PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole.

18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. METHODS: PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. RESULTS: PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. CONCLUSION: Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.     

Perforated colorectal neoplasms: correlation of clinical, contrast enema, and CT examinations

Results of clinical, contrast enema (CE), and computed tomographic (CT) examinations in 39 patients with perforated colorectal neoplasms were retrospectively reviewed. Twenty patients were toxemic at initial presentation, but in only four patients was the diagnosis of perforated colorectal neoplasm initially suspected clinically. CE study was performed in 22 patients and enabled the diagnosis of perforated neoplasm in 11 cases, neoplasm alone in eight, and neither neoplasm nor perforation in three. CT was performed in 38 patients and enabled the diagnosis of perforated neoplasm in 36; pericolic phlegmon but no mass lesion was evident in two. In 16 patients, CT also demonstrated metastatic disease. Because of its reliability in establishing the diagnosis and staging the extent of the inflammatory and neoplastic disease, CT is indicated in cases of suspected or proved perforated colorectal neoplasm and in cases in which CE study findings are indeterminate or suggestive of perforated neoplasm.     

Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients

OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence.METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography.RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups.CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.     

Left ventricular volumes measured by MR imaging

We assessed the potential of proton magnetic resonance (MR) imaging for accurately measuring left ventricular volumes using 15 latex casts of excised human left ventricles. The casts were submerged in water to stimulate the endocardial left ventricular cavity interface in in vivo imaging conditions. Tomographic image sections perpendicular to the long axis of the cast were obtained, spanning each cast from apex to base. Simpson's rule was used to calculate the cast volumes. Correlation between the actual cast volumes (as measured by the displacement method) and the calculated volumes using MR imaging for the 15 casts was excellent. Our data demonstrate that MR imaging accurately measures cardiac chamber volumes in this in vitro model.     

Mechanisms of hemorrhage in dengue without circulatory collapse.

To characterize the molecular basis for the hemostatic defects of dengue infections, a study was conducted in Bangkok, Thailand. Febrile children (n = 68) hospitalized with suspected dengue were enrolled before their clinical syndromes were classified as either dengue fever (DF) or dengue hemorrhagic fever (DHF). Hospital course and outcome were recorded; blood was obtained during the febrile illness (S1), after defervescence (S2), and 1 month after onset of disease (S4). Patients were classified as DF (n = 21) and DHF grades 1, 2, and 3; (DHF1, n = 8; DHF2, n = 30; and DHF3, n = 9). All had marked thrombocytopenia. Bleeding scores were assigned on the basis of bleeding site. Although there was no correlation between bleeding scores and pleural effusion index (a measure of vascular leakage) or bleeding scores and platelet counts, there was a correlation between pleural effusion index and platelet counts. Bleeding scores did not correlate with hemostatic data. Activated partial thromboplastin time was prolonged, with trends toward decreased fibrinogen and increased levels of prothrombin fragment F1.2 in the acute-phase samples. However, no factor level was dramatically decreased. We conclude that most patients with DF or DHF, even without overt hemorrhage, have consumptive coagulopathy. Nevertheless, hemorrhage in dengue without circulatory collapse is most likely due to activation of platelets rather than coagulopathy, which is well compensated. Our data suggest that vascular alteration may be the principal factor involved in the association of thrombocytopenia and hemorrhage with disease severity.     

n-6 Docosapentaenoic acid is not a predictor of low docosahexaenoic acid status in Canadian preschool children

BACKGROUND: The n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) is important for neural and visual functional development. In animals, 22:6n-3 deficiency is accompanied by increased docosapentaenoic acid (DPA; 22:5n-6), which suggests that the ratio of 22:6n-3 to 22:5n-6 could be a useful biochemical marker of low n-3 fatty acid status. The n-3 fatty acid status of preschool children has not been described, and data are lacking on whether low 22:6n-3 is accompanied by high 22:5n-6 in humans. OBJECTIVE: We determined n-3 fatty acid status and investigated the relation between 22:6n-3 and 22:5n-6 in children. DESIGN: In Canadian children aged 18-60 mo (n = 84), the n-3 and n-6 fatty acid status of erythrocyte phosphatidylethanolamine was measured, and dietary fat intake was estimated by using a food-frequency questionnaire. RESULTS: The mean (+/- SEM) 22:6n-3 concentration in erythrocyte phosphatidylethanolamine among children was 3.06 +/- 0.13 g/100 g fatty acids (5th-95th percentiles: 1.43-5.79 g/100 g fatty acids). Concentrations of 22:5n-6 increased with increasing 22:6n-3 concentrations in erythrocyte phosphatidylethanolamine (P < 0.01). Mean intakes of linoleic acid (18:2n-6), linolenic acid (18:3n-3), and trans fatty acids were 3.6 +/- 0.2%, 0.7 +/- 0.5%, and 2.0 +/- 1.3%, respectively. Phosphatidylethanolamine 22:6n-3 and 22:5n-3 concentrations were inversely related to the intakes of 18:2n-6 and trans fatty acids, but not to those of total fat or n-3 fatty acids. CONCLUSIONS: The concentration of 22:5n-6 is not a useful biochemical marker of low n-3 fatty acid intake or status in the membrane phosphatidylethanolamine of preschool children. High intakes of 18:2n-6 and trans fatty acids could compromise the incorporation of 22:6n-3 into membrane phospholipids.     

Healthy pregnant women in Canada are consuming more dietary protein at 16- and 36-week gestation than currently recommended by the Dietary Reference Intakes,primarily from dairy food sources

Adequate dietary protein intake throughout pregnancy is essential to ensure healthy fetal development. Insufficient and excessive maternal dietary protein intakes are both associated with intrauterine growth restriction, resulting in low birth weight infants. The aim of this study was to analyze the dietary protein intake patterns of healthy pregnant women in Vancouver, British Columbia, during early and late gestation. We hypothesized that women would be consuming higher protein during late stages of pregnancy compared with early stages of pregnancy. Interviewer-administered food frequency questionnaires were collected prospectively from 270 women at 16- and 36-week gestation; food frequency questionnaires from 212 women met study criteria. Maternal anthropometrics at both stages and infant weight at birth were collected. Wilcoxon signed rank tests were used to determine significant gestational differences in protein intakes. Spearman correlation was used to determine the influence of protein intakes and maternal anthropometrics on pregnancy outcomes. Median (25th and 75th percentiles) protein intakes adjusted for body weight were 1.5 (1.18 and 1.79) and 1.3 (1.04 and 1.60) g/kg per day at 16- than 36-week gestation, respectively. Primary protein sources were identified as dairy products. Protein intakes were negatively correlated with birth weight (P < .05), whereas maternal height, weight, body mass index, and weight gain to 36-week gestation were positively correlated with birth weight (P < .05). This study provides current dietary protein intake patterns among healthy Canadian women during pregnancy and indicates higher intakes than current Dietary Reference Intakes recommended dietary allowance of 1.1 g/kg per day, especially during early gestation.     

trans Fatty acids in human milk are inversely associated with concentrations of essential all-cis n-6 and n-3 fatty acids and determine trans, but not n-6 and n-3, fatty acids in plasma lipids of breast-fed infants.

BACKGROUND: Human milk fatty acids vary with maternal dietary fat composition. Hydrogenated dietary oils with trans fatty acids may displace cis n-6 and n-3 unsaturated fatty acids or have adverse effects on their metabolism. The effects of milk trans, n-6, and n-3 fatty acids in breast-fed infants are unclear, although n-6 and n-3 fatty acids are important in infant growth and development. OBJECTIVE: We sought to determine the relations between trans and cis unsaturated fatty acids in milk and plasma phospholipids and triacylglycerols of breast-fed infants, and to identify the major maternal dietary sources of trans fatty acids. DESIGN: We collected milk from 103 mothers with exclusively breast-fed 2-mo-old infants, blood from 62 infants, and 3-d dietary records from 21 mothers. RESULTS: Mean (+/-SEM) percentages of trans fatty acids were as follows: milk, 7.1 +/- 0.32%; infants' triacylglycerols, 6.5 +/- 0. 33%; and infants' phospholipids, 3.7 +/- 0.16%. Milk trans fatty acids, alpha-linolenic acid (18:3n-3), arachidonic acid (20:4n-6), docosahexaenoic acid (22:6n-3) (P < 0.001), and linoleic acid (18:2n-6) (P = 0.007) were each related to the same fatty acid in infant plasma phospholipids. Milk trans fatty acids were inversely related to milk 18:2n-6 and 18:3n-3, but not to milk or infant plasma 20:4n-6 or 22:6n-3. trans Fatty acids represented 7.7% of maternal total fat intake (2.5% of total energy); the major dietary sources were bakery products and breads (32%), snacks (14%), fast foods (11%), and margarines and shortenings (11%). CONCLUSIONS: There were comparable concentrations of trans fatty acids in the maternal diet, breast milk, and plasma triacylglycerols of breast-fed infants. Prepared foods were the major dietary source of trans fatty acids.     

Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2

Rationale Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Previous positron emission tomography (PET) studies had failed to demonstrate the feasibility of measuring a dose-dependent and saturable NET occupancy in human brain using [¹¹C]MeNER.Objectives To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[¹⁸F]FMeNER-D₂ in nonhuman primate brain.Methods A total of eight PET measurements were performed in two cynomolgus monkeys. Each monkey was examined four times with PET: under baseline conditions and after steady-state infusion with 0.03, 0.06, or 0.12 mg/kg/h of atomoxetine. A prolonged intravenous (i.v.) infusion design was developed rather than an i.v. bolus to better mimic an oral absorption profile and to reach plasma steady state.Results During baseline conditions, (S,S)-[¹⁸F]FMeNER-D₂ uptake was highest in the locus coeruleus, thalamus, mesencephalon, and the cingulate gyrus, whereas the radioactivity in the caudate was low. Peak equilibrium measurements were achieved using (S,S)-[¹⁸F]FMeNER-D₂ in contrast to the previously reported data for [¹¹C]MeNER. After administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET.Conclusions This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[¹⁸F]FMeNER-D₂. Furthermore, an asymptotic relationship between N-desmethylatomoxetine plasma concentration and NET occupancy was established. In total, these data encourage further PET studies using (S,S)-[¹⁸F]FMeNER-D₂ in humans.