Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

Gait Characteristics and Cognitive Function in Middle-Aged Adults with and without Type 2 Diabetes Mellitus: Data from ENBIND.

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life. Both gait speed and spatiotemporal gait characteristics have been associated with later cognitive decline in community-dwelling older adults. Thus, the assessment of gait characteristics in uncomplicated midlife T2DM may be important in selecting-out those with T2DM at greatest risk of later cognitive decline. We assessed the relationship between Inertial Motion Unit (IMUs)-derived gait characteristics and cognitive function assessed via Montreal Cognitive Assessment (MoCA)/detailed neuropsychological assessment battery (CANTAB) in middle-aged adults with and without uncomplicated T2DM using both multivariate linear regression and a neural network approach. Gait was assessed under (i) normal walking, (ii) fast (maximal) walking and (iii) cognitive dual-task walking (reciting alternate letters of the alphabet) conditions. Overall, 138 individuals were recruited (n = 94 with T2DM; 53% female, 52.8 ± 8.3 years; n = 44 healthy controls, 43% female, 51.9 ± 8.1 years). Midlife T2DM was associated with significantly slower gait velocity on both slow and fast walks (both p < 0.01) in addition to a longer stride time and greater gait complexity during normal walk (both p < 0.05). Findings persisted following covariate adjustment. In analyzing cognitive performance, the strongest association was observed between gait velocity and global cognitive function (MoCA). Significant associations were also observed between immediate/delayed memory performance and gait velocity. Analysis using a neural network approach did not outperform multivariate linear regression in predicting cognitive function (MoCA) from gait velocity. Our study demonstrates the impact of uncomplicated T2DM on gait speed and gait characteristics in midlife, in addition to the striking relationship between gait characteristics and global cognitive function/memory performance in midlife. Further studies are needed to evaluate the longitudinal relationship between midlife gait characteristics and later cognitive decline, which may aid in selecting-out those with T2DM at greatest-risk for preventative interventions.

HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study.

AIMS/HYPOTHESIS: The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes. METHODS: We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [3H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima-media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m2) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m2). RESULTS: Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 µmol/l [mean difference (MD) -3.32 µmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 µmol/l [MD +2.37 µmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p < 0.05 for all). Total CEC (14.57 ± 2.47%CEC/4 h vs 12.26 ± 3.81%CEC/4 h [MD +2.31%CEC/4 h]) was greater in participants with type 1 diabetes relative to non-diabetic participants. Increased HDL particle size was independently associated with increased total CEC; however, following adjustment for this in multivariable analysis, CEC remained greater in participants with type 1 diabetes. Both components of CEC, ABCA1-dependent (6.10 ± 2.41%CEC/4 h vs 5.22 ± 2.57%CEC/4 h [MD +0.88%CEC/4 h]) and ABCA1-independent (8.47 ± 1.79% CEC/4 h vs 7.05 ± 1.76% CEC/4 h [MD +1.42% CEC/4 h]) CEC, were greater in type 1 diabetes but the increase in ABCA1-dependent CEC was less marked and not statistically significant in multivariable analysis. CIMT was increased in participants with type 1 diabetes but in multivariable analysis it was only associated negatively with age and BMI. CONCLUSIONS/INTERPRETATION: HDL particle size but not HDL-cholesterol level is independently associated with enhanced total CEC. HDL particle size is greater in individuals with type 1 diabetes but even after adjusting for this, total and ABCA1-independent CEC are enhanced in type 1 diabetes. Further studies are needed to understand the mechanisms underlying these effects, and whether they help attenuate progression of atherosclerosis in this high-risk group. Graphical abstract.

Metabolic dysfunction and diabetes mellitus during long-term follow-up of severe acute pancreatitis: A case-matched study.

BACKGROUND/OBJECTIVES: Endocrine insufficiency following severe acute pancreatitis (SAP) leads to diabetes of the exocrine pancreas, (type 3c diabetes mellitus), however it is not known how this metabolic phenotype differs from that of type 2 diabetes, or how the two subtypes can be differentiated. We sought to determine the prevalence of diabetes following SAP, and to analyse the behaviour of glucose and pancreatic hormones across a 2-h oral glucose tolerance test (OGTT). METHODS: Twenty-six patients following SAP (mean (range) duration of first SAP episode to study time of 119.3 (14.8-208.9) months) along with 26 matched controls underwent an OGTT with measurement of glucose, insulin, c-peptide, glucagon and pancreatic polypeptide (PP) at fasting/15/90/120min. Beta-cell area was estimated using the 15min c-peptide/glucose ratio, and insulin resistance (IR) using homeostasis model assessment (HOMA) and oral glucose insulin sensitivity (OGIS) models. RESULTS: The prevalence of diabetes/prediabetes was 54% following SAP (38.5% newly-diagnosed compared to 19.2% newly-diagnosed controls). Estimated beta-cell area and IR did not differ between groups. AUC c-peptide was lower in SAP versus controls. AUC insulin and AUC c-peptide were lower in SAP patients with diabetes versus controls with diabetes; between-group differences were observed at the 90 and 120 min time-points only. Half of new diabetes cases in SAP patients were only identified at the 120min timepoint. CONCLUSIONS: Diabetes and pre-diabetes occur frequently following SAP and are difficult to distinguish from type 2 diabetes in controls but are characterised by reduced insulin and c-peptide at later stages of an OGTT. Consistent with this observation, most new post SAP diabetes cases were diagnosed by 2-h glucose levels only.

Outcomes of the short Synacthen test: what is the role of the 60 min sample in clinical practice?

In recent years, the short Synacthen test (SS) has become the most widely used test to assess adrenal reserve. Despite its frequent use, there are still several areas related to the short Synacthen test (SST), which have no consensus including the optimum sampling times, that is, whether a 60 min post-Synacthen administration cortisol is necessary or not. METHODOLOGY: We performed a retrospective data analysis of 492 SSTs performed on adult patients in a tertiary referral teaching hospital in Ireland. The SSTs were performed in the inpatient and outpatient setting and included patients across all medical disciplines and not exclusively to the endocrinology department. RESULTS: 313 patients had 0, 30 and 60 min samples available for analysis. A total of 270/313 (82%) were deemed to pass the test, that is, cortisol ≥500 nmol/L at both 30 and 60 min. Of the 313 patients, 19 (6%) patients had an indeterminate response, cortisol <500 nmol/L at 30 min, but rising to ≥500 nmol/L on the 60 min sample. Of these 19 patients, only 9/19 patients had a serum cortisol level at 30 min <450 nmol/L, requiring clinical treatment with glucocorticoid replacement. All 24/313 (8%) patients who had insufficient responses at 60 min were also insufficient at 30 min sampling. No individuals passed (≥500 nmol/L) at 30 min and then failed (<500 nmol/L) at 60 min. CONCLUSION: Using the 30 min cortisol sample post-Synacthen administration alone identifies clinically relevant adrenal insufficiency in the majority of cases. A small subset of patients have a suboptimal response at 30 min but have a 60 min cortisol concentration above the threshold for a pass. Data regarding the long-term outcomes and management of such patients are lacking and require further study.

Rates of abnormal aldosterone/renin ratio in African-origin compared to European-origin patients: A retrospective study.

INTRODUCTION: The aldosterone/renin ratio is the initial screening test for primary hyperaldosteronism (PHA), but little data exists regarding ethnic variations in this. METHODS: Following clinical observation of a high prevalence of abnormal aldosterone/renin ratio (ARR) in patients of African-origin, we retrospectively reviewed all ARR measurements in a single centre over 10 years. Rates of hypokalaemia, intraventricular septal thickness (IVS, by echocardiography) and adrenal imaging were recorded when available. RESULTS: Aldosterone/renin ratio was available in 1473 patients, and abnormal in 374 (25.4%). Abnormal ARR was observed in 305/1349 (22.6%) of European-origin and 69/124 (55.6%) of African-origin patients (P < 0.001). Among those with abnormal ARR, hypokalaemia (<3.5 mmol/L) was documented on at least one occasion in 171/305 (56.1%) European-origin and 43/69 (62.3%) African-origin patients (P = 0.35). Median (range) IVS was 1.57 (0.78-2.80) cm in African-origin and 1.20 (0.69-2.18) cm in European-origin patients (P < 0.002); IVS did not correlate with aldosterone or ARR however. Adrenal adenoma was identified in 41/170 (24.1%) of European-origin and 4/29 (13.7%) African-origin patients (P = 0.15), while hyperplasia was identified in 35/170 (20.5%) of European and 8/29 (27.5%) African patients (P = 0.39). CONCLUSION: In summary, ARR was abnormal in 55.6% of African-origin patients screened at an Irish hospital. Rates of hypokalaemia were similar between European-origin and African-origin patients. These findings have implications for the use of current screening guidelines for ARR in African-origin patients and also for the mechanistic role of aldosterone in hypertensive complications in African-origin patients.

EED and EZH2 constitutive variants: A study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome.

Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.

In women with PCOS, waist circumference is a better surrogate of glucose and lipid metabolism than disease status per se.

OBJECTIVE: Cardiometabolic abnormalities are recognized in polycystic ovary syndrome (PCOS). However, over-emphasis on PCOS as a risk factor potentially results in over-investigation and treatment of some women with and under-recognition of cardiometabolic risk in obese women without PCOS. Our objective was to explore the association between waist circumference (WC) and indices of glucose and lipid metabolism in women with and without PCOS. DESIGN, PATIENTS AND MEASUREMENTS: (i) An exploratory cross-sectional study investigating association of potential cardiometabolic risk markers (PCOS status, anthropometric measures, hsCRP, HOMA-IR, SHBG, testosterone) with indices of glucose (frequently sampled intravenous glucose tolerance test) and lipid metabolism (postprandial studies and lipoprotein particle size) in 61 women with (n = 29) and without (n = 32) PCOS; (ii) a cross-sectional study in 103 PCOS women and 102 BMI-matched controls to explore if between-group differences in indices of lipid and glucose metabolism persist after adjusting for WC. NIH criteria were used for PCOS diagnosis. RESULTS: Study 1: Univariate correlations and stepwise regression modelling identified waist circumference (WC), as a better surrogate than PCOS status, independently predicting multiple variables of glucose and lipid metabolism. Study 2: Fasting insulin and triglyceride, hsCRP and insulin resistance (according to HOMA-IR and SiM [Avignon index]) were greater, while fasting HDL was lower in women with PCOS compared to BMI-matched women without PCOS. None of these differences persisted when a subset of 80 women with PCOS was compared with 80 women without PCOS, pair-matched for WC. CONCLUSION: Some cardiometabolic abnormalities in PCOS are related to central obesity, and following adjustment for WC does not differ from normal subjects. Waist circumference measurement has potential to take precedence over PCOS status as part of the assessment of cardiometabolic risk in reproductive-age women.

Risk Stratification in Multinodular Goiter: A Retrospective Review of Sonographic Features, Histopathological Results, and Cancer Risk.

PURPOSE: In the management of thyroid nodules, although the potential for malignancy exists, there is also the potential for overtreatment of subclinical disease. Although the TI-RADS (Thyroid Imaging-Reporting and Data System) system outlines a risk stratification score based on suspicious ultrasound findings, it has not been universally accepted. Many TI-RADS 2 or 3 patients proceed to fine needle aspiration biopsy (FNAB), potentially unnecessarily. The aim of the study was to identify whether lesions within a multinodular goiter (MNG) without suspicious features can be followed with ultrasound rather than biopsied as is recommended for single nodules. METHODS: Pathology records were retrospectively analysed for proven MNGs over a 5-year period. A total of 293 cases were identified. FNAB, prebiopsy ultrasound images, and reports were identified for each case. Images were reviewed and assessed for sonographically suspicious criteria guided by TI-RADS. Logistic regression was applied to determine if any sonographic features were associated with neoplasia. Odds ratios with 95% confidence intervals were calculated. RESULTS: Of 293 samples, 14 (4.7%) were neoplastic. Having no suspicious features conferred an average risk of 0.0339 (95% confidence interval: 0.02831-0.04087) of neoplasia. Risk of neoplasm significantly increased by having 1 and >1 suspicious feature (P < .001). Regarding cytological results, of 237 patients with Thy-2 cytology, 159 were followed up and 8 had a neoplasm. CONCLUSION: Ultrasound can be used to estimate risk of neoplasia in MNG. In the absence of suspicious radiological findings, follow-up with ultrasound rather than FNAB may be appropriate in patients who have a low clinical suspicion for neoplasia.

Reconstruction of the Fully Edentulous Maxilla Using Sinus Grafts and Bone Expansion: A Retrospective Analysis of 50 Consecutive Cases.

A series of 50 cases involving reconstruction of the fully edentulous maxilla using sinus grafts, bone expansion, and classic crown and bridge to restore to normal contour, comfort, health, function, and esthetics is retrospectively analyzed using 25 years of follow-up data.

Oxidative stress and inflammation in lean and obese subjects with polycystic ovary syndrome.

OBJECTIVE: To determine whether polycystic ovary syndrome (PCOS) independently influences oxidative stress and inflammation or if the culprit is the comorbidities of obesity and/or insulin resistance common to this condition. STUDY DESIGN: Thirty women with PCOS were matched for age, body mass index and insulin resistance with 30 control subjects. Oxidative stress was examined by measuring the total oxidant status (TOS) and total antioxidant capacity (TAC) by spectrophotometric assay. The inflammatory biomarkers, C-reactive protein, plasminogen activator inhibitor-1, myeloperoxidase, neopterin, and serum amyloid A were measured by ELISA methodologies. RESULTS: Oxidative status was increased in the PCOS subjects relative to their weight-matched controls (TOS: obese PCOS patients vs. obese controls, 42.42 +/- 4.49 vs. 32.57 +/- 1.97, p<0.05; lean PCOS patients vs. lean controls, 33.69 +/- 1.59 vs. 28.69 +/- 1.18 micromol H2O2 Equiv/L, p < 0.05). Furthermore, antioxidant capacity was lower in the lean PCOS group relative to their weight-matched controls (TAC: lean PCOS patients vs. lean controls, 1.10 +/- 0.09 vs. 1.49 +/- 0.03 nmol Trolox Equiv/L, p < 0.05). CONCLUSION: These results suggest that PCOS independently influenced oxidative stress. Overall, the presence of PCOS may increase cardiovascular risk.

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

BACKGROUND: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. STUDY DESIGN AND METHODS: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. RESULTS: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11ß-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11ß-HSD2 activity. Hepatic 11ß-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11ß-HSD1 in subcutaneous adipose tissue. CONCLUSION: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Neuropsychological decrements in midlife type-2 diabetes are not associated with peripheral NLRP3 inflammasome responsiveness.

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of Alzheimer Disease (AD) in later life, with altered inflammatory responses postulated as key pathological drivers. Previous studies have demonstrated increased responsiveness to NLR family pyrin domain containing 3 (NLRP3) inflammasome agonists, both in individuals with untreated T2DM in addition to those with established AD. We hypothesised that peripheral NLRP3 inflammasome responses may be altered during the early stages of T2DM-related cognitive dysfunction. Here, we assessed the relationship between NLPR3 responses in peripheral blood mononuclear cells (including to Aß-42, the putative pathogenic protein in AD) and neuropsychological performance in uncomplicated midlife T2DM to identify early signatures of immune dysregulation which may predispose to later cognitive decline. We recruited a cross-sectional cohort of middle-aged adults with uncomplicated T2DM and matched Healthy Controls (HCs) for comprehensive neuropsychological assessment and in vitro PBMC responses to a range of NLRP3 agonists were assessed. T2DM was associated with subtle decrements on neuropsychological tests of delayed memory and executive function (both p<0.05). Overall, there were no differences between T2DM and HCs in immune responses induced by NLRP3 agonists. Further, we observed no relationship between the subtle neuropsychological decrements observed in T2DM and PBMC responsiveness to NLRP3 agonists. Our data suggests that peripheral NLRP3 inflammasome response dysregulation may not play a role in the early stages of cognitive dysfunction in midlife T2DM. Further longitudinal studies are warranted to examine the contribution of peripheral NLRP3 responses towards disease pathology and as cognitive decline accelerates in T2DM.

Imaging features of atypical adrenocortical adenomas: a radiological-pathological correlation.

OBJECTIVE: Adrenal adenomas are frequently picked up incidentally on cross-sectional imaging and are known to have a classic imaging appearance on CT and MRI. However, not all adrenal adenomas have this typical radiologic appearance. Our aim is to present the radiological features of atypical adrenocortical adenomas with pathological correlation. METHODS: All the imaging from the pathologically proven adrenal adenoma cases in our hospital (Tallaght University Hospital, Dublin, Ireland) database (from 2004 to 2019) was reviewed. 8 out of 48 cases (16%) had an atypical radiological appearance and were selected for presentation. RESULTS: Eight cases demonstrated atypical radiological features including heterogeneous density, incomplete washout on post-contrast imaging, the presence of macroscopic fat and calcification. Lipomatous metaplasia was present in two of the cases pathologically. CONCLUSION: Adrenocortical adenomas are the most common adrenal mass encountered on CT, however, may not always have classic imaging features. Radiologists should be familiar with both the typical and atypical imaging manifestations of these benign adrenal lesions. ADVANCES IN KNOWLEDGE: This paper comprehensively describes the atypical features of adrenocortical adenomas with case examples and radiologic-pathologic correlation. Guidelines and an approach to the work-up of adrenal lesions with atypical appearances are also provided.

The growth hormone/insulin-like growth factor-I axis in exercise and sport.

The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.

Cardiometabolic and psychological effects of dual-release hydrocortisone: a cross-over study.

BACKGROUND: Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. METHODS: An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. RESULTS: Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15-20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (-1.23 kg, P = 0.006) and BMI (-0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. CONCLUSION: Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.

The effect of growth hormone (GH) replacement on muscle strength in patients with GH-deficiency: a meta-analysis.

CONTEXT/OBJECTIVES: GH replacement increases muscle mass and reduces body fat in growth hormone deficiency (GHD) adults. A recent meta-analysis has demonstrated that this improvement in body composition is associated with improved exercise performance. The current meta-analysis was carried out to determine whether high-quality evidence exists to support a beneficial effect of GH replacement on strength. DESIGN/METHODS: An extensive Medline search/literature review identified eight studies with utilizable, robust data, involving 231 patients in nine cohorts. Previously unpublished data were sought from authors and obtained in two cases. All studies included were randomized, double-blind, placebo-controlled, of parallel or cross-over design and of an average 6.7 months duration. Information was retrieved in uniform format, with data pertaining to patient numbers, study-design, GH-dose, mean age, IGF-I levels and muscle strength measurements (isometric or isokinetic quadriceps strength) recorded. Data were analysed using a fixed-effects model, utilizing continuous data measured on different scales. A summary effect measure (d(s)) was derived for individual strength variables, whereas an overall summary effect was derived from the sum of all studies incorporating different variables; 95% CIs were calculated from the weighted variances of individual study effects. RESULTS: Analysis revealed no significant improvement, neither when all studies were combined (d(s) = +0.01 +/- 0.26) nor when measured individually (isometric quadriceps strength, d(s) = +0.02 +/- 0.32 and isokinetic quadriceps strength, d(s) = 0.00 +/- 0.45). CONCLUSIONS: Evidence from short-term controlled studies fails to support a benefit on muscle strength of GH replacement in GHD patients, which is likely to occur over a longer time-course, as seen in open-label studies.

Peripheral Inflammation and Cognitive Performance in Middle-Aged Adults With and Without Type 2 Diabetes: Results From the ENBIND Study.

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with a greater risk of dementia in later life. Peripheral inflammation and its impact on cognition is proposed as one of the pathological mechanisms mediating this link. However, studies have primarily focused on older individuals with established cognitive impairment and a long duration of T2DM. Importantly, knowledge of which individuals with midlife T2DM who are at greatest risk of later cognitive decline is lacking. We examined the cross-sectional relationship between serum levels of 8 pro-inflammatory markers (IL-1ß, IL-6, TNF-α, IL-8, MCP-1, CXCL10, IL-12p70, CRP) and performance on a detailed neuropsychological assessment battery in middle-aged adults with uncomplicated T2DM (N = 89; 52 ± 8.1 years, 47% female) and matched healthy controls (N = 50; 52 ± 8.3 years, 59% female). Linear regression was used to analyze associations between serum markers and cognitive performance in the overall cohort, followed by a T2DM∗protein concentration interaction analysis to identify any T2DM-specific effects. We observed a significant T2DM-specific association between serum TNF-α levels and scores on the Paired Associates Learning (PAL) task (ß: -3.16, SE: 1.32, p = 0.01, Std. Beta: -0.94), a task with significant working memory demands previously implicated in T2DM-related cognitive dysfunction. However, this did not persist on controlling for multiple testing. We provide exploratory evidence for a significant T2DM-specific relationship between serum TNF-α and memory performance. These findings require further replication and longitudinal analysis with the aim of selecting-out individuals with midlife T2DM at risk of future cognitive decline for potential preventative interventions.

Characterization of macroprolactin and assessment of markers of autoimmunity in macroprolactinaemic patients.

OBJECTIVE: It has been reported that macroprolactin is a complex of PRL and an immunoglobulin G (IgG). This study further characterizes macroprolactin and evaluates for other markers of autoimmunity using a cohort of macroprolactinaemic sera. PATIENTS AND NORMAL SUBJECTS: Following treatment of hyperprolactinaemic sera (n = 58) with polyethylene glycol (PEG), PRL values fell from 524-13 546 mU/l (Range) to 452-8455 mU/l, while in macroprolactinaemic sera (n = 41), PRL concentration fell from 525-5747 to 98-378 mU/l (PEG treated normoprolactinaemic reference range, 68-230 mU/l in males, 70-390 mU/l in females). DESIGN: PRL was measured in sera prior to and following gel filtration chromatography, ultrafiltration, treatment with protein A-sepharose, protein G-sepharose, antihuman IgG-agarose and sodium thiocyanate (NaSCN). The binding of radio-labelled PRL in macroprolactinaemic sera was also measured. Sera were assayed for antithyroid and antinuclear antibodies. C-reactive protein (CRP) and CD5 positive B cells were also measured. Comparisons were made between values obtained in normal, hyperprolactinaemic and macroprolactinaemic sera. Results Macroprolactinaemic sera indicated the presence of an IgG molecule and/or IgG fragments with one or more molecules of PRL. In 97% of the sera macroprolactin had a molecular weight of 204 kDa. Treatment of macroprolactinaemic sera with NaSCN caused dissociation of macroprolactin, releasing monomeric PRL. Macroprolactinaemic sera did not yield evidence of an increase in markers of autoimmunity when compared with hyperprolactinaemic or normal sera. CONCLUSIONS: Comprehensive analysis of macroprolactin confirmed its composition as an IgG molecule or fragment with a PRL molecule. The occurrence of macroprolactin does not appear to be associated with autoimmunity.