Miracle-dz/UniFAR-FTUs huggingface dataset:
Tonic autoinhibition contributes to the heterogeneity of evoked dopamine release in the rat striatum

Electrically evoked dopamine release as measured by voltammetry in the rat striatum is heterogeneous in both amplitude and temporal profile. Previous studies have attributed this heterogeneity to variations in the density of dopamine (DA) terminals at the recording site. We reach the alternate conclusion that the heterogeneity of evoked DA release derives from variations in the extent to which DA terminals are autoinhibited. We demonstrate that low‐amplitude, slow evoked DA responses occur even though recording electrodes are close to DA terminals. Moreover, the D2 agonist and antagonist, quinpirole and raclopride, respectively, affect the slow responses in a manner consistent with the known functions of pre‐synaptic D2 autoreceptors. Recording sites that exhibit autoinhibited responses are prevalent in the dorsal striatum. Autoinhibition preceded electrical stimulation, which is consistent with our prior reports that the striatum contains a tonic pool of extracellular DA at basal concentrations that exceed the affinity of D2 receptors. We conclude that the striatum contains DA terminals operating on multiple time courses, determined at least in part by the local variation in autoinhibition. Thus, we provide direct, real‐time observations of the functional consequence of tonic and phasic DAergic signaling in vivo.
A prospective clinico-hematological study in 100 cases of pancytopenia in capital city of India

Context: Pancytopenia is not a disease but a clinico-hematological entity encountered in clinical practice. A prompt intervention is required to avoid complications, which can occur in these patients. The relevant clinical history and complete hematological workup is required to treat patient of pancytopenia. The severity of pancytopenia and the underlying pathology determines the management and prognosis. Aims: To diagnose different conditions producing pancytopenia on the basis of clinical, hematological and bone marrow studies. To estimate the frequency of different diseases producing pancytopenia. Subjects and Methods: The study was conducted in Department of Hematology of our college in capital city of India. A prospective study was carried out among 100 consecutive patients with pancytopenia. Blood samples of the patients were analyzed for red cells, white cells and platelets morphology along with presence and absence of immature cells and abnormal cells. In bone marrow examination, morphology of all cells lineage, cellularity, parasite and abnormal cells were scrutinized. Trephine biopsy was done where ever indicated. Results: The age of patients ranged from 5 to 80 years. 74% of patients in this study were vegetarian. The most common cause of pancytopenia was megaloblastic anemia (66%) followed by aplastic anemia (18%), malaria (6%), kala-azar (4%), acute myeloid leukemia (2%), multiple myeloma (2%), myelodysplastic syndrome (1%), and tuberculosis (1%). Conclusions: The present study concludes that detailed primary hematological investigations along with bone marrow examination in cytopenic patients is helpful for understanding disease process, to diagnose or to rule out the causes of pancytopenia. It is also useful in planning further investigations and management.
Survey of ethics education in Australian university schools and departments of psychology

In 2000 the Ethics Committee of the APS conducted a survey of ethics education and training in all Australian University Psychology Academic Organisational Units (AOUs). Content analysis of course syllabi received directly from AOUs and/or obtained from accreditation documentation lodged by them with the APS as part of the 5-year APS course accreditation cycle showed that ethics education appeared in less that one quarter of syllabi for years 1–3 and approximately 90% of syllabi for years 4 and 5–7, with a clear emphasis on the integrative approach in years 1–3 and roughly equal emphasis on integration within or separation from the core curriculum in years 4 and 5–7, and with roughly equal emphasis on philosophical and code-based instruction in years 1–3, but mainly the latter instruction in years 4 and 5–7. Research ethics constituted the predominant theme in years 1–3; a comprehensive listing of professional topics was covered in years 4 and 5–7, with few thematic differences between these year levels.
Interleukin‐10 provides direct trophic support to neurons

Interleukin (IL)‐10, a prototypical anti‐inflammatory cytokine, has been shown to provide beneficial effects in neuronal injury in vivo but the full range of actions has not been established. In order to understand the neuronal mechanisms underlying IL‐10‐mediated neuroprotection, we examined the effect of IL‐10 on primary neurons in culture. We found that IL‐10 exerted a direct trophic influence on spinal cord neurons, and that activation of the neuronal IL‐10 receptor provided trophic support and survival cues to overcome the neurotoxic effects of glutamate in vitro. IL‐10 treatment resulted in activation of janus‐associated kinases/signal transducers and transcription factors and phosphatidylinositol 3‐kinase‐AKT pathways in neurons to enhance expression of Bcl‐2 and Bcl‐xL; under stress conditions IL‐10 blocks cytochrome c release and caspase cleavage. IL‐10 activation of the canonical nuclear factor κB pathway enhanced translocation of p50 and p65 and enhanced their binding to κB DNA sequences, with p50 playing a more prominent role in neuronal survival. These data indicate that in addition to known anti‐inflammatory effects through astroglia in other inflammatory cells, IL‐10 has direct neuronal effects with important implications for development and neuroprotection.
Intertester Reliability of the Talk Test in a Cardiac Rehabilitation Population

PURPOSE: The validity of the Talk Test (TT) is well documented, but the reliability of the test is not clear. The aim of this study was to assess the absolute and relative intertester reliability of the TT in cardiac patients. METHODS: Cardiac patients (n = 64) who had completed an exercise rehabilitation program were consecutively included in the study. Patients performed a submaximal ramp cycle ergometer test with the TT as intensity indicator. Every patient was tested twice on the same day by 2 different physiotherapists with a break of maximum 45 minutes between tests. Physiotherapists were randomized to tests. Workload in watts at the first negative stage of the TT was registered as the test result. Patients and physiotherapists were blinded to test results of the first test. Absolute reliability of the TT was assessed with Bland-Altman plot, standard error of measurement, and minimal detectable change. Relative reliability was assessed using the intraclass correlation coefficient (ICC). RESULTS: Mean difference in peak workload between test and retest was 0.8 W (95% CI: −4.8 to 3.3). Limit of agreement was estimated to be +31/−32 W. Standard error of measurement was 11 W (95% CI: 10-14), and minimal detectable change was 32 W. The ICC was 0.85 (95% CI: 0.78 to 0.91). CONCLUSIONS: Although the ICC was acceptable, we found a weak absolute intertester reliability of the TT and that the test is an insufficient measure to monitor exercise intensity and safety of cardiac patients when 2 or more physiotherapists may be administering the TT.
Physicomechanical properties of sintered scaffolds formed from porous and protein-loaded poly(DL-lactic-co-glycolic acid) microspheres for potential use in bone tissue engineering

An injectable poly(DL-lactic-co-glycolic acid) (PLGA) system comprising both porous and protein-loaded microspheres capable of forming porous scaffolds at body temperature was developed for tissue regeneration purposes. Porous and non-porous (lysozyme loaded) PLGA microspheres were formulated to represent ‘low molecular weight’ 22–34 kDa, ‘intermediate molecular weight’ (IMW) 53 kDa and ‘high molecular weight’ 84–109 kDa PLGA microspheres. The respective average size of the microspheres was directly related to the polymer molecular weight. An initial burst release of lysozyme was observed from both microspheres and scaffolds on day 1. In the case of the lysozyme-loaded microspheres, this burst release was inversely related to the polymer molecular weight. Similarly, scaffolds loaded with 1 mg lysozyme/g of scaffold exhibited an inverse release relationship with polymer molecular weight. The burst release was highest amongst IMW scaffolds loaded with 2 and 3 mg/g. Sustained lysozyme release was observed after day 1 over 50 days (microspheres) and 30 days (scaffolds). The compressive strengths of the scaffolds were found to be inversely proportional to PLGA molecular weight at each lysozyme loading. Surface analysis indicated that some of the loaded lysozyme was distributed on the surfaces of the microspheres and thus responsible for the burst release observed. Overall the data demonstrates the potential of the scaffolds for use in tissue regeneration.
Structure‐based discovery of low molecular weight compounds that stimulate neurite outgrowth and substitute for nerve growth factor

Olanzapine, an atypical antipsychotic drug, was previously shown to protect neuronal cells against nutrient deprivation and to enhance neurite outgrowth. In an effort to identify small molecules with greater potency, the structure of olanzapine was used as a template to search commercially available chemical inventories for compounds with similar features. These compounds were evaluated for their ability to protect cells against glutamine deprivation and low‐serum conditions. Positive compounds, ‘hits’ from initial screening, were then tested for stimulation of neurite outgrowth, alone and in combination with suboptimum concentrations of nerve growth factor (NGF). Numerous neuroprotective compounds (mw < 550 Da) were identified that significantly stimulated neurite outgrowth in PC12 cells. These included 4′, 6′‐diamidino‐2‐phenylindole, a nuclear stain; staurosporine, an antibiotic and kinase inhibitor; and 2‐phenylamino‐adenosine, an adenosine analog. The small molecules were comparable with NGF, and in fact, replaced NGF in outgrowth assays. Pharmacophore analysis of the hits led to the design and synthesis of an active compound, LSU‐D84, which represented an initial lead for drug discovery efforts.
Greater Improvement in Cardiorespiratory Fitness Using Higher-Intensity Interval Training in the Standard Cardiac Rehabilitation Setting

PURPOSE: We tested the hypothesis that higher-intensity interval training (HIIT) could be deployed into a standard cardiac rehabilitation (CR) setting and would result in a greater increase in cardiorespiratory fitness (ie, peak oxygen uptake, ) versus moderate-intensity continuous training (MCT). METHODS: Thirty-nine patients participating in a standard phase 2 CR program were randomized to HIIT or MCT; 15 patients and 13 patients in the HIIT and MCT groups, respectively, completed CR and baseline and followup cardiopulmonary exercise testing. RESULTS: No patients in either study group experienced an event that required hospitalization during or within 3 hours after exercise. The changes in resting heart rate and blood pressure at followup testing were similar for both HIIT and MCT. at ventilatory-derived anaerobic threshold increased more (P < .05) with HIIT (3.0 ± 2.8 mL·kg·−1min−1) versus MCT (0.7 ± 2.2 mL·kg·−1min−1). During followup testing, submaximal heart rate at the end of stage 2 of the exercise test was significantly lower within both the HIIT and MCT groups, with no difference noted between groups. Peak V˙o2 improved more after CR in patients in HIIT versus MCT (3.6 ± 3.1 mL·kg.−1·min−1 vs 1.7 ± 1.7 mL·kg.−1·min−1; P < .05). CONCLUSIONS: Among patients with stable coronary heart disease on evidence-based therapy, HIIT was successfully integrated into a standard CR setting and, when compared to MCT, resulted in greater improvement in peak exercise capacity and submaximal endurance.
Acquisition of and withdrawal from cocaine self‐administration regulates 5‐HT1B mRNA expression in rat striatum

This study investigated how different stages of cocaine self‐administration in rats affect the expression of two serotonin receptors in dorsal and ventral striatum, the 5‐HT1B and 5‐HT6 subtypes, which have both been implicated in mediating some aspects of cocaine‐related behaviors. In the first experiment, rats were trained to work for saccharin (oral) or cocaine (i.v.) reinforcers. We found that continuous access to cocaine for 23 days did not change the level of 5‐HT1B mRNA expression compared to control animals receiving saccharin. However, a single cocaine session, given either by self‐administration or non‐contingently, increased 5‐HT1B mRNA in dorsal striatum, whereas forced abstinence for two weeks after cocaine reduced 5‐HT1B mRNA expression in the same subregion. 5‐HT6 mRNA was not changed by any of these treatments. A follow‐up experiment investigated the effects of limited versus extended access to cocaine as well as forced abstinence, and we found that 14 days of forced abstinence significantly reduced 5‐HT1B mRNA throughout the dorsal and ventral striatum compared to no withdrawal. These results suggest that the influence of 5‐HT1B receptors in striatal projection neurons may be increased during cocaine acquisition and reduced after forced abstinence and may therefore be targets for pharmacological intervention in addiction.
Calcineurin dephosphorylates glycogen synthase kinase‐3 beta at serine‐9 in neuroblast‐derived cells

This study examined the role of calcineurin, a major calcium‐dependent protein phosphatase, in dephosphorylating Ser‐9 and activating glycogen synthase kinase‐3β (GSK‐3β). Treatment with calcineurin inhibitors increased phosphorylation of GSK‐3β at Ser‐9 in SH‐SY5Y human neuroblastoma cells. The over‐expression of a constitutively active calcineurin mutant, calcineurin A beta (1–401), led to a significant decrease in phosphorylation at Ser‐9, an increase in the activity of GSK‐3β, and an increase in the phosphorylation of tau. Km of calcineurin for a GSK‐3β phosphopeptide was 469.3 μM, and specific activity of calcineurin was 15.2 nmol/min/mg. In addition, calcineurin and GSK‐3β were co‐immunoprecipitated in neuron‐derived cells and brain tissues, and calcineurin formed a complex only with dephosphorylated GSK‐3β. We conclude that in vitro, calcineurin can dephosphorylate GSK‐3β at Ser‐9 and form a stable complex with GSK‐3β, suggesting the possibility that calcineurin regulates the dephosphorylation and activation of GSK‐3βin vivo.
Interaction of α‐conotoxin ImII and its analogs with nicotinic receptors and acetylcholine‐binding proteins: additional binding sites on Torpedo receptor

α‐Conotoxins interact with nicotinic acetylcholine receptors (nAChRs) and acetylcholine‐binding proteins (AChBPs) at the sites for agonists/competitive antagonists. α‐Conotoxins blocking muscle‐type or α7 nAChRs compete with α‐bungarotoxin. However, α‐conotoxin ImII, a close homolog of the α7 nAChR‐targeting α‐conotoxin ImI, blocked α7 and muscle nAChRs without displacing α‐bungarotoxin ( Ellison et al. 2003, 2004 ), suggesting binding at a different site. We synthesized α‐conotoxin ImII, its ribbon isomer (ImIIiso), ‘mutant’ ImII(W10Y) and found similar potencies in blocking human α7 and muscle nAChRs in Xenopus oocytes. Both isomers displaced [125I]‐α‐bungarotoxin from human α7 nAChRs in the cell line GH4C1 (IC50 17 and 23 μM, respectively) and from Lymnaea stagnalis and Aplysia californica AChBPs (IC50 2.0–9.0 μM). According to SPR measurements, both isomers bound to immobilized AChBPs and competed with AChBP for immobilized α‐bungarotoxin (Kd and IC50 2.5–8.2 μM). On Torpedo nAChR, α‐conotoxin [125I]‐ImII(W10Y) revealed specific binding (Kd 1.5–6.1 μM) and could be displaced by α‐conotoxin ImII, ImIIiso and ImII(W10Y) with IC50 2.7, 2.2 and 3.1 μM, respectively. As α‐cobratoxin and α‐conotoxin ImI displaced [125I]‐ImII(W10Y) only at higher concentrations (IC50≥ 90 μM), our results indicate that α‐conotoxin ImII and its congeners have an additional binding site on Torpedo nAChR distinct from the site for agonists/competitive antagonists.
Identification of novel spartin‐interactors shows spartin is a multifunctional protein

Hereditary spastic paraplegia describes a group of neurodegenerative diseases characterized by lower limb progressive weakness and spasticity. Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia caused by a frameshift mutation (1110delA) in the SPG20 gene encoding spartin protein, the cellular function of which remains unknown. Knowledge about spartin‐interactors is also very limited. In this study, we apply a broad spectrum of proteomics techniques to identify novel spartin‐binding proteins. We used a Tandem Affinity Purification technique followed by HPLC‐mass spectrometry to characterize potential spartin‐binding partners. Selected putative interactions were confirmed by co‐immunoprecipitation experiments. We identified 94 potential spartin‐binding proteins which were grouped into functional categories. We performed co‐immunoprecipitation experiments to confirm that spartin interacts with GRP78, GRP75 and nucleolin proteins. Additionally, our mass spectrometry results confirmed previously published information about spartin interaction with ubiquitin and the E3 ubiquitin‐protein ligases, AIP4/Itch and AIP5/WWP1. Our studies suggest that spartin is a multifunctional protein and for the first time we suggest a role for spartin in protein folding and turnover both in mitochondria and endoplasmic reticulum. We also show for the first time interaction between spartin and a nucleolar protein, nucleolin.
Mental Health Crisis/Respite Service: A Process Evaluation

This article describes a process evaluation of a mental health Crisis/Respite service in Ontario, Canada. Service users, referring organizations, and staff members were interviewed and surveyed about their experiences with the service. All three stakeholder groups identified the service as much needed, identifying its role as an alternative to more intrusive forms of crisis support, as a transition place, a safe place, and a place to take a break and work toward goals. As with any program, there are challenges in its development, some of which, the authors argue, are representative of the interaction of two very different approaches to providing mental health services that currently influence our mental health systems.
Effects of Neuromuscular Electrical Stimulation on Physiologic and Functional Measurements in Patients With Heart Failure: A SYSTEMATIC REVIEW WITH META-ANALYSIS

BACKGROUND: Neuromuscular electrical stimulation (NMES) is potentially attractive as a method of training in heart failure (HF) and could be performed in patients unable to participate in standard exercise training. PURPOSE: To examine the effects of NMES on physiologic and functional measurements in patients with HF. METHODS: MEDLINE, Cochrane, EMBASE, Scielo, and PEDro were searched from the earliest date available to July 2014. Two independent reviewers screened the titles and abstracts and selected randomized controlled trials, examining the effects of NMES versus exercise and/or of NMES versus control on physiologic and functional measurements in patients with HF. Two independent reviewers screened the randomized controlled trials. The PEDro score was used to evaluate methodological quality. Weighted mean differences and 95% CI were calculated. RESULTS: Thirteen studies met the study criteria. Neuromuscular electrical stimulation resulted in improvement in peak oxygen uptake ( O2) (4.86 mL·kg−1 ·min−1; 95% CI, 2.81-6.91), 6-minute walk test (6MWT) distance (63.54 m; 95% CI, 35.81-91.27), muscle strength (30.74 N; 95% CI, 3.67-57.81), flow-mediated dilatation (2.67%; 95% CI, 0.86-4.49), depressive symptoms (−3.86; 95% CI, −6.46 to −1.25), and global quality of life (0.89; 95% CI, 0.55-1.24). Nonsignificant differences in ( O2) peak, 6MWT, and quality of life were found for participants in the exercise group compared with NMES. CONCLUSIONS: Neuromuscular electrical stimulation improved peak O2, 6MWT distance, quality of life, muscle strength, endothelial function, and depressive symptoms in patients with HF and could be considered for inclusion in cardiac rehabilitation for selected patients.
Parathyroid hormone 2 receptor is a functional marker of nociceptive myelinated fibers responsible for neuropathic pain

We have previously demonstrated that parathyroid hormone 2 (PTH2) receptors are expressed in dorsal root ganglion (DRG) neurons and that its endogenous agonist tuberoinfundibular peptide of 39 residues (TIP39) causes nociceptive paw flexor responses after intraplantar administration. Here we found that the PTH2 receptor is selectively localized on myelinated A‐, but not unmyelinated C‐fibers using immunohistochemical labeling, based on PTH2 receptor expression on antibody N52‐positive medium/large‐sized DRG neurons, but not on TRPV1, substance P, P2X3 receptor or isolectin B4‐binding protein‐positive small‐sized DRG neurons. Pharmacological studies showed that TIP39‐induced nociceptive responses were mediated by activation of Gs and cAMP‐dependent protein kinase. We also found that nociceptive responses induced by TIP39‐ or the cAMP analog 8‐bromo‐cAMP were significantly greater following partial sciatic nerve injury induced neuropathic pain, without changes in PTH2 receptor expression. Together these data suggest that activation of PTH2 receptors stimulates nociceptive A‐fiber through Gs‐cAMP‐dependent protein kinase signaling, and this pathway has elevated sensitization following nerve injury.
Acessibilidade ao diagnóstico de tuberculose em município do Nordeste do Brasil: desafio da atenção básica

A cross-sectional study with the aim to analyze the performance of healthcare services with respect to diagnosing tuberculosis. We interviewed 101 users with tuberculosis, residents of a municipality in the Northeast region of Brazil. Bivariate analysis and the chi-squared test were applied for data treatment. We found a p<0.05 statistical significance between the first health service sought by user and the locale of diagnosis. Primary Health Care services (PHC) were chosen as the entryway by 46.5% of users. However, the Tuberculosis Control Program was responsible for 54.4% of diagnosed cases. Regarding time of diagnosis, 83.2% patients were diagnosed in a period of time equal to or less than 30 days. PHC services are still not efficient enough for guaranteeing access to the disease’s diagnosis, and it is the Reference Outpatient Clinic’s responsibility to offer actions for detecting and treating cases. doi: 10.5216/ree.v16i3. 23491.