Synthesis of Novel 6-(4-Substituted piperazine-1-yl)-9(b-D-ribofuranosyl) purine Derivatives, Which Lead to Senescence-Induced Cell Death in liver Cancer Cells

Cataloged from PDF version of article.Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N-6 were synthesized and evaluated for their cytotoxicity on Huh7, HepG2, FOCUS, Mahlavu liver, MCF7 breast, and HCT116 colon carcinoma cell lines. The purine nucleoside analogues were analyzed initially by an anticancer drug-screening method based on a sulforhodamine B assay. Two nucleoside derivatives with promising cytotoxic activities (11 and 12) were further analyzed on the hepatoma cells. The N-6-(4-Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC50 values between 5.2 and 9.2 mu M. Similar to previously described nucleoside analogues, compound 11 also interferes with cellular ATP reserves, possibly through influencing cellular kinase activities. Furthermore, the novel nucleoside analogue 11 was shown to induce senescence-associated cell death, as demonstrated by the SA beta-gal assay. The senescence-dependent cytotoxic effect of 11 was also confirmed through phosphorylation of the Rb protein by p15(INK4b) overexpression in the presence of this compound

Geriatric pharmacotherapy : optimisation through integrated approach in the hospital setting

Since older patients are more vulnerable to adverse drug-related events, there is a need to ensure appropriate prescribing in these patients in order to prevent misuse, overuse and underuse of drugs. Different tools and strategies have been developed to reduce inappropriate prescribing; the available measures can be divided into medication assessment tools, and specific interventions to reduce inappropriate prescribing. Implicit criteria of inappropriate prescribing focus on appropriate dosing, search for drug-drug interactions, and increase adherence. Explicit criteria are consensus-based standards focusing on drugs and diseases and include lists of drugs to avoid in general or lists combining drugs with clinical data. These criteria take into consideration differences between patients, and stand for a medication review, by using a systematic approach. Different types of interventions exist in order to reduce inappropriate prescribing in older patients, such as: educational interventions, computerized decision support systems, pharmacist-based interventions, and geriatric assessment. The effects of these interventions have been studied, sometimes in a multifaceted approach combining different techniques, and all types seem to have positive effects on appropriateness of prescribing. Interdisciplinary teamwork within the integrative pharmaceutical care is important for improving of outcomes and safety of drug therapy. The pharmaceutical care process consists offour steps, which are cyclic for an individual patient. These steps are pharmaceutical anamnesis, medication review, design and follow-up of a pharmaceutical care plan. A standardized approach is necessary for the adequate detection and evaluation of drug-related problems. Furthermore, it is clear that drug therapy should be reviewed in-depth, by having full access to medical records, laboratory values and nursing notes. Although clinical pharmacists perform the pharmaceutical care process to manage the patient’s drug therapy in every day clinical practice, the physician takes the ultimate responsibility for the care of the patient in close collaboration with nurses

What is the evidence for the contribution of forests to poverty alleviation? A systematic map protocol

This is the final version of the article. Available from BioMed Central via the DOI in this record.Background: Forests provide an essential resource that support the livelihoods of an estimated 20% of the global population. Forests are thought to serve in three primary roles to support livelihoods: subsistence, safety nets, and pathways to prosperity. While we have a working understanding of how poor people depend on forests in individual sites and countries, much of this evidence is dispersed and not easily accessible. Thus, while the importance of forest ecosystems and resources to contribute to poverty alleviation has been increasingly emphasized in international policies, conservation and development initiatives and investments- the strength of evidence to support how forests can affect poverty outcomes is still unclear. This study takes a systematic mapping approach to scope, identify and describe studies that measure the effect of forest-based activities on poverty outcomes at local and regional scales. This effort builds upon an existing systematic map on linkages between conservation and human well-being in order to make this process more efficient. We will conduct a refined and updated search strategy pertinent to forests-poverty linkages to glean additional evidence from studies outside the scope of the original map. Results of this study can be used for informing conservation and development policy and practices in global forest ecosystems and highlight evidence gaps where future primary studies and systematic reviews can add value. Methods: We build upon the search strategy outlined in McKinnon et al. (Environ Evid 1-25, 2016) and expand our search to cover a total of 7 bibliographic databases, 15 organizational websites, 8 existing systematic reviews and maps, and evidence gap maps, and solicit key informants. All searches will be conducted in English and encompass all nations. Search results will be screened at title, abstract, and full text levels, recording both the number of excluded articles and reasons for exclusion. Full text assessment will be conducted on all included article and extracted data will be reported in a narrative review that will summarize trends in the evidence, report any knowledge gaps and gluts, and provide insight for policy, practice and future research. The data from this systematic map will be made available as well, through an open access, searchable data portal and visualization tool.We are grateful for funding support from the Program on Forests (PROFOR) (SA, SO, SC, RG) and the USDA National Institute of Food and Agriculture, Hatch Project #1009327 (DM)

Medication use in Italian nursing homes: preliminary results from the national monitoring system

Background: The aging population has increased concerns about the affordability, quality, and nature of long-term care for older people, emphasizing the role of nursing homes. Unlike acute hospital and primary care, there is a lack of drug consumption data in long-term care to understand regional or national healthcare policies. Objectives: This study aimed to describe medication consumption by older adults and expenditure in Italian nursing homes (NHs). Methods: Data on drug consumption and costs from the administrative medicine informational flows that detect medicines packages supplied to patients in health facilities and NHs were used. Data on the characteristics of the healthcare residence were from the Italian Health Ministry. Records for the year 2019, selecting the nursing homes exclusively providing elderly or mixed (elderly and disabled) were used. Results: In 2019, the total expenditure on medicines in NHs amounted to 25.38 million euros, the average cost to 1.30 and the expenditure per bed to 436.18 euros. Cardiovascular drugs were the highest-consuming therapeutic class (177.0 defined daily doses—DDDs/100 days of NH stay; 22.2% of total) followed by drugs acting on the alimentary tract and metabolism (167.6% and 21.0%) and blood drugs (160.4% and 20.1%). The treatment of hypertension and heart failure was widely the most frequently used, with the consumption being driven mainly by furosemide and ramipril. Antiulcer drugs were used on average in more than half of the days of NH stay (58.5 DDDs/100 days of NH stay), representing a therapeutic category for which deprescribing initiatives are recommended. On average, almost all patients received a dose of benzodiazepines, antipsychotics and antidepressants (37.6, 35.9, and 17.7 DDDs/100 days of NH stay, respectively), confirming the high prevalence of use for these medicines. Antibiotics reached 6.8 DDDs/100 days of NH stay. Conclusion: The availability of data in this specific setting allows the identification of the main interventions toward improving appropriateness and represents a challenge for drug utilization research. Data from this study suggest that proton pump inhibitors (PPIs), benzodiazepines and antibacterials can be areas of improving prescribing appropriateness

Medication Use and Costs Among Older Adults Aged 90 Years and Older in Italy

Older adults are often affected by multiple chronic conditions and experience geriatric syndromes that may affect the risk/benefit profile of medications. Little is known about the use of such medications in the older population. This article describes medication use and costs in Italian adults aged ≥90 years. Data from the 2019 Pharmaceutical Prescriptions database, concerning data on medications reimbursed by the Italian National Health Service, were analyzed in terms of prevalence and amount of use expressed as defined daily dose/1,000 users (DDD/1,000 users/day), accounting for different age-groups and sex. All individuals aged ≥90 years used at least one medication, with a mean number of 3128 DDD/1,000 users/day corresponding to an annual cost of 683 euros per user. Both use and costs linearly decreased with increasing age, with men accounting for a higher amount of DDD/1,000 users and costs than women across all age-groups. Antihypertensives (1330 DDD/1,000 inhabitants), antiplatelet agents (337 DDD/1,000 inhabitants), medications for peptic ulcer and gastroesophageal reflux (328 DDD/1,000 inhabitants), and lipid-lowering agents (166 DDD/1,000 inhabitants) were the most frequently used medications. We observed a progressive decrease in the usage of the majority of medications with increasing age, with the exception of antibiotics and antipsychotics. Individuals aged ≥90 years used a lower DDD/1,000 users, with an associated decrease in annual costs. The persistent use of preventive medications highlights the potential lack of awareness regarding medication rationalization and guidance for optimizing prescriptions. Our findings highlight the need for further initiatives to improve medications’ appropriateness in these older age-groups

A systematic map of evidence on the contribution of forests to poverty alleviation

This is the final version. Available from the publisher via the DOI in this record.Background: Forests provide an essential resource to the livelihoods of an estimated 20% of the global population. The contribution of forest ecosystems and forest-based resources to poverty reduction is increasingly emphasized in international policy discourse and conservation and development investments. However, evidence measuring the effect of forest-based activities on poverty outcomes remains scattered and unclear. Lack of systematic understanding of forest-poverty relationships, in turn, inhibits research, policymaking, and efficient financial resource allocation. Methods: To identify relevant studies for inclusion in this systematic map we searched six bibliographic databases, 15 organizational websites, eight systematic evidence syntheses (reviews and maps), and solicited information from key informants. Search results were screened for relevance against predefined inclusion criteria at title, abstract, and full text levels, according to a published protocol. Included articles were coded using a predefined framework. Trends in the evidence, knowledge gaps and relatively well-researched sub-topics are reported in a narrative synthesis. Occurrence and extent of existing evidence about links between interventions and outcomes are presented in a visual heatmap. Data are available through the open access Evidence for Nature and People Data Portal (http://www.natureandpeopleevidence.org). Results: A total of 242 articles were included in the systematic map database. Included articles measured effects of 14 forest-based intervention types on 11 poverty dimensions. The majority of the evidence base (72%) examined links between productivity-enhancement strategies (e.g. forest management, agroforestry, and habitat management) and monetary income and/or social capital outcomes. Other areas with high occurrence of articles include linkages between interventions involving governance, individual rights/empowerment or linked enterprises/livelihood alternatives with impacts on monetary income from direct sale of goods. A key knowledge gap was on the impacts of investment-based interventions (i.e. enhancing produced, human, and social capitals). Another was the impacts of forest-based interventions on financial capital (savings, debt), non-monetary benefits, and health. Conclusions: The evidence base on forest-based productive activities and poverty alleviation is growing but displays a number of biases in the distribution of articles on key linkages. Priorities for future systematic reviews and evaluations include in-depth examinations into the impacts of rights-based activities (e.g. governance, empowerment) on poverty dimensions; and productivity-enhancing activities on social capital. More comprehensive and robust evidence is needed to better understand the synergies and trade-offs among the different objectives of forest conservation and management and variation in outcomes for different social groups in different social-ecological contexts

Anatomical and biomechanical evaluation of the tension band technique in patellar fractures

Tension band wiring for patellar fractures is common, but some recent reports refer to disadvantages of this approach. Our anatomical and biomechanical study focused on use of tension band techniques in patellar fractures. The anatomy of the patella and tendon insertion was examined with knee magnetic resonance imaging (MRI) and correlated with the technical requirements of the tension band. Tension band wiring over tendinous tissue was simulated and calculated with a cyclic biomechanical test on cow patellae. According to tension band templating on the MRI section, Kirschner wire insertion was needed for the tension band to turn over the tendinous tissue. The tension band became more stable while turning over less tendinous tissue and more adjacent bone surface. Nevertheless, cyclic loading tests indicate that all tension band applications in this study lose their initial stability. Excessive initial compression by the tension band resulted in bending of the Kirschner wire and thus reduction failure. For optimum stabilisation, tension force transfer should be done directly on bone or at least material that protects the tendon would be useful

The quorum sensing com system regulates pneumococcal colonisation and invasive disease in a pseudo-stratified airway tissue model.

BACKGROUND The effects of the com quorum sensing system during colonisation and invasion of Streptococcus pneumoniae (Spn) are poorly understood. METHODS We developed an ex vivo model of differentiated human airway epithelial (HAE) cells with beating ciliae, mucus production and tight junctions to study Spn colonisation and translocation. HAE cells were inoculated with Spn wild-type TIGR4 (wtSpn) or its isogenic ΔcomC quorum sensing-deficient mutant. RESULTS Colonisation density of ΔcomC mutant was lower after 6 h but higher at 19 h and 30 h compared to wtSpn. Translocation correlated inversely with colonisation density. Transepithelial electric resistance (TEER) decreased after pneumococcal inoculation and correlated with increased translocation. Confocal imaging illustrated prominent microcolony formation with wtSpn but disintegration of microcolony structures with ΔcomC mutant. ΔcomC mutant showed greater cytotoxicity than wtSpn, suggesting that cytotoxicity was likely not the mechanism leading to translocation. There was greater density- and time-dependent increase of inflammatory cytokines including NLRP3 inflammasome-related IL-18 after infection with ΔcomC compared with wtSpn. ComC inactivation was associated with increased pneumolysin expression. CONCLUSIONS ComC system allows a higher organisational level of population structure resulting in microcolony formation, increased early colonisation and subsequent translocation. We propose that ComC inactivation unleashes a very different and possibly more virulent phenotype that merits further investigation

Modified geodetic brane cosmology

We explore the cosmological implications provided by the geodetic brane gravity action corrected by an extrinsic curvature brane term, describing a codimension-1 brane embedded in a 5D fixed Minkowski spacetime. In the geodetic brane gravity action, we accommodate the correction term through a linear term in the extrinsic curvature swept out by the brane. We study the resulting geodetic-type equation of motion. Within a Friedmann-Robertson-Walker metric, we obtain a generalized Friedmann equation describing the associated cosmological evolution. We observe that, when the radiation-like energy contribution from the extra dimension is vanishing, this effective model leads to a self-(non-self)-accelerated expansion of the brane-like universe in dependence on the nature of the concomitant \beta-parameter associated with the correction, which resembles an analogous behaviour in the DGP brane cosmology. Several possibilities in the description for the cosmic evolution of this model are embodied and characterized by the involved density parameters related in turn to the cosmological constant, the geometry characterizing the model, the introduced \beta-parameter as well as the dark like-energy and the matter content on the brane.Comment: 15 pages, 3 figures. New version corresponds to the one published in CQ

Quantum Cosmology of Generalized Two--Dimensional Dilaton Gravity Models

The quantum cosmology of two-dimensional dilaton-gravity models is investigated. A class of models is mapped onto the constrained oscillator-ghost-oscillator model. A number of exact and approximate solutions to the corresponding Wheeler-DeWitt equation are presented. A wider class of minisuperspace models that can be solved in this fashion is identified. Supersymmetric extensions to the induced gravity theory and the bosonic string theory are then considered and closed-form solutions to the associated quantum constraints are derived. The possibility of applying the third-quantization procedure to two-dimensional dilaton-gravity is briefly discussed.Comment: 28 pages, late