Differential plasma branched-chain amino acid responses following the consumption of Greek-style yogurt and skimmed milk.

We examined postprandial branched-chain amino acid (BCAA), insulin, and glucose responses in blood for 4 h following the consumption of two isonitrogenous doses (2 × 20 g protein) of Greek-style yogurt (GY) and skimmed milk (MILK) in young males. Peak leucine and BCAA concentrations and areas under the curve were greater after GY versus MILK, and time to maximal leucine/BCAA concentrations was similar between conditions. We demonstrated that different protein-matched wholefood dairy products elicit different postprandial aminoacidemic responses.

The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status.

BACKGROUND: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. METHODS: Seventeen women with type 1 diabetes mellitus (T1DM) and nine age-matched healthy women with a median age of 22.6 years (range, 17.4, 23.8) were studied by 3T MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity (BMA). Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). RESULTS: Although women with T1DM had similar BMI and BMA to the controls, they had higher visceral and subcutaneous adiposity on MRI (P<.05) and total body FM by DXA (P=.03). Overall, in the whole cohort, a clear inverse association was evident between BMA and BMD at all sites (P<.05). These associations remained significant after adjusting for age, BMI, FM and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with BMA (r, .4, P=.03), and a negative association with total body BMD (r, .5, P=.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r, -.4, P=.04). CONCLUSION: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured BMA and DXA-based assessment of BMD. Furthermore, an association between BMA and visceral adiposity supports the notion of a common origin of these two fat depots.

Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement.

Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood.

An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland.

BACKGROUND: Adolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH). AIM: Retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. PATIENTS: Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1-16.4) with a stimulated GH peak of 2.3 µg/l (0.1-6.5). Median age at initiation of rhGH was 10.8 years (0.4-17.0). RESULTS: Of the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort. CONCLUSIONS: A substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland.

Educational innovations in clinical pharmacogenomics.

Genetic and genomic discovery is revolutionizing medicine at an extraordinary pace, leading to a better understanding of disease and improved treatments for patients. This advanced pace of discovery presents an urgency to expand medical school curricula to include genetic and genomic testing (including pharmacogenomics), and integration of genomic medicine into clinical practice. Consequently, organizations and healthcare authorities have charged medical schools with training future physicians to be competent in their knowledge of genomic implementation.

Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre.

BACKGROUND: Phaeochromocytoma (phaeo) and paraganglioma (PGL) are rare conditions, which are malignant in up to 30%. Optimal treatment is controversial, but in patients with metastatic iodine-131-meta-iodobenzylguanidine ((123)I-MIBG) avid tumours, we offer (131)I-MIBG therapy. We summarize response rates, survival and safety in a cohort of such patients treated with (131)I-MIBG in our centre from 1986 to 2012. DESIGN/METHODS: Retrospective analysis of the case notes of patients with metastatic phaeo/PGL who received (131)I-MIBG was undertaken; patients underwent clinical, biochemical and radiological evaluation within 6 months of each course of (131)I-MIBG therapy. RESULTS: Twenty-two patients (9 males) were identified, 12 with metastatic PGL and 10 with phaeo. Overall median follow-up time after first dose of (131)I-MIBG was 53 months. In total, 68 doses of (131)I-MIBG were administered; average dose was 9967 MBq (269.4 mCi). After the first dose, >50% of patients demonstrated disease stability or partial response; progressive disease was seen in 9%. A subset of patients underwent repeated treatment with the majority demonstrating partial response or stable disease. No life-threatening adverse events were reported, but three patients developed hypothyroidism and two developed ovarian failure after repeated dosing. Five-year survival after original diagnosis was 68% and median (+inter quartile range) survival from date of diagnosis was 17 years (7.6-26.4) with no difference in survival according to diagnosis (P < 0.1). CONCLUSIONS: (131)I-MIBG is well tolerated and associates with disease stabilization or improvement in the majority of patients with metastatic phaeo/PGL. However, stronger conclusions on treatment effectiveness are limited by lack of a directly comparable 'control group' as well as an alternative 'gold standard' treatment.

Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.

While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.

Trends in recorded capillary blood glucose and hypoglycaemia in hospitalised patients with diabetes.

AIMS: To utilise whole-system analysis of capillary glucose measurement results to examine trends in timing of glucose monitoring, and to investigate whether these timings are appropriate based on observed patterns of hypoglycaemia. METHODS: Near-patient capillary blood glucose results from eight acute hospitals collected over 57 months were analysed. Analysis of frequency of measurement, and measurements in the hypoglycaemic (<4mmol/l) and severe hypoglycaemic (<2.5mol/l) range per time of day was made. RESULTS: 3345241 capillary glucose measurements were analysed. 1657594 capillary blood glucose values were associated with 106624 admissions in those categorised as having diabetes. Large peaks in frequency of glucose measurements occurred before meals, with the highest frequency of capillary glucose measurement activity being seen pre-breakfast. Overnight, an increase in measurement activity was seen each hour. This pattern was mirrored by frequency of measured hypoglycaemia. 27968 admissions (26.2%) were associated with at least one hypoglycaemic measurement. A greater proportion of measurements were within the hypoglycaemic range overnight with 61.7% of all hypoglycaemia between 2100 and 0900h, with peak risk of measured capillary glucose being hypoglycaemic between 0300 and 0400h. CONCLUSIONS: Hypoglycaemic is common with the greatest risk of hypoglycaemia overnight and a peak percentage of all readings taken being in the hypoglycaemic range between 0300 and 0400h. Measurement activity overnight was driven by routine, with patterns of proportion of measurements in the hypoglycaemic range indicating that there may be a significant burden of undiscovered hypoglycaemia in the patients not routinely checked overnight.

The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma.

BACKGROUND: There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement. METHODS: We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total metanephrines (sum of the metanephrine fractions) 5163 nmol/day, normetanephrine fraction 4001 nmol/day, metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed. RESULTS: The diagnostic efficacy was as follows: normetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either normetanephrine or metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the normetanephrine fraction, 0.800 (0.741-0.858) for the metanephrine fraction, 0.991 (0.985-0.996) for total metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the metanephrine and normetanephrine fractions. CONCLUSION: Measurement of 24-h urinary fractionated metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.

Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions.

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.