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Lamina-specific AMPA receptor dynamics following visual deprivation in vivo.
Regulation of AMPA receptor (AMPAR) expression is central to synaptic plasticity and brain function, but how these changes occur in vivo remains elusive. Here, we developed a method to longitudinally monitor the expression of synaptic AMPARs across multiple cortical layers in awake mice using two-photon imaging. We observed that baseline AMPAR expression in individual spines is highly dynamic with more dynamics in primary visual cortex (V1) layer 2/3 (L2/3) neurons than V1 L5 neurons. Visual deprivation through binocular enucleation induces a synapse-specific and depth-dependent change of synaptic AMPARs in V1 L2/3 neurons, wherein deep synapses are potentiated more than superficial synapses. The increase is specific to L2/3 neurons and absent on apical dendrites of L5 neurons, and is dependent on expression of the AMPAR-binding protein GRIP1. Our study demonstrates that specific neuronal connections, across cortical layers and even within individual neurons, respond uniquely to changes in sensory experience
Anomalous Diffusion at Edge and Core of a Magnetized Cold Plasma
Progress in the theory of anomalous diffusion in weakly turbulent cold
magnetized plasmas is explained. Several proposed models advanced in the
literature are discussed. Emphasis is put on a new proposed mechanism for
anomalous diffusion transport mechanism based on the coupled action of
conductive walls (excluding electrodes) bounding the plasma drain current (edge
diffusion) together with the magnetic field flux "cutting" the area traced by
the charged particles in their orbital motion. The same reasoning is shown to
apply to the plasma core anomalous diffusion. The proposed mechanism is
expected to be valid in regimes when plasma diffusion scales as Bohm diffusion
and at high , when collisions are of secondary importance.Comment: 9 pages, 4 figure
Anomalous Workfunction Anisotropy in Ternary Acetylides
Anomalous anisotropy of workfunction values in ternary alkali metal
transition metal acetylides is reported. Workfunction values of some
characteristic surfaces in these emerging semiconducting materials may differ
by more than 2 eV as predicted by Density Functional Theory
calculations. This large anisotropy is a consequence of the relative
orientation of rod-like [MC] negatively charged polymeric
subunits and the surfaces, with M being a transition metal or metalloid element
and C refers to the acetylide ion C, with the rods embedded
into an alkali cation matrix. It is shown that the conversion of the seasoned
CsTe photo-emissive material to ternary acetylide CsTeC
results in substantial reduction of its 3 eV workfunction down to
1.71-2.44 eV on the CsTeC(010) surface while its high quantum yield
is preserved. Similar low workfunction values are predicted for other ternary
acetylides as well, allowing for a broad range of applications from improved
electron- and light-sources to solar cells, field emission displays, detectors
and scanners.Comment: Accepted for publication in Phys. Rev.
Emerging pharmacotherapy of tinnitus
Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Instituto de Investigaciones en IngenierÃa Genética y BiologÃa Molecular "Dr. Héctor N. Torres"; Argentin
Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications
Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor. Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors
How are falls and fear of falling associated with objectively measured physical activity in a cohort of community-dwelling older men?
BACKGROUND: Falls affect approximately one third of community-dwelling older adults each year and have serious health and social consequences. Fear of falling (FOF) (lack of confidence in maintaining balance during normal activities) affects many older adults, irrespective of whether they have actually experienced falls. Both falls and fear of falls may result in restrictions of physical activity, which in turn have health consequences. To date the relation between (i) falls and (ii) fear of falling with physical activity have not been investigated using objectively measured activity data which permits examination of different intensities of activity and sedentary behaviour.
METHODS: Cross-sectional study of 1680 men aged 71-92 years recruited from primary care practices who were part of an on-going population-based cohort. Men reported falls history in previous 12 months, FOF, health status and demographic characteristics. Men wore a GT3x accelerometer over the hip for 7 days.
RESULTS: Among the 12% of men who had recurrent falls, daily activity levels were lower than among non-fallers; 942 (95% CI 503, 1381) fewer steps/day, 12(95% CI 2, 22) minutes less in light activity, 10(95% CI 5, 15) minutes less in moderate to vigorous PA [MVPA] and 22(95% CI 9, 35) minutes more in sedentary behaviour. 16% (n = 254) of men reported FOF, of whom 52% (n = 133) had fallen in the past year. Physical activity deficits were even greater in the men who reported that they were fearful of falling than in men who had fallen. Men who were fearful of falling took 1766(95% CI 1391, 2142) fewer steps/day than men who were not fearful, and spent 27(95% CI 18, 36) minutes less in light PA, 18(95% CI 13, 22) minutes less in MVPA, and 45(95% CI 34, 56) minutes more in sedentary behaviour. The significant differences in activity levels between (i) fallers and non-fallers and (ii) men who were fearful of falling or not fearful, were mediated by similar variables; lower exercise self-efficacy, fewer excursions from home and more mobility difficulties.
CONCLUSIONS: Falls and in particular fear of falling are important barriers to older people gaining health benefits of walking and MVPA. Future studies should assess the longitudinal associations between falls and physical activity
Dietary carbohydrate restriction as the first approach in diabetes management:Critical review and evidence base
AbstractThe inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk, or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines. The benefits of carbohydrate restriction in diabetes are immediate and well documented. Concerns about the efficacy and safety are long term and conjectural rather than data driven. Dietary carbohydrate restriction reliably reduces high blood glucose, does not require weight loss (although is still best for weight loss), and leads to the reduction or elimination of medication. It has never shown side effects comparable with those seen in many drugs. Here we present 12 points of evidence supporting the use of low-carbohydrate diets as the first approach to treating type 2 diabetes and as the most effective adjunct to pharmacology in type 1. They represent the best-documented, least controversial results. The insistence on long-term randomized controlled trials as the only kind of data that will be accepted is without precedent in science. The seriousness of diabetes requires that we evaluate all of the evidence that is available. The 12 points are sufficiently compelling that we feel that the burden of proof rests with those who are opposed
Quantifying the effect of uncertainty in input parameters in a simplified bidomain model of partial thickness ischaemia
Reduced blood flow in the coronary arteries can lead to damaged heart tissue (myocardial ischaemia). Although one method for detecting myocardial ischaemia involves changes in the ST segment of the electrocardiogram, the relationship between these changes and subendocardial ischaemia is not fully understood. In this study, we modelled ST-segment epicardial potentials in a slab model of cardiac ventricular tissue, with a central ischaemic region, using the bidomain model, which considers conduction longitudinal, transverse and normal to the cardiac fibres. We systematically quantified the effect of uncertainty on the input parameters, fibre rotation angle, ischaemic depth, blood conductivity and six bidomain conductivities, on outputs that characterise the epicardial potential distribution. We found that three typical types of epicardial potential distributions (one minimum over the central ischaemic region, a tripole of minima, and two minima flanking a central maximum) could all occur for a wide range of ischaemic depths. In addition, the positions of the minima were affected by both the fibre rotation angle and the ischaemic depth, but not by changes in the conductivity values. We also showed that the magnitude of ST depression is affected only by changes in the longitudinal and normal conductivities, but not by the transverse conductivities
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