Principles of strategic drug delivery to the brain (SDDB): Development of anorectic and orexigenic analogs of leptin

The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85-leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease

Minimal Composite Higgs Model with Light Bosons

We analyze a composite Higgs model with the minimal content that allows a light Standard-Model-like Higgs boson, potentially just above the current LEP limit. The Higgs boson is a bound state made up of the top quark and a heavy vector-like quark. The model predicts that only one other bound state may be lighter than the electroweak scale, namely a CP-odd neutral scalar. Several other composite scalars are expected to have masses in the TeV range. If the Higgs decay into a pair of CP-odd scalars is kinematically open, then this decay mode is dominant, with important implications for Higgs searches. The lower bound on the CP-odd scalar mass is loose, in some cases as low as $\sim$ 100 MeV, being set only by astrophysical constraints.Comment: 33 pages, latex. Corrections in eqs. 3.21, 3.23, 4.1, 4.5-10. One figure adde

Wormholes and Ringholes in a Dark-Energy Universe

The effects that the present accelerating expansion of the universe has on the size and shape of Lorentzian wormholes and ringholes are considered. It is shown that, quite similarly to how it occurs for inflating wormholes, relative to the initial embedding-space coordinate system, whereas the shape of the considered holes is always preserved with time, their size is driven by the expansion to increase by a factor which is proportional to the scale factor of the universe. In the case that dark energy is phantom energy, which is not excluded by present constraints on the dark-energy equation of state, that size increase with time becomes quite more remarkable, and a rather speculative scenario is here presented where the big rip can be circumvented by future advanced civilizations by utilizing sufficiently grown up wormholes and ringholes as time machines that shortcut the big-rip singularity.Comment: 11 pages, RevTex, to appear in Phys. Rev.

Feeding your Inflaton: Non-Gaussian Signatures of Interaction Structure

Primordial non-Gaussianity is generated by interactions of the inflaton field, either self-interactions or couplings to other sectors. These two physically different mechanisms can lead to nearly indistinguishable bispectra of the equilateral type, but generate distinct patterns in the relative scaling of higher order moments. We illustrate these classes in a simple effective field theory framework where the flatness of the inflaton potential is protected by a softly broken shift symmetry. Since the distinctive difference between the two classes of interactions is the scaling of the moments, we investigate the implications for observables that depend on the series of moments. We obtain analytic expressions for the Minkowski functionals and the halo mass function for an arbitrary structure of moments, and use these to demonstrate how different classes of interactions might be distinguished observationally. Our analysis casts light on a number of theoretical issues, in particular we clarify the difference between the physics that keeps the distribution of fluctuations nearly Gaussian, and the physics that keeps the calculation under control.Comment: 33 pages (plus appendices), 3 figures. V2: references added, some minor clarifications. Accepted for publication in JCA

Comparing Dutch Case management care models for people with dementia and their caregivers: The design of the COMPAS study

<p>Abstract</p> <p>Background</p> <p>Dementia care in the Netherlands is shifting from fragmented, ad hoc care to more coordinated and personalised care. Case management contributes to this shift. The linkage model and a combination of intensive case management and joint agency care models were selected based on their emerging prominence in the Netherlands. It is unclear if these different forms of case management are more effective than usual care in improving or preserving the functioning and well-being at the patient and caregiver level and at the societal cost. The objective of this article is to describe the design of a study comparing these two case management care models against usual care. Clinical and cost outcomes are investigated while care processes and the facilitators and barriers for implementation of these models are considered.</p> <p>Design</p> <p>Mixed methods include a prospective, observational, controlled, cohort study among persons with dementia and their primary informal caregiver in regions of the Netherlands with and without case management including a qualitative process evaluation. Inclusion criteria for the cohort study are: community-dwelling individuals with a dementia diagnosis who are not terminally-ill or anticipate admission to a nursing home within 6 months and with an informal caregiver who speaks fluent Dutch. Person with dementia-informal caregiver dyads are followed for two years. The primary outcome measure is the Neuropsychiatric Inventory for the people with dementia and the General Health Questionnaire for their caregivers. Secondary outcomes include: quality of life and needs assessment in both persons with dementia and caregivers, activity of daily living, competence of care, and number of crises. Costs are measured from a societal perspective using cost diaries. Process indicators measure the quality of care from the participant’s perspective. The qualitative study uses purposive sampling methods to ensure a wide variation of respondents. Semi-structured interviews with stakeholders based on the theoretical model of adaptive implementation are planned.</p> <p>Discussion</p> <p>This study provides relevant insights into care processes, description of two case management models along with clinical and economic data from persons with dementia and caregivers to clarify important differences in two case management care models compared to usual care.</p