Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists

The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications.

Influence of different spacers on the biological profile of a DOTA-somatostatin analogue

Radiolabeled somatostatin analogues have been successfully used for targeted radiotherapy and for imaging of somatostatin receptor (sst1-5)-positive tumors. Nevertheless, these analogues are subject to improving their tumor-to-nontarget ratio to enhance their diagnostic or therapeutic properties, preventing nephrotoxicity. In order to understand the influence of lipophilicity and charge on the pharmacokinetic profile of [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)]-somatostatin-based radioligands such as [DOTA,1-Nal3]-octreotide (DOTA-NOC), different spacers (X) based on 8-amino-3,6-dioxaoctanoic acid (PEG2), 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG4), N-acetyl glucosamine (GlcNAc), triglycine, beta-alanine, aspartic acid, and lysine were introduced between the chelator DOTA and the peptide NOC. All DOTA-X-NOC conjugates were synthesized by Fmoc solid-phase synthesis. The partition coefficient (log D) at pH = 7.4 indicated that higher hydrophilicity than [111In-DOTA]-NOC was achieved with the introduction of the mentioned spacers, except with triglycine and beta-alanine. The high affinity of [InIII-DOTA]-NOC for human sst2 (hsst2) was preserved with the structural modifications, while an overall drop for hsst3 affinity was observed, except in the case of [InIII-DOTA]-beta-Ala-NOC. The new conjugates preserved the good affinity for hsst5, except for [InIII-DOTA]-Asn(GlcNAc)-NOC, which showed decreased affinity. A significant 1.2-fold improvement in the specific internalization rate in AR4-2J rat pancreatic tumor cells (sst2 receptor expression) at 4 h was achieved with the introduction of Asp as a spacer in the parent compound. In sst3-expressing HEK cells, the specific internalization rate at 4 h for [111In-DOTA]-NOC (13.1% +/- 0.3%) was maintained with [111In-DOTA]-beta-Ala-NOC (14.0% +/- 1.8%), but the remaining derivatives showed <2% specific internalization. Biodistribution studies were performed with Lewis rats bearing the AR4-2J rat pancreatic tumor. In comparison to [111In-DOTA]-NOC (2.96% +/- 0.48% IA/g), the specific uptake in the tumor at 4 h p.i. was significantly improved for the 111In-labeled sugar analogue (4.17% +/- 0.46% IA/g), which among all the new derivatives presented the best tumor-to-kidney ratio (1.9).

Invasive coronary treatment strategies for out-of-hospital cardiac arrest: a consensus statement from the European association for percutaneous cardiovascular interventions (EAPCI)/stent for life (SFL) groups

Due to significant improvement in the pre-hospital treatment of patients with out-of-hospital cardiac arrest (OHCA), an increasing number of initially resuscitated patients are being admitted to hospitals. Because of the limited data available and lack of clear guideline recommendations, experts from the EAPCI and "Stent for Life" (SFL) groups reviewed existing literature and provided practical guidelines on selection of patients for immediate coronary angiography (CAG), PCI strategy, concomitant antiplatelet/anticoagulation treatment, haemodynamic support and use of therapeutic hypothermia. Conscious survivors of OHCA with suspected acute coronary syndrome (ACS) should be treated according to recommendations for ST-segment elevation myocardial infarction (STEMI) and high-risk non-ST-segment elevation -ACS (NSTE-ACS) without OHCA and should undergo immediate (if STEMI) or rapid (less than two hours if NSTE-ACS) coronary invasive strategy. Comatose survivors of OHCA with ECG criteria for STEMI on the post-resuscitation ECG should be admitted directly to the catheterisation laboratory. For patients without STEMI ECG criteria, a short "emergency department or intensive care unit stop" is advised to exclude non-coronary causes. In the absence of an obvious non-coronary cause, CAG should be performed as soon as possible (less than two hours), in particular in haemodynamically unstable patients. Immediate PCI should be mainly directed towards the culprit lesion if identified. Interventional cardiologists should become an essential part of the "survival chain" for patients with OHCA. There is a need to centralise the care of patients with OHCA to experienced centres.

Design of equalized ROADMs devices with flexible bandwidth based on LCoS technology

This paper describes the theory, design, applications and performance of a new Reconfigurable Add-drop Multiplexer (ROADM) with flexible bandwidth allocation. The device can address several wavelengths at the input to four output fibers, according to the holograms stored in a SLM (Spatial Light Modulator), where all the outputs are equalized in power. All combinations of the input wavelengths are possible at the different output fibers. Each fiber has assigned all the signals with the same bandwidth; the possible bandwidths are 12.5GHz, 25GHz, 50GHz and 100GHz, according to ITU-T 694.1 Recommendation. It is possible to route several signals with different bandwidth in real time thanks to Liquid Crystal over Silicon (LCoS) technology.

Analysis of signal impairment and crosstalk penalty induced by different types of optical filters in 100 Gbps PM-DQPSK based systems

Optical filters are crucial elements in optical communication networks. Their influence toward the optical signal will affect the communication quality seriously. In this paper we will study and simulate the optical signal impairment and crosstalk penalty caused by different kinds of filters, which include Butterworth, Bessel, Fiber Bragg Grating (FBG) and Fabry-Perot (F-P). Signal impairment from filter concatenation effect and crosstalk penalty from out-band and in-band are analyzed from Q-penalty, eye opening penalty (EOP) and optical spectrum. The simulation results show that signal impairment and crosstalk penalty induced by the Butterworth filter is the minimum among these four types of filters. Signal impairment caused by filter concatenation effect shows that when center frequency of all filters is aligned perfectly with the laser's frequency, 12 50-GHz Butterworth filters can be cascaded, with 1-dB EOP. This value is reduced to 9 when the center frequency is misaligned with 5 GHz. In the 50-GHz channel spacing DWDM networks, total Q-penalty induced by a pair of Butterworth filters based demultiplexer and multiplexer is lower than 0.5 dB when the filter bandwidth is in the range of 42-46 GHz.

DPSK signals demodulation based on a multimode fiber with a central dip

Differential Phase Shift Keying (DPSK) modulation format has been shown as a robust solution for next-generation optical transmission systems. One key device enabling such systems is a delay interferometer, converting the phase modulation signal into the intensity modulation signal to be detected by the photodiodes. Usually, a standard Mach-Zehnder interferometer (MZI) is used for demodulating a DPSK signal. In this paper, we develop an MZI which is based on all-fiber Multimode Interference (MI) structure: a multimode fiber (MMF) with a central dip, located between two single-mode fibers (SMFs) without any transition zones. The MI based MZI (MI-MZI) is more stable than the standard MZI as the two arms share the same MMF, reducing the impact of the external effects, such as temperature and others. Performance of this MI-MZI is analyzed theoretically and experimentally from transmission spectrum. Experimental results shows that high interference extinction ratio is obtained, which is far higher than that obtained from a normal graded-index based MI-MZI. Finally, by software simulation, we demonstrate that our proposed MI-MZI can be used for demodulating a 40 Gbps DPSK signal. The performance of the MI-MZI based DPSK receiver is analyzed from the sensitivity. Simulation results show that sensitivity of the proposed receiver is about -22.3 dBm for a BER of 10-15 and about -23.8 dBm for a BER of 10-9.

Modelagem e simulação de redes em chip sem fio.

O paradigma das redes em chip (NoCs) surgiu a fim de permitir alto grau de integração entre vários núcleos de sistemas em chip (SoCs), cuja comunicação é tradicionalmente baseada em barramentos. As NoCs são definidas como uma estrutura de switches e canais ponto a ponto que interconectam núcleos de propriedades intelectuais (IPs) de um SoC, provendo uma plataforma de comunicação entre os mesmos. As redes em chip sem fio (WiNoCs) são uma abordagem evolucionária do conceito de rede em chip (NoC), a qual possibilita a adoção dos mecanismos de roteamento das NoCs com o uso de tecnologias sem fio, propondo a otimização dos fluxos de tráfego, a redução de conectores e a atuação em conjunto com as NoCs tradicionais, reduzindo a carga nos barramentos. O uso do roteamento dinâmico dentro das redes em chip sem fio permite o desligamento seletivo de partes do hardware, o que reduz a energia consumida. Contudo, a escolha de onde empregar um link sem fio em uma NoC é uma tarefa complexa, dado que os nós são pontes de tráfego os quais não podem ser desligados sem potencialmente quebrar uma rota preestabelecida. Além de fornecer uma visão sobre as arquiteturas de NoCs e do estado da arte do paradigma emergente de WiNoC, este trabalho também propõe um método de avaliação baseado no já consolidado simulador ns-2, cujo objetivo é testar cenários híbridos de NoC e WiNoC. A partir desta abordagem é possível avaliar diferentes parâmetros das WiNoCs associados a aspectos de roteamento, aplicação e número de nós envolvidos em redes hierárquicas. Por meio da análise de tais simulações também é possível investigar qual estratégia de roteamento é mais recomendada para um determinado cenário de utilização, o que é relevante ao se escolher a disposição espacial dos nós em uma NoC. Os experimentos realizados são o estudo da dinâmica de funcionamento dos protocolos ad hoc de roteamento sem fio em uma topologia hierárquica de WiNoC, seguido da análise de tamanho da rede e dos padrões de tráfego na WiNoC.

Las terminologías de enfermería y su representación en SNOMED CT

En los sistemas de información, y en concreto en las historias clínicas electrónicas, las terminologías actúan como una forma de entrada y de almacenamiento de datos estandarizados. Las terminologías normalizadas de enfermería (NANDA, NIC y NOC) son importantes y necesarias para fijar la práctica, hacer explícito el papel jugado por estos profesionales en el sistema sanitario y determinar el coste de los servicios realizados. Sin embargo, no son suficientes para compartir la información y reutilizar los datos entre distintos sistemas. En este artículo se realiza una breve descripción y análisis de las tres terminologías normalizadas en enfermería de uso más común. Se exponen las actuales limitaciones para compartir la información de los datos de enfermería en los sistemas informatizados. Por último, se muestran las opciones que ofrece la interconexión con SNOMED CT para superar estos obstáculos y facilitar la interoperabilidad semántica, así como las posibilidades de inferir nuevo conocimiento.

Prevención del Síndrome Confusional Agudo en pacientes ancianos hospitalizados con fractura de cadera

Introducción: Las consecuencias del síndrome confusional agudo en pacientes con fractura de cadera aumentan la morbilidad y la mortalidad de la persona, produciendo en numerosas ocasiones dependencia para el resto de su vida. El objetivo principal de esta revisión es la realización de un plan de actuación de enfermería, conociendo los factores de riesgo del delirium para la correcta prevención del mismo. Métodos: Se realiza una revisión bibliográfica en diferentes bases de datos para identificar cuáles son los factores predisponentes y precipitantes en ancianos hospitalizados con fractura de cadera susceptibles de padecer el síndrome confusional agudo. Resultados: No se han encontrado muchos artículos relacionados con la prevención no farmacológica del síndrome confusional agudo. A pesar de esto, las revisiones encontradas muestran que el delirium es una enfermedad prevenible mediante el conocimiento de los factores de riesgo y la correcta aplicación de cuidados de enfermería. En esta revisión se exponen los factores predisponentes y precipitantes del delirium y basado en diagnósticos NANDA, NOC y NIC se elabora un plan de cuidados para su prevención. Discusión: El delirium es una patología invalidante, pudiendo ser el precursor de la muerte de la persona, por lo que se le debe prestar la atención que merece. El anciano hospitalizado con fractura de cadera es un paciente de alto riesgo de padecerlo por todos los factores asociados que presenta. La prevención de factores de riesgo y el establecimiento de un plan de actuación son las medidas más útiles para evitar la aparición de esta enfermedad. En posteriores estudios de casos y controles se debería poner en práctica el plan de actuación realizado.

Terapêutica da amigdalite aguda em idade pediátrica : estudo transversal sobre antibioterapia nos cuidados de saúde primários e urgência hospitalar em 2012

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Normas de orientação clínica portuguesas : abordagem terapêutica de doenças e factores de risco cardiovasculares : que evidência, que método e que impacto?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Intervenções de enfermagem à pessoa com Diabetes Mellitus tipo 2 em cuidados de saúde primários: elaboração de uma norma de orientação clínica

Enquadramento: Vários estudos apontam que em contexto de Cuidados de Saúde Primários (CSP), programas organizados de cuidados de enfermagem podem promover significativamente melhores resultados de saúde em pessoas com diabetes. O Programa Nacional de Prevenção e Controlo da Diabetes estabelece, como objetivo, uniformizar as práticas profissionais em prol de uma efetiva qualidade clínica, organizacional e satisfação das pessoas com diabetes. A Federação Internacional de Diabetes e a OMS enfatizam a necessidade de os programas nacionais de saúde implementarem guias de boas práticas baseadas em evidência para a prevenção e controlo da DM. Tendo como principal problema a inexistência de uma orientação específica que norteie as intervenções a prestar na consulta de enfermagem à pessoa com Diabetes Mellitus tipo 2 (DM2) em CSP o presente trabalho teve por objetivos: (I) Consensualizar intervenções que devem ser realizadas pelos enfermeiros na consulta à pessoa com DM2 em CSP, (II) Elaborar uma Norma de Orientação Clinica (NOC) baseada em evidência científica para orientação da consulta de enfermagem à pessoa com DM2 em CSP. Metodologia: Foi realizado um Painel de Delphi, para a obtenção de consenso, acerca das intervenções a serem realizadas na consulta de enfermagem à pessoa com DM2 em CSP. Para suportar em evidência científica as intervenções obtidas por consenso e, consequentemente, elaborar a NOC utilizámos o Processo ADAPTE, que permite a adaptação de Normas já existentes através de uma abordagem sistemática para a aprovação e/ou modificação destas1. Resultados: Elaboração de uma NOC adaptada baseada em evidência científica, para suporte à consulta de enfermagem à pessoa com DM2 em CSP.

The Global Multistakeholder Meeting on the Future of Internet Governance (NETmundial)

This case study examines NETmundial, the Global Multistakeholder Meeting on the Future of Internet Governance, which was held in Sao Paulo, Brazil on April 23 and 24 of 2014. The meeting was convened by 1net, a coalition of This case study examines NETmundial, the Global Multistakeholder Meeting on the Future of Internet Governance, which was held in Sao Paulo, Brazil on April 23 and 24 of 2014. The meeting was convened by 1net, a coalition of stakeholder groups involved in Internet governance discussions, in partnership with the Brazilian Internet Steering Committee (CGI.br), in response to revelations of mass surveillance of communications by the United States. It sought to develop a set of universally acceptable Internet governance principles as well as a way forward for the evolution of the Internet governance system, which together could serve as a framework for the governance and use of the Internet. It convened 930 participants from 110 different countries, representing civil society, the private sector, academia, the technical community, governments and intergovernmental organizations, as well as over 1000 remote participants from 23 countries around the globe. It also employed a content contribution platform that sought to crowd source inputs from stakeholders for the production of the outcome document. The meeting served as a demonstration of the multistakeholder process in action: in the production of the outcome document, stakeholders with a diverse range of backgrounds and interests collectively negotiated the inclusion or exclusion of highly sensitive and complex issues. While the process of achieving rough consensus involved sometimes messy debates and there were procedural imperfections, the case is informative for its structured production of bottom-up multistakeholder outcomes.groups involved in Internet governance discussions, in partnership with the Brazilian Internet Steering Committee (CGI.br), in response to revelations of mass surveillance of communications by the United States. It sought to develop a set of universally acceptable Internet governance principles as well as a way forward for the evolution of the Internet governance system, which together could serve as a framework for the governance and use of the Internet. It convened 930 participants from 110 different countries, representing civil society, the private sector, academia, the technical community, governments and intergovernmental organizations, as well as over 1000 remote participants from 23 countries around the globe. It also employed a content contribution platform that sought to crowd source inputs from stakeholders for the production of the outcome document. The meeting served as a demonstration of the multistakeholder process in action: in the production of the outcome document, stakeholders with a diverse range of backgrounds and interests collectively negotiated the inclusion or exclusion of highly sensitive and complex issues. While the process of achieving rough consensus involved sometimes messy debates and there were procedural imperfections, the case is informative for its structured production of bottom-up multistakeholder outcomes.

Expression and putative role of lactoseries carbohydrates present on NCAM in the rat primary olfactory pathway

Primary olfactory neurons project axons from the olfactory neuroepithelium lining the nasal cavity to,the olfactory bulb in the brain. These axons grow within large mixed bundles in the olfactory nerve and then sort out into homotypic fascicles in the nerve fiber layer of the olfactory bulb before terminating in topographically fixed glomeruli. Carbohydrates expressed on the cell surface have been implicated in axon sorting within the nerve fiber layer. We have identified two novel subpopulations of primary olfactory neurons that express distinct alpha-extended lactoseries carbohydrates recognised by monoclonal antibodies LA4 and KH10. Both carbohydrate epitopes are present on novel glycoforms of the neural cell adhesion molecule, which we have named NOC-7 and NOC-8. Primary axon fasciculation is disrupted in vitro when interactions between these cell surface lactoseries carbohydrates and their endogenous binding molecules are inhibited by the LA4 and KH10 antibodies or lactosamine sugars. We report the expression of multiple members of the lactoseries binding galectin family in the primary olfactory system. In particular, galectin-3 is expressed by ensheathing cells surrounding nerve fascicles in the submucosa and nerve fiber layer, where it may mediate cross-linking of axons. Galectin-4, -7, and -8 are expressed by the primary olfactory axons as they grow from the nasal cavity to the olfactory bulb. A putative role for NOC-7 and NOC-8 in axon fasciculation and the expression of multiple galectins in the developing olfactory nerve suggest that these molecules may be involved in the formation of this pathway, particularly in the sorting of axons as they converge towards their target. (C) 2004Wiley-Liss, Inc.

Performance improvement of asymmetrical filtered 40GB/s RZ-DPSK receiver design-strong filtering considerations

We present a novel differential phase shift keying receiver design under strong optical filtering. The receiver design is based on asymmetrical filtering at the destructive port of the Mach Zehnder Interferometer. The asymmetrical filtered receiver design can significantly increase performance by 2 to 4.7dB in calculated "Q".