Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in mechanism-based inactivation.

Leukotriene A4 (LTA4) hydrolase [7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9 ,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme which converts LTA4 into the chemotactic agent leukotriene B4 (LTB4). Suicide inactivation, a typical feature of LTA4 hydrolase/aminopeptidase, occurs via an irreversible, apparently mechanism-based, covalent binding of LTA4 to the protein in a 1:1 stoichiometry. Differential lysine-specific peptide mapping of unmodified and suicide-inactivated LTA4 hydrolase has been used to identify a henicosapeptide, encompassing the amino acid residues 365-385 of human LTA4 hydrolase, which is involved in the binding of LTA4, LTA4 methyl ester, and LTA4 ethyl ester to the native enzyme. A modified form of this peptide, generated by lysine-specific digestion of LTA4 hydrolase inactivated by LTA4 ethyl ester, could be isolated for complete Edman degradation. The sequence analysis revealed a gap at position 14, which shows that binding of the leukotriene epoxide had occurred via Tyr-378 in LTA4 hydrolase. Inactivation of the epoxide hydrolase and the aminopeptidase activity was accompanied by a proportionate modification of the peptide. Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA4 hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s). It may now be possible to clarify the molecular mechanisms underlying suicide inactivation and epoxide hydrolysis by site-directed mutagenesis combined with structural analysis of the lipid molecule, covalently bound to the peptide.

Combination gene therapy for liver metastasis of colon carcinoma in vivo.

The efficacy of combination therapy with a "suicide gene" and a cytokine gene to treat metastatic colon carcinoma in the liver was investigated. Tumor in the liver was generated by intrahepatic injection of a colon carcinoma cell line (MCA-26) in syngeneic BALB/c mice. Recombinant adenoviral vectors containing various control and therapeutic genes were injected directly into the solid tumors, followed by treatment with ganciclovir. While the tumors continued to grow in all animals treated with a control vector or a mouse interleukin 2 vector, those treated with a herpes simplex virus thymidine kinase vector, with or without the coadministration of the mouse interleukin 2 vector, exhibited dramatic necrosis and regression. However, only animals treated with both vectors developed an effective systemic antitumoral immunity against challenges of tumorigenic doses of parental tumor cells inoculated at distant sites. The antitumoral immunity was associated with the presence of MCA-26 tumor-specific cytolytic CD8+ T lymphocytes. The results suggest that combination suicide and cytokine gene therapy in vivo can be a powerful approach for treatment of metastatic colon carcinoma in the liver.

Mary, Quite Contrary: The Novels of Mary Davys, 1700-1727

As a relatively unknown author, Mary Davys (1674-1732) has garnered scant scholarly attention and little admiration for her work. Those who have written on Davys’s prose fiction most often mention the last three texts she published, Familiar Letters betwixt a Gentleman and a Lady (1716), The Reform’d Coquet (1724), and The Accomplish’d Rake (1727), yet rare mention is made of her first three novels. Moreover, of her later novels, many scholars read them as socially conservative and as representations of Davys’s support of and belief in patriarchy. My project disproves the long-standing and generally agreed upon conceptions regarding Davys’s writings and demonstrates the significance of her life’s work to studies of the novel. By investigating contemporary cultural issues, discussing the popular genres and modes of early eighteenth-century England, and comparing and contrasting Davys’s fiction to other authors’, I explore the myriad ways in which Davys experimented with the formal properties of the novel. Also, by closely examining each novel independently, I foreground Davys’s willingness to engage with charged contemporary topics such as rape, suicide, the laws surrounding inheritance, and male privilege. Not only does she engage with these topics; there is a discernable voice of protest imbedded in the narratives. At times, the techniques Davys employed and the plots she created in her work obscured her social concerns, yet with close reading, subversion also surfaces as one of Davys’s methods. An analysis of Davys’s experimentations with prose fiction and form illuminates the ways in which those innovations allowed Davys to criticize the culture in which she lived. Furthermore, an investigation of the whole of Davys’s work and the totality of her novels—looking at both form and content—exemplifies the importance of Davys for students of feminist thought and the development of the novel.

Trends in socioeconomic inequalities in preventable mortality in urban areas of 33 Spanish cities, 1996–2007 (MEDEA project)

Background: Preventable mortality is a good indicator of possible problems to be investigated in the primary prevention chain, making it also a useful tool with which to evaluate health policies particularly public health policies. This study describes inequalities in preventable avoidable mortality in relation to socioeconomic status in small urban areas of thirty three Spanish cities, and analyses their evolution over the course of the periods 1996–2001 and 2002–2007. Methods: We analysed census tracts and all deaths occurring in the population residing in these cities from 1996 to 2007 were taken into account. The causes included in the study were lung cancer, cirrhosis, AIDS/HIV, motor vehicle traffic accidents injuries, suicide and homicide. The census tracts were classified into three groups, according their socioeconomic level. To analyse inequalities in mortality risks between the highest and lowest socioeconomic levels and over different periods, for each city and separating by sex, Poisson regression were used. Results: Preventable avoidable mortality made a significant contribution to general mortality (around 7.5%, higher among men), having decreased over time in men (12.7 in 1996–2001 and 10.9 in 2002–2007), though not so clearly among women (3.3% in 1996–2001 and 2.9% in 2002–2007). It has been observed in men that the risks of death are higher in areas of greater deprivation, and that these excesses have not modified over time. The result in women is different and differences in mortality risks by socioeconomic level could not be established in many cities. Conclusions: Preventable mortality decreased between the 1996–2001 and 2002–2007 periods, more markedly in men than in women. There were socioeconomic inequalities in mortality in most cities analysed, associating a higher risk of death with higher levels of deprivation. Inequalities have remained over the two periods analysed. This study makes it possible to identify those areas where excess preventable mortality was associated with more deprived zones. It is in these deprived zones where actions to reduce and monitor health inequalities should be put into place. Primary healthcare may play an important role in this process.

Representações de suicidas míticos na cerâmica grega: séculos VII-IV A.C.

Com a presente dissertação temos por objectivo problematizar, através da iconografia, as representações de suicidas míticos na cerâmica grega (séculos VII-IV a.C.). O corpus da pesquisa é constituído por 40 vasos com imagens de onze figuras mitológicas: Ájax, Alceste, Antígona, Ariadne, Cassandra, Fedra, Ifigénia, Macária, Medeia, Orestes e Políxena. Das 40 imagens analisadas, três são do séc. VII a.C., cinco do séc. VI a.C., onze do séc. V a.C. e 21 do séc. IV a.C. A dissertação é dividida em onze capítulos, um para cada figura mitológica, nos quais debateremos as fontes, a evolução do mito e a iconografia associada.

Suicídio : uma análise epidemiológica : estudo retrospetivo da casuística da Delegação do Sul do Instituto Nacional de Medicina Legal e Ciências Forenses, I.P. (2007-2012)

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

Comorbidity Between Major Depression and Alcohol Use Disorder From Adolescence to Adulthood

Background—Limited information exists regarding the long-term development of comorbidity between Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD; abuse/dependence). Using a representative prospective study, we examine multiple aspects pertaining to MDD+AUD comorbidity, with a focus on the relation between disorders across periods (adolescence, early adulthood, adulthood) and cumulative impairments by age 30. Method—816 participants were diagnostically interviewed at ages 16, 17, 24, and 30. Results—Rates of comorbid MDD+AUD were low in adolescence (2%), but increased in early adulthood (10%) and adulthood (7%). Rates of cumulative comorbidity were elevated (21%). Most individuals with a history of MDD or AUD had the other disorder, except for women with MDD. Prospectively, adolescent AUD predicted early adult MDD, while early adult MDD predicted adult AUD. Compared to pure disorders, MDD+AUD was associated with higher risk of alcohol dependence, suicide attempt, lower global functioning, and life dissatisfaction. Conclusions—Lifetime rates of comorbid MDD+AUD were considerably higher than in crosssectional studies. Comorbidity was partly explained by bidirectional and developmentally-specific associations and predicted selected rather than generalized impairments. Clinically, our findings emphasize the need to always carefully assess comorbidity in patients with MDD or AUD, taking into account concurrency and developmental timing.

THE NEW WALLS AND FENCES: CONSEQUENCES FOR ISRAEL AND PALESTINE. CEPS Middle East Working Paper No. 9, June 2003

Good fences make good neighbours’ wrote the poet Robert Frost. Israel and Palestine are certainly not good neighbours and the question that arises is will a fence between Israel and Palestine turn them into ‘good neighbours’. This paper deals with the Israeli decision to construct a fence that will divide Israel and the West Bank. Almost all public debate of the wall in Israel has been limited to the security aspects. In light of the success enjoyed so far by the wall or fence around the Gaza Strip in preventing suicide bombers from getting through, the defence for needing a similar wall around the West Bank seems like an easy task. One of the main proponents of the wall concept in Israel is Dan Scheuftan, whose book on the subject has served as a guide for policy-makers. The paper provides a critique of Scheuftan’s book. The paper addresses various aspects of the wall and focuses on the different consequences of building a barrier between the two entities. Significant attention is paid to the economic consequences of the wall. The paper also looks at other issues such as the impact the wall will have on future attempts of peace-making. The paper attempts to show that the prevention of Palestinian access to Israel – the main goal of the wall – may not really have the hoped for effect of enhancing Israel’s security

Turkey’s new election: War or peace? EPC Commentary, 30 October 2015

Turkey is headed to its second parliamentary election in five months with snap polls slated for November 1. The election will take place in a highly charged atmosphere with escalating violence and financial volatility. The renewed conflict between Turkey and the terrorist Kurdistan Workers' Party (PKK) is spreading throughout the country with the rise of ethnic tensions posing a big threat to internal harmony. Even a peace rally in the capital Ankara was hit by suicide bombers marking the deadliest terror attack in Turkey's history. Turkey, which has always been the most stable country in a turbulent region, risks its security being seriously jeopardised unless the violence is urgently stopped and the political ambiguity is ended through a stable government.

The AKP rebooted – What next for Turkey? EPC Commentary, 30 October 2015

Turkey is headed to its second parliamentary election in five months with snap polls slated for November 1. The election will take place in a highly charged atmosphere with escalating violence and financial volatility. The renewed conflict between Turkey and the terrorist Kurdistan Workers' Party (PKK) is spreading throughout the country with the rise of ethnic tensions posing a big threat to internal harmony. Even a peace rally in the capital Ankara was hit by suicide bombers marking the deadliest terror attack in Turkey's history. Turkey, which has always been the most stable country in a turbulent region, risks its security being seriously jeopardised unless the violence is urgently stopped and the political ambiguity is ended through a stable government.

Analysis of Protein Turnover by Quantitative SNAP-Based Pulse-Chase Imaging

Assessment of protein dynamics in living cells is crucial for understanding their biological properties and functions. The SNAP-tag, a self labeling suicide enzyme, presents a tool with unique features that can be adopted for determining protein dynamics in living cells. Here we present detailed protocols for the use of SNAP in fluorescent pulse-chase and quench-chase-pulse experiments. These time-slicing methods provide powerful tools to assay and quantify the fate and turnover rate of proteins of different ages. We cover advantages and pitfalls of SNAP-tagging in fixed- and live-cell studies and evaluate the recently developed fast-acting SNAPf variant. In addition, to facilitate the analysis of protein turnover datasets, we present an automated algorithm for spot recognition and quantification.

Perfil sociodemográfico das pessoas que cometeram suicídio no período de 2007 a 2013 em Arapiraca, Alagoas, e a possível exposição aos agrotóxicos

Trata-se de um estudo descritivo de série histórica, com os dados coletados do Sistema de Informação de Mortalidade, através de relatórios do TABWIN, gerados em Excel, com banco de dados e análise estatística feitas no programa estatístico SPSS. Tem por objetivo determinar a mortalidade por suicídio na população do município de Arapiraca-AL, no período de 2007 a 2013, caracterizar o perfil epidemiológico e verificar a existência da associação entre a exposição a agrotóxicos e o suicídio. Identificamos 76 óbitos por suicidio no periodo, porém 14 óbitos foram eliminados por apresentarem informações ignoradas. Dos 53 óbitos, que apresentou uma média de 7,6 óbitos/ano, 40 foram praticados por homens e 13 por mulheres, a faixa etária inferior a 30 anos teve 45% dos óbitos, concentrados entre 20 a 29 anos, com 32,1%; os solteiros representaram 64,1%; pessoas de cor parda, com 41 mortos, (77,3%); a escolaridade apresentou 50,9% com um a 7 anos de estudos; 73,6% das pessoas residiam na zona urbana; 37,7% eram trabalhadores da agricultura, e o meio mais utilizado foi o enforcamento com 28 dos óbitos, (52,9%), seguido do uso de pesticidas com 16 óbitos, (30,2%). O Teste Exato de Fisher utilizado para avaliar a associação entre os fatores que poderiam influenciar a prática do suicídio, mostrou não existir diferença estatística na prática do suicídio entre os trabalhadores com agrotóxicos (p=0,64), bem como em relação a ocupação (p=0,76). Porém, foram encontradas associações significativas entre o desfecho suicídio e a existência de quadro depressivo (p=0,001) e a utilização de medicamentos (p=0,03). Novos estudos devem ser realizados com o intuíto de melhor explicar a ocorrência de depressão e do suicídio e principalmente determinar a sua relação causal com a exposição aos agrotóxicos. Palavras-chave: Suicídio; Mortalidade; Agrotóxicos.

Perfil sociodemográfico dos sujeitos que tentaram o suicídio no município de Arapiraca, Alagoas

Introdução: as tentativas de suicídio são uma das causas mais frequentes de atendimento nos serviços de urgência no Brasil. Poucos estudos abordam as características epidemiológicas das tentativas de suicídio, principalmente na região nordeste. Diante da importância de se conhecer as características das tentativas de suicídio e propor estratégias de minimização é que o presente estudo caracterizou o perfil sociodemográfico das pessoas que tentaram suicídio em Arapiraca – AL, no período de 2009 a 2013. Metodologia: Trata-se de um estudo descritivo de série histórica, com dados obtidos através da ficha de notificação/ investigação individual de Intoxicação Exógena do SINAN, de pacientes que foram atendidos no serviço de urgência e emergência da Unidade de Emergência Doutor Daniel Houly em Arapiraca. Foram analisadas as seguintes variáveis das tentativas de suicídios: faixa etária, sexo, raça, idade gestacional, zona de residência, vínculo empregatício, agente tóxico, hospitalização e evolução. Resultados: Do ano de 2009 a 2013 o total de atendidos por tentativas de suicídios na referida unidade foi de 1.184 indivíduos, sendo 71,54% do sexo feminino e 28,46% do sexo masculino. A faixa etária de maior frequência foi à de 20-29 anos, correspondendo a 33 % e a raça parda foi a que apresentou maior número de casos, 21% (n= 239). Em relação à residência 77% (n = 922) dos casos residiam em zona urbana, e o principal agente tóxico utilizado nas tentativas de suicídio, foi a ingestão medicamentosa (n = 822, 72%). Cerca de 73% (n=865) tiveram que ser hospitalizados e 95% tiveram tratamento adequado, evoluindo para cura. Conclusão: A partir dos dados foi possível traçar o perfil sociodemográfico das tentativas de suicídio, alcançando os objetivos propostos. A discussão do tema bem como a implementação da educação em saúde se constituem em elementos primordiais para a identificação dos sujeitos com ideação suicida e a busca da evitabilidade de novos casos. Ações de vigilância são necessárias para minimizar as taxas de suicídio, bem como a formação e articulação de rede de assistência no agreste alagoano. Ainda ressalta-se a necessidade de mais estudos com a população que apresenta comportamento suicida no município. Palavras-chave: Tentativa de Suicídio. Saúde Pública. Saúde Mental.

Comorbidity Between Major Depression and Alcohol Use Disorder From Adolescence to Adulthood

Background—Limited information exists regarding the long-term development of comorbidity between Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD; abuse/dependence). Using a representative prospective study, we examine multiple aspects pertaining to MDD+AUD comorbidity, with a focus on the relation between disorders across periods (adolescence, early adulthood, adulthood) and cumulative impairments by age 30. Method—816 participants were diagnostically interviewed at ages 16, 17, 24, and 30. Results—Rates of comorbid MDD+AUD were low in adolescence (2%), but increased in early adulthood (10%) and adulthood (7%). Rates of cumulative comorbidity were elevated (21%). Most individuals with a history of MDD or AUD had the other disorder, except for women with MDD. Prospectively, adolescent AUD predicted early adult MDD, while early adult MDD predicted adult AUD. Compared to pure disorders, MDD+AUD was associated with higher risk of alcohol dependence, suicide attempt, lower global functioning, and life dissatisfaction. Conclusions—Lifetime rates of comorbid MDD+AUD were considerably higher than in crosssectional studies. Comorbidity was partly explained by bidirectional and developmentally-specific associations and predicted selected rather than generalized impairments. Clinically, our findings emphasize the need to always carefully assess comorbidity in patients with MDD or AUD, taking into account concurrency and developmental timing.

National independence; or, A common-sense policy,

Employment demands protection.--Why any exclusive policy?--The free trade trap.--Protection enriched us, not free trade.--Free trade poisons patriotism.--Kill industries and commerce dies.--Theories are dangerous guides.--Industrial displacements spell ruin.--Independence the only policy.--The fatal policy of laissez faire.--"Cheap and nasty."--Our unearned increment.--Free trade a spiteful mistress.--The fertility of character.--We cultivate weakness, not strength.--Britons can manage British business.--Second markets.--The country's average wage.--If trusts, then British trusts.--Labour's true interests.--Germany and her navy.--Class-hatred is suicide.--The tax on wheat.--The little-Englander rat.--The seeds of decay.--Education and patriotism.--Intemperate legislators.--National strongholds.--Futile scheming.--The balance of power.--The suffragette among nations.--Naval warfare in the future.--Universal service.--Broken reeds.