Ketamine's mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine's antidepressant effects?

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.

Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.

Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits. Our findings revealed potential roles of mitophagy and Mitochondrial antiviral-signaling protein (MAVS) in mediating chronic stress-induced changes in cf-mtDNA levels and social behavior. Furthermore, we showed that inhibition of Toll-like receptor 9 (TLR9) attenuates mtDNA-induced social behavior deficits. Together, these findings show that cf-mtDNA-TLR9 signaling is critical in mediating stress-induced social behavior deficits.

Chronic basal forebrain activation improves spatial memory, boosts neurotrophin receptor expression, and lowers BACE1 and Aß42 levels in the cerebral cortex in mice.

The etiology of Alzheimer's dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer's model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2-3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aß42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aß42 generation and accumulation. The observation that basal forebrain activation suppresses Aß42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aß42, documents bidirectional antagonism between acetylcholine and Aß42.

Sorption behavior studies of Cs and its migration in soil samples around Visakhapatnam, India.

Meeting the requirement of high specific activity of radioisotopes and carrying out comprehensive research and development activities in the nuclear field, different nuclear facilities, including their waste disposal facilities, are going to be operational at Visakhapatnam, India. Due to environmental processes, the engineered disposal modules may lose their structural integrity and may release some radioactivity to the geo-environment. The subsequent migration of radionuclides reaching the geological environment will be governed by the distribution coefficient (Kd). Cs was chosen for the sorption study in two soil samples (soil-29 and 31) and to estimate the Kd in all the 40 soil samples through the laboratory batch method at the new campus of DAE, Visakhapatnam, India. Different soil chemical parameters like pH, organic matter, CaCO3, and cation exchange capacity were determined in 40 soil samples and their effect on Cs sorption was investigated. The effect of solution pH and initial concentration of Cs on sorption was also studied. The results show that the sorption of Cs increases with increasing pH. The Cs sorption was well explained by Freundlich and Dubinin-Radushkevich (D-R) isotherm models. Site-specific distribution coefficients (Kd) were also estimated and the values were found to vary from 75 ± 1 to 540 ± 12 L kg-1. The observed wide variation in Kd could be due to large variations in the physico-chemical properties of collected soil. The competitive ions effect study suggests that K+ has higher interference for Cs+ sorption as compared to Na+. The present study results will help assess the environmental impact due to Cs release in any unforeseen scenario and in planning effective remediation strategies.

A crosstalk between gut and brain in sepsis-induced cognitive decline.

BACKGROUND: Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota-gut-brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors. METHODS: To test our hypothesis, adult Wistar rats were subjected to cecal-ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory. RESULTS: Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group. CONCLUSIONS: Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.

Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNß levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNß-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels.

AIM: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. METHOD: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. RESULTS: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. DISCUSSION: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.

Neogenin in Amygdala for Neuronal Activity and Information Processing.

Fear learning and memory are vital for livings to survive, dysfunctions in which have been implicated in various neuropsychiatric disorders. Appropriate neuronal activation in amygdala is critical for fear memory. However, the underlying regulatory mechanisms are not well understood. Here we report that Neogenin, a DCC (deleted in colorectal cancer) family receptor, which plays important roles in axon navigation and adult neurogenesis, is enriched in excitatory neurons in BLA (Basolateral amygdala). Fear memory is impaired in male Neogenin mutant mice. The number of cFos+ neurons in response to tone-cued fear training was reduced in mutant mice, indicating aberrant neuronal activation in the absence of Neogenin. Electrophysiological studies show that Neogenin mutation reduced the cortical afferent input to BLA pyramidal neurons and compromised both induction and maintenance of Long-Term Potentiation evoked by stimulating cortical afferent, suggesting a role of Neogenin in synaptic plasticity. Concomitantly, there was a reduction in spine density and in frequency of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents, suggesting a role of Neogenin in forming excitatory synapses. Finally, ablating Neogenin in the BLA in adult male mice impaired fear memory likely by reducing mEPSC frequency in BLA excitatory neurons. These results reveal an unrecognized function of Neogenin in amygdala for information processing by promoting and maintaining neurotransmission and synaptic plasticity and provide insight into molecular mechanisms of neuronal activation in amygdala.SIGNIFICANCE STATEMENT Appropriate neuronal activation in amygdala is critical for information processing. However, the underlying regulatory mechanisms are not well understood. Neogenin is known to regulate axon navigation and adult neurogenesis. Here we show that it is critical for neurotransmission and synaptic plasticity in the amygdala and thus fear memory by using a combination of genetic, electrophysiological, behavioral techniques. Our studies identify a novel function of Neogenin and provide insight into molecular mechanisms of neuronal activation in amygdala for fear processing.

Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior.

Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1ß in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1ß in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.

A Pilot, Randomized Clinical Trial of Bedtime Doses of Prazosin Versus Placebo in Suicidal Posttraumatic Stress Disorder Patients With Nightmares.

PURPOSE/BACKGROUND: Observational studies show an association between nightmares and suicide. Prazosin is proposed as a nightmare treatment. This pilot, randomized clinical trial tested whether treatment of nightmares with prazosin would reduce suicidal ideas in suicidal posttraumatic stress disorder (PTSD) patients. METHODS/PROCEDURES: Twenty adult, suicidal PTSD patients with nightmares were blindly and randomly assigned 1:1 to escalating doses of prazosin versus placebo at bedtime only for 8 weeks. All participants had comorbid mood disorders and received stable doses of mood disorder medication. Outcomes of interest were measured weekly and included severity of suicidal ideation, nightmares, PTSD, insomnia, and depression. Longitudinal mixed-effects models assessed change in outcomes over time. FINDINGS/RESULTS: All psychometric measures improved over 8 weeks. However, nighttime measures of nightmares and insomnia showed significantly less improvement in the prazosin group, whereas there was no significant change in daytime measures of suicidal ideation and daytime-only PTSD symptoms. Two patients required emergency psychiatric hospitalization, but there were no suicide attempts and no deaths. IMPLICATIONS/CONCLUSIONS: This study confirmed an effect of nighttime-only prazosin on nighttime symptoms of insomnia and nightmares in suicidal PTSD patients who are experiencing nightmares. Surprisingly, the effect was in the direction opposite of what we expected. Furthermore, prazosin showed no signal on daytime measures including suicidal ideation. The results do not support a larger study of nighttime-only prazosin in suicidal PTSD patients but leave open the possibility of benefit from daytime administration of prazosin.

Transglutaminase 2 Induces Deficits in Social Behavior in Mice.

Impairments in social behavior are highly implicated in many neuropsychiatric disorders. Recent studies indicate a role for endoplasmic reticulum (ER) stress in altering social behavior, but the underlying mechanism is not known. In the present study, we examined the role of transglutaminase 2 (TG2), a calcium-dependent enzyme known to be induced following ER stress, in social behavior in mice. ER stress induced by tunicamycin administration increased TG2 protein levels in the mouse prefrontal cortex (PFC). PFC-specific inhibition of TG2 attenuated ER stress-induced deficits in social behavior. Conversely, overexpression of TG2 in the PFC resulted in social behavior impairments in mice. In addition, systemic administration of cysteamine, a TG2 inhibitor, attenuated social behavior deficits. Our preliminary findings using postmortem human brain samples found increases in TG2 mRNA and protein levels in the middle frontal gyrus of subjects with autism spectrum disorder. These findings in mice and human postmortem brain samples identify changes in TG2 activity in the possible dysregulation of social behavior.

Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders.

Estrogens, the primary female sex hormones, were originally characterized through their important role in sexual maturation and reproduction. However, recent studies have shown that estrogens play critical roles in a number of brain functions, including cognition, learning and memory, neurodevelopment, and adult neuroplasticity. A number of studies from both clinical as well as preclinical research suggest a protective role of estrogen in neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. Alterations in the levels of estrogen receptors have been found in subjects with ASD or schizophrenia, and adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia. This review summarizes the findings on the role of estrogen in the pathophysiology of neurodevelopmental disorders with a focus on ASD and schizophrenia. We also discuss the potential of estrogen as a therapeutic target in the above disorders.

Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B.

Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.

TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis.

BACKGROUND: Neuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. NMDARs also promote many cellular events such as proliferation and survival of neuroblasts before synapse formation. Although many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied. RESULTS: NRG1 induces activation of NMDAR subunit NR2B, and tropomyosin-related kinase receptor B (TrkB), the receptor for BDNF via activation of phospholipase C-gamma (PLC-γ) in immature primary cortical neurons. Our data using TrkB inhibitor (K252a), TrkB siRNA and TrkB-/- neurons demonstrated that TrkB inhibition suppresses NRG1-induced NR2B activation in neurons. We found that NRG1 stimulation leads to GABAA receptor-mediated TrkB activation. Co-immunoprecipitation and proximity ligase assay showed that TrkB interacts with ErbB4 (NRG1 receptor) and the TrkB-ErbB4 interaction was increased following NRG1 treatment. A significant reduction in TrkB-ErbB4 interaction was observed in the prefrontal cortex of schizophrenia subjects. We found significant increase in released BDNF levels following NRG1 treatment, which was inhibited by ErbB4 inhibitor, AG1478. In addition, pretreatment with BDNF neutralizing antibody, but not control IgG abolished NRG1-induced increases in phospho-TrkB and phospho-NR2B levels. Moreover, studies using TrkB mutants showed that intercellular domain of TrkB is necessary for TrkB-ErbB4 interaction and NR2B activation. CONCLUSIONS: BDNF/TrkB signaling plays an important role in the NRG1-stimulated NR2B regulation. These findings could be of relevance to many neurodevelopmental disorders, as NRG1 and BDNF signaling pathways have been implicated in autism and schizophrenia.

Glucocorticoid regulates parkin expression in mouse frontal cortex: implications in schizophrenia.

Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of various psychiatric illnesses including schizophrenia and depression. Studies in rodents have reported dose and time dependent effects of glucocorticoids on the expression of proteins related to neuroplasticity. However, the mechanism(s) involved in the regulation of proteins by glucocorticoids are not clear. Ubiquitin ligases play important role in degradation, trafficking and stabilization of proteins. The present study investigated the effect of glucocorticoid on ubiquitin-proteasome system in mouse frontal cortex. A significant increase in mRNA and protein levels of parkin, an E3 ubiquitin ligase was found in cultured mouse primary cortical neurons following corticosterone treatment. An increase in parkin levels was also found in mouse frontal cortex in vivo following acute dexamethasone treatment. However, chronic treatment with corticosterone did not change parkin protein levels in mouse frontal cortex. Studies using postmortem brain samples from schizophrenia and control subjects indicated a significant increase in parkin protein levels in frontal cortex of schizophrenia subjects suggesting a response to increased stress conditions in schizophrenia. These findings suggest a possible role of parkin in the pathophysiology of stress-related psychiatric disorders.

The antipsychotic effects of ECT: a review of possible mechanisms.

OBJECTIVES: Electroconvulsive therapy (ECT) exhibits demonstrable effectiveness for psychotic symptoms associated with a broad range of neuropsychiatric conditions. However, the mechanism remains poorly understood particularly with regard to antipsychotic effects. METHODS: We examined studies of ECT in schizophrenia and mood disorders, as well as from animal models of psychotic disorders, and compared the results to those of antipsychotic medications. This review focuses on 3 potential domains of exploration of ECT's antipsychotic effects: dopamine and serotonin neurotransmitter activity, neurotrophic effects, and immune system modulation. RESULTS: Preliminary results support a putative role for all three of these domains but are limited by a lack of replicated findings, including negative studies. CONCLUSIONS: A comparison of the neurophysiologic and molecular properties of antipsychotic drugs and ECT reveals some overlap, but there are also distinctive differences; and the significance of these findings remains uncertain.

α7 nicotinic acetylcholine receptors are necessary for basal forebrain activation to increase expression of the nerve growth factor receptor TrkA.

Activation of the basal forebrain leads to increases in the expression of the nerve growth factor receptor, Tropomyosin receptor kinase A (TrkA) and decreases in expression of the beta amyloid cleavage enzyme 1 (BACE1) in the cerebral cortex of both sexes of 5xFAD mice. The studies described in this report were designed to determine if these changes were dependent on acetylcholine receptors. Mice were stimulated unilaterally in the basal forebrain for two weeks. Animals were administered a cholinergic antagonist, or saline, 30 minutes prior to stimulation. Animals administered saline exhibited significant increases in TrkA expression and decreases in BACE1 in the stimulated hemisphere relative to the unstimulated. While both nonselective nicotinic and muscarinic acetylcholine receptor blockade attenuated the BACE1 decline, only the nicotinic receptor antagonism blocked the TrkA increase. Next, we applied selective nicotinic antagonists, and the α7 antagonist blocked the TrkA increases, but the α4ß2 antagonist did not. BACE1 declines were not blocked by either intervention. Mice with a loxP conditional knockout of the gene for the α7 nicotinic receptor were also employed in these studies. Animals were either stimulated bilaterally for two weeks, or left unstimulated. With or without stimulation, the expression of TrkA receptors was lower in the cortical region with the α7 nicotinic receptor knockdown. We thus conclude that α7 nicotinic receptor activation is necessary for normal expression of TrkA and increases caused by basal forebrain activation, while BACE1 declines caused by stimulation have dependency on a broader array of receptor subtypes.

Greater physician involvement improves coding outcomes in endobronchial ultrasound-guided transbronchial needle aspiration procedures.

BACKGROUND: Correct coding is essential for accurate reimbursement for clinical activity. Published data confirm that significant aberrations in coding occur, leading to considerable financial inaccuracies especially in interventional procedures such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Previous data reported a 15% coding error for EBUS-TBNA in a U.K. service. OBJECTIVES: We hypothesised that greater physician involvement with coders would reduce EBUS-TBNA coding errors and financial disparity. METHODS: The study was done as a prospective cohort study in the tertiary EBUS-TBNA service in Bristol. 165 consecutive patients between October 2009 and March 2012 underwent EBUS-TBNA for evaluation of unexplained mediastinal adenopathy on computed tomography. The chief coder was prospectively electronically informed of all procedures and cross-checked on a prospective database and by Trust Informatics. Cost and coding analysis was performed using the 2010-2011 tariffs. RESULTS: All 165 procedures (100%) were coded correctly as verified by Trust Informatics. This compares favourably with the 14.4% coding inaccuracy rate for EBUS-TBNA in a previous U.K. prospective cohort study [odds ratio 201.1 (1.1-357.5), p = 0.006]. Projected income loss was GBP 40,000 per year in the previous study, compared to a GBP 492,195 income here with no coding-attributable loss in revenue. CONCLUSIONS: Greater physician engagement with coders prevents coding errors and financial losses which can be significant especially in interventional specialties. The intervention can be as cheap, quick and simple as a prospective email to the coding team with cross-checks by Trust Informatics and against a procedural database. We suggest that all specialties should engage more with their coders using such a simple intervention to prevent revenue losses.

Pimavanserin treatment increases plasma brain-derived neurotrophic factor levels in rats.

Background: Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play a key role in neuroplasticity and neurogenesis. The present study tested the hypothesis that treatment with Pimavanserin is associated with higher and sustained elevations of mBDNF. Methods: Adult Sprague-Dawley male rats were treated with Pimavanserin, Fluoxetine or vehicle for 4 weeks (chronic) or 2 h (acute). BDNF levels were determined by enzyme-linked Immunosorbent assay (ELISA). Results: We found significant increases in plasma mBDNF levels in rats following chronic Pimavanserin treatment, but not in Fluoxetine-treated rats. No significant changes in mBDNF levels were found in the prefrontal cortex or hippocampus following Pimavanserin or Fluoxetine treatment. Conclusion: These findings suggest that increase in mBDNF levels could be a contributing mechanism for the neuroprotective potential of Pimavanserin.

Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice.

Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine.