Patients' experiences with coercive mental health treatment in Flexible Assertive Community Treatment: a qualitative study.

BACKGROUND: Flexible Assertive Community Treatment (FACT) teams have been implemented in Norwegian health and social services over the last years, partly aiming to reduce coercive mental health treatment. We need knowledge about how service users experience coercion within the FACT context. The aim of this paper is to explore service user experiences of coercive mental health treatment in the context of FACT and other treatment contexts they have experienced. Are experiences of coercion different in FACT than in other treatment contexts? If this is the case, which elements of FACT lead to a different experience? METHOD: Within a participatory approach, 24 qualitative interviews with service users in five different FACT teams were analyzed with thematic analysis. RESULTS: Participants described negative experiences with formal and informal coercion. Three patterns of experiences with coercion in FACT were identified: FACT as clearly a change for the better, making the best of FACT, and finding that coercion is just as bad in FACT as it was before. Safety, improved quality of treatment, and increased participation were described as mechanisms that can prevent coercion. CONCLUSION: Results from this study support the argument that coercion is at odds with human rights and therefore should be avoided as far as possible. Results suggest that elements of the FACT model may prevent the use of coercion by promoting safety, improved quality of treatment and increased participation.

Service User Experiences of How Flexible Assertive Community Treatment May Support or Inhibit Citizenship: A Qualitative Study.

The aim of this study was to explore and describe service user experiences of how receiving services from a Flexible Assertive Community Treatment (FACT) team may support or inhibit citizenship. Within a participatory design, individual interviews with 32 service users from five Norwegian FACT teams were analyzed using thematic, cross-sectional analysis. The findings showed that FACT may support citizenship by relating to service users as whole people, facilitating empowerment and involvement, and providing practical and accessible help. Experiences of coercion, limited involvement and authoritarian aspects of the system surrounding FACT had inhibited citizenship for participants in this study.

Dilemmas in recovery-oriented practice to support people with co-occurring mental health and substance use disorders: a qualitative study of staff experiences in Norway.

BACKGROUND: Recovery-oriented practice is recommended in services for people with co-occurring mental health and substance use disorders. Understanding practitioners' perceptions of recovery-oriented services may be a key component of implementing recovery principles in day-to-day practice. This study explores and describes staff experiences with dilemmas in recovery-oriented practice to support people with co-occurring disorders. METHODS: Three focus group interviews were carried out over the course of 2 years with practitioners in a Norwegian community mental health and addictions team that was committed to developing recovery-oriented services. Thematic analysis was applied to yield descriptions of staff experiences with dilemmas in recovery-oriented practice. RESULTS: Three dilemmas were described: (1) balancing mastery and helplessness, (2) balancing directiveness and a non-judgmental attitude, and (3) balancing total abstinence and the acceptance of substance use. CONCLUSIONS: Innovative approaches to practice development that address the inherent dilemmas in recovery-oriented practice to support people with co-occurring disorders are called for.

Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy.

Perinatal hypoxic-ischemic brain injury is a major health problem. Adjuvant treatments that improve the neuroprotective effect of the current treatment, therapeutic hypothermia, are urgently needed. The growing knowledge about the complex pathophysiology of hypoxia-ischemia (HI) has led to the discovery of several important targets for neuroprotection. Early interventions should focus on the preservation of energy metabolism, the reduction of glutamate excitotoxicity and oxidative stress, the maintenance of calcium homeostasis, and the prevention of apoptosis. Delayed interventions should promote injury repair. The multiple metabolic changes following HI as well as the metabolic effects of potential treatments can be observed noninvasively by magnetic resonance spectroscopy (MRS). This mini-review provides an overview of the neuroprotective pharmacological agents that have been evaluated with 1H/31P/13C MRS. A better understanding of how these agents influence cerebral metabolism and the use of relevant translational MRS biomarkers can guide future clinical trials.

Glucose and Intermediary Metabolism and Astrocyte-Neuron Interactions Following Neonatal Hypoxia-Ischemia in Rat.

Neonatal hypoxia-ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI.

Anaplerosis for Glutamate Synthesis in the Neonate and in Adulthood.

A central task of the tricarboxylic acid (TCA, Krebs, citric acid) cycle in brain is to provide precursors for biosynthesis of glutamate, GABA, aspartate and glutamine. Three of these amino acids are the partners in the intricate interaction between astrocytes and neurons and form the so-called glutamine-glutamate (GABA) cycle. The ketoacids α-ketoglutarate and oxaloacetate are removed from the cycle for this process. When something is removed from the TCA cycle it must be replaced to permit the continued function of this essential pathway, a process termed anaplerosis. This anaplerotic process in the brain is mainly carried out by pyruvate carboxylation performed by pyruvate carboxylase. The present book chapter gives an introduction and overview into this carboxylation and additionally anaplerosis mediated by propionyl-CoA carboxylase under physiological conditions in the adult and in the developing rodent brain. Furthermore, examples are given about pathological conditions in which anaplerosis is disturbed.

Glucose metabolism and astrocyte-neuron interactions in the neonatal brain.

Glucose is essentially the sole fuel for the adult brain and the mapping of its metabolism has been extensive in the adult but not in the neonatal brain, which is believed to rely mainly on ketone bodies for energy supply. However, glucose is absolutely indispensable for normal development and recent studies have shed light on glycolysis, the pentose phosphate pathway and metabolic interactions between astrocytes and neurons in the 7-day-old rat brain. Appropriately (13)C labeled glucose was used to distinguish between glycolysis and the pentose phosphate pathway during development. Experiments using (13)C labeled acetate provided insight into the GABA-glutamate-glutamine cycle between astrocytes and neurons. It could be shown that in the neonatal brain the part of this cycle that transfers glutamine from astrocytes to neurons is operating efficiently while, in contrast, little glutamate is shuttled from neurons to astrocytes. This lack of glutamate for glutamine synthesis is compensated for by anaplerosis via increased pyruvate carboxylation relative to that in the adult brain. Furthermore, compared to adults, relatively more glucose is prioritized to the pentose phosphate pathway than glycolysis and pyruvate dehydrogenase activity. The reported developmental differences in glucose metabolism and neurotransmitter synthesis may determine the ability of the brain at various ages to resist excitotoxic insults such as hypoxia-ischemia.

Altered astrocyte-neuronal interactions after hypoxia-ischemia in the neonatal brain in female and male rats.

BACKGROUND AND PURPOSE: Increased susceptibility to excitotoxicity of the neonatal brain after hypoxia-ischemia (HI) may be caused by limited capacity of astrocytes for glutamate uptake, and mitochondrial failure probably plays a key role in the delayed injury cascade. Male infants have poorer outcome than females after HI, possibly linked to differential intermediary metabolism. METHODS: [1-(13)C]glucose and [1,2-(13)C]acetate were injected at zero, 6, and 48 hours after unilateral HI in 7-day-old rats. Intermediary metabolism was analyzed with magnetic resonance spectroscopy. RESULTS: Mitochondrial metabolism was generally reduced in the ipsilateral hemisphere for ≤6 hours after HI, whereas contralaterally, it was reduced in neurons but not in astrocytes. Transfer of glutamate from neurons to astrocytes was increased in the contralateral, but not in the ipsilateral hemisphere at 0 hour, and reduced bilaterally at 6 hours after HI. The transfer of glutamine from astrocytes to glutamatergic neurons was unaltered in both hemispheres, whereas the transfer of glutamine to GABAergic neurons was increased ipsilaterally at 0 hour. Anaplerosis (astrocytes) was decreased, whereas partial pyruvate recycling (astrocytes) was increased directly after HI. Male pups had lower astrocytic mitochondrial metabolism than females immediately after HI, whereas that of females was reduced longer and encompassed both neurons and astrocytes. CONCLUSIONS: The prolonged depression in mitochondrial metabolism indicates that mitochondria are vulnerable targets in the delayed injury after neonatal HI. The degree of astrocytic malfunction may be a valid indicator of outcome after hypoxic/HI brain injury and may be linked to the differential outcome in males and females.

The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury.

The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-(13)C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using (1)H- and (13)C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress.

Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.

Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.

Quantitative importance of the pentose phosphate pathway determined by incorporation of 13C from [2-13C]- and [3-13C]glucose into TCA cycle intermediates and neurotransmitter amino acids in functionally intact neurons.

The brain is highly susceptible to oxidative injury, and the pentose phosphate pathway (PPP) has been shown to be affected by pathological conditions, such as Alzheimer's disease and traumatic brain injury. While this pathway has been investigated in the intact brain and in astrocytes, little is known about the PPP in neurons. The activity of the PPP was quantified in cultured cerebral cortical and cerebellar neurons after incubation in the presence of [2-(13)C]glucose or [3-(13)C]glucose. The activity of the PPP was several fold lower than glycolysis in both types of neurons. While metabolism of (13)C-labeled glucose via the PPP does not appear to contribute to the production of releasable lactate, it contributes to labeling of tricarboxylic acid (TCA) cycle intermediates and related amino acids. Based on glutamate isotopomers, it was calculated that PPP activity accounts for ~6% of glucose metabolism in cortical neurons and ~4% in cerebellar neurons. This is the first demonstration that pyruvate generated from glucose via the PPP contributes to the synthesis of acetyl CoA for oxidation in the TCA cycle. Moreover, the fact that (13)C labeling from glucose is incorporated into glutamate proves that both the oxidative and the nonoxidative stages of the PPP are active in neurons.

Direct measurement of backflux between oxaloacetate and fumarate following pyruvate carboxylation.

Pyruvate carboxylation (PC) is thought to be the major anaplerotic reaction for the tricarboxylic acid cycle and is necessary for de novo synthesis of amino acid neurotransmitters. In the brain, the main enzyme involved is pyruvate carboxylase, which is predominantly located in astrocytes. Carboxylation leads to the formation of oxaloacetate, which condenses with acetyl coenzyme A to form citrate. However, oxaloacetate may also be converted to malate and fumarate before being regenerated. This pathway is termed the oxaloacetate-fumarate-flux or backflux. Carbon isotope-based methods for quantification of activity of PC lead to underestimation when backflux is not taken into account and critical errors have been made in the interpretation of results from metabolic studies. This study was conducted to establish the degree of backflux after PC in cerebellar and neocortical astrocytes. Astrocyte cultures from cerebellum or neocortex were incubated with either [3-(13) C] or [2-(13) C]glucose, and extracts were analyzed using mass spectrometry or nuclear magnetic resonance spectroscopy. Substantial PC compared with pyruvate dehydrogenase activity was observed, and extensive backflux was demonstrated in both types of astrocytes. The extent of backflux varied between the metabolites, reaffirming that metabolism is highly compartmentalized. By applying our calculations to published data, we demonstrate the existence of backflux in vivo in cat, rat, mouse, and human brain. Thus, backflux should be taken into account when calculating the magnitude of PC to allow for a more precise evaluation of cerebral metabolism.