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1.
Trials ; 23(1): 596, 2022 Jul 26.
Article in English | MEDLINE | ID: mdl-35883143

ABSTRACT

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.


Subject(s)
Dementia , Malus , Aged , Cost-Benefit Analysis , Humans , Life Style , Quality of Life , Single-Blind Method , Tea , Technology
2.
Acad Med ; 91(3): 338-44, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26606723

ABSTRACT

Whether patient satisfaction scores can act as a catalyst for improving health care is highly debated. Some argue that pursuing patient satisfaction is overemphasized and potentially at odds with providing good care because it leads providers to overtest and overtreat patients and to bend to unreasonable patient demands, all to improve their ratings. Others cite studies showing that high patient satisfaction scores correlate with improved health outcomes. Ideally, assessing patient satisfaction metrics will encourage empathy, communication, trust, and shared decision making in the health care delivery process. From the patient's perspective, sharing such metrics motivates physicians to provide patient-centered care and meets their need for easily accessible information about their providers. In this article, the authors describe a seven-year initiative, which began in 2008, to change the culture of the University of Utah Health Care system to deliver a consistently exceptional patient experience. Five factors affected the health system's ability to provide such care: (1) a lack of good decision-making processes, (2) a lack of accountability, (3) the wrong attitude, (4) a lack of patient focus, and (5) mission conflict. Working groups designed initiatives at all levels of the health system to address these issues. What began as a patient satisfaction initiative evolved into a model for physician engagement, values-based employment practices, enhanced professionalism and communication, reduced variability in performance, and improved alignment of the mission and vision across hospital and faculty group practice teams.


Subject(s)
Academic Medical Centers , Patient Satisfaction , Patient-Centered Care , Attitude of Health Personnel , Clinical Decision-Making , Communication , Humans , Physician's Role , Physician-Patient Relations , Social Responsibility , Utah
3.
Neuroscience ; 310: 242-51, 2015 Dec 03.
Article in English | MEDLINE | ID: mdl-26383253

ABSTRACT

The complex neuronal circuitry of the cerebellum is embedded within its lamina, folia, and lobules, which together play an important role in sensory and motor function. Studies in mouse models have demonstrated that both cerebellar lamination and lobule/fissure development are under genetic control. The cerebellar vermis of C57BL/6 mice exhibits spontaneous malformations of neuronal migration of posterior lobules (VIII-IX; molecular layer heterotopia); however, the extent to which other inbred mice also exhibit these malformations is unknown. Using seven different inbred mouse strains and two first filial generation (F1) hybrids, we show that only the C57BL/6 strain exhibits heterotopia. Furthermore, we observed heterotopia in consomic and recombinant inbred strains. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1 and the sex chromosomes. Additional morphological analyses showed no relationship between heterotopia formation and other features of lobule/fissure organization. These data are relevant toward understanding normal cerebellar development and disorders affecting cerebellar foliation and lamination.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cerebellar Vermis/abnormalities , Cerebellar Vermis/growth & development , Malformations of Cortical Development/pathology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Animals , Databases, Genetic , Gene Expression Regulation , Malformations of Cortical Development/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Transgenic , MutL Protein Homolog 1 , Mutation/genetics
4.
Nano Lett ; 15(7): 4622-7, 2015 Jul 08.
Article in English | MEDLINE | ID: mdl-26047255

ABSTRACT

We report the dispersive readout of the spin state of a double quantum dot formed at the corner states of a silicon nanowire field-effect transistor. Two face-to-face top-gate electrodes allow us to independently tune the charge occupation of the quantum dot system down to the few-electron limit. We measure the charge stability of the double quantum dot in DC transport as well as dispersively via in situ gate-based radio frequency reflectometry, where one top-gate electrode is connected to a resonator. The latter removes the need for external charge sensors in quantum computing architectures and provides a compact way to readout the dispersive shift caused by changes in the quantum capacitance during inter-dot charge transitions. Here, we observe Pauli spin-blockade in the high-frequency response of the circuit at finite magnetic fields between singlet and triplet states. The blockade is lifted at higher magnetic fields when intra-dot triplet states become the ground state configuration. A line shape analysis of the dispersive phase shift reveals furthermore an intra-dot valley-orbit splitting Δvo of 145 µeV. Our results open up the possibility to operate compact complementary metal-oxide semiconductor (CMOS) technology as a singlet-triplet qubit and make split-gate silicon nanowire architectures an ideal candidate for the study of spin dynamics.

5.
Nat Commun ; 6: 6084, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25600002

ABSTRACT

Quantum computation requires a qubit-specific measurement capability to readout the final state of individual qubits. Promising solid-state architectures use external readout electrometers but these can be replaced by a more compact readout element, an in situ gate sensor. Gate-sensing couples the qubit to a resonant circuit via a gate and probes the qubit's radiofrequency polarizability. Here we investigate the ultimate performance of such a resonant readout scheme and the noise sources that limit its operation. We find a charge sensitivity of 37 µe Hz(-1/2), the best value reported for this technique, using the example of a gate sensor strongly coupled to a double quantum dot at the corner states of a silicon nanowire transistor. We discuss the experimental factors limiting gate detection and highlight ways to optimize its sensitivity. In total, resonant gate-based readout has advantages over external electrometers both in terms of reduction of circuit elements as well as absolute charge sensitivity.

6.
Phys Rev Lett ; 109(5): 056805, 2012 Aug 03.
Article in English | MEDLINE | ID: mdl-23006198

ABSTRACT

We have investigated the energy loss of hot electrons in metallic graphene by means of GHz noise thermometry at liquid helium temperature. We observe the electronic temperature T ∝ V at low bias in agreement with the heat diffusion to the leads described by the Wiedemann-Franz law. We report on T ∝ √V behavior at high bias, which corresponds to a T(4) dependence of the cooling power. This is the signature of a 2D acoustic phonon cooling mechanism. From a heat equation analysis of the two regimes we extract accurate values of the electron-acoustic phonon coupling constant Σ in monolayer graphene. Our measurements point to an important effect of lattice disorder in the reduction of Σ, not yet considered by theory. Moreover, our study provides a strong and firm support to the rising field of graphene bolometric detectors.

7.
Placenta ; 32 Suppl 4: S285-90, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21575989

ABSTRACT

The International Placenta Stem Cell Society (IPLASS) was founded in June 2010. Its goal is to serve as a network for advancing research and clinical applications of stem/progenitor cells isolated from human term placental tissues, including the amnio-chorionic fetal membranes and Wharton's jelly. The commitment of the Society to champion placenta as a stem cell source was realized with the inaugural meeting of IPLASS held in Brescia, Italy, in October 2010. Officially designated as an EMBO-endorsed scientific activity, international experts in the field gathered for a 3-day meeting, which commenced with "Meet with the experts" sessions, IPLASS member and board meetings, and welcome remarks by Dr. Ornella Parolini, President of IPLASS. The evening's highlight was a keynote plenary lecture by Dr. Diana Bianchi. The subsequent scientific program consisted of morning and afternoon oral and poster presentations, followed by social events. Both provided many opportunities for intellectual exchange among the 120 multi-national participants. This allowed a methodical and deliberate evaluation of the status of placental cells in research in regenerative and reparative medicine. The meeting concluded with Dr. Parolini summarizing the meeting's highlights. This further prepared the fertile ground on which to build the promising potential of placental cell research. The second IPLASS meeting will take place in September 2012 in Vienna, Austria. This meeting report summarizes the thought-provoking lectures delivered at the first meeting of IPLASS.


Subject(s)
Fetal Stem Cells/cytology , Placenta/cytology , Female , Fetus , Humans , Pregnancy
8.
Neuroscience ; 163(1): 97-108, 2009 Sep 29.
Article in English | MEDLINE | ID: mdl-19467297

ABSTRACT

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.


Subject(s)
Adenosine A2 Receptor Antagonists , Corpus Striatum/drug effects , Pimozide/antagonists & inhibitors , Purines/pharmacology , Tremor/drug therapy , Tropicamide/pharmacology , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/antagonists & inhibitors , Biomarkers/analysis , Biomarkers/metabolism , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Disease Models, Animal , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Drug Interactions , Male , Masticatory Muscles/innervation , Masticatory Muscles/physiopathology , Muscarinic Antagonists/pharmacology , Pimozide/adverse effects , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D2/metabolism , Tremor/chemically induced , Tremor/physiopathology , Up-Regulation/drug effects , Up-Regulation/physiology
9.
Opt Lett ; 30(14): 1837-9, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-16092362

ABSTRACT

We have locked the frequency of a 3 THz quantum cascade laser (QCL) to that of a far-infrared gas laser with a tunable microwave offset frequency. The locked QCL line shape is essentially Gaussian, with linewidths of 65 and 141 kHz at the -3 and -10 dB levels, respectively. The lock condition can be maintained indefinitely, without requiring temperature or bias current regulation of the QCL other than that provided by the lock error signal. The result demonstrates that a terahertz QCL can be frequency controlled with 1-part-in-10(8) accuracy, which is a factor of 100 better than that needed for a local oscillator in a heterodyne receiver for atmospheric and astronomic spectroscopy.

10.
Psychopharmacology (Berl) ; 179(2): 383-92, 2005 May.
Article in English | MEDLINE | ID: mdl-15619122

ABSTRACT

RATIONALE: Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. OBJECTIVE: The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. METHODS: The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. RESULTS: Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED50 for suppression of jaw movements divided by the ED50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. CONCLUSIONS: On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.


Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Clozapine/pharmacology , Dibenzothiazepines/pharmacology , Jaw , Movement/drug effects , Animals , Benzodiazepines/pharmacology , Conditioning, Operant/drug effects , Dose-Response Relationship, Drug , Male , Nootropic Agents/pharmacology , Olanzapine , Quetiapine Fumarate , Rats , Rats, Sprague-Dawley , Reinforcement Schedule , Tacrine/pharmacology
11.
Behav Brain Res ; 148(1-2): 47-54, 2004 Jan 05.
Article in English | MEDLINE | ID: mdl-14684247

ABSTRACT

Recent evidence indicates that adenosine A2A receptors modulate the activity of striatal neurons, and that antagonists of this receptor may have actions in various animal models related to motor function. Four experiments were conducted to study the effects of systemic injections of the adenosine A2A antagonist KF17837 on the behavioral effects produced by repeated administration of the dopamine (DA) antagonist haloperidol. In the first two experiments, it was shown that repeated 0.5 mg/kg haloperidol severely suppressed open-field locomotor activity, and that KF17837 (0.0-20.0 mg/kg) did not significantly increase open-field locomotor activity. The third experiment demonstrated that injections of KF17837 (0.0-20.0 mg/kg) completely reversed the suppression of locomotion induced by haloperidol, and also increased rearing behavior in haloperidol-treated rats. Previous research has reported that haloperidol induces tremulous jaw movements that have many of the characteristics of parkinsonian tremor. The fourth experiment demonstrated that i.p. injections of KF17837 (0.0-20.0 mg/kg) also suppressed haloperidol-induced tremulous jaw movements. Taken together, the results of these experiments indicate that adenosine A2A antagonism can reverse the locomotor suppression and tremulous movements induced by DA antagonism. This profile of activity is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in an antiparkinsonian effect in animal models.


Subject(s)
Adenosine A2 Receptor Antagonists , Jaw/drug effects , Motor Activity/drug effects , Movement/drug effects , Tremor/physiopathology , Xanthines/pharmacology , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Haloperidol , Inhibition, Psychological , Male , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Tremor/chemically induced , Tremor/drug therapy , Xanthines/therapeutic use
12.
Life Sci ; 74(8): 1001-11, 2004 Jan 09.
Article in English | MEDLINE | ID: mdl-14672756

ABSTRACT

Biochemical investigations have identified putative enzymatic pathways for the synthesis and metabolism of endogenous cannabinoids. Anandamide amidase is an enzyme that metabolizes anandamide into arachadonic acid and ethanolamine. Using in vitro methods, various inhibitors of amidase have been identified. The present studies were undertaken to determine if the amidase inhibitor AM 374 could enhance the effects of intraperitoneal (IP) injections of anandamide. Three studies were conducted to investigate the effects of various drug treatments on fixed ratio 5 operant lever pressing for food reinforcement. In the first study, the effects of different doses of anandamide were assessed, and it was demonstrated that 5.0 and 10.0 mg/kg anandamide IP significantly suppressed lever pressing, while 2.5 mg/kg produced very little effect. The second study tested the effects of intraventricular (ICV) injections of AM 374, and it was observed that doses up to 10.0, 20.0 and 40 microg AM 374 had no significant effect upon lever pressing. The third study investigated the combined effect of AM374 with a low dose of anandamide. Rats received two drug injections: one ICV and one IP. Four different drug treatments were assessed: 1) ICV vehicle + IP vehicle, 2) ICV vehicle + 2.5 mg/kg anandamide IP, 3) ICV 20.0 microg AM 374 + IP vehicle, and 4) ICV 20 microg AM 374 + 2.5 mg/kg anandamide IP. Combined administration of AM 374 plus anandamide led to a significant decrease in lever pressing compared to either AM374 or anandamide administered alone. Observations of the animals treated with the combination of AM374 plus anandamide indicated that the drug combination resulted in motor slowing, which is consistent with the notion that stimulation of cannabinoid receptors produced a motor deficit that interfered with lever pressing. Although AM374 produced no effect on its own, this amidase inhibitor did enhance the behavioral effect of a low dose of anandamide. These results are consistent with the notion that AM 374 inhibited the enzymatic breakdown of exogenously injected anandamide. This type of procedure can be used to assess a variety of different compounds for their ability to inhibit cannabinoid metabolism.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Arachidonic Acids/pharmacology , Behavior, Animal/drug effects , Cannabinoids/metabolism , Conditioning, Operant/drug effects , Enzyme Inhibitors/pharmacology , Palmitates/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Synergism , Endocannabinoids , Injections, Intraperitoneal , Injections, Intraventricular , Male , Polyunsaturated Alkamides , Rats , Rats, Sprague-Dawley , Reinforcement Schedule
13.
Behav Pharmacol ; 14(8): 583-8, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14665975

ABSTRACT

Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.


Subject(s)
Feeding Behavior/drug effects , Receptor, Cannabinoid, CB1/drug effects , Receptor, Cannabinoid, CB1/physiology , Animals , Appetite/drug effects , Bradykinin/antagonists & inhibitors , Cannabinoids/antagonists & inhibitors , Dose-Response Relationship, Drug , Male , Piperidines , Pyrazoles , Rats , Rats, Sprague-Dawley , Receptors, Drug/antagonists & inhibitors , Reinforcement Schedule , Rimonabant
14.
Brain Res Bull ; 62(3): 197-202, 2003 Dec 30.
Article in English | MEDLINE | ID: mdl-14698353

ABSTRACT

The typical response to acute peripheral administration of low to high doses of ethanol in rats is a dose-dependent depression of motor activity. Nevertheless, recent studies indicate that intraventricular (ICV) injections of ethanol can produce signs of behavioral activation. In addition, considerable evidence indicates that brain metabolism of ethanol is involved in modulating some of the behavioral effects of this drug, which suggests that ethanol may have active metabolites with central actions. The present study was undertaken to investigate the effects of ICV ethanol, and its two major metabolites acetaldehyde and acetate, on open field locomotor activity in rats. Male Sprague-Dawley rats received different doses of ethanol, acetaldehyde or acetate ICV and immediately were placed in an open field chamber in which locomotion was measured. Rats injected with ICV ethanol or acetaldehyde showed an inverted U-shaped dose-response curve, with moderate doses increasing motor activity. In contrast, acetate produced a dose-dependent decrease in motor activity. These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats, and suggest that acetaldehyde may be an active metabolite of ethanol that also can facilitate locomotor activity. Moreover, it is possible that some of the motor suppression or sedation produced by ethanol is due to the central actions of acetate.


Subject(s)
Acetaldehyde/pharmacology , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Motor Activity/drug effects , Acetates/pharmacology , Animals , Anxiety , Behavior, Animal/drug effects , Central Nervous System Depressants/metabolism , Ethanol/metabolism , Injections, Intraventricular , Male , Rats , Rats, Sprague-Dawley
15.
Psychopharmacology (Berl) ; 170(4): 368-75, 2003 Dec.
Article in English | MEDLINE | ID: mdl-12955297

ABSTRACT

RATIONALE: Low doses of ethanol stimulate locomotion in mice, but in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of locomotion. Moreover, chronic ethanol administration fails to produce signs of locomotor sensitization in rats. OBJECTIVE: The present study was undertaken to determine whether intraventricular (i.c.v.) infusions of low doses of ethanol (as determined by comparisons with systemic doses, and by analyses of brain extract ethanol levels) could increase locomotor activity in rats after acute or repeated administration. METHODS: Male rats received acute doses of ethanol i.p. (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) or i.c.v. (0.0, 0.7, 1.4, or 2.8 micromol) and were tested for motor activity. In a third experiment, repeated i.c.v. vehicle or ethanol (2.8 micromol) was administered for 15 sessions over a 30-day period, and motor activity was recorded. This phase was followed by a single challenge session, in which a low dose of ethanol (0.7 micromol) was injected i.c.v. to both groups of rats. RESULTS: Rats injected with i.p. ethanol showed no increase in activity at low doses, with higher doses suppressing activity. In contrast, i.c.v. injections of low doses of ethanol increased motor activity. After repeated administration, ethanol-treated rats were more sensitive than control-treated rats to the locomotor stimulant effect of ethanol. CONCLUSIONS: These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats and suggest that i.c.v. ethanol can produce some signs of motor sensitization, a characteristic that has been related to the potential addictive properties of many drugs.


Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Locomotion/drug effects , Animals , Central Nervous System Depressants/administration & dosage , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Injections, Intraperitoneal , Injections, Intraventricular , Male , Rats , Rats, Sprague-Dawley
16.
Neuroscience ; 119(3): 759-66, 2003.
Article in English | MEDLINE | ID: mdl-12809696

ABSTRACT

Substantia nigra pars reticulata (SNr) is an important mesencephalic nucleus that functions as a relay area for basal ganglia output. SNr receives GABAergic inputs from the neostriatum and globus pallidus, and in turn sends projections to a variety of motor areas. Although a large number of studies have focused upon the behavioral functions of basal ganglia dopamine, much less is known about the behavioral functions of SNr GABA. The present studies were undertaken to investigate the role of SNr GABA in lever pressing behavior. In the first experiment, the GABA(A) antagonist bicuculline was infused locally into SNr to determine if blockade of GABA receptors interfered with the performance of lever pressing on a fixed ratio 5 schedule. SNr injections of bicuculline produced a dose-related suppression of operant responding. Analysis of interresponse time bins showed that SNr bicuculline produced a response slowing characterized by a relative reduction in the number of fast interresponse times, and an increase in the relative number of pauses. In an additional experiment, microdialysis methods were used to determine if extracellular GABA is elevated during the performance of fixed ratio five lever pressing. During the 30 min lever pressing session, extracellular GABA showed a significant and substantial increase relative to baseline levels. These data support the hypothesis that SNr GABA is involved in the regulation of motor output, and indicate that GABA release in this structure is increased during behavioral stimulation.


Subject(s)
Basal Ganglia/metabolism , Efferent Pathways/metabolism , Motor Activity/physiology , Movement/physiology , Neural Inhibition/physiology , Substantia Nigra/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Basal Ganglia/cytology , Basal Ganglia/drug effects , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Dose-Response Relationship, Drug , Efferent Pathways/cytology , Efferent Pathways/drug effects , Extracellular Space/metabolism , GABA Antagonists/pharmacology , GABA-A Receptor Antagonists , Male , Microdialysis , Movement/drug effects , Neural Inhibition/drug effects , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Reaction Time/physiology , Receptors, GABA-A/metabolism , Substantia Nigra/cytology , Substantia Nigra/drug effects , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Up-Regulation/drug effects , Up-Regulation/physiology
18.
Nat Immunol ; 2(12): 1126-32, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11702067

ABSTRACT

Using gene expression profiling, we show here that activation of B cells and professional antigen-presenting cells (APCs) induces the expression of common chemokines. Among these, CCL4 was the most potent chemoattractant of a CD4+CD25+ T cell population, which is a characteristic phenotype of regulatory T cells. Depletion of either regulatory T cells or CCL4 resulted in a deregulated humoral response, which culminated in the production of autoantibodies. This suggested that the recruitment of regulatory T cells to B cells and APCs by CCL4 plays a central role in the normal initiation of T cell and humoral responses, and failure to do this leads to autoimmune activation.


Subject(s)
Antigen-Presenting Cells/immunology , Autoimmunity , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Chemotaxis, Leukocyte , Macrophage Inflammatory Proteins/physiology , Animals , Antigen-Presenting Cells/drug effects , Autoantibodies/biosynthesis , CD4-Positive T-Lymphocytes/drug effects , Cells, Cultured , Chemokine CCL4 , Chemokines/biosynthesis , Gene Expression Profiling , Germinal Center/cytology , Immunophenotyping , Lymphocyte Activation , Lymphocyte Depletion , Macrophage Inflammatory Proteins/pharmacology , Mice , RNA, Messenger/biosynthesis , Receptors, Interleukin-2/physiology , T-Lymphocyte Subsets/classification , Up-Regulation
19.
J Pharmacol Exp Ther ; 298(3): 1172-8, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11504817

ABSTRACT

Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell factor receptor were inhibited with an IC(50) of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms-like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC(50) of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.


Subject(s)
Carotid Artery Injuries/pathology , Neovascularization, Pathologic/prevention & control , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Angioplasty, Balloon , Animals , CHO Cells , Cell Division/drug effects , Cell Movement/drug effects , Cricetinae , Cytoplasm/drug effects , Cytoplasm/enzymology , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Humans , Neovascularization, Pathologic/pathology , Phosphorylation , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Recombinant Proteins/biosynthesis , Recombinant Proteins/isolation & purification , Signal Transduction/drug effects , Thymidine/metabolism
20.
Proc Natl Acad Sci U S A ; 98(17): 9563-8, 2001 Aug 14.
Article in English | MEDLINE | ID: mdl-11504941

ABSTRACT

Transcriptional activation by, and therefore the physiologic impact of, activated tyrosine-phosphorylated STATs (signal transducers and activators of transcription) may be negatively regulated by proteins termed PIAS (protein inhibitors of activated stats), as shown by previous experiments with mammalian cells in culture. Here, by using the genetic modifications in Drosophila, we demonstrate the in vivo functional interaction of the Drosophila homologues stat92E and a Drosophila PIAS gene (dpias). To this end we use a LOF allele and conditionally overexpressed dpias in JAK-STAT pathway mutant backgrounds. We conclude that the correct dpias/stat92E ratio is crucial for blood cell and eye development.


Subject(s)
Carrier Proteins/physiology , DNA-Binding Proteins/antagonists & inhibitors , Drosophila Proteins , Drosophila melanogaster/metabolism , Insect Proteins/physiology , Intracellular Signaling Peptides and Proteins , Proteins/physiology , Trans-Activators/antagonists & inhibitors , Alleles , Animals , Carrier Proteins/genetics , Drosophila melanogaster/embryology , Drosophila melanogaster/genetics , Eye/embryology , Eye/ultrastructure , Eye Abnormalities/genetics , Gene Expression Regulation, Developmental , Insect Proteins/genetics , Janus Kinases , Morphogenesis , Mutagenesis, Insertional , Neoplasms, Experimental/genetics , Phosphorylation , Protein Inhibitors of Activated STAT , Protein Processing, Post-Translational , Protein-Tyrosine Kinases/metabolism , Proteins/genetics , Recombination, Genetic , STAT Transcription Factors , Signal Transduction , Transcription Factors
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