Antidepressant-like drug effects in juvenile and adolescent mice in the tail suspension test: relationship with hippocampal serotonin and norepinephrine transporter expression and function

Nathan C. Mitchell, Georgianna G. Gould, Corey M. Smolik, Wouter Koek and Lynette C. Daw

Competitive and uncompetitive N -methyl- d -aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine

The purpose of the present studies was to examine representative uncompetitive and competitive NMDA antagonists, as well as the glycine/NMDA antagonist, HA 966, in pigeons trained to discriminate either PCP or CGS 19755 from saline. Separate groups of pigeons were trained to discriminate either the uncompetitive, phencyclidine (PCP; 0.32 and 1.0 mg/kg, IM), or the competitive, CGS 19755 ( cis -4-phosphonomethyl-2-piperidine-carboxylic acid; 1.8 mg/kg, IM), NMDA antagonists from saline. Uncompetitive and competitive NMDA antagonists were examined in generalization studies, as were the racemate and the (+) and (−) stereoisomers of HA 966 (3-amino-1-hydroxypyrrolid-2-one). Dizocilpine (MK 801) was fully generalized to PCP but not to CGS 19755. All competitive NMDA antagonists tested were fully generalized to CGS 19755, but not to PCP. The competitive antagonists, however, produced >50% PCP-appropriate responding. The (+) isomer of HA 966 was fully generalized by three of four pigeons discriminating PCP (1.0 mg/kg) or CGS 19755, whereas the racemate and the (−) isomer produced 10% drug-appropriate responding in either discrimination group. The competitive antagonists tended to produce peak drug-appropriate responding at times greater than 60 min after administration, whereas uncompetitive antagonists produced peak drug-appropriate responding at earlier times. HA 966 also had a relatively slow onset of action as compared to PCP. These results suggest that antagonists acting at different modulatory sites of the NMDA receptor complex produce similar, but not identical, discriminative stimuli.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46346/1/213_2005_Article_BF02245248.pd

COVID-19 Related Mobility Reduction: Heterogenous Effects on Sleep and Physical Activity Rhythms

Mobility restrictions imposed to suppress coronavirus transmission can alter physical activity (PA) and sleep patterns. Characterization of response heterogeneity and their underlying reasons may assist in tailoring customized interventions. We obtained wearable data covering baseline, incremental movement restriction and lockdown periods from 1824 city-dwelling, working adults aged 21 to 40 years, incorporating 206,381 nights of sleep and 334,038 days of PA. Four distinct rest activity rhythms (RARs) were identified using k-means clustering of participants' temporally distributed step counts. Hierarchical clustering of the proportion of time spent in each of these RAR revealed 4 groups who expressed different mixtures of RAR profiles before and during the lockdown. Substantial but asymmetric delays in bedtime and waketime resulted in a 24 min increase in weekday sleep duration with no loss in sleep efficiency. Resting heart rate declined 2 bpm. PA dropped an average of 38%. 4 groups with different compositions of RAR profiles were found. Three were better able to maintain PA and weekday/weekend differentiation during lockdown. The least active group comprising 51 percent of the sample, were younger and predominantly singles. Habitually less active already, this group showed the greatest reduction in PA during lockdown with little weekday/weekend differences. Among different mobility restrictions, removal of habitual social cues by lockdown had the largest effect on PA and sleep. Sleep and resting heart rate unexpectedly improved. RAR evaluation uncovered heterogeneity of responses to lockdown and can identify characteristics of persons at risk of decline in health and wellbeing.Comment: 30 pages, 3 main figures, 3 tables, 4 supplementary figure

A comparative study of software programmes for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed tomography scans of rectal cancer patients

__Background:__ The association between body composition (e.g. sarcopenia or visceral obesity) and treatment outcomes, such as survival, using single-slice computed tomography (CT)-based measurements has recently been studied in various patient groups. These studies have been conducted with different software programmes, each with their specific characteristics, of which the inter-observer, intra-observer, and inter-software correlation are unknown. Therefore, a comparative study was performed. __Methods:__ Fifty abdominal CT scans were randomly selected from 50 different patients and independently assessed by two observers. Cross-sectional muscle area (CSMA, i.e. rectus abdominis, oblique and transverse abdominal muscles, paraspinal muscles, and the psoas muscle), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) were segmented by using standard Hounsfield unit ranges and computed for regions of interest. The inter-software, intra-observer, and inter-observer agreement for CSMA, VAT, and SAT measurements using FatSeg, OsiriX, ImageJ, and sliceOmatic were calculated using intra-class correlation coefficients (ICCs) and Bland-Altman analyses. Cohen's κ was calculated for the agreement of sarcopenia and visceral obesity assessment. The Jaccard similarity coefficient was used to compare the similarity and diversity of measurements. __Results:__ Bland-Altman analyses and ICC indicated that the CSMA, VAT, and SAT measurements between the different software programmes were highly comparable (ICC 0.979-1.000, P<0.001). All programmes adequately distinguished between the presence or absence of sarcopenia (κ=0.88-0.96 for one observer and all κ=1.00 for all comparisons of the other observer) and visceral obesity (all κ=1.00). Furthermore, excellent intra-observer (ICC 0.999-1.000, P<0.001) and inter-observer (ICC 0.998-0.999, P< 0.001) agreement for all software programmes were found. Accordingly, excellent Jaccard similarity coefficients were found for all comparisons (mean≥0.964). __Conclusions:__ FatSeg, OsiriX, ImageJ, and sliceOmatic showed an excellent agreement for CSMA, VAT, and SAT measurements on abdominal CT scans. Furthermore, excellent inter-observer and intra-observer agreement were achieved. Therefore, results of studies using these different software programmes can reliably be compared

A simple and rapid method for assessing similarities among directly observable behavioral effects of drugs: PCP-like effects of 2-amino-5-phosphonovalerate in rats

Directly observable behavioral effects of the N-methyl- D -aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (AP5) (10–1,000 mg/kg IP, 0.18–5.6 μmol/rat ICV) and of phencyclidine (PCP) (3.2–56 mg/kg IP, 0.032–3.2 mg/rat ICV), ketamine (10–100 mg/kg), amphetamine (1–18 mg/kg), apomorphine (0.1–5.6 mg/kg), chlordiazepoxide (1–100 mg/kg), and pentobarbital (3.2–56 mg/kg) were studied in rats. Pharmacologically specific results were obtained rapidly and reliably, using a cumulative dosing procedure. Cluster analysis grouped the drug treatments, on the basis of their similarities in producing different behavioral activities, into three main clusters; characteristically, stimulant drugs (amphetamine, apomorphine) produced sniffing and gnawing; PCP-like drugs (PCP, ketamine) produced locomotion, sniffing, swaying and falling; sedative drugs (pentobarbital, chlordiazepoxide) produced loss of righting. The behavioral effects of ICV administration of AP5 were more similar to the effects of PCP-like drugs than to the effects of either stimulant or sedative drugs, thus supporting the hypothesis that the behavioral effects of PCP-like drugs may result from reduced neurotransmission at excitatory synapses utilizing NMDA preferring receptors. The present procedure is simple, rapid and may provide a useful approach in the classification of behaviorally active drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46445/1/213_2004_Article_BF00518181.pd

Experimental Bearing Capacity Determination of Bonded Rock Bolts

Import 26/02/2015Diplomová práce se zabývá únosností tmelených horninových svorníků a jejím experimentální stanovením. Tato práce analyzuje a poukazuje na možné způsoby porušení, které vznikají zatížením v těsné blízkosti svorníkové tyče a to především v prstenci tmele na kontaktech svorník – tmel a tmel – hornina. V teoretické části byl navržen způsob měření a stanovení pevnostních a deformačních charakteristik tahem zatížených tmelených svorníků napodobujících zatížení v kořenové délce svorníkové výztuže. V praktické části byly pak navržené postupy uskutečněny sérií laboratorních zkoušek. Výstupem z provedených zkoušek je pracovně-deformační charakteristika tmelené svorníkové výztuže zvoleného testovaného materiálu.The thesis focuses on the bearing capacity of bonded rock bolts and experimental determination of this capacity. Possible ways of failure, which is caused by the load near the rock bolt, especially in the circular ring of the grout and between the rock bolt - the grout and between the grout - the rock, are analysed. The theoretical part includes design of measuring and assessment of strength and deformation characteristics on drawn rock bolts as it simulates the load in the root length of bolt reinforcement. This theory was applied in the laboratory tests and presents the practical part of the thesis. In conclusion, the load - deformation characteristics of bonded rock bolt reinforcement made from chosen material are stated.224 - Katedra geotechniky a podzemního stavitelstvívýborn

Acute myocardial infarction incidence and hospital mortality: routinely collected national data versus linkage of national registers

Background and Objective To compare levels of and trends in incidence and hospital mortality of first acute myocardial infarction (AMI) based on routinely collected hospital morbidity data and on linked registers. Cases taken from routine hospital data are a mix of patients with recurrent and first events, and double counting occurs when cases are admitted for an event several times during 1 year. By linkage of registers, recurrent events and double counts can be excluded. Study Design and Setting In 1995 and 2000, 28,733 and 25,864 admissions for AMI were registered in the Dutch national hospital discharge register. Linkage with the population register yielded 21,565 patients with a first AMI in 1995 and 20,414 in 2000. Results In 1995 and 2000, the incidence based on the hospital register was higher than based on the linked registers in men (22% and 23% higher) and women (18% and 20% higher). In both years, hospital mortality based on the hospital register and on linked registers was similar. The decline in incidence between 1995 and 2000 was comparable whether based on standard hospital register data or linked data (18% and 20% in men, 15% and 17% in women). Similarly, the decline in hospital mortality was comparable using either approach (11% and 9% in both men and women). Conclusion Although the incidence based on routine hospital data overestimates the actual incidence of first AMI based on linked registers, hospital mortality and trends in incidence and hospital mortality are not changed by excluding recurrent events and double counts. Since trends in incidence and hospital mortality of AMI are often based on national routinely collected data, it is reassuring that our results indicate that findings from such studies are indeed valid and not biased because of recurrent events and double counts

Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression

Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential.Rebecca E. Horton, Deana M. Apple, W. Anthony Owens, Nicole L. Baganz, Sonia Cano, Nathan C. Mitchell, Melissa Vitela, Georgianna G. Gould, Wouter Koek and Lynette C. Daw