What's known on the subject? and What does the study add?• Stretch of the urothelium, as occurs during bladder filling, is associated with a release of ATP that is postulated to act as a sensory neurotransmitter. The regulation of ATP release is poorly understood and in particular if there is a feedback mechanism provided by ATP itself.• Adenosine, a breakdown product of ATP, is a potent inhibitor of stretch-induced ATP release, acting through and A1 receptor; endogenous levels are about 0.6mM . Data are consistent with ATP release relying on the rise of intracellular Ca2+. Transepithelial potential also controls ATP release, also acting via an A1 receptor-dependent pathway. Objectives• To test the hypothesis that distension-induced ATP release from the bladder urothelium is regulated by adenosine as well as changes to transurothelial potential (TEP).• To examine the role of changes to intracellular [Ca 2+ ] in ATP release. Materials and Methods• Rabbit urothelium/suburothelium membranes were used in an Ussing chamber system. Distension was induced by fluid removal from the chamber bathing the serosal (basolateral) membrane face.• The TEP and short-circuit current were measured. ATP was measured in samples aspirated from the serosal chamber by a luciferin-luciferase assay. • Intracellular [Ca 2+ ] was measured in isolated urothelial cells using the fluorochrome Fura-2. All experiments were performed at 37°C. Results• Distension-induced ATP release was decreased by adenosine (1-10 mM) and enhanced by adenosine deaminase and A1-(but not A2-) receptor antagonists.• Distension-induced ATP release was reduced by 2-APB, nifedipine and capsazepine; capsaicin induced ATP release in the absence of distension.• ATP and capsaicin, but not adenosine, generated intracellular Ca 2+ transients; adenosine did not affect the ATP-generated Ca 2+ transient.• ATP release was dependent on a finite transepithelial potential. Changes to TEP, in the absence of distension, generated ATP release that was in turn reduced by adenosine. Conclusion• Adenosine exerts a powerful negative feedback control of ATP release from the urothelium via A1 receptor activation.• Distension-induced ATP release may be mediated by a rise of the intracellular [Ca 2+ ].• Modulation of distension-induced ATP release by adenosine and TEP may have a common pathway.
BackgroundProgressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder.MethodChildren with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra–interfamilial phenotypic correlations and genotype–phenotype correlations when pathological mutations were identified.ResultsTwenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl’s DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes.ConclusionsWe found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities—and are phenotypic endpoints of many severe genetic encephalopathies.
Purpose: Increasingly non-cardiac tertiary neonatal intensive care units (NCTNs) manage newborns with CHD prior to planned transfer to specialist cardiac surgical centres (SCSC). It improves patient flow in SCSCs, enables families to be nearer home, and improves psychological well-being1. This practice has gradually increased as the number of SCSCs has decreased. This study examines the effectiveness of this expanding practice. The management provided, length of stay and outcomes are described for one UK NCTN situated at a significant distance from its SCSC. Methods: A retrospective observational study of cardiac-related admissions to a NCTN between January 2010 and December 2019 was conducted. Results: 190 neonates were identified: 41 had critical CHD; 64 had major CHD. The cohort includes babies with a wide range of cardiac conditions and additional complexities. 23.7% (n=45) required transfer to a specialist centre after a period of stabilisation and growth ranging from several hours to 132 days. 68% (n=130) were discharged home or repatriated to a local NICU. Of the remaining 15 babies, 13 were transferred to other specialties including the hospice. Two died on NICU.The mortality was consistent with the medical complexity of the group2,3. 8.9% (n=17) died before age 2. Nine babies had care redirected due to an inoperable cardiac condition or life-limiting comorbidities.Conclusion: Our study demonstrates a complex neonatal cohort with CHD can be managed effectively in a NCTN, supporting the current model of care. The NCTN studied was well supported by paediatricians with expertise in cardiology alongside visiting paediatric cardiologists.
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