Pharmacy-Based Opportunistic Atrial Fibrillation Screening at a Community Level: A Real-Life Study.

PURPOSE: Opportunistic pharmacy-based screening of atrial fibrillation (AF) appears effective, but the proportion of detected citizens is unknown. The aim of our real-life study was to determine rates of screening in a community population according to age group and gender. METHODS: We conducted four community campaigns of pharmacy-based single-time point AF screening that involved individuals ≥65 years. We used a single-lead and hand-held device MyDiagnostick (6229 EV Maastricht, The Netherlands) that generates a 60-s ECG trace. All pharmacies of the communities (n = 54) were involved. Rates of screening were assessed on the base of the French National Institute for Statistics and Economic Studies data and were expressed as percentage and 95% Confidence interval (CI). RESULTS: We screened 4208 individuals (Mean age, 74.2 ± 6.6 years; females, 60.2%). The screening rate in citizens aged ≥65 years was 17.2% (16.6-17.7), and higher in females than in males (17.9% [17.3-18.6] versus 16.0 [15.3-16.8], p < 0.001). The 70-74 age group showed the highest rate (25.7% [24.4-27]) compared to other groups. After 74 years, screening rates decreased steadily with age and dropped to 4.8% [3.8-6.1] in very elderly (≥90). Among the 188 (4.47%) positive screening, 117 (2.78%) showed an AF that was unknown in 53 (1.26%). Increasing age (OR: 1.05 [1.00-1.09], p = 0.04), male sex (OR: 4.30 [2.33-7.92], p < 0.0001) and high CHA2DS2-Vasc (OR: 1.59 [1.21-2.09], p = 0.0008) were independent predictors of unknown AF. CONCLUSION: Single-lead AF detection performed in community pharmacies result in screening one in six elderly citizens. Although male sex and elderly predicted unknown AF diagnosis, they were less involved in such designed campaigns.

3-D motion capture for long-term tracking of spontaneous locomotor behaviors and circadian sleep/wake rhythms in mouse.

BACKGROUND: Locomotor activity provides an index of an animal's behavioral state. Here, we report a reliable and cost-effective method that allows long-term (days to months) simultaneous tracking of locomotion in mouse cohorts (here consisting of 24 animals). NEW METHOD: The technique is based on a motion capture system used mainly for human movement study. A reflective marker was placed on the head of each mouse using a surgical procedure and labeled animals were returned to their individual home cages. Camera-recorded data of marker displacement resulting from locomotor movements were then analyzed with custom built software. To avoid any data loss, data files were saved every hour and automatically concatenated. Long-term recordings (up to 3 months) with high spatial (<1mm) and temporal (up to 100Hz) resolution of animal movements were obtained. RESULTS: The system was validated by analyzing the spontaneous activity of mice from post-natal day 30-90. Daily motor activity increased up to 70days in correspondence with maturational changes in locomotor performance. The recorded actigrams also permitted analysis of circadian and ultradian rhythms in cohort sleep/wake behavior. COMPARISON WITH EXISTING METHOD(S): In contrast to traditional session-based experimental approaches, our technique allows locomotor activity to be recorded with minimal experimenter manipulation, thereby minimizing animal stress. CONCLUSIONS: Our method enables the continuous long-term (up to several months) monitoring of tens of animals, generating manageable amounts of data at minimal costs without requiring individual dedicated devices. The actigraphic data collected allows circadian and ultradian analysis of sleep/wake behaviors to be performed.

Age-Related Changes in Pre- and Postsynaptic Partners of the Cholinergic C-Boutons in Wild-Type and SOD1G93A Lumbar Motoneurons.

Large cholinergic synaptic terminals known as C-boutons densely innervate the soma and proximal dendrites of motoneurons that are prone to neurodegeneration in amyotrophic lateral sclerosis (ALS). Studies using the Cu/Zn-superoxide dismutase (SOD1) mouse model of ALS have generated conflicting data regarding C-bouton alterations exhibited during ALS pathogenesis. In the present work, a longitudinal study combining immunohistochemistry, biochemical approaches and extra- and intra-cellular electrophysiological recordings revealed that the whole spinal cholinergic system is modified in the SOD1 mouse model of ALS compared to wild type (WT) mice as early as the second postnatal week. In WT motoneurons, both C-bouton terminals and associated M2 postsynaptic receptors presented a complex age-related dynamic that appeared completely disrupted in SOD1 motoneurons. Indeed, parallel to C-bouton morphological alterations, analysis of confocal images revealed a clustering process of M2 receptors during WT motoneuron development and maturation that was absent in SOD1 motoneurons. Our data demonstrated for the first time that the lamina X cholinergic interneurons, the neuronal source of C-boutons, are over-abundant in high lumbar segments in SOD1 mice and are subject to neurodegeneration in the SOD1 animal model. Finally, we showed that early C-bouton system alterations have no physiological impact on the cholinergic neuromodulation of newborn motoneurons. Altogether, these data suggest a complete reconfiguration of the spinal cholinergic system in SOD1 spinal networks that could be part of the compensatory mechanisms established during spinal development.

Monoaminergic control of spinal locomotor networks in SOD1G93A newborn mice.

Mutations in the gene that encodes Cu/Zn-superoxide dismutase (SOD1) are the cause of approximately 20% of familial forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While ALS symptoms appear in adulthood, spinal motoneurons exhibit functional alterations as early as the embryonic and postnatal stages in the murine model of ALS, the SOD1 mice. Monoaminergic - i.e., dopaminergic (DA), serotoninergic (5-HT), and noradrenergic (NA) - pathways powerfully control spinal networks and contribute significantly to their embryonic and postnatal maturation. Alterations in monoaminergic neuromodulation during development could therefore lead to impairments in the motoneuronal physiology. In this study, we sought to determine whether the monoaminergic spinal systems are modified in the early stages of development in SOD1 mice. Using a post-mortem analysis by high performance liquid chromatography (HPLC), monoaminergic neuromodulators and their metabolites were quantified in the lumbar spinal cord of SOD1 and wild-type (WT) mice aged one postnatal day (P1) and P10. This analysis underscores an increased content of DA in the SOD1 lumbar spinal cord compared to that of WT mice but failed to reveal any modification of the other monoaminergic contents. In a next step, we compared the efficiency of the monoaminergic compounds in triggering and modulating fictive locomotion in WT and SOD1 mice. This study was performed in P1-P3 SOD1 mice and age-matched control littermates using extracellular recordings from the lumbar ventral roots in the in vitro isolated spinal cord preparation. This analysis revealed that the spinal networks of SOD1(G93A) mice could generate normal locomotor activity in the presence of NMA-5-HT. Interestingly, we also observed that SOD1 spinal networks have an increased sensitivity to NA compared to WT spinal circuits but exhibited similar DA responses.

Noradrenergic terminals regulate L-DOPA-derived dopamine extracellular levels in a region-dependent manner in Parkinsonian rats.

AIMS: Serotonin (5-HT) neurons mediate the ectopic release of dopamine (DA) induced by L-DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of L-DOPA in extrastriatal regions compared with the striatum. METHODS: Using a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5-HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6-hydroxydopamine-lesioned rats. RESULTS: L-DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated L-DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated L-DOPA effect in the SNr and HIPP. 5-HT extracellular levels were enhanced only when L-DOPA was combined to NET blockers. CONCLUSION: Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions.

Catecholamine/Serotonin interactions: systems thinking for brain function and disease.

This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative.