Reprint of “The clinical impact of deficiency in DNA non-homologousend-joining”

DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway inmammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models,since radiation potently induces DSBs. The process of V(D)J recombination functions during the devel-opment of the immune response, and involves the introduction and rejoining of programmed DSBs togenerate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJdeficiency confers (severe) combined immunodeficiency – (S)CID – due to a failure to carry out V(D)Jrecombination efficiently. NHEJ also functions in class switch recombination, another step enhancing Tand B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patientsrevealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syn-dromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have beenidentified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCIDpatients frequently display additional characteristics including microcephaly, dysmorphic facial featuresand growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our currentunderstanding of the underlying biology

Implementação do preparo de medicação à beira-leito em terapia intensiva: auditorias clínicas pós-ciclo de melhoria

Objetivo: Avaliar a implementação do processo de preparo de medicamentos à beira-leito em um Centro de Terapia Intensiva, após um ciclo de melhoria.Método: Estudo quase-experimental com amostras não pareadas, pré e pós-implementação, realizado em um Centro de Terapia Intensiva de um hospital público no sul do Brasil, de setembro de 2022 a abril de 2023, seguindo as diretrizes do Standards for Quality Improvement Reporting Excellence 2.0. Avaliou-se a adesão à preparação do medicamento à beira-leito, interrupções durante o preparo, acondicionamento adequado, identificação e validade de medicamentos multidose, e registro da temperatura da geladeira de armazenamento. Para análise dos dados utilizaram-se os testes de Shapiro-Wilk e Teste U de Mann-Whitney, e para determinar a conformidade das práticas observadas, utilizou-se o Índice de Positividade de Carter.Resultados: Realizaram-se 45 auditorias pré intervenção e 122 três meses após a implementação do ciclo de melhoria. Todas as variáveis apresentaram melhorias significativas. A conformidade geral aumentou de 46% para 80% nos períodos pré e pós-implementação, respectivamente, indicando a transição do estrato de assistência “indesejada” para “segura”.Conclusão: O estudo revelou uma relação positiva entre a implementação de um ciclo de melhoria da qualidade, centrado no preparo de medicamentos, e melhorias na segurança do paciente.Descritores: Segurança do paciente. Erros de medicação. Unidades de terapia intensiva

Mental health status of infrequent adolescent substance users

Article copies available from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address: ; The Haworth Press, Inc. .Frequent substance use has a strong association with poor mental health. The relationship between infrequent substance use and mental health is less clear. The present study investigated this relationship in a large group (n = 2118) of 12-19-year-olds from Alberta, Canada. Results indicated that adolescents who used tobacco or alcohol once a month or less tended to have equivalent mental health status to abstainers. Using cannabis 3-5 times/year or less had no adverse mental health associations. However, poorer mental health was associated with single time use of hallucinogens or other drugs. In general, substance usage tended to have more negative mental health associations for younger compared to older adolescents.Ye

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.This research was supported by USPHS grant NS073976 (TKH) and P30 ES 06676 that support the NIEHS Center Cell Biology Core and Molecular Genomics Core of UTMB’s NIEHS Center for DNA sequencing. TKP is supported by CA129537 and CA154320. This work was also supported by Fundação para a Ciência e Tecnologia through the project [PTDC/SAU-GMG/101572/2008] and through fellowships [SFRH/BPD/91562/2012 to ASF, SFRH/BD/51059/2010 to ANC]. IB is supported by NIEHS R01 ES018948 and NIAID/AI06288

[angioedema Related To The Use Of Streptokinase].

Angioedema is a rare reaction to streptokinase, acute and potentially fatal, which should be quickly diagnosed and treated to guarantee the best prognosis for the patient. We describe here the case of a 65-year-old man, who displayed an anaphylactic reaction after the beginning of thrombolysis with streptokinase, which was quickly treated, and remained hospitalized for one week in the Intensive Care Unit.85131-

Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage

Human polynucleotide kinase/phosphatase (PNKP) is a dual specificity 5′-DNA kinase/3′-DNA phosphatase, with roles in base excision repair, DNA single-strand break repair and non-homologous end joining (NHEJ); yet precisely how PNKP functions in the repair of DNA double strand breaks (DSBs) remains unclear. We demonstrate that PNKP is phosphorylated by the DNA-dependent protein kinase (DNA-PK) and ataxia-telangiectasia mutated (ATM) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Ionizing radiation (IR)-induced phosphorylation of cellular PNKP on S114 was ATM dependent, whereas phosphorylation of PNKP on S126 required both ATM and DNA-PK. Inactivation of DNA-PK and/or ATM led to reduced PNKP at DNA damage sites in vivo. Cells expressing PNKP with alanine or aspartic acid at serines 114 and 126 were modestly radiosensitive and IR enhanced the association of PNKP with XRCC4 and DNA ligase IV; however, this interaction was not affected by mutation of PNKP phosphorylation sites. Purified PNKP protein with mutation of serines 114 and 126 had decreased DNA kinase and DNA phosphatase activities and reduced affinity for DNA in vitro. Together, our results reveal that IR-induced phosphorylation of PNKP by ATM and DNA-PK regulates PNKP function at DSBs

Reconstructing national boundaries : debates on national identities and immigration in France and in Denmark

Defence date: 11 June 1998Supervisor: Prof. Bernhard Giesen, Universität Giessen ; Co-Supervisor: Prof. Laurence Fontaine, European University InstitutePDF of thesis uploaded from the Library digitised archive of EUI PhD theses completed between 2013 and 2017Why are national identities imagined in one way rather than in another? The book analyses national imaginations as an on-going reconstruction process in a political and social context in which several imaginations of the nation struggle to impose their conception. Focusing on a fundamental element of any collective identity, namely the «Other», the book looks at the reconstruction of national identities by actors in political debates on immigration in the late 1980s and 1990s, particularly associations and political clubs which were in favour of and against the presence of immigrant minorities in their respective countries. Thus, the book investigates different ways of imagining the same nation in two old European nation-states, namely France and Denmark, which differ with regard to their nation-building processes, their Second World War history, their memory of colonialism and their experience of immigration. It is thus possible to illustrate that existing ideas of the nation and memories of historical events shape the way in which the nation could be re-imagined in the 1980s and 1990s