Hannah Forde

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study

The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency.

Parathyroid adenoma in a patient with familial hypocalciuric hypercalcaemia

A 57-year-old man with symptoms of fatigue, joint pains and insomnia was found to have hypercalcaemia secondary to hyperparathyroidism with a corrected calcium of 2.61 mmol/L (2.2–2.6 mmol/L) and a serum parathyroid hormone (PTH) of 86 pg/mL (10–65 pg/mL). Preoperative workup demonstrated a parathyroid adenoma in the right upper position and he proceeded to surgery. Postoperatively, however, his symptoms remained unchanged and the corrected calcium remained elevated at 2.87 mmol/L with a PTH of 59 pg/mL. He had no family history of hypercalcaemia. Further investigations revealed low 24 h urinary calcium level and a low urine calcium to creatinine ratio. Genetic testing revealed a mutation in exon 4 of the calcium sensing receptor (CaSR) confirming a diagnosis of familial hypocalciuric hyercalcaemia (FHH). The case is an example of a rare phenomenon when a parathyroid adenoma develops in patients with FHH.

TRAIL attenuates RANKL-mediated osteoblastic signalling in vascular cell mono-culture and co-culture models

Background and objectives Vascular calcification (VC) is a major risk factor for elevated cardiovascular morbidity/mortality. Underlying this process is osteoblastic signalling within the vessel wall involving complex and interlinked roles for receptor-activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). RANKL promotes vascular cell osteoblastic differentiation, whilst OPG acts as a neutralizing decoy receptor for RANKL (and TRAIL). With respect to TRAIL, much recent evidence points to a vasoprotective role for this ligand, albeit via unknown mechanisms. In order to shed more light on TRAILs vasoprotective role therefore, we employed in vitro cell models to test the hypothesis that TRAIL can counteract the RANKL-mediated signalling that occurs between the vascular cells that comprise the vessel wall. Methods and results Human aortic endothelial and smooth muscle cell mono-cultures (HAECs, HASMCs) were treated with RANKL (0–25 ng/mL ± 5 ng/mL TRAIL) for 72 hr. Furthermore, to better recapitulate the paracrine signalling that exists between endothelial and smooth muscle cells within the vessel wall, non-contact transwell HAEC:HASMC co-cultures were also employed and involved RANKL treatment of HAECs (±TRAIL), subsequently followed by analysis of pro-calcific markers in the underlying subluminal HASMCs. RANKL elicited robust osteoblastic signalling across both mono- and co-culture models (e.g. increased BMP-2, alkaline phosphatase/ALP, Runx2, and Sox9, in conjunction with decreased OPG). Importantly, several RANKL actions (e.g. increased BMP-2 release from mono-cultured HAECs or increased ALP/Sox9 levels in co-cultured HASMCs) could be strongly blocked by co-incubation with TRAIL. In summary, this paper clearly demonstrates that RANKL can elicit pro-osteoblastic signalling in HAECs and HASMCs both directly and across paracrine signalling axes. Moreover, within these contexts we present clear evidence that TRAIL can block several key signalling actions of RANKL in vascular cells, providing further evidence of its vasoprotective potential.

RANKL Inhibits the Production of Osteoprotegerin from Smooth Muscle Cells under Basal Conditions and following Exposure to Cyclic Strain

Receptor activator of nuclear factor-κB ligand (RANKL) promotes vascular calcification, while osteoprotegerin (OPG) opposes it by blocking RANKL activity. It remains unclear which vascular cell populations produce and secrete OPG/RANKL. This study characterizes the production of OPG/RANKL from human aortic endothelial and smooth muscle cells (HAECs and HASMCs) under various conditions. HAECs and HASMCs were exposed to inflammatory stimuli (tumor necrosis factor-α or hyperglycemia) or physiological levels of hemodynamic (cyclic) strain. After 72 h, both cells and supernatant media were harvested for assessment of OPG/RANKL production. Based on initial findings, the experiments involving HASMCs were then repeated in the presence of exogenous RANKL. OPG was produced and secreted by HASMCs and (to a considerably lesser degree) HAECs under basal conditions. Inflammatory stimuli upregulated OPG production in both cell populations. Cyclic strain significantly upregulated OPG production in HASMCs. Neither cell population produced RANKL. Exposing HASMCs to exogenous RANKL inhibited basal OPG production and completely abrogated the strain-mediated upregulation of OPG. These data suggest that HASMCs are a significant source of OPG within the vasculature but that RANKL, once present, downregulates this production and appears capable of preventing the “protective” upregulation of OPG seen with HASMCs exposed to physiological levels of cyclic strain.

Glucose sensing technology—current practice?

There are approximately 28,500 people with type 1 diabetes (T1DM) in the Republic of Ireland. Frequent self-monitoring of blood glucose (SMBG) allows accurate and directed selfmanagement for patients with T1DM and is imperative in attaining glycaemic targets [1]. From testing for glycosuria to measuring capillary blood glucose levels with a portable glucometer, there have been considerable technological advances over the past 60 years to facilitate SMBG in patients with diabetes. However, even when patients test their glucose level 4–5 times per day, they remain at risk of hypoglycaemia and significant glucose variability. Hence, the development of continuous glucose monitoring systems (CGMS) has been a welcome addition to the ever-evolving field of diabetes technologies. The concept of glucose sensing technology is not new. In 1962, Clark and Lyons described the principle of ‘enzyme containing membrane electrodes’ [2]. They proposed utilising a glucose permeable membrane to trap a thin layer of glucose oxidase containing solution and measuring the oxygen consumption by the enzyme catalysed reaction (i.e. glucose + O2 — > gluconic acid + H202) with an adjacent electrode [2]. This concept was refined further by Guilbault and Lubrano, who described an enzyme electrode for glucose detection based on the measurement of the hydrogen peroxide product of the reaction [3]. Subsequently, a third strategy for electrochemical sensing was developed. The addition of a redox mediator to the reaction, to facilitate the efficient transfer of electrons between the glucose oxidase enzyme and the electrode is the principle on which the current market leading sensors are based. Thirty years after Clark and Lyons published their seminal work, Moatti-Sirat et al., implanted glucose sensors into the subcutaneous tissue of rats and demonstrated accurate estimations of blood glucose concentrations by the sensors for up to 10 days [4]. It is now clear that a good linear relationship exists between subcutaneous interstitial fluid (ISF) glucose concentrations and plasma glucose levels. However, there is approximately a 5–10-minute delayed response in post prandial ISF measurements compared to blood glucose concentrations [5]. In 2006, the FDA approved the DEXCOM SEVEN device, the first continuous glucose monitoring (CGM) system for patients with diabetes. Since then, several CGM systems have become commercially available and emerging research is now focussed on developing non-invasive sensing techniques, i.e. optical/transdermal sensors. CGM provides patients with information on the duration, magnitude and frequency of blood glucose fluctuations by measuring ISF glucose levels every 1–10 minutes. Data can be accessed by the patient in Breal-time^ or retrospectively depending on the sensor [6]. This facilitates the identification of glucose trends and may help prevent episodes of hyperor hypoglycaemia. Some sensors have an additional alarm feature which alerts the patient when they are hyperor hypoglycaemic. Multiple clinical trials have demonstrated that CGM is better than SMBG for improving glycaemic control in select patient groups. Battelino et al. compared CGM with SMBG in 120 adults and children using multiple daily injections (MDI) over a 6-month period and demonstrated improved glycaemic control and reduced time spent in hypoglycaemia in those patients using CGM [7]. Sensor technology has also been used in conjunction with insulin pump therapy with encouraging results. In the STAR3 study, sensor augmented pump (SAP) therapy was associated with significant reductions in glycated haemoglobin (HbA1c) (− 0.8%) compared with MDI (− 0.2%) in almost 500 patients after 12 months [8]. Some SAPs have a threshold suspend feature which interrupts the delivery of insulin at a preset sensor glucose value. These are particularly useful for patients with impaired awareness of hypoglycaemia and have been shown to signif icant ly reduce the frequency of nocturnal hypoglycaemia compared with SAP alone [9]. Despite the promising results emerging from clinical trials, there are a number of limitations to CGM. Firstly, patient selection is of critical importance. The American Diabetes * Hannah E. Forde hannahforde@gmail.com