Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application

Objectives: This study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques. Methods: Avaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC-mass spectrometry. Results: CMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration. Conclusions: The study provides clear evidence for vaginal-rectal and rectal-vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products. ©The Author 2013.

The Role of Aquaporin 3 (AQP3) in Breast Cancer

The increasing prevalence of breast cancer (BC) in different parts of the world, particularly in the UK, highlights the importance of research into the aetiology and pathology of the disease. BC is the most common malignancy affecting women worldwide. Aquaporins (AQPs) are membrane protein channels that regulate cellular water flow. Recently, studies have demonstrated that expression of AQP3 is up-regulated in cancerous breast tissue. The present study examines the role of AQP3 in BC cell biology. Examination of clinical cases of BC showed higher AQP3 gene and protein expression in cancer tissues compared to healthy border tissues. In distinct clinicopathological groups however there were no differences observed with regards to AQP3 expression, suggesting that AQP3 expression may not be a predictor of lymph node infiltration or tumour grade. shRNA technology was used to knockdown gene expression of AQP3 in the invasive MDA-MB-231 BC cellular model. Cellular proliferation, migration, invasion, adhesion and response to the 5- fluorouracil (5-FU) based chemotherapy treatment were investigated in parental and knockdown cell line. AQP3 knockdown cells showed reduction in cellular proliferation, migration, invasion and increase in cell sensitivity to 5-FU compared with wild type (WT) or scrambled control (SC) cells. The effects of AQP3 knockdown on cellular glycolytic ability and ATP cellular content were quantified. Indirect glucose uptake was also measured by quantifying reconditioned media. AQP3 knockdown cells showed significantly lower levels of glucose uptake as compared to WT or SC. However there was no difference in the glycolytic ability and ATP content of the cells suggesting AQP3 has no role in cancer cell energetics. These data collectively suggest AQP3 expression is associated with the BC disease clinically and plays a role in multiple important aspects of BC pathophysiology, thus AQP3 represents a novel target for therapeutic intervention.

Discrimination of healthy and cancer cells of the bladder by metabolic state, based on autofluorescence

Bladder cancer is among the most common cancers worldwide (4th in men). It is responsible for high patient morbidity and displays rapid recurrence and progression. Lack of sensitivity of gold standard techniques (white light cystoscopy, voided urine cytology) means many early treatable cases are missed. The result is a large number of advanced cases of bladder cancer which require extensive treatment and monitoring. For this reason, bladder cancer is the single most expensive cancer to treat on a per patient basis. In recent years, autofluorescence spectroscopy has begun to shed light into disease research. Of particular interest in cancer research are the fluorescent metabolic cofactors NADH and FAD. Early in tumour development, cancer cells often undergo a metabolic shift (the Warburg effect) resulting in increased NADH. The ratio of NADH to FAD ("redox ratio") can therefore be used as an indicator of the metabolic status of cells. Redox ratio measurements have been used to differentiate between healthy and cancer breast cells and to monitor cellular responses to therapies. Here, we have demonstrated, using healthy and bladder cancer cell lines, a statistically significant difference in the redox ratio of bladder cancer cells, indicative of a metabolic shift. To do this we customised a standard flow cytometer to excite and record fluorescence specifically from NADH and FAD, along with a method for automatically calculating the redox ratio of individual cells within large populations. These results could inform the design of novel probes and screening systems for the early detection of bladder cancer.

Aid allocation of the emerging Central and Eastern European donors

This paper examines the main characteristics of the (re-)emerging foreign aid policies of the Visegrád countries (the Czech Republic, Hungary, Poland, Slovakia), concentrating on the allocation of their aid resources. I adopt an econometric approach, similar to the ones used in the literature, for analysing the aid allocation of the OECD DAC donors. Using this approach, I examine the various factors that influence aid allocation of the Visegrád countries, using data for the years between 2001 and 2008. The most important conclusion is that the amount of aid a partner country gets from the four emerging donors is not influenced by the level of poverty or the previous performance of the recipients (measured by the level of economic growth or the quality of institutions). The main determining factor seems to be geographic proximity, as countries in the Western Balkans and the Post-Soviet region receive much more aid from the Visegrád countries than other recipients. Historical ties (pre-1989 development relations) and international obligations in the cases of Afghanistan and Iraq are also found to be significant explanatory factors. This allocation is in line with the foreign political and economic interests of these new donors. Although there are clear similarities between the four donors, this paper also identifies some individual country characteristics.

A component model of methods for evaluation of the quality in education

Report published in the Proceedings of the National Conference on "Education in the Information Society", Plovdiv, May, 2013

Stabilization of catalyst particles against sintering on oxide supports with high oxygen ion lability exemplified by Ir-catalyzed decomposition of N2O

Iridium nanoparticles deposited on a variety of surfaces exhibited thermal sintering characteristics that were very strongly correlated with the lability of lattice oxygen in the supporting oxide materials. Specifically, the higher the lability of oxygen ions in the support, the greater the resistance of the nanoparticles to sintering in an oxidative environment. Thus with γ-Al2O3 as the support, rapid and extensive sintering occurred. In striking contrast, when supported on gadolinia-ceria and alumina-ceria-zirconia composite, the Ir nanoparticles underwent negligible sintering. In keeping with this trend, the behavior found with yttria-stabilized zirconia was an intermediate between the two extremes. This resistance, or lack of resistance, to sintering is considered in terms of oxygen spillover from support to nanoparticles and discussed with respect to the alternative mechanisms of Ostwald ripening versus nanoparticle diffusion. Activity towards the decomposition of N2O, a reaction that displays pronounced sensitivity to catalyst particle size (large particles more active than small particles), was used to confirm that catalytic behavior was consistent with the independently measured sintering characteristics. It was found that the nanoparticle active phase was Ir oxide, which is metallic, possibly present as a capping layer. Moreover, observed turnover frequencies indicated that catalyst-support interactions were important in the cases of the sinter-resistant systems, an effect that may itself be linked to the phenomena that gave rise to materials with a strong resistance to nanoparticle sintering.

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.

A vállalati likviditáskezelés szerepe eszközfedezettel rendelkező hitelszerződésekben. Az alkun alapuló megközelítés eredményei (The role of corporate liquidity management under secured debt financing Results of the bargaining approach)

A szerző azt a kérdést vizsgálja, hogy a vállalat működése során a likvid eszközök mekkora arányát tartsa fenn. A kérdést a finanszírozás szemszögéből veti fel, mivel a hitelezés okozta korlátok jelentősen befolyásolják a likvid eszköz tartalékolásának motivációit. A cikk a vállalkozói-hitelezői információs kapcsolat háromféle esetében mutatja be az eszközfedezettel rendelkező hitelek adósságszolgálatát meghatározó tényezőket. Elsőként a teljes információs viszony melletti stratégiákkal meghatározott adósságszolgálatot vizsgálja, majd a második típusú információs kapcsolatban a nem megfigyelhető vállalkozói erőfeszítéseket feltételezve adja meg az adósságszolgálat fizetésének ex ante és ex post egyensúlyát. Harmadikként, a nem igazolható vállalati adatok feltevése mellett teljes és részleges eszközfedezetre is meghatározza az optimális vállalkozói likviditási politikát, és tárgyalja az itt fennálló ellentéteket. Megmutatja, hogy részleges eszközfedezet mellett 1. újratárgyalható a hitelszerződés, és a stratégiai adósságszolgálatot nem lehet elkerülni, 2. a likviditásoptimalizálásnak nincs ex post Pareto-egyensúlyi megoldása, ugyanis a hitelszerződésben részt vevő felek alkuereje határozza meg a vállalat likviditásának szintjét. / === / This paper investigates what the liquid asset ratio for firms should be. Financing constraints significantly influence motivations for liquidity hoarding. The article shows the determinants of secured debt services for three different information cases of a lender-borrower relationship. First, it examines the strategic debt service under full information, and then, assuming non-observable entrepreneurial efforts, it gives the ex ante and ex post equilibria of the strategic debt service. The third case supposes non-verifiable firm information; this provides the optimal corporate liquidity policy and explains the contrary propositions. It shows that under not fully secured collateral, 1. the debt contract is renegotiable; the lender cannot avoid the strategic debt service, 2. there is no ex post optimal Pareto efficient solution to liquidity policy, because the corporate liquidity ratio is determined by the bargaining power of the partners in the debt contract.

A desztináció menedzsment szerepe a desztinációs versenyképességben – Hazai és dán tapasztalatok tükrében = The role of destination management in the destinations’ competitiveness – Hungarian and Danish experiences

A desztináció menedzsment valamennyi desztinációs versenyképesség modell középponti eleme, és „csodaszerként” jelenik meg, különösen azokban az országokban, amelyek a desztináció menedzsment eszközrendszerét a közelmúltban vezették be, annak érdekében, hogy a desztinációk lépést tudjanak tartani a versenytársaikkal, mint ahogyan ez hazánkban is történt. Jelen tanulmány alapját a témában írt PhD Értekezésem (Sziva, I. (2010)) adja, amelynek fókuszában a desztinációs versenyképesség értelmezése, az ex ante oldali tényezők feltárása állt. A téziskutatás során feltárt tényezők, és a Bírálóim konstruktív fejlesztési javaslatai a téma továbbkutatására ösztönöztek. Mindezért tartottam elengedhetetlennek, hogy a tézisemben összefoglalt hazai és osztrák kutatások legfontosabb eredményeit további nemzetközi színtéren, ezúttal Dániában vizsgáljam, jelen esetben a fókuszt a desztináció menedzsment tényezőire, és annak kiemelt kontextusaira helyezve. Jelen tanulmány legfontosabb célja az, hogy egyrészt összefoglalást adjon a desztináció menedzsment szerepéről a desztinációs versenyképesség elméleti megközelítéseit tekintve. Továbbá, hogy a hazai tapasztalatok összevetésre kerüljenek a szakértői interjúk során megismert dán tapasztalatokkal és további kutatási irányok kerüljenek meghatározásra. Ezúton szeretném megköszönni dániai kutatásom interjú-alanyainak részvételét és a Budapesti Corvinus Egyetem TÁMOP 4.2.1.B-09/1/KMR-2010-0005 projekt keretében nyújtott támogatását! _________ Destination management is the central element of the model concerning destinations’ competitiveness, and appears as „wonder medicine”, particularly in those countries, where the tools of destination management was introduced in the near past, as it happened in Hungary. The baseline of this study is given by my PhD Dissertation (Sziva, I. (2010)), which was focusing on interpretation and the ex ante factors of destinations’ competitiveness. The factors identified during my thesis research, and the constructive recommendations of my Reviewer gave the motivation for further analysis. That is why was it important to make further researchers based on the results identified in the Hungarian and Austrian cases of my thesis research, and add further international, this time Danish context to the research, by focusing on destination management among the factors of competitiveness. The aim of the article is to give a summary about the theoretical approach of destination management and compare the Hungarian experiences with that of the results of the Danish research based on experts’ interviews. Hereby I would like to thank my interviewees their participation, and the support of Corvinus University Budapest in the framework of TÁMOP 4.2.1.B-09/1/KMR-2010-0005 project.

Tények, adatok és mutatószámok felhasználásának anomáliái (The anomalies of the usage of facts, data, and indexes)

Tudomány nem létezik a tények felmérése, adatok gyűjtése és felhasználása nélkül. A tényeket azonban el lehet hallgatni vagy ferdíteni, az adatokat sokféleképpen lehet összeválogatni, az azokból készült mutatószámokat pedig a bonyolult és változó valóság leegyszerűsítő, sőt meghamisító ábrázolására, illetve magyarázatára is fel lehet használni. _____ Economics cannot do without measuring. However, the required data are not always available or they are not reliable, as some cases of population census exemplify it. The indicators we use, particularly composite indexes, are often misleading because they oversimplify complex phenomena or processes, and neglect important non-measurable ones, as the examples of the per capita GDP indicator measuring the development level of countries, and the composite indexes measuring the “human development” of countries (HDI), or their “national competitiveness” (GCI) may show. To avoid the enchantment of numbers, the quantitative approach must always be combined and corrected by a critical, holistic and qualitative approach.

Olcsó és okos – a frugal innováció és a tudásmenedzsment szimbiózisa (Cheap and clever – symbiosis of frugal innovation and knowledge management)

A tudásmenedzsment-rendszerek működtetése lassan elfogadottá, és a nagyobb vállalatok életében a mindennapok részévé vált az elmúlt években. A rendszer hordozta előnyök, lehetőségek teljes körű kiaknázása azonban közel sem mutat ilyen reményteli képet. Különösen igaz ez, ha a vállalati működés kulcsfolyamataival való kapcsolatát, egymásba épülését vizsgáljuk. E folyamatok közé tartozik az innováció is. Bár minden szakmabeli és laikus gondolkodás egyértelműen látja, hogy az innovációhoz tudás kell, és a tudásmenedzsment-rendszernek is a tudás az alapja, mégsem valósul meg e két terület szoros kapcsolata, együtt mozgása a siker érdekében. Különösen igaz ez a hiányosság a legújabb innovációs megoldásokban. A tanulmány a tudásmenedzsment-rendszer és a frugal innováció kapcsolatát, elvi és gyakorlati lehetőségeit mutatja be. ____ To operate a knowledge management system has become an accepted method and a part of everyday life in the biggest companies. The full circle exploitation of advantages and possibilities of this system does not show a hopeful picture. It is especially true when we examine relationships and constructions with other key processes in the operation of a company. Innovation belongs to above mentioned processes. Though every outsider and professional way of thinking sees clearly that knowledge is needed to innovate and knowledge is a basis of knowledge management, but the close connection of the two important processes has not been realized on behalf of success. Defectiveness is especially true in cases of the newest innovation methods. The paper shows the connection of frugal innovation and knowledge management, its theoretical and practical possibilities

Links between migration and the presence of foreign combatants in armed conflict

This article explores the connections between migration and foreign combat, offering an improved definition of „foreign fighters,” and a general concept of foreign combatants’ behaviour as an anomalous form of migration. In contrast with the popular discourse and terrorism-related concerns about present-day Western European foreign fighters in Iraq and Syria (and their return to Europe) and Middle Eastern migrant refugees (and their arrival in Europe), the intention of this article is to offer a conceptually thorough consideration of the causal connections between movements of migration and the presence of foreign combatants in armed conflict, informed by a wide sample of cases. Such an assessment has to take place with a view to all forms of migration (including forced migration), all forms of foreign combat (not only foreign combat on the side of non-state actors as David Malet's oft-cited but overly restrictive definition would imply), and regions of the world beyond the Middle East and Islamic countries. Along these guiding lines, the article points out many comparatively rarely considered cases of foreign combat as well as the underestimated obstacles in the way of fighting abroad. Taking account of the latter allows refutation of a key implication of „new war theory” (its focus on „greed” as a motive of combatants), in light of the continued importance of cultural factors and ideological motives for participation in foreign combat.

An autoregressive conditional filtering process to remove intraday seasonal volatility and its application to testing the noisy rational expectations model

We develop a new autoregressive conditional process to capture both the changes and the persistency of the intraday seasonal (U-shape) pattern of volatility in essay 1. Unlike other procedures, this approach allows for the intraday volatility pattern to change over time without the filtering process injecting a spurious pattern of noise into the filtered series. We show that prior deterministic filtering procedures are special cases of the autoregressive conditional filtering process presented here. Lagrange multiplier tests prove that the stochastic seasonal variance component is statistically significant. Specification tests using the correlogram and cross-spectral analyses prove the reliability of the autoregressive conditional filtering process. In essay 2 we develop a new methodology to decompose return variance in order to examine the informativeness embedded in the return series. The variance is decomposed into the information arrival component and the noise factor component. This decomposition methodology differs from previous studies in that both the informational variance and the noise variance are time-varying. Furthermore, the covariance of the informational component and the noisy component is no longer restricted to be zero. The resultant measure of price informativeness is defined as the informational variance divided by the total variance of the returns. The noisy rational expectations model predicts that uninformed traders react to price changes more than informed traders, since uninformed traders cannot distinguish between price changes caused by information arrivals and price changes caused by noise. This hypothesis is tested in essay 3 using intraday data with the intraday seasonal volatility component removed, as based on the procedure in the first essay. The resultant seasonally adjusted variance series is decomposed into components caused by unexpected information arrivals and by noise in order to examine informativeness.

A Mixed Method Study of Spirituality and the Influence on TB Medication Adherence

Nonadherence to medication for tuberculosis (TB) can lead to new cases of TB and death. Interest in spirituality in healthcare has grown among adult educators, health educators and healthcare workers (Tisdell, 2003). This mixed-method study will explore spirituality and TB medication adherence among African American and Haitian populations.

Integration of Colombian refugees in Costa Rica : an ethnographic approach to the refugees' legal, economic, and social experiences

This qualitative study, based on interviews to 17 refugee families, attempts to identify the reasons behind the lack of integration of Colombian refugees in Costa Rica. The model of Immigrant Modes of Incorporation and the studies of Alejandro Portes and Julia Sensenbrenner about the sources of social capital on migrant communities provided the theoretical framework used to identify the roots of the integration challenges. The findings suggest that Costa Rican policies towards the reception and integration of Colombian refugees are exclusionary. The host labor market is marked by sentiments of xenophobia towards the sample population while reported cases of persecution in the country also inhibit this population's economic integration. The lack of social capital sources contributes to inhibit this community's development, despite their participation in informal networks. There were signs of collective action. Yet, the refugee community fails to come together, while it also seems alienated from the community of Colombian entrepreneurs in Costa Rica.