Influence of shear stress magnitude and direction on atherosclerotic plaque composition

British Heart Foundation (BHF) grants (no. RG/11/13/29055 and PG/15/49/31595), awarded to R.K. and E.P. who are employed by Bioengineering and the MRC Clinical Sciences Centre at Imperial College London. The grants also supported R.M.P. and S.M.B. V.V.M. was supported by a BHF. PhD studentship

Lempel-Ziv Complexity Analysis of Local Field Potentials in Different Vigilance States with Different Coarse-Graining Techniques

Analysis of electrophysiological signals recorded from the brain with Lempel-Ziv (LZ) complexity, a measure based on coarse-graining of the signal, can provide valuable insights into understanding brain activity. LZ complexity of local field potential signals recorded from the neocortex of 11 adult male Wistar-Kyoto rats in different vigilance states - waking, non-rapid-eye movement (NREM) and REM sleep - was estimated with different coarse-graining techniques (median, LZCm, and k-means, LZCkm). Furthermore, surrogate data were used to test the hypothesis that LZ complexity results reveal effects accounted for by temporal structure of the signal, rather than merely its frequency content. LZ complexity values were significantly lower in NREM sleep as compared to waking and REM sleep, for both real and surrogate signals. LZCkm and LZCm values were similar, although in NREM sleep the values deviated in some epochs, where signals also differed significantly in terms of temporal structure and spectral content. Thus, the interpretation of LZ complexity results should take into account the specific algorithm used to coarse-grain the signal. Moreover, the occurrence of high amplitude slow waves during NREM sleep determines LZ complexity to a large extent, but characteristics such as the temporal sequence of slow waves or cross-frequency interactions might also play a role. © Springer International Publishing Switzerland 2014

Cancer and thrombosis: Managing the risks and approaches to thromboprophylaxis

Patients with cancer are at increased risk of venous thromboembolism (VTE) compared with patients without cancer. This results from both the prothrombotic effects of the cancer itself and iatrogenic factors, such as chemotherapy, radiotherapy, indwelling central venous devices and surgery, that further increase the risk of VTE. Although cancer-associated thrombosis remains an important cause of morbidity and mortality, it is often underdiagnosed and undertreated. However, evidence is accumulating to support the use of low-molecular-weight heparins (LMWHs) in the secondary prevention of VTE in patients with cancer. Not only have LMWHs been shown to be at least as effective as coumarin derivatives in this setting, but they have a lower incidence of complications, including bleeding, and are not associated with the practical problems of warfarin therapy. Furthermore, a growing number of studies indicate that LMWHs may improve survival among patients with cancer due to a possible antitumor effect. Current evidence suggests that LMWHs should increasingly be considered for the long-term management of VTE in patients with cancer

Coalition-structured governance improves cooperation to provide public goods

While the benefits of common and public goods are shared, they tend to be scarce when contributions are provided voluntarily. Failure to cooperate in the provision or preservation of these goods is fundamental to sustainability challenges, ranging from local fisheries to global climate change. In the real world, such cooperative dilemmas occur in multiple interactions with complex strategic interests and frequently without full information. We argue that voluntary cooperation enabled across overlapping coalitions (akin to polycentricity) not only facilitates a higher generation of non-excludable public goods, but it may also allow evolution toward a more cooperative, stable, and inclusive approach to governance. Contrary to any previous study, we show that these merits of multi-coalition governance are far more general than the singular examples occurring in the literature, and they are robust under diverse conditions of excludability, congestion of the non-excludable public good, and arbitrary shapes of the return-to-contribution function. We first confirm the intuition that a single coalition without enforcement and with players pursuing their self-interest without knowledge of returns to contribution is prone to cooperative failure. Next, we demonstrate that the same pessimistic model but with a multi-coalition structure of governance experiences relatively higher cooperation by enabling recognition of marginal gains of cooperation in the game at stake. In the absence of enforcement, public-goods regimes that evolve through a proliferation of voluntary cooperative forums can maintain and increase cooperation more successfully than singular, inclusive regimes.Supported by US Defense Advanced Research Projects Agency (D17AC00005), National Science Foundation grant GEO-1211972, and Fundacao para a Ciencia e Tecnologia (FCT) through grants PTDC/MAT/STA/3358/2014, PTDC/EEI-SII/5081/2014, and UID/BIA/04050/2013. P.M.H. was supported by the Walbridge Fund at the Princeton Environmental Institute

Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid beta (Aβ1-40) administration in mice

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1-40 (Aβ1-40 ) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD

Inducing persistent flow disturbances accelerates atherogenesis and promotes thin cap fibroatheroma development in D374Y-PCSK9 hypercholesterolemic minipigs

BACKGROUND: -Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). METHODS AND RESULTS: -D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (p<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (p<0.002) and multidirectional (p<0.002) shear stress. TCFA regions demonstrated significantly lower shear stress that persisted over the duration of the study compared to other plaque types (p<0.005). CONCLUSIONS: -These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA

Social research on neglected diseases of poverty: Continuing and emerging themes

Copyright: © 2009 Manderson et al.Neglected tropical diseases (NTDs) exist and persist for social and economic reasons that enable the vectors and pathogens to take advantage of changes in the behavioral and physical environment. Persistent poverty at household, community, and national levels, and inequalities within and between sectors, contribute to the perpetuation and re-emergence of NTDs. Changes in production and habitat affect the physical environment, so that agricultural development, mining and forestry, rapid industrialization, and urbanization all result in changes in human uses of the environment, exposure to vectors, and vulnerability to infection. Concurrently, political instability and lack of resources limit the capacity of governments to manage environments, control disease transmission, and ensure an effective health system. Social, cultural, economic, and political factors interact and influence government capacity and individual willingness to reduce the risks of infection and transmission, and to recognize and treat disease. Understanding the dynamic interaction of diverse factors in varying contexts is a complex task, yet critical for successful health promotion, disease prevention, and disease control. Many of the research techniques and tools needed for this purpose are available in the applied social sciences. In this article we use this term broadly, and so include behavioral, population and economic social sciences, social and cultural epidemiology, and the multiple disciplines of public health, health services, and health policy and planning. These latter fields, informed by foundational social science theory and methods, include health promotion, health communication, and heath education

Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance

Acute myeloid leukaemia (AML) is a blood/bone marrow cancer originating from myeloid cell precusors capable of self-renewing. AML cells implement biochemical mechanisms which allow them not only to survive, but also to successfully escape immune surveillance. ln this work, we discuss crucial molecular mechanisms used by human AML cells in order to evade immune attack

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin