Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Potassium control in chronic kidney disease: implications for neuromuscular function

In Australia, approximately 1.7 million adults have evidence of chronic kidney disease (CKD). This complex disease can result in a multitude of complications, including hyperkalaemia, which is common and well recognised. The advent of new therapeutics aimed at lowering serum potassium has raised the possibility of optimising potassium control to enable greater use of renin–angiotensin–aldosterone system inhibitors in the management of CKD. Recent studies suggest that hyperkalaemia also has implications for peripheral neuropathy in CKD, a complication that substantially contributes to patient morbidity. This review examines evidence of the relationship between potassium and peripheral neuropathy, with a discussion of clinical implications. We searched PubMed for original and review articles using pre-specified key words, clinical guidelines and population data. The major findings were that contemporary CKD cohorts demonstrate a high prevalence of peripheral neuropathy, even in stage 3–4 CKD, including those without diabetes. The severity of the problem has been emphasised by an ominous rise in foot complications and amputation rates in dialysis patients, highlighting the need for increased awareness of the condition in earlier stages of CKD and targeted treatment strategies. It is likely that the pathophysiology of peripheral neuropathy in CKD is multifaceted, with potential influences from potassium, vascular abnormalities, diabetes, inflammation and unknown middle molecules. Despite these complexities, the relationship between potassium and nerve function in dialysis has been well established, and recent research in stage 3–4 CKD suggests that assertive potassium control may improve neuromuscular outcomes in CKD. These small studies should be confirmed in large, multicentre settings

Peripheral neuropathy: An important contributor to physical limitation and morbidity in stages 3 and 4 chronic kidney disease

Background: Impaired physical function drives adverse outcomes in chronic kidney disease (CKD). Peripheral neuropathy is highly prevalent in CKD, though its contribution to physical function in CKD patients is unknown. This study examined the relationships between peripheral neuropathy, walking speed and quality of life (QoL) in stages 3 and 4 CKD. Methods: This was a prospective observational study investigating neuropathy in CKD patients with an estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73 m2. A total of 109 patients were consecutively recruited. The presence and severity of peripheral neuropathy was determined using the total neuropathy score. Walking speed was assessed at both usual and maximal speed, and QoL was assessed using the Short- Form 36 (SF-36) questionnaire. Results: Peripheral neuropathy was highly prevalent: 40% demonstrated mild neuropathy and 37% had moderate-severe neuropathy. Increasing neuropathy severity was the primary predictor of reduced walking speed (R2 = -0.41, P < 0.001) and remained so after multivariable analysis adjustment for diabetes. This association was evident for both usual and maximal walking speeds. Neuropathy correlated significantly with low scores on multiple domains of SF-36 including physical function (r = -0.570, P < 0.001). Subanalysis according to diabetic status revealed a high prevalence of neuropathy both with and without diabetes; relationships to walking speed remained evident in subgroup analysis. However, those with diabetes demonstrated greater severity of neuropathy, slower walking speed and lower scores in QoL. Conclusions: Moderate to severe peripheral neuropathy was common in stages 3 and 4 CKD, associated with reduced walking speed independent of diabetes status and was correlated with patient-reported QoL. This suggests that neuropathy is an important contributor to declining physical function in CKD irrespective of diabetes status. Targeted diagnosis and management of peripheral neuropathy during CKD progression may improve functional outcomes and QoL

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being

Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury

Extensive structural damage within the kidney must be present before serum creatinine increases. However, a subclinical phase of chronic kidney disease (CKD) usually goes undetected. Here we tested whether experimental subclinical CKD would modify functional and damage biomarker profiles of acute kidney injury (AKI). Subclinical CKD was induced in rats by adenine or aristolochic acid models but without increasing serum creatinine. After prolonged recovery (three to six weeks), AKI was induced with a subnephrotoxic dose of cisplatin. Urinary levels of kidney injury molecule-1 (KIM-1), cytochrome C, monocyte chemotactic protein-1 (MCP-1), clusterin, and interleukin-18 increased during CKD induction, without an increase in serum creatinine. After AKI in adenine-induced CKD, serum creatinine increased more rapidly, while increased urinary KIM-1, clusterin, and MCP-1 were delayed and reduced. Increased serum creatinine and biomarker excretion were associated with diffuse tubulointerstitial injury in the outer stripe of outer medulla coupled with over 50% cortical damage. Following AKI in aristolochic acid–induced CKD, increased serum creatinine, urinary KIM-1, clusterin, MCP-1, cytochrome C, and interleukin-18 concentrations and excretion were greater at day 21 than day 42 and inversely correlated with cortical injury. Subclinical CKD modified functional and damage biomarker profiles in diametrically opposite ways. Functional biomarker profiles were more sensitive, while damage biomarker diagnostic thresholds and increases were diminished and delayed. Damage biomarker concentrations and excretion were inversely linked to the extent of prior cortical damage. Thus, thresholds for AKI biomarkers may need to be lower or sampling delayed in the known presence of CKD

Potassium control in chronic kidney disease: implications for neuromuscular function

In Australia, approximately 1.7 million adults have evidence of chronic kidney disease (CKD). This complex disease can result in a multitude of complications, including hyperkalaemia, which is common and well recognised. The advent of new therapeutics aimed at lowering serum potassium has raised the possibility of optimising potassium control to enable greater use of renin-angiotensin-aldosterone system inhibitors in the management of CKD. Recent studies suggest that hyperkalaemia also has implications for peripheral neuropathy in CKD, a complication that substantially contributes to patient morbidity. This review examines evidence of the relationship between potassium and peripheral neuropathy, with a discussion of clinical implications. We searched PubMed for original and review articles using pre-specified key words, clinical guidelines and population data. The major findings were that contemporary CKD cohorts demonstrate a high prevalence of peripheral neuropathy, even in stage 3-4 CKD, including those without diabetes. The severity of the problem has been emphasised by an ominous rise in foot complications and amputation rates in dialysis patients, highlighting the need for increased awareness of the condition in earlier stages of CKD and targeted treatment strategies. It is likely that the pathophysiology of peripheral neuropathy in CKD is multifaceted, with potential influences from potassium, vascular abnormalities, diabetes, inflammation and unknown middle molecules. Despite these complexities, the relationship between potassium and nerve function in dialysis has been well established, and recent research in stage 3-4 CKD suggests that assertive potassium control may improve neuromuscular outcomes in CKD. These small studies should be confirmed in large, multicentre settings

A Comparison of the Ability of Levels of Urinary Biomarker Proteins and Exosomal mRNA to Predict Outcomes after Renal Transplantation

BACKGROUND: mRNA for biomarkers of kidney injury extracted from urinary exosomes may reflect or predict levels of the corresponding protein after transplantation and clinical outcomes. METHODS: Urinary exosomes were isolated from patients following renal transplantation, from healthy controls, and patients with CKD. Expression of exosomal mRNA for the injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and cystatin C was compared with the concentrations of corresponding urinary proteins, 18S RNA and serum creatinine. RESULTS: All biomarker protein concentrations increased after transplantation, and urinary NGAL and IL-18 at 24 and 168 h correlated with the day 7 creatinine reduction ratio (CRR). Exosomal18S RNA increased after transplantation, but exosomal mRNA for NGAL, IL-18 and cystatin C did not correlate with the day 7 CRR, or urinary biomarker concentrations at any time after transplantation. Exosomal NGAL mRNA was lower 4 h after transplantation than in control exosomes. In contrast, exosomal mRNA for cystatin C was unchanged after transplantation and in CKD, although urinary cystatin C temporarily increased following transplantation. Urinary KIM-1 increased after transplantation, but exosomal mRNA for KIM-1 remained undetectable. In CKD 18S RNA was raised, and exosomal mRNA for NGAL, IL-18 and cystatin C was detected in all patients. While urinary NGAL was greater in CKD than control subjects, exosomal NGAL mRNA was unchanged. Exosomal IL-18 mRNA was increased in CKD, but not IL-18 protein. CONCLUSIONS: After renal transplantation, urinary NGAL and IL-18 levels reflect the day 7 CRR. However, while mRNA for these biomarkers is present in exosomes, their levels do not reflect or predict urinary biomarker levels or the CRR. This likely reflects the fact that packaging of mRNA in exosomes is selective, and is not necessarily representative of mRNA in the parent cells responsible for biomarker production

Dexamethasone Modifies Cystatin C-Based Diagnosis of Acute Kidney Injury During Cisplatin-Based Chemotherapy

© 2017 The Author(s)Published by S. Karger AG, BaselBackground/Aims: Plasma cystatin C (pCysC) may be superior to serum creatinine (sCr) as a surrogate of GFR. However, the performance of pCysC for diagnosing acute kidney injury (AKI) after cisplatin-based chemotherapy is potentially affected by accompanying corticosteroid anti-emetic therapy and hydration. Methods: In a prospective observational study pCysC, sCr, urinary kidney injury molecule-1 (KIM-1), and urinary clusterin were measured over 2 weeks in 27 patients given first-cycle chemotherapy. The same variables were measured over 2 weeks in Sprague–Dawley rats given a single intraperitoneal injection of dexamethasone, cisplatin, or both, and in controls. Results: In patients, pCysC increases were greater than sCr 41% vs. 16%, mean paired difference 25% (95% CI: 16–34%)], relative increases were ≥ 50% in 9 patients (35%) for pCysC compared with 2 (8%) for sCr (p = 0.04) and increases in sCr were accompanied by increased KIM-1 and clusterin excretion, but increases in pCysC alone were not. In rats, dexamethasone administration produced dose-dependent increases in pCysC (and augmented cisplatin-induced increases in pCysC), but did not augment histological injury, increases in sCr, or KIM-1 and clusterin excretion. Conclusions: In the presence of dexamethasone, elevation of pCysC does not reliably diagnose AKI after cisplatin-based chemotherapy

Effects of Hemodiafiltration and High Flux Hemodialysis on Nerve Excitability in End-Stage Kidney Disease

OBJECTIVES: Peripheral neuropathy is the most common neurological complication in end-stage kidney disease. While high flux hemodialysis (HFHD) and hemodiafiltration (HDF) have become the preferred options for extracorporeal dialysis therapy, the effects of these treatments on nerve excitability have not yet been examined. METHODS: An observational proof-of-concept study of nerve excitability and neuropathy was undertaken in an incident dialysis population (n = 17) receiving either HFHD or HDF. Nerve excitability techniques were utilised to assess nerve ion channel function and membrane potential, in conjunction with clinical assessment and standard nerve conduction studies. A mathematical model of axonal excitability was used to investigate the underlying basis of the observed changes. Nerve excitability was recorded from the median nerve, before, during and after a single dialysis session and correlated with corresponding biochemical markers. Differences in nerve excitability were compared to normal controls with longitudinal follow-up over an 18 month period. RESULTS: Nerve excitability was performed in patient cohorts treated with either HFHD (n = 9) or online HDF (n = 8), with similar neuropathy status. Nerve excitability measures in HDF-treated patients were significantly closer to normal values compared to HFHD patients obtained over the course of a dialysis session (p<0.05). Longitudinal studies revealed stability of nerve excitability findings, and thus maintenance of improved nerve function in the HDF group. CONCLUSIONS: This study has provided evidence that nerve excitability in HDF-treated patients is significantly closer to normal values prior to dialysis, across a single dialysis session and at longitudinal follow-up. These findings offer promise for the management of neuropathy in ESKD and should be confirmed in randomised trials