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23% of the total global burden of disease is attributable to disorders in people aged 60 years and older. Although the proportion of the burden arising from older people (≥60 years) is highest in high-income regions, disability-adjusted life years (DALYs) per head are 40% higher in low-income and middle-income regions, accounted for by the increased burden per head of population arising from cardiovascular diseases, and sensory, respiratory, and infectious disorders. The leading contributors to disease burden in older people are cardiovascular diseases (30·3% of the total burden in people aged 60 years and older), malignant neoplasms (15·1%), chronic respiratory diseases (9·5%), musculoskeletal diseases (7·5%), and neurological and mental disorders (6·6%). A substantial and increased proportion of morbidity and mortality due to chronic disease occurs in older people. Primary prevention in adults aged younger than 60 years will improve health in successive cohorts of older people, but much of the potential to reduce disease burden will come from more effective primary, secondary, and tertiary prevention targeting older people. Obstacles include misplaced global health priorities, ageism, the poor preparedness of health systems to deliver age-appropriate care for chronic diseases, and the complexity of integrating care for complex multimorbidities. Although population ageing is driving the worldwide epidemic of chronic diseases, substantial untapped potential exists to modify the relation between chronological age and health. This objective is especially important for the most age-dependent disorders (ie, dementia, stroke, chronic obstructive pulmonary disease, and vision impairment), for which the burden of disease arises more from disability than from mortality, and for which long-term care costs outweigh health expenditure. The societal cost of these disorders is enormous.

Actin is one of the most ubiquitous protein playing fundamental roles in a variety of cellular processes. Since early in the 1980s, it was evident that filamentous actin (F-actin) formed a peripheral cortical barrier that prevented vesicles to access secretory sites in chromaffin cells in culture. Later, around 2000, it was described that the F-actin structure accomplishes a dual role serving both vesicle transport and retentive purposes and undergoing dynamic transient changes during cell stimulation. The complex role of the F-actin cytoskeleton in neuroendocrine secretion was further evidenced when it has been proved to participate in the scaffold structure holding together the secretory machinery at active sites and participate in the generation of mechanical forces that drive the opening of the fusion pore, during the first decade of the present century. The complex vision of the multiple roles of F-actin in secretion we have acquired to date comes largely from studies performed on traditional 2D cultures of primary cells; however, recent evidences suggest that these may not accurately mimic the 3D in vivo environment, and thus, more work is now needed on adrenomedullary cells kept in a more “native” configuration to fully understand the role of F-actin in regulating chromaffin granule transport and secretion under physiological conditions.

The difficulty of obtaining funding often places the continuity of research projects at risk, forcing researchers to resort to low-cost methodologies. Such methodologies sometimes require a high degree of technical knowledge which, in many cases, poses an insurmountable obstacle to the development of a project. This article shows a low-cost, easy-way methodology for diachronically analysing terrain in search of archaeological evidence on different scales (micro and semi-micro) in both already known and new archaeological sites through the analysis of orthophotographs taken with UAVs, the DEMs generated from them, and public LiDAR data. It allows researchers with small budgets but with a basic knowledge of GIS and photogrammetry to undertake some aspects of their project without necessarily having to call on the assistance or support of specialists. Thanks to this methodology, the researcher will be able to continue until they are able to obtain the funding that will enable them to take their research further, with specialists. This article presents the first conclusions obtained after applying the proposed methodology at the Giribaile (Vilches, Spain) archaeological site—a site of interest in its territory which possibly functioned as an advance defensive post for the town, a hypothesis based on the towers and numerous internal structures that have been identified.

The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma.

α‐Synuclein is a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease. The precise functions of this small cytosolic protein are still under investigation. α‐Synuclein has been proposed to regulate soluble N ‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) proteins involved in vesicle fusion. Interestingly, α‐synuclein fails to interact with SNARE proteins in conventional protein‐binding assays, thus suggesting an indirect mode of action. As the structural and functional properties of both α‐synuclein and the SNARE proteins can be modified by arachidonic acid, a common lipid regulator, we analysed this possible tripartite link in detail. Here, we show that the ability of arachidonic acid to stimulate SNARE complex formation and exocytosis can be controlled by α‐synuclein, both in vitro and in vivo . α‐Synuclein sequesters arachidonic acid and thereby blocks the activation of SNAREs. Our data provide mechanistic insights into the action of α‐synuclein in the modulation of neurotransmission. The fatty acid‐binding protein alpha‐synuclein has been proposed to regulate SNARE proteins. This report shows that alpha‐synuclein sequesters fatty acids to down‐regulate SNARE assembly thereby inhibiting exocytosis.

FTY-720 (Fingolimod) was one of the first compounds authorized for the treatment of multiple sclerosis. Among its other activities, this sphingosine analogue enhances exocytosis in neuroendocrine chromaffin cells, altering the quantal release of catecholamines. Surprisingly, the size of chromaffin granules is reduced within few minutes of treatment, a process that is paralleled by the homotypic fusion of granules and their heterotypic fusion with mitochondria, as witnessed by dynamic confocal and TIRF microscopy. Electron microscopy studies support these observations, revealing the fusion of several vesicles with individual mitochondria to form large, round mixed organelles. This cross-fusion is SNARE-dependent, being partially prevented by the expression of an inactive form of SNAP-25. Fused mitochondria exhibit an altered redox potential, which dramatically enhances cell death. Therefore, the cross-fusion of intracellular organelles appears to be a new mechanism to be borne in mind when considering the effect of FTY-720 on the survival of neuroendocrine cells.

Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons.

Neuroendocrine chromaffin cells represent an excellent model to study the molecular mechanisms associated with the exo-endocytotic cycle of neurotransmitter release. In this study, EGFP-Lifeact and confocal microscopy has been used to analyze the re-organization of the cortical F-actin cytoskeleton associated to organelle transport during secretion with unprecedented detail. In these cells secretory events accumulate in temperature-sensitive and myosin II-dependent F-actin expansions and retractions affecting specific regions of the sub-membrane space. Interestingly, not only vesicles but also mitochondria are transported toward the plasmalemma during these expansions. Simultaneously, we found F-actin cytoskeletal retraction withdraws vesicles from the sub-plasmalemmal space, forming novel empty internal spaces into which organelles can be transported. In addition to these well-coordinated, F-actin-myosin II dependent processes that drive the transport of the majority of vesicles, fast transport of chromaffin vesicles was observed, albeit less frequently, which used F-actin comet tails nucleated from the granular membrane. Thus, upon cell stimulation F-actin structures use diverse mechanisms to transport organelles to and from the membrane during the exo-endocytotic cycle taking place in specific areas of cell periphery.

Cultured bovine chromaffin cells have been used extensively as a neuroendocrine model to study regulated secretion. In order to extend such experimental findings to the physiological situation, it is necessary to study mayor cellular structures affecting secretion in cultured cells with their counterparts present in the adrenomedullary tissue. F-actin concentrates in a peripheral ring in cultured cells, as witnessed by phalloidin-rodhamine labeling, while extends throughout the cytoplasm in native cells. This result is also confirmed when studying the localization of α-fodrin, a F-actin-associated protein. Furthermore, as a consequence of this redistribution of F-actin, we observed that chromaffin granules and mitochondria located into two different cortical and internal populations in cultured cells, whereas they are homogeneously distributed throughout the cytoplasm in the adrenomedullary tissue. Nevertheless, secretion from isolated cells and adrenal gland pieces is remarkably similar when measured by amperometry. Finally, we generate mathematical models to consider how the distribution of organelles affects the secretory kinetics of intact and cultured cells. Our results imply that we have to consider F-actin structural changes to interpret functional data obtained in cultured neuroendocrine cells.

Background Worldwide population aging has been considered one of the most important demographic phenomena, and is frequently referred as a determinant of health costs and expenditures. These costs are an effect either of the aging process itself (social) or because of the increase that comes with older age (individual). Objective To analyze health expenditures and its determinants in a sample of Mexican population, for three dimensions acute morbidity, ambulatory care and hospitalization focusing on different age groups, particularly the elderly. Methods A secondary analysis of the Mexican National Health and Nutrition Survey (ENSANUT), 2006 was conducted. A descriptive analysis was performed to establish a health profile by socio-demographic characteristics. Logistic regression models were estimated to determine the relation between acute morbidity, ambulatory care, hospitalization and age group; to establish the determinants of hospitalization among the population 60 years and older; and to determine hospitalization expenditures by age. Results Higher proportion of elderly reporting health problems was found. Average expenditures of hospitalization in households were $240.6 am dlls, whereas in households exclusively with elderly the expenditure was $308.9 am dlls, the highest among the considered age groups. The multivariate analysis showed higher probability of being hospitalized among the elderly, but not for risks for acute morbidity and ambulatory care. Among the elderly, older age, being male or living in a city or in a metro area implied a higher probability of hospitalization during the last year, with chronic diseases playing a key role in hospitalization. Conclusions The conditions associated with age, such as chronic diseases, have higher weight than age itself; therefore, they are responsible for the higher expenditures reported. Conclusions point towards a differentiated use and intensity of health services depending on age. The projected increase in hospitalization and health care needs for this group requires immediate attention.