The majority of research on suicide has focused on the role of direct risk factors in the development of suicidal intent, including personal characteristics and psychiatric illness. While research on the wider influence of socio-economic circumstances is not uncommon, most research has considered single risk factors, and often limits the scope of the research to small groups or small areas. This research attempted to provide a unified and comprehensive analysis, and used mainly aggregate data to consider the extent to which socio-economic factors explain geographic and temporal variations in suicide. Variations in suicide over the local authority districts of England and Wales were found to be significantly associated with several ecological predictors, including male unemployment, lone households, low social class and divorce. The importance of the predictors varied according to age and sex, and the results corresponded well to those from individual level studies. The research also considered the geographical differences between suicide and undetermined death verdicts, and found that the latter have a significant urban bias. These cross- 3ectional results were used as the basis for a study of the changes that took place in suicide rates during the 1980s, to determine the extent to which changes in the area characteristics that were significant at a given point in time accounted for changes in suicide rates over time. Particular attention was given to the dramatic rise in rates among younger males (aged 15-44). Little evidence was found at the ecological level to support the hypothesis that changes in unemployment and/or deprivation, the proportion of people living alone, or the divorce rate might have been responsible for the increase in suicide among younger men, while the rates for all other groups declined. Individual data for Norfolk were also used, and the predictors of geographic variation were found to be very similar for Norfolk and England and Wales. Furthermore, although the sexand age-specific changes in rates during the 1980s were also similar, the ecological variable~ again failed to adequately predict the changes. Analysis did not support the hypothesis tha1 suicide rates increased solely because of the increased availability of motor vehicle exhaus1 fumes as a suicide method, though there was some suggestion that this may have contributec to the trends. Further analysis of individual deaths found strong evidence to suggest the urbar bias of undetennined death to be an artifact of the reporting of suicide, whereby mon equivocal methods, more likely to lead to an undetermined death verdict, tend to be use( more often in urban areas. Two main conclusions are reached. First, the extent of the urban-rural variation between tbl verdicts was such that studies using different definitions of suicide over the same study are; could possibly derive diifering conclusions. Combining the verdicts is therefore encouragec Second, while the geography of suicide may be explained in tenns of socio-economic facton changes in suicide rates appear to have little or no geographic and socio-economi manifestation. Detennining the role of cultural change, presently the only theory t adequately account for the divergence in rates, requires more psychologically and socially orientated research.

Seja Ω ⊂ ℝ2 aberto contendo a origem. Denotando as variáveis por (x,t), provamos a resolubilidade local, em um disco D aberto centrado na origem, D ⊂ Ω, de equações semilineares da forma Pu = f(x,t,u); onde P = ∂t + a(x,t)∂x, a ∈ C2 (Ω), Im ≠ 0 e f ∈ C2 (Ω × ℂ), usando o princípio da contração; P = ∂t - itk∂x, k: número inteiro positivo par e f ∈ C∞(ℝ2 × ℂ), usando o teorema da resolubilidade local de Hounie e Santiago. / Let Ω be an open set of ℝ2 containing the origin. Using the variables (x,t), we prove the local solvability, on an open ball D centered at the origin, D ⊂ Ω, of semilinear equations of the form Pu = f(x,t,u); where P = ∂t + a(x,t)∂x, a ∈ C2 (Ω), Im ≠ 0 and f ∈ C2 (Ω × ℂ), using the principle of contracting mappings; P = ∂t - itk∂x, k: even positive integer number and f ∈ C∞(ℝ2 × ℂ), using the local solvability theorem of Hounie and Santiago.

Seja Ω ⊂ ℝ2 aberto contendo a origem. Denotando as variáveis por (x,t), provamos a resolubilidade local, em um disco D aberto centrado na origem, D ⊂ Ω, de equações semilineares da forma Pu = f(x,t,u); onde P = ∂t + a(x,t)∂x, a ∈ C2 (Ω), Im ≠ 0 e f ∈ C2 (Ω × ℂ), usando o princípio da contração; P = ∂t - itk∂x, k: número inteiro positivo par e f ∈ C∞(ℝ2 × ℂ), usando o teorema da resolubilidade local de Hounie e Santiago. / Let Ω be an open set of ℝ2 containing the origin. Using the variables (x,t), we prove the local solvability, on an open ball D centered at the origin, D ⊂ Ω, of semilinear equations of the form Pu = f(x,t,u); where P = ∂t + a(x,t)∂x, a ∈ C2 (Ω), Im ≠ 0 and f ∈ C2 (Ω × ℂ), using the principle of contracting mappings; P = ∂t - itk∂x, k: even positive integer number and f ∈ C∞(ℝ2 × ℂ), using the local solvability theorem of Hounie and Santiago.

Multiple myeloma is a malignant bone marrow plasma cell tumor which is responsible for approximately 12,000 deaths per year in the United States and two percent of all cancer deaths. It is recognized clinically by the presence of more than ten percent bone marrow plasma cells, the detection of a monoclonal protein (M-protein), anemia, hypercalcemia, renal insufficiency, and lytic bone lesions. The disease is usually preceded by a premalignant tumor called monoclonal gammopathy of undetermined significance (MGUS), which is present in one percent of adults over the age of fifty, three percent over the age of seventy and ten percent of those in the tenth decade. MGUS is also recognized by the detection of M-protein, but with less than ten percent bone marrow plasma cells and without the other features exhibited by myeloma. The majority of MGUS patients remain stable for long periods without ever developing myeloma. Only a small percentage of patients with MGUS eventually develop multiple myeloma. However, the reason for this is not yet known. Once the myeloma stage is reached, a sequence of well-understood mutational evets eventually lead to the escape of the tumor from the control of the immune system. We propose a mathematical model of tumor-immune system interactions at the onset of the disease in an effort to better understand the early events that take place and their influence on the outcome of the disease. The model is calibrated with parameter values obtained from available data and we study the resulting dynamics. Next, we study how the behavior of the system is affected as parameters are varied. Finally, we interpret the results and draw some conclusions.

While it implies aimless movement, the act of wandering is an act of discovery and can become a search for the unexpected. Wandering, as a metaphor for making, creates opportunities to work in ways where the final outcome is unknown. This can be accomplished by the creation of methods and instructions designed for wandering-the act of discovery. In the field of design, these ideas can be incorporated as methods for making that guide the design process in ultimately unknowable ways, resulting in products that bear little trace of preconception. The role of chance and indeterminacy as methods for relinquishing control and generating narrative are explored in three projects relying on video and interactivity.

We hypothesized that the presence of monoclonal free light chains (FLC) in the serum of patients with monoclonal gammopathy of undetermined significance (MGUS) is a marker of clonal evolution and a risk factor for progression. Forty-seven patients with MGUS and documented progression to myeloma or related malignancy were compared with 50 age- and gender-matched patients with MGUS and no evidence of progression after 5 or more years of follow-up. The presence of an abnormal kappa/lambda FLC ratio in the serum was associated with a higher risk of MGUS progression (relative risk 2.5; 95% confidence interval: 1.6-4.0; P < 0.001).

Introdução: O gene MAMLD1 tem sido relacionado à etiologia da hipospádia penoescrotal por ser fundamental para produção adequada de testosterona durante o período crítico do desenvolvimento sexual masculino. Até o momento, 3 mutações nonssense com perda de função foram identificadas em pacientes japoneses com hipospadia. Objetivo: Pesquisar a presença de mutações no gene MAMLD1, em uma grande casuística de pacientes brasileiros portadores de DDS 46,XY de origem indeterminada e realizar estudo funcional de possíveis alterações encontradas. Pacientes e Métodos: Avaliamos 50 pacientes com DDS 46.XY de causa indeterminada nos quais havia se excluído, previamente, os defeitos de síntese da testosterona, deficiência da 5 alfa-redutase 2 e insensibilidade parcial a andrógenos, por critérios laboratoriais e sequenciamento gênico. Toda região codificadora do MAMLD1 e os sítios de splice que flanqueiam essas regiões foram amplificados e sequenciados a partir do DNA genômico. Seis marcadores de microssatélites que flanqueiam o gene foram utilizados para analisar o efeito fundador da nova variante alélica identificada. A função de transativação do MAMLD1 foi analisada através de ensaio de luciferase. Células COS-1 foram distribuídas em placas de 12 poços e transitoriamente transfectadas com o vetor repórter de luciferase (p-Hes1, p-Hes3 e p-Hes5), vetor de expressão para MAMLD1 (selvagem e contendo a variante alélica) e o vetor PRL-CMV como um controle interno. Resultados: Identificamos uma variante alélica, a p.H347Q, no exon 3 em 4 pacientes brasileiros não relacionados (3 casos esporádicos e 1 caso familiar). Dois pacientes foram submetidos à gonadectomia na infância e foram criados no sexo social feminino. A ultrassonografia pélvica demonstrou a presença de útero em uma delas. Os outros dois pacientes do sexo masculino apresentavam micropênis, criptorquidia e hipospádia perineal. Esta variante alélica foi encontrada em apenas 1 de 250 controles brasileiros estudados frequência 0,4%. A atividade de transativação da variante protéica do MAMLD1 foi 2,0 vezes maior do que a proteína selvagem para ativar a transcriação do p-Hes3. Nenhum efeito fundador foi demonstrado nestas famílias. Discussão: A variante alélica está localizada em uma região altamente conservada do MAMDL1 que é essencial para o desenvolvimento da genitália masculina. Os genes Hes constituem uma família genes de repressor transcricional de sinalização intracelular Notch. Os genes Hes exibem um padrão de expressão oscilatório e controlam o momento exato de diversos eventos biológicos. O padrão de expressão dos genes Hes nas gônadas não é bem estabelecido. Hirata e col. demonstraram que tanto a ausência quanto a persistência da expressão dos genes Hes resultam nos mesmos defeitos na somitogênese. Nossa hipótese é que a superexpressão do gene Hes3 poderia prejudicar a diferenciação sexual masculina normal pela continua supressão de genes essenciais envolvidos posteriormente na cascata do desenvolvimento sexual masculino. Conclusão: Essa é a primeira descrição de uma variante alélica do gene MAMLD1 com ganho de função em pacientes com 46, XY DDS de causa indeterminada. O papel desta variante protéica do MAMDL1 na etiologia DDS 46,XY deve ser melhor determinada através de estudos in vivo / Introduction: MAMLD1 has been shown to be implicated in the etiology of penoscrotal hypospadias. To date, 3 loss-of-function nonsense mutations have been identified in Japanese patients with hypospadias. Objective: To screen MAMLD1 for mutations in a large cohort of Brazilian patients with undetermined 46,XY DSD. Patients and Methods: We evaluated 50 patients in which defects of testosterone synthesis, 5 alfa-reductase 2 deficiency and partial androgen insensitivity were previously excluded. The entire coding region and the flanking splicing sites of MAMLD1 were amplified and sequenced from genomic DNA. Six microsatellite markers flanking the gene were used to analyze founder effect of new allelic variant. Transactivation function of MAMLD1 was analyzed by a luciferase assays. COS-1 cells seeded in 12-well dishes were transiently transfected with luciferase reporter vector (p-Hes1, p-Hes3 and p-Hes5), expression vector for MAMLD1 (WT and allelic variant) and pRL-CMV vector as an internal control. All experiments were performed in triplicates and repeated 3 times. Results: We identified an allelic variant, the p.H347Q on exon 3 in 4 unrelated patients (3 sporadic and 1 familial cases). Two patients underwent gonadectomy in infancy and were raised as girls. Pelvic ultrasound showed a uterus in one of them. The other two male patients had micropenis, cryptorchidism and perineal hypospadias. This allelic variant was found in 1 out of 250 Brazilian controls frequency 0,4%. The transactivation activities of the variant protein were 2.0 folds higher than the WT with p-Hes3. No founder effect was demonstrated in these families. Discussion: The allelic variant is located in a highly conserved region of MAMDL1 which is essential for male genitalia development. HES is a family of transcriptional repressors of Notch signaling. Hes gene expression pattern is tissue and cell specific and control the timing of biological events. In gonads, their expression pattern remained to be elucidated. In somitogenesis, Hirata showed that both loss of expression or persistent expression of Hes genes result in the same defects. Therefore, overexpression of Hes genes should impair the normal male differentiation by continuous suppression of downstream genes involved in male sex development. Conclusion: This is the first report of an allelic variant of MAMLD1 determining a gain of function in its protein in patients with 46,XY DSD. The role of this variant protein of MAMDL1 in the etiology of 46, XY DDS should be better determined by in vivo studies

When a mechanical system is subject to constraints its motion is in some way restricted. In accordance with Newton's second law, motion is a direct result of forces acting on a system; hence, constraint is inextricably linked to force. The presence of a constraint implies the application of particular forces needed to compel motion in accordance with the constraint; absence of a constraint implies the absence of such forces. The objective of this thesis is to formulate a comprehensive, consistent, and concise method for identifying a set of forces needed to constrain the behavior of a mechanical system modeled as a set of particles and rigid bodies. The goal is accomplished in large part by expressing constraint equations in vector form rather than entirely in terms of scalars. The method developed here can be applied whenever constraints can be described at the acceleration level by a set of independent equations that are linear in acceleration. Hence, the range of applicability extends to servo-constraints or program constraints described at the velocity level with relationships that are nonlinear in velocity. All configuration constraints, and an important class of classical motion constraints, can be expressed at the velocity level by using equations that are linear in velocity; therefore, the associated constraint equations are linear in acceleration when written at the acceleration level. Two new approaches are presented for deriving equations governing motion of a system subject to constraints expressed at the velocity level with equations that are nonlinear in velocity. By using partial accelerations instead of the partial velocities normally employed with Kane's method, it is possible to form dynamical equations that either do or do not contain evidence of the constraint forces, depending on the analyst's interests.

Made available in DSpace on 2016-08-03T12:19:47Z (GMT). No. of bitstreams: 1 LivanChiroma.pdf: 788891 bytes, checksum: 3f7b1dafb48e0b89fdeb85b435d6befc (MD5) Previous issue date: 2014-10-04 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This text is the presentation of the results of a study on the rise of a movement here conventionally called Organic Church (OC). For the present study, among hundreds of groups met during the research period, Caminho da Graça (CdG), a community founded by mid-2004 and currently numbering around seventy groups in Brazil and abroad, was chosen as the object of analysis. The group was started by the (ex-) Rev. Caio Fábio de Araújo, or simply Caio Fábio, backed by a message of Evangelical counterculture or a return to the Christian Church as it was in the New Testament. Although CdG categorically denies the OC label, we can fit them into the movement observing the practices and discourse of the main leadership. The consolidation of Neo-Pentecostalism, especially in the 1990s, is seen as the beginning of suspiciousness and mass disappointment with the Evangelical, and above all the Neo-Pentecostal, worldview. Thus, these alternative communities welcome dissidents hurt by these contexts. It was therefore necessary, firstly, to understand the morphology of churches in the original Christianity period, since one of these groups points of dispute is the return to community experiences lived in the New Testament; secondly, to expose the biographies of the main leaders of the movement; thirdly, to emphasize the conflicts and motivations both within the church context and outside of it in order to understand the exodus and the movement of believers towards a more thorough faith experience; and lastly, to perform ethnographically-inspired participative observation in order to conduct theoretical approaches. / Este texto é a apresentação do resultado de uma pesquisa empreendida sobre o recrudescimento de um movimento que convencionamos denominar de Igreja Orgânica (IO). Para este estudo, diante de centenas de grupos encontrados durante o período da pesquisa, escolhemos a análise do Caminho da Graça (CdG), comunidade iniciada em meados de 2004, e que atualmente conta com cerca de 70 grupos no Brasil e no exterior. O grupo foi iniciado pelo (ex) reverendo Caio Fábio de Araújo Filho, ou simplesmente Caio Fábio, sustentados por uma mensagem de contracultura evangélica ou um retorno da Igreja cristã tal como era no Novo Testamento. Embora o CdG categoricamente não se auto declare uma IO, pudemos enquadrá-lo nesta tipologia observando as práticas e discurso das principais lideranças. Vemos na consolidação do Neopentecostalismo, especialmente nos anos de 1990, o início das suspeitas e decepções em massa com o universo evangélico, sobretudo advindas deste segmento do cristianismo; sendo assim estas comunidades alternativas vêm acolher dissidentes decepcionados e feridos por estas expressões religiosas. Fez-se necessário, portanto, compreender a morfologia das igrejas no período do cristianismo original, uma vez que um dos pontos de contestação destes grupos é o retorno às experiências comunitárias dos primeiros cristãos, tais quais narradas no Novo Testamento; evidenciar a biografia das principais lideranças do movimento e; enfatizar os conflitos e as motivações intracampo e extracampo existentes para compreender o êxodo e circulação dos fiéis em direção a uma experiência de fé mais pormenorizada e pós moderna; houve também necessidade de uma observação participativa, de inspiração etnográfica, para a condução de abordagens teóricas.

Introdução: O gene MAMLD1 tem sido relacionado à etiologia da hipospádia penoescrotal por ser fundamental para produção adequada de testosterona durante o período crítico do desenvolvimento sexual masculino. Até o momento, 3 mutações nonssense com perda de função foram identificadas em pacientes japoneses com hipospadia. Objetivo: Pesquisar a presença de mutações no gene MAMLD1, em uma grande casuística de pacientes brasileiros portadores de DDS 46,XY de origem indeterminada e realizar estudo funcional de possíveis alterações encontradas. Pacientes e Métodos: Avaliamos 50 pacientes com DDS 46.XY de causa indeterminada nos quais havia se excluído, previamente, os defeitos de síntese da testosterona, deficiência da 5 alfa-redutase 2 e insensibilidade parcial a andrógenos, por critérios laboratoriais e sequenciamento gênico. Toda região codificadora do MAMLD1 e os sítios de splice que flanqueiam essas regiões foram amplificados e sequenciados a partir do DNA genômico. Seis marcadores de microssatélites que flanqueiam o gene foram utilizados para analisar o efeito fundador da nova variante alélica identificada. A função de transativação do MAMLD1 foi analisada através de ensaio de luciferase. Células COS-1 foram distribuídas em placas de 12 poços e transitoriamente transfectadas com o vetor repórter de luciferase (p-Hes1, p-Hes3 e p-Hes5), vetor de expressão para MAMLD1 (selvagem e contendo a variante alélica) e o vetor PRL-CMV como um controle interno. Resultados: Identificamos uma variante alélica, a p.H347Q, no exon 3 em 4 pacientes brasileiros não relacionados (3 casos esporádicos e 1 caso familiar). Dois pacientes foram submetidos à gonadectomia na infância e foram criados no sexo social feminino. A ultrassonografia pélvica demonstrou a presença de útero em uma delas. Os outros dois pacientes do sexo masculino apresentavam micropênis, criptorquidia e hipospádia perineal. Esta variante alélica foi encontrada em apenas 1 de 250 controles brasileiros estudados frequência 0,4%. A atividade de transativação da variante protéica do MAMLD1 foi 2,0 vezes maior do que a proteína selvagem para ativar a transcriação do p-Hes3. Nenhum efeito fundador foi demonstrado nestas famílias. Discussão: A variante alélica está localizada em uma região altamente conservada do MAMDL1 que é essencial para o desenvolvimento da genitália masculina. Os genes Hes constituem uma família genes de repressor transcricional de sinalização intracelular Notch. Os genes Hes exibem um padrão de expressão oscilatório e controlam o momento exato de diversos eventos biológicos. O padrão de expressão dos genes Hes nas gônadas não é bem estabelecido. Hirata e col. demonstraram que tanto a ausência quanto a persistência da expressão dos genes Hes resultam nos mesmos defeitos na somitogênese. Nossa hipótese é que a superexpressão do gene Hes3 poderia prejudicar a diferenciação sexual masculina normal pela continua supressão de genes essenciais envolvidos posteriormente na cascata do desenvolvimento sexual masculino. Conclusão: Essa é a primeira descrição de uma variante alélica do gene MAMLD1 com ganho de função em pacientes com 46, XY DDS de causa indeterminada. O papel desta variante protéica do MAMDL1 na etiologia DDS 46,XY deve ser melhor determinada através de estudos in vivo / Introduction: MAMLD1 has been shown to be implicated in the etiology of penoscrotal hypospadias. To date, 3 loss-of-function nonsense mutations have been identified in Japanese patients with hypospadias. Objective: To screen MAMLD1 for mutations in a large cohort of Brazilian patients with undetermined 46,XY DSD. Patients and Methods: We evaluated 50 patients in which defects of testosterone synthesis, 5 alfa-reductase 2 deficiency and partial androgen insensitivity were previously excluded. The entire coding region and the flanking splicing sites of MAMLD1 were amplified and sequenced from genomic DNA. Six microsatellite markers flanking the gene were used to analyze founder effect of new allelic variant. Transactivation function of MAMLD1 was analyzed by a luciferase assays. COS-1 cells seeded in 12-well dishes were transiently transfected with luciferase reporter vector (p-Hes1, p-Hes3 and p-Hes5), expression vector for MAMLD1 (WT and allelic variant) and pRL-CMV vector as an internal control. All experiments were performed in triplicates and repeated 3 times. Results: We identified an allelic variant, the p.H347Q on exon 3 in 4 unrelated patients (3 sporadic and 1 familial cases). Two patients underwent gonadectomy in infancy and were raised as girls. Pelvic ultrasound showed a uterus in one of them. The other two male patients had micropenis, cryptorchidism and perineal hypospadias. This allelic variant was found in 1 out of 250 Brazilian controls frequency 0,4%. The transactivation activities of the variant protein were 2.0 folds higher than the WT with p-Hes3. No founder effect was demonstrated in these families. Discussion: The allelic variant is located in a highly conserved region of MAMDL1 which is essential for male genitalia development. HES is a family of transcriptional repressors of Notch signaling. Hes gene expression pattern is tissue and cell specific and control the timing of biological events. In gonads, their expression pattern remained to be elucidated. In somitogenesis, Hirata showed that both loss of expression or persistent expression of Hes genes result in the same defects. Therefore, overexpression of Hes genes should impair the normal male differentiation by continuous suppression of downstream genes involved in male sex development. Conclusion: This is the first report of an allelic variant of MAMLD1 determining a gain of function in its protein in patients with 46,XY DSD. The role of this variant protein of MAMDL1 in the etiology of 46, XY DDS should be better determined by in vivo studies