Diagnosis and management of hyponatraemia: AGREEing the guidelines

Hyponatraemia is a common electrolyte disorder associated with significant complications and controversies regarding its optimal management. Clinical practice guidelines and consensus statements have attempted to provide clinicians with evidence-based diagnostic and treatment strategies for hyponatraemia. Recently published guidance documents differ in their methods employed to review the quality of available evidence. Nagler et al. used the Appraisal of Guideline for Research and Evaluation (AGREE II) instrument in a systematic review of guidelines and consensus statements for the diagnosis and management of hyponatraemia. Nagler and colleagues highlighted the variability in methodological rigour applied to guideline development and inconsistencies between publications in relation to management of hyponatraemia (including the recommended rate of correction of a low serum sodium concentration). These differences could cause confusion for practising physicians managing patients with hyponatraemia. Please see related article: http://www.biomedcentral.com/1741-7015/12/231

Development of next generation sequencing panel for UMOD and association with kidney disease

Chronic kidney disease (CKD) has a prevalence of approximately 10% in adult populations. CKD can progress to end-stage renal disease (ESRD) and this is usually fatal unless some form of renal replacement therapy (chronic dialysis or renal transplantation) is provided. There is an inherited predisposition to CKD with several genetic risk markers now identified. The UMOD gene has been associated with CKD of varying aetiologies. An AmpliSeq next generation sequencing panel was developed to facilitate comprehensive sequencing of the UMOD gene, covering exonic and regulatory regions. SNPs and CpG sites in the genomic region encompassing UMOD were evaluated for association with CKD in two studies; the UK Wellcome Trust Case-Control 3 Renal Transplant Dysfunction Study (n = 1088) and UK-ROI GENIE GWAS (n = 1726). A technological comparison of two Ion Torrent machines revealed 100% allele call concordance between S5 XL™ and PGM™ machines. One SNP (rs183962941), located in a non-coding region of UMOD, was nominally associated with ESRD (p = 0.008). No association was identified between UMOD variants and estimated glomerular filtration rate. Analysis of methylation data for over 480,000 CpG sites revealed differential methylation patterns within UMOD, the most significant of these was cg03140788 p = 3.7 x 10-10

Histotripsy Erosion of Model Urinary Calculi

Background and Purpose: Histotripsy is a pulsed focused ultrasound technology in which initiation and control of acoustic cavitation allow for precise mechanical fractionation of tissues. The present study examines the feasibility of using histotripsy for erosion of urinary calculi. Materials and Methods: Histotripsy treatment was delivered from a 750-kHz transducer in the form of 5-cycle acoustic pulses at a 1-kHz pulse repetition frequency. Model stones were sonicated for 5 minutes at peak negative pressures (p-) of 10, 15, 19, 22, and 24-MPa. Resulting fragment sizes and comminution rates were assessed and compared with those achieved with a piezoelectric lithotripter (Wolf Piezolith 3000) operated at 2-Hz pulse repetition frequency and power level 17 (p- = 14-MPa). Results: Histotripsy eroded the surface of stones producing fine (<100--m) particulate debris in contrast to the progressive and incomplete subdivision of stones achieved with piezoelectric lithotripsy. The histotripsy erosion rate increased with increasing peak negative pressure from 10 to 19-MPa and then saturated, yielding an average rate of 87.9+/-12.8 mg/min at maximum treatment intensity. Piezoelectric lithotripsy achieved an average treatment rate of 110.7+/-27.4 mg/min. Conclusions: Histotripsy comminution of urinary calculi is a surface erosion phenomenon that is mechanistically distinct from conventional shockwave lithotripsy (SWL), producing only fine debris as opposed to coarse fragments. These characteristics suggest that histotripsy offers a potential adjunct to traditional SWL procedures, and synergistic interplay of the two modalities may lead to possible increases in both rate and degree of stone fragmentation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90440/1/end-2E2010-2E0407.pd

TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation

BACKGROUND: CCN2/CTGF is an established effector of TGFβ driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFβ leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function. RESULTS: From a panel of genes regulated by TGFβ and CCN2, we used co-inertia analysis to identify and then experimentally verify a subset of transcription factors, E2F1 and CREB, that regulate an expression fingerprint implicated in altered actin dynamics and cell hypertrophy. Importantly, actin related genes containing E2F1 and CREB binding sites, stratified by expression profile within the dataset. Further analysis of actin and cytoskeletal related genes from patients with diabetic nephropathy suggests recapitulation of this programme during the development of renal disease. The Rho family member Cdc42 was also found uniquely to be activated in cells treated with TGFβ and CCN2; Cdc42 interacting genes were differentially regulated in diabetic nephropathy. CONCLUSIONS: TGFβ and CCN2 attenuate CREB and augment E2F1 transcriptional activation with the likely effect of altering actin cytoskeletal and cell growth/hypertrophic gene activity with implications for cell dysfunction in diabetic kidney disease. The cytoskeletal regulator Cdc42 may play a role in this signalling response

Hyperamylasemia post living donor nephrectomy does not relate to pain

Introduction The aetiology of pain after laparoscopic donor nephrectomy remains unclear. Given the proximity of the left kidney to the tail of the pancreas, we aimed to assess whether mobilisation and retrieval of the left kidney might inflame the pancreas, leading to pain and hyperamylasaemia in the post-operative period. Patient and methods In the present study, 16 consecutive live kidney donors were analysed in the same three months period. Amylase levels were measured on days 1 and 2. For each 24-hour period postoperatively analgesia consumption was recorded, as well as pain scores at rest on a visual analogue scale (VAS). Results Three out of 16 donors presented hyperamylasemia. A multiple regression analysis found levobupivacaine dose, propofol dose, transversus abdominis plane block and day 1 amylase did not significantly predict pain scores. Interestingly, body mass index significantly correlated with increased pain scores (p = 0.041). Also, increasing CO2 insufflation pressure and use of local anaesthetic infusion catheters predicted a decreased deep pain score (p = 0.036 and p = 0.037). Conclusion There was no correlation of amylase levels and pain scores. Pancreatitis is a rare complication of nephrectomy and no overt cases were seen in the case of donor nephrectomy

Comprehensive Investigation of the Caveolin 2 Gene: Resequencing and Association for Kidney Transplant Outcomes

Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study

Platelet-Induced Clumping of Plasmodium falciparum–Infected Erythrocytes from Malawian Patients with Cerebral Malaria—Possible Modulation In Vivo by Thrombocytopenia

Platelets may play a role in the pathogenesis of human cerebral malaria (CM), and they have been shown to induce clumping of Plasmodium falciparum–parasitized red blood cells (PRBCs) in vitro. Both thrombocytopenia and platelet-inducedPRBCclumping are associated with severe malaria and, especially, withCM.In the present study, we investigated the occurrence of the clumping phenomenon in patients with CM by isolating and coincubating their plasma and PRBCs ex vivo. Malawian children with CM all had low platelet counts, with the degree of thrombocytopenia directly proportional to the density of parasitemia. Plasma samples obtained from these patients subsequently induced weak PRBC clumping. When the assays were repeated, with the plasma platelet concentrations adjusted to within the physiological range considered to be normal, massive clumping occurred. The results of this study suggest that thrombocytopenia may, through reduction of platelet-mediated clumping of PRBCs, provide a protective mechanism for the host during CM

Retinal microvascular network attenuation in Alzheimer's disease

AbstractIntroductionCerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD). The retinal microvasculature enables the noninvasive visualization and evaluation of the systemic microcirculation. We evaluated retinal microvascular parameters in a case-control study of AD patients and cognitively normal controls.MethodsRetinal images were computationally analyzed and quantitative retinal parameters (caliber, fractal dimension, tortuosity, and bifurcation) measured. Regression models were used to compute odds ratios (OR) and confidence intervals (CI) for AD with adjustment for confounders.ResultsRetinal images were available in 213 AD participants and 294 cognitively normal controls. Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77 [CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97]) were more likely to have AD after appropriate adjustment.DiscussionPatients with AD have a sparser retinal microvascular network and retinal microvascular variation may represent similar pathophysiological events within the cerebral microvasculature of patients with AD

Resonance-Induced Effects in Photonic Crystals

For the case of a simple face-centered-cubic photonic crystal of homogeneous dielectric spheres, we examine to what extent single-sphere Mie resonance frequencies are related to band gaps and whether the width of a gap can be enlarged due to nearby resonances. Contrary to some suggestions, no spectacular effects may be expected. When the dielectric constant of the spheres $\epsilon_s$ is greater than the dielectric constant $\epsilon_b$ of the background medium, then for any filling fraction $f$ there exists a critical $\epsilon_c$ above which the lowest lying Mie resonance frequency falls inside the lowest stop gap in the (111) crystal direction, close to its midgap frequency. If $\epsilon_s <\epsilon_b$, the correspondence between Mie resonances and both the (111) stop gap and a full gap does not follow such a regular pattern. If the Mie resonance frequency is close to a gap edge, one can observe a resonance-induced widening of a relative gap width by $\approx 5$.Comment: 14 pages, 3 figs., RevTex. For more info look at http://www.amolf.nl/external/wwwlab/atoms/theory/index.htm