Ectopic adrenal cortical tissue is not an infrequent incidental finding during abdominal and inguinal operations in infants; however, it is a rare finding in adults with only a few case reports described in the literature. We report a case of adrenal heterotopia as an incidental finding in a hernia sac from a 56 year-old man. We review the literature and discuss the importance of recognizing this rare finding.

The adrenal medulla is the inner part of adrenal glands located above each kidney, that produces catecholamines. Neuroblastoma and pheochromocytoma are the most prevalent malignancies of the adrenal medulla. Quantitative diagnosis of urinary catecholamines using HPLC-coupled Mass detectors is the current method for the diagnosis of neuroblastoma and pheochromocytoma. There are two major problems with this approach, (i) Because the catecholamines concentrations have short half-life (10-100 s), a series of urine tests must be performed throughout 24hr, detecting each catecholamine separately, is inconvenient and time-consuming; (ii) mass detectors are expensive, bulky, and require highly skilled personal. Vanillylmandelic (VMA), and homavanillic acid (HVA) are the by-products of catecholamines and are emerging alternative biomarker for catecholamines due to their high stability. Here, we developed a rapid, sensitive, miniaturized, and cheaper sensing platform for simultaneous quantifications of dopamine (DA), VMA, and HVA, with the aid of iron single-atom catalysts (Fe-SACs), based electrochemical sensor. SACs are atomically distributed metal atoms that have a maximum atomic utility rate of nearly 100%, compared to 30% for traditional metal nanoparticles. MXene sheets are employed to stabilize Fe-SACs, where, the exposed lone pairs of MXene serve as sites covalently linking high-energy single Fe atoms. MXene/Fe-SACs were synthesized by treating Ti3C2TxMXene with Iron chloride via freeze-drying followed by annealing. The successful formation of the material was verified by state-of-the-art characterizations. The MXene/Fe-SACs show superior electrocatalytic performance to the commonly used Fe- nanomaterials. Then, it was coated on the electrode surface and used to analyze DA, VMA, and HVA simultaneously via cyclic voltammetry (CV) and square-wave voltammetry (SWV). Under optimized conditions, the MXene/Fe-SACs electrochemical sensor showed detection limits as low as 1 nM and a linear range between 1 nM-100 μM for DA, LOD of 5 nM & linear range of 10 nM-100 μM VMA, and LOD of 10 nM & linear range of 20 nM-100 μM HAV. The method proved successful in detecting biomarkers in (spiked) synthetic urine and human serum. Furthermore, the method was successfully demonstrated in the determination of DA release from PC12 live cells, suggesting the wide practical use of SACs in sensing catecholamines-related metabolites.

<p> Asphyxia (hypoxia, hypercapnia, and acidosis) sensing by neonatal adrenal chromaffin cells (AMC) plays a key role in the adaptation of the neonate to extrauterine environment. During birth, exposure of the neonate to episodes of acute asphyxia results in secretion of catecholamines from AMC, independent of neural inputs. This catecholamine (CAT) secretion promotes re-absorption of fluid and surfactant production in the lung, improved cardiac conductance, and assists in neonatal arousal. The asphyxia-sensing responses in AMC are lost postnatally during a time course that parallels splanchnic innervation. </p> </p> <p> The primary goal of this thesis was to uncover the mechanisms of asphyxia sensing in neonatal rat AMC, using primary and immortalized chromaffin cells, and to elucidate the potential role of innervation in the postnatal loss of these mechanisms. The experimental approaches relied on patch clamp techniques to record ionic currents and membrane potential, carbon fiber amperometry to monitor CAT secretion, chemiluminescence to measure reactive oxygen species (ROS) production and ATP secretion, and molecular techniques to examine protein and gene expression. </p> <p> In primary neonatal, but not juvenile AMC, hypoxia (PO₂ = 15 mmHg) caused a suppression of outward K⁺ current, membrane depolarization, and increased secretion. These effects were associated with a decrease in mitochondrial ROS production, were reversed by exogenous H₂O₂, and where mimicked by antioxidants. Of several mitochondrial electron transport chain (ETC) inhibitors tested, only rotenone, a complex I blocker, mimicked and occulded the effects of hypoxia. The immortalized chromaffin cell line (MAH cells) behaved similarly, and became hypoxia-insensitive when depleted of functional mitochondria (ρ0 MAH). Both neonatal AMC and immortalized MAH cells also responded to increased CO₂ (hypercapnia) with K⁺ current inhibition, membrane depolarized, increased intracellular Ca²⁺, and CAT secretion. However, these responses were independent of functional mitochondria and were associated with the expression of carbonic anhydrase II (CAII). </p> <p> Since the splanchnic nerve supplies both cholinergic and opioid peptidergic innervation to AMC, I tested the hypothesis that postsynaptic activation of the corresponding receptors might underlie the postnatal loss of asphyxia-sensing. First, to determine whether nicotinic acetylcholine receptor stimulation was involved, pregnant rats were exposed to nicotine (or saline) during gestation and AMC were examined in the offspring, soon after birth. Control AMC isolated from pups born to saline-treated dams displayed typical responses to hypoxia and hypercapnia, including inhibition of outward K⁺ current, membrane depolarization, increased cytosolic calcium, and CAT secretion. In contrast, AMC from pups born to nicotine-treated dams showed a dramatic loss of hypoxic sensitivity, though hypercapnic sensitivity and the expression of CO₂ markers (i.e. carbonic anhydrase I and II) appeared normal. This effect of chronic nicotine could be reproduced in cultured chromaffin cells in vitro and was mediated via activation of α7-nicotinic acetylcholine receptors (nAChR), leading to upregulation of ATP-dependent (K_ATP) K⁺ channels, which open during hypoxia and cause membrane hyperpolarization. The upregulation of K_ATP channels involved expression ofthe hypoxia inducible transcription factor (HIF 2α). Second, to determine whether opioid receptor stimulation was also involved, cultured chromaffin cells were chronically exposed to mu, delta, or kappa opioid agonists in vitro. Treatment with both mu and delta, but not kappa, agonists resulted in the loss of both hypoxia and hypercapnia sensing and a decrease in CAII expression. </p> <p> Taken together, these studies suggest that neonatal chromaffin cells sense hypoxia via a reduction in ROS generation located at or upstream of mitochondrial complex I. Chronic stimulation of nicotinic α7 ACh receptors leads to a selective loss of hypoxia sensing and this appears to be mediated via a HIF 2α-dependent upregulation of K_ATP channels. These channels open during hypoxia causing membrane hyperpolarization and reduced excitability. The result of this upregulation of K_ATP channels results in cells deficient in the ability to respond to hypoxia. </p> / Thesis / Doctor of Philosophy (PhD)

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No / Gestational stress (GS) produces profound behavioural impairments in the offspring and may permanently programme hypothalamic¿pituitary¿adrenal (HPA) axis function. We investigated whether or not GS produced changes in the maternal behaviour of rat dams, and measured depression-like behaviour in the dam, which might contribute to effects in the progeny. We used the Porsolt test, which measures immobility in a forced-swim task, and models depression in rodents, while monitoring maternal care (arched-back nursing, licking/grooming, nesting/grouping pups). Pregnant rats underwent daily restraint stress (1 h/day, days 10¿20 of gestation), or were left undisturbed (control). On post-parturition days 3 and 4, dams were placed into a swim tank, and time spent immobile was measured. GS significantly elevated immobility scores by approximately 25% above control values on the second test day. Maternal behaviours, in particular arched-back nursing and nesting/grouping pups, were reduced in GS dams over post-natal days 1¿10. Adult offspring showed increased immobility in the Porsolt test, and also hypersecreted ACTH and CORT in response to an acute stress challenge. These data show that GS can alter maternal behaviour in mothers, and this might contribute to alterations in the offspring. GS may be an important factor in maternal post-natal depression, which may in turn detrimentally effect the offspring because depressed mothers do not sufficiently care for their offspring.

Thesis (PhD)-- Stellenbosch University, 2013. / ENGLISH ABSTRACT: Although the effect of inhaled corticosteroids (ICS) on the hypothalamic- pituitary-adrenal axis (HPA) has been regarded as a “benign physiological response”, a survey published in 2002 suggested that adrenal crisis is more common in asthmatic children on ICS than previously thought. Relying on clinical features to detect chronic adrenal insufficiency secondary to corticosteroids may not be wise, as these are non-specific and can therefore easily be missed. Accurate biochemical assessment of the whole axis to detect subclinical HPA suppression (HPAS) is thus desirable. A review of the literature indicates that basal adrenal function tests, including plasma cortisol profiles, do not identify which children can appropriately respond to stress. There is no evidence to suggest that the degree of the physiological adjustment of the HPA to ICS and/or nasal steroids (by reducing basal cortisol production), predicts HPAS. Cortisol profiles should therefore only be used to demonstrate differences in systemic activity of various ICS and delivery devices. Only two tests, considered as gold standard adrenal function tests [the insulin tolerance test (ITT) and the metyrapone test] can assess the integrity of the whole axis. / AFRIKAANSE OPSOMMING: Die outeurs van ´n opname wat in 2002 gepubliseer is stel voor dat ´n bynierkrisis meer algemeen by asmatiese kinders, wat inhalasie kortikosteroïede ontvang, voorkom as wat voorheen gedink is. Dit is strydig met die gevestigde opvatting dat die effek van IKS op die hipotalamiese-hipofise-bynier-as (HHB) ’n “goedaardige fisiologiese reaksie” is. Die kliniese kenmerke van kroniese bynierontoereikendheid sekondêr tot die gebruik van kortikosteroïede (KS) is nie-spesifiek en gevolglik onbetroubaar. ´n Akkurate biochemiese toets van subkliniese HBB onderdrukking (HHBO) sou gevolglik waardevol wees. ´n Literatuur oorsig toon dat toetse van basale bynierfunksie, insluitend plasma kortisol (K) profiele, nie kinders uitken wat toepaslik op stres sal reageer nie. Daar is geen bewyse dat die graad van fisiologiese aanpassing van die HHB, soos aangedui deur laer K-vlakke, na die gebruik van IKS en/of nasale steroïede (NS), HHBO voorspel nie. Serum K profiele is dus slegs van waarde om die sistemiese aktiwiteit van verskillende IKS en toedieningsstelsels te ondersoek. Slegs twee toetse, naamlik die insulien toleransie toets (ITT) en die metyrapone -(MTP)-toets (wat beide as die goue standaard van bynier funksie beskou word), kan die integriteit van die hele as meet. / Stellenbosch University / Medical Research Council / SA Thoracic Society / Harry Crossley Foundation / Red Cross Children’s Hospital.