Impact of Intraprocedural Sedation on Adrenal Vein Sampling without Corticotropin Stimulation.

See also the editorial by Georgiades in this issue.

Age- and sex-specific reference ranges are needed for the aldosterone/renin ratio.

OBJECTIVE: Current Endocrine Society Clinical Practice Guidelines use a specific aldosterone/renin ratio (ARR) threshold to screen for primary aldosteronism (a treatable disease causing up to 15% of hypertension in primary care) in all patients. We sought to characterize demographic variations in the ARR, hypothesizing a need for age- and sex-specific reference ranges to improve the accuracy of the test. DESIGN: Retrospective cross-sectional analysis of ARR measurements at a single tertiary hospital from December 2016 to June 2018. PATIENTS: A total of 442 patients with clinically indicated ARR were included, after excluding those who were on spironolactone or the oral contraceptive pill, were pregnant or had an existing adrenal condition. MEASUREMENTS: Aldosterone, renin and the ARR. RESULTS: Among those aged 20-39 years (n = 74), females had significantly higher median aldosterone (369 vs 244 pmol/L, P = .028), lower median renin (17.0 vs 27.6 mIU/L, P = .034) and higher median ARR (20.7 vs 10.3 (pmol/L)/(mIU/L), P = .001) than males, despite having lower systolic (135 vs 145 mmHg, P = .021) and diastolic (89 vs 96.5 mmHg, P = .007) blood pressure. The ≥ 60-year age group (n = 157) also had significant sex differences in the ARR. With increasing age (20-39 vs ≥ 60 years), there was a significant fall in plasma aldosterone in females (369 pmol/L vs 264 pmol/L, P = .005), with no change observed in males. CONCLUSIONS: For those 20-39 years old, aldosterone and the ARR are significantly higher in females despite a lower systolic and diastolic BP, highlighting the potential for false-positive results. Our findings indicate the need for prospective studies with a control population to define age- and sex-specific ARR reference ranges.

Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization.

BACKGROUND: Adrenal vein sampling (AVS) is crucial for accurate lateralization of aldosterone excess but it is technically challenging due to the difficulty of adrenal vein cannulation. The use of adrenocorticotropic hormone (ACTH) to improve cannulation success is controversial and can lead to discordant lateralization outcomes. OBJECTIVE: To evaluate the utility of ACTH in two centres with different levels of AVS expertise and formulate a strategy for interpreting discordant results. DESIGN: A retrospective cross-sectional analysis of AVS results and postoperative patient outcomes. SETTING: Two large tertiary hospitals with harmonized AVS protocols where adrenal venous samples are collected both before and after ACTH stimulation. MEASUREMENTS: Cannulation success (measured by selectivity index, SI), lateralization (measured by lateralization index, LI) and postoperative biochemical cure. RESULTS: Number of AVS procedures judged to have successful bilateral adrenal vein cannulation increased from 53% pre- to 73% post-ACTH. The increase in cannulation success was significantly higher in centre where AVS was performed by multiple radiologists with a lower basal success rate. In both centres, the proportion of cases deemed to display lateralization significantly decreased with the use of ACTH (70% pre- to 52% post-ACTH). Based on postoperative outcomes of patients with discordant results who underwent unilateral adrenalectomy, the combination of LI >3 pre-ACTH and LI >2 post-ACTH was predictive of a biochemical cure. CONCLUSION: Adrenocorticotropic hormone can increase the rate of cannulation success during AVS at the expense of reduced lateralization. The criteria for lateralization should be carefully determined based on local data when ACTH is used.

Comparison of the efficacy of tea tree (Melaleuca alternifolia) oil with other current pharmacological management in human demodicosis: A Systematic Review.

Various treatments are found to be moderately effective in managing Demodex-related diseases except tea tree oil (TTO) and terpinen-4-ol (T4O), which showed superior miticidal and anti-inflammatory effects in numerous clinical studies. Their possible effects include lowering mite counts, relieving Demodex-related symptoms, and modulating the immune system. This review summarizes the current clinical topical and oral treatments in human demodicosis, their possible mechanisms of action, side-effects and resistance in treating this condition. TTO (especially T4O) is found to be the most effective followed by metronidazole, ivermectin and permethrin in managing the disease. This is because TTO has anti-parasitic, anti-bacterial, anti-fungal, anti-inflammatory and wound-healing effects. Furthermore, nanoTTO can even release its contents into fungus and Pseudomonas biofilms. Combinations of different treatments are occasionally needed for refractory cases, especially for individuals with underlying genetic predisposal or are immuno-compromised. Although the current treatments show efficacy in controlling the Demodex mite population and the related symptoms, further research needs to be focused on the efficacy and drug delivery technology in order to develop alternative treatments with better side-effects profiles, less toxicity, lower risk of resistance and are more cost-effective.

Artemisinin and its derivatives: a potential treatment for leukemia.

Artemisinin (ART) and its derivatives are one of the most important classes of antimalarial agents, originally derived from a Chinese medicinal plant called Artemisia annua L. Beyond their outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess both in-vitro and in-vivo activities against various types of cancer. Their anticancer effects range from initiation of apoptotic cell death to inhibition of cancer proliferation, metastasis and angiogenesis, and even modulation of the cell signal transduction pathway. This review provides a comprehensive update on ART and its derivatives, their mechanisms of action, and their synergistic effects with other chemicals in targeting leukemia cells. Combined with limited evidence of drug resistance and low toxicity profile, we conclude that ART and its derivatives, including dimers, trimers, and hybrids, might be a potential therapeutic alternative to current chemotherapies in combating leukemia, although more studies are necessary before they can be applied clinically.

Saline suppression test parameters may predict bilateral subtypes of primary aldosteronism.

BACKGROUND: The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA) whilst adrenal vein sampling (AVS) is used to determine whether the aldosterone hypersecretion is unilateral or bilateral. An accurate prediction of bilateral PA based on SST results could reduce the need for AVS. AIM: We sought to identify SST parameters that reliably predict bilateral PA. METHODS: The results from 121 patients undergoing SSTs at Monash Health from January 2010 to January 2018 including screening blood tests, imaging, AVS and histopathology results were evaluated. Patients were subtyped into unilateral or bilateral PA based on AVS and surgical outcomes. RESULTS: Of 113 patients with confirmed PA, 33 had unilateral disease whilst 42 had bilateral disease. In those with bilateral disease, plasma aldosterone concentration (PAC) was significantly lower post-SST, together with a significant fall in the aldosterone-renin ratio (ARR). The combination of PAC < 300 pmol/L and a reduction in ARR post-SST provided 96.8% specificity in predicting bilateral disease. Eighteen of 39 patients (49%) with bilateral PA could have avoided AVS using these criteria. CONCLUSION: A combination of PAC < 300 pmol/L and a lower ARR post-SST could reliably predict bilateral PA. An independent cohort will be needed to validate these findings.

Can the tea tree oil (Australian native plant: Melaleuca alternifolia Cheel) be an alternative treatment for human demodicosis on skin?

Australian tea tree oil (TTO) and its extract terpinen-4-ol (T4O) are found to be effective in moderating demodex-related diseases. Their possible effects are lowering the mite counts, relieving the demodex-related symptoms and modulating the immune system especially the inflammatory response. This review summarizes the topical treatments of TTO and T4O in human demodicosis, their possible mechanism of actions, side-effects and potential resistance in treating this condition. Although current treatments other than TTO and T4O are relatively effective in controlling the demodex mite population and the related symptoms, more research on the efficacy and drug delivery technology is needed in order to assess its potential as an alternative treatment with minimal side-effect profile, low toxicity and low risk of demodex resistance.

Use of deferasirox (Exjade) for iron overload in peritoneal dialysis patients.

A 54 year old male with b-Thalassemia major developed ESRD and was managed with continuous ambulatory peritoneal dialysis. Although not able to be transfused due to high titre red cell antibodies he did require management of iron overload. Deferasirox (Exjade) was administered orally. There was concern that excretion of iron via the peritoneal dialysate may raise the risk of iron-dependent infections (Yersinia and Rhizopus).Whilst receiving Exjade 1000mg /day, a total collection of 12.7L of peritoneal dialysate was collected over a 24 hour period by the patient. The dialysate total iron levels were measured by ICP-MS at 0.46mmol/L which equates to 0.33mg of Fe in total. Over a 6 month period his serum ferritin fell from 3869µg/l to 1545µg/l. There were no episodes of peritonitis. Since only 7-8% of the deferasirox and iron complex is excreted through the urine, the amount of Fe seen in the patient's dialysate might be expected to be up to 1.5-1.6mg. Yet, the results of the Fe levels in the patient's PD fluid was a meagre 0.33mg, about five times lower than expected.Whilst only moderately effective at a dosage of 1000mg/day, deferasirox may be a safe agent for iron removal in iron overloaded peritoneal dialysis patients, as relatively low dialysate iron levels reduces the risk of Yersinia and Rhizopus infection.

Maternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin.

OBJECTIVE: Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. STUDY DESIGN AND MEASUREMENTS: Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P < 0·05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. CONCLUSIONS: These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children.

Urolithiasis is prevalent and associated with reduced bone mineral density in ß-thalassaemia major.

Asymptomatic urolithiasis is common and of mixed composition in patients with ß-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.

Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants.

AIM: There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. METHODS: This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. RESULTS: Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). CONCLUSION: Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study.

Vitamin D testing in pregnancy: Does one size fit all?

BACKGROUND: Vitamin D deficiency is common. What the optimum level of vitamin D in pregnancy and whether vitamin D supplementation in pregnancy confers improved health benefits remain controversial. AIM: To assess vitamin D status in pregnant women in a maternity service that recommends routine antenatal screening and advises supplementation where necessary, and to assess relationships between early pregnancy vitamin D levels and changes in vitamin D across pregnancy with pregnancy outcomes. MATERIALS AND METHODS: Vitamin D serum concentrations were measured in early and late pregnancy. The relationships between initial vitamin D status, maternal factors and pregnancy outcomes were estimated. Change in vitamin D over pregnancy was quantified. The relationship between change in vitamin D over pregnancy and pregnancy outcomes was also estimated. RESULTS: Of 1550 women, 849 (55%) were vitamin D deficient (<50 nmol/L), 571 (37%) were insufficient (50-74 nmol/L), and 130 (8%) were replete (≥75 nmol/L) in early pregnancy. Factors associated with deficiency were increased body mass index, pregnancy in either winter or spring months, and maternal country of birth (South-East, South and East Asia, and Africa). Vitamin D deficiency or insufficiency in early pregnancy was significantly associated with developing gestation diabetes mellitus. Levels of vitamin D significantly increased over pregnancy among nonreplete women. Increasing vitamin D over pregnancy was not related to pregnancy outcomes. CONCLUSION: Vitamin D 'deficiency' is common but may not be associated with most adverse pregnancy outcomes. Routine vitamin D testing of all pregnant women does not appear warranted.

Preterm lambs given intravenous dopamine show increased dopamine in their cerebrospinal fluid.

AIM: Dopamine is used as an inotropic medication in preterm infants. The preterm human blood brain barrier (BBB) is permeable to intravascular dopamine, and the impact of exogenous dopamine on the preterm brain remains unknown. The preterm lamb model may be suitable for studying the cerebral impact of dopamine therapy whether its BBB permeability is similar to preterm human infants. We aimed to examine BBB permeability to exogenous dopamine in the preterm lamb, by measuring dopamine levels in the cerebrospinal fluid (CSF). METHODS: Nine preterm foetal lambs (125-130 days, term = 147 days) were given either dopamine at 10 µg/kg/min (dopamine, n = 4) or saline (control, n = 5). CSF, and plasma samples were taken for dopamine assay. RESULTS: The median (range) baseline CSF dopamine level for the combined control and dopamine groups (n = 9) was 0.10(0.03-0.16) ng/mL, and baseline plasma dopamine was 0.30(0.13-0.84) ng/mL. The dopamine lambs showed increase in CSF dopamine to 3.91(1.87-11.35) ng/mL with plasma dopamine increased to 14.2 (9.1-57.9) ng/mL. No change was found in the control lambs. CONCLUSION: In the preterm lamb, the BBB permeability and pharmacokinetics to dopamine infusion are similar to findings in the preterm human infant, supporting applicability of the preterm lamb model for studying effects of dopamine infusion in the preterm human brain.

The where, who and how of adrenal vein sampling in Australia and New Zealand.

INTRODUCTION: Primary aldosteronism (PA) causes 10-15% of cases of hypertension, and it is increasingly recognised as being under-diagnosed. An interventional radiology procedure, adrenal vein sampling (AVS), is a necessary and important diagnostic procedure for complete workup of PA. There is an anticipated increase in demand for AVS as detection of PA improves. This study aims to describe the current landscape of AVS in Australia and New Zealand (NZ). METHODS: Two surveys exploring AVS methodology and performance were conducted of (i) Endocrinology Unit Heads and (ii) interventional radiologists who perform AVS, at public hospitals with Endocrinology Units across Australia and NZ. RESULTS: Responses were received from 48/53 Endocrinology Unit Heads (91%) and 35 radiologists from 26 sites (87% of AVS sites). AVS was provided at 28/48 Endocrinology sites (58%) across Australia and NZ. In Australia, sites were concentrated in Victoria, New South Wales and Queensland with none in the Northern Territory; in NZ, sites were more evenly distributed across the North and South Islands. AVS was performed by 1-2 dedicated radiologists at 24 sites, 2-3 radiologists at two sites and a rotating roster of radiologists at two sites. Responses to both surveys revealed significant variation in AVS methodology and interpretation of AVS results. CONCLUSION: There is significant heterogeneity in the availability of AVS, the procedural details and the interpretation of results across Australia and NZ, which potentially impacts the quality of patient care and ability to scale up AVS capacity to meet increasing demand.

Cortisol: ACTH ratio to test for primary hypoadrenalism: a pilot study.

INTRODUCTION: A standard short Synacthen test (SST) is the conventional diagnostic test for primary hypoadrenalism. Measuring simultaneous plasma cortisol and adrenocorticotrophin hormone (ACTH) and using the cortisol: ACTH ratio as a first-line test may be safer and more convenient than performing a SST. METHODS: A retrospective study of 349 patients who had a SST with simultaneous baseline plasma cortisol and ACTH performed between 2005 and 2010 in two separate Australian health centres. The plasma cortisol: ACTH ratio was calculated for each patient and their final diagnosis was determined based on their SST result and a review of their clinical notes. RESULTS: Eighteen patients had primary hypoadrenalism, 46 patients had secondary hypoadrenalism and 285 patients had normal adrenal function. All the patients with primary hypoadrenalism had a plasma cortisol: ACTH ratio <3, while none of the patients with normal adrenal function or secondary hypoadrenalism had a cortisol: ACTH ratio <3. Therefore, a cortisol: ACTH ratio <3 had a 100% sensitivity and specificity for the diagnosis of primary hypoadrenalism. Patients with secondary hypoadrenalism had a cortisol: ACTH ratio >3, while subjects with normal adrenal function had a cortisol: ACTH ratio >15. There was overlap in cortisol: ACTH ratios of patients with secondary hypoadrenalism and normal adrenal function. CONCLUSIONS: Although the cortisol: ACTH ratio predicts primary hypoadrenalism, its value is limited to diagnosing primary hypoadrenalism as it does not distinguish secondary hypoadrenalism from normal adrenal function. Larger prospective studies that include patients with early primary hypoadrenalism are needed to confirm the reliability of plasma cortisol: ACTH ratio as a diagnostic test for primary hypoadrenalism.

Saline suppression to distinguish the primary aldosteronism subtype: a diagnostic study.

OBJECTIVES: The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA), while adrenal vein sampling (AVS) is used to subtype PA as unilateral or bilateral. Criteria that can accurately identify those with bilateral PA based on SST results could reduce the need for AVS. We previously demonstrated that a combination of plasma aldosterone concentration (PAC) < 300 pmol L-1 and a reduction in aldosterone-to-renin ratio (ARR) following recumbent SST had high specificity for predicting bilateral PA in an Australian cohort of 92 patients with PA who have undergone AVS. We sought to validate our predictive criteria in larger, independent cohorts of patients with PA. DESIGN: An international, multi-centre cohort study. METHODS: Data from 55 patients at Monash Health, Victoria, Australia, 106 patients from the First Affiliated Hospital of Chongqing Medical University, China, and 105 patients from Nihon University Itabashi Hospital, Japan were analysed. RESULTS: A combination of PAC <300 pmol L-1 and a reduction in ARR following recumbent SST predicted bilateral PA with specificities of 88.2%, 97.0%, and 100.0% in Australian, Chinese, and Japanese cohorts, respectively. This criterion could allow 22%-38% of patients with PA to bypass AVS and proceed directly to medical treatment. CONCLUSION: In patients undergoing the recumbent SST, a post-saline PAC <300 pmol L-1 together with a reduction in ARR can predict bilateral PA with high specificity and may allow targeted treatment to be commenced without AVS in up to a third of patients.

The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review.

OBJECTIVES: To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human. METHODS: A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605). DATA SOURCES: Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period. RESULTS: We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated. LIMITATION: Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English. CONCLUSION: Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.

Aldosterone, Renin, and Aldosterone-to-Renin Ratio Variability in Screening for Primary Aldosteronism.

CONTEXT: The plasma aldosterone concentration (PAC), renin, and aldosterone-to-renin ratio (ARR) are used to screen for primary aldosteronism (PA). Substantial intra-individual variability of PAC and ARR using plasma renin activity in the context of usual antihypertensive therapy has been described, but there is no data on ARR variability calculated using direct renin concentration (DRC). OBJECTIVE: To describe the intra-individual variability of PAC, DRC, and ARR in the absence of interfering medications in patients with and without PA. DESIGN: Retrospective cohort study. PATIENTS: Hypertensive patients referred for investigation of PA, with at least 2 ARR measurements while off interfering medications. SETTING: Endocrine hypertension service of a tertiary center, from May 2017 to July 2021. MAIN OUTCOME MEASURES: PAC, DRC, and ARR variability was calculated as coefficient of variation (CV) and percent difference (PD). RESULTS: Analysis of 223 patients (55% female, median age 52 years), including 162 with confirmed PA, demonstrated high variability with a sample CV of 22-25% in the PAC and sample CV of 41% to 42% in the DRC and ARR in both the PA and non-PA groups. The degree of variability was substantially higher than the assays' analytical CV. Sixty-two patients (38%) with PA had at least one ARR below 70 pmol/L:mU/L (2.4 ng/dL:mU/L), a cut-off for first-line screening of PA. CONCLUSIONS: Significant intra-individual variability in PAC, DRC, and hence ARR occurs in a large proportion of patients being investigated for PA. These findings support the need for at least 2 ARR before PA is excluded or further investigated.