Oxidation of 3-hydroxyanthranilic acid to the phenoxazinone cinnabarinic acid by peroxyl radicals and by compound I of peroxidases or catalase

Since 3-hydroxyanthranilic acid (3HAA), an oxidation product of tryptophan metabolism, is a powerful radical scavenger [Christen, S., Peterhans, E., ; Stocker, R. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 2506], its reaction with peroxyl radicals was investigated further. Exposure to aqueous peroxyl radicals generated at constant rate under air from the thermolabile radical initiator 2,2'-azobis[2-amid-inopropane] hydrochloride (AAPH) resulted in rapid consumption of 3HAA with initial accumulation of its cyclic dimer, cinnabarinic acid (CA). The initial rate of formation of the phenoxazinone CA accounted for approximately 75% of the initial rate of oxidation of 3HAA, taking into account that 2 mol of 3HAA are required to form 1 mol of CA. Consumption of 3HAA under anaerobic conditions (where alkyl radicals are produced from AAPH) was considerably slower and did not result in detectable formation of CA. Addition of superoxide dismutase enhanced autoxidation of 3HAA as well as the initial rates of peroxyl radical-induced oxidation of 3HAA and formation of CA by approximately 40-50%, whereas inclusion of xanthine/xanthine oxidase decreased the rate of oxidation of 3HAA by approximately 50% and inhibited formation of CA almost completely, suggesting that superoxide anion radical (O2.-) was formed and reacted with reaction intermediate(s) to curtail formation of CA. Formation of CA was also observed when 3HAA was added to performed compound I of horseradish peroxidase (HRPO) or catalytic amounts of either HRPO, myeloperoxidase, or bovine liver catalase together with glucose/glucose oxidase.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer

Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Src-blocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Src-responsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)-induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1.

Coupling of mutated Met variants to DNA repair via Abl and Rad51

Abnormal activation of DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems is a compelling likelihood with significant implications in both cancer biology and treatment. Here, we show that due to a potential substrate switch, mutated variants of the receptor for hepatocyte growth factor Met, but not the wild-type form of the receptor, directly couple to the Abl tyrosine kinase and the Rad51 recombinase, two key signaling elements of homologous recombination-based DNA repair. Treatment of cells that express the mutated receptor variants with the Met inhibitor SU11274 leads, in a mutant-dependent manner, to a reduction of tyrosine phosphorylated levels of Abl and Rad51, impairs radiation-induced nuclear translocation of Rad51, and acts as a radiosensitizer together with the p53 inhibitor pifithrin-alpha by increasing cellular double-strand DNA break levels following exposure to ionizing radiation. Finally, we propose that in order to overcome a mutation-dependent resistance to SU11274, this aberrant molecular axis may alternatively be targeted with the Abl inhibitor, nilotinib.

Family Reunion Services: An Examination of a Process Used to Successfully Reunite Families

Family Reunion Services, an intensive-home-based service for families whose children are unlikely to return home without additional services, was evaluated. The 196 children who received FRS services and remained home had fewer previous placements, were more likely to be black and to come from families where the FRS worker intervened in the areas of parenting skills or communication. FRS workers' activities are described.

Endovascular treatment for acute ischemic stroke patients: implications and interpretation of IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials: A report from the Working Group of International Congress of Interventional Neurology

OBJECTIVE The results of Interventional Management of Stroke (IMS) III, Magnetic Resonance and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE), and SYNTHESIS EXPANSION trials are expected to affect the practice of endovascular treatment for acute ischemic stroke. The purpose of this report is to review the components of the designs and methods of these trials and to describe the influence of those components on the interpretation of trial results. METHODS A critical review of trial design and conduct of IMS III, MR RESCUE, and SYNTHESIS EXPANSION is performed with emphasis on patient selection, shortcomings in procedural aspects, and methodology of data ascertainment and analysis. The influence of each component is estimated based on published literature including multicenter clinical trials reporting on endovascular treatment for acute ischemic stroke and myocardial infarction. RESULTS We critically examined the time interval between symptom onset and treatment and rates of angiographic recanalization to differentiate between "endovascular treatment" and "parameter optimized endovascular treatment" as it relates to the IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials. All the three trials failed to effectively test "parameter optimized endovascular treatment" due to the delay between symptom onset and treatment and less than optimal rates of recanalization. In all the three trials, the magnitude of benefit with endovascular treatment required to reject the null hypothesis was larger than could be expected based on previous studies. The IMS III and SYNTHESIS EXPANSION trials demonstrated that rates of symptomatic intracerebral hemorrhages subsequent to treatment are similar between IV thrombolytics and endovascular treatment in matched acute ischemic stroke patients. The trials also indirectly validated the superiority/equivalence of IV thrombolytics (compared with endovascular treatment) in patients with minor neurological deficits and those without large vessel occlusion on computed tomographic/magnetic resonance angiography. CONCLUSIONS The results do not support a large magnitude benefit of endovascular treatment in subjects randomized in all the three trials. The possibility that benefits of a smaller magnitude exist in certain patient populations cannot be excluded. Large magnitude benefits can be expected with implementation of "parameter optimized endovascular treatment" in patients with ischemic stroke who are candidates for IV thrombolytics.

Beyond Symptoms: Typical Plans and Motives of Suicide Attempters Compared to Non-Suicidal Depressive Individuals

Aim: A major depressive episode is still a frequently discussed risk factor of suicidal behaviour. However, current studies suggest that depression is predictive of suicidal ideas but much less of suicidal act (Nock et al., 2009). This implies that suicidal behaviour should not only be seen as a symptom of a depressive disorder, but should be understood as an independent behaviour, which must be examined separately. The present qualitative study focuses on typical Plans and motives of suicide attempters compared to non-suicidal depressive individuals.Methods: Plan Analysis (Caspar, 2007), a clinical case conceptualization approach was used to analyze the instrumental relations between participants' behaviours and the hypothetical Plans and motives "behind" this behaviour. Video taped narrative interviews of 17 suicide attempters and intake interviews of 17 non‐suicidal depressive patients were investigated with the Plan Analysis procedure and a Plan structure was developed for each participant. These were used for establishing a prototypical Plan structure for each clinical group.Results: Results indicate that suicidal behaviour serves various Plans and motives only found in suicide attempters. Furthermore depressive patients pursue interpersonal control strategies which may serve as a protective factor for not evolving suicidal behaviour.Discussion. Findings are discussed with respect to current theoretical models of suicidality as well as implications for suicide prevention.

Capitalisation of Experiences of the Swiss Support to Sustainable Management of Natural Resources (SMNR) in Bulgaria

Following the collapse of the communist regime in 1989, Bulgaria has undergone dramatic political, economic and social transformations. The transition process of the past two decades was characterized by several reforms to support democratisation of the political system and the functioning of a free-market economy. Since 1992, Switzerland has been active in Bulgaria providing assistance to the transition process, with support to Sustainable Management of Natural Resources (SMNR) starting in 1995. The SMNR Capitalisation of Experiences (CapEx) took place between March and September 2007, in the context of SDC phasing out its programmes in Bulgaria by the end of 2007 due to the country’s accession to the European Union. The CapEx exercise has culminated in the identification of 17 lessons learned. In the view of the CapEx team, many of these lessons are relevant for countries that are in the process of joining the EU, facing similar democratisation challenges as Bulgaria. Overall, the Swiss SMNR projects have been effective entry points to support areas that are crucial to democratic transitions, namely participation in public goods management, decentralisation, human capacity development in research and management, and preparation for EU membership. The specificity of the Swiss support stems from an approach that combines a long-term commitment with a clear thematic focus (forestry, biodiversity conservation and organic agriculture). The multistakeholder approach and diversification of support between local, regional and national levels are also important elements that contributed to make a difference in relation to other donors supporting the Bulgarian transition. At the institutional level, there are a number of challenges where the contribution of SMNR activities was only modest, namely improving the legal framework and creating more transparency and accountability, both of which are time and resource-consuming processes. In addition, the emergence of competent and sustainable non-government organisations (NGOs) is a complex process that requires support to membership based organisations, a challenge that was hardly met in the case of SMNR. Finally, reform of government institutions involved in management of natural resources is difficult to achieve via project support only, as it requires leverage and commitment at the level of policy dialogue. At the programme management level, the CapEx team notes that corruption was not systematically addressed in SMNR projects, indicating that more attention should be given to this issue at the outset of any new project.

Sensitivity of the WRF model to PBL parametrisations and nesting techniques: evaluation of wind storms over complex terrain

Simulating surface wind over complex terrain is a challenge in regional climate modelling. Therefore, this study aims at identifying a set-up of the Weather Research and Forecasting Model (WRF) model that minimises system- atic errors of surface winds in hindcast simulations. Major factors of the model configuration are tested to find a suitable set-up: the horizontal resolution, the planetary boundary layer (PBL) parameterisation scheme and the way the WRF is nested to the driving data set. Hence, a number of sensitivity simulations at a spatial resolution of 2 km are carried out and compared to observations. Given the importance of wind storms, the analysis is based on case studies of 24 historical wind storms that caused great economic damage in Switzerland. Each of these events is downscaled using eight different model set-ups, but sharing the same driving data set. The results show that the lack of representation of the unresolved topography leads to a general overestimation of wind speed in WRF. However, this bias can be substantially reduced by using a PBL scheme that explicitly considers the effects of non-resolved topography, which also improves the spatial structure of wind speed over Switzerland. The wind direction, although generally well reproduced, is not very sensitive to the PBL scheme. Further sensitivity tests include four types of nesting methods: nesting only at the boundaries of the outermost domain, analysis nudging, spectral nudging, and the so-called re-forecast method, where the simulation is frequently restarted. These simulations show that restricting the freedom of the model to develop large-scale disturbances slightly increases the temporal agreement with the observations, at the same time that it further reduces the overestimation of wind speed, especially for maximum wind peaks. The model performance is also evaluated in the outermost domains, where the resolution is coarser. The results demonstrate the important role of horizontal resolution, where the step from 6 to 2 km significantly improves model performance. In summary, the combination of a grid size of 2 km, the non-local PBL scheme modified to explicitly account for non-resolved orography, as well as analysis or spectral nudging, is a superior combination when dynamical downscaling is aimed at reproducing real wind fields.

Shifts in microbial communities do not explain the response of grassland ecosystem function to plant functional composition and rainfall change

Ecosystem functioning in grasslands is regulated by a range of biotic and abiotic factors, and the role of microbial communities in regulating ecosystem function has been the subject of much recent scrutiny. However, there are still knowledge gaps regarding the impacts of rainfall and vegetation change upon microbial communities and the implications of these changes for ecosystem functioning. We investigated this issue using data from an experimental mesotrophic grassland study in south-east England, which had been subjected to four years of rainfall and plant functional composition manipulations. Soil respiration, nitrogen and phosphorus stocks were measured, and the abundance and community structure of soil microbes were characterised using quantitative PCR and multiplex-TRFLP analysis, respectively. Bacterial community structure was strongly related to the plant functional composition treatments, but not the rainfall treatment. However, there was a strong effect of both rainfall change and plant functional group upon bacterial abundance. There was also a weak interactive effect of the two treatments upon fungal community structure, although fungal abundance was not affected by either treatment. Next, we used a statistical approach to assess whether treatment effects on ecosystem function were regulated by the microbial community. Our results revealed that ecosystem function was influenced by the experimental treatments, but was not related to associated changes to the microbial community. Overall, these results indicate that changes in fungal and bacterial community structure and abundance play a relatively minor role in determining grassland ecosystem function responses to precipitation and plant functional composition change, and that direct effects on soil physical and chemical properties and upon plant and microbial physiology may play a more important role.

Measuring College Student Satisfaction: A Multi-Year Study of the Factors Leading to Persistence

Using Tinto's (1987) social integration theory as a framework, this study measured student satisfaction in six transformative areas: educational experience, skills development, faculty interaction, personal growth, sense of community, and overall expectations. Emerging as a strategic planning process priority, this project sought to identify those areas where students succeeded or were at risk. Employing a three-phase mixed methods approach, this descriptive, longitudinal study was conducted from 1990-2004 at a highly selective specialized college and assisted college administrators in developing or modifying programs that would enhance student satisfaction to ensure degree completion.

Efficiency and Continuity in Public Finance: The Ottoman System of Taxation

Economic historians have recently emphasized the importance of integrating economic and historical approaches in studying institutions. The literature on the Ottoman system of taxation, however, has continued to adopt a primarily historical approach, using ad hoc categories of classification and explaining the system through its continuities with the historical precedent. This paper integrates economic and historical approaches to examine the structure, efficiency, and regional diversity of the tax system. The structure of the system made it possible for the Ottomans to economize on the transaction cost of measuring the tax base. Regional variations resulted from both efficient adaptations and institutional rigidities.

The normal range of the leukocyte count: Implications for surveillance of occupational and environmental exposure and the practice of preventive medicine

Leukopenia, the leukocyte count, and prognosis of disease are interrelated; a systematic search of the literature was undertaken to ascertain the strength of the evidence. One hundred seventy-one studies were found from 1953 onward pertaining to the predictive capabilities of the leukocyte count. Of those studies, 42 met inclusion criteria. An estimated range of 2,200cells/μL to 7,000cells/μL was determined as that which indicates good prognosis in disease and indicates the least amount of risk to an individual overall. Tables of the evidence are included indicating the disparate populations examined and the possible degree of association. ^

Distribution of radiolaria in Oligocene to Pleistocene sediments of the North-West Pacific

Neogene stratigraphy of the tropical and subtropical Pacific on radiolaria is studied in the book. A detailed comparison of coeval systems from tropics and subtropics is given. A possibility of use of a uniform zonal scale in these areas is proved. Magnitude of changes of complexes on borders of Neogene zones is studied in detail. Six stages in development of radiolarians are identified in the tropics in Neogene. Stratigraphic levels, where the greatest changes of fauna occurred, are natural boundaries of these stages. 72 species of radiolarians (two of which are new) are described in the book.

The Economic Value of Residential Land in Historical Areas: An Application of the Residual Method to the Secondary Market

Land value bears significant weight in house prices in historical town centers. An essential aim for regulating the mortgage market, particularly in the financial and property crisis that countries such as Spain are undergoing, is to have at hand objective procedures for its valuation, whatever the conditions (location, construction, planning). Of all the factors contributing to house price make-up, the land is the only one whose value does not depend on acquisition cost, but rather on the location-time binomial. That is to say, the specific circumstances at that point and at the exact moment of valuation. For this reason, the most commonly applied procedure for land valuation in town centers is the use of the residual method: once the selling price of new housing in a district is known, the other necessary costs and expenses of development are deducted, including those of building and the developer’s profit. The value left is that of the land. To apply these procedures it is vital to have figures such as building costs, technical fees, tax costs, etc. But, above all, it is essential to obtain the selling price of the new housing. This is not always feasible, on account of the lack of newbuild development in this location. This shortage of information occurs in historical town cities, where urban renewal is slight due to the heritage-protection policies, and where, nevertheless there is substantial activity in the secondary market. In these circumstances, as an alternative for land valuation in consolidated urban areas, we have the adaptation of the residual method to the particular characteristics of the secondary market. To these ends, there is the proposal for the appreciation of the dwelling which follows, in a backwards direction, the application of traditional depreciation methods proposed by the various valuation manuals and guidelines. The reliability of the results obtained is analyzed by contrasting it with published figures for newly-built properties, according to different rules applied in administrative appraisals in Spain and the incidence of an eventual correction due to conservation state.

Applicability of the GP Device to the Circle of Willis Arteries by Using a Mathematical Model

According to the World Health Organization, 15 million people suffer stroke worldwide each year, of these, 5 million die and 5 million are permanently disabled. Stroke is therefore a major cause of mortality world-wide. The majority of strokes are caused by a blood clot that occludes an artery in the brain, and although thrombolytic agents such as Alteplase are used to dissolve clots that arise in the arteries of the brain, there are limitations on the use of these thrombolytic agents. However over the past decade, other methods of treatment have been developed which include Thrombectomy Devices e.g. the 'GP' Thrombus Aspiration Device ('GP' TAD). Such devices may be used as an alternative to thrombolytics or in conjunction with them to extract blood clots in arteries such as the middle cerebral artery of the midbrain brain, and the posterior inferior cerebellar artery (PICA) of the posterior aspect of the brain. In this paper, we mathematically model the removal of blood clots using the 'GP' TAD from selected arteries of the brain where blood clots may arise taking into account factors such as the resistances, compliances and inertances effects. Such mathematical modelling may have potential uses in predicting the pressures necessary to extract blood clots of given lengths, and masses from arteries in the Circle of Willis - posterior circulation of the brain