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The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic signaling wherein it controls both the spatial and temporal actions of dopamine. Here we evaluated the behavioral and neurochemical consequences of increased DAT function by generating DAT transgenic mice (DAT-tg) that overexpress the transporter. These mice were generated by pronuclear injection of a bacterial artificial chromosome containing the mouse DAT locus, yielding an anatomical expression pattern of DAT-tg identical to WT. In DAT-tg mice there is a 3-fold increase in the levels of total and membrane-expressed DAT, but synaptic plasma membrane fractions of DAT-tg mice show only a 30% increase in transporter levels. Functional studies reveal that in the DAT-tg animals there is a 50% increase in the rate of dopamine (DA) uptake resulting in extracellular levels of DA that are decreased by [almost equal to]40%. Behaviorally, DAT-tg animals display similar locomotor stimulation when treated with DAT blockers such as GBR12909, methylphenidate, and cocaine. However, these mice demonstrate markedly increased locomotor responses to amphetamine compared with WT animals. Furthermore, compared with controls, there is a 3-fold greater increase in the amount of DA released by amphetamine in DAT-tg mice that correlates with the 3-fold increase in protein expression. Finally, DAT-tg animals show reduced operant responding for natural reward while displaying preference for amphetamine at much lower doses (0.2 and 0.5 mg/kg) than WT mice (2 mg/kg). These results suggest that overexpression of DAT leads to a marked increase in sensitivity to psychomotor and rewarding properties of amphetamine.

The reeler mouse ( Reln) has been proposed as a neurodevelopmental model for certain neurological and psychiatric conditions and has been studied by qualitative histochemistry and electron microscopy. Using magnetic resonance microscopy (MRM), we have quantitated for the first time the neuromorphology of Reln mice at a resolution of 21.5 μm. The neuroanatomical phenotypes of heterozygous and homozygous mutant Reln mice were compared to those of wild type (WT) littermates using morphometry and texture analysis. The cortical, hippocampal, and cerebellar phenotypes of the heterozygous and homozygous mutant Reln mice were confirmed, and new features were revealed. The Reln rl/rl mice possessed a smaller brain, and both Reln rl/+ and Reln rl/rl mice had increased ventricles compared to WT controls. Shape differences were found between WT and Reln rl/rl brains, specifically in cerebellum, olfactory bulbs, dorsomedial frontal and parietal cortex, certain regions of temporal and occipital lobes, as well as in the lateral ventricles and ventral hippocampus. These findings suggest that certain brain regions may be more severely impacted by the Reln mutation than others. Gadolinium-based active staining demonstrated that layers of the hippocampus were disorganized in Reln rl/rl mice and differences in thickness of these layers were identified between WT and Reln rl/rl mice. The intensity distributions characteristic to the dorsal, middle, and ventral hippocampus were altered in the Reln rl/rl , especially in the ventral hippocampus. These differences were quantified using skewness and modeling the intensity distributions with a Gaussian mixture. Our results suggest that structural features of Reln rl/rl brain most closely phenocopy those of patients with Norman–Roberts lissencephaly.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR’s pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

The receptors for interleukin 2 (IL‐2) and interleukin 15 (IL‐15) in T cells share the IL‐2Rβ subunit (CD122) and γC subunit but have private α subunits. Despite utilizing the same receptor chains known to be necessary and sufficient to transduce IL‐2 signals the two cytokines manifest different cellular effects. It is commonly held that the α subunit of the IL‐2R (CD25) is involved solely in the generation of a high affinity receptor complex. This is questioned by the development of autoimmune diseases in instances where the expression of CD25 is absent. The timely expression of CD25 in the thymus has been linked with clonal deletion. Evidence from peripheral T cells indicates that survival signals arising from the intermediate affinity IL‐2R (lacking CD25) do not require the activation of Janus kinase 3 (Jak3) but do require the presence of the membrane proximal region of the γC chain. This particular signalling pathway is not observed in the high affinity receptor complex where Jak3 is activated. Recent data point to CD25 having a surface distribution consistent with it being localized within membrane microdomains. Here we suggest that in the absence of CD25 expression, IL‐2R activation occurs within the soluble membrane fraction. This membrane environment and the absence of CD25 promotes Jak3 independent signal transduction and induction of antiapoptotic mechanisms. T cell antigen receptor (TCR) signalling leads to the induction of CD25 expression, which localizes to membrane microdomains. There is a dynamic pre‐association of CD25 and CD122 leading to the loose association of the heterodimer with membrane microdomains. High affinity IL‐2R signalling in the context of CD25 and the microdomain environment is characterized by Jak3 activation. The relative levels of high to intermediate affinity receptor signalling determines whether a cell proliferates or undergoes activation induced cell death dependent upon cell status.

Background: The World Health Organization’s global strategy presents compelling evidence for the need to develop people-centred and integrated health services. However, there is a dearth of literature on learning at the macro-systems level focused on ‘place’ that is required to meet these ambitions. Aims: This article positions place-based learning at the heart of integrated care to contribute understanding of learning for transformation to inform continuous improvement and workforce development. Second, using practice development methodology, it demonstrates how to develop a shared understanding for place-based learning, sustained through a co-created implementation and impact framework. Methods: Five facilitated co-creation workshops with key stakeholders drew on participants’ collective knowledge, expertise and values to develop a shared understanding and direction. Collaborative themes arising from the workshops were used to populate a concept analysis framework for place-based learning, to identify its attributes, enablers and impacts. Findings: A shared purpose for and definition of place-based learning resulted, with three interdependent value themes: people-centred learning; cultures of teamwork to enable learning; and networks for learning together. Enablers, attributes and other factors were identified to support successful implementation and evaluation across one region in England. Conclusion: Place-based learning is a new concept previously undefined in the context of health education and integrated healthcare systems. The insights that emerged increase our understanding about how this concept can support local, national and global strategies, optimising the contribution of learning to integrated health and social care. Implications for practice: Integrated health and social care services need to: Grow a critical mass of skilled facilitators with the capabilities to integrate learning and improvement with other functions (such as embedded research) so as to develop systemwide   Enable leaders to create learning cultures collectively with facilitators to increase understanding about the impact of culture on learning and improvement Develop indicators of the impact of learning across place

The Web site for the Anxiety Disorders Association of America (ADAA) receives more than 5 million visits per month and thus represents a unique medium for the study of anxiety disorders. ADAA Web site users from October 2002 to January 2003 were invited to complete a survey oriented toward trauma history and psychiatric sequelae. A diagnostic approximation of posttraumatic stress disorder (PTSD) was based on responses to the Trauma Questionnaire, the Davidson Trauma Scale, and questions about impairment. The Connor-Davidson Resilience Scale was also used. Variables were tested for their association with PTSD. Among 1558 participants, 87% had a history of trauma, and 38% had current PTSD. The population was comprised predominantly of white middle-class women, half of whom were married. More than 90% were first-time users of the site. Factors associated with PTSD included death of, or harm to, a loved one; personal history of incest, rape, or physical abuse; lower age; lower income; unemployment; missed work; increased medical care; dissatisfaction with psychotropic medication; depressive symptoms; and lower resilience. In this selective convenience sample, there were high rates of traumatization and PTSD. The demographics of this group are similar to those seen in previously studied populations that had contacted the ADAA. Furthermore, the factors associated with PTSD were like those in many community surveys. The ADAA Web site has the opportunity to benefit large numbers of highly distressed individuals.

Heavy-chain-only antibodies make up a considerable proportion of class G immunoglobulin (IgG) within camelid sera and are characterized by the absence of the first constant heavy domain (CH1), a region encoded by a separate exon within conventional antibody loci. The loss of this domain reduces the length of the antibody and prevents interactions that would normally take place between the heavy and light chains and between variable and constant domains. The analysis of an unrearranged llama genomic DNA library has enabled us to confirm that different llama hinge types are the products of separate constant region genes. The exon/intron arrangement of a llama classical IgG gene has been determined and, in addition, we show that CH1-like sequence is present upstream of the hinge exon in two llama IgG isotypes representing the long- and short-hinge heavy-chain-only antibodies. The acceptor splice sites adjacent to both hinge and CH1 exons are found to adhere to established consensi, whereas the donor splice site flanking the CH1 exon is mutated in the heavy chain but not classical CH genes. We predict that splicing of the CH1 domain sequence to the hinge exon is prohibited as a result of this mutation, leading to the production of antibodies lacking the CH1 domain.

Let Γ\\Gamma be a discrete group acting in the unit ball BB of euclidean nn-space and T(B)T(B) the unit tangent space of BB. We define the geodesic flow gt{g_t} on the quotient space Ω=T(B)/Γ\\Omega = T(B)/\\Gamma and show that for discrete groups of infinite volume the flow is of zero type—namely, for measurable subsets A,BA,B of Ω\\Omega which are of finite measure, limt→∞gt(A)∩B=0{\\lim _{t \\to \\infty }}{g_t}(A) \\cap B = 0. Using this result, we give a new and elementary proof of the fact that for a discrete group of infinite volume, N(r)=o(V{x:|x|>r})N(r) = o(V\\{ x:\\left | x \\right | > r\\} ) as r→1r \\to 1, where N(r)N(r) is the orbital counting function and VV denotes hyperbolic volume.

DURING a storm in Kuala Lumpur on March 23, I foolishly attempted to run The wonderful staff from Starbucks in The Mall opposite the Pan Pacific Hotel then escorted me to the Kuala Lumpur Hospital where I received