Genetic associations in diabetic nephropathy: a meta-analysis

Diabetes mellitus: pathophysiological changes and therap

Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver

Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process

Altered ureteric branching morphogenesis and nephron endowment in offspring of diabetic and insulin-treated pregnancy

<div><p>There is strong evidence from human and animal models that exposure to maternal hyperglycemia during <i>in utero</i> development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified <i>ex vivo</i> using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7±23.3 vs. STZ 153.2±24.6, mean±SEM, <i>p</i>&lt;0.01) and ureteric tree length (control 33.1±2.6 mm vs. STZ 17.6±2.7 mm, <i>p</i> = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2±64.9 vs. STZ 822.4±74.0, <i>p&lt;</i>0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.</p> </div

Bayesian Computation with Intractable Likelihoods

This article surveys computational methods for posterior inference with intractable likelihoods, that is where the likelihood function is unavailable in closed form, or where evaluation of the likelihood is infeasible. We review recent developments in pseudo-marginal methods, approximate Bayesian computation (ABC), the exchange algorithm, thermodynamic integration, and composite likelihood, paying particular attention to advancements in scalability for large datasets. We also mention R and MATLAB source code for implementations of these algorithms, where they are available.Comment: arXiv admin note: text overlap with arXiv:1503.0806

Care management for Type 2 diabetes in the United States: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes.</p> <p>Methods</p> <p>A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures.</p> <p>Results</p> <p>Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to -0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02).</p> <p>Conclusions</p> <p>Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions.</p

The Molecular Evolution of the p120-Catenin Subfamily and Its Functional Associations

p120-catenin (p120) is the prototypical member of a subclass of armadillo-related proteins that includes δ-catenin/NPRAP, ARVCF, p0071, and the more distantly related plakophilins 1–3. In vertebrates, p120 is essential in regulating surface expression and stability of all classical cadherins, and directly interacts with Kaiso, a BTB/ZF family transcription factor.To clarify functional relationships between these proteins and how they relate to the classical cadherins, we have examined the proteomes of 14 diverse vertebrate and metazoan species. The data reveal a single ancient δ-catenin-like p120 family member present in the earliest metazoans and conserved throughout metazoan evolution. This single p120 family protein is present in all protostomes, and in certain early-branching chordate lineages. Phylogenetic analyses suggest that gene duplication and functional diversification into “p120-like” and “δ-catenin-like” proteins occurred in the urochordate-vertebrate ancestor. Additional gene duplications during early vertebrate evolution gave rise to the seven vertebrate p120 family members. Kaiso family members (i.e., Kaiso, ZBTB38 and ZBTB4) are found only in vertebrates, their origin following that of the p120-like gene lineage and coinciding with the evolution of vertebrate-specific mechanisms of epigenetic gene regulation by CpG island methylation.The p120 protein family evolved from a common δ-catenin-like ancestor present in all metazoans. Through several rounds of gene duplication and diversification, however, p120 evolved in vertebrates into an essential, ubiquitously expressed protein, whereas loss of the more selectively expressed δ-catenin, p0071 and ARVCF are tolerated in most species. Together with phylogenetic studies of the vertebrate cadherins, our data suggest that the p120-like and δ-catenin-like genes co-evolved separately with non-neural (E- and P-cadherin) and neural (N- and R-cadherin) cadherin lineages, respectively. The expansion of p120 relative to δ-catenin during vertebrate evolution may reflect the pivotal and largely disproportionate role of the non-neural cadherins with respect to evolution of the wide range of somatic morphology present in vertebrates today

Chronic kidney disease after liver, cardiac, lung, heart–lung, and hematopoietic stem cell transplant

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease

Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development