Brief trauma therapy for occupational trauma-related PTSD/CPTSD in UK police.

BACKGROUND: Police are frequently exposed to occupational trauma, making them vulnerable to post-traumatic stress disorder (PTSD) and other mental health conditions. Through personal and occupational trauma police are also at risk of developing Complex PTSD (CPTSD), associated with prolonged and repetitive trauma. Police Occupational Health Services require effective interventions to treat officers experiencing mental health conditions, including CPTSD. However, there is a lack of guidance for the treatment of occupational trauma. AIMS: To explore differences in demographics and trauma exposure between police with CPTSD and PTSD and compare the effectiveness of brief trauma-focused therapy between these diagnostic groups. METHODS: Observational cohort study using clinical data from the Trauma Support Service, providing brief trauma-focused therapy for PTSD (cognitive behavioural therapy/eye movement desensitization and reprocessing) to UK police officers. Demographics, trauma exposure, baseline symptom severity and treatment effectiveness were compared between police with PTSD and CPTSD. Changes in PTSD, depression and anxiety symptoms were used to measure treatment effectiveness. RESULTS: Brief trauma therapy reduced symptoms of PTSD, depression and anxiety. Treatment effectiveness did not differ between CPTSD and PTSD groups. Police with CPTSD exposed to both primary and secondary occupational trauma had poorer treatment outcomes than those exposed to a single occupational trauma type. CONCLUSIONS: Brief trauma-focused interventions are potentially effective in reducing symptoms of PTSD, depression and anxiety in police with CPTSD and PTSD. Further research is needed to establish whether additional CPTSD symptoms (affect dysregulation, self-perception and relational difficulties) are also reduced.

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells.

T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.

Evaluating the success of a marine protected area: A systematic review approach.

Marine Protected Areas (MPAs), marine areas in which human activities are restricted, are implemented worldwide to protect the marine environment. However, with a large proportion of these MPAs being no more than paper parks, it is important to be able to evaluate MPA success, determined by improvements to biophysical, socio-economic and governance conditions. In this study a systematic literature review was conducted to determine the most frequently used indicators of MPA success. These were then applied to a case study to demonstrate how success can be evaluated. The fifteen most frequently used indicators included species abundance, level of stakeholder participation and the existence of a decision-making and management body. Using the indicator framework with a traffic light system, we demonstrate how an MPA can be evaluated in terms of how well it performs against the indicators using secondary data from the literature. The framework can be used flexibly. For example, where no MPA data currently exist, the framework can be populated by qualitative data provided by local stakeholder knowledge. This system provides a cost-effective and straightforward method for managers and decision-makers to determine the level of success of any MPA and identify areas of weakness. However, given the variety of motivations for MPA establishment, this success needs to be determined in the context of the original management objectives of the MPA with greater weighting being placed on those objectives where appropriate.

Clinical dietetic practice in the treatment of severe acute malnutrition in a high HIV setting.

BACKGROUND: In Sub-Saharan Africa, children commonly present with severe acute malnutrition (SAM) complicated by HIV/AIDS. In 2005, the South African Department of Health implemented the World Health Organization (WHO) Ten Step programme for the inpatient treatment of SAM. Dietary management with F75 and F100 (where the terms F75 and F100 refer to a mixture of milk, sugar, oil and a vitamin and mineral mix) may not be appropriate for relatively well resourced settings such as South Africa. METHODS: A structured questionnaire aiming to determine current clinical practice was e-mailed to all dietitians working in hospitals (n = 53) in KwaZulu-Natal who routinely treated SAM. RESULTS: When initially refeeding with no diarrhoea (ND), F75 was used exclusively by 16% of dietitians to treat infants, and by 42% of dietitians to treat children. If diarrhoea, 16% of dietitians used F75 to treat infants/children. Acidified infant formula (IF) was given if ND and lactose-free IF was given if diarrhoea. Children were often started on a lactose-free F100 equivalent omitting cautious refeeding. Some gave reduced amounts for cautious refeeding; however, the feeds osmolality was too high. The use of partially hydrolysed feeds increased if the child/infant presented with diarrhoea and/or hypoalbuminea. In the post-initial feeding phase, approximately 14% of dietitians used F100 to treat infants/children. Most gave F100 equivalents as high-energy infant/paediatric formulas. CONCLUSIONS: The dietetic practices for infants with SAM followed current expert opinion closely rather than the WHO protocol. The omission of cautious refeeding follows neither current expert opinion, nor the WHO protocol, and may predispose to the refeeding syndrome. Limited evidence indicates that partially hydrolysed formulas are less effective than low lactose low osmolality feeds in the treatment of SAM.

HostSeq: a Canadian whole genome sequencing and clinical data resource.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Bacterial water quality and network hydraulic characteristics: a field study of a small, looped water distribution system using culture-independent molecular methods.

AIMS: To determine the spatial and temporal variability in the abundance, structure and composition of planktonic bacterial assemblages sampled from a small, looped water distribution system and to interpret results with respect to hydraulic conditions. METHODS AND RESULTS: Water samples were collected from five sampling points, twice a day at 06:00 h and 09:00 h on a Monday (following low weekend demand) and a Wednesday (higher midweek demand). All samples were fully compliant with current regulated parameter standards. This study did not show obvious changes in bacterial abundance (DAPI count) or community structure Denaturing gradient gel electrophoresis analysis with respect to sample site and hence to water age; however, the study did show temporal variability with respect to both sampling day and sample times. CONCLUSIONS: Data suggests that variations in the bacterial assemblages may be associated with the local system hydraulics: the bacterial composition and numbers, over short durations, are governed by the interaction of the bulk water and the biofilm influenced by the hydraulic conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates general stability in bacterial abundance, community structure and composition within the system studied. Trends and patterns supporting the transfer of idealized understanding to the real world were evident. Ultimately, such work will help to safeguard potable water quality, fundamental to public health.

Sensory wellbeing workshops for inpatient and day-care patients with anorexia nervosa.

BACKGROUND: The wellbeing of patients with eating disorders is one of the priorities in the "bigger picture" of treatment for eating disorders. Sensory soothing strategies for sensory sensitivities are supportive tools which could be useful in day-care and inpatient clinical programmes. METHODS: Evaluation of multiple separate sensory wellbeing workshops consisting of psychoeducation and experiential components delivered in inpatient and intensive day-care services was performed. Participants' self-report questionnaires were evaluated pre- and post-workshop. Additionally, patients' comments and qualitative feedback was collected after completion of the workshop. RESULTS: There was strong evidence that self-reported awareness of sensory wellbeing, awareness of strategies to enhance sensory wellbeing, and confidence in managing sensory wellbeing increased after the workshops with positive qualitative feedback from participants. The feedback questionnaires highlighted that patients found the sessions useful and were able to use some of the skills and strategies they learned in the workshop. CONCLUSION: This pilot work on sensory wellbeing workshops with a protocol-based format was feasible and beneficial for the patient group. Preliminary evidence suggests that delivery of similar workshops could be sensible in addition to treatment as usual in inpatient and day-care programmes.

Community pharmacist-initiated screening program for osteoporosis: randomized controlled trial.

SUMMARY: This study evaluated the effect of a multifaceted intervention (screening and patient education) by community pharmacists on testing or treatment of osteoporosis. One hundred and twenty-nine patients randomized to receive the intervention were compared to 133 patients who did not receive the intervention. Twice as many patients who got the intervention received further testing or treatment for osteoporosis. INTRODUCTION: The objective of this study was to determine the effect of a community pharmacist screening program on testing and treatment of osteoporosis. METHODS: In this randomized, controlled trial, 262 patients meeting bone mineral density (BMD) testing guidelines [men or women aged > or = 65 years or 50-64 years with one major risk factor including previous fracture, family history of osteoporosis, glucocorticoids for > 3 months, or early menopause] were allocated to intervention (129) or control (133). Intervention consisted of printed materials, education, and quantitative ultrasound. Primary outcome was a composite endpoint of BMD or prescription for osteoporosis medication within 4 months. RESULTS: Primary endpoint of BMD or osteoporosis treatment was achieved by 28 intervention patients (22%) compared with 14 controls (11%) (RR 2.1, 95% CI 1.1-3.7). This was driven by BMD testing (28 (22%) vs. 13 (10%) for controls, p = 0.011). Calcium intake increased more among intervention patients than controls (30% vs. 19%, RR 1.6, 95% CI 1.0-2.5). There was no effect on knowledge or quality of life. CONCLUSION: A pharmacist screening program doubled the number of patients tested for osteoporosis. Nevertheless, many patients eligible for BMD did not receive appropriate care suggesting more intensive interventions are needed.

Performance of influenza rapid antigen testing in influenza in emergency department patients.

BACKGROUND: The use of rapid antigen tests to triage specimens for polymerase chain reaction (PCR) testing from emergency department patients with influenza-like illness during surveillance for novel influenza viruses has been suggested. OBJECTIVE: To measure the observed sensitivity and specificity for a widely used rapid antigen test (Binax) using a PCR-based assay (Medical Diagnostic Laboratories). METHODS: Nasopharyngeal samples were taken with flocked swabs (Copan Diagnostics) from patients presenting to the emergency department of a community hospital. Samples were analysed using a rapid antigen and a PCR-based test. PCR testing was used as the criterion reference. Sensitivity and specificity were calculated for influenza and influenza A. Positive predictive values were calculated over a range of possible prevalence. RESULTS: Samples from 566 unique patients were tested using both methods. Sensitivity was 69.1% (95% CI 58.9% to 78.1%) and specificity was 97.7% (95% CI 95.8% to 98.8%) for the detection of any influenza and 75.3% (95% CI 64.7% to 84.0%) and 97.8% (95% CI 95.9% to 98.9%), respectively, for influenza A only. The resultant positive predictive value ranges from 23% to 77% when the prevalence ranges from 1% to 10%. CONCLUSION: When planning early outbreak surveillance, provision of adequate PCR testing capacity rather than triaging specimens using rapid antigen testing for influenza is advisable.

Investigating the effect of storm events on the particle size distribution in a combined sewer simulator.

The changes in particle size of sewer sediment particles rapidly eroded from a previously deposited sediment bed are described, using a rotating annular flume as a laboratory scale sewer simulator. This is the first time that particle size distributions of eroded sewer sediments from a previously deposited sediment bed have been monitored in such a controlled experimental environment. Sediments from Loenen, The Netherlands and Dundee, UK were used to form deposits in the base of the annular flume (WL Delft Netherlands) with varying conditions for consolidation in order to investigate the effect of changing consolidation time, temperature and sediment type on the amount and size of particles eroded from a bed under conditions of increasing shear. The median size of the eroded particles did not change significantly with temperature, although the eroded suspended solids concentration was greater for the higher temperature under the same shear stresses, indicating a weaker bed deposit. An increase in consolidation time caused an increase in median size of eroded solids at higher bed shear stresses, and this was accompanied by higher suspended solids concentrations. As the shear stress increased, the solids eroded from the bed developed under a longer consolidation time (56 hours) tended towards a broad unimodal distribution, whilst the size distribution of solids eroded from beds developed under shorter consolidation times (18 or 42 hours) retained a bi- or tri-modal distribution. Using different types of sediment in the flume had a marked effect on the size of particles eroded.

Extracellular vesicles such as prostate cancer cell fragments as a fluid biopsy for prostate cancer.

Extracellular vesicles (EVs) are cell-derived vesicles generated through a process of cell membrane shedding or storage vesicle release, as occurs during apoptosis, necrosis or exocytosis. Initially perceived as cellular by-products or 'dust' of insignificant biological importance, recent research has shed light on the role of EVs as mediators of intercellular communication, blood coagulation and disease progression. The prostate is a source of EVs and their abundance in complex biological fluids such as plasma, serum and urine make them compelling entities for a 'fluid biopsy'. As such, prostate cancer cell fragments (PCCF) are EVs generated by the tumor resident within the prostate and are also present in blood, expressing a portion of biomarkers representative of the primary tumor. High-throughput analytical techniques to determine biomarker expression on EVs is the last hurdle towards translating the full potential of prostate EVs for clinical use. We describe current state-of-the-art methods for the analysis of prostate-derived EVs in patient fluids such as plasma and the challenges that lie ahead in this emerging field of translational research.

Dopamine and glutamate control each other's release in the basal ganglia: a microdialysis study of the entopeduncular nucleus and substantia nigra.

This study utilized microdialysis in conscious rats to investigate dopaminergic control of excitatory amino acid release in the entopeduncular nucleus (EPN), and glutamatergic control of dopamine release in the substantia nigra pars reticulata (SNr). EPN dialysates contained both glutamate and aspartate, which were elevated by dopamine depletion with reserpine and 6-hydroxydopamine (6-OHDA), reduced by the D2/3 agonist LY 171555 and unaffected by the D1 agonist SKF 38393, in line with current theory. The D2/3 agonist RU 24213 was behaviourally active but paradoxically increased glutamate and aspartate release in EPN, possibly via kappa opioid receptor blockade. 6-OHDA-hemilesioned rats also showed a significant increase in glutamate and aspartate contralaterally, suggesting that nigrostriatal dopamine affects EPN neurotransmission bilaterally. In reserpine-treated rats, basal levels of dopamine in the SNr were greatly reduced, and were further lowered by focal application of NMDA antagonists, suggestive of the removal of a high glutamatergic tone. A threshold amount of L-DOPA applied to the SNr elevated dopamine output about two-fold and 5-HT output about 13-fold, indicating L-DOPA effects the release of monoamines other than dopamine. Concomitant addition of the NMDA antagonists potentiated these releases synergistically, suggesting that this could be how they facilitate the antiparkinsonian action of L-DOPA.

Tonic desensitization of hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors regulates 5-hydroxytryptamine release in vivo.

Strong evidence implicates glutamate as an excitatory neurotransmitter in the central nervous system. In the present study we have investigated the effects of different concentrations of the excitatory amino acid agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid on release of 5-hydroxytryptamine in rat hippocampus using in vivo microdialysis. Infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid at 1 microM led to an increase in dialysate 5-hydroxytryptamine. In contrast 100 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid decreased extracellular 5-hydroxytryptamine, collected in 30 min samples, and this decrease was sustained for several hours. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization is well documented in vitro, and is reversed by the drug diazoxide. We therefore studied the possibility that this was occurring in hippocampus in vivo. Collection of dialysates at 5 min time intervals revealed a brief increase in dialysate 5-hydroxytryptamine in response to 100 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, although basal level of 5-hydroxytryptamine was below the level of detection. When 100 microM agonist was co-infused with 500 microM diazoxide, a substantial and prolonged increase in dialysate 5-hydroxytryptamine was seen. Diazoxide alone was observed to cause an increase in extracellular 5-hydroxytryptamine. Diazoxide is known to active ATP-dependent K+ channels, however, cromakalim (100 microM), an activator of ATP-dependent K+ channels, reduced hippocampal 5-hydroxytryptamine release, suggesting that the effect of diazoxide is not the result of such an action.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent.

The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.

Periovulatory endocrinology in high ovulating Meishan sows.

The present study was designed to investigate the hormone profiles (oestradiol, LH, FSH, inhibin, progesterone) in high ovulating Meishan sows (MS; n = 9) and in contemporary Large-White hybrid control sows (LW; n = 9) during the follicular phase, the periovulatory period and the early luteal phase. Ovulation rate was higher in MS than LW animals (23.7 and 16.6 respectively; P < 0.001) and overall was correlated with the area of the oestradiol peak (P < 0.05) and inhibin concentrations (P < 0.05). Both the duration of and the area of the oestradiol peak were greater in MS than LW (P < 0.01; P < 0.02), as were inhibin concentrations both before and after the LH surge (P < 0.05). Neither basal nor peak concentrations of LH or FSH differed between the breeds (P > 0.05), although FSH concentrations were correlated with the area under the oestradiol peak (P < 0.05). Finally, the time-interval from the onset of the LH surge until the rise in plasma progesterone was shorter in MS than LW (54.5 and 74.3 h respectively; P < 0.01). In conclusion, these results show for the first time that the higher ovulation rate in MS is associated with enhanced oestradiol and inhibin secretion with no significant difference in LH or FSH concentrations. The more rapid luteinization response to the LH surge by MS in terms of plasma progesterone concentrations may be important in ensuring the high level of embryo survival in this breed.

AMPA receptors modulate extracellular 5-hydroxytryptamine concentration and metabolism in rat striatum in vivo.

We have investigated the effects of infusing the excitatory amino acid agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on extracellular levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum using in vivo microdialysis. AMPA (50-500 microM) caused a concentration-dependent increase in extracellular 5-HT, while having the converse effect on 5-HIAA. At the highest agonist dose the decrease in dialysate 5-HIAA was followed by a significant increase in this metabolite. Two hundred micromolar 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a competitive non-NMDA glutamate receptor antagonist, reversed the effects of a 100 microM AMPA on dialysate 5-HT and 5-HIAA. Co-infusion of AMPA with tetrodotoxin (TTX) abolished the effects of 100 microM AMPA, but only partially reversed the effect of 500 microM AMPA on 5-HT release. We have also investigated whether AMPA receptor desensitization, a well documented event, plays a role in AMPA receptor modulation of striatal 5-HT release. Diazoxide (500 microM), a drug which prevents AMPA receptor desensitization, failed to augment the effect of 100 microM AMPA on 5-HT release. Diazoxide alone significantly decreased 5-HT release, as did the drug cromakalim (100 microM), probably as a result of their common action as activators of ATP-dependent K+ channels. It is concluded that AMPA receptors play a role in regulating both 5-HT release and metabolism in rat striatum. However, AMPA receptor desensitization does not appear to play a role in this process in this structure.

Reverse transcriptase PCR amplification of EWS/FLI-1 fusion transcripts as a diagnostic test for peripheral primitive neuroectodermal tumors of childhood.

The peripheral primitive neuroectodermal tumors (pPNETs) of childhood, including Ewing's sarcoma, peripheral neuroepithelioma, and Askin's tumor, often present significant diagnostic challenges for the anatomic pathologist. One consistent feature of these tumors is the presence of the t(11;22)(q24;q12) in tumor cells, and this translocation has been useful as a marker for this group of tumors. The recent cloning of the t(11;22) breakpoint has revealed the fusion of the human FLI-1 gene on chromosome 11q24 with a gene of unknown function called EWS on 22q12, and fusion transcripts have been detected. These findings have raised the possibility of using molecular genetic analysis as a tool to diagnose pPNETs. To this end, we have tested pPNETs for the presence of EWS/FLI-1 fusion transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR) using EWS and FLI-1 specific primers. Eight (80%) of 10 pPNET cell lines were positive for amplified products using this technique. These results were confirmed by Southern analysis, which revealed rearrangements of EWS using genomic EWS probes in all eight positive cell lines. We then tested 20 primary pPNET tumors, and identified fusion transcripts by RT-PCR in 18 (90%) of these cases. Cloning and sequencing of PCR products confirmed the presence of EWS and FLI-1 sequences in these products. Furthermore, fusion transcripts were not detected by this technique in a series of non-pPNET pediatric solid tumors. Detection of EWS/FLI-1 fusion transcripts by RT-PCR therefore provides a novel adjunctive tool in the diagnosis of pPNETs.

Differential effects of NMDA and non-NMDA antagonists on the activity of aromatic L-amino acid decarboxylase activity in the nigrostriatal dopamine pathway of the rat.

This study examined the acute effects of a variety of NMDA and non-NMDA antagonists on the activity of aromatic l-amino acid decarboxylase (AADC) in the corpus striatum (CS) and substantia nigra (SN) of the rat. Sixty min pretreatment with the high affinity NMDA receptor-channel blockers MK 801 (0.01, 0.1 and 1 mg/kg) and phencyclidine (4 mg/kg) elevated AADC activity in both the CS and SN (2- to 3-fold). Even more striking increases in AADC were noted with 40 mg/kg amantadine (3.8-fold for CS, 9.0-fold for SN), 40 mg/kg memantine (3.4-fold for CS, 3.1-fold for SN; 20 mg/kg no effect) and 40 mg/kg dextromethorphan (3.4-fold for CS, 6.2-fold for SN, in 6/10 'responders'). Similarly pronounced increases in AADC activity in CS (1.9-fold) and SN (2.8-fold) were detected after administering clonidine (2 mg/kg). R-HA 966 (5 mg/kg, not 1 mg/kg) modestly raised AADC activity in CS (0.45-fold) and not SN. Other drugs had no effect on the activity of the decarboxylase enzyme, including CGP 40116 (1 and 5 mg/g), eliprodil (10 mg/kg), NBQX (10 mg/kg, 30 min pretreatment) and atropine (1 mg/kg). These experiments indicate that blocking the NMDA receptor-channel (and to a lesser extent the glycine site) or stimulating alpha2-adrenoceptors, profoundly increases AADC activity, more especially in the SN than CS. By contrast, inhibiting the NMDA glutamate recognition or polyamine sites, AMPA or muscarinic receptors is without effect on AADC in either brain region. The ability of amantadine and memantine to potentiate the antiparkinsonian actions of l-DOPA in the clinic, may be due to facilitated decarboxylation of l-DOPA by the brain.

N-methyl-d-aspartate receptors modulate extracellular dopamine concentration and metabolism in rat hippocampus and striatum in vivo.

The effects of infusing N-methyl-D-aspartate (NMDA), and the specific NMDA receptor antagonist D-2-amino-5-phosphono-propionic acid (D-AP5) into rat hippocampus and striatum on extracellular dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were studied using intracerebral microdialysis. In striatum NMDA increased DA extracellularly in a concentration-dependent manner. Against a 10 microM concentration of NMDA the increase in striatal DA was opposed by D-AP5 (10 microM in all experiments), which when infused alone significantly reduced DA concentration. Infusion of NMDA altered DOPAC level in a complex manner, with 10 microM concentration causing a significant increase 2 h after infusion, while 100 microM NMDA caused a transient decrease in the metabolite. None of treatments altered striatal dialysate HVA. In hippocampus NMDA infusion decreased dialysate DA in a concentration-dependent manner, and the decrease caused by 10 microM NMDA was reversed by D-AP5. When given alone the antagonist was without effect. NMDA infusion elevated hippocampal dialysate DOPAC and HVA, while HVA was decreased following D-AP5 infusion. These data indicate that DA release is regionally controlled by excitatory amino acids, but in differential manner.

The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study.

We report the effects of i.p. administration of sodium valproate (VPA) on extracellular concentrations of various amino acids in the rat ventral hippocampus studied using in vivo microdialysis, followed by HPLC with fluorometric detection. At the doses used (100, 200 and 400 mg/kg), VPA had no effect on extracellular aspartate, glutamine and taurine, whilst inducing a small, but not statistically significant increase in glutamate at 200 and 400 mg/kg. In contrast, VPA administration produced a biphasic effect on extracellular GABA levels which was dependent on the dose used. At 100 mg/kg, VPA reduced GABA concentrations by 50% when compared to basal. 200 mg/kg VPA had virtually no effect, whilst 400 mg/kg VPA raised extracellular GABA levels to 200% of basal. The results are discussed in relation to the known pharmacological and anticonvulsant actions of VPA.