Use of erythropoiesis-stimulating agents in children with chronic kidney disease: a systematic review.

Background: Erythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Although systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of the MEDLINE, CINAHL and Embase databases was conducted by two independent reviewers. Inclusion criteria were published trials in English, children with chronic and end-stage kidney disease and use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out in all included randomized trials using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Two tables were used for data extraction for randomized and observational studies. Study type, participants, inclusion criteria, case characteristics, follow-up duration, ESA type and dosage, interventions and outcomes were extracted by one author. Results: Of 965 identified articles, 58 were included covering 54 cohorts. Six were randomized trials and 48 were observational studies. A total of 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin alpha (DA) and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The most common adverse effect was hypertension, although confounding effects often limited direct correlation. Two large cohort studies demonstrated a greater hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient, evoked potentials and platelet function. Conclusions: All ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualizing treatments, with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomized trials comparing the efficacy of different preparations, treatment options in apparently ESA-resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices.

Bilateral primary renal diffuse large B-cell lymphoma: a rare presentation of paediatric renal disease mimicking juvenile nephronophthisis.

A 12-year-old boy presented with a prolonged history of headache, fatigue and hypertension. Initial investigations were consistent with presumed non-oliguric end-stage renal disease, leading to a provisional diagnosis of juvenile nephronophthisis. Subsequent imaging demonstrated bilaterally enlarged kidneys without cystic change. Mutation analysis was negative for nephronophthisis, causing diagnostic uncertainty which prompted renal biopsy. Histology revealed a primary renal diffuse large B-cell lymphoma which was highly responsive to chemotherapy, including the anti-CD20 monoclonal agent, rituximab. Renal function improved during lymphoma treatment, with residual chronic kidney disease stage 3a once chemotherapy was completed. Atypical diagnostic features should always prompt re-evaluation of a patient. In this case, the delayed malignancy diagnosis did not have an adverse effect on patient survival or morbidity. The outcome for primary renal lymphoma (PRL) has improved markedly following the introduction of rituximab.

Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair.

Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting. Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (~2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting. The ability to create mechanically strong 'cancellous bone-like' printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.

Quantification of urinary sodium concentrations in term infants.

BACKGROUND: Infants with gastrointestinal conditions and poor weight gain are administered sodium supplementation based on urinary sodium concentrations. However, the reference range of urinary electrolytes is unknown. The aim of this study was to ascertain the normal values of urinary electrolytes in healthy, term infants. Secondary aims were to establish the relationship between urinary electrolytes with weight velocity and feeding practices. METHODS: Healthy, term (≥37 weeks' gestation) infants were recruited. Parental questionnaires were completed before discharge and at six weeks. Electrolytes were quantified from a urine sample at six weeks. t-Tests and Mann-Whitney U tests were conducted for parametric and non-parametric electrolytes, respectively. RESULTS: A total of 200 infants were recruited before discharge. Twenty-nine follow-up questionnaires and urine samples were returned (nine female; mean gestational age 39 + 6 weeks [SD 9.9 days]; mean birthweight 3350 g [SD 483 g]; 17 breastfed, nine formula and three mixed; mean change in Z score for weight -0.914 [SD 0.814]). Majority (25/29) of infants had urinary sodium <20 mmo/L. Change in Z score for weight was similar between infants with sodium <20 mmol/L and >20 mmol/L ( P = 0.78). All exclusively breastfed infants had sodium <20 mmol/L, however, not statistically dissimilar to formula-fed infants ( P = 0.27). CONCLUSION: Most term infants in this study had urinary sodium values <20 mmol/L with no identified relationship to weight velocity. Lower concentrations of sodium could be not quantified reliably because of the limitations of the analytical method that were used. More evidence is required to identify candidates for sodium supplementation.

Photosensitiser-gold nanoparticle conjugates for photodynamic therapy of cancer.

Gold nanoparticles (AuNPs) have been extensively studied within biomedicine due to their biocompatibility and low toxicity. In particular, AuNPs have been widely used to deliver photosensitiser agents for photodynamic therapy (PDT) of cancer. Here we review the state-of-the-art for the functionalisation of the gold nanoparticle surface with both photosensitisers and targeting ligands for the active targeting of cancer cell surface receptors. From the initial use of the AuNPs as a simple carrier of the photosensitiser for PDT, the field has significantly advanced to include: the use of PEGylated modification to provide aqueous compatibility and stealth properties for in vivo use; gold metal-surface enhanced singlet oxygen generation; functionalisation of the AuNP surface with biological ligands to specifically target over-expressed receptors on the surface of cancer cells and; the creation of nanorods and nanostars to enable combined PDT and photothermal therapies. These versatile AuNPs have significantly enhanced the efficacy of traditional photosensitisers for both in vitro and in vivo cancer therapy. From this review it is apparent that AuNPs have an important future in the treatment of cancer.

Protecting the heart through MK2 modulation, toward a role in diabetic cardiomyopathy and lipid metabolism.

Various signaling pathways have been identified in the heart as important players during development, physiological adaptation or pathological processes. This includes the MAPK families, particularly p38MAPK, which is involved in several key cellular processes, including differentiation, proliferation, apoptosis, inflammation, metabolism and survival. Disrupted p38MAPK signaling has been associated with several diseases, including cardiovascular diseases (CVD) as well as diabetes and its related complications. Despite efforts to translate this knowledge into therapeutic avenues, p38 inhibitors have failed in clinical trials due to adverse effects. Inhibition of MK2, a downstream target of p38, appears to be a promising alternative strategy. Targeting MK2 activity may avoid the adverse effects linked to p38 inhibition, while maintaining its beneficial effects. MK2 was first considered as a therapeutic target in inflammatory diseases such as rheumatoid polyarthritis. A growing body of evidence now supports a key role of MK2 signaling in the pathogenesis of CVD, particularly ischemia/reperfusion injury, hypertrophy, and hypertension and that its inhibition or inactivation is associated with improved heart and vascular functions. More recently, MK2 was shown to be a potential player in diabetes and related complications, particularly in liver and heart, and perturbations in calcium handling and lipid metabolism. In this review, we will discuss recent advances in our knowledge of the role of MK2 in p38MAPK-mediated signaling and the benefits of its loss of function in CVD and diabetes, with an emphasis on the roles of MK2 in calcium handling and lipid metabolism. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

[Ecological indicators of habitat and biodiversity in a Neotropical landscape: multitaxonomic perspective]. / Indicadores ecológicos de hábitat y biodiversidad en un paisaje neotropical: perspectiva multitaxonómica.

Ecological indicators of habitat and biodiversity in a Neotropical landscape: multitaxonomic perspective. The use of indicator species to characterize specific ecological areas is of high importance in conservation/restoration biology. The objective of this study was to identify indicator species of diverse taxa that characterize different landscape units, and to better understand how management alters species composition. We identified two ecomosaics, tropical rain forest and the agricultural matrix, each one comprised of four landscape units. The taxonomic groups studied included birds (highly mobile), butterflies (moderately mobile), terrestrial gastropods (less mobile) and trees (sessile). Sampling efficiency for both ecomosaics was > or = 86%. We found 50 mollusks, 74 butterflies, 218 birds and 172 tree species, for a total of 514 species. Using ordination and cluster analysis, we distinguished three habitat types in the landscape: tropical rainforest, secondary vegetation and pastures with scattered trees and live fences. The InVal (> or = 50%) method identified 107 indicator species, including 45 tree species, 38 birds, 14 butterflies and 10 gastropods. Of these, 35 trees, 10 birds, four butterflies and eight gastropods were forest indicators. Additionally, 10, 28, 10 and two species, respectively per group, were characteristic of the agricultural matrix. Our results revealed a pattern of diversity decrease of indicator species along the rainforest-secondary forest-pasture gradient. In the forest, the gastropods Carychium exiguum, Coelocentrum turris, Glyphyalinia aff. indentata y Helicina oweniana were significantly correlated (p < 0.05) with 90% of the other groups of flora and fauna indicator species. These findings suggest that gastropods may be good indicators of forest habitat quality and biodiversity. The secondary vegetation is an intermediate disturbance phase that fosters high diversity in the agricultural matrix. We exemplify a multitaxa approach, including mesofauna, for ecological monitoring of agricultural landscapes.

Estimating waste transfer station delays using GPS.

This paper examines the use of on-board global positioning system (GPS) data recorders as a method to collect field data on the movements of solid waste collection vehicles at transfer stations. The movements of five waste collection vehicles using four different transfer facilities were compared over a period of 1 year. The spatial data were analyzed using geofences to determine the amount of time each truck spent on each of four activities: queuing for access to the weigh scale, sitting on the weigh scale, queuing for access to the tipping floor, and unloading waste. The study found that queuing delays can be identified and measured using GPS data. The average time at a facility for all trucks was 16.4 min per visit, with a standard deviation of 14.3 min. Time at the facility ranged between 2 and 111 min per visit and the distribution of time at the facility was positively skewed. Multi-compartment vehicles (co-collection and recycling trucks) spent significantly more time at unloading facilities. There were also significant differences in the length and the location of the queues at different facilities. At one facility, the longest delays were encountered while waiting for the weigh scale, at two facilities trucks experienced delays in obtaining access to the tipping floor, while at the fourth facility no significant delays developed.