How local and state regulations affect the child care food environment: A qualitative study of child care center directors' perspectives.

Almost one-third of preschoolers spend regular time in child care centers where they can consume the majority of their daily dietary intake. The child care setting influences children's dietary intake. Thus, it is important to examine factors, such as local and state regulations, that influence the food environment at the center. This qualitative study explored directors' perceptions of how regulations influence the foods available at child care centers. Ten directors of centers in Travis County, Texas completed semi-structured interviews. Directors reported that changes in local health department regulations (e.g., kitchen specifications) result in less-healthful foods being served (e.g., more prepackaged foods). Directors of centers that do not participate in the federal Child and Adult Care Food Program (CACFP) said the state licensing regulations clarify the portion size and nutritional requirements for preschoolers thereby improving the nutritional quality of the food served. Directors of centers participating in CACFP said they are not affected by state mandates, because the CACFP regulations are more stringent. These findings suggest that state regulations that specify and quantify nutritional standards may beneficially impact preschoolers' diets. However, local health department regulations enacted to improve food safety may negatively influence the nutritional value of food served in centers.

Problems associated with long-term treatment with selective serotonin reuptake inhibitors.

Although the selective serotonin reuptake inhibitors (SSRIs), which are now widely used as a first-line treatment for depression and many other psychiatric conditions, are generally well tolerated, they are not devoid of side effects. Most short-term treatment-related side effects of SSRIs are transient and disappear after a few days or weeks. However, following long-term treatment with the SSRIs, some serious adverse events may occur. Some of them can be difficult to recognise because they can resemble residual symptoms of depression. The most serious can be life threatening. They all have a negative influence on the patient's quality of life and are frequently a prime reason for a lack of long-term compliance with the associated increased risk of recurrence of a depressive episode. This article is an overview of the more common adverse events, which are seen with non-acute treatment with the SSRIs.

Improving the sensitivity of stereotactic core biopsy to diagnose ductal carcinoma in situ of the breast: a mathematical model.

Stereotactic core biopsy (SCB) is performed on mammographically suspicious, non-palpable lesions of the breast. Reported sensitivities of SCB for the detection of ductal carcinoma in situ (DCIS) vary from 41% to 93%. We have developed a simple mathematical model to predict the probability of retrieving at least one diagnostic core from a focus of DCIS. We make recommendations of the number of samples needed for different sized areas of microcalcification. The sensitivity of SCB is affected by needle placement accuracy, diameter of the area of microcalcification (d), histological density of DCIS (x) (calculated as 7.5% by previous studies) and number of core samples (n) removed. The probability of achieving at least one representative core sufficient for diagnosis (P(core)) is defined as: P(core) = 1-(1 + p ([1- (x/100)]d - 1 ))n, where rho is the probability of a SCB accurately targeting the area of microcalcification. At least seven core samples should be removed in small foci (<5 mm) of DCIS to achieve a 0.75 probability of an accurate diagnosis. The probability of a diagnostic biopsy of larger areas of DCIS (>10 mm) is 0.95 when five cores are removed. This formula serves as an explanation to patients why SCB may fail to diagnose DCIS, and justifies the retrieval of more core samples to increase the probability of an accurate diagnosis and to reduce the chance of a non-representative core. In the absence of sufficient samples, a wire-guided open biopsy is necessary to exclude DCIS.

The role and histological classification of needle core biopsy in comparison with fine needle aspiration cytology in the preoperative assessment of impalpable breast lesions.

AIMS: To investigate the role of needle core biopsy (NCB) in the preoperative assessment of impalpable breast lesions, mainly derived from the NHS Breast Screening Programme (NHSBSP) and to assess our own modifications to a suggested system for the classification of breast NCBs. METHODS: The NCB, fine needle aspiration cytology (FNAC), and radiology scores from 298 women with non-palpable breast lesions presenting between January 1997 and December 1998, together with the open biopsy results (where available) were collated and analysed. RESULTS: The mean follow up period was 15.8 months (range, 5-28). The 298 NCB specimens were categorised as follows: unsatisfactory/non-representative (B1; n = 61; 20.5%), benign but uncertain whether representative (B2r; n = 52; 17.4%), benign (B2; n = 103; 34.6%), lesions possibly associated with malignancy but essentially benign (B3a; n = 9; 3.0%), atypical epithelial proliferations (B3b; n = 10; 3.4%), suspicious of malignancy (B4; n = 7; 2.3%), and malignant (B5; n = 56; 18.7%). Excision biopsy was performed in 43 cases within the B1 (n = 19), B2r (n = 8), B2 (n = 8), and the B3a (n = 8; data unavailable in one case) categories, revealing malignancy in 18 (42.8%) cases and in 65 cases within the B3b, B4, and B5 categories, revealing malignancy in 64 cases (98.5%). The sensitivity of NCB for malignancy was 87.7%, with a specificity and positive predictive value of 99.3% and 98.5%, respectively. FNAC had an inadequacy rate of 58.7%, a complete sensitivity of 34.5% and a specificity of 47.6%. CONCLUSIONS: This study confirms the value of NCB in the preoperative assessment of impalpable breast lesions. Two new categories are suggested for the NCB classification; category B2r for benign breast tissue where representativeness is uncertain, and the subdivision of category B3 into B3a for benign lesions potentially associated with malignancy (for example, radial scars and intraduct papillomas) and B3b for more worrisome atypical epithelial proliferations. These will aid the accurate audit of NCB and identify more clearly the intellectual pathway leading to a particular assessment.

Where are the new therapies for anxiety and obsessive-compulsive disorders?

The benzodiazepines have monopolized the acute anxiety market for about 40 years, but their potential for tolerance and dependency has stimulated an interest in alternative anxiolytics. Until recently, however, attention has focused on existing drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors. The 5-HT1A partial agonist, buspirone (Bristol-Myers-Squibb), is one of the few compounds developed principally as an anxiolytic since the benzodiazepines. The challenge for the future is not only to find efficacious treatments with a rapid onset of action and an acceptable side effect profile but also to determine the optimal compounds for each of the different anxiety disorders.

The possible role of 5-HT(1B/D) receptors in psychiatric disorders and their potential as a target for therapy.

Serotonin (5-hydroxytryptamine, 5-HT) is implicated in several psychiatric diseases. Is this also true for 5-HT(1B/D) receptors? These receptors are found in high density in substantia nigra, globus pallidus, striatum and basal ganglia and in other brain regions. This ubiquity makes 5-HT(1B/D) receptors responsible for many physiological and behavioural functions. This review focuses on the role of 5-HT(1B) receptors in the regulation of 5-HT release and synthesis. Microdialysis experiments performed on freely moving animals are an interesting in vivo model to study the function of the terminal 5-HT(1B) autoreceptor. Synthesis of 5-HT, estimated by the measurement of the accumulation of 5-hydroxytryptophan (5-HTP) ex vivo or in vitro, is modulated by the 5-HT(1B) autoreceptors. Many reports have shown that chronic administration with selective serotonin reuptake inhibitors leads to the desensitisation of the terminal 5-HT(1B) autoreceptors. With the help of some animal models of depression and anxiety and with some data from clinical studies it has been hypothesised that 5-HT(1B) receptors may be supersensitive in depression, anxiety and obsessive compulsive disorder. Thus, since the dysfunction of 5-HT(1B) receptors may be involved in some pathological states, particularly in the psychiatric field, these receptors represent important potential targets for drugs to treat mental diseases.

Pharmacodynamics of milnacipran in young and elderly volunteers.

AIMS: To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. METHODS: Randomized double-blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days' dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). RESULTS: Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0. 05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. CONCLUSIONS: The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.

Dietary intake at child-care centers and away: are parents and care providers working as partners or at cross-purposes?

OBJECTIVE: To examine how meals and snacks children consume before and after their time at a child-care facility complement the menu at the facility. DESIGN: Dietary intake of children at and away from the child-care center was compared with recommended standards for child nutrition. Registered dietitians observed foods consumed at the center during 3 consecutive days. Parents reported foods consumed away from the center during the same 3 days. SUBJECTS/SETTING: Six nonprofit child-care centers with strong menus (i.e., menus that come close to meeting dietary recommendations) and 6 with menus supplying less than 50% of the Recommended Dietary Allowance were selected for study. Five families at each center were invited to participate. Complete data sets were obtained for 51 children aged 3 to 6 years. STATISTICAL ANALYSES PERFORMED: Descriptive and inferential statistics were calculated to compare the children's dietary intake during center time and family time and over a full day with recommended standards. Energy and nutrient profiles and food frequencies were included in the analysis. RESULTS: Children consumed plenty of foods at the center and away from the following groups: meat, poultry, fish, dry beans, eggs, nuts; milk, yogurt, cheese; and fruit, fruit juice. Most children failed to consume enough vegetables. Nearly all the children failed to consume enough bread, cereal, pasta, and rice, especially while at the center. The majority ate more than sparing amounts of fats, oils, and sweets, especially during family time. Average percentage of energy from fat was 33 +/- 4. Intakes of concern for the full day were energy, iron, sodium, and zinc. APPLICATIONS: Child-care menus are an appropriate target for increasing iron and zinc by serving more cereal and whole grains. Families are an appropriate target for reducing young children's consumption of fats, oils, and sweets. Nutrition education and advocacy are needed to strengthen the partnership between parents and caregivers.

The role of transvaginal ultrasound in the investigation of women with post-menopausal bleeding.

One-hundred and eighty-two women with post menopausal bleeding were examined with transvaginal ultrasound (TVUS) over a 16-month period. The imaging findings were correlated with the pathological specimens. One-hundred and forty had pipelle aspiration cytology and 35 hysteroscopy, dilatation and currettage and seven a hysterectomy. Endometrial thickness on TVUS was classified as either thin (equal to or less than 5 mm), thick (greater than 5 mm), or not seen. A thin endometrium was noted in 87 patients, in whom no pathological abnormality was found in 84 (negative predictive value 95%). There were three cases of hyperplasia or polyps but no carcinomas occurred in this group (negative predictive value for carcinoma 100%). A thickened endometrium was noted in 82 patients. In this group there were five carcinomas, nine polyps and eight cases of endometrial hyperplasia (positive predictive value 29%). In five patients the endometrium could not be identified. One carcinoma occurred in this group. There were an additional eight patients who were taking tamoxifen who were grouped separately. If a clear symmetrical endometrial stripe measuring less than or equal to 5 mm in thickness on TVUS is seen the probability of malignancy is extremely low and endometrial biopsy can probably be avoided in this group particularly in the context of an isolated episode of postmenopausal bleeding. If the endometrium is not seen or is thicker than 5 mm then endometrial biopsy is indicated.

Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor.

Milnacipran is a new antidepressant which inhibits equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo with no effect on dopamine reuptake. Microdialysis studies have shown increased extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor. In particular, and unlike tricyclic antidepressants (TCAs), it has no activity at noradrenergic, muscarinic or histaminergic receptors. Contrary to TCAs, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. Milnacipran has a high bioavailability, low plasma protein binding, and is largely eliminated in the urine as the parent drug or as a glucuronide. These features suggest that interactions with other drugs given concurrently are unlikely. Studies in patients with liver dysfunction and in the elderly suggest that dose adjustment is not necessary. In patients with renal impairment, decreased elimination of milnacipran is correlated to the degree of renal impairment allowing an easy dosage adjustment. An intermediate half-life of approximately 8 h is compatible with twice-daily administration. Clinical studies comparing milnacipran, placebo and other antidepressants provide evidence of its efficacy in moderate to severe depression in both hospitalized and outpatient settings. Meta-analyses of the original data of controlled trials comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs) show that milnacipran provides antidepressant efficacy similar to that of TCAs and significantly superior to that of SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of TCAs with notably less cholinergic side effects. The tolerance of milnacipran was comparable to that of SSRIs with a higher incidence of dysuria with milnacipran but a higher frequency of nausea and anxiety with the SSRIs. Milnacipran represents an interesting new therapeutic option in depression, being as well tolerated as the SSRIs but offering clinical efficacy similar to the TCAs.

Pasteur Euroconference on future therapies for an anxious world.

The aim of this meeting was to explore the molecular targets for tomorrow's drugs with a group of European and North American speakers from the pharmaceutical industry and academia presenting both data and ideas. Several speakers considered 5-hydroxytryptamine(1B/D) (5-HT(1B/D)) receptor antagonists to be a promising target for the treatment of obsessive compulsive disorders (OCD). 5-HT moduline, a peptide modulator of the 5-HT(1B/D) receptor, presents a potentially subtle way of intervention. No clinical data are as yet available on 5-HT(1B/D) receptor antagonists. The paradox of agonists, partial agonists and antagonists at the 5-HT(1A) receptor (all having anxiolytic activity in animal models) was discussed. Although the 5-HT(1A) agonists tested in clinical trials to date have been disappointing, the clinical potential of 5-HT(1A) antagonists still has to be evaluated. Similarly, both agonists and antagonists at the 5-HT(2C) receptor have been shown to be active in animal models of anxiety. It seems, however, that 5-HT(2C) agonists may have a therapeutic potential in panic disorders and OCD, while the antagonists may be more appropriate in generalised anxiety. Cholecystokinin (CCK) has been shown to be implicated in panic attacks which can be induced by agonists at the CCK-B subtype. CCK-B antagonists are thus potential antipanic agents although this has not yet been confirmed by clinical trials. Finally, inhibition of glutamatergic neurotransmission produces anxiolytic effects in a wide-range of animal models and the new antagonists at the metabotropic glutamate receptors may have potential as anti-anxiety agents. This report focuses on the presentations that addressed novel drug candidates or potential new drug targets.

Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea pig hypothalamus.

Milnacipran, a dual noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitor, increased extracellular levels of NA and 5-HT in hypothalamus of freely moving guinea pigs as measured by microdialysis. The basal levels of both monoamines, which were tetrodotoxin sensitive, were increased in a dose-dependent manner and to a similar extent after the intraperitoneal administration of milnacipran (10 and 40 mg/ kg i.p.). Levels of the NA metabolite 4-hydroxy-3-methoxyphenylglycol (MHPG) were decreased by milnacipran at 10 and 40 mg/kg i.p., whereas those of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) showed no effect. Subcutaneous injection of 5-HT1A and beta-adrenergic receptor antagonist (-)-pindolol alone, at 10 mg/kg, had no effect on the extracellular levels of NA or 5-HT. The concomitant administration of (-)-pindolol (10 mg/kg s.c.) with milnacipran (10 mg/kg i.p.) increased severalfold the effect of milnacipran on the extracellular levels of NA and 5-HT. These results indicate that milnacipran, by blocking the uptake of NA and 5-HT, increases virtually equipotently the extracellular levels of NA and 5-HT, confirming previous in vitro studies. In addition, the antagonism of 5-HT1A autoreceptors by (-)-pindolol potentiates the action of milnacipran on both NA and 5-HT systems, without modifying the ratio of these activities.

Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability.

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.

Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.

Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administrative of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1A agonists, (+/-) 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1A/B agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo[1,2-a]-quinox ali ne (CGS 12066B), the 5-HT1A/B ligands and beta-adrenoceptor antagonists, (+/-) pindolol and (+/-) alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1A/5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1A antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (+/-)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1A or 5-HT2 receptors and that other receptors may be involved.

5-HT autoreceptors in the regulation of 5-HT release from guinea pig raphe nucleus and hypothalamus.

5-HT autoreceptors involved in the regulation of 5-HT release in the guinea pig dorsal raphe nucleus have been studied in comparison with those in the hypothalamus. In vitro release was measured in slices of raphe and hypothalamus prelabelled with [3H]5-HT, superfused with Krebs solution and depolarized electrically. The non-selective 5-HT receptor agonist, 5-carboxamidotryptamine (5-CT) (0.1-10 nM for raphe: 1-100 nM for hypothalamus) and antagonist, methiothepin (10-1000nM), decreased and increased, respectively, the release of [3H]5-HT evoked by electrical stimulation in either of these regions when given alone. The selective 5-HT1B/D receptor antagonist, GR127935 (100-1000 nM), and the 5-HT1D receptor antagonist, ketanserin (300-1000 nM), had no significant effect on this release in either of these regions. Methiothepin and GR127935 (100-1000 nM) shifted to the right the concentration-effect curve of 5-CT in both the raphe and the hypothalamus. At 300 nM, ketanserin shifted to the right the concentration-effect curve of 5-CT in the raphe but did not modify the 5-CT curve in the hypothalamus. In microdialysis experiments ketanserin, applied locally at 10 microM, increased the extracellular levels of 5-HT in the dorsal raphe nucleus of the freely moving guinea pig, whereas 5-HT levels were unchanged in the hypothalamus. Ketanserin at 1 microM did not affect the decrease in 5-HT output induced by the selective 5-HT1B/D receptor agonist, naratriptan (used at 10 microM in raphe and 0.1 microM in hypothalamus), in the raphe or the hypothalamus. In the raphe, WAY100635, a 5-HT1A receptor antagonist, at 1 microM, did not prevent naratriptan (10 microM) from reducing the extracellular levels of 5-HT. These results suggest that, in the conditions used in this study, the release of 5-HT in the dorsal raphe nucleus is possibly modulated in part by 5-HT1B receptors but essentially the control is through 5-HT receptors whose subtype is still to be determined. In the hypothalamus, however, it is clear that only 5-HT1B receptors are involved in the modulation of 5-HT neurotransmission.

Preclinical pharmacology of milnacipran.

Milnacipran (Ixel) is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake and its lack of affinity for neurotransmitter receptors. It inhibits virtually equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo, as demonstrated by the antagonism of centrally acting monoamine displacers. It has no effect on dopamine reuptake. In addition, milnacipran has been shown by intracerebral microdialysis to increase the extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor or ion channel. In particular, and unlike tricyclic antidepressants, it does not act at noradrenergic, muscarinic or histaminergic receptors. Contrary to tricyclic antidepressants, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. This pharmacological profile, associated with an excellent bioavailability in man, was predicted to be that required for a powerful and well-tolerated antidepressant. Subsequent clinical development has shown this prediction to be well founded.