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This contribution presents part of the results produced by the University of Naples Federico II in the project PRIN 2017 TECH-START. The research investigates how the challenges of the circular economy and climate mitigation, combined with digital technologies, require new organisations for contemporary dwelling, including the need for healthy and safe environments. The contribution studies the concept of emergent dwelling with the aim of achieving a set of design requirements consistent with the many, diverse forms of living. These requirements apply to the project of a multigenerational lifetime house, selecting those most suitable for a smart residency that integrates the socio-productive and health care chain into the territory, with particular reference to the elderly population and the most fragile groups in a lifecourse perspective. [ABSTRACT FROM AUTHOR]

Frailty is a multifaceted condition that affects many older adults and marks decline on areas such as cognition, physical condition, and nutritional status. Frail individuals are at increased risk for the development of disability, dementia, and falls. There are hardly any health services that enable the identification of prefrail individuals and that focus on prevention of further functional decline. In this paper, we discuss the development of a community-based, technology-supported health service for detecting prefrailty and preventing frailty and further functional decline via participatory design with a wide range of stakeholders. The result is an innovative service model in which an online platform supports the integration of traditional services with novel, Information Communication Technology supported tools. This service is capable of supporting the different phases of screening and offers training services, by also integrating them with community-based services. The service model can be used as a basis for developing similar services within a wide range of healthcare systems. We present the service model, the general functioning of the technology platform, and the different ways in which screening for and prevention of frailty has been localized. Finally, we reflect on the added value of participatory design for creating such health services. [ABSTRACT FROM AUTHOR]

Long-living individuals (LLIs) are used to study exceptional longevity. A number of genetic variants have been found associated in LLIs to date, but further identification of variants would improve knowledge on the mechanisms regulating the rate of aging. Therefore, we performed a genome-wide association study on 410 LLIs and 553 young control individuals with a 317K single-nucleotide polymorphism (SNP) chip to identify novel traits associated with aging. Among the top ( p < 1 × 10−4) SNPs initially identified, we found rs10491334 ( CAMKIV) (odds ratio [OR] = 0.55; 95% confidence interval [CI] 0.42-0.73; p = 2.88 × 10−5), a variant previously reported associated with diastolic blood pressure, associated also in a replication set of 116 LLIs and 160 controls (OR = 0.54; 95% CI 0.32-0.90; p = 9 × 10−3). Furthermore, in vitro analysis established that calcium/calmodulin-dependent protein kinase IV (CAMKIV) activates the survival proteins AKT, SIRT1, and FOXO3A, and we found that homozygous carriers of rs10491334 have a significant reduction in CAMKIV expression. This, together with the observed reduction in minor-allele carriers among centenarians, points to a detrimental role for the SNP. In conclusion, prolongevity genes are activated by CAMKIV, the levels of which are influenced by rs10491334, a SNP associated with human longevity. [ABSTRACT FROM AUTHOR]

Abstract: Cellular growth and glucose uptake are regulated by multiple signals generated by the insulin receptor. The mechanisms of individual modulation of these signals remain somewhat elusive. We investigated the role of CaMKII in insulin signalling in a rat skeletal muscle cell line, demonstrating that CaMKII modulates the insulin action on DNA synthesis and the negative feedback that down regulates glucose uptake. Insulin stimulation generated partly independent signals leading to the rapid activation of Akt, Erk-1/2 and CaMKII. Akt activation was followed by Glut-4 translocation to the plasma membrane and increase of glucose uptake. Then, IRS-1 was phosphorylated at S612, the IRS-1/p85PI3K complex was disrupted, Akt was no more phosphorylated and both Glut-4 translocation and glucose uptake were reduced. Inhibition of CaMKII abrogated the insulin-induced Erk-1/2 activation, DNA synthesis and phosphorylation of IRS-1 at S612. Inhibition of CaMKII also abrogated the down-regulation of insulin-stimulated Akt phosphorylation, Glut-4 membrane translocation and glucose uptake. These results demonstrate that: 1 — CaMKII modulates the insulin-induced Erk-1/2 activation and cell proliferation; 2 — after the initial stimulation of the IRS-1/Akt pathway, CaMKII mediates the down-regulation of stimulated glucose uptake. This represents a novel mechanism in the selective control of insulin signals, and a possible site for pharmacological intervention. [Copyright &y& Elsevier]

Pathological cardiac hypertrophy is an adaptive response to certain cardiovascular conditions. Such hypertrophy is often maladaptive in the long term and a prognosis for cardiac failure. The reversal of cardiac hypertrophy in animal models can correlate with reversal of negative prognosis. Therefore, the discovery of an effective treatment to reverse cardiac hypertrophy is an important aim in the field of cardiology. In order to design such an effective treatment, we need to understand the biochemical basis for the development of cardiac hypertrophy. One particular pathway that is activated during this process is the calcium/calmodulin/calmodulin-dependent protein kinase II (CaMKII) signalling pathway. Recently, there have been substantial advances in our understanding of how the untoward activation of CaMKII may result in cardiomyocyte hypertrophy. For example, expression of an inhibitory peptide specific for CaMKII in mouse heart resulted in protection against the development of cardiac hypertrophy. In the relevant signalling cascade, inositol triphosphate receptors play a critical role that leads to activation of CaMKII in the nucleus, whereas important targets downstream of CaMKII include members of the histone deacetylase (HDAC) family, which are important in mediating changes in gene expression that lead to cardiac hypertrophy. In this review we summarise the current knowledge of how certain hormones and factors induce CaMKII activation in the heart, resulting in HDAC removal from the nucleus and reactivation of the fetal gene programme. [ABSTRACT FROM AUTHOR]

Integrin activation generates different signalings in a cell type-dependent manner and stimulates cell proliferation through the Ras/Raf-1/Mek/Erk pathway. In this study, we demonstrate that integrin stimulation by fibronectin (FN), besides activating the Ras/Erk pathway, generates an auxiliary calcium signal that activates calmodulin and the Ca[sup 2+]/calmodulin-dependent protein kinase II (CaMKII). This signal regulates Raf-1 activation by Ras and modulates the FN-stimulated extracellular signal-regulated kinase (Erk-½). The binding of soluble FN to integrins induced increase of intracellular calcium concentration associated with phosphorylation and activation of CaMKII. In two different cell lines, inhibition of CaMKII activity by specific inhibitors inhibited Erk-½ phosphorylation. Whereas CaMK inhibition affected neither integrin-stimulated Akt phosphorylation nor p21Ras or Mek-1 activity, it was necessary for Raf-1 activity. FN-induced Raf-1 activity was abrogated by the CaMKII specific inhibitory peptide antCaNtide. Integrin activation by FN induced the formation of a Raf-1/CaMKII complex, abrogated by inhibition of CaMKII. Active CaMKII phosphorylated Raf-1 in vitro. This is the first demonstration that CaMKII interplays with Raf-1 and regulates Erk activation induced by Ras-stimulated Raf-1. These findings also provide eridence supporting the possible existence of cross-talk between other intracellular pathways involving CaMKII and Raf-1. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the biochemical and structural changes occurring in the periodontal ligament (PDL) during orthodontic-force application using micro-Raman spectroscopy ( μ-RS). Adolescent and young patients who needed orthodontic treatment with first premolar extractions were recruited. Before extractions, orthodontic forces were applied using a closed-coil spring that was positioned between the molar and premolar. Patients were randomly divided into three groups, whose extractions were performed after 2, 7, and 14 days of force application. From the extracted premolars, PDL samples were obtained, and a fixation procedure with paraformaldehyde was adopted. Raman spectra were acquired for each PDL sample in the range of 1000–3200 cm−1 and the more relevant vibrational modes of proteins (Amide I and Amide III bands) and CH2 and CH3 modes were shown. Analysis indicated that the protein structure in the PDL samples after different time points of orthodontic-force application was modified. In addition, changes were observed in the CH2 and CH3 high wavenumber region due to local hypoxia and mechanical force transduction. The reported results indicated that μ-RS provides a valuable tool for investigating molecular interchain interactions and conformational modifications in periodontal fibers after orthodontic tooth movement, providing quantitative insight of time occurring for PDL molecular readjustment. [ABSTRACT FROM AUTHOR]

People in need of care, chronic or acute, often present problematic food intake and special nutritional needs. Integrated, person-centred and pro-active food and nutritional care delivery has been proven effective for people in health care. However, skills mismatches have been reported in different professions involved, which also applies to the role of chefs in healthcare. The EU funded project NECTAR aims at closing this gap by creating a new job profile, called Chef Gastro-Engineering (CGE). The current publication summarizes the status quo in hospitals and gives a perspective on the future role of chefs in integrated healthcare delivery. [ABSTRACT FROM AUTHOR]

• A highly innovative network project involving five centers across Italy. • The main principle of MULTIPLAT_Age is "aging in place" using ICT. • Data are stored in a shared online platform allowing the exchange of information. The prevention and treatment of frailty condition among multimorbid older adults, in community and hospital settings, is becoming a healthcare priority. Growing evidence suggests that a multidimensional approach could help not only in the early identification of older patients' needs but also in designing personalized preventive interventions. However, in clinical practice, the effectiveness of such interventions is limited by a lack of continuity of care and poor compliance of patients. The widespread diffusion of the information and communication technology (ICT) could offer an excellent way to implement and monitor multidimensional and personalized interventions for multimorbid older adults. In this scenario, the MULTIPLAT_AGE, is a network project involving five research centers with the main objective to supply multidimensional interventions targeted to cognitive, motor, pharmacological, and functional domains including ICT-based: i) transitional care model from the hospital to a protected home area; ii) automatic home-care system to improve activities of daily living; iii) program to improve appropriate drug prescription in nursing-home residents; iv) tele-rehabilitation program to reduce the risk of falls and v) cognitive stimulation delivered by remote in older adults with neurological disorders. Each project is linked to the others by employing a shared online platform, in a perspective of technological-supplied multicomponent interventions according to the concept of "aging in place" as the best solution for the treatment and healthcare of older people. Here we describe the general framework of the MULTIPLAT_AGE, and we examine every single project, pointing out innovative aspects, and discussing the expected results. [ABSTRACT FROM AUTHOR]

The hematopoietic stem cell (HSC) gives rise to all mature, terminally differentiated cells of the blood. Here we show that calmodulin-dependent protein kinase IV (CaMKIV) is present in c-Kit+ScaI+ Lin-/low hematopoietic progenitor cells (KLS cells) and that its absence results in hematopoietic failure, characterized by a diminished KLS cell population and by an inability of these cells to reconstitute blood cells upon serial transplantation. KLS cell failure in the absence of CaMKIV is correlated with increased apoptosis and proliferation of these cells in vivo and in vitro. In turn, these cell biological defects are correlated with decreases in CREB-serine 133 phosphorylation as well as in CREB-binding protein (CBP) and Bcl-2 levels. Re-expression of CaMKIV in Camk4-/- KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels. These studies show that CaMKIV is a regulator of HSC homeostasis and suggest that its effects may be in part mediated via regulation of CBP and Bcl-2. [ABSTRACT FROM AUTHOR]

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed. [ABSTRACT FROM AUTHOR]

Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit. [ABSTRACT FROM AUTHOR]

Background Frailty is associated with a prodromal stage called pre-frailty, a potentially reversible and highly prevalent condition before frailty becomes established. Despite this, there is no widely accepted definition of pre-frailty to support its early identification and management. This study applied an international consensus approach to define and better understand pre-frailty. Methods A modified electronic two-round Delphi Consensus study was conducted. In all, 23 experts from 12 countries with different backgrounds participated. The questionnaire was developed following a systematic literature review. An online consensus meeting was conducted with eight Delphi participants and two external experts. Qualitative and quantitative methods were employed for data analysis. An agreement level of 70% was applied for accepting statements. Results A total of 71 statements were circulated in Round 1. Of these, 52.8% were accepted. Fifty-one statements were re-circulated in Round 2, of which 92.1% were accepted. The online consensus meeting produced a consensus statement describing the concept, multi-factorial nature, and mechanism of pre-frailty as well as assessment, prevention and management approaches. All experts agreed that physical and non-physical factors such as psychological and social capacity are involved in the development of pre-frailty, potentially adversely affecting health and health-related quality of life outcomes. Practitioners should regard pre-frailty as a multi-factorial, multi-dimensional, and non-linear process that does not inevitably lead to frailty. It might be reversed or attenuated by targeted interventions. Brief, feasible and validated tools are recommended for opportunistic screening or case-finding followed by confirmation with multi-dimensional assessment. Conclusion It is difficult to establish consensus on one compact definition of pre-frailty, which is a multi-dimensional concept not only associated with physical impairment, but also with cognitive, nutritional, socioeconomic and other aspects of frailty. However, it may be too early to agree on an operational definition of pre-frailty since none yet exists for frailty. [ABSTRACT FROM AUTHOR]

Introduction: Telemedicine is becoming increasingly important for delivering top-quality care to European citizens to cope the aging populations, rising costs and higher demand of care [1]. It is already established that telemedicine adoption varies among different countries [2]. Furthermore, the increased need for effective business models to implement eHealth solutions is already shown [3]. A one-size-fits-all implementation strategy (derived from a generic business model) for a Pan-European e-Health innovation, will most likely not succeed without either adapting the technology and services or differentiating the business models, according to differing health and social systems [4]. This is already indicated in similar studies with Electronic Health Record cases [5]. This case study examines a European, ICT-supported e-Health service in two different health and social systems and the subsequent implementation strategies. Methods: The PERSSILAA project was chosen as a case. This community-based, ICT supported service model was developed to detect and prevent frailty and functional decline in older adults [6]. We identified differences in a descriptive between-case-analysis for Italy and The Netherlands. Five steps were taken: 1) an inventory of the barriers, 2) review of the evidence 3) tailoring of the business models 4) implementation of the innovation and 5) assessment of the effects. Results: A one-size-fits-all business model and hence implementation strategy turned out to fail due to differences in adoption and implementation possibilities in the two different health and social systems. We present the Italian and Dutch and implementation strategy for the PERSSILAA eHealth solution and compare the differences in the business models. These differences results in different strategies, as example how to use the innovation when Dutch users use it privately at home on a multiple devices while the innovation in Italian is community-based and use one device in a group meeting. Conclusion and discussion: A pan-European eHealth business model and implementation strategy is an illusion. We reflect on the necessity of tailoring business models to regional context in order to allow further (business) exploitation and scale-up of eHealth solutions. [ABSTRACT FROM AUTHOR]

Introduction: Rates of falls increase with ageing and age-related biological and functional changes. Most falls in later life occur as a result of a complex interaction between multiple intrinsic and environmental risk factors. Falls and falls-related injuries are major public health problems that often require healthcare intervention and rehabilitation (1) and recurrent falls are a frequent trigger for older people and their families seeking long term institutional care. Therefore, the prevention and management of falls has substantial relevance for integrated care systems. This study sought to obtain international insight into the implementation of pathways or programs addressing balance, mobility and/or falls prevention in primary care or community services. Methods: A survey template was created to include the key elements detected during a literature review conducted by MUG. The template included questions on screening, assessment, intervention components, target group, professionals involved and tools used for assessment and/or monitoring experience and outcomes. Members of IFIC's international Special Interest Groups(SIGs) on Ageing and Frailty, Intermediate Care were invited to complete an online EU Survey tool available from 01.06-01.08.2021. Responses were analysed by two researchers and results considered by the co-authors in an online focus group. Results: 16 people from 11 countries completed the online survey. 9/16 reported fully implemented falls programs or care pathways in their region or country: UK (3), Ireland (1), Spain (1), Indonesia (1), Peru (1), Australia (1) and Northwest USA (1). Seven examples are focused on older citizens but one is for older people with frailty & neurodegenerative diseases (New South Wales, Australia) and one is a pathway for patients in Indonesia, independent of disease and/or age limits. Professional disciplines involved differed across countries but allied health professionals and nurses were commonly involved. Family physicians were involved in only the examples from the USA and Indonesia. Specialist physicians in geriatric medicine were involved in five of the examples. Five programs involved pharmacists to advise on medication and two programs involved trained volunteers. Public/patient information and education was the most common intervention and was the sole intervention in the Spanish example reported. Three of the nine programs did not routinely evaluate patient experience or functional outcomes. Only three pathways enabled patient level data to flow through the electronic care record. Conclusion: The international survey offers initial insight into implemented pathways and programs for the prevention and management of falls in primary care and community settings in different countries. It paves the way for a more targeted survey and Delphi consensus process on the design and benchmarking of integrated services to address the challenge of falls in ageing societies. Implications: The evidence-based examples in the survey highlight processes and interventions that are readily transferable and where adoption will facilitate standardization and improved quality of care. The next phase aims to agree key components and performance indicators to allow future benchmarking and system-based evidence generation on prevention and management of falls in the community. [ABSTRACT FROM AUTHOR]

Background: Visit-to-visit blood pressure (BP) variability (VVV) is increasingly recognized as a marker of cardiovascular risk. Although implicated in cognitive decline, few studies are currently available assessing its effects on established dementia.Objective: To investigate if VVV is associated with one-year rate of decline in measures of cognition and function in patients with mild to moderate Alzheimer's disease (AD) in the Doxycycline And Rifampicin for Alzheimer's Disease study.Methods: Patients were included if ≥3 BP readings were available (n = 392). VVV was defined using different approaches including the coefficient of variation (CV) in BP readings between visits. Outcomes included rates of decline in the Standardized Alzheimer's Disease Assessment Scale-Cognitive Subscale (SADAS-cog), Standardized MMSE, Clinical Dementia Rating Scale, the Quick Mild Cognitive Impairment screen and the Lawton-Brody activities of daily living (ADL) scale.Results: Half of the patients (196/392) had a ≥4-point decline in the SADAS-cog over one-year. Using this cut-off, there were no statistically significant associations between any measures of VVV, for systolic or diastolic BP, with and without adjustment for potential confounders including treatment allocation, history of hypertension and use of anti-hypertensive and cognitive enhancing medications. Multiple regression models examining the association between systolic BP CV by quartile and decline over one-year likewise showed no clinically significant effects, apart from a U-shaped pattern of ADL decline of borderline clinical significance.∥Conclusions: This observational study does not support recent research showing that VVV predicts cognitive decline in AD. Further studies are needed to clarify its effects on ADL in AD. [ABSTRACT FROM AUTHOR]

Animal-assisted therapy (AAT) includes a set of nonpharmacological interventions aimed at improving human health through the use of trained or untrained animals. In recent decades, AAT has been trialed for different neurological and psychiatric disorders. In patients with dementia, interaction with animals seems to have a positive influence on aggressiveness and anxiety and to ameliorate quality of life and relationship skills. In psychiatric patients, AAT seems to increase motivation and self-esteem, improve prosocial conduct, and decrease behavioral problems. The aim of this study is to review the literature on AAT for elderly people with dementia and psychiatric disorders. Other fields of possible application for AAT are suggested. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity and its associated polypharmacy contribute to an increase in adverse drug events, hospitalizations, and healthcare spending. This study aimed to address: what exists regarding polypharmacy management in the European Union (EU); why programs were, or were not, developed; and, how identified initiatives were developed, implemented, and sustained. Methods: Change management principles (Kotter) and normalization process theory (NPT) informed data collection and analysis. Nine case studies were conducted in eight EU countries: Germany (Lower Saxony), Greece, Italy (Campania), Poland, Portugal, Spain (Catalonia), Sweden (Uppsala), and the United Kingdom (Northern Ireland and Scotland). The workflow included a review of country/region specific polypharmacy policies, key informant interviews with stakeholders involved in policy development and implementation and, focus groups of clinicians and managers. Data were analyzed using thematic analysis of individual cases and framework analysis across cases. Results: Polypharmacy initiatives were identified in five regions (Catalonia, Lower Saxony, Northern Ireland, Scotland, and Uppsala) and included all care settings. There was agreement, even in cases without initiatives, that polypharmacy is a significant issue to address. Common themes regarding the development and implementation of polypharmacy management initiatives were: locally adapted solutions, organizational culture supporting innovation and teamwork, adequate workforce training, multidisciplinary teams, changes in workflow, redefinition of roles and responsibilities of professionals, policies and legislation supporting the initiative, and data management and information and communication systems to assist development and implementation. Depending on the setting, these were considered either facilitators or barriers to implementation. Conclusion: Within the studied EU countries, polypharmacy management was not widely addressed. These results highlight the importance of change management and theory-based implementation strategies, and provide examples of polypharmacy management initiatives that can assist managers and policymakers in developing new programs or scaling up existing ones, particularly in places currently lacking such initiatives. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE). These results were confirmed in vivo in spontaneously hypertensive rats (SHR), in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB), which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes. [ABSTRACT FROM AUTHOR]

On March 29, 2017, a European Summit on the Prevention and Self-Management of Chronic Respiratory Diseases (CRD) was organized by the European Forum for Research and Education in Allergy and Airway Diseases. The event took place in the European Parliament of Brussels and was hosted by MEP David Borrelli and MEP Sirpa Pietikainen. The aim of the Summit was to correspond to the needs of the European Commission and of patients suffering from CRD to join forces in Europe for the prevention and self-management. Delegates of the European Rhinologic Society, European Respiratory Society, European Academy of Allergy and Clinical Immunology, European Academy of Paediatrics, and European Patients Organization EFA all lectured on their vision and action plan to join forces in achieving adequate prevention and self-management of CRD in the context of Precision Medicine. Recent data highlight the preventive capacity of education on optimal care pathways for CRD. Self-management and patient empowerment can be achieved by novel educational on-line materials and by novel mobile health tools enabling patients and doctors to monitor and optimally treat CRDs based on the level of control. This report summarizes the contributions of the representatives of different European academic stakeholders in the field of CRD. [ABSTRACT FROM AUTHOR]

Background and aims Atherosclerosis is a degenerative process of the arterial wall implicating activation of macrophages and proliferation of vascular smooth muscle cells. Calcium-calmodulin dependent kinase type II (CaMKII) in vascular smooth muscle cells (VSMCs) regulates proliferation, while in macrophages, this kinase governs diapedesis, infiltration and release of extracellular matrix enzymes. We aimed at understanding the possible role of CaMKII in atherosclerosis plaques to regulate plaque evolution towards stability or instability. Methods Clinically defined stable and unstable plaques obtained from patients undergoing carotid end arteriectomy were processed for evaluation of CaMKs protein expression, activity and localization. Results The larger content of CaMKII was found in CD14 + myeloid cells that were more abundant in unstable rather than stable plaques. To test the biological effect of activated CD14 + myeloid cells, VSMCs were exposed to the conditioned medium (CM) of macrophages extracted from carotid plaques. CM induced attenuation of CaMKs expression and activity in VSMCs, leading to the reduction of VSMCs proliferation. This appears to be due to the CaMKII dependent release of cytokines. Conclusions These results indicate a pivotal role of CaMKs in atherosclerosis by regulating activated myeloid cells on VSMCs activity. CaMKII could represent a possible target for therapeutic strategies based on macrophages specific inhibition for the stabilization of arteriosclerotic lesions. [ABSTRACT FROM AUTHOR]

An affinity capillary electrophoresis (ACE) method to estimate apparent dissociation constants between bovine brain calmodulin (CaM) and non-peptidic ligands was developed. The method was validated reproducing the dissociation constants of a number of well-known CaM ligands. In particular, the potent antagonist 125-C9 was ad hoc synthesized through an improved synthetic procedure. The ACE method was successfully applied to verify CaM affinity for lubeluzole, a well-known neuroprotective agent recently proved useful to potentiate the activity of anti-cancer drugs. Lubeluzole was slightly less potent than 125-C9 ( K d = 2.9 ± 0.7 and 0.47 ± 0.06 μM, respectively) and displayed Ca 2+ /calmodulin-dependent kinase II (CaMKII) inhibition (IC 50 = 40 ± 1 μM). Possible binding modes of lubeluzole to CaM were explored by docking studies based on the X-ray crystal structures of several trifluoperazine-CaM complexes. An estimated dissociation constant in good agreement with the experimental one was found and the main aminoacidic residues and interactions contributing to complex formation were highlighted. The possibility that interference with Ca 2+ pathways may contribute to the previously observed chemosensitizing effects of lubeluzole on human ovarian adenocarcinoma and lung carcinoma cells are discussed. [ABSTRACT FROM AUTHOR]

The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability by inducing apoptosis and necrosis, without affecting primary normal breast cells. The antitumor activity of nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to cancer cells. Nelfinavir treated tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by nelfinavir in breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Subjects with chronic diseases are more likely to be nonpersistent to pharmacological treatment. Lack of persistence is common among subjects using oral anti-osteoporotic drugs, and leads to increased risk of fragility fracture. The aim of our retrospective study is to analyze the rates and reasons for discontinuation of anti-osteoporotic drugs in the Campania Region. Subjects aged over 40 years were included if they had received at least one prescription for any anti-osteoporotic drugs. Data were obtained from an administrative database of regional data on outpatient drug prescriptions reimbursed by the National Health Service. Patients were followed until the discontinuation of anti-osteoporotic therapy or until the end of the observation period. A total of 30,048 were incident users of anti-osteoporotic drugs: 28,317 (94.2%) females. The mean age of the cohort was 69.0±10.0 years. Weekly bisphosphonates (51.1%) were the most commonly prescribed drugs. In the overall population, persistence rates were 34.8% after 6 months and 13.4% at one year. A multivariate Cox proportional hazard analysis showed that daily regimen (HR 1.9) treatments remained at higher risk of early discontinuation compared to weekly regimen therapies. Our data showed that the persistence to osteoporosis therapy is significantly worse than reported in literature. [ABSTRACT FROM AUTHOR]

Objectives. The aim of the study was to assess self-reported medication adherence measure in patients selected during a health education and health promotion focused event held in the Campania region. The study also assessed sociodemographic determinants of adherence. Methods. An interviewer assisted survey was conducted to assess adherence using the Italian version of the 8-item Morisky Medication Adherence Scale (MMAS-8). Participants older than 18 years were interviewed by pharmacists while waiting for free-medical checkup. Results. A total of 312 participants were interviewed during the Health Campus event. A total of 187 (59.9%) had low adherence to medications. Pearson’s bivariate correlation showed positive association between the MMAS-8 score and gender, educational level and smoking (P<0.05). A multivariable analysis showed that the level of education and smoking were independent predictors of adherence. Individuals with an average level of education (odds ratio (OR), 2.21, 95% confidence interval (CI), 1.08–4.52) and nonsmoker (odds ratio (OR) 1.87, 95% confidence interval (CI), 1.04–3.35) were found to be more adherent to medication than those with a lower level of education and smoking. Conclusion. The analysis showed very low prescription adherence levels in the interviewed population. The level of education was a relevant predictor associated with that result. [ABSTRACT FROM AUTHOR]

Aims: Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. Methods and Results: In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. Conclusion: These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

CaMKs link transient increases in intracellular Ca 2 + with biological processes. In myeloid leukemia cells, CaMKII, activated by the bcr-abl oncogene, promotes cell proliferation. Inhibition of CaMKII activity restricts cell proliferation, and correlates with growth arrest and differentiation. The mechanism by which the inhibition of CaMKII results in growth arrest and differentiation in myeloid leukemia cells is still unknown. We report that inhibition of CaMKII activity results in an upregulation of CaMKIV mRNA and protein in leukemia cell lines. Conversely, expression of CaMKIV inhibits autophosphorylation and activation of CaMKII, and elicits G 0 /G 1 cell cycle arrest,impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27 kip1 and p16 ink4a and reduced levels of cyclins A, B 1 and D 1 . These findings were also confirmed in the K562 leukemic cell line. The relationship between CaMKII and CaMKIV is also observed in primary acute myeloid leukemia (AML) cells, and it correlates with their immunophenotypic profile. Indeed, immature MO/M1 AML showed increased CaMKIV expression and decreased pCaMKII, whereas highly differentiated M4/M5 AML showed decreased CaMKIV expression and increased pCaMKII levels. Our data reveal a novel cross-talk between CaMKII and CaMKIV and suggest that CaMKII suppresses the expression of CaMKIV to promote leukemia cell proliferation. [ABSTRACT FROM AUTHOR]

CaMKs are a widely distributed family of kinases with multiple and often cell specific effects on intracellular signal transduction pathway. In endothelial cells, it has been recognized a role for CamKII in several pathways such as eNOS activation and nitric oxide production. It is not clear though, whether CaMKII interfere with other endothelial cell functions such as ERK activation and cell proliferation. We explored this issue in primary cultured rat endothelial cells and we evaluated the effect on endothelial cell proliferation and DNA synthesis. CaMKII inhibition through Cantide, conducted into the cell through Antoennapedia (ANT-CN), showed positive effects on proliferation and H3-thimdine incorporation similar to insulin stimulation. Accordingly, both CaMKII pharmacological inhibition and silencing through shRNA produced activation of the p44/42 MAPK. These observations leaded to the hypothesis that CamKII could regulate p44/p42 by interfering with specific ERK phosphatases. Indeed, we found that CaMKII interacts and protect the dual specific phosphatase MKP-1 from proteasome mediated degradation while this complex is disrupted by CaMKII inhibitors. This study reveals that CaMKII, besides phosphorylation through the known ras-raf-mek pathway, can regulate also dephosphorylation of p44/p42 by modulation of MKP-1 level. This novel finding opens to a novel scenario in regulation of endothelial cell functions. [ABSTRACT FROM AUTHOR]

• Given the growing importance of the early identification of frailty to prevent subsequent functional decline and disability at both individual and population-level, we have conducted an international delphi study to identify defining characteristics of pre-frailty. • The final consensus statement produced by this international collaboration of experts in the field describes pre-frailty as an aged-associated, multi-factorial, multi-dimensional, and non-linear prodromal risk-state associated with one or more of physical impairment, cognitive decline, nutritional deficiencies, and socioeconomic inequalities, predisposing to the development of frailty. • Further study is required to fully operationalise this definition of pre-frailty for use in clinical practice including the development of improved screening and assessment tools. : Frailty is associated with a prodromal stage called pre-frailty, a potentially reversible and highly prevalent intermediate state before frailty becomes established. Despite being widely-used in the literature and increasingly in clinical practice, it is poorly understood. : To establish consensus on the construct and approaches to diagnose and manage pre-frailty. : We conducted a modified (electronic, two-round) Delphi consensus study. The questionnaire included statements concerning the concept, aspects and causes, types, mechanism, assessment, consequences, prevention and management of pre-frailty. Qualitative and quantitative analysis methods were employed. An agreement level of 70% was applied. : Twenty-three experts with different backgrounds from 12 countries participated. In total, 70 statements were circulated in Round 1. Of these, 52.8% were accepted. Following comments, 51 statements were re-circulated in Round 2 and 92.1% were accepted. It was agreed that physical and non-physical factors including psychological and social capacity are involved in the development of pre-frailty, potentially adversely affecting health and health-related quality of life. Experts considered pre-frailty to be an age-associated multi-factorial, multi-dimensional, and non-linear process that does not inevitably lead to frailty. It can be reversed or attenuated by targeted interventions. Brief, feasible, and validated tools and multidimensional assessment are recommended to identify pre-frailty. : Consensus suggests that pre-frailty lies along the frailty continuum. It is a multidimensional risk-state associated with one or more of physical impairment, cognitive decline, nutritional deficiencies and socioeconomic disadvantages, predisposing to the development of frailty. More research is needed to agree an operational definition and optimal management strategies. [ABSTRACT FROM AUTHOR]

Analoguesof the previously described spiro[imidazo[1,5-c]thiazole-3,3′-indoline]-2′,5,7(6H,7aH)-trione p53 modulators were preparedto explore new structural requirements at the thiazolidine domainfor the antiproliferative activity and p53 modulation. In cell, antiproliferativeactivity was evaluated against two human tumor cell lines. Derivative5-bromo-3′-(cyclohexane carbonyl)-1-methyl-2-oxospiro[indoline-3,2′-thiazolidine](4n) emerged as the most potent compound of this series,inhibiting in vitro 30% of p53–MDM2 interaction at 5 μMand the cell growth of different human tumor cells at nanomolar concentrations.Docking studies confirmed the interactions of 4nwiththe well-known Trp23 and Phe19 clefts, explaining the reasons forits binding affinity for MDM2. 4nat 50 nM is capableof inducing the accumulation of p53 protein, inducing significantapoptotic cell death without affecting the cell cycle progression.Comparative studies using nutlin in the same cellular system confirmthe potential of 4nas a tool for increasing understandingof the process involved in the nontranscriptional proapoptotic activitiesof p53. [ABSTRACT FROM AUTHOR]

Abstract: Analogs of potent CaMKinase II inhibitor, CaM-KNtide, were prepared to explore new structural requirements for the inhibitory activity. The full potency of CaMKII inhibition by CaM-KIINα is contained within a minimal region of 19 amino acids. Here, analysis of the homologous CaM-KIINβ showed that a 17 mer peptide (CN17β) was the shortest sequence that still retained useful inhibitory potency. Ala substitution of almost any residue of CN17β dramatically reduced potency, except for substitution of P3, R14, and V16. Fusion with the tat sequence generated the cell-penetrating inhibitor version tat-5. This tat-5 fusion peptide maintained selectivity for CaMKII over CaMKI and CaMKIV, and appeared to slightly further enhance potency (IC50 ∼30 nM). Within a breast cancer cell line and in primary human fibroblasts, tat-5 inhibited the Erk signaling pathway and proliferation without any measurable cytotoxicity. Structural analysis of CN17β by CD and NMR indicated an α-helix conformation in the Leu6-Arg11 segment well overlapping with the crystal structure of 21-residue segment of CaM-KNtide bound to the kinase domain of CaMKII. [Copyright &y& Elsevier]

Abstract: Recently a series of chiral N-(phenoxyalkyl)amides have been reported as potent MT1 and MT2 melatonergic ligands. Some of these compounds were selected and tested for their antioxidant properties by measuring their reducing effect against oxidation of 2′,7′-dichlorodihydrofluorescein (DCFH) in the DCFH-diacetate (DCFH-DA) assay. Among the tested compounds, N-[2-(3-methoxyphenoxy)propyl]butanamide displayed potent antioxidant activity that was stereoselective, the (R)-enantiomer performing as the eutomer. This compound displayed strong cytoprotective activity against H2O2-induced cytotoxicity resulting slightly more active than melatonin, and performed as Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor, too. [Copyright &y& Elsevier]

A series of 3-acyl derivatives of the dihydronaphtho[2,3-b]thiophen-4,9-dione system were studied with respect to cytotoxicity and topoisomerase II inhibitory activity. These analogues were designed as electron-deficient anthraquinone analogues with potential intercalation ability. Derivatives 3-(diethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11m) and 3-(2-(dimethylamino)ethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11p) showed a high efficacy in cell lines that were highly resistant to treatment with doxorubicin, such as MDA-MB435 (melanoma), IGROV (ovarian), and SF-295 (glioblastoma) human cell lines. Both compounds inhibit topoisomerase II mediated relaxation of DNA, while only 11pincites arrest at the S phase in Caco-2 cells, inducing a delay of cell cycle progression and an increase of cell differentiation. The ability of these derivatives to modulate small heat shock proteins and cardiotoxicy effects was also explored. In addition, the DNA-binding properties of these compounds were investigated and discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: The involvement of GRK2 in cancer growth and an inverse correlation with p53 levels were suggested in breast cancer. Furthermore, increased GRK2 expression and activity were detected in thyroid cancer, but its effects and mechanisms of action were not investigated yet. This study aimed to explore the role of GRK2 in thyroid cancer both in vitro and in vivo and its crosstalk with p53. We demonstrated that thyroid cancer cells bearing a mutant form of p53 but not p53 null cells rely on GRK2 as a mechanism of proliferation by regulating p53 levels. Indeed, GRK2 indirectly induces p53 degradation through means of its catalytic activity. The pharmacological inhibition of the kinase effectively inhibits cancer growth by inducing p53-dependent mitochondrial pathways of apoptosis. Our results demonstrate a p53-dependent effect of GRK2 in cancer and suggest kinase inhibition as a potential therapeutic strategy for thyroid cancer. The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers. [ABSTRACT FROM AUTHOR]

Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Food supply in the Mediterranean area has been recently modified by big retail distribution; for instance, industrial retail has favored shipments of groceries from regions that are intensive producers of mass food, generating a long supply chain (LSC) of food that opposes short supply chains (SSCs) that promote local food markets. However, the actual functional role of food retail and distribution in the determination of the risk of developing metabolic syndrome (MetS) has not been studied hitherto. The main aim of this study was to test the effects of food chain length on the prevalence of MetS in a population accustomed to the Mediterranean diet. We conducted an observational study in Southern Italy on individuals adhering to the Mediterranean diet. We examined a total of 407 subjects (41% females) with an average age of 56 ± 14.5 years (as standard deviation) and found that being on the Mediterranean diet with a SSC significantly reduces the prevalence of MetS compared with the LSC (SSC: 19.65%, LSC: 31.46%; p: 0.007). Our data indicate for the first time that the length of food supply chain plays a key role in determining the risk of MetS in a population adhering to the Mediterranean diet. [ABSTRACT FROM AUTHOR]

Introduction: Polypharmacy and medication non-adherence in the older population are growing public health issues throughout the European Union (EU), and are critical issues in integrated care. SIMPATHY (Stimulating Innovation Management of Polypharmacy and Adherence in The Elderly) is a consortium of 10 organizations representing 8 EU countries with the goal of stimulating innovation around polypharmacy and adherence, ultimately providing the tools for EU policy makers to adopt new programs addressing this issue into existing healthcare systems. Methods: A mixed-methods case study is ongoing to characterize the Italian policies on the management of polypharmacy in the elderly. A desk review of these policy documents and guidelines at the national, regional and local level has been completed. Documents from the Scientific Societies (Italian Society of Pharmacy Hospital, Italian Society of Pharmacoeconomics, Geriatric and Gerontology Society, Internal Medicine Society, General Practioners Italian Society), Italian Medicine Agency (AIFA), were included for analysis. Next to that documents from the Campania region (about 6 millions), and specifically Naples metropolitan area (about 1 million inhabitants) were taken as an example of regional and local implementation. Key informant interviews will be conducted with policymakers and clinicians responsible for developing these activities, to highlight the lack of specific policies and delineating strategies for implementing polypharmacy programs. Focus groups consisting of policymakers, clinicians and patients will then be used to validate the research findings. Final analysis will be completed in April 2016. Progress report: The issue of management of polypharmacy in the elderly has not been fully addressed on a national level in Italy. Some region developed polypharmacy consensus papers or local policies (Toscana, Lombardia, Emilia Romagna) just suggesting some alert or warnings on potential inappropriateness prescription in the elderly. Although the awareness of stakeholders on the needing for developing strategies for polypharmacy management; the present desk review analysis highlights the lack of policies at a national level and the need for developing a comprehensive practical guideline. In addition, a lack of a specific multidisciplinary approach for polipharmacy management was further addressed. Full results including key informant interview and focus groups will be presented. Conclusion: Results from key informants will further elucidate _why_ polypharmacy policies have never been implemented and _how_ these policies can be developed. These results combined with the other SIMPATHY case studies with lack of policies wil l provide valuable tools for policymakers, researchers, and clinicians throughout Europe as they move to integrate polypharmacy and adherence activities into existing health care systems. Funding: This poster is part of the SIMPATHY project (663082) which has received funding from the European Union's Health Programme (2014-2020). [ABSTRACT FROM AUTHOR]