De Novo Thrombotic Microangiopathy After Kidney Transplantation: Clinical Features, Treatment, and Long-Term Patient and Graft Survival

Introduction. Posttransplant thrombotic microangiopathy (TMA)/hemolytic uremic syndrome (HUS) can occur as a recurrent or de novo disease. Methods. A retrospective single-center observational study was applied in order to examine the incidence and outcomes of de novo TMA/HUS among transplantations performed between 2000 and 2010. Recurrent HUS or antibody-mediated rejections were excluded. Results. Seventeen (1.1%) among 1549 kidney transplant recipients fulfilled criteria for de novo TMA. The mean follow-up was 572 days (range, 69-1769). Maintenance immunosuppression was prednisone, tacrolimus (TAC), and mycophenolic acid in 14 (82%) patients. Mean age at onset was 40 +/- 15 years, and serum creatinine was 6.1 +/- 4.1 mg/dL. TMA occurred at a median of 25 days (range, 1-1755) after transplantation. Nine (53%) patients developed TMA within 1 month of transplantation and only 12% after 1 year. Clinical features were anemia (hemoglobin < 10 g/dL) in 9 (53%) patients, thrombocytopenia in 7 (41%), and increased lactate dehydrogenase in 12 (70%). Decreased haptoglobin was observed in 64% and schistocytes in 35%. Calcineurin inhibitor (CM) withdrawal or reduction was the first step in the management of 10/15 (66%) patients, and 6 (35%) received fresh frozen plasma (FFP) and/or plasmapheresis. TAC was successfully reintroduced in six patients after a median of 17 days. Eight (47%) patients needed dialytic support after TMA diagnosis and 75% remained on dialysis. At 4 years of follow-up, death-censored graft survival was worse for TMA group (43.0% versus 85.6%, log-rank = 0.001; hazard ratio = 3.74) and there was no difference in patient survival (53.1% versus 82.2%, log-rank = 0.24). Conclusion. De novo TMA after kidney transplantation is a rare but severe condition with poor graft outcomes. This syndrome may not be fully manifested, and clinical suspicion is essential for early diagnosis and treatment, based mainly in CM withdrawal and FFP infusions and/or plasmapheresis.

The antioxidative effect of de novo generated vitamin B-6 in Plasmodium falciparum validated by protein interference

The malaria parasite Plasmodium falciparum is able to synthesize de novo PLP (pyridoxal 5'-phosphate), the active form of vitamin B-6. In the present study, we have shown that the de novo synthesized PLP is used by the parasite to detoxify O-1(2) (singlet molecular oxygen), a highly destructive reactive oxygen species arising from haemoglobin digestion. The formation of O-1(2) and the response of the parasite were monitored by live-cell fluorescence microscopy, by transcription analysis and by determination of PLP levels in the parasite. Pull-down experiments of transgenic parasites overexpressing the vitamin B-6-biosynthetic enzymes PfPdx1 and PfPdx2 clearly demonstrated an interaction of the two proteins in vivo which results in an elevated PLP level from 12.5 mu M in wild-type parasites to 36.6 mu M in the PfPdx1/PfPdx2-overexpressing cells and thus to a higher tolerance towards O-1(2). In contrast, by applying the dominant-negative effect on the cellular level using inactive mutants of PfPdx1 and PfPdx2, P. falciparum becomes susceptible to O-1(2). Our results demonstrate clearly the crucial role of vitamin B-6 biosynthesis in the detoxification of O-1(2) in P falciparum. Besides the known role of PLP as a cofactor of many essential enzymes, this second important task of the vitamin B-6 de novo synthesis as antioxidant emphasizes the high potential of this pathway as a target of new anti-malarial drugs.

The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia

Abstract Background The association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences. Case presentation We report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917–855 kb and 601–585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932–789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601–585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517–595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex-chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development. Conclusions These two novel translocations illustrate the clinical variability in carriers of balanced translocations with breakpoints near SOX9. The translocation t(17;20) breakpoint provides further evidence for an additional testis-specific SOX9 enhancer 517 to 595 kb upstream of the SOX9 gene.

ATENDIMENTO ONLINE POR CHAT: ADEQUANDO OS SERVIÇOS DE BIBLIOTECA A UM NOVO PÚBLICO

O trabalho relata a experiência da Biblioteca Virginie Buff D’Ápice da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo (FMVZ/USP) na implantação do sistema de atendimento online por chat e analisa estatística e qualitativamente os 527 atendimentos realizados entre Agosto de 2009 e Junho de 2010. Além disso, apresenta o impacto direto desse sistema na readequação do Serviço de Atendimento ao Usuário

Atuação missionária jesuítica na América portuguesa: a peculiar via renascentista, sacramental e tridentina à salvação no(s) Novo(s) Mundo(s)

A Companhia de Jesus foi o emblema mais representativo da transformação e realização da nova prática da catequese na sua atuação missionária,durante a primeira Idade Moderna. A transformação vinha ocorrendo a partir da contraposição entre Reforma e Contrarreforma, no estabelecimento de analogias e diferenças da missão entre Europa, América e Ásia, e, finalmente, na esteira dos ecos das decisões conciliares de Trento em Lima. A partir dos tópicos que dividem o texto, o presente trabalho percorre - em uma síntese inevitavelmente esquemática, mas aberta à perspectiva de recentes investigações sobre o tema - essas problemáticas. Pensamos assim que elas possam ganhar clareza e coerência expositiva, mas, sobretudo, uma capacidade de inteligibilidade dos temas propostos, tendo em vista um resultado que não seja apenas uma aquisição (sempre parcial), mas, sobretudo, um novo ponto de partida para ulteriores investigações sobre as diretrizes apontadas.

Irrigação localizada subsuperfical: gotejador convencional e novo protótipo

A irrigação por gotejamento subsuperficial, que utiliza um sistema protetor do emissor para evitar entupimento do mesmo por raiz e partículas sólida do solo, pode ser viável em relação a um sistema convencional. Propôs-se, com este trabalho, avaliar o desempenho de um sistema para proteção de emissor e comparar os resultados com um sistema que utiliza emissor convencional para irrigação por gotejamento subsuperficial. O sistema com protetor foi construído com materiais de baixo custo: mangueira de polietileno, microtubo, conector e um gotejador para controlar a vazão e no sistema convencional utilizou-se um emissor comercial. Após 12 meses de avaliação o sistema com protetor demonstrou bom desempenho com vazão relativa média de 0,97 e 0,98 em vasos com e sem cultura, respectivamente, não apresentando problemas de entupimento e tendo menor custo. No sistema convencional constatou-se vazão relativa de 0,51 e 0,98 em vasos com e sem cultura, respectivamente, grau de entupimento por raiz de 49,22% e emissores com solo em seu interior. Desta forma, o uso do emissor com sistema de proteção indicou viabilidade para irrigação subsuperficial por gotejamento, nas condições desta pesquisa.

Novo modelo de endoprótese traqueal autoexpansível de fabricação nacional: estudo experimental em coelhos

Objetivamos testar um novo modelo de endoprótese traqueal autoexpansível para que esse possa ser futuramente disponibilizado para o uso clínico. As endopróteses de nitinol revestidas de poliuretano foram alocadas no terço médio da traqueia de 25 coelhos da raça Nova Zelândia sob laringoscopia direta. Após um período de observação médio de 26 dias, avaliou-se a migração da prótese, grau de dilatação, incorporação, aderência, formação de tecido de granulação, presença de infiltrado inflamatório, envolvimento parietal e revestimento epitelial. Os resultados demonstraram completa expansibilidade radial, pouca aderência à mucosa traqueal e baixa incorporação tecidual, assim como alta taxas de formação de granulomas e de migração. Esse novo modelo demonstrou ser biocompatível e teve comportamento semelhante ao de outras próteses disponíveis no mercado.

Um novo escore para dependência a nicotina e uma nova escala de conforto do paciente durante o tratamento do tabagismo

O tabagismo é considerado a maior causa evitável de morbidade e mortalidade. O manuseio farmacológico da síndrome de abstinência de nicotina possibilita melhores taxas de cessação. Desenvolvemos um sistema de coleta de dados em nosso programa de assistência ao fumante, que inclui dois instrumentos novos: um escore para dependência de nicotina em fumantes de < 10 cigarros/dia e uma escala de conforto do paciente durante o tratamento do tabagismo. Descrevemos aqui os dois instrumentos, que estão em processo de validação.

O Estado Novo e as críticas a Machado de Assis na primeira metade dos anos 1940

Este artigo tem como objetivo analisar o tratamento conferido pelo Estado Novo brasileiro (1937-1945) a Machado de Assis, depois das celebrações oficiais do centenário do autor de Dom Casmurro em 1939. Se, no ano da efeméride, o governo se empenhou em alçar o romancista à condição de maior escritor brasileiro, no início dos anos 1940, no âmbito do Departamento de Imprensa e Propaganda (DIP), o tom passa a ser outro: num contexto de prevalência de certo caráter social e documental da obra de arte, o próprio Getúlio Vargas, o ideólogo Cassiano Ricardo e os principais periódicos estadonovistas fazem menção ao suposto absenteísmo e à falta de "cor local" do fundador da Academia Brasileira de Letras.

O novo Direito Internacional Privado e o conflito de fontes na cooperação jurídica internacional

O Direito Internacional Privado contemporâneo possui na cooperação jurídica internacional uma de suas áreas de maior dinamismo. A existência de fontes internacionais e internas da cooperação jurídica internacional exige uma análise da solução dos conflitos de fontes.

Novo espaço para a cartografia histórica

A Biblioteca Digital de Cartografia Histórica da Universidade de São Paulo disponibiliza uma série de versões em alta resolução de mapas impressos entre os séculos XV e XIX, acompanhados de referências biográficas, cartobibliográficas, editoriais e históricas. Concebida para rastrear dados de outros sites similares, ela se constitui também em uma útil ferramenta de pesquisa

De Novo Design of secondary structures: Synthesis and conformational studies

Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low molecular weight catalysts and receptors; however, biological systems themselves rely almost exclusively on polymers, proteins and RNA, to perform complex chemical functions. Proteins and RNA are unique in their ability to adopt compact, well-ordered conformations, and specific folding provides precise spatial orientation of the functional groups that comprise the “active site”. These features suggest that identification of new polymer backbones with discrete and predictable folding propensities (“foldamers”) will provide a basis for design of molecular machines with unique capabilities. The foldamer approach complements current efforts to design unnatural properties into polypeptides and polynucleotides. The aim of this thesis is the synthesis and conformational studies of new classes of foldamers, using a peptidomimetic approach. Moreover their attitude to be utilized as ionophores, catalysts, and nanobiomaterials were analyzed in solution and in the solid state. This thesis is divided in thematically chapters that are reported below. It begins with a very general introduction (page 4) which is useful, but not strictly necessary, to the expert reader. It is worth mentioning that paragraph I.3 (page 22) is the starting point of this work and paragraph I.5 (page 32) isrequired to better understand the results of chapters 4 and 5. In chapter 1 (page 39) is reported the synthesis and conformational analysis of a novel class of foldamers containing (S)-β3-homophenylglycine [(S)-β3-hPhg] and D- 4-carboxy-oxazolidin-2-one (D-Oxd) residues in alternate order is reported. The experimental conformational analysis performed in solution by IR, 1HNMR, and CD spectroscopy unambiguously proved that these oligomers fold into ordered structures with increasing sequence length. Theoretical calculations employing ab initio MO theory suggest a helix with 11-membered hydrogenbonded rings as the preferred secondary structure type. The novel structures enrich the field of peptidic foldamers and might be useful in the mimicry of native peptides. In chapter 2 cyclo-(L-Ala-D-Oxd)3 and cyclo-(L-Ala-DOxd) 4 were prepared in the liquid phase with good overall yields and were utilized for bivalent ions chelation (Ca2+, Mg2+, Cu2+, Zn2+ and Hg2+); their chelation skill was analyzed with ESI-MS, CD and 1HNMR techniques and the best results were obtained with cyclo-(L-Ala-D-Oxd)3 and Mg2+ or Ca2+. Chapter 3 describes an application of oligopeptides as catalysts for aldol reactions. Paragraph 3.1 concerns the use of prolinamides as catalysts of the cross aldol addition of hydroxyacetone to aromatic aldeydes, whereas paragraphs 3.2 and 3.3 are about the catalyzed aldol addition of acetone to isatins. By means of DFT and AIM calculations, the steric and stereoelectronic effects that control the enantioselectivity in the cross-aldol addition of acetone to isatin catalysed by L-proline have been studied, also in the presence of small quantities of water. In chapter 4 is reported the synthesis and the analysis of a new fiber-like material, obtained from the selfaggregation of the dipeptide Boc-L-Phe-D-Oxd-OBn, which spontaneously forms uniform fibers consisting of parallel infinite linear chains arising from singleintermolecular N-H···O=C hydrogen bonds. This is the absolute borderline case of a parallel β-sheet structure. Longer oligomers of the same series with general formula Boc-(L-Phe-D-Oxd)n-OBn (where n = 2-5), are described in chapter 5. Their properties in solution and in the solid state were analyzed, in correlation with their attitude to form intramolecular hydrogen bond. In chapter 6 is reported the synthesis of imidazolidin-2- one-4-carboxylate and (tetrahydro)-pyrimidin-2-one-5- carboxylate, via an efficient modification of the Hofmann rearrangement. The reaction affords the desired compounds from protected asparagine or glutamine in good to high yield, using PhI(OAc)2 as source of iodine(III).