A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.

An automated tool for semantic accessing to formal software models

Many software engineers have found that it is difficult to understand, incorporate and use different formal models consistently in the process of software developments, especially for large and complex software systems. This is mainly due to the complex mathematical nature of the formal methods and the lack of tool support. It is highly desirable to have software models and their related software artefacts systematically connected and used collaboratively, rather than in isolation. The success of the Semantic Web, as the next generation of Web technology, can have profound impact on the environment for formal software development. It allows both the software engineers and machines to understand the content of formal models and supports more effective software design in terms of understanding, sharing and reusing in a distributed manner. To realise the full potential of the Semantic Web in formal software development, effectively creating proper semantic metadata for formal software models and their related software artefacts is crucial. This paper proposed a framework that allows users to interconnect the knowledge about formal software models and other related documents using the semantic technology. We first propose a methodology with tool support is proposed to automatically derive ontological metadata from formal software models and semantically describe them. We then develop a Semantic Web environment for representing and sharing formal Z/OZ models. A method with prototype tool is presented to enhance semantic query to software models and other artefacts. © 2014.

Exploration by Means of Computer Simulation of Nonlinear Hierarchical Structure of Neuronal Memory on the Model of Olfactory Bulb

Results of numerical experiments are introduced. Experiments were carried out by means of computer simulation on olfactory bulb for the purpose of checking of thinking mechanisms conceptual model, introduced in [2]. Key role of quasisymbol neurons in processes of pattern identification, existence of mental view, functions of cyclic connections between symbol and quasisymbol neurons as short-term memory, important role of synaptic plasticity in learning processes are confirmed numerically. Correctness of fundamental ideas put in base of conceptual model is confirmed on olfactory bulb at quantitative level.

Founders' human capital and the performance of UK new technology based firms

This paper investigates the role of entrepreneurs' general and specific human capital on the performance of UK new technology based firms using a resource based approach to the entrepreneurship theory. The effect of entrepreneurial human capital on the performance of NTBFs is investigated using data derived from a survey of 412 firms operating in both high-tech manufacturing and the services sectors. According to the resource based theory it is found that specific human capital is more important for the performance of NTBFs in relation to general. More specifically individual entrepreneurs or entrepreneurial teams with high levels of formal business education, commercial, managerial or same sector experience are found to have created better performing NTBFs. Finally it is found that the performance of a NTBF can improve through the combination of heterogeneous but complementary skills, including, for example, technical education and commercial experience or managerial technical and managerial commercial experience. © 2010 Springer Science+Business Media, LLC.

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

Public R&D policies and private R&D investment:a survey of the empirical evidence

The importance of R&D investment in explaining economic growth is well documented in the literature. Policies by modern governments increasingly recognise the benefits of supporting R&D investment. Government funding has, however, become an increasingly scarce resource in times of financial crisis and economic austerity. Hence, it is important that available funds are used and targeted effectively. This paper offers the first systematic review and critical discussion of what the R&D literature has to say currently about the effectiveness of major public R&D policies in increasing private R&D investment. Public policies are considered within three categories, R&D tax credits and direct subsidies, support of the university research system and the formation of high-skilled human capital, and support of formal R&D cooperations across a variety of institutions. Crucially, the large body of more recent literature observes a shift away from the earlier findings that public subsidies often crowd-out private R&D to finding that subsidies typically stimulate private R&D. Tax credits are also much more unanimously than previously found to have positive effects. University research, high-skilled human capital, and R&D cooperation also typically increase private R&D. Recent work indicates that accounting for non-linearities is one area of research that may refine existing results. © 2014 John Wiley & Sons Ltd.

Application of Statistical Experimental Design in Food Sciences

The development of new, health supporting food of high quality and the optimization of food technological processes today require the application of statistical methods of experimental design. The principles and steps of statistical planning and evaluation of experiments will be explained. By example of the development of a gluten-free rusk (zwieback), which is enriched by roughage compounds the application of a simplex-centroid mixture design will be shown. The results will be illustrated by different graphics.

Formal methods @ runtime

Heuristics, simulation, artificial intelligence techniques and combinations thereof have all been employed in the attempt to make computer systems adaptive, context-aware, reconfigurable and self-managing. This paper complements such efforts by exploring the possibility to achieve runtime adaptiveness using mathematically-based techniques from the area of formal methods. It is argued that formal methods @ runtime represents a feasible approach, and promising preliminary results are summarised to support this viewpoint. The survey of existing approaches to employing formal methods at runtime is accompanied by a discussion of their challenges and of the future research required to overcome them. © 2011 Springer-Verlag.

Perceptions of self-testing for chlamydia:understanding and predicting self-test use

Background: Self-testing technology allows people to test themselves for chlamydia without professional support. This may result in reassurance and wider access to chlamydia testing, but anxiety could occur on receipt of positive results. This study aimed to identify factors important in understanding self-testing for chlamydia outside formal screening contexts, to explore the potential impacts of self-testing on individuals, and to identify theoretical constructs to form a Framework for future research and intervention development. Methods: Eighteen university students participated in semi-structured interviews; eleven had self-tested for chlamydia. Data were analysed thematically using a Framework approach. Results: Perceived benefits of self-testing included its being convenient, anonymous and not requiring physical examination. There was concern about test accuracy and some participants lacked confidence in using vulvo-vaginal swabs. While some participants expressed concern about the absence of professional support, all said they would seek help on receiving a positive result. Factors identified in Protection Motivation Theory and the Theory of Planned Behaviour, such as response efficacy and self-efficacy, were found to be highly salient to participants in thinking about self-testing. Conclusions: These exploratory findings suggest that self-testing independently of formal health care systems may no more negatively impact people than being tested by health care professionals. Participants’ perceptions about self-testing behaviour were consistent with psychological theories. Findings suggest that interventions which increase confidence in using self-tests and that provide reassurance of test accuracy may increase self-test intentions.

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy:effects of genetic, demographic and neuropathological variables

Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND) but increased with Alzheimer's disease (AD) or hippocampal sclerosis (HS) co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI) while increased survival was associated with greater densities of enlarged neurons (EN) in the frontal and temporal lobes. The data suggest that: (1) survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA), (2) MND co-morbidity predicts poor survival, and (3) NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.

Pathology of the superior colliculus in chronic traumatic encephalopathy

PURPOSE: To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. METHODS: The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. RESULTS: Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tau-immunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. CONCLUSIONS: The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis.

Formal professional relationships between general practitioners and specialists: possible associations with patient health and pharmacy costs

This article investigates whether the strength of formal professional relationships between general practitioners (GPs) and specialists (SPs) affects either the health status of patients or their pharmacy costs. To this end, it measures the strength of formal professional relationships between GPs and SPs through the number of shared patients and proxies the patient health status by the number of comorbidities diagnosed and treated. In strong GP–SP relationships, the patient health status is expected to be high, due to efficient care coordination, and the pharmacy costs low, due to effective use of resources. To test these hypotheses and compare the characteristics of the strongest GP–SP connections with those of the weakest, this article concentrates on diabetes—a chronic condition where patient care coordination is likely important. Diabetes generates the largest shared patient cohort in Hungary, with the highest traffic of specialist medication prescriptions. This article finds that stronger ties result in lower pharmacy costs, but not in higher patient health statuses. Key points for decision makers • The number of shared patients may be used to measure the strength of formal professional relationships between general practitioners and specialists. • A large number of shared patients indicates a strong, collaborative tie between general practitioners and specialists, whereas a low number indicates a weak, fragmented tie. • Tie strength does not affect patient health—strong, collaborative ties between general practitioners and specialists do not involve better patient health than weak, fragmented ties. • Tie strength does affect pharmacy costs—strong, collaborative ties between general practitioners and specialists involve significantly lower pharmacy costs than weak, fragmented ties. • Pharmacy costs may be reduced by lowering patient care fragmentation through channelling a general practitioner’s patients to a small number of specialists and increasing collaboration between general practitioner and specialists. • Limited patient choice is financially more beneficial than complete freedom of choice, and no more detrimental to patient health.

The Central Agency for Jewish Education: Fifty years of Jewish education in Dade County

The purpose of the study was to provide a historical record of the Bureau of Jewish Education/Central Agency for Jewish Education and its role in Jewish education in Miami since its inception in 1944 as well as to provide a sociological context within which to view the growth and development of the community. During the past 50 years of the Agency's existence, Dade County's Jewish population has undergone many changes including a huge population increase in the 1960s and 1970s and then a decrease in the 1980s and 1990s, and a shift from postwar business class of store owners to turn of the century professional class.^ The methodology used in this study was threefold. First, document analysis of formal and informal documents dating from 1944 to the present was conducted. Second, personal interviews were conducted with the Executive Directors of the B.J.E./C.A.J.E., long-time B.J.E./C.A.J.E. staff, present staff, Greater Miami Jewish Federation leaders, and lay leadership of C.A.J.E. Third, national trends in Jewish education were cited as a basis for the comparison and contrast of the achievements of C.A.J.E.^ The historiography concluded that the Agency had come full circle in its programs. Analysis of the services provided to religious and day schools, early childhood education, the High Schools, teacher services, adult education, and the library indicated that in some areas C.A.J.E. was an innovator, in other areas it followed national trends, and in others it was deficient. Recommendations included a reeducative process for the community with Jewish education made top priority, more visibility and publicity for the work of C.A.J.E. that would enhance its prestige and improve support, and holistic planning of programs for the future. ^

Health care utilization behavior of elders in a multicultural urban environment

The objective of this research is to determine the influences of social, environmental, behavioral, and economic forces on the health care service utilization of four racial/ethnic groups of non-institutionalized elders in a multicultural urban environment. To address these issues this dissertation examines three intertwined themes of culture, aging, and health, using a sample of elders residing in Miami-Dade County, FL in four racial/ethnic groups: white non-Hispanic; black non-Hispanic English speakers; Cuban; and non-Cuban Hispanic. ^ The research questions were analyzed using both quantitative and qualitative data. Data for the quantitative component uses telephone survey data from the Dade County Needs Assessment. The purpose of this component is to develop a more comprehensive model of elder health care utilization behavior. The qualitative component uses data from focus groups from Dade County Needs Assessment, archival data and a literature review of previous ethnographic research. The purpose of this component is to gain a better understanding of the social construction of the terms “age”' and “aging,” as well as to place issues of health and health care in the lives of elders. ^ The findings raised several important issues. First, just because people share a common chronological age does not mean that they are the same in every other respect. Examining elders as a homogeneous group of users of formal health care services in a community is simplistic. Placing “aging” and “health” in a cultural context is important. My findings confirm that the meaning of “aging” and “old” are socially constructed. Further, the term “aging” is NOT synonymous with ill health or frailty. This was a consistent finding in both the quantitative and qualitative results. ^ While all aging individuals share a mutual orientation toward aging (i.e., biological process), they do not age the same way (i.e., social construction of “aging”). Thus, policymakers and others serving the elder population must be aware of the particular cultural context, as well as the previous life experiences of the individuals that they serve. This analysis documents the importance of culture and geographic community in understanding health care service utilization of elders. ^

The maintenance of tracking: The role of organizational culture

Modern comprehensive high schools do not formally track students into different programs, but schools offer different curricular sequences with important and stratified consequences for students' post-secondary education. This study used qualitative methodology to examine how schools' organizational cultures influence the maintenance of tracking practices in four comprehensive high schools in Miami. The methodology included long-term participant observation in each of the four schools, unstructured and semi-structured interviews and the collection of written documents produced by the district. A framework based on the concepts of environment, mission, information, strategy, and leadership was used to analyze the data. ^ It was found that school cultures shared deeply held beliefs that regard ability as a fixed trait. This prevented schools from providing access to information about the consequences of course selection to the majority of the student body, with the exception of those students defined as “college bound.” State and County level policies that reward achievement in standardized tests combined with school overcrowding, resulted in organizational cultures that favored the adoption of strategies stressing efficiency, as opposed to a challenging education for all students. Only one of the four schools in the study had a policy requiring students to attempt courses that were more challenging. The practice was resented by both teachers and counselors, since it was perceived as interfering with other goals of the institution, i.e.: graduating students in four years. ^ The culture of the schools stressed college as the only legitimate post-secondary option; consequently, the majority of counselors did not encourage students—even those already defined as “not college material”—to consider other alternatives, such as vocational education. The elimination of formal tracks in these comprehensive high schools resulted in the school culture lacking a clear mission in regards to non-college bound students. Findings are discussed in relation to current theoretical explanations for educational policy and equality of opportunity. ^