[Impact of maternal risky behaviors on the behaviors of children born to adolescent and young mothers].

Objective: To examine the impact of maternal risky behaviors on the behaviors of children born to adolescent and young mothers. Methods: Adolescents and young Chinese mothers were recruited from an integrated young mother supportive program in Hong Kong between January and June 2015. Eligible mothers were asked to complete a questionnaire on their sociodemographic characteristics and history of risky behavior as well as their children's behaviors. Multiple regression analyses were conducted to explore the association between maternal risky behaviors and their children's behaviors. Results: Among 201 respondents, there were 187 (93.0%) ex-drinkers, 136 (67.7%) ex-smokers, and 83 (41.3%) ex-addicts. Compared to the reference group, children of mothers with drug use behaviors were more likely to have abnormal SDQ total difficulties scores (odds ratio 2.60, P=0.01), those of ex-drinking mothers had more behavioral difficulties and more conduct problems (B=3.82 and 1.37, P both=0.01) and those of ex-smoking mothers had more conduct problems (B=0.74, P=0.01) after adjustment for confounders. Children of active drug-taking mothers also had more emotional symptoms (B=1.77, P=0.04) and hyperactivity/inattention problems (B=2.14, P=0.03). Conclusion: The history of mother's risky behavior was significantly associated with the behavioral problems of the children.

Evaluation of dopaminergic presynaptic integrity: 6-[18F]fluoro-L-dopa versus 6-[18F]fluoro-L-m-tyrosine.

The effectiveness of 6-[18F]fluoro-L-m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function (Ki) or the activity in the occipital cortex as the input function (Kc), the rate of loss of striatal radioactivity (k(loss)), and an index of "effective turnover" of dopamine (k(loss)/Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L-m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using k(loss) or k(loss)/Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.

Reproducibility studies with 11C-DTBZ, a monoamine vesicular transporter inhibitor in healthy human subjects.

UNLABELLED: The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. METHODS: The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. RESULTS: The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. CONCLUSION: Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipital cortex or the cerebellum may be altered.

Quantitative comparison of three- and two-dimensional PET with human brain studies.

UNLABELLED: The aim of this study was to test the quantitation accuracy of three-dimensional PET in brain scanning. METHODS: Three-dimensional data from 11 human subjects were tested using 11C-dihydrotetrabenazine, 11C-Schering 23390 and 18F-FDG as tracers. Two-dimensional scans were performed on the same subjects and the distribution volume, distribution volume ratio and local metabolic rate of glucose (LMRGlu) values obtained from these were used as reference. Three-dimensional data were processed as follows: iterative convolution subtraction scatter correction, detector normalization including radial and axial geometric factors, attenuation correction extracted from a two-dimensional transmission scan, Kinahan-Rogers reconstruction and region-of-interest-based sensitivity calibration. RESULTS: No major systematic differences between the two methods were found. The agreement between the two-dimensional and three-dimensional data was within 5%. Although statistical analysis generally did not show this difference to be significant, reliability analysis indicated that comparing two-dimensional and three-dimensional data might introduce some inaccuracies. CONCLUSION: Three-dimensional PET yields quantitatively valid results for brain scanning.

Age-dependent decline of dopamine D1 receptors in human brain: a PET study.

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.

6-[18F]Fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys.

This report describes a method to assess, in vivo, the turnover of dopamine (DA) and describes its application to the evaluation of DA function in normal monkeys and monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the DA nigro-striatal pathway. Using positron emission tomography with the tracer of presynaptic DA function, 6-[18F]fluoro-L-DOPA (FDOPA), and an extension of the graphical method of analysis, we measured the striatal FDOPA uptake rate constant, Ki, and the rate of reversibility of FDOPA trapping k(loss) in normal and MPTP-treated monkeys, either neurologically normal or displaying a parkinsonian symptomatology. An index of effective DA turnover was defined as the ratio of k(loss)/Ki. Compared to normal controls, Ki was decreased and k(loss) was increased in the MPTP-lesioned monkeys. The index of DA turnover was significantly increased in the monkeys displaying a parkinsonian symptomatology as compared to the controls and the neurologically normal MPTP-treated monkeys. The DA turnover index was also significantly increased in the neurologically normal MPTP-lesioned animals compared to normals. This suggests that an increase in DA turnover develops early in the disease process and may be one of the compensatory mechanisms partly responsible for the delay in the development of the clinical manifestations in Parkinson's disease.

Reproducibility of the distribution of carbon-11-SCH 23390, a dopamine D1 receptor tracer, in normal subjects.

UNLABELLED: The reproducibility of [11C]SCH 23390 in PET was studied in 10 normal human subjects. METHODS: The scan-to-scan variation of several measures used in PET data analysis, including the radioactivity ratio, plasma-input Logan total distribution volume (DV), plasma-input Logan DV ratio (DVR) and tissue-input Logan Bmax/Kd values, was determined. RESULTS: There were significant correlations among the radioactivity ratio, plasma-input DVR and tissue-input Bmax/Kd. With the cerebellum as the reference region, these three measures also had high reliability (86%-95%), high between-subject s.d. (7.7%-11.3%) and small within-subject s.d. (2.3%-3.6%), indicating that they are comparable and useful measures for the assessment of dopamine D1 receptor binding. CONCLUSION: The radioactivity ratio and the tissue-input Bmax/Kd may be preferred methods for the evaluation of dopamine D1 receptor binding because these two methods do not require arterial blood sampling and metabolite analysis. Our results show that cerebellum is a reliable reference region for SCH 23390. When the Logan plasma-input function method is used in data analysis for SCH 23390, DVRs rather than total DV values should be used because of the poor reliability of the DV values and their lack of correlation with other measures. Carbon-11-SCH 23390 is thus a reliable and reproducible ligand for the study of dopamine D1 receptor binding by PET.

Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover: a PET study with 6-[18F]L-DOPA.

The consequences of monoamine oxidase and catechol-O-methyltransferase inhibition on the effective turnover of dopamine were investigated using 6-[18F]L-3-4-dihydroxyphenylalanine (6-[18F]L-DOPA) and positron emission tomography. The effective dopamine turnover was expressed as the ratio between the rate of reversibility of 6-[18F]L-DOPA trapping (k[loss]) and the rate of uptake of 6-[81F]L-DOPA (Ki) in the striatum of normal cynomolgus monkeys. The monkeys received 6-[18F]L-DOPA scans, untreated or after pretreatment with either the peripheral catechol-O-methyltransferase inhibitor nitecapone; the peripheral and central catechol-O-methyltransferase inhibitor tolcapone; the monoamine oxidase inhibitors deprenyl or pargyline; a combination of tolcapone and the monoamine oxidase inhibitors. Tolcapone alone or combined with the monoamine oxidase inhibitors produced a significant decrease in the dopamine turnover (55 to 65%). Neither nitecapone nor monoamine oxidase inhibition alone produced significant changes. These results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.

Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.

UNLABELLED: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Effects of catechol-O-methyltransferase inhibition on the rates of uptake and reversibility of 6-fluoro-L-Dopa trapping in MPTP-induced parkinsonism in monkeys.

The uptake rate constant and the loss rate constant that expresses the reversibility of the uptake process of 6-[18F]fluoro-L-Dopa (FDOPA) were measured by positron emission tomography in the striatum of normal rhesus monkeys and in monkeys with unilateral lesions of the dopaminergic nigro-striatal pathway, induced by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Each animal was studied twice: with and without pretreatment of the catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592, tolcapone. After pretreatment with tolcapone, there was a very significant increase in plasma FDOPA throughout the course of the study, accompanied by a significant decrease in its main metabolite, 3-O-methylfluorodopa. Tolcapone did not induce a significant change in the uptake rate constant in either the normal or the MPTP-treated striatum. However, after tolcapone pretreatment, there was a significant decrease in the loss rate constant in the MPTP-treated striatum (25%) and a smaller, non-significant decrease in the normal striatum (13%). It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity. As compared to peripheral COMT inhibitors, this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of L-DOPA therapy in parkinsonian patients.

Effect of prior sternotomy on mortality and morbidity after heart transplantation. Cardiac Transplant Team.

A retrospective analysis to evaluate the impact of prior sternotomy on the outcome of cardiac transplantation was undertaken. Some 165 patients who received primary heart transplantation were classified into three groups. There were 102 patients in group 1 (no prior sternotomy), 47 in group 2 (one prior sternotomy), and 16 in group 3 (more than one prior sternotomy). The three groups were demographically similar. Coronary artery bypass was the indication for prior sternotomy in 77% of patients in group 2 and in 94% in group 3. Mortality within 30 days post-transplant was significantly different among the three groups (group 1, 7.8%; group 2, 8.5%; group 3, 31%; P = 0.0148). The 1-year actuarial survival was also significantly lower in group 3 (52%) compared with groups 1 (83%) and 2 (81%) (P = 0.0311). Multivariate analysis identified more than one prior sternotomy and pulmonary hypertension as risk factors for death within 30 days post-transplant. Patients who had prior sternotomy also had a higher incidence of coagulopathy (group 1, 17%; group 2, 49%; group 3, 38%; P = 0.0002), and re-exploration due to excessive bleeding (group 1, 5%; group 2, 11%; group 3, 25%; P = 0.0225). Requirement for blood products for transfusion was also higher in groups 2 and 3. There was no significant difference among the three groups in the incidence of early infections (50% versus 53% versus 44%), renal failure (6% versus 11% versus 19%), or allograft rejection in patients who survived the first 30 days (95% versus 86% versus 82%).(ABSTRACT TRUNCATED AT 250 WORDS)

Urgent heart transplantation in patients with previous sternotomies. Cardiac Transplant Team.

Critically ill patient status and prior sternotomy have separately been associated with increased risk of mortality and morbidity after heart transplantation. Consequently, the justification of assigning urgent priority for transplantation to critically ill patients with prior sternotomy may be arguable. The authors therefore undertook a retrospective analysis to evaluate the outcome of urgent and elective heart transplantation in 64 patients who had undergone one to four previous sternotomies. Patients in group 1 (n = 23) were critically ill and underwent urgent heart transplantation. Group 2 (n = 41) consisted of more stable patients who received heart transplantation as an elective procedure. Intravenous inotropes or mechanical circulatory support were required by all patients in group 1 but by none in group 2. The mortality rate within 30 days post-transplant was higher in group 1 than in group 2 (22% versus 10%), though the difference was not statistically significant. The 1-year actuarial allograft survival was similar between the two groups (72% versus 74%). In addition, there was no significant difference between groups 1 and 2 in the incidence of postoperative coagulopathy (57% versus 42%), re-exploration (13% versus 15%), early infections (57% versus 49%), renal failure (17% versus 10%) or rejection episodes in the first 3 months (65% versus 78%). The authors' findings suggest that despite higher operative mortality in critically ill patients with previous sternotomies, the intermediate-term outcome of heart transplantation in these patients is similar to that in more stable patients. Critically ill patients with prior sternotomies should therefore continue to be considered for urgent heart transplantation.

Treatment of recalcitrant cardiac allograft rejection with methotrexate. Cardiac Transplant Team.

Acute rejection continues to be a major cause of mortality and morbidity among cardiac allograft recipients. In this retrospective analysis, we evaluated the efficacy and safety of methorexate in the treatment of recalcitrant rejection in 16 heart transplant patients. Methotrexate was initiated in these patients for rejection refractory to conventional therapy or for multiple, recurrent rejection episodes. Before methotrexate therapy, these patients had experienced 3.2 +/- 1.1 (mean +/- SD) episodes of allograft rejection. Methotrexate was administered at 5.9 +/- 5.3 months postransplant, at a starting oral dose of 7.8 +/- 2.7 mg/week. The methotrexate dose was increased as tolerated by white blood cell counts to 10-25 mg/week. These patients had been followed for 26 +/- 12 months after initiation of methotrexate. All ongoing rejection episodes were reversed with methotrexate. Rejection resolution was typically delayed and was observed at 19 +/- 15 days after methotrexate initiation. Compared to the 6 months before methotrexate therapy, there was significant reduction in the linearized rejection rate (0.44 +/- 0.14 vs 0.06 +/- 0.09 episodes/patient/month), and the time spent in rejection (29.8 +/- 14.0 vs 5.8 +/- 8.7 days) in the 6 months after methotrexate initiation. Nadir white blood cell counts were observed at 4.0 +/- 1.8 weeks after methotrexate initiation, but were above 2000/mm3 in all patients. Multiple infections occurred in 2 patients who received repeat courses of methotrexate and the highest cumulative doses of methotrexate. These findings suggest that methotrexate may be effective in the management of recalcitrant cardiac allograft rejection. Methotrexate therapy appears to be well tolerated by most patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Routes of administration and effect of carbidopa pretreatment on 6-[18F]fluoro-L-dopa/PET scans in non-human primates.

In 6-[18F]fluoro-L-dopa (Fdopa)/positron emission tomography (PET) studies, carbidopa pretreatment increases the Fdopa bioavailability to the brain and enhances the intensity of striatal PET images. Different PET research teams have used various carbidopa doses and routes of administration in non-human primate studies. The purpose of this study was to examine the plasma profiles of carbidopa and the effect of the route of administration of carbidopa on a Fdopa/PET scan. Cynomolgus monkeys were given carbidopa either orally (5 mg/kg), intraperitoneally (2.5 and 5 mg/kg) or intravenously (5 mg/kg) 60-90 min prior to the Fdopa injection. Carbidopa-treated monkeys were compared to monkeys without carbidopa treatment. No carbidopa was detected in the plasma samples when it was given orally, possibly due to poor absorption in the gastrointestinal tract. In addition, the striatal and cortical activities were not statistically different from those of the untreated monkeys, indicating that little or no inhibition of the peripheral decarboxylation of Fdopa by carbidopa had taken place. When carbidopa was given intraperitoneally at a dose of 2.5 and 5 mg/kg and intravenously at 5 mg/kg, plasma carbidopa concentrations at the time of Fdopa injection were 0.95 +/- 0.26, 2.22 +/- 0.23 and 2.79 +/- 0.26 micrograms/ml, respectively. Because of inhibition of peripheral decarboxylation of Fdopa by carbidopa, more Fdopa was available for transport into the brain and as a result, both the striatal and cortical activities were significantly higher than those of the untreated monkeys. Carbidopa administration had no effect on either the striatal-to-cortical activity ratio or the striatum uptake value.

The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.

Plasma L-[18F]6-fluorodopa input function: a simplified method.

This article describes a simplified method for the determination of the L-[18F]6-fluorodopa (FDOPA) fraction time course that takes advantage of the strong correlation between the radioactivity ratio (metabolites/FDOPA) and time. Serial arterial blood samples are collected for assay of plasma total radioactivities following an intravenous injection of FDOPA into carbidopapretreated subjects. In addition, a single plasma sample, collected late in the study and analyzed for FDOPA fraction, is sufficient to determine accurately the time course of the FDOPA concentration in plasma. The validated straight-line method greatly simplifies blood analysis for routine positron emission tomography FDOPA studies.

Relative performance of specific and nonspecific fluorescence polarization immunoassay for cyclosporine in transplant patients.

The analytical performance of specific and nonspecific fluorescence polarization immunoassays (FPIAs, Abbott Laboratories) for cyclosporine was compared. Both specific and nonspecific FPIAs demonstrated excellent between-run coefficients of variation (5.9% vs. 3.9%) at three levels of control, and a high degree of between-center reproducibility (r2 greater than 0.96). In addition, the correlation between cyclosporine levels measured by specific and nonspecific FPIAs was statistically significant, though imperfect, in both renal (r2 = 0.70) and cardiac transplant patients (r2 = 0.55). In kidney transplant patients, the nonspecific/specific ratio was significantly higher in patients with serum bilirubin concentration exceeding 3 mg/dl (5.9 +/- 2.6 vs. 2.8 +/- 1.1), due to impaired elimination of cyclosporine metabolites in the bile. The nonspecific/specific ratio was also significantly higher in heart transplant patients early (less than 1 month) posttransplant compared with patients in the late posttransplant period (3.4 +/- 0.8 vs. 2.9 +/- 0.8). The Abbott FPIA provides a highly precise method for measuring cyclosporine, with a turnaround time of 15-20 min. The specific monoclonal FPIA has the additional advantage of measuring primarily unchanged cyclosporine and thus has an imperfect correlation with the nonspecific polyclonal FPIA. Together with clinical data, the use of FPIAs may help to improve the efficiency of cyclosporine therapeutic drug monitoring.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.