples were collected beginning after d 2 of treatment administration. Whole blood serotonin concentrations were higher in cows dosed with 2 mg/kg of BW of intraruminal 5-HTP immediately after dosing when compared with cows dosed with 0 mg/kg of BW of 5-HTP on d 2, but were similar on d 3 and 4 of the experimental period. Cows receiving IV 5-HTP had the highest circulating serotonin concentrations relative to all other treatments. These findings demonstrated that 2 intraruminal dosings of 5-HTP at 2 mg/kg of BW resulted in elevated circulating serotonin concentrations relative to the control immediately after dosing. This supports the potential for 5-HTP to be used orally to manipulate circulating serotonin concentrations.

The application of "CrimeLite" to examination of computer components "in situ".

The authors consider the problem of identifying potential fingerprints and other marks in a computer system, having regard for the damage which conventional print enhancement techniques may cause. They evaluate a non-invasive method of mark location and recommend a new procedure for the handling of digital evidence sources which may contain "conventional" evidence.

An improved protocol for the examination of rogue WWW sites.

Internet server managers have a range of techniques available to help them improve service performance and security. These techniques can become barriers to the investigation of illicit or illegal activity. This paper describes some of the legitimate techniques which can be used to improve server performance or security, and which present challenges for the investigator. Furthermore, it proposes a rigorous procedure which should be followed to ensure that any investigation of a web site or server has been complete and accurate, and that all possible useful information has been extracted and examined.

Ondansetron attenuates CCK induced satiety and c-fos labeling in the dorsal medulla.

Serotonin 5-HT(3) antagonists have been suggested for treatment of several disorders involving altered gastrointestinal (GI) function. CCK also has well documented GI actions on both food intake and vago-vagal reflexes. To evaluate potential interactions, the effect of a 5-HT(3) antagonist, ondansetron, on exogenous CCK induced satiety and c-fos activation was determined. Ondansetron reduced both actions of CCK by approximately 50%. The reduction in c-fos was localized to a specific subregion of the dorsal medulla, suggesting that a distinct subpopulation of CCK receptive fibers are modulated by 5-HT(3) ligands. Treatments using 5-HT(3) antagonists also may affect endogenous CCK functions.

Effect of decreasing afferent vagal activity with ondansetron on symptoms of bulimia nervosa: a randomised, double-blind trial.

BACKGROUND: Several lines of evidence have led us to postulate that afferent vagal hyperactivity could be an important factor in the pathophysiology of the eating disorder bulimia nervosa. Ondansetron is a peripherally active antagonist of the serotonin receptor 5-HT3, and is marketed for prevention of vagally-mediated emesis caused by cancer chemotherapeutic agents. We investigated the effects of ondansetron on bulimic behaviours in patients with severe and chronic bulimia nervosa in a randomised, double-blind, placebo-controlled study. METHODS: We enrolled patients with severe bulimia nervosa (at least seven coupled binge/vomit episodes per week). The patients were otherwise healthy, their weight was normal, and they were not receiving medical or psychiatric treatment. During the first week of the study, patients recorded all eating-behaviour events to establish a baseline. In the second week, all patients received placebo, but were told that they were receiving either placebo or active drug. At the end of this single-blind phase, patients were randomly assigned placebo or ondansetron (24 mg daily) for a further 4 weeks. The primary outcome measure was the number of binge/vomit episodes per week. Data were analysed by intention to treat. FINDINGS: 29 patients met the inclusion criteria, of whom 28 completed the baseline study, and 26 completed the single-blind placebo week. 12 patients were assigned placebo, and 14 ondansetron; one patient in the ondansetron group dropped out owing to accidental injury. During the 4th week of double-blind treatment, mean binge/vomit frequencies were 13.2 per week (SD 11.6) in the placebo group, versus 6.5 per week (3.9) in the ondansetron group (estimated difference 6.8 [95% CI 4.0-9.5]; p<0.0001). The ondansetron group also showed significant improvement, compared with the placebo group, in two secondary indicators of disease severity. The amount of time spent engaging in bulimic behaviours was decreased on average by 7.6 h per week in the ondansetron group, compared with 2.3 h in the placebo group (estimated difference 5.1 [0.6-9.7]). Similarly, the number of normal meals and snacks increased on average by 4.3 normal eating episodes without vomiting per week in the ondansetron group, compared with 0.2 in the placebo group (estimated difference 4.1 [1.0-7.2]). INTERPRETATION: The decrease in binge-eating and vomiting under ondansetron treatment was not achieved by compensatory changes in eating behaviour such as by a smaller number of binges of longer duration, or by not eating, or by binge-eating without vomiting. Instead, our findings indicate a normalisation of the physiological mechanism(s) controlling meal termination and satiation. Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission.

A large open-label study of venlafaxine in depressed outpatients by community-based physicians.

BACKGROUND: Studies to date suggest that venlafaxine is effective, well tolerated, and safe in a broad spectrum of patients. We examined the clinical utility and tolerability of venlafaxine in patients treated by community-based psychiatrists and family physicians in a naturalistic clinical setting. METHOD: Nineteen physicians each recruited 10 to 20 physicians to enroll 5 patients each maximum, diagnosed with DSM-IV major depression or dysthymia. The patients were at least moderately ill (Clinical Global Impressions) with a score of at least 32 on the Zung Self-Rating Depression Scale. After baseline clinical and laboratory assessments, each patient received 37.5 mg of venlafaxine b.i.d., with adjustments possible at the 5 visits during the next 8 weeks. RESULTS: Of the 880 patients at baseline, 682 completed the 8-week study. The daily doses of venlafaxine ranged between 18.75 mg and 375 mg, with 80% receiving between 75 and 150 mg/day by 8 weeks. The intent-to-treat analysis revealed that at 8 weeks, 62% (522 of 843) of patients were either much or very much improved. Nausea was the most frequent side effect, followed by somnolence, headache, and dry mouth. CONCLUSION: Venlafaxine has good clinical utility and tolerability in a community-based sample of a broad spectrum of depressed outpatients.

Genetic testing for breast cancer susceptibility: frequency of BRCA1 and BRCA2 mutations.

Genetic testing for breast cancer susceptibility became a reality after two cancer predisposition genes, BRCA1 and BRCA2, were identified. Mutations in these two genes were predicted to account for 85% to 90% of hereditary breast and ovarian cancer syndromes. We present results of mutation analysis of the coding sequence of these two genes in 110 consecutive non-Jewish breast cancer patients with a positive family history of breast and/or ovarian cancer. The individuals were identified in various cancer risk evaluation centers in the country. Twenty-two (20%) mutations in the BRCA1 gene and 8 mutations (7%) in the BRCA2 gene were detected. We also analyzed 52 Ashkenazi Jewish breast cancer patients for mutations in the BRCA1 and BRCA2 genes. Eleven Jewish individuals (21%) carried either one of the two common mutations, 185delAG and 5382InsC, in the BRCA1 gene and 4 individuals (8%) had the 6174delT mutation in the BRCA2 gene. The frequency of mutations in BRCA genes in affected people in this ethnic group was not significantly different from the non-Jewish population. On further analysis, the data demonstrate that neither age of onset nor phenotype of the disease had any significant predictive value for the frequency of mutations in these genes. These data confirm the lower prevalence of mutations in either of the BRCA genes in clinical families when compared to high-risk families used for obtaining linkage data in a research setting.

A model of numbers of births in three countries, with persistent forty-year cycles.

PIP: This paper describes a model which relates fertility to partner availability, an aspect of relative cohort size. Partner availability is affected by the tendency for males to reproduce at a later age than females. For women born at a time of rising birth rates, there is a shortage of slightly older men as potential partners. Women born when birthrates are falling enjoy a surplus of older men from which to choose. This model is believed to be the first non-linear demographic feedback model involving feedbacks through marriage squeezes in which empirically estimated values of the parameters imply persistent limit cycles. The deterministic model makes births in each five-year period a function of births in previous five-year periods. The form of the function is chosen to model the effect of partner availability upon entry into reproductive relationships, and therefore on age-specific fertility. Marriage rates are not modeled directly. The model was developed from data for more than a century from England and Wales, New Zealand, and the US. The demographic transition is modeled with a logistic function and age-specific fertility rates are estimated using lognormal distributions. The stepwise inclusion of a partner availability estimate in the model showed that it accounts for 29% of otherwise unexplained variance. Projected future births stabilize in sustained or limit cycles with periods a little longer than 40 years, and amplitudes of at least 7% of the mean. The necessary conditions for cycle persistence are outlined on a graph of maximum and minimum fertility parameters.^ieng

Measurement of nuclear oestrogen receptors in human breast tumours.

Recent reports suggest that oestrogen receptors detected in the cytosolic fraction of homogenized human breast tumours might be mainly nuclear receptor released into the cytoplasm during tissue processing. This study thus compares the tumour content of steroid hormone receptors in conventional cytosolic receptor assays with direct measurements of receptor in the cell nucleus. Unoccupied cytoplasmic oestrogen receptors (cER), cytoplasmic progesterone receptors (cPR) and total (occupied plus unoccupied) nuclear oestrogen receptors (nER) have been measured in parallel in human breast tumour tissue using biochemical radioreceptor assay. Of 125 tumours, 62% and 61% were positive for cER and cPR, respectively, 50% contained nER with high affinity for oestradiol (nER I) and 13% expressed nER with low affinity for oestradiol (nER II). The concentration of cER correlated significantly with age, cPR and log nER I. A significant proportion of tumours which were positive for both cytosol receptors also possessed nuclear receptors with high and low affinity for oestrogen. It is possible that this group of tumours which are positive for cER, cPR, nER I and nER II will respond well to hormone therapy.

Reducing self-injury and corresponding self-restraint through the strategic use of protective clothing.

We examined the use of protective clothing to reduce a retarded male's face-punching and leg-kicking and two corresponding forms of self-restraint--arm and leg self-restraint. The resident was observed each day in three sessions of randomly ordered conditions (one condition per session): without any protective clothing, with a padded helmet, and with a padded helmet and padded slippers. Use of the padded helmet substantially reduced face-punching and arm self-restraint. The addition of padded slippers reduced leg-kicking and leg self-restraint. These results suggest a practical and effective means of controlling self-injury and self-restraint. They are also consistent with the possibility that the resident's arm restraint was maintained in part by escape or avoidance of face-punching and that his leg restraint was maintained in part by escape or avoidance of leg-kicking.

Factors affecting solubilized dopamine-sensitive adenylate cyclase.

Bovine striatal adenylate cyclase was solubilized with sodium cholate and assayed for its responsiveness to a variety of agents. Magnesium ions (0-20 mM), guanylyl-imidodiphosphate (10-50 microM), and striatal lipids were effective in increasing enzyme activity. The adenylate cyclase could be stimulated by dopamine, and neuroleptic drugs inhibited the effect of dopamine (50 microM) with potencies that paralleled their clinical potencies. The IC50 values for spiroperidol, haloperidol and chlorpromazine were 0.2, 3 and 500 nM respectively.

The unit play manager as facilitator of purposeful activities among institutionalized profoundly and severely retarded boys.

Child care workers were trained in specified techniques (play manager routines) in an effort to increase purposeful activity among a group of profoundly and severely retarded institutionalized boys. A system of prompts, increasing the availability of toys and regular staff monitoring, were alternated with normal institutional routines in an ABA reversal design. On the average, activity level increased from 10% to a mean of 70% during treatment conditions. Correspondingly, stereotyped or harmful behaviors decreased from an average of 20% to 70% during treatment.

Concerning the decarboxylation of 3-carboxysalsolinol.

3-Carboxysalsolinol (14C-COOH) was prepared from DOPA (1-14C). Both in vitro and in vivo studies were conducted to examine the possibility that this amino-acid tetrahydroisoquinoline is converted to salsolinol in a parallel manner to the formation of dopamine from its amino-acid precursor. The results showed that this is not so for DOPA is decarboxylated far more readily than is 3-carboxysalsolinol. Small quantities of carbon dioxide (14C) are liberated from 3-carboxysalsolinol (14C-COOH), but this may reflect non-enzymatic decarboxylation.

An ecobehavioral examination of a simple strategy for increasing mealtime language in residential facilities.

Typically in large residential facilities for retarded person, meals are served in an institutional style that does not appear to encourage appropriate peer interactions. An ecological program alternative is serving meals in a family style. The present study was designed to examine both the feasibility of serving family style meals and the effects of family style meal service on mealtime language. Five retarded young adult male residents, who had some conversational skills and appropriate table manners, participated in this study. The experimental design involved a multiple baseline analysis across meals (dinner, lunch, and breakfast). Observers coded the youths' mealtime verbalizations according to the type, content, and direction of the verbalizations and they recorded the length of the meals. The analysis of the verbalization data indicated that during family style meals the participants spoke substantially more often than during institutional style meals. Increases in peer-directed conversation about the meals primarily accounted for the verbalization changes. Family style serving also resulted in the youths spending more time with their meals. In addition, social validation measures suggested that the family style procedures were preferred by the consumers (participants, staff, and concerned community members).

Supersensitivity in rat caudate nucleus: effects of 6-hydroxydopamine on the time course of dopamine receptor and cyclic AMP changes.

The intranigral administration of 6-hydroxydopamine resulted in the destruction of dopaminergic nerve terminals in the rat caudate nucleus and a 98% decrease in dopamine content. The time courses of the effects of this treatment on dopamine stimulated cyclic 3',5'-AMP accumulation in slices of caudate nucleus and on dopamine receptors in two behaviorally distinct denervation syndromes were determined in an investigation of the mechanisms underlying supersensitivity in this system. The density of dopamine receptors was determined by measuring the high affinity binding of the dopamine receptor antagonist [3H]haloperidol. The density of dopamine receptors was decreased 4 days after the lesion surgery and this effect was probably due to the loss of presynaptic receptors. The density of dopamine receptors and the acumulation of cyclic AMP then increased, with a slower time course, reaching peak levels 10 days after lesioning. The maximal increase in density of dopamine receptors was 70% in both denervation syndromes, while the maximal increase in dopamine-stimulating cyclic 3',5'-AMP levels was 300% at maximally stimulating concentration. The equilibrium dissociation constant (Kd) for haloperidol remained unchanged for 3 weeks following denervation, but there was a slight increase in Kd 40 days post-surgery. The turning behaviour in both syndromes was correlated with a decrease in doapmine levels. The present results are consistent with the notion that the supersensitivity to dopamine that occurs in caudate nucleus following 6-hydroxydopamine lesions has both pre- and post-synaptic components in both syndromes.

Time delay: a technique to increase language use and facilitate generalization in retarded children.

Institutional breakfast-serving procedures were manipulated to assess what effect changes in that aspect of the environment would have on requests for food. During baseline, six severely retarded children were required to pick up their food trays and return to their seats. The first manipulation, delaying the giving of the food tray for 15 seconds, served as a cue to evoke meal requests by three of the six children. Two of the remaining three required a model of an appropriate meal request (i.e., "Tray, please.") at the end of the 15-second delay before they began requesting their meals. To evoke meal requests from the sixth child, an intensive training procedure, consisting of massed trials of delay and modeling, was required. Three different probes were administered to assess generalization across the people serving the meals, across mealtimes, and across both people and mealtimes. Typically, generalized responding in these new situations could be prompted by use of the 15-second delay procedure. Functional aspects of the delay procedure and its potential usefulness for evoking speech and facilitating generalization are discussed.