ABSTRACT
Kleefstra syndrome is a disorder caused by a mutation in the EHMT1 gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized cumulative memory in the Ehmt1+/- mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model, and a trial-based classifier. Ehmt1+/- mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration, Ehmt1+/- show increased expression of cumulative memory, but a deficit in a more simple, control memory condition. Using our automatic classifier to differentiate between genotypes, we found that cumulative memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of the Ehmt1+/- mouse model.
Subject(s)
Behavior, Animal/physiology , Craniofacial Abnormalities/physiopathology , Exploratory Behavior/physiology , Heart Defects, Congenital/physiopathology , Intellectual Disability/physiopathology , Memory/physiology , Animals , Chromosome Deletion , Chromosomes, Human, Pair 9/genetics , Craniofacial Abnormalities/genetics , Deep Learning , Disease Models, Animal , Heart Defects, Congenital/genetics , Histone-Lysine N-Methyltransferase/genetics , Intellectual Disability/genetics , Male , MiceABSTRACT
OBJECTIVE: According to a report published by the federation of Dutch patients' associations, patients would like to see a pharmacist, who acts more as a personal adviser. This raised the question, how often Dutch community pharmacists have personal consultations with their patients in daily practice, on which factors this depends, and what kind of topics are discussed during these meetings. SETTING: Community pharmacies in the Netherlands. METHOD: A questionnaire was distributed among 800 randomly selected pharmacies. Questions were restricted to consultations characterized by one-to-one contact, drug therapy related content, and adequate privacy. These consultations were labelled as pharmaceutical consultations in private to distinguish them from other contacts between pharmacists and patients. MAIN OUTCOME MEASURE: Number, content, and character of consultations. RESULTS: 198 (24.8%) community pharmacies responded. The pharmacists provide an average of roughly 1.2 consultations in private per working day. The vast majority of respondents provided face-to-face and telephone consultations (94.4 and 91.9%, respectively), only a minority gave consultations by e-mail (30.8%). These consultations primarily dealt with topics related to medication safety. The mean overall time spent was 290 min per month. A relatively high frequency of personal consultations was significantly associated with the absolute number of full-time equivalent pharmacists in the pharmacy. CONCLUSION: The frequency of pharmaceutical consultations in private is low, but may be improved by reorganisation of the pharmacist's activities. The possibility of personal consultations by e-mail is not yet well-developed. Further research is needed to assess the patient's view of pharmaceutical consultations in private.
Subject(s)
Community Pharmacy Services/statistics & numerical data , Patient Education as Topic/standards , Pharmacists , Professional Role , Professional-Patient Relations , Referral and Consultation/statistics & numerical data , Adult , Communication , Community Pharmacy Services/standards , Drug-Related Side Effects and Adverse Reactions , Female , Health Care Surveys , Humans , Male , Netherlands , Patient Satisfaction , Task Performance and Analysis , Workforce , WorkloadABSTRACT
Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation.
