Renal iron overload in rats with diabetic nephropathy.

Diabetic nephropathy (DN) remains incurable and is the main cause of end‐stage renal disease. We approached the pathophysiology of DN with systems biology, and a comprehensive profile of renal transcripts was obtained with RNA‐Seq in ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) rats, a model of diabetic nephropathy. We included sham‐operated lean control rats (LS), sham‐operated diabetic (DS), and diabetic rats with induced renal ischemia (DI). Diabetic nephropathy in DI was accelerated by the single episode of renal ischemia. This progressive renal decline was associated with renal iron accumulation, although serum and urinary iron levels were far lower in DI than in LS. Furthermore, obese/diabetic ZS rats have severe dyslipidemia, a condition that has been linked to hepatic iron overload. Hence, we tested and found that the fatty acids oleic acid and palmitate stimulated iron accumulation in renal tubular cells in vitro. Renal mRNAs encoding several key proteins that promote iron accumulation were increased in DI. Moreover, renal mRNAs encoding the antioxidant proteins superoxide dismutase, catalase, and most of the glutathione synthetic system were suppressed, which would magnify the prooxidant effects of renal iron loads. Substantial renal iron loads occur in obese/diabetic rats. We propose that in diabetes, specific renal gene activation is partly responsible for iron accumulation. This state might be further aggravated by lipid‐stimulated iron uptake. We suggest that progressive renal iron overload may further advance renal injury in obese/diabetic ZS rats

Renal C3 complement component: feed forward to diabetic kidney disease

BACKGROUND: Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions. METHODS: Comprehensive genomic profiling (RNAseq) was employed in the ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates. RESULTS: Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by the activation of the renal complement system in DI, and to a lesser extent in sham-operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8, and C9 over sham-operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibit the membrane attack complex. C3, C4, and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3-generating renal tubular cells and other immune competent migratory cells. CONCLUSIONS: We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy

Peer-to-peer support on Facebook for caregivers of children and youth with complex care needs in New Brunswick: An environmental scan

This environmental scan aimed to describe the purpose, use, and reach of health-related peer-to-peer support groups on Facebook for caregivers of children and youth with complex care needs in New Brunswick. A total of 3,104 searches on Facebook and consultations with thirty-two stakeholders led to the identification of forty-seven Facebook support groups (twenty-one active). Groups targeted a range of conditions, with autism and related intellectual disabilities appearing most frequently. Content analysis of posts indicated that groups were primarily used to exchange informational support. This study showed that Facebook-based peer-to-peer support groups are available to families of children and youth with complex care needs in the province. This work also lays a foundation for future scans of Facebook-based support groups in other Canadian provinces and beyond.La présente analyse du milieu visait à décrire l’objectif, l’utilisation et la portée des groupes de soutien entre pairs liés à la santé sur Facebook pour les personnes qui s’occupent d’enfants et de jeunes ayant des besoins de soins complexes au Nouveau-Brunswick. En tout, 3 104 recherches sur Facebook et des consultations auprès de 32 intervenants ont permis de repérer 47 groupes de soutien sur Facebook, dont 21 groupes actifs. Des groupes ciblaient un éventail de troubles; l’autisme et les déficiences intellectuelles connexes étaient ceux qui étaient les plus fréquents. Les analyses de contenu des messages ont révélé que les groupes étaient principalement utilisés pour échanger des informations de soutien. Selon cette étude, des groupes de soutien entre pairs sur Facebook sont offerts aux familles d’enfants et de jeunes ayant des besoins de soins complexes dans la province. De plus, ce travail jette les bases de futures analyses de groupes de soutien sur Facebook d’autres provinces canadiennes et d’ailleurs

Evaluating Participatory Modeling: Developing a Framework for Cross-case Analysis

Participatory modeling is increasingly recognised as an effective way to assist collective decision-making processes in the domain of natural resource management. This paper introduces a framework for evaluating projects that have adopted a participatory modeling approach. This framework – known as the ‘Protocol of Canberra’ – was developed through a collaboration between French and Australian researchers engaged in participatory modeling and evaluation research. The framework seeks to assess the extent to which different participatory modeling practices reinforce or divert from the theoretical assumptions they are built upon. The paper discusses the application of the framework in three case-studies, two from Australia and one from the Pacific island of the Republic of Kiribati. The paper concludes with some comments for future use of the framework in a range of participatory modeling contexts, including fostering consideration of why and how different methodological approaches are used to achieve project aims and to build a collective vision amongst diverse stakeholders.participation, modeling, evaluation, complex systems science

Strategy for Generating Blinded Evidence for Single-Arm Trials with External Controls Using Expert Review of Home Video

Introduction Neurodegenerative diseases cause developmental delays and loss of milestones in infants and children. However, scalable outcome measures that quantify features meaningful to parents/caregivers (P/CGs) and have regulatory precedence are lacking for assessing the effectiveness of treatments in clinical trials of neurodegenerative disorders. To address this gap, we developed an innovative, blinded strategy for single-arm trials with external controls using expert panel review of home video. Method We identified meaningful, observable, and objective developmental milestones from iterative interviews with P/CGs and clinical experts. Subsequently, we standardized video recording procedures and instructions to ensure consistency in how P/CGs solicited each activity. In practice, videos would be graded by an expert panel blinded to treatment. To ensure blinding and quality control, video recordings from interim time points would be randomly interspersed. We conducted a pilot study and a pretest of grading to test feasibility and improve the final strategy. Results The five P/CGs participating in the pilot study found the instructions clear, selected activities important and reflective of their children’s abilities, and recordings at-home preferrable to in-clinic assessments. The three grading experts found the videos easy to grade and the milestones clinically meaningful. Conclusion Our standardized strategy enables expert panel grading of developmental milestone achievements using at-home recordings, blinded to treatment and post-baseline time points. This rigorous and objective scoring system has broad applicability in various disease contexts, with or without external controls. Moreover, our strategy facilitates flexible, continued data collection and the videos can be archived for future analyses

Ecological insights into abyssal bentho-pelagic fish at 4000 m depth using a multi-beam echosounder on a remotely operated vehicle

Ecological and behavioral data on mobile, low density, benthopelagic animals is difficult to collect in the abyssal environment. However, these species occupy an important position in the abyssal food chain. At-depth ROV-mounted echosounder studies provide a powerful tool to gather in-situ information on abyssal benthopelagic assemblages and discern their distribution, behavior and habitat associations. This study presents a new perspective on mobile benthopelagic assemblages at the long-term study site, Station M (∼4000 m), using a Seabat T20-S MBES mounted on the ROV Doc Ricketts. The targets (∼45 m off the seafloor) are believed to be the abyssal grenadier of the species Coryphaenoides armatus or C. yaquinae, species known to dominate the mobile benthopelagic fauna at Station M. The swimming behavior of the targets indicated little evidence of avoidance or attraction to the slowly moving ROV and demonstrates the effectiveness of this platform to collect data on benthopelagic fish. The information on targets in close (<1 m) association with the seafloor from the MBES corresponded well to target densities recorded by the video transects. However, in addition the MBES resolved the distribution of targets up to 45 m above the seafloor. Target density had a small peak close to the seafloor (<1 m) but increased in density with height above the seafloor, exceeding the maximum near-bottom density by ∼50 times. ROV-mounted MBES surveys can effectively provide data on the distribution and behavior of benthopelagic fish and further understanding of the pelagic-benthic links in the abyssal deep-sea.acceptedVersio

Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy

Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy but severely limited by the availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic Zucker/SHHF F1 hybrid (ZS) female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 wk of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 wk of age. Rats were euthanized at 34 wk of age. IRCT with cells expressing serum amyloid A had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 wk after the second infusion. The results indicate that IRCT with serum amyloid A-positive cells is effective in preventing the progression of chronic kidney disease in rats with diabetic and ischemic nephropathy

Renal Tubular Cell-Derived Extracellular Vesicles Accelerate the Recovery of Established Renal Ischemia Reperfusion Injury

Ischemic renal injury is a complex syndrome; multiple cellular abnormalities cause accelerating cycles of inflammation, cellular damage, and sustained local ischemia. There is no single therapy that effectively resolves the renal damage after ischemia. However, infusions of normal adult rat renal cells have been a successful therapy in several rat renal failure models. The sustained broad renal benefit achieved by relatively few donor cells led to the hypothesis that extracellular vesicles (EV, largely exosomes) derived from these cells are the therapeutic effector in situ We now show that EV from adult rat renal tubular cells significantly improved renal function when administered intravenously 24 and 48 hours after renal ischemia in rats. Additionally, EV treatment significantly improved renal tubular damage, 4-hydroxynanoneal adduct formation, neutrophil infiltration, fibrosis, and microvascular pruning. EV therapy also markedly reduced the large renal transcriptome drift observed after ischemia. These data show the potential utility of EV to limit severe renal ischemic injury after the occurrence