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A three-dimensional, prognostic Atmospheric Boundary Layer Environment–Lattice Boltzmann Model (ABLE-LBM) using the multiple-relaxation-time lattice Boltzmann method was developed for large-eddy simulation of urban boundary layer atmospheric flows. In this article we describe the details of the ABLE-LBM for urban flow, its implementation of complex boundaries, and the subgrid turbulence parameterizations. As a first validation of this newly developed model, the simulation results were evaluated with two wind-tunnel datasets that were collected using particle image velocimetry and Irwin probes, respectively. The ABLE-LBM simulations use the same building layout and Reynolds numbers used in the laboratory wind tunnels. The ABLE-LBM simulations compare favorably to both laboratory studies in terms of the mean wind fields. The turbulent fluxes simulated by the model in the observational planes also agreed reasonably well with the laboratory results. The model produced urban canyon flows and vortices on the lee side and over the building tops that are similar to those of the laboratory studies in strength and location. This validation study using laboratory data indicates that our new ABLE-LBM is a viable approach for modeling atmospheric turbulent flows in urban environments. A numerical implementation using a graphics processing unit shows that real-time simulations are achieved for these two validation cases.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (&lt, 50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

We investigated if obesity/steatosis promotes mitochondrial remodeling in the liver of ob/ob mice (an obesity model). Liver mitochondria from ob/ob mice (21 weeks with significant steatosis) had ~ 2-fold increases in state III respiration compared with control (C57BL/6J, C57BL/6NJ) for all respiratory substrates examined (glutamate/malate, succinate, octanoate, and glycerol 3-phosphate). A corresponding 2-fold increase in the expression of respiratory complexes (I, IV, and V) and other respiratory proteins (glycerol phosphate dehydrogenase-2 and medium-chain acyl-coenzyme A dehydrogenase) occur in liver mitochondria of mature ob/ob mice. Conversely, respiration in liver mitochondria from young ob/ob mice (6 weeks) does not differ from control with any respiratory substrates examined. Overall, mitochondrial remodeling that enhances respiration increases with obesity/steatosis in the liver of ob/ob mice.

A prototype of a three-dimensional (3-D) radiation model is developed using the lattice Boltzmann method (LBM) and implemented on a graphical processing unit (GPU) to accelerate the model’s computational speed. This radiative transfer-lattice Boltzmann model (RT-LBM) results from a discretization of the radiative transfer equation in time, space, and solid angle. The collision and streaming computation algorithm, widely used in LBM for fluid flow modeling, is applied to speed up the RT-LBM computation on the GPU platform. The isotropic scattering is assumed in this study. The accuracy is evaluated using Monte Carlo method (MCM) simulations, showing RT-LBM is quite accurate when typical atmospheric coefficients of scattering and absorption are used. RT-LBM runs about 10 times faster than the MCM in a same CPU. When implemented on a NVidia Tesla V100 GPU in simulation with a large number of computation grid points, for example, RT-LBM runs ~120 times faster than running on a single CPU. The test results indicate RT-LBM is an accurate and fast model and is viable for simulating radiative transfer in the atmosphere with ranges for the isotropic atmosphere radiative parameters of albedo scattering (0.1~0.9) and optical depth (0.1~12).

Radiation protection factor (RPF) values are relevant to various US defense and civil support organizations. An equation was developed to quantify the angular-dependent protection of a shielding configuration in the presence of a mono-energetic radiation field. Values of ambient dose equivalent, H*(10), were computed with version 6.1 of the Monte Carlo N-Particle Code (MCNP6.1) for more than 70 distinct, mono-energetic, planar photon and neutron fields using both the kerma approximation and energy deposition from primary and secondary radiations. The two computational approaches were compared, and the MCNP6.1 models were then modified to simulate the same radiation fields and compute values of directional dose equivalent, H′(10,α), in a tissue sphere centered inside a surrogate vehicle for 13 angles of incidence. Values of H*(10) and H′(10,α) were recast as energy- and angular-dependent RPF values for the incident field–shielding geometries and tabulated. Examples of implementation are provided, and limitations are discussed.

The feeding of alcohol orally (Lieber-DeCarli diet) to rats has been shown to cause declines in mitochondrial respiration (state III), decreased expression of respiratory complexes, and decreased respiratory control ratios (RCR) in liver mitochondria. These declines and other mitochondrial alterations have led to the hypothesis that alcohol feeding causes "mitochondrial dysfunction" in the liver. If oral alcohol feeding leads to mitochondrial dysfunction, one would predict that increasing alcohol delivery by intragastric (IG) alcohol feeding to rats would cause greater declines in mitochondrial bioenergetics in the liver. In this study, we examined the mitochondrial alterations that occur in rats fed alcohol both orally and intragastrically. Oral alcohol feeding decreased glutamate/malate-, acetaldehyde- and succinate-driven state III respiration, RCR, and expression of respiratory complexes (I, III, IV, V) in liver mitochondria, in agreement with previous results. IG alcohol feeding, on the other hand, caused a slight increase in glutamate/malate-driven respiration, and significantly increased acetaldehyde-driven respiration in liver mitochondria. IG feeding also caused liver mitochondria to experience a decline in succinate-driven respiration, but these decreases were smaller than those observed with oral alcohol feeding. Surprisingly, oral and IG alcohol feeding to rats increased mitochondrial respiration using other substrates, including glycerol-3-phosphate (which delivers electrons from cytoplasmic NADH to mitochondria) and octanoate (a substrate for beta-oxidation). The enhancement of glycerol-3-phosphate- and octanoate-driven respiration suggests that liver mitochondria remodeled in response to alcohol feeding. In support of this notion, we observed that IG alcohol feeding also increased expression of mitochondrial glycerol phosphate dehydrogenase-2 (GPD2), transcription factor A (TFAM), and increased mitochondrial NAD+-NADH and NADP+-NADPH levels in the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake.

PURPOSE: The ColoCare Study is an international cohort of men and women (>18 years age) newly diagnosed with stage I-IV colorectal cancer from seven centers in the United States and Germany. Study enrollment is currently ongoing. Here, we describe the clinical and demographic characteristics of this large cohort of prospectively followed colorectal cancer patients and describe differences in demographic, lifestyle, and clinical characteristics by age of onset and tumor site. METHODS: Data on demographics (sex, age, race, ethnicity) and lifestyle factors (smoking, body mass index) collected at baseline are included in this analysis, in addition to information on tumor characteristics (tumor stage and site), treatment (neoadjuvant and adjuvant therapy), and clinical outcomes (vital status, recurrence). Patients were categorized into early- ( RESULTS: Data on 1,933 stage I-IV colorectal cancer cases were included in this study, 19% of which were deceased at the time of this analysis. On average, patients were 60 years old, had a BMI of 29 kg/m2, and were predominantly diagnosed with stage II (25%) and stage III (33%) colorectal cancer. Fifty three percent of cases were diagnosed with colon cancer, while 47% were rectal cancer cases. Twenty percent (n=364) of patients were diagnosed before age 50 (i.e. early-onset cases). The early-onset group presented with a higher percentage of rectal cancer (52%) and more advanced disease (64% stage III-IV cancer) compared to late-onset cases (46% and 48%, respectively). Percentages of ever smokers were higher among late-onset compared to early-onset patients (51% vs. 38%), independent of tumor site. Early-onset cancers were more likely to originate in the rectum compared to colon, particularly among women (61% vs. 51%). Early-onset rectal cancer cases were more likely to be female as compared to late-onset rectal cancer cases (61% vs. 36%). Corresponding with national trends, early-onset cases received more aggressive adjuvant therapy after surgical resection compared to late-onset patients (54% vs. 40%). DISCUSSION: Within this large international multi-center cohort, patients with early-onset colorectal cancer were more likely to be diagnosed with rectal cancer and advanced stage disease. The majority of early-onset cases in the ColoCare Study were non-smokers. As expected, more aggressive treatment modalities were used in patients with early-onset disease. Citation Format: Caroline Himbert, Jane Figueiredo, Lyen Huang, Biljana Gigic, Courtney L. Scaife, Bartley Pickron, Laura Lambert, Jessica Cohan, Mary Bronner, Jolanta Jedrzkiewicz, Esther Herpel, Matthias Kloor, Johanna Nattenmueller, Hans-Ulrich Kauczor, Alexis Ulrich, Seth Felder, Julian Sanchez, Sophie Dessureault, Nathan Hinkle, Justin Monroe, Matthew Mutch, Cory Bernadt, Deyali Chatterjee, Mika Sinanan, Stacey Cohen, Ulrik Wallin, Deepti Reddi, Mukta Krane, Afshin E. Gabayan, David M. Hoffman, Yosef Y. Nasseri, Robert W. Decker, Karen Zaghiyan, Zuri A. Murrell, Andrew E. Hendifar, Jun Gong, Eiman Firoozmand, Alexandra Gangi, Beth A. Moore, Kyle G. Cologne, Maryliza El-Masry, William Grady, Martin Schneider, Stephanie L. Schmit, Erin Siegel, David Shibata, Adetunji Toriola, Christopher Li, Cornelia Ulrich, Sheetal Hardikar. Clinical characteristics and outcomes of colorectal cancer in the ColoCare Study: Differences by age of onset [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2364.

SUMMARYAlzheimer’s disease (AD) is a complex and heterogenous brain disease that affects multiple inter-related biological processes. This complexity contributes, in part, to existing difficulties in the identification of successful disease-modifying therapeutic strategies. To address this, systems approaches are being used to characterize AD-related disruption in molecular state. To evaluate the consistency across these molecular models, a consensus atlas of the human brain transcriptome was developed through coexpression meta-analysis across the AMP-AD consortium. Consensus analysis was performed across five coexpression methods used to analyze RNA-seq data collected from 2114 samples across 7 brain regions and 3 research studies. From this analysis, five consensus clusters were identified that described the major sources of AD-related alterations in transcriptional state that were consistent across studies, methods, and samples. AD genetic associations, previously studied AD-related biological processes, and AD targets under active investigation were enriched in only three of these five clusters. The remaining two clusters demonstrated strong heterogeneity between males and females in AD-related expression that was consistently observed across studies. AD transcriptional modules identified by systems analysis of individual AMP-AD teams were all represented in one of these five consensus clusters except ROS/MAP-identified Module 109, which was specific for genes that showed the strongest association with changes in AD-related gene expression across consensus clusters. The other two AMP-AD transcriptional analyses reported modules that were enriched in one of the two sex-specific Consensus Clusters. The fifth cluster has not been previously identified and was enriched for genes related to proteostasis. This study provides an atlas to map across biological inquiries of AD with the goal of supporting an expansion in AD target discovery efforts.

Computational and experimental estimates of radiation protection factor (RPF) values are of significant interest to various defense-related organizations. Values of the operational quantity of ambient dose equivalent were computed, using version 6.1 of the Monte Carlo N-Particle® code (MCNP6.1), for 25 photon energies and 53 neutrons energies. Energy-dependent values for absorbed dose at a 10-mm depth in the 30-cm-diameter ICRU tissue-equivalent sphere, D * ( 10 ) , were estimated using the kerma approximation for photon (MCNP F6:p tally) and neutron (MCNP F6:n tally) radiation fields, and then transformed to fluence-to-ambient dose equivalent conversion coefficients, H * ( 10 ) / ϕ , using appropriate quality factors, Q, and radiation fluences. MCNP6.1-computed values of H * ( 10 ) / ϕ were compared with tabulated values from ICRP Publication 74. The published conversion coefficients for photon radiation fields were within the error bounds of all MCNP6.1-calculated values. For neutron fields, the computed and published conversion coefficients agreed within calculated error bounds for neutron energies of 100 keV and above, while responses to neutron fields below 100 keV exhibited the same shape and were consistent with the kerma approximation applied in the computational model. The MCNP6.1 models were then modified to simulate the same radiation fields, but H * ( 10 ) / ϕ conversion coefficients were calculated in the shielded environment of a surrogate vehicle (steel cube)—in keeping with historical and recent studies—and the ratios of shielded and unshielded vehicle response functions were expressed as energy-dependent RPF values. The MCNP6.1-computed neutron RPF values were compared with two prior experimental studies involving a mono-energetic neutron source and a high-yield, short-duration fission neutron spectrum and found to agree within the uncertainty of the experimentally-measured values. Limitations of the computed RPF values are discussed.

Background ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated squirrel monkeys with moderate and more severe nigrostriatal damage. Methods Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. Results With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. Conclusion The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society

L-dopa is the gold standard treatment for Parkinson’s disease motor symptoms 1, 2. However, although L-dopa improves the tremor, rigidity and bradykinesia, particularly in the early stages, there is a loss of efficacy with disease progression. Moreover, side effects arise including abnormal involuntary movements or dyskinesias that limit its usefulness 3, 4. New treatment strategies to reduce L-dopa-induced dyskinesias (LIDs) are therefore a key research focus. Extensive studies show that drugs targeting the serotonergic, glutamatergic adrenergic, noradrenergic, cannabinoid and histaminergic systems attenuate LIDs to varying extents in animal models of Parkinson’s disease 4-9. Furthermore, L-dopa treatment modulates expression of numerous molecular and cellular markers linked to these neurotransmitters. Thus drugs targeting these CNS systems have potential as antidyskinetic agents. However, useful clinical candidates have proved elusive because they cause parkinsonism or lead to other adverse side effects 4. Recent pre-clinical studies show that drugs directed to the nicotinic cholinergic system improve LIDs in parkinsonian mice, rats and monkeys 10-14. Nicotine reduced LIDs using several methods of administration including oral application, injection and slow-release minipump with no decline in its effectiveness with time 10-14. Nicotine acts at nAChRs, of which there are multiple subtypes. This includes receptors in both the peripheral and central nervous system, such as α1β1*, α3β4*, α4β2*, α6β2* and α7 as well as other minor receptor subtypes 15, 16. The asterisk denotes the possible presence of other nAChR subunits in the receptor. Notably, the α4β2* and α6β2* nAChR subtypes are expressed only in the brain 15, 17. These subtypes are of relevance to LIDs, as studies in α4, α6, and β2 nAChR null mutant mice show that they regulate LIDs 14. Thus, drugs targeting α4β2* and α6β2* nAChRs may yield a selective therapy to reduce LIDs. Studies have been done to evaluate whether such drugs reduce LIDs in parkinsonian animals. The general nAChR agonist varenicline, as well as several β2* selective agonists including A-85380, sazetidine, TC-2696, TI-10165, TC-8831 and TC-10600 reduced LIDs to varying extents in rats with a unilateral 6-hydroxydopamine lesion 18, 19. Additionally, varenicline and TC-8831 decreased LIDs ~50% in nonhuman primates with no development of tolerance 20, 21. These combined results suggest that nAChR drugs may be useful for the management of LIDs, although a limitation of the drugs tested to date in nonhuman primates was the development of emesis 22. The objective of the present experiments was to investigate the potential of two β2* selective nAChR agonists that had previously been evaluated in phase 2 clinical trials for other indications with minimal side effects. This included ABT-089, a partial nAChR agonist 23-27, as well as the full agonist ABT-894 28-30. The results show that ABT-089 and ABT-894 reduced LIDs in nonhuman primates with no adverse responses, suggesting they may be a useful treatment for LIDs in Parkinson’s disease.

A proposed simply structured gated silicon (Si) drift X-ray detector operated using Peltier cooling and only a single high-voltage source is investigated. Because the device structure is much simpler than that of commercial Si drift detectors (SDDs), which require at least two high-voltage sources, the cost of the X-ray detection system can be reduced. The absorption of cadmium X-ray fluorescence photons (energy: 23.1 keV) in 0.3-mm-thick Si is only 19% in commercial SDDs. Toward realizing detectors with thicker Si substrates, we simulate the electric potential distribution in the proposed detector with a Si substrate having thickness of 0.625 mm and resistivity of 10 kΩ·cm, and we perform fundamental experiments on a fabricated prototype. The simulation result is in good agreement with the experimental result that the effective active area of the detector is approximately 18 mm2 by using incident X-rays passed through a 0.1-mm-diameter pinhole. An energy resolution of 145 eV at 5.9 keV is experimentally obtained from an 55Fe source at -38 °C.

This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco's professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco's expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco's laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco's influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world.

One-second-long increases in prefrontal cholinergic activity (“transients”) were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes (“cue detection”). Nicotine and, more robustly, selective agonists at α4β2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of β2-containing and α7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transientsin vivo. Transients were evoked by nicotine, the α4β2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the α7 nAChR agonist A-582941 [2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking β2 or α7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of α4β2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking β2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by β2* knock-out. Conversely, in mice lacking the α7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of α7 nAChR in controlling the duration of release events, stimulation of α7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. α7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal α4β2* nAChRs play a key role in evoking and facilitating the transient glutamatergic–cholinergic interactions that are necessary for cue detection and attentional performance.

Background— American College of Cardiology/American Heart Association guidelines recommend a door-to-balloon time (DTB) Methods and Results— The Mayo Clinic STEMI protocol was implemented in April 2004 and included activation of the cardiac catheterization laboratory by the emergency medicine physician; a single call system to activate the catheterization laboratory; catheterization laboratory staff arrival within 20 to 30 minutes of activation; and real-time performance feedback within 24 to 48 hours. Data were collected on nontransferred STEMI patients. The preimplementation group (June 2002 to March 2004) comprised 96 patients with a median DTB of 97 (interquartile range, 82, 130) minutes, and 40% had a DTB P P =0.41). Conclusions— The Mayo Clinic STEMI protocol implemented strategies to reduce DTB for nontransferred patients with STEMI. DTB was significantly reduced, and the results were sustained over the 4-year follow-up period. Our experience demonstrates the effectiveness and durability of process changes targeting timeliness of primary percutaneous coronary intervention.

Background and purpose: Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain. Experimental approach: WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB1 and CB2 receptor antagonists. Key results: WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB1 versus CB2 receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB1 receptor antagonist, but not with a CB2 receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB1 and CB2 antagonists blocked systemic WIN-induced analgesic activity. Conclusions and implications: Both CB1 and CB2 receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB1 but not CB2 receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB1 receptors in the brain. British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009

Background Exercise treadmill testing (ETT) has been standard for evaluating outpatients at risk for cardiovascular events. Few studies have demonstrated its prognostic usefulness in emergency department chest pain units or have used the Duke score [(exercise duration in minutes) − (5 × ST-segment deviation in millimeters) − (4 × treadmill angina index)] to grade its performance. Aims Our objective was to assess the usefulness of this score in a chest pain unit to predict cardiovascular events. Methods From November 2000 to October 2001, we retrospectively studied consecutive patients in the chest pain unit. Those undergoing ETT were stratified into “low” (Duke score ≥ 5) and “moderate/high” risk groups ( 24 h after presentation, revascularization, acute congestive heart failure, stroke or arrhythmia were identified within 1 year after presentation. Differences in risk of having a cardiovascular event among low-risk and moderate/high-risk groups are presented. Results During the study period, 1,048 patients entered the chest pain unit; 800 met inclusion criteria. Of these, 599 received ETT and 201 had contraindications or a positive finding in the chest pain unit protocol before ETT. Cardiovascular event rates were 0.7% (3/454), 15.2% (22/145) and 14.9% (30/201) after 1 month of follow-up for low-risk, moderate/high-risk and no-ETT groups, respectively. Conclusions According to the Duke score, the low-risk group developed minimal cardiovascular events compared with the moderate/high-risk group. The Duke score appears effective for risk stratification of chest pain patients in chest pain units.

Because modulation of cortical cholinergic neurotransmission has been hypothesized to represent a necessary mechanism mediating the beneficial cognitive effects of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists, we used choline-sensitive microelectrodes for the real-time measurement of ACh releasein vivo, to characterize cholinergic transients evoked by nicotine and the α4β2*-selective nAChR partial agonist 2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride (ABT-089), a clinically effective cognition enhancer. In terms of cholinergic signal amplitudes, ABT-089 was significantly more potent than nicotine in evoking ACh cholinergic transients. Moreover, cholinergic signals evoked by ABT-089 were characterized by faster signal rise time and decay rate. The nAChR antagonist mecamylamine attenuated the cholinergic signals evoked by either compound. Cholinergic signals evoked by ABT-089 were more efficaciously attenuated by the relatively β2*-selective nAChR antagonist dihydro-β-erythroidine. The α7 antagonist methyllycaconitine did not affect choline signal amplitudes but partly attenuated the relatively slow decay rate of nicotine-evoked cholinergic signals. Furthermore, the AMPA receptor antagonist DNQX as well as the NMDA receptor antagonist APV more potently attenuated cholinergic signals evoked by ABT-089. Using glutamate-sensitive microelectrodes to measure glutamatergic transients, ABT-089 was more potent than nicotine in evoking glutamate release. Glutamatergic signals were highly sensitive to tetrodotoxin-induced blockade of voltage-regulated sodium channels. Together, the present evidence indicates that compared with nicotine, ABT-089 evokes more potent and sharper cholinergic transients in prefrontal cortex. Glutamatergic mechanisms necessarily mediate the cholinergic effects of nAChR agonists in the prefrontal cortex.

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach.

The α7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel α7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki= 10.8 nm) and human (Ki= 16.7 nm) α7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the α7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that α7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of α7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked α7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that α7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys with moderate and more severe nigrostriatal damage.Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured.With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism.The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease.

Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7±3.9 and 1.0±0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50=23 μmol kg−1) and monoiodoacetate-induced joint pain (ED50=43 μmol kg−1). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50=28 and 27 μmol kg−1, respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications. The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans. British Journal of Pharmacology (2006) 149, 761–774. doi:10.1038/sj.bjp.0706877

Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similarin vitropotency but different CNS penetration were comparedin vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.

ABT-594 [(R)-5-(2-azetedinylmethoxy)-2-chloropyridine mono-tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT-594 at α4β2-containing nAChRs is comparable to that of (±)-epibatidine, ABT-594 has lower affinity than (±)-epibatidine at α3-containing nAChRs. Similarly, ABT-594 is approximately equivalent to (±)-epibatidine in a Ca2+ flux assay in K-177 cells that express 04132 nAChRs but less potent than (±)-epibatidine in the IMR-32 (α3-containing) cell line. ABT-594 is active in a variety of rodent models of acute thermal (mouse hot-plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT-594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT-594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT-594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT-594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT-594 (AUC0–12)

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D(3) and D(2) receptors in these effects is unknown since all antipsychotics are D(2)/D(3) antagonists with limited binding preference at D(2) receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D(3) vs D(2) receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D(2)/D(3) antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D(3)/D(2) antagonist, BP 897 at 8 mg/kg, and the selective D(3) antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D(3) antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D(3) antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D(3) receptors.

As the marketplace for academic positions in emergency medicine grows more competitive, it becomes increasingly important for residents who desire academic careers to distinguish themselves during their residency. This report attempts to outline a road map for department and residency program leaders to help their houseofficers become successful candidates for an academic emergency medicine position. Specific ways a resident can enhance his or her "academic marketability" include 1) involvement in research, 2) establishment of a track record of productivity via scholarly writing, 3) awareness of the literature in the specialty, 4) involvement in specialty organizations and hospital committees, 5) competition for national awards, 6) gaining education skills, 7) developing an academic niche, and 8) fellowship training.

Pompe's disease is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA is synthesized as a 110-kDa precursor containing N-linked carbohydrates modified with mannose 6-phosphate groups. Following trafficking to the lysosome, presumably via the mannose 6-phosphate receptor, the 110-kDa precursor undergoes a series of complex proteolytic and N-glycan processing events, yielding major species of 76 and 70 kDa. During a detailed characterization of human placental and recombinant human GAA, we found that the peptides released during proteolytic processing remained tightly associated with the major species. The 76-kDa form (amino acids (aa) 122-782) of GAA is associated with peptides of 3.9 kDa (aa 78-113) and 19.4 kDa (aa 792-952). The 70-kDa form (aa 204-782) contains the 3.9- and 19.4-kDa peptide species as well as a 10.3-kDa species (aa 122-199). A similar set of proteolytic fragments has been identified in hamster GAA, suggesting that the multicomponent character is a general phenomenon. Rabbit anti-peptide antibodies have been generated against sequences in the proteolytic fragments and used to demonstrate the time course of uptake and processing of the recombinant GAA precursor in Pompe's disease fibroblasts. The results indicate that the observed fragments are produced intracellularly in the lysosome and not as a result of nonspecific proteolysis during purification. These data demonstrate that the mature forms of GAA characterized by polypeptides of 76 or 70 kDa are in fact larger molecular mass multicomponent enzyme complexes.

Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D(2)-like receptor subtypes (D(2), D(3), D(4)) to depression is not known. We present evidence that activation of D(2)/D(3), but not D(4) receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 micromol/kg); quinpirole, a D(2)-like receptor and agonist (0.4, 1.0, and 2.0 micromol/kg); PD 12,8907, a preferential D(3) receptor agonist (0.17, 0.35, and 0.7 micromol/kg); PD 168077 (0.1, 0.3, and 1.0 micromol/kg) and CP 226269 (0.3, 1.0, and 3.0 micromol/kg), both selective D(4) receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D(2)-like receptor antagonist (0.27 micromol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D(3) receptor antagonist (17.46 micromol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D(4) receptor antagonist (1.15 micromol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D(2) and to a lesser extent by D(3) but not D(4) receptors.

Objectives: To date, no studies in emergency medicine (EM) have addressed the educational value of the Residency Review Committee for Emergency Medicine's (RRC-EM) requirement for patient follow-up (FU). The authors examined whether performance of patient FU improved EM resident education. Methods: All EM resident FU encounters from September 25, 2001, through September 24, 2002, were documented and analyzed. All EM residents at a regional tertiary referral emergency department (ED) initiated patient FU encounters by entering information regarding patients' initial ED presentations into a Web-based follow-up system (WBFUS), subsequently entered FU information, and indicated whether they thought that the specific FU encounters improved their education (yes/no). Supervising faculty members then reviewed the residents' completed FU entries. Blinded to residents' responses regarding educational utility, faculty members evaluated whether they thought the specific FU encounters were educational for the residents (yes/no). Data entered into the WBFUS were then summarized as percentages. Results: Eight hundred forty-seven FU encounters were completed by 18 EM residents and 29 EM faculty. Ninety-three percent of the FU entries were deemed by at least one evaluator (resident or faculty) to have educational value. Residents found the act of performing FU educational in 81.3% of cases, whereas faculty thought 80.4% were educational for the resident. Although the residents and faculty agreed on the educational value in 75.4% of cases, the overall strength of the agreement was slight to fair (kappa statistic = 0.21). Conclusions: This study indicates that EM residents and faculty believe that the act of performing patient FU has educational value for EM residents; however, the interobserver agreement between residents and faculty was low.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015.

The finding that smoking is inversely correlated with Parkinson's disease and that nicotine attenuates nigrostriatal damage in Parkinsonian animals supports the idea that nicotine may be neuroprotective. Nicotine is thought to exert this effect by acting at nicotinic receptors (nAChRs), including the α7 subtype. The objective of this study was twofold: first, to test the protective potential of ABT-107, an agonist with high selectivity for α7 nAChRs; and second, to investigate its cellular mechanism of action. Rats were implanted with minipumps containing ABT-107 (0.25mg/kg/d). In addition, we tested the effect of nicotine (1mg/kg/d) as a positive control, and also DMXB (2mg/kg/d) which acts primarily with α7 but also α4β2* nAChRs. Two weeks after minipump placement, the rats were lesioned by unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Lesioning alone decreased contralateral forelimb use and adjusted stepping, two measures of Parkinsonism. ABT-107 and nicotine treatment significantly improved these behaviors at all weeks tested, with variable improvement with DMXB. We next investigated the cellular mechanism involved. The striatal dopamine transporter (DAT), a marker of dopaminergic integrity, was reduced ~70% with lesioning. ABT-107 or nicotine treatment significantly increased DAT levels in lesioned striatum; these drugs did not alter DAT levels in intact striatum. ABT-107 and nicotine also significantly improved basal dopamine release from lesioned striatum, as well as nicotine-stimulated dopamine release mediated via α4β2* and α6β2* nAChRs. These data suggest that α7 nAChR agonists may improve motor behaviors associated with nigrostriatal damage by enhancing striatal dopaminergic function.

The effects of injections of low (105 ng) and high (210 ng) doses of the cholinergic-selective neurotoxin 192IgG-saporin (SAP) into the nucleus basalis magnocellularis on both the acquisition and performance of a go/no-go operant task in Long-Evans rats were examined and were correlated with regional changes in choline acetyltransferase (ChAT) activity. The go/no-go procedure rewards a rat for pressing a lever on alternate trials, with intertrial intervals (i.e., delays) of 5, 20, and 40 sec. Over a period of 15 days, normal rats rapidly become proficient in this task, so that the ratio of latency to the first press on the rewarded go trial to latency to press on the nonrewarded no-go trial is significantly less than 1. With injections made prior to acquisition, there was a significant disruptive effect of both doses of SAP that was not delay dependent. In previously trained rats, SAP disrupted performance during a 2-week training period, with the high dose of SAP having a more pronounced effect. A uniform 60% reduction of cortical ChAT activity relative to control was found after either high- or low-SAP injections; however, there was a dose-dependent reduction in hippocampal ChAT activity with SAP treatment (low dose [20%–29%] and high dose [39%–44%]). Thus, the dose-dependent disruption in rats trained prior to injection may be related to combined cortical and hippocampal cholinergic deficits. The presence of an impairment at even the shortest delay suggests that impaired working memory may play only a minor role in the go/no-go deficit produced by disruption of the basal forebrain cholinergic system and that impaired attention may be more important.

Increased susceptibility to distraction is a symptom of normal aging and several clinical syndromes, including Alzheimer's disease and attention deficit disorders. In the present study, aged and young adult macaques were well-trained to perform an automated delayed matching-to-sample (DMTS) task which assesses both attention and short-term memory. On 19% of all trials, a task-relevant distracting stimulus was presented during either the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired delayed recall on trials with the shortest delay intervals, but did not affect accuracy on trials with long delay intervals. In contrast, young adult monkeys were impaired only by the presence of an early onset distractor lasting 3 s. Impairment was selective for only those trials with the shortest delay intervals. Late onset distractors were relatively ineffective in producing distractibility in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce distractibility in aged monkeys, producing locomotor abnormalities and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however, distractibility was significantly attenuated by administration of the 0.125 mg/kg dose. Habituation to the distracting stimulus (under saline conditions) was assessed throughout the study and was not evident at any time point of testing. These data indicate that attention and recall after brief delays are impaired following exposure to a task-relevant distracting stimulus in both aged and young adult monkeys, but that aged monkeys are more susceptible to distraction and do not receive significant benefit from MPH administration.

Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.

In this study we investigated the effects of 192 IgG saporin injections into the medial septal area (MSA), or nucleus basalis magnocellularis (NBM), and combined injections into the MSA and NBM, on the water maze and radial arm maze performance in the male rat. The results of the present study reveal a dissociation between the effects of 192 IgG saporin injections into the basal forebrain on the performance of two tasks of spatial learning in the rat. Bilateral injections of 192 IgG saporin into the NBM, MSA or combined MSA/NBM failed to disrupt water maze performance when compared to controls. In contrast, injections of 192 IgG saporin into the MSA, NBM or MSA/NBM induced mild impairments on a radial arm maze task. Overall, the disruption of spatial learning observed in this study however was relatively mild compared to deficits in spatial learning reported using less selective lesions of the cholinergic basal forebrain. Consequently, the results of this study suggest that a selective reduction in cholinergic transmission in the basal forebrain is by itself, insufficient to account for the functional impairments observed in spatial learning in the rat. Although our data does support the use of 192 IgG saporin as a selective cholinergic toxin in the basal forebrain, it further suggests that assessment of spatial learning in the rat following 192 IgG saporin lesions of the basal forebrain in combination with lesions to other neurotransmitter systems, may be a more viable approach to the elucidation of the neuropathological mechanisms that are associated with the cognitive deficits seen in Alzheimer's Disease.

Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease.

Alzheimer disease (AD) is a progressive neurodegenerative disorder with associated memory loss, spatial disorientation, and other psychiatric problems. Cholinergic system dysfunction is an early and salient feature of AD, and enhancing cholinergic signaling with acetylcholinesterase inhibitors is currently the primary strategy for improving cognition. The beneficial effects of acetylcholinesterase inhibitors, however, are typically short-lived and accompanied by adverse effects. Recent evidence suggests that activating α7 nicotinic acetylcholine receptors (α7 nAChR) may facilitate the specific modulation of brain cholinergic signaling, leading to cognitive enhancement and possibly to amelioration of AD pathologic findings. In the present study, we determined the effect of long-term treatment with the selective α7 nAChR agonist A-582941 in aged 3xTg-AD mice with robust AD-like pathology, which is particularly significant not only because this is the only mouse model that co-develops amyloid plaques and neurofibrillary tangles but also because it enabled us to explore whether A-582941 is able to restore brain function after the severe damage associated with AD. Analysis of β-amyloid deposits, tau phosphorylation, and inflammatory cells revealed that, overall, pathologic findings were unchanged. Rather, α7 nAChR activation induced expression of c-Fos and brain-derived neurotrophic factor and phosphorylation of cyclic adenosine monophosphate response element binding and neurotrophic tyrosine receptor kinase type 2. More important, A-582941 completely restored cognition in aged 3xTg-AD mice to the level of that in age-matched nontransgenic mice. These novel findings indicate that activating α7 nAChR is a promising treatment for cognitive impairment in AD.

Introduction Research has consistently demonstrated positive benefits from physical activity (PA) in the primary and secondary prevention of chronic diseases and conditions such as CVD. Even the person going from doing nothing to doing something will see the benefits. The specific aim of this study was to implement and evaluate the short-term effects of walking, bicycling, and community gardening approaches to enhancing PA among urban-dwelling older adults and low-income ethnic minorities. Methods Participants included 157 adults of all races/ethnicities who self-selected into one of three interventions: walking ( n = 47), bicycling ( n = 35), or gardening ( n = 75). Interventions were 10 weeks long, with follow-up data collection every 3 months until 1 year. Data collection included self-report questionnaires (Self-efficacy for Exercise Habits Survey, Lubben Social Network Scale, Perceived Environments Attributes scale, Behavioral Risk Factor Surveillance System, self-reported frequency, duration, and distance of PA performed), measured PA (7-day accelerometry), and PA focus groups. Results Throughout the course of the intervention and the 9-month follow-up period, only three significant differences in self-reported questionnaire data arose. These differences occurred among bicyclists, with a significant increase ( p < 0.01) in social networks from pre- to post-intervention, which remained stable across time, to the 9-month data collection. The bicyclists also reported a significant improvement ( p < 0.001) in the perceived environmental attributes. Bicyclists also reported an increase in duration, frequency, and distance of bicycling. Themes emerging from the focus groups included: meeting new people, a spirit of community, accountability, increasing exercise, and developing community awareness. Conclusions The purpose of this study was to increase the overall PA of the participants, not specific exercise routines. However, there were no significant differences from pre- to post-intervention (3 month interval) or to the 9-month follow-up except for the increase in social networks and perceived environmental attributes reported by the bicyclists. They also reported an increase in duration, frequency and distance ridden. In this study, gardening was the most successful intervention, with a greater percentage of individuals who wanted to participate, completed data collection, and continued beyond that time. Walkers demonstrated a lack of sustainability past the intervention period among individual participants. Although there were few statistically significant findings regarding PA and its influences, the results should be considered in their entirety. Participant verbal comments and feedback throughout the study, in addition to during focus groups, reflected the positive impacts that these interventions had upon the participants’ lives.

The Microsoft Kinect for Xbox 360 (“Kinect”) provides a convenient and inexpensive depth sensor and, with the Microsoft software development kit, a skeleton tracker (Figure 2). These have great potential to be useful as virtual environment (VE) control interfaces for avatars or for viewpoint control. In order to determine its suitability for our applications, we devised and conducted tests to measure standard performance specifications for tracking systems. We evaluated the noise, accuracy, resolution, and latency of the skeleton tracking software. We also measured the range in which the person being tracked must be in order to achieve these values.

The use of von Frey filaments, originally developed by Maximilian von Frey, has become the cornerstone for assaying mechanical sensitivity in animal models and is widely used for human assessment. While there are certain limitations associated with their use that make comparisons between studies not straightforward at times, such as stimulus duration and testing frequency, von Frey filaments provide a good measurement of mechanosensation. Here we describe the application of von Frey filaments to testing in animal models, specifically with respect to determining changes in sensory thresholds in a pain state using the Dixon up-down method. In a literature survey, we found that up to 75% of reports using this method analyze the data with parametric statistical analysis and of those that used nonparametric analysis, none took into account that mechanical sensation is perceived on a logarithmic scale (Weber's Law) when calculating efficacy. Here we outline a more rigorous analysis for calculating efficacy and ED 50 's from von Frey data that incorporates Weber's Law. We show that this analysis makes statistical and biological sense and provide a specific example of how this change affects data analysis that brings results from animal models more in line with clinical observations. Perspective This focus article argues that analyzing von Frey paw withdrawal threshold data obtained by using the Dixon up-down method without considering Weber's Law is inappropriate. An analysis method that incorporates how mechanical sensation is perceived and how its application brings results from animal models more in line with clinical data is presented.

Introduction. Etiology of acute ischemic stroke (AIS) is known to significantly influence management, prognosis, and risk of recurrence.Objective. To determine if ischemic stroke subtype based on TOAST criteria influences mortality.Methods. We conducted an observational study of a consecutive cohort of patients presenting with AIS to a single tertiary academic center.Results. The study population consisted of 500 patients who resided in the local county or the surrounding nine-county area. No patients were lost to followup. Two hundred and sixty one (52.2%) were male, and the mean age at presentation was 73.7 years (standard deviation, SD = 14.3). Subtypes were as follows: large artery atherosclerosis 97 (19.4%), cardioembolic 144 (28.8%), small vessel disease 75 (15%), other causes 19 (3.8%), and unknown 165 (33%). One hundred and sixty patients died: 69 within the first 30 days, 27 within 31–90 days, 29 within 91–365 days, and 35 after 1 year. Low 90-, 180-, and 360-day survival was seen in cardioembolic strokes (67.1%, 65.5%, and 58.2%, resp.), followed for cryptogenic strokes (78.0%, 75.3%, and 71.1%). Interestingly, when looking into the cryptogenic category, those with insufficient information to assign a stroke subtype had the lowest survival estimate (57.7% at 90 days, 56.1% at 180 days, and 51.2% at 1 year).Conclusion. Cardioembolic ischemic stroke subtype determined by TOAST criteria predicts long-term mortality, even after adjusting for age and stroke severity.

Solutions of the mass transfer equation in the stagnation cell are described. It is shown that the application of the stagnation cell can be used for the determination of Da s , distinguishing different types of process control, sensoring gas phase condensation and homogeneous nucleation. The results obtained with cylindrical cell for MOCVD of YBCO are discussed

YBCO thin films are obtained by low-pressure aerosol version of MOCVD technique. The effects of different process factors are studied. The conclusion is made that the main disadvantage of the process is the high partial pressure of carbon dioxide in the deposition zone. The ways to improve the situation are considered.