Analysis of the substrate specificity of human sulfotransferases SULT1A1 and SULT1A3: Site-directed mutagenesis and kinetic studies

Sulfonation is an important metabolic process involved in the excretion and in some cases activation of various endogenous compounds and xenobiotics. This reaction is catalyzed by a family of enzymes named sulfotransferases. The cytosolic human sulfotransferases SULT1A1 and SULT1A3 have overlapping yet distinct substrate specificities. SULT1A1 favors simple phenolic substrates such as p-nitrophenol, whereas SULT1A3 prefers monoamine substrates such as dopamine. In this study we have used a variety of phenolic substrates to functionally characterize the role of the amino acid at position 146 in SULT1A1 and SULT1A3. First, the mutation A146E in SULT1A1 yielded a SULT1A3-like protein with respect to the Michaelis constant for simple phenols. The mutation E146A in SULT1A3 resulted in a SULT1A1-like protein with respect to the Michaelis constant for both simple phenols and monoamine compounds. When comparing the specificity of SULT1A3 toward tyramine with that for p-ethylphenol (which differs from tyramine in having no amine group on the carbon side chain), we saw a 200-fold preference for tyramine. The kinetic data obtained with the E146A mutant of SULT1A3 for these two substrates clearly showed that this protein preferred substrates without an amine group attached. Second, changing the glutamic acid at position 146 of SULT1A3 to a glutamine, thereby neutralizing the negative charge at this position, resulted in a 360-fold decrease in the specificity constant for dopamine. The results provide strong evidence that residue 146 is crucial in determining the substrate specificity of both SULT1A1 and SULT1A3 and suggest that there is a direct interaction between glutamic acid 146 in SULT1A3 and monoamine substrates.

Reaching those most in need: a review of diabetes self-management interventions in disadvantaged populations

There has been increased recognition of the importance of developing diabetes self-management education (DSME) interventions that are effective with under-served and minority populations. Despite several recent studies in this area, there is to our knowledge no systematic review or synthesis of what has been learned from this research. An electronic literature search identified five formative evaluations and ten controlled DSME intervention trials focused on under-served (low-income, minority or aged) populations. The RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) evaluation framework was used to evaluate the controlled studies on the dimensions of reach, efficacy, adoption, implementation, and maintenance. Fifty percent of the studies identified reported on the percentage of patients who participated, and the percentages were highly variable. The methodological quality of the articles was generally good and the short-term results were encouraging, especially on behavioral outcomes. Data on adoption (representativeness of settings and clinicians who participate) and implementation were almost never reported. Studies of modalities in addition to group meetings are needed to increase the reach of DSME with under-served populations. The promising formative evaluation work that has been conducted needs to be extended for more systematic study of the process of intervention implementation and adaptation with special populations. Studies that explicitly address the community context and that address multiple issues related to public health impact of DSME interventions are recommended to enhance long-term results. Copyright (C) 2002 John Wiley Sons, Ltd.

Limited Ca(2+) and PKA-pathway dependent neurogenic differentiation of human adult mesenchymal stem cells as compared to fetal neuronal stem cells

The ability of mesenchymal stem cells to generate functional neurons in culture is still a matter of controversy. In order to assess this issue, we performed a functional comparison between neuronal differentiation of human MSCs and fetal-derived neural stem cells (NSCs) based on morphological, immunocytochemical, and electrophysiological criteria. Furthermore, possible biochemical mechanisms involved in this process were presented. NF200 immunostaining was used to quantify the yield of differentiated cells after exposure to CAMP. The addition of a PKA inhibitor and Ca(2+) blockers to the differentiation medium significantly reduced the yield of differentiated cells. Activation of CREB was also observed on MSCs during maturation. Na(+)-, K(+)-, and Ca(2+)-voltage-dependent currents were recorded from MSCs-derived cells. In contrast, significantly larger Na(+) currents, firing activity, and spontaneous synaptic currents were recorded from NSCs. Our results indicate that the initial neuronal differentiation of MSCs is induced by CAMP and seems to be dependent upon Ca(2+) and the PKA pathway. However, compared to fetal neural stem cells, adult mesenchymal counterparts are limited in their neurogenic potential. Despite the similar yield of neuronal cells, NSCs achieved a more mature functional state. Description of the underlying mechanisms that govern MSCs` differentiation toward a stable neuronal phenotype and their limitations provides a unique opportunity to enhance our understanding of stem cell plasticity. (C) 2009 Elsevier Inc. All rights reserved.

Development of human minor salivary glands: expression of mucins according to stage of morphogenesis

The formation of salivary glands entails the proliferation of epithelial cells from the stomatodeum into the underlying ectomesenchyme, culminating in a complex network of ducts and acinar bulbs. The extent to which mucins regulate this process is unknown, but they appear to mediate luminal space formation and maturation. Our aim was to examine mucin expression patterns during the morphogenesis of human salivary glands. Mucin expression - MUC1, 2, 3, 4, 5AC, 5B, 6, and 16 - was analyzed in specimens of developing human salivary glands, obtained from fetuses at 4-24 weeks` gestation, and fully developed salivary glands by immunohistochemistry. Expression patterns were analyzed qualitatively according to the development stage of the salivary glands. Mucins 1, 3, 4, 5B, and 16 were expressed during salivary gland development - being stronger in all ductal segments by the final phases of branching morphogenesis and in mature glands. Acinar cells were negative for most mucins, including MUC1 in mature salivary glands. Mucins 2, 5AC, and 6 were not expressed. Mucins MUC1, 3, 4, 5B, and 16 are expressed in developing human salivary glands and in mature glands, suggesting important roles in the maturation and maintenance of the ductal network.

Benchmarking regional planning arrangements for natural resource management 2004–05: Progress, constraints and future directions for regions

This report provides a benchmark of progress in regional planning for natural resource management in Queensland and the tropical savannas region of northern Australia during 2004. It is based on a review of regional plans and planning processes against a set of pre-defined criteria designed specifically to evaluate regional planning arrangements.

Influence of nicotine on healing process of autogenous bone block grafts in the mandible: A histomorphometric study in rats

Purpose: The aim of this study was to perform qualitative and quantitative analyses of the effect of nicotine on autogenous bone block grafts and to describe events in the initial healing phase and the differences in the repair processes between animals exposed to nicotine and controls. Materials and Methods: Forty-eight female Wistar rats were randomly divided into 2 groups, the nicotine group and the saline group. All animals received either nicotine (3 mg/kg) or saline 4 weeks before the surgical procedure and continued to receive nicotine from surgery to sacrifice at 7, 14, or 28 days. The autogenous bone block graft was harvested from the calvaria and stabilized on the external cortical area near the angle of the mandible. Results: The histologic analyses of the nicotine group depicted a delay in osteogenic activity at the bed-graft interface, as well as impairment of the organization of the granulation tissue that developed instead of blood clot. Nicotine-group specimens exhibited less bone neoformation, and the newly formed bone was poorly cellularized and vascularized. The histometric analysis revealed significantly less bone formation in the nicotine group at both 14 days (23.75% +/- 6.18% versus 51.31% +/- 8.31%) and 28 days (42.44% +/- 8.70% versus 73.00% +/- 4.99%). Conclusion: Nicotine did jeopardize the early healing process of autogenous bone block grafts in rats but did not prevent it.

Assessment and management of dysphagia following pharyngolaryngectomy with free jejunal interposition: A series of eight case studies

The physiological and structural deficits contributing to swallowing complications in the pharyngolaryngectomy patient population are not homogeneous. Consequently, a team approach, involving medical investigations as well as clinical and radiological assessments of swallowing, is necessary to facilitate diagnosis of the underlying impairment and assist the medical/surgical and speech pathology team members in the process of individualizing the management plan for each patient. In the present study, the clinical assessment and management of eight pharyngolaryngectomy patients who presented with a decline in swallowing function unrelated to immediate postsurgical effects or direct effects of radiotherapy are reported. Clinical and radiological investigations revealed a heterogeneous group of factors contributing to their swallowing impairments and disability levels, including difficulty with graft and anastomotic patency and graft motility, impaired lingual coordination, increased bolus transit time, nasal and oral regurgitation, patient distress, and recurrence. Variation between the cases supported the need for differential intervention and management plans for all eight patients. Ratings of perceived swallowing disability, handicap, and well-being/distress levels at initial assessment and again six months following dysphagia intervention revealed a pattern of reduced levels of impairment, functional disability, and overall patient distress levels following informed intervention. The present case study data highlights the key role thorough clinical and radiological investigations play in the process of diagnosing the factors contributing to dysphagia and guiding the management of the resultant swallowing disability in the pharyngolaryngectomy population.

O modelo organiza????es sociais: li????es e oportunidades de melhoria

As Organiza????es Sociais (OS) s??o organiza????es sem fins lucrativos, ???qualificadas??? para absorver atividades executadas por organiza????es p??blicas, nos termos e condi????es estabelecidas em contratos de gest??o firmados entre organiza????es e o governo. Este artigo relata os principais resultados do semin??rio ???O modelo OS: li????es e oportunidades de melhorias???, realizado em outubro de 2001, do qual participaram gestores e t??cnicos da Secretaria de Gest??o (SEGES), de OS, de ??rg??os supervisores dessas organiza????es, de ??rg??os intervenientes, e especialistas em gest??o p??blica. Com rela????o ??s OS analisadas, pode-se perceber que: a) h?? controv??rsias e ambig??idades quanto ?? sua natureza jur??dica e quanto ao processo de avalia????o dessas organiza????es; b) a gest??o de recursos humanos ?? afetada pela exist??ncia de grupos submetidos a distintos regimes de trabalho, isto ??, Estatuto dos Funcion??rios P??blicos e Consolida????o das Leis do Trabalho; c) a gest??o de recursos financeiros ?? marcada pela irregularidade no fluxo dos referidos recursos; e d) o controle dos bens p??blicos ocorre de forma fr??gil e o processo de compra est?? sendo realizado sem problemas. Com base nessas considera????es, o documento prop??e algumas sugest??es de aperfei??oamento do modelo OS.

Fortalecer o servi??o p??blico e valorizar a cidadania: a op????o australiana

O artigo analisa o processo de reforma administrativa empreendida na Austr??lia ao longo das d??cadas de 70-80, destacando duas de suas principais tend??ncias: o fortalecimento da ???Fun????o Executiva Superior???e a valoriza????o da cidadania. Nele s??o descritos os princ??pios b??sicos norteadores da reforma ao longo dos anos 70, bem como, os objetivos visados com a segunda fase das reformas executadas a partir da d??cada de 80, implementadas por governos trabalhistas. Destaca-se a organiza????o e o funcionamento do sistema das Ag??ncias de Ombudsmen e dos Comiss??rios de Contas respons??veis pela fiscaliza????o e gest??o or??ament??ria. A seguir, s??o descritas algumas das a????es encaminhadas pela Public Service Commission (PSC) no sentido de aperfei??oar o gerenciamento e o melhor desempenho dos recursos humanos, destacando a introdu????o do importante conceito de Novo Profissionalismo, assentado em valores como responsabilidade para com o governo, foco nos resultados, m??rito como valor b??sico, altos n??veis de integridade e probidade na conduta, desempenho com accountability e melhoramento cont??nuo do desempenho das equipes e indiv??duos. Outro importante instrumento analisado ?? o Human Resource Management, atrav??s do qual as autoridades australianas introduziram novas pr??ticas como negocia????o no local de trabalho, plano de oportunidades igualit??rias no local de trabalho e o plano de treinamento e especializa????o. Para finalizar, o artigo enfoca a pol??tica de contratualiza????o de servi??os p??blicos adotada na Austr??lia ??? os Competitive Tendering and Contracting, evidenciando os fatores indutores da ado????o desta nova pr??tica de gest??o.

Improving the public management career: report for the ministry of planning, budgeting e management, federal government of Brazil

This report sets out the findings and recommendations of a review of the Public Management Career (EPPGG) undertaken between 5 and 9 January 2009. The purpose of the review was to clarify EPPGG???s role, functions and profile, and to develop proposals for improving its effectiveness and management, taking account of the context within which such improvements would have to be implemented. Specific objectives were to examine a number of human resources management (HRM) aspects of the career in the light of international practice, including recruitment; initial education; professional development; performance evaluation; deployment; mobility and networking.

The international harmonization process of public accounting in Portugal: the perspective of different stakeholders

This paper investigates the reform of public accounting in Portugal through the IPSAS adoption highlighting the perception of different stakeholders. Two competing theories (NPM and the institutional theory) are used to understand public accounting changes within the Portuguese context. In general, different stakeholders agree with the favorable moment and the context of the reform. The context of financial crises and the great external pressures to cut public deficits and to improve the quality of financial information seem to be the most important factors to stimulate changes in public accounting. In addition, stakeholders recommend the use of different strategies to ensure success.

The internationally standardized process of public accounting: the perspective of different stakeholders in Portugal

New Public Management (NPM) led to great pressures for to introduce and adapt businesslike accounting in the public sector (Hood, 1995; Lapsley, 2008; Lapsley et al., 2009), specially the transition from cash basis to accrual-based accounting. In consequence, since the last 20 years we assist to a movement towards internationally standardized of public sector accounting that led to the publication of 32 International Public Sector Accounting Standards (IPSAS) for all public sector entities from national central governments to local governments (IFAC, 2008). These standards are accrual-basis and they emphasize the balance sheet approach, the fair value measurement and the revenue-expense approach (Hints, 2007). The main innovations are associated with the use of the balance sheet approach and the fair value measurement because, traditionally, public accounting systems are mainly focused on the revenue-expense approach and on historical cost valuation (Oulasvirta, 2014).