Probable tacrolimus toxicity from tibolone co-administration in a woman: a case report

Introduction: Tibolone is a synthetic steroid, used with increasing frequency to treat symptoms of menopause, including patients with solid-organ transplants who are taking concurrent immune suppression. To the best of our knowledge, there are no reported drug interactions between tibolone and tacrolimus, one of the principal immune suppressants used in kidney transplantation. Case presentation: We report the case of a 49-year-old Caucasian woman who had received a kidney transplant and who developed acute kidney injury secondary to tacrolimus toxicity 10 days after starting tibolone therapy. No alternative causes were found. Tibolone is known to be a weak competitive inhibitor of CYP3A4, which is involved in tacrolimus metabolism. Conclusions: Despite a careful evaluation, no alternative reason was found for the acute kidney injury, and her kidney function returned to the previous baseline within several days of cessation of the medication, and with no other specific treatment. Using the Drug Interaction Probability Scale we conclude that she experienced a probable drug interaction. We believe that transplant clinicians should utilise frequent therapeutic drug monitoring of tacrolimus in patients starting or stopping tibolone therapy

Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction – a randomised placebo-controlled trial (KARE): study protocol

Abstract Background Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover. Methods/design This will be a prospective, randomised, double-blind, allocation-concealed, placebo-controlled, phase 2, multicentre trial. Randomisation will be stratified by presence of severe sepsis requiring vasopressors. Patients in an ICU fulfilling the American–European Consensus Conference Definition of acute lung injury will be randomised in a 1:1 ratio to receive an intravenous bolus of either keratinocyte growth factor (palifermin, 60 μg/kg) or placebo (0.9% sodium chloride solution) daily for a maximum of 6 days. The primary endpoint of this clinical study is to evaluate the efficacy of palifermin to improve the oxygenation index at day 7 or the last available oxygenation index prior to patient discontinuation from the study.A formal statistical analysis plan has been constructed. Analyses will be carried out on an intention-to-treat basis. A single analysis is planned at the end of the trial. P = 0.05 will be considered statistically significant and all tests will be two-sided. For continuously distributed outcomes, differences between groups will be tested using independent-sample t tests, analysis of variance and analysis of covariance with transformation of variables to normality or nonparametric equivalents. The trial will be reported in line with the Consolidated Standards of Reporting Trials (Consort 2010 guidelines). Trial registration http://ISRCTN9569067

Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5′UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3′ end of the 5′UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding

Selected problems of updating lands use at example of roads investments

W pracy przeanalizowano uwarunkowania aktualizacji użytków gruntowych w procesie przygotowania i realizacji inwestycji drogowych. W celu prawidłowego określenia zasięgu użytku „drogi” porównano definicje pasa drogowego i drogi. Na przykładzie wybranych inwestycji drogowych z obszaru m. st. Warszawy, zbadano czasochłonność procesu zmiany kwalifikacji użytków gruntowych w katastrze. Określono zespół czynników wpływających na możliwości zmiany dotychczasowego użytku gruntowego na potrzeby opracowania dokumentacji geodezyjnej oraz rejestracji przez organ prowadzący ewidencję gruntów i budynków. Zbadano dokumenty, stanowiące podstawę dokonania zmiany użytku w ewidencji gruntów i budynków na „drogi”, niezależnie od trybu realizacji inwestycji w zakresie dróg. Zaprezentowano dwa rozwiązania, różniące się momentem dokonania zmiany użytku w długotrwałym procesie budowy drogi. Na podstawie analizy SWOT dokonano identyfikacji i bilansu silnych i słabych stron każdego z przyjętych rozwiązań. Określono konsekwencje nieaktualności danych ewidencyjnych w zakresie gruntów i budynków. Podkreślono istotność aktualizacji użytku gruntowego dla gospodarki przestrzennej. Zaproponowano uspójnienie regulacji celem ujednolicenia procedur weryfikacji użytków gruntowych w obszarze prowadzonej inwestycji.The subject of this article is an analysis of updating lands use in process of preparation and setting out of roads investments. In order to determine the proper range of land use the terms of road and road right-of-way were compared. With an example of selected roads investments from capital city of Warsaw area, it has been investigated the time consumption of changing existing lad use in cadastre. The complex of factors having impact on possibilities of changing former land use on needs for elaboration of serveying documentation and registering by administrative power running cadastre were detarmined . Documents being basis for making change in land use and in cadastre for "roads", independently from investment fullfilment course in investment within range of roads, have been examined. There were presented two solutions , differing in moment of making change of land use long-lasting process of road construction. On the basis of SWOT analysis one identified strong and weak points of each approved solution. Consequences of out-of-date cadastre data have been determined. Land use updating importance for spatial planning was stressed. Regulation cohering was proposed in order to unify land use verification procedure in pursued investment