Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥ 5.5 mmol/L: pooled analysis from two phase 3 trials.

BackgroundReliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤ 48 h in patients with baseline serum potassium level ≥ 5.5 mmol/L.MethodsData were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤ 5.5 and ≤ 5.0 mmol/L, and proportion achieving potassium level ≤ 5.5 and ≤ 5.0 mmol/L at 4, 24, and 48 h. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated.ResultsAt baseline, 125 of 170 patients (73.5%) had potassium level 5.5-< 6.0, 39 (22.9%) had potassium level 6.0-6.5, and 6 (3.5%) had potassium level > 6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1 h post-initial dose. By 4 and 48 h, 37.5% and 85.0% of patients achieved potassium level ≤ 5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤ 5.5 and ≤ 5.0 mmol/L were 2.0 (1.1-2.0) and 21.6 (4.1-22.4) h, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious.ConclusionsSZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile.Trial registrationClinicalTrials.gov identifiers: ZS-003: NCT01737697 and HARMONIZE: NCT02088073

Development of a fast screening method for the direct determination of chlorinated persistent organic pollutants in fish oil by high-resolution continuum source graphite furnace molecular absorption spectrometry

The authors are grateful to the Conselho Nacional de Desenvolvimento Científico and Tecnológico (CNPq); the present research was mostly financed through Project no. CNPq 406877/2013-0. The authors are also grateful to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support and scholarships, and to Analytik Jena for financial support and donation of the contrAA 600 high-resolution continuum source atomic absorption spectrometer.Peer reviewedPostprin

New concepts and objectives for protein-amino acid nutrition in rabbits: a review

In the European context, the new legislation to avoid mineral contamination and the ban on antibiotics as growth promoters has led to the definition of new objectives in respect of nitrogen supply. The present study summarizes the state of nitrogen nutrition in rabbits and reviews the role of protein and amino acids in rabbit health and the new nitrogen value of protein sources based on true ileal digestibility (TID) for future recommendations. The main sources of nitrogen for microbial growth are ammonia, urea and protein (endogenous and dietary). The surplus of nitrogen flow to the caecum increases mortality rates during fattening by favouring the growth of potential pathogenic bacteria. Accordingly, feeding strategies to reduce ileal nitrogen flow have been reviewed. A large reduction of dietary protein level might have negative consequences on growth performances and mortality. In order to formulate balanced low protein diets, data on ileal and faecal amino acid digestibility of 14 raw materials is summarized. The use of this different unit for amino acid digestibility is also discussed

Differential gene expression in tilapia Oreochromis niloticus (L., 1758) under feeding stress

Feeding stress or suboptimal feeding in fish can have a direct impact on their energy metabolism and feed use efficiency, and thus on productivity. That impact can be quantified objectively by comparing the expression of genes between fish fed ad libitum and fish fed suboptimally. Moreover, some of the genes expressed in animals fed suboptimally can also be used as candidate genes to identify feeding stress in general. To identify some of those genes, a group of 60 tilapia Oreochromis niloticus (L., 1758) was divided into two batches (fed ad libitum or suboptimally for 22 days) with two replicates. For this purpose, we carried out differential display analysis in brain tissue samples using 36 combinations of 3 polyT anchoring primers and 12 random primers. An average of 25 bands was produced per primer pair, with 31 bands expressed differentially which were excised from the gels, sequenced, and annotated with information available on public databases. Some sequences matched genes with different binding activities, regulation of transcription, and those playing a role in synapses. One of the most interesting findings was the ALOX5 gene, which plays a role in the production of lukotrienes, important mediators in inflammatory processes. The identification of genes corresponding to those bands will provide more information about mechanisms that play a role in stressful situations produced by suboptimal feeding, as well as other causes.El estrés alimentario o subalimentación de los peces afecta directamente al metabolismo energético, a la eficacia de utilización del alimento y, por tanto, a su productividad. Este efecto se puede cuantificar de forma objetiva mediante comparaciones de expresión génica con respecto a aquellos peces que han sido alimentados a saciedad. Además, algunos de los genes expresados por los peces subalimentados pueden usarse como genes candidatos para identificar estrés alimentario en general. Para identificar estos genes se dividió un grupo de 60 tilapias Oreochromis niloticus (L., 1758) en dos tratamientos (alimentado ad líbitum o con alimentación subóptima, durante 22 días) con dos réplicas. Se utilizó la técnica de differential display en muestras de cerebro con 36 combinaciones resultado de tres cebadores polyT de anclaje y 12 cebadores aleatorios. Se expresaron una media de 25 bandas por pareja de cebadores y un total de 31 bandas expresadas diferencialmente, se extrajeron, secuenciaron y anotaron con la ayuda de la información disponible en bases de datos públicas. Algunas secuencias coinciden con genes cuya función es de unión a diferentes proteínas y de regulación de la transcripción, y juegan un papel importante en la sinapsis. Es destacable el gen ALOX5, que interviene en la producción de leucotrienos, importantes mediadores de procesos inflamatorios. La identificación de los genes que corresponden a estas bandas aportará conocimiento sobre los mecanismos que intervienen en situaciones de estrés, tanto producidas por una alimentación subóptima como por otras causas.Instituto Español de Oceanografí

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

MBD4 binds to methylated DNA and acts as a thymine DNA glycosylase in base excision repair. Deficiency of MBD4 in mice enhances mutation at CpG sites and alters apoptosis in response to DNA damage, but does not increase tumorigenesis in mismatch repair-deficient mice. However, in humans, frameshift mutation of MBD4, rather than deletion, is what occurs in up to 43% of microsatellite unstable colon cancers. There is no murine equivalent of this mutation. We now show that recombinant truncated MBD4 (MBD4tru) inhibits glycosylase activities of normal MBD4 or Uracil DNA glycosylase in cell-free assays as a dominant negative effect. Furthermore, overexpression of MBD4tru in Big Blue (lacI)-transfected, MSI human colorectal carcinoma cells doubled mutation frequency, indicating that the modest dominant negative effect on DNA repair can occur in living cells in short-term experiments. Intriguingly, the whole mutation spectrum was increased, not only at CpG sites, suggesting that truncated MBD4 has a more widespread effect on genomic stability. This demonstration of a dominant negative effect may be of significance in tumour progression and acquisition of drug resistance

Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication

Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases, as well as on the potential of these kinases as targets for cancer treatment

Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression

Background and Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS

The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome

Germline mutations in the mismatch repair (MMR) genes are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Here, we characterise a variant of hMLH1 that confers a loss-of-function MMR phenotype. The mutation changes the highly conserved Gly67 residue to a glutamate (G67E) and is reminiscent of the hMLH1-p.Gly67Arg mutation, which is present in several Lynch syndrome cohorts. hMLH1-Gly67Arg has previously been shown to confer loss-of-function (Shimodaira et al, 1998), and two functional assays suggest that the hMLH1-Gly67Glu protein fails to sustain normal MMR functions. In the first assay, hMLH1-Gly67Glu abolishes the protein's ability to interfere with MMR in yeast. In the second assay, mutation of the analogous residue in yMLH1 (yMLH1-Gly64Glu) causes a loss-of-function mutator phenotype similar to yMLH1-Gly64Arg. Despite these molecular similarities, an unusual spectrum of tumours is associated with hMLH1-Gly67Glu, which is not typical of those associated with Lynch syndrome and differs from those found in families carrying the hMLH1-Gly67Arg allele. This suggests that hMLH1 may have different functions in certain tissues and/or that additional factors may modify the influence of hMLH1 mutations in causing Lynch syndrome