3,667 research outputs found

    Cortical circuit alterations precede motor impairments in Huntington's disease mice

    Get PDF
    Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD

    Short-term health effects in the general population following a major train accident with acrylonitrile in Belgium

    Get PDF
    Background: Following a train derailment, several tons of acrylonitrile (ACN) exploded, inflamed and part of the ACN ended up in the sewage system of the village of Wetteren. More than 2000 residents living in the close vicinity of the accident and along the sewage system were evacuated. A human biomonitoring study of the adduct N-2-cyanoethylvaline (CEV) was carried out days 14-21 after the accident. Objectives: (1) To describe the short-term health effects that were reported by the evacuated residents following the train accident, and (2) to explore the association between the CEV concentrations, extrapolated at the time of the accident, and the self-reported short-term health effects. Methods: Short-term health effects were reported in a questionnaire (n=191). An omnibus test of independence was used to investigate the association between the CEV concentrations and the symptoms. Dose-response relationships were quantified by Generalized Additive Models (GAMs). Results: The most frequently reported symptoms were local symptoms of irritation. In non-smokers, dose-dependency was observed between the CEV levels and the self-reporting of irritation (p=0.007) and nausea (p=0.007). Almost all non-smokers with CEV concentrations above 100 pmol/g globin reported irritation symptoms. Both absence and presence of symptoms was reported by non-smokers with CEV concentrations below the reference value and up to 10 times the reference value. Residents who visited the emergency services reported more symptoms. This trend was seen for the whole range of CEV concentrations, and thus independently of the dose. Discussion and conclusion: The present study is one of the first to relate exposure levels to a chemical released during a chemical incident to short-term (self-reported) health effects. A dose-response relation was observed between the CEV concentrations and the reporting of short-term health effects in the non-smokers. Overall, the value of self-reported symptoms to assess exposure showed to be limited. The results of this study confirm that a critical view should be taken when considering self-reported health complaints and that ideally biomarkers are monitored to allow an objective assessment of exposure

    Introduction of Macromolecules into Bovine Adrenal Medullary Chromaffin Cells and Rat Pheochromocytoma Cells (PC12) by Permeabilization with Streptolysin O: Inhibitory Effect of Tetanus Toxin on Catecholamine Secretion

    Get PDF
    Conditions are described for controlled plasma membrane permeabilization of rat pheochromocytoma cells (PC12) and cultured bovine adrenal chromaffin cells by Streptolysin O (SLO). The transmembrane pores created by SLO invoke rapid efflux of intracellular 86Rb+ and ATP, and also permit passive diffusion of proteins, including immunoglobulins, into the cells. SLO-permeabilized PC12 cells release [3H]dopamine in response to micromolar concentrations of free Ca2+. Permeabilized adrenal chromaffin cells present a similar exocytotic response to Ca2+ in the presence of Mg2+/ ATP. Permeabilized PC12 cells accumulate antibodies against synaptophysin and calmodulin, but neither antibody reduces the Ca2+-dependent secretory response. Reduced tetanus toxin, although ineffective when applied to intact chromaffin cells, inhibits Ca2+-induced exocytosis by both types of permeabilized cells studied. Omission of dithiothreitol, toxin inactivation by boiling, or preincubation with neutralizing antibodies abolishes the inhibitory effect. The data indicate that plasma membrane permeabilization by Streptolysin O is a useful tool to probe and define cellular components that are involved in the final steps of exocytosis

    Exact ground states for a class of one-dimensional frustrated quantum spin models

    Full text link
    We have found the exact ground state for two frustrated quantum spin-1/2 models on a linear chain. The first model describes ferromagnet- antiferromagnet transition point. The singlet state at this point has double-spiral ordering. The second model is equivalent to special case of the spin-1/2 ladder. It has non-degenerate singlet ground state with exponentially decaying spin correlations and there is an energy gap. The exact ground state wave function of these models is presented in a special recurrent form and recurrence technics of expectation value calculations is developed.Comment: 16 pages, 3 figures, RevTe

    Advancing a global pharmacy support workforce through a global strategic platform

    Get PDF
    The pharmacy support workforce (PSW) is the mid-level cadre of the global pharmacy profession, referring to pharmacy technicians, assistants and other cadres that assist in the delivery of pharmaceutical services in a variety of practice contexts. The PSW undertake technical tasks delegated under the supervision of a pharmacist or performed collaboratively. The PSW are not intended to replace pharmacists, but rather work side-by-side with the pharmacist to achieve a shared goal. However, extensive variation in the PSW exists globally, ranging from an educated, regulated, and highly effective workforce in some countries to unrecognized or non-existent in others. Vast differences in education requirements, specific roles, regulatory oversight, and need for pharmacist supervision, inhibit the development and advancement of a global PSW. As clinical care providers, pharmacists worldwide need for a competent support workforce. Without the confidence to delegate technical responsibilities to a well-trained and capable PSW, pharmacists will be unable to fully deliver advanced clinical roles. A clear vision for the role of the PSW in the expanding scope of pharmacy practice is needed. One organization working to unite global efforts in this area is the International Pharmaceutical Federation (FIP). The FIP Workforce Development Hub Pharmacy Technicians & Support Workforce Strategic Platform was established to address the pharmacy workforce shortage in low and middle-income countries. Further developments were made in 2019, with the creation of a representative global PSW advisory panel, to provide guidance towards the development of the global PSW. Provision of frameworks and strategic input to support quality in education, development of legislative frameworks, guidelines for registration and licensure, and advice on appropriate role advancement are critical to move the PSW forward. In order to produce substantial advancement of roles and recognition of the PSW and advancement of pharmacists as patient care providers, global collaborative work is needed

    Bradykinin-induced microglial migration mediated by B1-bradykinin receptors depends on Ca2+ influx via reverse-mode activity of the Na+/Ca2+ exchanger

    Get PDF
    Bradykinin (BK) is produced and acts at the site of injury and inflammation. In the CNS, migration of microglia toward the lesion site plays an important role pathologically. In the present study, we investigated the effect of BK on microglial migration. Increased motility of cultured microglia was mimicked by B1 receptor agonists and markedly inhibited by a B1 antagonist but not by a B2 receptor antagonist. BK induced chemotaxis in microglia isolated from wild-type and B2-knock-out mice but not from B1-knock-out mice. BK-induced motility was not blocked by pertussis toxin but was blocked by chelating intracellular Ca2+ or by low extracellular Ca2+, implying that Ca2+ influx is prerequisite. Blocking the reverse mode of Na+/Ca2+ exchanger (NCX) completely inhibited BK-induced migration. The involvement of NCX was further confirmed by using NCX+/- mice; B1-agonist-induced motility and chemotaxis was decreased compared with that in NCX+/+ mice. Activation of NCX seemed to be dependent on protein kinase C and phosphoinositide 3-kinase, and resultant activation of intermediate-conductance (IK-type) Ca2+-dependent K+ currents (I(K(Ca))) was activated. Despite these effects, BK did not activate microglia, as judged from OX6 staining. Using in vivo lesion models and pharmacological injection to the brain, it was shown that microglial accumulation around the lesion was also dependent on B1 receptors and I(K(Ca)). These observations support the view that BK functions as a chemoattractant by using the distinct signal pathways in the brain and, thus, attracts microglia to the lesion site in vivo

    Where do Children Travel to and What Local Opportunities Are Available? The Relationship Between Neighborhood Destinations and Children’s Independent Mobility

    Full text link
    Associations between access to local destinations and children’s independent mobility (IM) were examined. In 2007, 10- to 12-year-olds (n = 1,480) and their parents (n = 1,314) completed a survey. Children marked on a map the destinations they walked or cycled to (n = 1,132), and the availability of local destinations was assessed using Geographic Information Systems. More independently mobile children traveled to local destinations than other children. The odds of IM more than halved in both boys and girls whose parents reported living on a busy road (boys, OR = 0.48; girls, OR = 0.36) and in boys who lived near shopping centers (OR = 0.18) or community services (OR = 0.25). Conversely, the odds of IM more than doubled in girls living in neighborhoods with well-connected low-traffic streets (OR = 2.32) and increased in boys with access to local recreational (OR = 1.67) and retail (OR = 1.42) destinations. Creating safe and accessible places and routes may facilitate children’s IM, partly by shaping parent’s and children’s feelings of safety while enhancing their confidence in the child’s ability to use active modes without an adult

    A lattice in more than two Kac--Moody groups is arithmetic

    Full text link
    Let Γ\Gamma be an irreducible lattice in a product of n infinite irreducible complete Kac-Moody groups of simply laced type over finite fields. We show that if n is at least 3, then each Kac-Moody groups is in fact a simple algebraic group over a local field and Γ\Gamma is an arithmetic lattice. This relies on the following alternative which is satisfied by any irreducible lattice provided n is at least 2: either Γ\Gamma is an S-arithmetic (hence linear) group, or it is not residually finite. In that case, it is even virtually simple when the ground field is large enough. More general CAT(0) groups are also considered throughout.Comment: Subsection 2.B was modified and an example was added ther
    • …
    corecore