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  • Munthe, Christian, 1962-, et al. (författare)
  • The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening
  • 2015
  • Ingår i: Public Health Ethics. - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283
  • Tidskriftsartikel (refereegranskat)abstract
    • The vision of legendary criminologist Cesare Lombroso to use scientific theories of individual causes of crime as a basis for screening and prevention programmes targeting individuals at risk for future criminal behaviour has resurfaced, following advances in genetics, neuroscience and psychiatric epidemiology. This article analyses this idea and maps its ethical implications from a public health ethical standpoint. Twenty-seven variants of the new Lombrosian vision of forensic screening and prevention are distinguished, and some scientific and technical limitations are noted. Some lures, biases and structural factors, making the application of the Lombrosian idea likely in spite of weak evidence are pointed out and noted as a specific type of ethical aspect. Many classic and complex ethical challenges for health screening programmes are shown to apply to the identified variants and the choice between them, albeit with peculiar and often provoking variations. These variations are shown to actualize an underlying theoretical conundrum in need of further study, pertaining to the relationship between public health ethics and the ethics and values of criminal law policy.
  • Birnir, Bryndis, et al. (författare)
  • The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors
  • 2007
  • Ingår i: Current Pharmaceutical Design. - Bentham Science Publishers. - 1381-6128. ; 13:31, s. 3169-3177
  • Tidskriftsartikel (refereegranskat)abstract
    • Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
  • Curmi, J P, et al. (författare)
  • The influence of membrane potential on chloride channels activated by GABA in rat cultured hippocampal neurons
  • 1993
  • Ingår i: Journal of Membrane Biology. - Springer. - 0022-2631. ; 136:3, s. 273-280
  • Tidskriftsartikel (refereegranskat)abstract
    • Chloride currents were activated by a low concentration of GABA (0.5 microM) in neonatal rat hippocampal neurons cultured for up to 14 days. Currents elicited by 0.5 microM GABA in neurons, voltage-clamped using the whole-cell technique with pipettes containing 149 mM Cl-, reversed close to 0 mV whether pipettes contained 144 mM Na+ or 140 mM Cs+, and were blocked by 100 microM bicuculline. Current-voltage curves showed outward rectification. Single channel currents appeared in cell-attached patches when the pipette tip was perfused with pipette solution containing 0.5 microM GABA and disappeared when a solution containing 100 microM bicuculline plus 0.5 microM GABA was injected into the pipette tip. The channels showed outward rectification and, in some patches, had a much lower probability of opening at hyperpolarized potentials. The average chord conductance in 10 patches hyperpolarized by 80 mV was 7.8 +/- 1.6 pS (SEM) compared with a chord conductance of 34.1 +/- 3.5 pS (SEM) in the same patches depolarized by 80 mV. Similar single channel currents were also activated in cell-free, inside-out patches in symmetrical chloride solutions when 0.5 microM GABA was injected into the pipette tip. The channels showed outward rectification similar to that seen in cell-attached patches, and some channels had a lower probability of opening at hyperpolarized potentials. The average chord conductance in 13 patches hyperpolarized by 80 mV was 11.8 +/- 2.3 pS (SEM) compared with 42.1 +/- 3.1 pS (SEM) in the same patches depolarized by 80 mV.
  • Eghbali, M, et al. (författare)
  • Hippocampal GABA(A) channel conductance increased by diazepam
  • 1997
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836. ; 388:6637, s. 71-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.
  • Lindquist, Catarina E L, et al. (författare)
  • Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice
  • 2003
  • Ingår i: Molecular and Cellular Neuroscience. - Elsevier. - 1044-7431. ; 24:1, s. 250-257
  • Tidskriftsartikel (refereegranskat)abstract
    • Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 muM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 muM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 muM THIP plus 1 muM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 AM) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input. (C) 2003 Elsevier Science (USA). All rights reserved.
  • Rask-Andersen, Mathias, et al. (författare)
  • Advances in kinase targeting : current clinical use and clinical trials
  • 2014
  • Ingår i: TIPS - Trends in Pharmacological Sciences. - 0165-6147. ; 35:11, s. 60-76
  • Forskningsöversikt (övrigt vetenskapligt)abstract
    • Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
  • Rostami, Elham, 1979-, et al. (författare)
  • Mechanisms of Blast Induced Brain Injuries, Experimental Studies in Rats.
  • 2011
  • Ingår i: NeuroImage. - 1095-9572 .- 1053-8119. ; 54S1 2011/Epub 2010:54 suplement 1, s. S89-S97
  • Tidskriftsartikel (refereegranskat)abstract
    • Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2 mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects.
  • Wallén-Mackenzie, Åsa, et al. (författare)
  • Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
  • 2009
  • Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 29:7, s. 2238-51
  • Tidskriftsartikel (refereegranskat)abstract
    • A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
  • Wernstedt Asterholm, Ingrid, et al. (författare)
  • Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.
  • 2014
  • Ingår i: Cell metabolism. - 1932-7420. ; 20:1, s. 103-18
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae. In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion. Three mouse models with an adipose tissue-specific reduction in proinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaltered in vitro. Upon high-fat-diet exposure, the expansion of visceral adipose tissue is prominently affected. This is associated with decreased intestinal barrier function, increased hepatic steatosis, and metabolic dysfunction. An impaired local proinflammatory response in the adipocyte leads to increased ectopic lipid accumulation, glucose intolerance, and systemic inflammation. Adipose tissue inflammation is therefore an adaptive response that enables safe storage of excess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin.
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