Individualizing Pharmacotherapy in Patients with Renal Impairment: The Validity of the Modification of Diet in Renal Disease Formula in Specific Patient Populations with a Glomerular Filtration Rate below 60 Ml/Min. A Systematic Review

Background

The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus.

Methods and Findings

We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m²), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P₃₀% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used.

Conclusion

In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity.     

Bioconversions of aliphatic compounds by Pseudomonas oleovorans in multiphase bioreactors: background and economic potential.

Pseudomonas oleovorans can grow on linear alkanes and alkenes in the hexane to dodecane range by virtue of enzymes encoded by the alk genes. By introducing selected alk genes into Pseudomonas strains and by supplying alkanes in the growth medium as a bulk liquid phase, specific alkane oxidation products can be accumulated in the alkane phase. We review the genetics and enzymology of the alk system and the potential of bioconversions in two-liquid-phase bioreactors, and suggest that such systems might eventually allow the biotechnological production of intermediate value compounds.     

Unbiased random mutagenesis contributes to a better understanding of the virulent behaviour of Paenibacillus larvae

Aims

American foulbrood, caused by the Gram‐positive bacteria Paenibacillus larvae, is one of the most severe bacterial diseases of the European honey bee. The bacterium has been known for long, but only the last decade the mechanisms used by the pathogen to cause disease in its host are starting to unravel. In this study, the knowledge of this virulent behaviour is expanded and several possible virulence factors are suggested.

Methods and Results

Identification of possible virulence factors has been done by random mutagenesis to ensure an unbiased approach. A library of mutants was tested for a significant difference in virulence using in vitro exposure assays. Affected loci were characterized and their potential to contribute in virulence of the pathogen was assessed.

Conclusions

The identified mutated loci dacB, dnaK, metN, ywqD, lysC, serC and gbpA are known to encode for virulence factors in other bacteria and are suggested to play a similar role in P. larvae.

Significance and Impact of the Study

The study identified new possible virulence factors for P. larvae genotype ERIC I in an unbiased way. This contributes to the knowledge and understanding of the possible mechanisms used by this pathogen to colonize and kill its host.     

The Xerobranching Response Represses Lateral Root Formation When Roots Are Not in Contact with Water

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Variability in storage potential of banana shoot cultures under medium term storage conditions

Shoot cultures of 401 banana clones were conserved under slow growth conditions (16±1°C, 25mol m^–2 s^–1). Storage duration-defined as 60% survival time of 20 shoot cultures of a clone-averaged 334 days. However, large differences occurred among the different genomic (sub)groups and even within the same (sub)group. East-African highland bananas and non-plantain AAB bananas can be stored for significantly longer periods. Shoot tip cultures of another 41 banana clones conserved at higher ambient temperature (22±3°C) needed to be subcultured sooner (every 220 days on average).Abbreviations BA 6-benzyladenine - CIRAD Centre de Coopération Internationale en Recherche Agronomique pour le Développement - IAA indole-3-acetic acid - IBPGR International Board for Plant Genetic Resources - INIBAP International Network for the Improvement of Banana and Plantain - PPF photosynthetic photon flux - QDPI Queensland Department of Primary Industries     

Life cycle inventory data

This article describes the work carried out by the Promoting Sound Practices (PSP) working group of SPOLD (Society for the Promotion of Lifecycle Development) on the development of a common format for reporting life cycle inventory data in a comparable and transparent way, and hence towards the eventual goal of a decentralised network of life cycle inventory databases. Establishing such a database network depends on the achievement of consensus amongst potential users, data owners and data generators. Accordingly, building consensus has been, and will continue to be given, a high priority in this work. As well as a summary of the consensus building activities, this article provides an outline of the developing format and an indication of the next steps planned, some of which are already underway.     

Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio?, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory.

We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.     

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study

ObjectiveTo study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring.DesignCross-sectional comparison of serum biomarkers.SettingUniversity Medical Center Utrecht.PatientsHyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6–8 years), and a paedriatic reference population (n = 30).ResultsThe cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R² = 0.219) and adiponectin (R² = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing.ConclusionIn this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.