Pharmacokinetics of melatonin in preterm infants

Aims: Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods: Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6μgkg^-1 over 0.5-6h. Pharmacokinetic profiles were analyzed individually and by population methods. Results: Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1μgkg^-1h^-1 for 2h showed a median half-life of 15.82h and median maximum plasma concentration of 203.3pgml^-1. On population pharmacokinetics, clearance was 0.045lh^-1, volume of distribution 1.098l and elimination half-life 16.91h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions: A 2h infusion of 0.1μgkg^-1h^-1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants. © 2013 The British Pharmacological Society.

Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment

The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.

The novel pyrrolo-1,5-benzoxazepine, PBOX-21, potentiates the apoptotic efficacy of STI571 (imatinib mesylate) in human chronic myeloid leukaemia cells

The Bcr-Abl kinase inhibitor, STI571, is the first line treatment for chronic myeloid leukaemia (CML), but the recent emergence of STI571 resistance has led to the examination of combination therapies. In this report, we describe how a novel non-toxic G1-arresting compound, pyrrolo-1,5-benzoxazepine (PBOX)-21, potentiates the apoptotic ability of STI571 in Bcr-Abl-positive CML cells. Co-treatment of CML cells with PBOX-21 and STI571 induced more apoptosis than either drug alone in parental (K562S and LAMA84) and STI571-resistant cells lines (K562R). This potentiation of apoptosis was specific to Bcr-Abl-positive leukaemia cells with no effect observed on Bcr-Abl-negative HL-60 acute myeloid leukaemia cells. Apoptosis induced by PBOX-21/STI571 resulted in activation of caspase-8, cleavage of PARP and Bcl-2, upregulation of the pro-apoptotic protein Bim and a downregulation of Bcr-Abl. Repression of proteins involved in Bcr-Abl transformation, the anti-apoptotic proteins Mcl-1 and Bcl-(XL) was also observed. The combined lack of an early change in mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9 suggests that this pathway is not involved in the initiation of apoptosis by PBOX-21/STI571. Apoptosis was significantly reduced following pre-treatment with either the general caspase inhibitor Boc-FMK or the chymotrypsin-like serine protease inhibitor TPCK, but was completely abrogated following pre-treatment with a combination of these inhibitors. This demonstrates the important role for each of these protease families in this apoptotic pathway. In conclusion, our data highlights the potential of PBOX-21 in combination with STI571 as an effective therapy against CML.

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia:a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring

Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (P<0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (P<0.01) compared to patients with other or no chromosomal aberrations. Older children (> or =10 years) expressed higher WT1 levels than children under 10 years of age (P<0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) > or =50 x 10(9)/l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P=0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P=0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.

Does Basel Compliance Matter for Bank Performance?

The global financial crisis underscored the importance of regulation and supervision to a well-functioning banking system that efficiently channels financial resources into investment. In this paper, we contribute to the ongoing policy debate by assessing whether compliance with international regulatory standards and protocols enhances bank operating efficiency. We focus specifically on the adoption of international capital standards and the Basel Core Principles for Effective Bank Supervision (BCP). The relationship between bank efficiency and regulatory compliance is investigated using the Simar and Wilson (2007. J. Econ. 136 (1), 31) double bootstrapping approach on an international sample of publicly listed banks. Our results indicate that overall BCP compliance, or indeed compliance with any of its individual chapters,has no association with bank efficiency.

Avaliação de uma nova abordagem comercial na banca de retalho com recurso à metodologia DEA

O presente trabalho, além de dar a conhecer o grupo BCP e de caracterizar as minhas atuais funções no seio de uma agência do Millennium bcp, tem como objetivo analisar se a nova abordagem comercial aos clientes, que este banco se encontra a implementar, permite melhorar a eficiência das suas agências. A eficiência é analisada através do estudo da produtividade técnica, com recurso à técnica de programação linear: Data Envelopment Analysis – DEA, na abordagem do modelo BCC, com orientação output. Considerou-se como variáveis input: o número de empregados, os gastos com pessoal e o total dos gastos operacionais, e como variáveis output: o número de contactos telefónicos, o número de transações e o número de vendas. Foram analisadas 109 agências, 9 que já implementaram a nova abordagem comercial e 100 que ainda utilizam a abordagem comercial tradicional. Verificou-se que até ao ano 2011, as agências que implementaram a nova abordagem comercial detinham um nível de eficiência significativamente inferior ao das agências que utilizam a abordagem comercial tradicional. Em 2012, ano em que foi implementada a nova abordagem comercial nas 9 agências, verificou-se que estas conseguiram melhorar significativamente o seu nível de eficiência, enquanto as agências que continuaram a usar a abordagem comercial tradicional diminuíram-no ligeiramente.

Case-series Evaluating a Transdiagnostic Cognitive-behavioral Treatment For Co-occurring Anxiety Disorders.

Background. Patients with anxiety disorder diagnoses commonly have more than one anxiety diagnosis. While cognitive-behavioral interventions have proven efficacy in treating single anxiety disorder diagnoses, there has been little investigation of their efficacy in treating cooccurring anxiety disorders. Aims. To evaluate the efficacy of a transdiagnostic cognitive-behavioral intervention for treating co-occurring anxiety disorders. Methods. An A-B single case study design (N = 6) was used to evaluate the efficacy of a 12 to 13 session modular transdiagnostic cognitive-behavioral intervention for treating co-occurring anxiety disorders across patients with at least two of the following diagnoses: GAD, Social Phobia, Panic Disorder and/or OCD. Results. Five of the six participants completed treatment. At post-treatment assessment the five treatment completers achieved diagnostic and symptomatic change with three participants being diagnosis free. All participants who completed treatment no longer met criteria for any DSM-IV-TR Axis-I diagnosis at the three-month follow-up assessment, and demonstrated reliable and clinically-significant improvements in symptoms. Across the participants, statistically significant improvements from pre- to post-intervention were found on measures of anxiety, depression and general well-being, and all improvements were maintained at three-month follow-up. Conclusions. Results suggest that transdiagnostic cognitive behavioral interventions can be of benefit to patients with co-occurring anxiety disorders.

The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions.

Abstract AIMS: The aim of the present study was to investigate whether selective antagonism of the cysteine-X-cysteine chemokine receptor-2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens. METHODS: In a double-blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte-colony stimulating factor (G-CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli. RESULTS: AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of -1.67 (0.67) ×10(9) l(-1) vs. 0.19 (0.78) ×10(9) l(-1) for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10-min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G-CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo- and AZD5069-treated subjects. Superoxide anion production in E. coli-stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated. CONCLUSIONS: CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.

Risco reputacional na banca portuguesa

A reputação é intangível, pode mudar durante o tempo (para melhor ou pior), é difícil de definir, é difícil de medir e difícil de ser traduzida em valor. Mas a maioria dos stakeholders e CEOs concorda que a reputação é dos riscos emergentes mais preocupantes com que as organizações se deparam - pode explicar o porquê dos clientes escolherem um produto ou serviço e pode determinar o sucesso ou o insucesso da organização. O objetivo desta dissertação é o estudo da reação do mercado de ações ao anúncio de eventos de risco operacionais na banca portuguesa. Assim, compreender quais os eventos operacionais que têm um impacto positivo ou negativo sobre a imagem/reputação de um Banco. A metodologia usada nesta dissertação é baseada numa amostra de 114 eventos operacionais ocorridos em Bancos portugueses, nomeadamente, o Banco Espírito Santo (BES), o Banco Comercial Português (BCP), o Banco Português de Investimento (BPI) e o Banif. Os eventos operacionais ocorreram no período de 29 de Outubro de 2007 a 07 de Abril de 2014. Com base nos resultados obtidos, a variação das cotações de mercado, é possível perceber se os efeitos foram positivos ou negativos para a imagem das instituições financeiras e, assim construir matrizes que ilustram o impacto no valor das instituições quando ocorre um evento operacional.

Entrevista com Suzanne Cotter

Fundação para a Ciência e a Tecnologia (FCT), Fundação Millennium bcp

La série, la crise, le monde

Fundação para a Ciência e a Tecnologia (FCT), Fundação Millennium bcp

Pourquoi nous avons besoin de la critique?

Fundação para a Ciência e a Tecnologia (FCT), Fundação Millennium bcp

Breaking Down and Breaking Out: Beckett’s ‘Absolute Liminality’ in the Third Age of Capitalist Traumas

Fundação para a Ciência e a Tecnologia (FCT), Fundação Millennium bcp

History of Art and Art Criticism: A System in Crisis

This article aims to reconstruct the critical debate regarding the examination of the crisis in the disciplines of art history and criticism with a particular focus on the proposal formulated by U.S. theorists who contributed to October journal. The discrediting of many modernist critical methods, particularly that of Clement Greenberg – the formalist diktat – marked the birth of the journal and gave rise to proposals set forth by critics committed to a new approach. Their divergent positions, nonetheless, have contributed to undermining the traditional concepts of the autonomy of art and criticism. The proposals discussed over the course of publication were the result of a reappraisal of the disciplinary instruments of art history and criticism pursuant to the crucial cultural changes which took place in the 1980s.

Breaking the Pattern and Creating New Paths – Feminist Mizrahi Women Artists in Israel

This article addresses the work of Mizrahi women artists, i.e., Israeli-Jewish women of Asian or African ethnic origin, using the artist Vered Nissim as a case study. Nissim seeks to affirm the politics of identity and recognition, as well as feminism in order to create a paradigm shift with regards to the local regime of cultural representations in the Israeli art scene. Endeavouring to find ways of undermining the rigid imbalances between different social groups, she calls for a comprehensive reform of the status quo through artistic activism. Nissim employs a style, content, and medium that disrupts the accepted social order, using humour and irony as unique weapons with which she takes liberties with conventional moral, social, and economic values. Placing issues of race, class and gender at the centre of her work, she seeks to undermine and problematize essentialist attitudes, highlighting the political intersections of different identity categories as the critical analysis of intersectionality unfolds.