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Background: Paediatric kidney transplant recipients may be at a particular risk of dehydration due to poor kidney concentrating capacity and illness associated with poor fluid intake or losses. In this population, creatinine rise may be more likely with relatively mild dehydration, which may trigger hospital admission. This study describes hospital admissions in the first 12 months after transplantation with diagnosis of graft dysfunction associated with dehydration due to illness or poor fluid intake. We assess risk factors for these admissions., Methods: Data was extracted from medical records of patients transplanted in two tertiary children hospitals. Following descriptive analysis, multiple failure regression analyses were used to identify factors associated with admission for acute kidney allograft dysfunction associated with dehydration., Results: Of 92 children, 42% had at least 1 dehydration admission in the 12 months following transplantation. Almost half of the dehydration admissions were due to poor fluid intake, which accounted for 1/5 of all unplanned hospital admissions. Target fluid intake at first discharge of > 100 ml/kg/day was associated with dehydration admissions of all types (hazard ratio (HR) 2.04 (95% CI 1.13-3.68)). Teen age was associated with poor fluid intake dehydration admissions (HR 4.87 (95% CI 1.19-19.86)), which were more frequent in mid-summer. Use of enteric feeding tube, which correlated with age under 4, associated with contributing illness dehydration admissions (HR 2.18 (95% CI 1.08-4.41))., Conclusions: Dehydration admissions in the 12 months following childhood kidney transplantation are common. Highlighted admission risk factors should prompt further study into optimal fluid intake prescription and hydration advice given to children, teenagers, and their carers following kidney transplantation. Use of an enteric feeding tube may not protect patients from admission with dehydration associated with contributing illness. A highger resolution version of the Graphical abstract is available as Supplementary information., (© 2023. Crown.)

Transthoracic echocardiography is commonly used to identify structural and functional cardiac abnormalities that can be prevalent in childhood chronic kidney failure (KF). Left ventricular mass (LVM) increase is most frequently reported and may persist post-kidney transplant especially with hypertension and obesity. While systolic dysfunction is infrequently seen in childhood chronic KF, systolic strain identified by speckle tracking echocardiography has been frequently identified in dialysis and it can also persist post-transplant. Echocardiogram association with long-term outcomes has not been studied in childhood KF but there are many adult studies demonstrating associations between increased LVM, systolic dysfunction, strain, diastolic dysfunction, and cardiovascular events and mortality. There has been limited study of interventions to improve echocardiogram status. In childhood, improved blood pressure has been associated with better LVM, and conversion from hemodialysis to hemodiafiltration has been associated with better diastolic and systolic function. Whether long-term cardiac outcomes are also improved with these interventions is unclear. Echocardiography is a well-established technique, and regular use in childhood chronic KF seems justified. A case can be made to extend screening to include speckle tracking echocardiography and intradialytic studies in high-risk populations. Further longitudinal studies including these newer echocardiogram modalities, interventions, and long-term outcomes would help clarify recommendations for optimal use as a screening tool., (© 2022. The Author(s).)

Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS "derived" haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an "ancestral" haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design., Competing Interests: FC is a co-founder of a start-up company TyrianOmega, which focuses on the production of omega-3 PUFAs by cyanobacteria, largely for animal feeds and aquaculture. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chilton, Manichaikul, Yang, O'Connor, Johnstone, Blomquist, Schembre, Sergeant, Zec, Tsai, Rich, Bridgewater, Mathias and Hallmark.)

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk., (© 2021. The Author(s).)

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy., Case Presentation: 45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable., Conclusions: Immunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.

Background: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported., Objective: To report a case of neonatal severe PB toxicity and review the elimination of PB by PD., Methods: Assessment of PD drug clearance., Results: A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications., Conclusions: PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination., (© 2017 S. Karger AG, Basel.)

DD kidney allocation protocols may influence timing of transplantation and graft quality for pediatric recipients. This study aimed to evaluate the effects of these protocols, including pediatric priority, on waiting time on dialysis, transplant type, donor age, and HLA matching according to state of transplant in Australia. De-identified information on patients <15 yr of age who commenced RRT in NSW, Qld, and Victoria from 2002 to 2011 was retrieved from the ANZDATA. Transplant type, donor age, and HLA mismatching were compared between states, with competing risk regression used to examine the time to transplant. There were significant differences in waiting time to DD transplantation between the three states. Children in NSW and Qld waited a median of 14 and 11 months vs. 21 months in Victoria. The ratio of LD to DD transplants was lower in NSW and Qld. Differences correlated with DD pediatric priority in NSW and Qld. DDs in NSW were older than in the other states. HLA matching did not differ. DD kidney allocation protocols with pediatric priority in Australian states were associated with shorter waiting times and increased DD proportion., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

NODAT is increasingly prevalent. Compared with adult recipients, NODAT is less prevalent in pediatric renal transplant recipients; however, some risk factors for its development in young patients have been defined. We report four pediatric renal transplant recipients with ARPKD who developed NODAT. We review the current pediatric NODAT literature and hypothesize that ARPKD may be an additional risk factor for NODAT., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.

A 14-year-old boy with known stable cystinosis, treated with cysteamine since infancy, presented with a deterioration of renal function with haematuria in conjunction with a nodular rash, arthralgia, leucopenia, hypocomplementaemia and raised antinuclear antibodies. He was diagnosed with spontaneous onset of systemic lupus erythematosus (SLE), and his renal biopsy was consistent with lupus nephritis. It is unusual for patients with one severe disease to develop another disease process completely unrelated to their original condition, but it can occur. However, other distinct variants of lupus have been described, including drug-induced lupus (DIL), which have features that over-lap with SLE. The potential differential diagnosis of the SLE as a form of DIL in association with cysteamine is discussed.

Background: Alginate-based gastroesophageal reflux disease treatments have been used extensively and fall into two main categories. Those containing alginate as the principle active agent and those containing alginate in combination with a significant amount of antacid., Method: The effectiveness of the raft formed by a new alginate/antacid suspension (Gaviscon Double Action Liquid, GDAL), in which calcium carbonate was the main antacid ingredient, was compared with those of existing alginate/antacid suspensions., Result: GDAL had similar raft strength and improved raft resilience than Gaviscon Liquid (GL), and both were significantly greater than five other products tested. Gastric retention of GDAL was similar to that of GL., Conclusion: the in vitro and in vivo performance is maintained in the new GDAL formulation even with higher antacid levels and the product is as good as, or better than, previous formulations.

Objectives: During a reflux event the oesophagus is exposed to a heterogeneous mixture of gastric juice components. The role of non-acid components of the refluxate in causing damage to the oesophagus is now well established but no therapeutic option exists to address this., Methods: The role of Gaviscon Advance (GA), a raft-forming alginate suspension, in protecting the oesophagus from damage by pepsin and bile acids (aggressors) was investigated using a series of in-vitro models., Key Findings: GA was able to dose-dependently inhibit pepsin activity over and above the neutralisation effect of the formulation. This was evident against both protein and collagen substrates using two distinct colorimetric assays. GA was able to retard the diffusion of pepsin and multiple bile acids using a Franz cell model. Using the raft-forming mode of action GA was able to remove both pepsin and multiple bile acids from a simulated reflux event. There was capacity in the GA raft to accommodate aggressors from multiple reflux events., Conclusions: GA can specifically remove both pepsin and bile acids from the refluxate, limit their diffusion and affect enzymatic activity of pepsin. There is a role for GA to reduce the damaging potential of the refluxate and thus protect the oesophagus.

Neurogenesis in the central olfactory pathway of decapod crustaceans persists throughout life. Here we describe the structural basis of neurogenesis within the olfactory deutocerebrum of the crayfish Procambarus clarkii from hatchlings to adults. Using a proliferation marker and immunostaining, we found that throughout development each hemibrain contains a neurogenic complex consisting of five parts: two proliferation zones, each within the neuronal soma clusters containing local or projection interneurons, a tail of proliferating cells extending from each proliferation zone, and an elongated clump of cells where the two tails meet. The clump of cells comprises two subdivisions joined at a nucleus-free central area. Each subdivision consists of a dense group of clump cells with small, spindle-shaped nuclei and is connected to one of the proliferation zones by a strand of fibrous material encompassing the tail of proliferating cells extending from it. We identify one proliferating cell with a large nucleus in each subdivision as a putative neuroblast. Its daughter cells migrate through the strands to the associated proliferation zones, but in the strand leading to the soma cluster of local interneurons this is masked by local proliferation. We conclude that neurogenesis in the olfactory deutocerebrum of juvenile and adult P. clarkii is based on a few neuroblasts that are associated with unique clumps of cells likely representing stem cell niches.

Laryngopharyngeal reflux (LPR) refers to the backflow of stomach contents into the laryngopharynx. Increasing evidence has demonstrated that LPR is a contributing factor in some cases of hoarseness, vocal fatigue, voice breaks, cough and globus and chronic throat clearing. However, several randomised placebo-controlled trials of proton pump inhibitors in the treatment of LPR have been reported with the majority showing no significant benefit in patient symptom scores over placebo. The aim of this pilot clinical study was to investigate whether any improvement in LPR-related symptoms, using the Reflux Symptom Index (RSI), and clinical findings, using the Reflux Finding Score (RFS), could be achieved with treatment with a liquid alginate suspension compared to control (no treatment). Patients presenting with the symptoms of LPR to the Otorhinolaryngology Outpatient Department at the Queen's Medical Centre, Nottingham, UK were considered eligible if they had an RSI of greater than 10 and an RFS greater than 5 based on a fibreoptic examination of the larynx. A total of 49 patients were randomised into the open, parallel group study; 24 patients were randomised to receive 10 ml liquid alginate suspension (Gaviscon Advance) four times daily after meals and at bedtime, and 25 patients into the control group (no treatment). Patients were assessed pre-treatment and at 2, 4 and 6 months post treatment. Mean (SD) RSI and RFS pre-treatment scores were 23.9 (7.0) and 10.4 (3.6) for the treatment group and 24.6 (7.4) and 10.3 (3.3) for the control group, respectively. Significant differences between treatment and control were observed for RSI at the 2-month (11.2 (7.0) vs. 16.8 (6.4), P=0.005) and 6-month (11.2 (8.1) vs. 18.3 (9.4), P=0.008) assessments and for RFS at the 6-month (7.1 (2.8) vs. 9.5 (3.4), P=0.005) assessment. Significant improvement in symptom scores and clinical findings were achieved with liquid alginate suspension (Gaviscon Advance) compared to control and further evaluation for the management of patients presenting with LPR is warranted.

Aims: The aim of this study was to compare alginate products with the same amount of active ingredients but different dosage forms, in the suppression of reflux provoked by a standard meal in healthy human volunteers, using ambulatory oesophageal pH monitoring., Methods: This was a single centre, randomised, open, three-period crossover, controlled study comparing Gaviscon Advance (10 ml) with a control (10 ml water) and with a new tablet product containing the same active ingredients as Gaviscon Advance. Volunteers who had oesophageal pH < 4 for at least 2% of the 4-h period after ingestion of a test meal followed by control at a reflux screening visit were included in the study., Results: The difference between Gaviscon Advance and control in the mean angular transformed percentage of time for which oesophageal pH fell below four was statistically significant (p < 0.0001) demonstrating the sensitivity of the method. No significant difference between the two alginate products was found based on the least squares adjusted mean angular transformed percentage of time for which pH fell below four. There were also no significant differences between the two alginate dosage forms in the angular transformed percentage of time for which oesophageal pH fell below five and in the log-transformed number of occasions on which oesophageal pH fell below four and five., Discussion and Conclusion: The study shows that alginate reflux suppressants containing a low amount of antacid are effective in suppressing acid reflux and that suspension and tablet forms are able to give equivalent acid suppression.

Olfactory cues are among the sensory inputs that crayfish use in establishing dominance hierarchies. Throughout their lives, new neurons are continuously added into brain cell clusters 9 and 10, which contain somata of olfactory local and projection interneurons, respectively. Using markers for DNA synthesis (bromodeoxyuridine) and mitosis (phospho-histone-3), we tested juvenile crayfish (Procambarus clarkii) to examine effects of pairwise social experience on proliferation and survival of cells in these brain regions. Proliferating and mitotic cells appeared within restricted neurogenic areas in both clusters and in ;tails' extending from them. These tails, embedded in tubulin-positive strands, are linked by a patch of cells. Neither cell proliferation nor mitotic activity was affected by social dominance. Cell survival of neuronal precursors was affected by dominance: compared to dominants, subordinates had fewer newborn cells surviving in cluster 9 after 14 days of social experience. Social experience also affected body growth rate, but the effect of social experience on neurogenesis remained when differences in body growth rate were statistically controlled. We conclude that social domination enhances survival of new olfactory interneuronal precursors compared to social subordination but not compared to social isolation.

The cardiac abnormalities that complicate chronic renal failure and renal replacement therapy are not well characterized in young people. These abnormalities are becoming more important because successful renal transplantation has resulted in children with end-stage renal failure living longer. Echocardiographic abnormalities of cardiac function and structure were studied in children and young adults (< 27 years old) with chronic renal failure (CRF, N = 32), end-stage renal failure treated with chronic peritoneal dialysis (CPD, N = 10) or renal transplantation (N = 30) or controls (N = 60). Left ventricular mass indexed for height (LVM/Ht and LVM/Ht2.7) and body surface area (LVM/SA), fractional shortening, measurement of left ventricular diastolic function (peak E and A wave velocities and the EA ratio) and structural (such as valvular) abnormalities were determined by echocardiography. The median (and range) of LVM/Ht in the groups were control 51.8 (23.1 to 119.8), CRF 60.2 (22.2 to 135.8), CPD 80.2 (14.5 to 100.9) and transplant group 97.8 (51.2 to 182.1) g/m. The increases in LVM/Ht, LVM/Ht2.7 and LVM/SA in the transplant group were significant (P < 0.01). The CRF group had significantly increased LVM/Ht2.7 and LVM/SA (P < 0.01). Systolic function was not significantly different between the groups. A significant correlation between creatinine and LVM indexed for height was found in the CRF group. Systolic or diastolic blood pressure could not be correlated with LVM indices in the transplant group. Changes in diastolic function were found (increased peak A wave velocity and decreased E/A ratios in the CRF and CPD groups, and increased peak E wave velocity in the transplant group). The study demonstrated that left ventricular hypertrophy is a frequent and often severe finding in children with chronic renal failure and those treated with renal replacement therapy. Factors other than hypertension and anaemia are important, and evidence was found for a link between serum creatinine and increased left ventricular mass prior to end-stage renal failure.

A male infant is described who had polyuria over the 4 months of his life with urine volumes exceeding 1,000 ml/kg per day, severe serum electrolyte losses, metabolic alkalosis and increased plasma renin activity (56 ng/ml per hour). He had a normal blood pressure and glomerular filtration rate when fluid replete. The urine flow rate was about 25% of the glomerular filtration rate. Renal histology showed hyperplasia of the juxtaglomerular apparatus and abnormalities of the proximal tubules. The features of this case suggest an extreme form of Bartter's syndrome presenting from the first days of life.

Tamm-Horsfall protein (THP) has been found in the renal interstitium in patients with obstructive uropathy. The aim of this study was to investigate whether serum concentrations of THP could serve as a screening test for urinary tract obstruction. The presence of THP in normal human serum was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis and Western blotting. A specific enzyme immunoassay was then used to measure the serum concentration of THP. Serum THP concentrations were estimated in a cross-sectional study of a group of 23 patients who had technetium-99m-diethylene-triaminepenta-acetic acid (DTPA) nuclear urinary excretion studies to define urinary tract obstruction, and in longitudinal studies in 2 patients who developed acute bilateral ureteric obstruction following operations for ureteric reimplantation. The subjects with DTPA-proven urinary tract obstruction had higher concentrations of serum THP (n = 10, median = 43.9 ng/ml, range 10.4-152.1 ng/ml) than those who did not have obstruction (n = 13, median = 9.6 ng/ml, range 1.26-61.9 ng/ml). While this difference was significant (P < 0.01, Mann-Whitney U test), 6 of the 10 patients with obstruction had serum THP concentrations within the range of those patients without obstruction. The patients who developed acute bilateral ureteric obstruction both had increases in serum THP concentrations with obstruction and decreases in serum THP concentrations following relief of obstruction. These changes paralleled those in serum creatinine. The studies indicate that urinary tract obstruction results in increases in serum THP concentrations but these changes are not sufficient in magnitude to allow screening of children for urinary tract obstruction.