The Dangers of Being a Small, Oligotrophic and Light Demanding Freshwater Plant across a Spatial and Historical Eutrophication Gradient in Southern Scandinavia.

European freshwater habitats have experienced a severe loss of plant diversity, regionally and locally, over the last century or more. One important and well-established driver of change is eutrophication, which has increased with rising population density and agricultural intensification. However, reduced disturbance of lake margins may have played an additional key role. The geographical variation in water chemistry, which has set the scene for - and interacted with - anthropogenic impact, is much less well understood. We took advantage of some recently completed regional plant distribution surveys, relying on hundreds of skilled citizen scientists, and analyzed the hydrophyte richness to environment relations in five contiguous South-Scandinavian regions. For three of the regions, we also assessed changes to the freshwater flora over the latest 50-80 years. We found a considerable variation in background total phosphorus concentrations and alkalinity, both within and between regions. The prevalence of functional groups differed between regions in accordance with the environmental conditions and the species' tolerance to turbid waters. Similarly, the historical changes within regions followed the same trend in correspondence to the altered environmental conditions over time. Small submerged species decreased relative to tall submerged and floating-leaved species along the regional and historical eutrophication gradients. These changes were accompanied by systematically greater relative abundance of species of higher phosphorus prevalence. We conclude that species traits in close correspondence with anthropogenic impacts are the main determinants of local, regional and historical changes of species distribution and occupancy, while pure biogeography plays a minor role. Conservation measures, such as re-oligotrophication and re-established disturbance regimes through grazing and water level fluctuations, may help reduce the tall reed vegetation, restore the former richness of the freshwater flora and safeguard red-listed species, although extended time delays are anticipated in nutrient-rich regions, in which species only survive at minute abundance in isolated refugia.

Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms.

STUDY OBJECTIVE: To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. BACKGROUND: Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. METHODS: Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". RESULTS: There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (premenstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (rs = -0.635; 0.027). The control group showed no such correlation. CONCLUSION: Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[ß -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.

Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders.

BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography.

Background Brain activation resulting from acute postoperative pain has to our knowledge not previously been studied using positron emission tomography, except from one case study. The aim of this study was to monitor activation in brain sensory pathways during acute pain after surgery of the hand. A secondary aim was to compare brain activation in clinical postoperative pain to that previously reported, by the same research group, for a model of experimental pain from the same body area. Increase in regional cerebral blood flow (rCBF) is presumed to indicate neuronal activation and decrease in blood flow decreased neuronal firing. An increase in blood flow in a brain region may represent stimulatory activity as well as inhibitory. Methods Brain activity was measured during clinical postoperative pain and a pain free state in six patients with positron emission tomography (PET) as changes in regional cerebral blood flow (rCBF). rCBF during pain from surgery of the right thumb base was compared with a pain free state achieved by regional anaesthesia of the painful area. Results In postoperative pain, patients had a significantly higher CBF in the contralateral/primary and secondary somatosensory cortices as well as in the contralateral motor cortex compared to the pain free stat during local regional anaesthesia. Relatively lower rCBF during the pain state was observed in clusters in the contralateral tertiary sensory cortex, ipsilateral and contralateral secondary visual cortex, prelimbic cortex, ipsilateral prefrontal as well as anterior cingulate cortex and contralateral secondary somatosensory cortex. The increased rCBF in primary and somatosensory cortices probably correspond to pain localizing processing. We also compared the findings in cerebral activation patterns of the postoperative pain state as described above, with the results from a previously published study by the same research group, using an experimental pain model when pain was inflicted with application of mustard oil in the same location, the thumb base region of the right hand. Since no formal statistical analysis was carried out between the two studies, the data are not very strong, but the differences reported were obvious when comparing the two situations. The comparison gave the following outcome: Digit activation occurred in identical sensory brain areas, i.e. primary and secondary somatosensory cortices, as compared to the changes in this study, supporting that pain localization processes use similar sensory pathways in a nociceptive acute experimental pain model, and in clinical acute postoperative nociceptive pain. Dissimilarities were observed between the models in activation of brain areas coding of the emotional pain qualities, indicating some differences between the experimental and "real" acute nociceptive pain. Conclusion We have reported a distinct cerebral activation pattern produced by acute postoperative pain following hand surgery. The findings were compared to data obtained in a previously published report of the cerebral activation pattern from an acute experimental pain model in volunteers. We found similarities as well as some differences in the activation pattern between the two situations.

Treatment response in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission.

BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

Access to health care in relation to socioeconomic status in the Amazonian area of Peru.

BACKGROUND: Access to affordable health care is limited in many low and middle income countries and health systems are often inequitable, providing less health services to the poor who need it most. The aim of this study was to investigate health seeking behavior and utilization of drugs in relation to household socioeconomic status for children in two small Amazonian urban communities of Peru; Yurimaguas, Department of Loreto and Moyobamba, Department of San Martin, Peru. METHODS: Cross-sectional study design included household interviews. Caregivers of 780 children aged 6-72 months in Yurimaguas and 793 children of the same age in Moyobamba were included in the study. Caregivers were interviewed on health care seeking strategies (public/private sectors; formal/informal providers), and medication for their children in relation to reported symptoms and socio-economic status. Self-reported symptoms were classified into illnesses based on the IMCI algorithm (Integrated Management of Childhood Ilness). Wealth was used as a proxy indicator for the economic status. Wealth values were generated by Principal Component Analysis using household assets and characteristics. RESULTS: Significantly more caregivers from the least poor stratum consulted health professionals for cough/cold (p < 0.05: OR = 4.30) than the poorest stratum. The poorest stratum used fewer antibiotics for cough/cold and for cough/cold + diarrhoea (16%, 38%, respectively) than the least poor stratum (31%, 52%, respectively). For pneumonia and/or dysentery, the poorest used significantly fewer antibiotics (16%) than the least poor (80%). CONCLUSION: The poorest seek less care from health professionals for non-severe illnesses as well as for severe illnesses; and treatment with antibiotics is lacking for illnesses where it would be indicated. Caregivers frequently paid for health services as well as antibiotics, even though all children in the study qualified for free health care and medicines. The implementation of the Seguro Integral de Salud health insurance must be improved.

Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting.

RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data.

Although numerous studies have dealt with changes in blood brain-derived neurotrophic factor (BDNF), methodological issues about BDNF measurements have only been incompletely resolved. We validated BDNF ELISA with respect to accuracy, reproducibility and the effect of storage and repeated freezing cycles on BDNF concentrations. Additionally, the effect of demographic characteristics in healthy subjects on BDNF was verified. Whole blood and serum was collected from 206 healthy subjects and a subgroup was genotyped for BDNF Val66Met polymorphism. The effect of age, gender, BDNF genotype and thrombocyte count on whole blood BDNF was assessed. The BDNF ELISA measurement was accurate, 91.6+/-3.0%, and showed high reproducibility, whereas inter-assay and intra-subject variations were modest, 8.4+/-5.2% and 17.5+/-14.1%, respectively. Storage of whole blood samples at 4 degrees C significantly decreased BDNF concentration, while repeated freezing cycles and storage at -20 degrees C was without any effect. Storage at -20 degrees C of serum, but not whole blood, was associated with a significant decrease in BDNF concentration. Women had significantly higher whole blood BDNF concentrations than men (18.6+/-1.3 ng/ml versus 16.5+/-1.4 ng/ml), and showed a right-skewed BDNF concentration distribution. No association between whole blood BDNF concentrations and thrombocyte count, age, or BDNF genotype was found. In conclusion, the BDNF ELISA assay determines whole blood BDNF accurately and with high reproducibility. Female gender is associated with higher whole blood BDNF concentrations whereas age, thrombocyte count and BDNF Val66Met polymorphism were un-associated.

Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration: positron emission tomography studies in monkeys and rats.

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [(11)C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [(11)C]DASB. The binding of [(11)C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [(11)C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.

5-Hydroxy-L-[beta-11C]tryptophan versus alpha-[11C]methyl-L-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain.

The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n=4) on the same day. alpha-[11C]Methyl-L-tryptophan ([11C]AMT) and 5-Hydroxy-L-[beta-11C]tryptophan ([11C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [11C]HTP into the brain (K1) was higher than that for [11C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k3) was also higher for [11C]HTP than for [11C]AMT in the striatum (0.046+/-0.024 versus 0.019+/-0.006 min(-1)) and thalamus (0.039+/-0.013 versus 0.016+/-0.007 min(-1)). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (K(acc)) for [11C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [11C]AMT K(acc) values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.

Physical exercise for cytotoxic drug-induced fatigue.

STUDY OBJECTIVES: Cancer-related fatigue (CRF) is frequently reported by cancer patients receiving cytotoxic drugs. The specific mechanism of CRF in cancer patients is not completely known. In recent years, convincing evidence supports the management of fatigue with physical exercise. This study investigated a recommendation that physical activity, eg, a 30-minute daily walk, would decrease fatigue in cancer patients receiving cytotoxic drugs at an outpatient ward. METHOD: In total, 89 patients were interviewed about their fatigue and were asked to complete a questionnaire, the Fatigue Symptom Inventory (FSI), once a week over several treatment cycles of cytotoxic drugs. On inclusion, all patients received similar information about fatigue. After randomization, information about the positive effects of exercise was given to half of the patients after one cycle of cytotoxic drugs, and to the remaining patients after two cycles of cytotoxic drugs. RESULTS: A total of 74 patients completed the study and returned useable questionnaires. The fatigue prevalence was 89% after one cytotoxic drug cycle. According to the FSI ratings, the group who received information about physical exercise after one cycle scored significantly lower ratings than the other group throughout the study (P = 0.034). The patient interviews confirmed that physical activity helped them to better battle fatigue. Intensity of other symptoms and side effects from cytotoxic drugs closely paralleled the fatigue ratings. CONCLUSION: Fatigue was commonly found in the study population. Though small improvements followed physical exercise, results pointed towards the fact that information and exercise may support patients to combat fatigue. Early and frequent information would probably support patients to better combat fatigue by physical exercise.

Fatigue in cancer patients treated with cytotoxic drugs.

STUDY OBJECTIVES: Cancer-related fatigue is a significant and distressing problem for the cancer patient, affecting their physical and psychosocial function negatively, and reducing their quality of life. The aims of this study were to assess frequency, severity, and the consequence of fatigue in cancer outpatients receiving cytotoxic drugs, using an existing international fatigue scale applied for Swedish use. METHODS: The study used a non-randomized, prospective design to evaluate fatigue and its impact on quality of life in outpatients receiving cytotoxic drugs. Once a week, 147 cancer patients, in an outpatient ward for cytotoxic drug administration, filled out questionnaires containing 13 items from the Fatigue Symptom Inventory (FSI), and five additional questions. RESULTS: Prevalence of fatigue was 92% in the week after all patients had received cytotoxic drugs, and patients were statistically significantly more fatigued during than before treatment. The degree of fatigue was highest the week after treatment, and declined over the following week. Other symptoms, especially depressed mood, showed a strong correlation with cancer and cytotoxic-induced fatigue. Lung and breast cancer patients experienced the highest degree of fatigue. Some cytotoxic drug regimens were, apart from the underlying disease, associated with high fatigue scores, eg, those with cyclophosphamide or gemcitabine. Patients not receiving first line treatment scored significantly higher fatigue with more influence on daily living. CONCLUSION: The study verified that fatigue is a common side effect, and affects quality of life negatively, even for outpatients receiving cytotoxic drugs. The clinical oncology pharmacist must inform patients that a severe tiredness, fatigue, may follow cytotoxic drug administration.

Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis.

The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.

Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria.

The cardinal mood symptoms of premenstrual dysphoria can be effectively treated by serotonin-augmenting drugs. The aim of the study was to test the serotonin hypothesis of this disorder, i.e. of an association between premenstrual decline in brain serotonin function and concomitant worsening of self-rated cardinal mood symptoms. Positron emission tomography was used to assess changes in brain trapping of 11C-labeled 5-hydroxytryptophan, the immediate precursor of serotonin, in the follicular and premenstrual phases of the menstrual cycle in eight women with premenstrual dysphoria. Changes in mood and physical symptoms were assessed from daily visual analog scale ratings. Worsening of cardinal mood symptoms showed significant inverse associations with changes in brain serotonin precursor trapping; for the symptom "irritable", r(s)=-0.83, and for "depressed mood" r(s)=-0.81. Positive mood variables showed positive associations, whereas physical symptoms generally displayed weak or no associations. The data indicate strong inverse associations between worsening of cardinal symptoms of premenstrual dysphoria and brain serotonin precursor (11C-labeled 5-hydroxytryptophan) trapping. The results may in part support a role for serotonin in premenstrual dysphoria and may provide a clue to the effectiveness of serotonin-augmenting drugs in this disorder but should, due to small sample size and methodological shortcomings, be considered preliminary.

Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study.

Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.

Potential of [11C]DASB for measuring endogenous serotonin with PET: binding studies.

The serotonin transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [11C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [11C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [11C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [11C]DASB for transporter binding.

Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease.

During the period February 1997 to April 2000, 15 patients with clinical symptoms of Creutzfeldt-Jakob disease (CJD) were referred to Uppsala University PET Centre. Positron emission tomography (PET) was performed to detect characteristic signs of the disease, e.g. neuronal death and/or astrocytosis in the brain. The examinations were performed in one session starting with oxygen-15 labelled water scan to measure regional cerebral blood flow, followed by imaging with the monoamine oxidase B inhibitor N-[(11)C-methyl]- L-deuterodeprenyl (DED) to assess astrocytosis in the brain and finally imaging with fluor-18 2-fluorodeoxyglucose (FDG) to assess regional cerebral glucose metabolism (rCMR(glu)) [corrected]. Nine of the patients fulfilled the clinical criteria of probable CJD. In eight of them, FDG and DED imaging revealed, in comparison with normal controls, a typical pattern characterized by a pronounced regional decrease (<2SD) in glucose brain metabolism, indicative of neuronal dysfunction; this was accompanied by a similar increase (>2SD) in DED binding, indicating astrocytosis. These changes were most pronounced in the cerebellum and the frontal, occipital and parietal cortices, whereas the pons, the thalamus and the putamen were less affected and the temporal cortex appeared unaffected. The cerebral blood flow showed a pattern similar to that observed with FDG. In the ninth patient, analysis with DED was not possible. The diagnosis of definite CJD according to international consensus criteria was confirmed in six of these patients. In one patient with probable CJD, protease-resistant prion protein (PrPres) could not be demonstrated. In two patients with probable CJD, autopsy was not allowed. Computed tomography and magnetic resonance imaging, performed in four and seven of these nine patients respectively, showed unspecific, mainly atrophic changes. In six other patients, the PET examinations gave a different pattern. In three of them, high rCMR(glu) was noticed in parts of the brain, particularly in the temporal lobes and basal ganglia, which could suggest encephalitis. One of the patients had Sjögren's syndrome, one had paraneoplastic limbic encephalitis and the third recovered spontaneously. In the other three patients, the DED binding was normal despite a hypometabolic glucose pattern. In conclusion, the PET findings obtained using DED and FDG paralleled neuropathological findings indicating neuronal dysfunction and astrocytosis, changes that are found in CJD.