Experiences of transition to adulthood and transfer to adult care in young adults with type 1 diabetes: A qualitative study.

AIM: To explore young adults' experiences of living with type 1 diabetes in the transition to adulthood, including experiences of the transfer from paediatric to adult care. DESIGN: A qualitative approach was used. METHOD: Ten young adults, six women and four men, aged 19-29 years, participated. Participants were recruited at their regular diabetes clinic from spring 2021 to spring 2022. Semi-structured interviews were transcribed and analysed using qualitative content analysis. FINDINGS: Dreaming of being nurtured towards self-reliance was the overarching theme. Personal experiences of the transition to adulthood, including the transfer from paediatric to adult care, were described in terms of struggling to find balance in daily life, dealing with feelings of being different, being gradually supported to achieve independence, and wishing to be approached as a unique person in healthcare. CONCLUSION: In healthcare, it is important to emphasize not only diabetes-related factors but also emotional and psychosocial aspects of life connected to the transition to adulthood, including the transfer to adult care. The young adults wished to be seen as unique persons in healthcare during their emerging adulthood and should therefore be supported to achieve self-reliance through personal preparations for new challenges and for the consequences of transitioning to adulthood. Specialist nurses can provide appropriate knowledge and leadership. IMPLICATIONS FOR THE PROFESSION: These findings can guide nurse specialists in support for emerging adults to achieve self-reliance and indicate the importance of person-centred care when experiencing transition and transfer. REPORTING METHOD: The study adhered to EQUATOR guidelines, and the COREQ checklist for qualitative studies was used as the reporting method.

Are bicycle streets cyclist-friendly? Micro-environmental factors for improving perceived safety when cycling in mixed traffic.

A bicycle street is a mixed traffic street where motor vehicles are forced to adapt their speed to bicycle traffic, for example by encouraging cycling in the middle of the street using centered bicycle lanes. The objective safety of cyclists increases with lower vehicle speeds and fewer motor vehicles. Despite this, cyclists' perception of their safety is often reduced in mixed traffic streets. Subjective unsafety and risk constitute a major barrier to increased cycling. This study investigates how the design of the micro-environment of bicycle streets can improve cyclists' perceived safety in mixed traffic. A quasi-experimental survey in which 371 participants rated their perceived safety in photo-manipulated bicycle streets was conducted. 52% of the participants were male, the mean age was 43 (20-77) years, and 76% reported that they cycle 4-5 days a week or more. The focus was on evaluating micro-environmental factors such as different designs of centered bicycle lanes, road markings, signs, traffic volume, and parked cars. It is concluded that the micro-environment has important effects on the perceived safety of cyclists. Important gains in subjective safety can be achieved with fairly simple design efforts. Many participants felt safe when there were clearly demarcated red-colored bicycle lanes in the center of the street accompanied by road markings for cyclists. The strongest effect, however, comes from reducing traffic volume. Most participants felt safe in micro-environments in which the traffic volume had been reduced, including those where no design changes had been made. Important differences between different groups of cyclists were also found.

Poorer mental well-being and prior unmet need for mental healthcare: a longitudinal population-based study on men in Sweden.

BACKGROUND: Depression and anxiety disorder contribute to a significant part of the disease burden among men, yet many men refrain from seeking care or receive insufficient care when they do seek it. This is plausibly associated with poorer mental well-being, but there is a lack of population-based research. This study investigated 1) if men who had refrained from seeking mental healthcare at any time in life had poorer mental well-being than those who sought care, 2) if those who had sought care but perceived it as insufficient had poorer mental well-being than those who had perceived care as sufficient, and 3) if these differences persisted after 1 year. METHODS: This longitudinal study used questionnaire data from a population-based sample of 1240 men, aged 19-64 years, in Sweden. Having refrained from seeking mental healthcare, or perceiving the care as insufficient, at any time in life, was assessed in a questionnaire, 2008. Current mental well-being was assessed in 2008 and 2009 using mean scores on the WHO (Ten) Well-being Index. Lower scores indicate poorer mental well-being. Group differences were calculated using t-tests and multivariable linear regression analysis. RESULTS: Of the men who had perceived a need for mental healthcare, 37% had refrained from seeking such care. They had lower mental well-being scores in 2008, compared to those who sought care. Of those seeking care, 29% had perceived it as insufficient. They had lower mental well-being scores in 2008, compared to those who perceived the care as sufficient, but this was not statistically significant when controlling for potential confounders. There were no differences in mental well-being scores based on care-seeking or perceived care-sufficiency in 2009. CONCLUSIONS: This population-based study indicates that men who have previously refrained from seeking mental healthcare, or perceived the care as insufficient, have poorer mental well-being. However, the lack of differences at the one-year follow-up contradicts these results. The results highlight the need for larger longitudinal studies, measuring care-seeking within a more specified time frame. This should be combined with efforts to increase men's mental healthcare-seeking and to provide mental healthcare that is perceived as sufficient.

Unmet Need for Mental Healthcare in a Population Sample in Sweden: A Cross-Sectional Study of Inequalities Based on Gender, Education, and Country of Birth.

This cross-sectional study investigated if gender, education, and country of birth were associated with perceived need and unmet need for mental healthcare (i.e., refraining from seeking care, or perceiving care as insufficient when seeking it). Questionnaire and register data from 2008 were collected for 3987 individuals, aged 19-64 years, in a random population-based sample from western Sweden. Descriptive statistics and logistic regression analyses were used. Men were less likely to perceive a need for care than were women, even after adjusting for mental well-being. Men were also less likely to seek care and perceiving care as sufficient. People with secondary education were less likely to seek care than those with university education. There were no statistically significant differences based on country of birth. The observed gender and education-based inequalities increases our understanding of where interventions can be implemented. These inequalities in unmet need for mental healthcare should be targeted by the healthcare system.

Demographic factors in the choice of coronal restoration after root canal treatment in the Swedish adult population.

BACKGROUND: After root canal treatment, a choice is made between different coronal restorations which in the long run could affect the survival of the tooth. OBJECTIVE: To compare demographic characteristics between individuals choosing an indirect coronal restoration (crown, inlay/onlay) and individuals choosing other restorations after completion of a root filling. METHODS: The cohort consisted of all root-filled upper first molars that were reported to the tax-funded Swedish Social Insurance Agency (SSIA) during 2009. After registration of the root filling, any subsequent coronal restorations within 2 years were identified. The crown group consisted of individuals registered with an indirect coronal restoration and the restoration group was the remaining individuals with a direct coronal restoration or lacking registration. Demographic data (gender, disposable income, age, educational level, civil status and country of birth) were received from Statistics Sweden or the SSIA. Statistical analyses included chi-square test, t test and logistic regression analysis. P < 0.05 was considered statistically significant. RESULTS: An indirect coronal restoration was received by 7806 individuals (21.9%), and 27 886 individuals (78.1%) received a direct restoration. All demographic variables except gender differed significantly between groups. Logistic regression analysis found significant associations for all demographic variables and the registration of an indirect restoration except for country of birth and gender. CONCLUSIONS: The identified demographic differences between individuals choosing to restore their newly root-filled teeth with an indirect restoration compared to those receiving other restorations may indicate that the tax-funded Swedish dental insurance fails to provide dental care on equal terms for Swedish citizens.

Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons.

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4-6 after administration. Pretreatment with d-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain.

A system for remote dosimetry audit of 3D-CRT, IMRT and VMAT based on lithium formate dosimetry.

The aim of this work was to develop and test a remote end-to-end audit system using lithium formate EPR dosimeters. Four clinics were included in a pilot study, absorbed doses determined in the PTV agreed with TPS calculated doses within ±5% for 3D-CRT and ±7% (k=1) for IMRT/VMAT dose plans.

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment--role of brain kynurenic acid.

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with L-kynurenine (2×200 mg/kg/day) at P7-16. In mice neonatally treated with L-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally L-kynurenine treated mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, D-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.

Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder.

OBJECTIVES: Kynurenic acid (KYNA), an end metabolite of tryptophan degradation, antagonizes glutamatergic and cholinergic receptors in the brain. Recently, we reported elevated levels of cerebrospinal fluid (CSF) KYNA in male patients with bipolar disorder. Here, we investigate the relationship between symptomatology and the concentration of CSF KYNA in patients with bipolar I disorder. METHODS: CSF KYNA levels from euthymic male {n = 21; mean age: 41 years [standard deviation (SD) = 14]} and female [n = 34; mean age: 37 years (SD = 14)] patients diagnosed with bipolar I disorder were analyzed using high-performance liquid chromatography (HPLC). RESULTS: Euthymic bipolar I disorder patients with a lifetime occurrence of psychotic features had higher CSF levels of KYNA {2.0 nm [standard error of the mean (SEM) = 0.2]; n = 43} compared to patients without any history of psychotic features [1.3 nm (SEM = 0.2); n = 12] (p = 0.01). Logistic regression, with age as covariate, similarly showed an association between a history of psychotic features and CSF KYNA levels [n = 55; odds ratio (OR) = 4.9, p = 0.03]. Further, having had a recent manic episode (within the previous year) was also associated with CSF KYNA adjusted for age (n = 34; OR = 4.4, p = 0.03), and the association remained significant when adjusting for a lifetime history of psychotic features (OR = 4.1, p = 0.05). CONCLUSIONS: Although the causality needs to be determined, the ability of KYNA to influence dopamine transmission and behavior, along with previous reports showing increased brain levels of the compound in patients with schizophrenia and bipolar disorder, may indicate a possible pathophysiological role of KYNA in the development of manic or psychotic symptoms.

Investigation of signal fading in lithium formate EPR dosimeters using a new sensitive method.

The aim of this study was to investigate signal fading in lithium formate electron paramagnetic resonance (EPR) dosimeters used for clinical applications in radiotherapy. A new experimental method for determination of signal fading, designed to resolve small changes in signal from slowly decaying unstable radicals, was used. Possible signal fading in lithium formate due to different storage temperatures was also tested. Air humidity was kept at a constant level of 33% throughout the experiments. The conclusion drawn from the investigations was that the EPR signal from lithium formate is stable during at least 1 month after irradiation and is not sensitive to variations in storage temperature <40 °C when kept at a relative air humidity of 33%. This makes lithium formate a suitable dosimeter for transfer dosimetry in clinical audits.

Determination of absorbed dose to water around a clinical HDR (192)Ir source using LiF:Mg,Ti TLDs demonstrates an LET dependence of detector response.

PURPOSE: Experimental radiation dosimetry with thermoluminescent dosimeters (TLDs), calibrated in a (60)Co or megavoltage (MV) photon beam, is recommended by AAPM TG-43U1for verification of Monte Carlo calculated absorbed doses around brachytherapy sources. However, it has been shown by Carlsson Tedgren et al. [Med. Phys. 38, 5539-5550 (2011)] that for TLDs of LiF:Mg,Ti, detector response was 4% higher in a (137)Cs beam than in a (60)Co one. The aim of this work was to investigate if similar over-response exists when measuring absorbed dose to water around (192)Ir sources, using LiF:Mg,Ti dosimeters calibrated in a 6 MV photon beam. METHODS: LiF dosimeters were calibrated to measure absorbed dose to water in a 6 MV photon beam and used to measure absorbed dose to water at distances of 3, 5, and 7 cm from a clinical high dose rate (HDR) (192)Ir source in a polymethylmethacrylate (PMMA) phantom. Measured values were compared to values of absorbed dose to water calculated using a treatment planning system (TPS) including corrections for the difference in energy absorption properties between calibration quality and the quality in the users' (192)Ir beam and for the use of a PMMA phantom instead of the water phantom underlying dose calculations in the TPS. RESULTS: Measured absorbed doses to water around the (192)Ir source were overestimated by 5% compared to those calculated by the TPS. Corresponding absorbed doses to water measured in a previous work with lithium formate electron paramagnetic resonance (EPR) dosimeters by Antonovic et al. [Med. Phys. 36, 2236-2247 (2009)], using the same irradiation setup and calibration procedure as in this work, were 2% lower than those calculated by the TPS. The results obtained in the measurements in this work and those obtained using the EPR lithium formate dosimeters were, within the expanded (k = 2) uncertainty, in agreement with the values derived by the TPS. The discrepancy between the results using LiF:Mg,Ti TLDs and the EPR lithium formate dosimeters was, however, statistically significant and in agreement with the difference in relative detector responses found for the two detector systems by Carlsson Tedgren et al. [Med. Phys. 38, 5539-5550 (2011)] and by Adolfsson et al. [Med. Phys. 37, 4946-4959 (2010)]. CONCLUSIONS: When calibrated in (60)Co or MV photon beams, correction for the linear energy transfer (LET) dependence of LiF:Mg,Ti detector response will be needed as to measure absorbed doses to water in a (192)Ir beam with highest accuracy. Such corrections will depend on the manufacturing process (MTS-N Poland or Harshaw TLD-100) and details of the annealing and read-out schemes used.

Subchronic elevation of brain kynurenic acid augments amphetamine-induced locomotor response in mice.

The neuromodulating tryptophan metabolite kynurenic acid (KYNA) is increased in the brain of patients with schizophrenia. In the present study we investigate the spontaneous locomotor activity as well as the locomotor response to d-amphetamine [5 mg/kg, administered intraperitoneal (i.p.)] after increasing endogenous levels of brain KYNA in mice by acute (10 mg/kg, i.p., 60 min) or subchronic (100 mg/kg i.p., twice daily for 6 days) pretreatment with the blood-brain crossing precursor, L: -kynurenine. We found that an acute increase in the brain KYNA levels caused increased corner time and percent peripheral activity but did not change the d-amphetamine-induced locomotor response. In contrast, subchronic elevation of KYNA did not change the spontaneous locomotor activity but produced an exaggerated d-amphetamine-induced hyperlocomotion. These results cohere with clinical studies of patients with schizophrenia, where a potentiated DA release associated with exacerbation of positive symptoms has been observed following d-amphetamine administration. Present results further underscore KYNA as a possible mediator of the aberrant dopaminergic neurotransmission seen in schizophrenia.

Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia.

BACKGROUND: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and α7* nicotinic receptors. METHODS: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n = 16) was compared with healthy male volunteers (n = 29). RESULTS: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 ± 4.37 nM and 2.03 ± 0.23 nM, respectively) compared with healthy volunteers (28.6 ± 1.44 nM and 1.36 ± 0.08 nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. CONCLUSION: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.

Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder.

BACKGROUND: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. METHODS: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. RESULTS: The mean interleukin (IL)-1ß level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1ß (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). LIMITATIONS: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. CONCLUSION: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1ß in bipolar disorder.

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.

BACKGROUND: Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. METHODS: We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. RESULTS: Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. LIMITATIONS: The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. CONCLUSION: Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.

Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders.

The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic alpha(7) acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.

Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia.

Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.

Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis.

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the alpha7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague-Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the alpha7* nicotinic receptor methyllycaconitine (MLA; 1-4mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.

EPR dosimetric properties of 2-methylalanine: EPR, ENDOR and FT-EPR investigations.

To find an EPR dosimeter material that is sensitive enough for clinical use, the substance 2-methylalanine (2MA) with the chemical structure (CH(3))(2)C(NH(3)(+))COO(-) was tested for its sensitivity to ionizing radiation, dose response, and radical stability over time. At equal and moderate settings of microwave power and modulation amplitude, 2MA was found to be 70% more sensitive than L-alpha-alanine, which is the most common EPR dosimeter material today. The dose response is linear, at least in the dose range of interest (0.5-00 Gy), and the time-dependent variations in signal intensity are very small and may be corrected for easily. The energy dependence of the stopping power and energy absorption was calculated and was found to be similar to that of alanine. The dependence of the signal intensity on microwave power and modulation amplitude was investigated, and the optimal settings were found to be 25 mW (Bruker ER 4102ST) and 12 gauss, respectively. Single crystals of 2MA were analyzed using ENDOR and ENDOR-induced EPR to identify the radiation-induced radicals that formed. Only one radical, in which the amino group is detached from the original molecule, was identified. This radical is obviously dominating and is apparently the only one relevant for dosimetry purposes. The complete set of coupling parameters for three hyperfine couplings is reported. The power saturation properties and spectral line width are ruled by the relaxation times T(1) and T(2). To determine the relaxation times of 2MA, pulsed EPR experiments were performed on single crystals. Two different values of T(1) were obtained, one in the range 1-3 micros, shown to be of importance for the dosimetry properties, and another that is strongly anisotropic with a value between 10 and 35 micros that does not seem to affect the saturation behavior. T(2) was estimated to be of the order of 200-300 ns.