Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed

Knowledge based cloud FE simulation of sheet metal forming processes

The use of Finite Element (FE) simulation software to adequately predict the outcome of sheet metal forming processes is crucial to enhancing the efficiency and lowering the development time of such processes, whilst reducing costs involved in trial-and-error prototyping. Recent focus on the substitution of steel components with aluminum alloy alternatives in the automotive and aerospace sectors has increased the need to simulate the forming behavior of such alloys for ever more complex component geometries. However these alloys, and in particular their high strength variants, exhibit limited formability at room temperature, and high temperature manufacturing technologies have been developed to form them. Consequently, advanced constitutive models are required to reflect the associated temperature and strain rate effects. Simulating such behavior is computationally very expensive using conventional FE simulation techniques. This paper presents a novel Knowledge Based Cloud FE (KBC-FE) simulation technique that combines advanced material and friction models with conventional FE simulations in an efficient manner thus enhancing the capability of commercial simulation software packages. The application of these methods is demonstrated through two example case studies, namely: the prediction of a material's forming limit under hot stamping conditions, and the tool life prediction under multi-cycle loading conditions

Design optimization of hot stamping tooling produced by additive manufacturing

The design flexibility of Additive Manufacturing (AM) can be utilized to develop innovative and sustainable hot stamping tools with enhanced quenching capability compared to tools manufactured by conventional manufacturing processes. This study proposes a concept for hot stamping tools with integrated lattice structures that selectively substitute a die's solid areas. A lattice structure demonstrates reduced thermal mass and can affect the ability of the tool to absorb heat from the blank and the rate at which the tool is cooled between two consecutive stamping cycles. This study explores the design space of a hot stamping tool with integrated lattice structures. It presents the optimized design for an effective compromise between cooling performance, structural integrity, and several other design parameters shown in the study. The proposed method utilizes a 2D thermo-mechanical finite element analysis model of a single cooling channel combined with Design of Experiments (DoE) to reduce the computational cost. The results show that the integration of lattice structure cannot only deliver improved cooling performance with minimum change in the dimensions of the cooling system but also achieves a faster AM build time since less material is required to be printed

A novel test method for continuous nonlinear biaxial tensile deformation of sheet metals by bulging with stepped-dies

In this paper, a novel test method named bulging with stepped-dies is proposed to overcome the difficulty of traditional test methods in realizing continuous nonlinear loading paths from initial yield up to fracture on a sheet metal. To achieve this aim, the section shape of a stepped-die cavity is varied with increasing depth. During bulging with a stepped-die, the stress state at the pole of bulging area of the sheet changes continuously with the increase in bulging height, which results in a specific nonlinear loading path. A theoretical model is established to calculate the stress components at the pole based on the assumption that the bulged surface near the pole was approximated by a rotational ellipsoid. Bulging experiments with three different stepped-dies are performed by using ST16 steel sheet. Stress and strain paths up to fracture and equivalent stress-strain curves at the pole are analyzed and compared with the results of bulging with elliptical dies. It is shown that continuous nonlinear loading paths can be effectively realized through bulging with stepped-dies and the stress ratio at the pole changes from 0.5 up to 2.0 at most in one bulging experiment. The feasibility of the novel test method is validated successfully. And the experimental data obtained are useful to determine constitutive and forming limit models suitable for complex loading conditions

A simple scheme for allocating capital in a foreign exchange proprietary trading firm

We present a model of capital allocation in a foreign exchange proprietary trading firm. The owner allocates capital to individual traders, who operate within strict risk limits. Traders specialize in individual currencies, but are given discretion over their choice of trading rule. The owner provides the simple formula that determines position sizes – a formula that does not require estimation of the firm-level covariance matrix. We provide supporting empirical evidence of excess risk-adjusted returns to the firm-level portfolio, and we discuss a modification of the model in which the owner dictates the choice of trading rule

Doing what we know, knowing what to do: Californians Linking Action with Science for Prevention of Breast Cancer (CLASP-BC)

Given the lack of progress in breast cancer prevention, the California Breast Cancer Research Program (CBCRP) plans to apply current scientific knowledge about breast cancer to primary prevention at the population level. This paper describes the first phase of Californians Linking Action with Science for Prevention of Breast Cancer (CLASP-BC). The foci of Phase 1 are building coalitions and coalition capacity building through community engagement in community-based participatory research (CBPR) and dissemination and implementation (D&I) research training. Based on the successful implementation and evaluation of Phase 1, the foci of Phase 2 (presented separately in this special issue) will be to translate the California Breast Cancer Prevention Plan overarching goal and specific intervention goals for 23 breast cancer risk and protective factors strategies into evidence-informed interventions (EIIs) that are disseminated and implemented across California. CLASP-BC is designed to identify, disseminate and implement high-impact, population-based prevention approaches by funding large scale EIIs, through multi-jurisdictional actions, with the intent to decrease the risk of breast cancer and other chronic diseases (sharing common risk factors), particularly among racial/ethnic minorities and medically underserved populations in California

Inconsistency of the MLE for the joint distribution of interval censored survival times and continuous marks

This paper considers the nonparametric maximum likelihood estimator (MLE) for the joint distribution function of an interval censored survival time and a continuous mark variable. We provide a new explicit formula for the MLE in this problem. We use this formula and the mark specific cumulative hazard function of Huang and Louis (1998) to obtain the almost sure limit of the MLE. This result leads to necessary and sufficient conditions for consistency of the MLE which imply that the MLE is inconsistent in general. We show that the inconsistency can be repaired by discretizing the marks. Our theoretical results are supported by simulations.Comment: 27 pages, 4 figure