Inhibition of gastric acid secretion by stress: A protective reflex mediated by cerebral nitric oxide

Moderate somatic stress inhibits gastric acid secretion. We have investigated the role of endogenously released NO in this phenomenon. Elevation of body temperature by 3°C or a reduction of 35 mmHg (1 mmHg = 133 Pa) in blood pressure for 10 min produced a rapid and long-lasting reduction of distension-stimulated acid secretion in the rat perfused stomach in vivo. A similar inhibitory effect on acid secretion was produced by the intracisternal (i.c.) administration of oxytocin, a peptide known to be released during stress. Intracisternal administration of the NO-synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME) reversed the antisecretory effect induced by all these stimuli, an action prevented by intracisternal coadministration of the NO precursor, l-arginine. Furthermore, microinjection of l-NAME into the dorsal motor nucleus of the vagus nerve reversed the acid inhibitory effects of mild hyperthermia, i.v. endotoxin, or i.c. oxytocin, an action prevented by prior microinjection of l-arginine. By contrast, microinjection of l-NAME into the nucleus tractus solitarius failed to affect the inhibitory effects of hyperthermia, i.v. endotoxin, or i.c. oxytocin. Immunohistochemical techniques demonstrated that following hyperthermia there was a significant increase in immunoreactivity to neuronal NO synthase in different areas of the brain, including the dorsal motor nucleus of the vagus. Thus, our results suggest that the inhibition of gastric acid secretion, a defense mechanism during stress, is mediated by a nervous reflex involving a neuronal pathway that includes NO synthesis in the brain, specifically in the dorsal motor nucleus of the vagus.

Methionine residues as endogenous antioxidants in proteins

Cysteine and methionine are the two sulfur-containing residues normally found in proteins. Cysteine residues function in the catalytic cycle of many enzymes, and they can form disulfide bonds that contribute to protein structure. In contrast, the specific functions of methionine residues are not known. We propose that methionine residues constitute an important antioxidant defense mechanism. A variety of oxidants react readily with methionine to form methionine sulfoxide, and surface exposed methionine residues create an extremely high concentration of reactant, available as an efficient oxidant scavenger. Reduction back to methionine by methionine sulfoxide reductases would allow the antioxidant system to function catalytically. The effect of hydrogen peroxide exposure upon glutamine synthetase from Escherichia coli was studied as an in vitro model system. Eight of the 16 methionine residues could be oxidized with little effect on catalytic activity of the enzyme. The oxidizable methionine residues were found to be relatively surface exposed, whereas the intact residues were generally buried within the core of the protein. Furthermore, the susceptible residues were physically arranged in an array that guarded the entrance to the active site.

Ascorbate recycling in human neutrophils: Induction by bacteria

Ascorbate (vitamin C) recycling occurs when extracellular ascorbate is oxidized, transported as dehydroascorbic acid, and reduced intracellularly to ascorbate. We investigated microorganism induction of ascorbate recycling in human neutrophils and in microorganisms themselves. Ascorbate recycling was determined by measuring intracellular ascorbate accumulation. Ascorbate recycling in neutrophils was induced by both Gram-positive and Gram-negative pathogenic bacteria, and the fungal pathogen Candida albicans. Induction of recycling resulted in as high as a 30-fold increase in intracellular ascorbate compared with neutrophils not exposed to microorganisms. Recycling occurred at physiologic concentrations of extracellular ascorbate within 20 min, occurred over a 100-fold range of effector/target ratios, and depended on oxidation of extracellular ascorbate to dehydroascorbic acid. Ascorbate recycling did not occur in bacteria nor in C. albicans. Ascorbate did not enter microorganisms, and dehydroascorbic acid entry was less than could be accounted for by diffusion. Because microorganism lysates reduced dehydroascorbic acid to ascorbate, ascorbate recycling was absent because of negligible entry of the substrate dehydroascorbic acid. Because ascorbate recycling occurs in human neutrophils but not in microorganisms, it may represent a eukaryotic defense mechanism against oxidants with possible clinical implications.

ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles establishes MRP as a broad specificity transporter.

MRP is a recently isolated ATP-binding cassette family transporter. We previously reported transfection studies that established that MRP confers multidrug resistance [Kruh, G. D., Chan, A., Myers, K., Gaughan, K., Miki, T. & Aaronson, S. A. (1994) Cancer Res. 54, 1649-1652] and that expression of MRP is associated with enhanced cellular efflux of lipophilic cytotoxic agents [Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A. & Kruh, G. D. (1995) Cancer Res. 55, 5342-5347]. To examine the biochemical mechanism by which MRP confers multidrug resistance, drug uptake experiments were performed using inside-out membrane vesicles prepared from NIH 3T3 cells transfected with an MRP expression vector. ATP-dependent transport was observed for several lipophilic cytotoxic agents including daunorubicin, etoposide, and vincristine, as well as for the glutathione conjugate leukotriene C4 (LTC4). However, only marginally increased uptake was observed for vinblastine and Taxol. Drug uptake was osmotically sensitive and saturable with regard to substrate concentration, with Km values of 6.3 microM, 4.4 microM, 4.2 microM, 35 nM, and 38 microM, for daunorubicin, etoposide, vincristine, LTC4, and ATP, respectively. The broad substrate specificity of MRP was confirmed by the observation that daunorubicin transport was competitively inhibited by reduced and oxidized glutathione, the glutathione conjugates S-(p-azidophenacyl)-glutathione (APA-SG) and S-(2,4-dinitrophenyl)glutathione (DNP-SG), arsenate, and the LTD4 antagonist MK571. This study establishes that MRP pumps unaltered lipophilic cytotoxic drugs, and suggests that this activity is an important mechanism by which the transporter confers multidrug resistance. The present study also indicates that the substrate specificity of MRP is overlapping but distinct from that of P-glycoprotein, and includes both the neutral or mildly cationic natural product cytotoxic drugs and the anionic products of glutathione conjugation. The widespread expression of MRP in tissues, combined with its ability to transport both lipophilic xenobiotics and the products of phase II detoxification, indicates that the transporter represents a widespread and remarkably versatile cellular defense mechanism.

Normal human serum contains a natural IgM antibody cytotoxic for human neuroblastoma cells.

Neuroblastoma (NB) is characterized by the second highest spontaneous regression of any human malignant disorder, a phenomenon that remains to be elucidated. In this study, a survey of 94 normal human adult sera revealed a considerable natural humoral cytotoxicity against human NB cell lines in approximately one-third of the tested sera of both genders. Specific cell killing by these sera was in the range of 40% to 95%. Serum cytotoxicity was dependent on an intact classical pathway of complement. By several lines of evidence, IgM antibodies were identified as the cytotoxic factor in the sera. Further analyses revealed that a 260-kDa protein was recognized by natural IgM of cytotoxic sera in Western blots of NB cell extracts. The antigen was expressed on the surface of seven human NB cell lines but not on human melanoma or other control tumor cell lines derived from kidney, pancreas, colon, bone, skeletal muscle, lymphatic system, and bone marrow. Furthermore, no reactivity was observed with normal human fibroblasts, melanocytes, and epidermal keratinocytes. The antigen was expressed in vivo as detected by immunohistochemistry in both the tumor of a NB patient and NB tumors established in nude rats from human NB cell lines. Most interestingly, the IgM anti-NB antibody was absent from the sera of 11 human NB patients with active disease. The anti-NB IgM also could not be detected in tumor tissue obtained from a NB patient. Collectively, our data suggest the existence of a natural humoral immunological tumor defense mechanism, which could account for the in vivo phenomenon of spontaneous NB tumor regression.

Efeitos do oxigênio umidificado e não umidificado via cateter nasal sobre o transporte mucociliar e muco nasal

O transporte mucociliar (TMC) é um mecanismo básico de defesa do sistema respiratório necessário na resistência à infecção. A efetividade desse mecanismo de defesa depende da composição e profundidade do muco, da integridade e da função dos cílios e da interação muco-cílio. O objetivo deste estudo foi investigar os efeitos crônicos do oxigenoterapia de baixo fluxo via cateter nasal com e sem umidificação sobre o TMC nasal, nas propriedades físicas do muco, na inflamação e nos sintomas de vias aéreas em pacientes com hipoxemia crônica com necessidade de oxigenoterapia domiciliar de longo prazo (>15 horas/dia). Dezoito pacientes (idade média de 68 anos, 7 do sexo masculino, índice de massa corpórea (IMC) médio de 26 kg/m2, 66% com doença pulmonar obstrutiva crônica (DPOC), 60% com hipertensão arterial (HAS) e ex-tabagistas) iniciando oxigenoterapia de baixo fluxo via cateter nasal foram randomizados para o grupo Oxigênio Seco (n=10) ou Oxigênio Umidificado (n=9). Os pacientes foram avaliados nos tempos: basal, 12 horas, 7 dias, 30 dias, 12 meses e 24 meses para o TMC nasal por meio do teste de trânsito da sacarina, as propriedades físicas do muco por meio de ângulo de contato, a inflamação por meio de quantificação do número total de células e diferenciais e da concentração de citocinas no lavado nasal assim como para sintomas por meio do questionário SNOT-20. O sintoma mais importante relatado por pacientes no basal foi tosse que melhorou após 7 dias de oxigenoterapia. No nosso estudo, os pacientes de ambos grupos apresentaram prolongamento significativo (40%) do TMC nasal ao longo do estudo. O lavado nasal mostrou um aumento das proporções de neutrófilos, das células caliciformes e da concentração do fator de crescimento epidermal (EGF) assim como reduções em macrófagos e concentrações de interferon alfa (IFN-alfa), interleucina (IL)-8 e IL-10 ao longo do estudo. Não houve alterações na proporção de células ciliadas, na concentração de IL-6 e no ângulo de contato do muco em ambos os grupos. A tosse e os sintomas de sono diminuiram significativamente em ambos os grupos. Nosso estudo sugere que a umidificação não tem impacto sobre o TMC nasal, as propriedades do muco, a inflamação e os sintomas em pacientes com baixo fluxo de oxigênio via cateter nasal (BFON)

Efeitos da imunossupressão sobre a depuração mucociliar de ratos: comparação entre dois esquemas de terapia tríplice

INTRODUÇÃO: O transplante de pulmão é parte fundamental no tratamento das doenças terminais do pulmão, constituindo uma modalidade terapêutica eficaz para pacientes com doença pulmonar incapacitante, progressiva e em estágio final. No entanto, as drogas imunossupressoras usadas para evitar a rejeição do enxerto podem causar efeitos colaterais em diversos tecidos. O sistema mucociliar, presente nas vias aéreas, é um dos principais mecanismos de defesa do trato respiratório e pode ser alterado por ação das drogas imunossupressoras. Desta forma, o objetivo deste estudo foi avaliar o sistema mucociliar traqueobrônquico de ratos submetidos a dois esquemas de terapia tríplice imunossupressora. MÉTODOS: Foram utilizados 90 ratos machos Wistar distribuídos em 3 grupos conforme o tratamento: controle (C) = solução salina; terapia 1 (TI) = tacrolimus + micofenolato de mofetil + prednisona; terapia 2 (TII) = ciclosporina + azatioprina + prednisona. Após o período de tratamento (7, 15 ou 30 dias), os animais foram sacrificados e realizadas as seguintes medidas: transportabilidade do muco (TM), frequência de batimento ciliar (FBC), quantificação de muco neutro e ácido, velocidade de transporte mucociliar (VTMC), e contagem total e diferencial de células no lavado broncoalveolar (LBA). RESULTADOS: A TM não foi afetada pelas terapias em nenhum dos tempos estudados. Ambas as terapias causaram significativa redução da FBC dos animais tratados por 7 e 15 dias. A produção de muco neutro foi menor nos animais tratados com a TI por 7, 15 e 30 dias. Porém, com a TII, essa redução ocorreu apenas aos 7 dias. Por outro lado, a quantidade de muco ácido foi significativamente maior em todos os animais tratados com as duas terapias. Todos os animais tratados com as terapias imunossupressoras apresentaram redução da VTMC nos três tempos. Houve aumento do número total de células e de macrófagos e neutrófilos no grupo TI em 7 dias. CONCLUSÕES: Ambas as terapias imunossupressoras foram prejudiciais ao transporte mucociliar das vias aéreas de ratos, tanto pela redução da FBC e da VTMC, quanto pela maior produção de muco ácido e menor produção de muco neutro. A TI foi mais prejudicial ao sistema mucociliar em comparação à TII

Marine isocyanides and related natural products structure, biosynthesis and ecology

This review highlights structural and biosynthetic work on a group of nitrogen-functionalised terpenes that are almost exclusively found in marine invertebrates and the animals that feed on them. The chemical functionality reviewed includes isocyanides, isothiocyanates, formamides, thiocyanates, isocyanates, and dichloroimines. The literature through mid 2003 is reviewed and there are 143 citations.

Complement factor 5a as a therapeutic target

The complement system is an innate immune defense mechanism that protects the host from infection and injury. Complement activation results in the formation of anaphylatoxins, including the biologically active protein C5a. This anaphylatoxin is a potent chemotactic agent for immune and inflammatory cells and induces cell activation. In situations of excessive or uncontrolled complement activation, the overproduction of C5a can cause deleterious effects to the host, and this process is implicated in the pathogenesis of numerous immunoinflammatory disease states, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, ischemia-reperfusion injuries and others. The presence of C5a in a wide variety of condition's has prompted many groups to examine the potential of inhibiting this complement activation product, with the aim of controlling these diseases and reducing the pathologic process. However, to date there is no clinically available specific C5a inhibitor and development of this new drug class is still in a relatively early stage, although limited phase I and phase II human clinical trials have been undertaken in the last few years with selected agents. In this review, examination of the current evidence supporting a specific role of C5a in selected disease states and an overview of potential therapeutic C5a inhibitors will enable the critical evaluation of the potential for C5a as a therapeutic target.

Computer Networks Security Models - A New Approach for Denial-of-Services Attacks Mitigation

Computer networks are a critical factor for the performance of a modern company. Managing networks is as important as managing any other aspect of the company’s performance and security. There are many tools and appliances for monitoring the traffic and analyzing the network flow security. They use different approaches and rely on a variety of characteristics of the network flows. Network researchers are still working on a common approach for security baselining that might enable early watch alerts. This research focuses on the network security models, particularly the Denial-of-Services (DoS) attacks mitigation, based on a network flow analysis using the flows measurements and the theory of Markov models. The content of the paper comprises the essentials of the author’s doctoral thesis.

Building Regional Security: Cooperation in the 21st Century: The Case of the Caribbean Regional Security System [RSS]

Small states that lack capacity and act on their own may fall victim to international and domestic terrorism, transnational organized crime or criminal gangs. The critical issue is not whether small Caribbean states should cooperate in meeting security challenges, but it is rather in what manner, and by which mechanisms can they overcome obstacles in the way of cooperation. The remit of the Regional Security System (RSS) has expanded dramatically, but its capabilities have improved very slowly. The member governments of the RSS are reluctant to develop military capacity beyond current levels since they see economic and social development and disaster relief as priorities, requiring little investment in military hardware. The RSS depends on international donors such as the USA, Canada, Great Britain, and increasingly China to fund training programs, maintain equipment and acquire material. In the view of most analysts, an expanded regional arrangement based on an RSS nucleus is not likely in the foreseeable future. Regional political consensus remains elusive and the predominance of national interests over regional considerations continues to serve as an obstacle to any CARICOM wide regional defense mechanism. Countries in the Caribbean, including the members of the RSS, have to become more responsible for their own security from their own resources. While larger CARICOM economies can do this, it would be difficult for most OECS members of the RSS to do the same. The CARICOM region including the RSS member countries, have undertaken direct regional initiatives in security collaboration. Implementation of the recommendations of the Regional Task Force on Crime and Security (RTFCS) and the structure and mechanisms created for the staging of the Cricket World Cup (CWC 2007) resulted in unprecedented levels of cooperation and permanent legacy institutions for the regional security toolbox. The most important tier of security relationships for the region is the United States and particularly USSOUTHCOM. The Caribbean Basin Security Initiative [CBSI] in which the countries of the RSS participate is a useful U.S. sponsored tool to strengthen the capabilities of the Caribbean countries and promote regional ownership of security initiatives. Future developments under discussion by policy makers in the Caribbean security environment include the granting of law enforcement authority to the military, the formation of a single OECS Police Force, and the creation of a single judicial and law enforcement space. The RSS must continue to work with its CARICOM partners, as well as with the traditional “Atlantic Powers” particularly Canada, the United States and the United Kingdom to implement a general framework for regional security collaboration. Regional security cooperation should embrace wider traditional and non-traditional elements of security appropriate to the 21st century. Security cooperation must utilize to the maximum the best available institutions, mechanisms, techniques and procedures already available in the region. The objective should not be the creation of new agencies but rather the generation of new resources to take effective operations to higher cumulative levels. Security and non-security tools should be combined for both strategic and operational purposes. Regional, hemispheric, and global implications of tactical and operational actions must be understood and appreciated by the forces of the RSS member states. The structure and mechanisms, created for the staging of Cricket World Cup 2007 should remain as legacy institutions and a toolbox for improving regional security cooperation in the Caribbean. RSS collaboration should build on the process of operational level synergies with traditional military partners. In this context, the United States must be a true partner with shared interests, and with the ability to work unobtrusively in a nationalistic environment. Withdrawal of U.S. support for the RSS is not an option.

The effects of content-based ESOL instruction on the overall English proficiency of foreign -born college students

This study investigates the effects of content-based ESOL instruction on the overall English proficiency of foreign-born college students. Based on various psychological and social factors which affect second language acquisition, it is suggested that the techniques of content-based instruction, while focusing on subject matter, allow the learners to overcome the language barrier by neutralizing their subconscious defense mechanism, thus attaining greater proficiency.^ Two groups of Miami-Dade Community College ESOL students were chosen as subjects for this study: a control group composed of students from the North and Wolfson campuses, where the ESOL program is based predominantly on structural or structural-functional approach, and an experimental group of Medical Center campus students, where content-based instruction is incorporated into curriculum. Ethnicity, gender, age, and other differences in the population are discussed in the study.^ The students' English Placement Test (EPT) scores were used as covariate, and the scores on Multiple Assessment Programs and Services (MAPS) test as dependent variables. Multivariate analysis of variance (MANOVA) was applied to test significant difference between the means. The results of the analysis of data indicate that there is a consistent difference in the mean performance of the Medical Center campus ESOL students demonstrated by their scores on MAPS. Although neither ethnicity, nor gender of the subjects has affected the outcome, age had a contributing effect. The implications of these findings suggest that content-based instruction facilitates greater overall English proficiency in foreign-born college students. ^

Las edades de Hitler. De Satán a un ser de carne y hueso, y su representación en clave paródica

Adolf Hitler suscitó desde su entrada en la escena política alemana una fascinación perversa, un sentimiento que, con el tiempo, ha dado lugar a numerosas representaciones culturales sobre el Führer. La muestra, rica y variada tanto en el fondo como en la forma, nos permitirá trazar tres estadios en lo referente al proceso de construcción historiográfica del hitlerismo, iniciado con la caída del Tercer Reich. Estos responden en buena medida al devenir sociopolítico y cultural de la sociedad a escala global desde el final de la guerra y hasta nuestros días y pueden resumirse en tres: primero, la satanización; segundo, la humanización; tercero, el retrato caricaturesco. Proponemos un recorrido histórico por diversos productos culturales del dictador alemán cuyo propósito es desentrañar el retrato psicológico poliédrico que se ha construido en torno a la figura de Hitler.

The complexity of Drosophila innate immunity

Metazoans rely on efficient mechanisms to oppose infections caused by pathogens. The immediate and first-line defense mechanism(s) in metazoans, referred to as the innate immune system, is initiated upon recognition of microbial intruders by germline encoded receptors and is executed by a set of rapid effector mechanisms. Adaptive immunity is restricted to vertebrate species and it is controlled and assisted by the innate immune system. Interestingly, most of the basic signaling cascades that regulate the primeval innate defense mechanism(s) have been well conserved during evolution, for instance between humans and the fruit fly, Drosophila melanogaster. Being devoid of adaptive signaling and effector systems, Drosophila has become an established model system for studying pristine innate immune cascades and reactions. In general, an immune response is evoked when microorganisms pass the fruit fly’s physical barriers (e.g. cuticle, epithelial lining of gut and trachea), and it is mainly executed in the hemolymph, the equivalent of the mammalian blood. Innate immunity in the fruit fly consists of a phenoloxidase (PO) response, a cellular response (hemocytes), an antiviral response, and the NF-κB dependent production of antimicrobial peptides referred to as the humoral response. The JAK/STAT and Jun kinase signaling cascades are also implicated in the defence against pathogens.

Canais calcificados

A abordagem Endodôntica tem como grandes objetivos a manutenção funcional e estética do dente no sistema estomatognático. O sucesso desta abordagem terapêutica depende da realização eficiente da desinfeção, conformação e obturação do canal radicular. Estas etapas podem tornar-se difíceis de realizar na presença de dentes calcificados. A localização e manipulação dos canais calcificados são considerados um grande desafio durante a abordagem Endodôntica. Na tentativa de localização dos canais podem ocorrer erros de procedimento, como perfurações, fraturas de instrumentos e desvios do trajeto original do canal. Atualmente, vários recursos clínicos são utilizados para auxiliar estes procedimentos, como radiografias, microscópio operatório e o ultrassom. A calcificação pode ser resultado do processo fisiológico de envelhecimento, ou da deposição de dentina como mecanismo de defesa da polpa contra agentes agressores externos. Os dentes com calcificação não costumam apresentar sintomatologia, sendo o diagnóstico muitas vezes acidental. Clinicamente, a coroa dentária apresenta coloração alterada, e radiograficamente os canais apresentam os seus limites pulpares apagados, revelando obstrução parcial ou completa da câmara pulpar e dos canais, devido à deposição excessiva de dentina. A abordagem apropriada para dentes calcificados pode ser um dilema para o clínico. Esta deve ser feita a partir de decisão prudente entre a intervenção Endodôntica para o dente envolvido e outras intervenções restauradoras estéticas disponíveis. A maioria da literatura não apoia a intervenção Endodôntica a menos que seja detetado patologia apical ou sintomatologia do dente envolvido. A observação e o exame periódico do dente calcificado são as opções geralmente adotadas.