Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer's Disease.

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aß) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.

Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: Implications for Alzheimer's disease.

One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid-ß (Aß) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aß-production and -degradation is necessary to prevent pathological Aß-accumulation. Here, we investigate the molecular mechanism how insulin-degrading enzyme (IDE), one of the major Aß-degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aß-degradation is linked in a regulatory cycle to achieve this balance. In absence of Aß-production caused by APP or Presenilin deficiency, IDE-mediated Aß-degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ-secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH-SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aß-production and Aß-degradation forming a regulatory cycle in which AICD promotes Aß-degradation via IDE and IDE itself limits its own production by degrading AICD.

Hospital staff shortages: Environmental and organizational determinants and implications for patient satisfaction.

Recent discussions and previous research often indicate that German hospitals are affected by a shortage of healthcare personnel on the labor market. However, until now, research has provided only limited insights into how environmental and organizational factors explain variations in staff shortages, how staff shortage measures relate to staffing ratios, and what relevance staff shortages have for patients. Regression analyses based on survey data of 104 German hospitals from 2015 to 2016, combined with labor market and patient satisfaction data, show that several environmental and organizational factors are significantly related to hospital staff shortages, measured by self-reports, vacancies, and turnover. These three measures of staff shortage do not correlate to the same degree for physicians and nurses, and none of the three significantly relate to nursing ratios, which indicates that the latter is a distinct concept rather than a direct consequence of staff shortage. The analyses further show that hospital staff shortages relate significantly to patient satisfaction with physician and nursing care. The findings suggest that hospitals are, to a certain extent, able to influence the degree to which they are affected by staff shortages and that hospitals' decisions about staffing levels depend on more than staff availability.

Effect of Caffeine and Other Methylxanthines on Aß-Homeostasis in SH-SY5Y Cells.

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer's disease (AD). All MTXs decreased amyloid-ß (Aß) level by shifting the amyloid precursor protein (APP) processing from the Aß-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas ß-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased ß-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aß1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aß and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD.

Profiling of Alzheimer's disease related genes in mild to moderate vitamin D hypovitaminosis.

A vast majority of the elderly population shows a mild to moderate vitamin D deficiency. Besides the well-known function of vitamin D, vitamin D receptor is also expressed in brain and is discussed to regulate several genes. However very little is known whether genes are regulated, associated with Alzheimer's disease (AD). Here we investigate 117 genes, known to be affected in AD, in mouse brain samples with a mild vitamin D hypovitaminosis comparable to the vitamin D status of the elderly population (20%-30% deficiency). The 117 genes include two positive controls, Nep and Park7, already known to be affected by both AD and vitamin D hypovitaminosis. The 25 most promising candidates were verified in a second independent mouse cohort, resulting in eleven genes further evaluated against three additional housekeeping genes. Three of the remaining eight significantly altered genes are involved in APP homeostasis (Snca, Nep, Psmb5), and each one gene in oxidative stress (Park7), inflammation (Casp4), lipid metabolism (Abca1), signal transduction (Gnb5) and neurogenesis (Plat). Our results tighten the link of vitamin D and AD and underline that vitamin D influences several genes also in brain, highlighting that a strong link not only to AD but also to other neurodegenerative diseases might exist.

Board characteristics, governance objectives, and hospital performance: An empirical analysis of German hospitals.

BACKGROUND: There is a growing need for hospital supervisory boards to support hospital management in different areas, including (financial) monitoring, resource provision, stakeholder relationships, and strategic decision-making. Little is currently known about how boards' emphases on these various governance objectives contribute to performance. PURPOSE: Using a dominant logics perspective, this article aims to detect the governance logics that hospital boards emphasize, to determine whether there are distinct clusters of hospitals with the same sets of emphases, and to show how cluster membership relates to board characteristics and financial performance. METHODOLOGY: Using factor analysis, we identify latent classes of governance objectives and use hierarchical cluster analysis to detect distinct clusters with varying emphasis on the classes. We then use multinomial regression to explore the associations between cluster membership and board characteristics (size, gender diversity, and occupational diversity) and examine the associations between clusters and financial performance using OLS regression. RESULTS: Classes of objectives reflecting three governance theories-agency theory, stewardship theory, and stakeholder theory-can be distinguished, and hospitals can be divided into four clusters based on their board's relative emphasis on the classes. Cluster membership is significantly associated with board characteristics. There is also a significant association between cluster membership and hospital financial performance, with two of three groups performing significantly better than the reference group. CONCLUSION: High performance in hospitals can be the result of governance logics, which, compared to simple board characteristics, are associated with better financial outcomes. PRACTICE IMPLICATIONS: Hospitals can influence the emphasis placed on different governance objectives and enhance organizational success by creating boards that are small enough to be effective yet diverse enough to profit from a wide variety of expertise and experience.

Vitamin D and Its Analogues Decrease Amyloid-ß (Aß) Formation and Increase Aß-Degradation.

Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-ß (Aß), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aß-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D2 and D3 analogues decreased Aß-production and increased Aß-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aß-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased ß-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer's Disease.

One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk of AD due to its antioxidative properties. However, epidemiological studies and nutritional approaches of vitamin E treatment are controversial. Here, we investigate the effect of α-tocotrienol, which belongs to the group of vitamin E, on AD-relevant processes in neuronal cell lines. In line with the literature, α-tocotrienol reduced the ROS level in SH-SY5Y cells. In the presence of tocotrienols, cholesterol and cholesterol esters, which have been shown to be risk factors in AD, were decreased. Besides the unambiguous positive effects of tocotrienol, amyloid-ß (Aß) levels were increased accompanied by an increase in the activity of enzymes responsible for Aß production. Proteins and gene expression of the secretases and their components remained unchanged, whereas tocotrienol accelerates enzyme activity in cell-free assays. Besides enhanced Aß production, tocotrienols inhibited Aß degradation in neuro 2a (N2a)-cells. Our results might help to understand the controversial findings of vitamin E studies and demonstrate that besides the known positive neuroprotective properties, tocotrienols also have negative characteristics with respect to AD.