An Analysis of Orientation and Preceptorship Influence on Nurse Job Satisfaction Across Two States.

A large public nursing data set was used to determine whether orientation and/or preceptor programs impact job satisfaction among registered nurses in Maine and Massachusetts. There was no association between orientation and preceptor programs and satisfaction, nor evidence that new nurse status modified the relationship. There is a need for evaluation of orientation and preceptor programs' structure and effectiveness, and innovation is needed in promoting job satisfaction, thereby increasing nurse retention.

Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Exploring the incidence of inadequate response to antidepressants in the primary care of depression.

Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness.

When a test is more than just a test: Findings from patient interviews and survey in the trial of a technology to measure antidepressant medication response (the PReDicT Trial).

BACKGROUND: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found. METHODS: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together. OUTCOMES: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment. INTERPRETATION: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients.

Characteristics of Maine and Massachusetts nurses interested in advanced nursing degrees.

BACKGROUND: Maine (ME) and Massachusetts (MA) nursing programs aim to develop collaborative training programs, but need to identify which nurses have interest in such programs. PURPOSE: We sought to determine sociodemographics of nurses seeking advanced nursing degrees nationally, and in ME and MA using the 2018 publicly available, National Sample Survey of Registered Nurses (NSSRN). METHODS: Weighted multivariable logistic regression for advanced degree-seeking, adjusted for sociodemographics. RESULTS: Of the n = 47,274 nurses (weighted n [Wn] = 3,608,633), 90.7 % were female, 74.1 % were white, and 15.8 % sought an advanced nursing degree on average 12.7 (SD 0.2) years after their first. Females vs. males had lower odds (OR 0.63, 95%CI [0.44-0.90]) and Black vs. White race had higher odds (OR 1.30, 95%CI [1.05-1.60]) of seeking doctorates. In Maine (Wn = 20,389), age 24-29 had higher odds (OR 2.98 (95%CI [1.06-3.74]), but in Massachusetts (Wn = 101,984), age 30+ had lower odds (OR 0.32, 95%CI [0.13-0.78]) of degree-seeking vs. <24 years. Initial nursing degrees earned between 1980 and 1989 had higher odds (OR 1.99, 95%CI [1.06-3.74]) in Maine, but between 2010 and 2014 had lower odds (OR 0.32, 95%CI [0.14-0.72]) in Massachusetts of degree-seeking, vs. before 1980. CONCLUSIONS: Targets for advanced nursing training programs may vary by state and sociodemographic profile.

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

The Effect of Simulation on Nursing Student Perceptions of Readiness to Provide End-of-Life Care.

Evidence suggests that nursing students in a prelicensure nursing program lack the required preparation to care for patients at the end of life (EOL), causing feelings of inadequacy and stress. New graduate nurses (years 0-5) struggle to address the needs of this patient population, leading to considering career changes. Nursing simulation has been shown to enhance competency and is gaining increasing favor in prelicensure nursing education. Little research has been conducted on the application of simulation using standardized patients in EOL patient scenarios. This study used live standardized patients who simulated a home health patient encounter with the nursing student acting as a home health hospice nurse. Watson's theory of caring and interpretive phenomenological analysis guided the qualitative research method and analysis. Five students chose to participate in this simulation and completed 6 reflective questions. After simulation, they felt more comfortable having difficult discussions about EOL care, treatment options, and patient fears. Participants noted the importance of communication in a team setting, which included the caregiver as an integral member. The use of standardized patient-simulated experiences increases realism and provides students the opportunity to bridge the gap between didactic education and clinical practice. This will enhance their readiness and confidence in providing EOL care.

Control of phosphatidylinositol-3-kinase signaling by nanoscale membrane compartmentalization.

Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that produce 3-phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3-phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K-derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts.

Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling.

The epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology. EGF binding to EGFR elicits the membrane recruitment and activation of phosphatidylinositol-3-kinase, leading to Akt phosphorylation and activation. Concomitantly, EGFR is recruited to clathrin-coated pits (CCPs), eventually leading to receptor endocytosis. Previous work uncovered that clathrin, but not receptor endocytosis, is required for EGF-stimulated Akt activation, and that some EGFR signals are enriched in CCPs. Here, we examine how CCPs control EGFR signaling. The signaling adaptor TOM1L1 and the Src-family kinase Fyn are enriched within a subset of CCPs with unique lifetimes and protein composition. Perturbation of TOM1L1 or Fyn impairs EGF-stimulated phosphorylation of Akt2 but not Akt1. EGF stimulation also triggered the TOM1L1- and Fyn-dependent recruitment of the phosphoinositide 5-phosphatase SHIP2 to CCPs. Thus, the recruitment of TOM1L1 and Fyn to a subset of CCPs underlies a role for these structures in the support of EGFR signaling leading to Akt activation.

The clinical effectiveness of using a predictive algorithm to guide antidepressant treatment in primary care (PReDicT): an open-label, randomised controlled trial.

Depressed patients often do not respond to the first antidepressant prescribed, resulting in sequential trials of different medications. Personalised medicine offers a means of reducing this delay; however, the clinical effectiveness of personalised approaches to antidepressant treatment has not previously been tested. We assessed the clinical effectiveness of using a predictive algorithm, based on behavioural tests of affective cognition and subjective symptoms, to guide antidepressant treatment. We conducted a multicentre, open-label, randomised controlled trial in 913 medication-free depressed patients. Patients were randomly assigned to have their antidepressant treatment guided by a predictive algorithm or treatment as usual (TaU). The primary outcome was the response of depression symptoms, defined as a 50% or greater reduction in baseline score of the QIDS-SR-16 scale, at week 8. Additional prespecified outcomes included symptoms of anxiety at week 8, and symptoms of depression and functional outcome at weeks 8, 24 and 48. The response rate of depressive symptoms at week 8 in the PReDicT (55.9%) and TaU (51.8%) arms did not differ significantly (odds ratio: 1.18 (95% CI: 0.89-1.56), P = 0.25). However, there was a significantly greater reduction of anxiety in week 8 and a greater improvement in functional outcome at week 24 in the PReDicT arm. Use of the PReDicT test did not increase the rate of response to antidepressant treatment estimated by depressive symptoms but did improve symptoms of anxiety at week 8 and functional outcome at week 24. Our findings indicate that personalisation of antidepressant treatment may improve outcomes in depressed patients.

Detection of Plasma Membrane Phosphoinositide Dynamics Using Genetically Encoded Fluorescent Protein Probes.

The dynamic phosphorylation of phosphatidylinositol produces seven distinct but interconvertible phosphatidylinositol phosphates (PIPs). Each PIP exhibits specific enrichment in a subset of membrane compartments as a result of dynamic phosphorylation and dephosphorylation by lipid kinases and phosphatases, and/or by vesicle-mediated transport. Several PIPs are found within the plasma membrane, such as phosphatidylinositol-4-phosphate [PI(4)P], phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2], and phosphatidylinositol-3,4,5-trisphosphate (PIP3), and these control many aspects of cell physiology, including receptor signaling and membrane traffic. As a result, measurement of the cell surface abundance of these PIPs is a valuable resource to allow understanding of the regulation and function of these cell surface lipids. Here, we describe methods based on quantification of the localization of genetically encoded fluorescent PIP probes to the cell surface by either spinning disc confocal microscopy or total internal reflection fluorescence microscopy that allow detection of changes in cell surface levels of PI(4,5)P2, PI(3,4)P2, and PIP3. These methods can also be applied to the measurement of other PIPs or lipid species at the cell surface, and thus represent a useful resource for the study of the cell biology of PIPs.

Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.

Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

Análise de redes sociais na atenção primária em saúde: revisão integrativa / Análisis de redes sociales en la atención primaria de salud: revisión integrativa / Social network analysis in primary health care: an integrative review

Resumo Objetivo: Redes sociais são entendidas como as relações que conectam pessoas, grupos ou instituições, e exercem influência no acesso aos serviços de saúde. A análise de redes sociais é um método quantitativo, usado em estudos sobre relações sociais de diversas áreas, incluindo a saúde, sendo de incorporação recente pela Saúde Coletiva e Enfermagem. O objetivo foi o de conhecer como vem sendo aplicada a metodologia de análise de redes sociais em estudos que têm como cenário a Atenção Primária à Saúde. Métodos: A metodologia foi a de revisão interativa de literatura, e cumpridas as suas etapas de definição de critério de busca, seleção de artigos e análise segundo as categorias definidas de distribuição temporal e geográfica, tipos de redes e atores selecionados e principais resultados. As categorias temáticas após a análise foram: A análise de redes sociais como estratégia de análise da rede de profissionais, e a análise de redes sociais como estratégia de análise da rede social de usuários. Resultados: Os resultados indicam que as publicações tendem a se concentrar nos últimos cinco anos, e a metodologia é mais utilizada em países de língua inglesa. Todos os estudos usaram outras abordagens metodológicas juntamente com a análise de redes sociais. Nas redes de profissionais, destacam-se as relações interinstitucionais e interpessoais, reafirmando a atenção primária à saúde como ordenadora da rede de cuidados. Com usuários, a análise de redes sociais destacou a relevância das redes primárias e das organizações de apoio. Conclusão: Conclui-se que a análise de redes sociais possui potencialidade para evidenciar estruturas e fluxos relacionais na Atenção Primária à Saúde, com interesse para estudos em saúde coletiva e enfermagem.

Resumen Objetivo: Se entiende por redes sociales a las relaciones que conectan personas, grupos o instituciones, y ejercen influencia en el acceso a servicios de salud. El análisis de redes sociales es un método cuantitativo, utilizado en estudios sobre relaciones sociales de diversas áreas, incluyendo la salud, habiéndose incorporado recientemente a la Salud Colectiva y a la Enfermería. Se objetivó conocer cómo se aplica la metodología de análisis de redes sociales en estudios cuyo ámbito es la Atención Primaria de Salud. Métodos: Se realizó revisión interactiva de literatura, y se cumplieron sus dos etapas de definición de criterios de búsqueda, selección de artículos y análisis según las características definidas de distribución temporal y geográfica, tipos de redes y actores seleccionados y principales resultados. Las categorías temáticas luego del análisis fueron: El análisis de redes sociales como estrategia de análisis de la red de profesionales, y El análisis de redes sociales como estrategia de la red social de usuarios. Resultados: Indican que las publicaciones tienden a concentrarse en los últimos cinco años, y que la metodología es más utilizada en países de habla inglesa. Todos los estudios aplicaron otros abordajes metodológicos conjuntamente con el análisis de redes sociales. En redes de profesionales se destacaron las relaciones interinstitucionales e interpersonales, reafirmando la atención primaria de salud como ordenadora de la red de cuidados. Con usuarios, el análisis de redes sociales destacó la relevancia de las redes primarias y las organizaciones de apoyo. Conclusión: El análisis de redes sociales tiene potencial para evidenciar estructuras y flujos relacionales en Atención Primaria de Salud, siendo de interés para estudios en salud colectiva y de enfermería.

Abstract Objective: Social networks are considered as the relationships that connect people, groups or institutions and influence the access to health services. Social Network Analysis is a quantitative method, used in social relationship studies in different areas, including health. It has recently been incorporated in Collective Health and Nursing. The objective was to know how the social network analysis method has been applied in studies undertaken in Primary Health Care. Methods: The integrative literature review method was used, including the following phases: definition of search criterion, selection of articles and analysis according to the defined temporal and geographical distribution categories, selected types of networks and actors and main outcomes. The thematic categories after the analysis were: Social Network Analysis as an analysis strategy of the professional network, and Social Network Analysis as an analysis strategy of users' social network. Results: The results indicate that the publications tend to concentrate in the past five years and that the method is more used in English-speaking countries. All studies used other methodological approaches together with Social Network Analysis. In the professional networks, the interinstitutional and interpersonal relationships stand out, reaffirming the ordering role of primary health care in the care network. With users, the social network analysis highlighted the relevance of the primary networks and support organizations. Conclusion: In conclusion, the social network analysis can evidence relational structures and flows in Primary Health Care, which are of interest for collective health and nursing studies.

The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial.

BACKGROUND: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. METHODS/DESIGN: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. DISCUSSION: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02790970 . Registered on 30 March 2016.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

The attentional set-shifting test paradigm in rats for the screening of novel pro-cognitive compounds with relevance for cognitive deficits in schizophrenia.

Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected preclinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional setshifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise.

The hippocampal physiology of approaching middle-age: early indicators of change.

Age-related cognitive decline presents serious lifestyle challenges, and anatomical changes to the hippocampus are often implicated in clinical conditions later in life. However, relatively little is known about how hippocampal physiology is altered in the transition to middle-age, when early detection may offer the best opportunity for successful treatment. High-yield extracellular recording is a powerful tool for understanding brain function in freely moving animals at single-cell resolution and with millisecond precision. We used this technique to characterize changes to hippocampal physiology associated with maturation in 35-week-old rats. Combining a series of behavioral tasks with recordings of large numbers of neurons, local field potentials (LFP), and network patterns of activation, we were able to generate a comprehensive picture based on more than 25 different assays for each subject. Notable changes associated with aging included increased firing rates in interneurons, reduced LFP power but increased frequency in the 4-12 Hz theta band, and impairment in hippocampal pattern-separation for different environments. General properties of pyramidal cell firing and spatial map integrity were preserved. There was no impairment in theta phase-precession, experience-dependent place field expansion, or sleep reactivation of waking network patterns. There were however changes in foraging strategy and behavioral responses to the introduction of a novel environment. Taken together the results reveal a diverse pattern of changes which are of increasing relevance in an aging population. They also highlight areas where high-yield electrophysiological assays can be used to provide the sensitivity and throughput required for pre-clinical drug-discovery programs.

Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.

Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model.

RATIONALE: Executive function impairment, as classically assessed using the Wisconsin Card Sort Test or intradimensional/extradimensional tests, is a key feature of schizophrenia but remains inadequately treated by existing therapies. Recently, however, erythropoietin has been shown to improve attentional set-shifting performance in schizophrenic patients. OBJECTIVE: The present study utilized the rat intradimensional/extradimensional task to investigate the potential of erythropoietin to reverse a phencyclidine-induced extradimensional shift impairment when given alone or in combination with subchronic haloperidol treatment. METHODS: Rats were subjected to a subchronic systemic administration (7 days, b.i.d) of either saline vehicle or phencyclidine (5 mg/kg) followed by a 7-day washout period during which haloperidol was given. Subsequently, rats were trained to dig in baited bowls for a food reward and to discriminate on the basis of digging media or bowl odor. In experiment 1, rats performed a series of discriminations following acute administration of vehicle, erythropoietin, or modafinil. In a second experiment, rats receiving either haloperidol in the drinking water or just normal drinking water were run in the attentional set-shifting task after acute administration of erythropoietin (1,000 or 10,000 IU/ml i.p., selected from experiment 1). RESULTS: The subchronic phencyclidine-induced extradimensional deficit was ameliorated by both erythropoietin and modafinil. When combined with subchronic haloperidol, the higher dose of erythropoietin tested was able to reverse the extradimensional shift impairment. CONCLUSIONS: Overall, these findings further support the use of erythropoietin as an adjunct to antipsychotic therapy in order to address, at least part of, the cognitive dysfunction associated with schizophrenia.