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There is limited evidence supporting the recommendation that drivers with insulin-treated diabetes need to start journeys with glucose90 mg/dL. Glucose levels of drivers with type 1 diabetes were monitored for 3 weeks using masked continuous glucose monitoring (CGM). Eighteen drivers (median [IQR] age 40 [35, 51] years; 11 men) undertook 475 trips (duration 15 [13, 21] min). Hypoglycemia did not occur in any trip starting with glucose90 mg/dL (92%

The objective of this study is to assess the relationship between hypothalamic-pituitary-adrenal (HPA) axis activity, vascular function and insulin sensitivity in healthy adults.Open observational study.Thirty healthy adults were studied at the Endocrine Research Unit, Repatriation General Hospital, Adelaide, SA, Australia.HPA activity was assessed from the serum cortisol 30 min after 1 µg ACTHThere were no significant differences in age (61 ± 9 vs. 64 ± 7 years, p = .19), body mass index (BMI; 26 ± 3 vs. 24 ± 4 kg/mIn healthy adults, endothelial dysfunction is likely to contribute to the association between HPA hyperactivity and increased cardiovascular risk. As insulin sensitivity was not different in high and low responders, endothelial dysfunction is not primarily secondary to insulin resistance.

Background: This prerandomization analysis from the Australian HCL-Adult trial (registration number: ACTRN12617000520336) compared masked continuous glucose monitoring (CGM) metrics among adults using insulin pumps versus multiple daily injections (MDIs), who were all self-monitoring blood glucose (SMBG). Methods: Adults with type 1 diabetes, using an insulin pump or MDIs without real-time CGM (and entering a trial of closed-loop technology), were eligible. MDI users were given an insulin dosage calculator. All participants received diabetes and carbohydrate-counting education, then wore masked CGM sensors for 3 weeks. Ethics Approval: HREC-D 088/16 Results: Adults using MDIs (n = 61) versus pump (n = 59) did not differ by age, sex, diabetes duration, insulin total daily dose, or HbA1c at baseline. After education, median (interquartile range) CGM time in range (TIR) 70-180 mg/dL (3.9-10.0 mmol/L) was 54% (47, 62) for those using MDIs and 56% (48, 66) for those using pump (P = 0.40). All CGM metrics were equivalent for 24 h/day for MDI and pump users. Overnight, those using MDIs (vs. pump) spent more time with glucose

OBJECTIVES To determine whether relative hyperglycemia was associated with in-hospital mortality in critically ill patients independent of other prognostic variables and whether this association is affected by background glycemia. DESIGN Prospective observational study. SETTING Mixed medical-surgical ICU in a metropolitan teaching hospital. PATIENTS From 2,617 admissions to ICU between January 27, 2016, and March 30, 2017, 1,262 consecutive patients who met inclusion and exclusion criteria were studied. INTERVENTIONS Glycosylated hemoglobin was used to estimate average glucose concentration over the prior 3 months. Glucose concentration on ICU admission was divided by estimated average glucose concentration to calculate the stress hyperglycemia ratio, an index of relative glycemia. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. MEASUREMENTS AND MAIN RESULTS In this study, there were 186 deaths (14.7%). Admission glucose was significantly associated with mortality in univariate analysis (odds ratio = 1.08 per mmol/L glucose increment; p < 0.001) but not after adjustment for risk of death score (odds ratio = 1.01; p = 0.338). In contrast, stress hyperglycemia ratio was significantly associated with mortality both in univariate analysis (odds ratio = 1.09 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and after adjustment for risk of death score (odds ratio = 1.03; p = 0.014). Unlike admission glucose concentration, stress hyperglycemia ratio was significantly associated with mortality in patients with glycosylated hemoglobin less than 6.5% (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and glycosylated hemoglobin greater than or equal to 6.5% (48 mmol/mol) (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p = 0.005). CONCLUSIONS Unlike absolute hyperglycemia, relative hyperglycemia, as assessed by the stress hyperglycemia ratio, independently predicts in-hospital mortality in critically ill patients across the glycemic spectrum. Future studies should investigate whether using measures of relative hyperglycemia to determine individualized glycemic treatment targets improves outcomes in ICU.

OBJECTIVE To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes). RESEARCH DESIGN AND METHODS Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70–180 mg/dL) during the final 3 weeks. RESULTS Participants were randomized to HCL (n = 61) or control (n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; P < 0.0001). For HCL, HbA1c was lower (median [95% CI] difference −0.4% [−0.6, −0.2]; −4 mmol/mol [−7, −2]; P < 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; P < 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively. CONCLUSIONS In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA1c, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous.

Tailoring self-treatment by adding exacerbation phenotyping could be explored. Evidence on phenotyping effects, an accurate tool to identify eosinophilic exacerbations, and a validated cut-off point are needed before eosinophils can be used in practice.http://bit.ly/2L4b6SR

Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short term at medium-high doses to treat an acute inflammatory illness or long term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia, there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low-dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low-dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials.

Aims To compare meal-time glycaemia in adults with type 1 diabetes mellitus (T1D) managed with multiple daily injections (MDI) vs. insulin pump therapy (IPT), using self-monitoring blood glucose (SMBG), following diabetes education. Methods Adults with T1D received carbohydrate-counting education and a bolus calculator: MDI (Roche Aviva Expert) and IPT (pump bolus calculator). All then wore 3-weeks of masked-CGM (Enlite, Medtronic). Meal-times were assessed by two approaches: 1) Set time-blocks (breakfast 06:00–10:00hrs; lunch 11:00–15:00hrs; dinner 17:00–21:00hrs) and 2) Bolus-calculator carbohydrate entries signalling meal commencement. Post-meal masked-CGM time-in-range (TIR) 3.9–10.0 mmol/L was the primary outcome. Results MDI(n = 61) and IPT (n = 59) participants were equivalent in age, sex, diabetes duration and HbA1c. Median (IQR) education time provided did not differ (MDI: 1.1 h (0.75, 1.5) vs. IPT: 1.1 h (1.0, 2.0); p = 0.86). Overall, daytime (06:00–24:00hrs), lunch and dinner TIR did not differ for MDI vs. IPT participants but was greater for breakfast with IPT in both analyses with a mean difference of 12.8%, (95 CI 4.8, 20.9); p = 0.002 (time-block analysis). Conclusion After diabetes education, MDI and IPT use were associated with similar day-time glycemia, though IPT users had significantly greater TIR during the breakfast period. With education, meal-time glucose levels are comparable with use of MDI vs. pumps.

Background and aims Glucocorticoids could impair vascular function directly, or indirectly by reducing insulin sensitivity. The aim of this study was to determine the direct and indirect effects of acute and chronic low dose prednisolone on arterial stiffness and endothelial function. Methods Twelve subjects with inflammatory arthritis, who had not taken oral glucocorticoids for ≥6 months, and 12 subjects with inflammatory arthritis, taking chronic (>6 months) low dose (6.3 ± 2.2 mg/day) prednisolone, were studied. Patients not on glucocorticoids underwent measurement of arterial stiffness (pulse wave velocity (PWV)) and endothelial function (reactive hyperaemia index (RHI)) before and after 7–10 days of prednisolone (6 mg/day), to assess the acute effects of prednisolone. Baseline data from patients not on glucocorticoids were compared with patients on long-term prednisolone to assess the chronic effects of prednisolone. Hepatic insulin sensitivity was estimated from percentage suppression of endogenous glucose production and peripheral insulin sensitivity as glucose infusion rate (M/I) during a hyperinsulinaemic-euglycaemic clamp. Results There were no significant changes in PWV with acute (9.2 ± 0.8 vs. 8.9 ± 0.8 m/sec, p = 0.33) or chronic (8.9 ± 0.8 vs. 9.0 ± 0.7 m/sec, p = 0.69) prednisolone. In multiple regression analysis, PWV was negatively associated with M/I during hyperinsulinemic-euglycemic clamp ( p = 0.02), but not with suppression of endogenous glucose production ( p = 0.15) or glucocorticoid use ( p = 0.70). Chronic (2.4 ± 0.2 vs. 1.9 ± 0.1, p = 0.02), but not acute (1.8 ± 0.2 vs. 1.9 ± 0.1, p = 0.24), prednisolone resulted in a higher RHI. Conclusions Arterial stiffness is not affected by low dose prednisolone per se , but is negatively associated with peripheral insulin sensitivity. Patients with rheumatoid arthritis taking long-term prednisolone had better endothelial function.

SummaryObjective Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. Design An open interventional and cross-sectional study was undertaken. Patients and measurements Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. Results There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (−2·1 ± 6·2 vs −16·3 ± 4·8 mg/min, P = 0·01) and chronic (−1·4 ± 2·8 vs −16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. Conclusions Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.

Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality.We examined whether critical illness is more strongly associated with relative or absolute hyperglycemia.The study was an observational cohort study.A total of 2290 patients acutely admitted to a tertiary hospital.The relative hyperglycemia (stress hyperglycemia ratio [SHR]) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined.In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment [95% confidence interval, 1.18-1.28]; P.001) and glucose (odds ratio, 1.18 per mmol/L [1.13-1.23]; P.001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment [1.13-1.28]; P.001), but not glucose (odds ratio, 1.03 per mmol/L [0.97-1.11]; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose ≤ 10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 [1.4-4.2]; P = .001) and fifth (3.9 [2.3-6.8]; P.001) SHR quintiles than in the lowest SHR quintile.SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients.

IntroductionManual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months’ closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes.Methods and analysisThis open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged ≥25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9–10.0 mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA1c, severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users.Ethics and disseminationThe study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications.Trial registration numberNCT12617000520336.

Growth hormone (GH) replacement therapy was recently recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme for adults with severe GH deficiency and impaired quality of life. This approval was significant for two reasons. First, the application was initiated and coordinated by a health professional working group, who prepared a 'public interest' submission to PBAC. Second, it resulted in a recommendation to subsidise therapy for a rare disease after two prior rejections on the basis of uncertainty about efficacy and cost effectiveness. There are important lessons to learn about the power of professional groups to drive health policy and attain funding for rare diseases.

Background Hyperglycemia is associated with increased morbidity and mortality in patients with an acute myocardial infarction (AMI). We evaluated whether complications after AMI are associated with absolute or relative glycemia. Methods A total of 192 patients with AMI were randomized to intensive or conventional insulin therapy. Absolute glycemia was defined as mean blood glucose level (BGL) during the first 24 h following randomization. Relative glycemia was defined by the stress hyperglycaemia ratio (SHR), calculated as mean BGL divided by average glucose concentration over the prior 3 months estimated from glycosylated haemoglobin. The primary endpoint was a “complicated AMI”, defined as an AMI complicated by death, congestive cardiac failure, arrhythmia, cardiac arrest, reinfarction, cardiogenic shock, inotrope use or emergency revascularization. Results There was not a significant association between mean BGL and complicated AMI (odds ratio (OR) 1.05 per mmol/L glucose increment, 95% confidence intervals (CI) 0.93–1.19). In contrast, SHR was positively associated with a complicated myocardial infarction (OR 1.22 per 0.1 SHR increment, 95% CI 1.06–1.42), and individual complications of death (OR 1.55, 95% CI 1.14–2.11), congestive cardiac failure (OR 1.27, 95% CI 1.05–1.54), arrhythmia (OR 1.31, 95% CI 1.12–1.54) and cardiogenic shock (OR 1.42, 95% CI 1.03–1.97). The relationship between SHR and a complicated AMI was independent of diabetic status, intensive insulin therapy, sex and hypoglycemia. Conclusions Relative, but not absolute, glycemia during insulin treatment is independently associated with complications after an AMI. Future studies should investigate whether basing therapeutic glycaemic targets on relative glycemia improves patient outcomes.

The effects of low dose prednisolone on circulating markers of endothelial function, the arginine metabolites asymmetric dimethyl arginine (ADMA), mono methyl arginine (MMA), and homoarginine, are uncertain. We assessed whether patients with rheumatoid arthritis have perturbations in arginine metabolite concentrations that are reversed by low dose prednisolone.Eighteen rheumatoid arthritis patients who had not taken prednisolone for6 months (non-glucocorticoid (GC) users), 18 rheumatoid arthritis patients taking continuous oral prednisolone (6.5 ± 1.8 mg/day) for6 months (GC users) and 20 healthy controls were studied. Fasting plasma concentrations of ADMA, MMA, and homoarginine were measured by ultra-performance liquid-chromatography. Baseline data from non-GC users were compared with healthy controls to assess the effect of rheumatoid arthritis. The change in arginine metabolites in non-GC users after 7 days of prednisolone (6 mg/day) was used to assess the acute effects of prednisolone. Baseline data from non-GC users were compared with GC users to assess the chronic effects of prednisolone.Non-GC users had higher ADMA (0.59 ± 0.03 vs. 0.47 ± 0.01 μM, p = 0.004) and MMA concentrations (0.10 ± 0.01 vs. 0.05 ± 0.00 μM, p0.001) than controls. The only change with acute prednisolone was a reduction in homoarginine (1.23 ± 0.06 vs. 1.08 ± 0.06 μM, p = 0.04) versus baseline. GC users had lower concentrations of ADMA (0.51 ± 0.02 vs. 0.59 ± 0.03 μM, p = 0.03) than non-GC users.Rheumatoid arthritis patients have higher concentrations of ADMA and MMA, inhibitors of endothelial function. Chronic, but not acute, prednisolone therapy is associated with a lower ADMA concentration, suggesting a salutary effect of long-term glucocorticoid treatment on endothelial function.

Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined.The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect.We conducted an open interventional study between 2011 and 2013.The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia.Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied.Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d.The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load.Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose.Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.

OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

Previous studies have assessed the efficacy of basal-bolus insulin (BBI) in hospitalized patients by measuring four finger-prick blood glucose levels (BGLs) per day. The aim of this study was to investigate whether this BGL monitoring regimen provides an accurate reflection of glycemia in hospitalized patients administered BBI. We hypothesized that, as three of four readings are preprandial, finger-prick BGLs would underestimate the mean glucose concentration.Twenty-six consecutive consenting subjects with type 1 (n=3) or type 2 (n=23) diabetes mellitus admitted to the hospital and administered insulin glargine once daily and rapid-acting insulin before meals underwent continuous glucose monitoring for up to 72 h. Finger-prick BGLs were performed before each main meal (0700, 1200, and 1700 h) and at 2100 h.Mean daily glucose concentration was not significantly different when assessed by continuous glucose monitoring and finger-prick BGLs (9.6±2.4 vs. 9.6±2.7 mmol/L, P=0.84). A Bland-Altman plot revealed some variability but no bias between the two methods of measurement of glucose concentration. There were 88 postprandial hyperglycemic excursions recorded on continuous glucose monitoring; 61 (69%) were identified by finger-prick BGL monitoring. There were 10 glucose excursions4 mmol/L during continuous glucose monitoring; only one was detected by finger-prick BGL monitoring.Traditional finger-prick BGL monitoring provides a reasonable approximation of mean daily glucose concentration in the majority of hospitalized patients receiving BBI but underestimates the prevalence of postprandial hyperglycemia and hypoglycemia.

ObjectiveLong-term pharmacological glucocorticoid (GC) therapy leads to skeletal muscle atrophy and weakness. The objective of this study was to investigate whether short-term treatment with GH and testosterone (T) can increase lean mass without major impairment of glucose homoeostasis in patients on GC therapy.Design, materials and methodsThis was a prospective, open-label, randomised, crossover study. Twelve men (age 74±6 years) on chronic GC treatment participated. The effects of 2 weeks' treatment with GH, testosterone and the combination of both on lean body mass (LBM), appendicular skeletal muscle mass (ASMM), extracellular water (ECW), body cell mass (BCM) and plasma glucose concentrations were investigated.ResultsLBM increased significantly after GH (Δ1.7±1.4 kg;P=0.007) and GH+testosterone (Δ2.4±1.1 kg;P=0.003), but not testosterone alone. ASMM increased after all three treatment periods; by 1.0±0.8 kg after GH (P=0.005), 1.7±0.4 kg after GH+testosterone (P=0.002) and 0.8±1.0 kg after testosterone (P=0.018). The increase in ASMM was larger with combined treatment than either GH or testosterone alone (PP=0.038) but not after GH or testosterone alone. BCM increased slightly after single and combined treatments, but the changes were not significant. Fasting glucose increased significantly after GH (Δ0.4±0.4 mmol/l,P=0.006) while both fasting (Δ0.2±0.3 mmol/l,P=0.045) and post glucose-load (Δ1.8±2.3 mmol/l,P=0.023) plasma glucose concentrations increased after GH+testosterone.ConclusionsGH and testosterone induce favourable and additive body compositional changes in men on chronic, low-dose GC treatment. In the doses used, combination therapy increases fasting and postprandial glucose concentration.

Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients.Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system.On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%, P = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L, P = .57) or glucose4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%, P = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P = .02) and the insulin dose was increased over time ( P = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P = .45) or between groups ( P = .24).There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia.

Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m2, 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies.

Objective: To determine if the improvement in inpatient glycaemic control observed with basal–bolus insulin (BBI) over sliding-scale insulin (SSI) in the formal study setting translates to routine clinical conditions. Design, setting and patients: Cross-sectional study in which capillary blood glucose levels (BGLs) were prospectively measured four times daily for up to 8 days in 124 patients with type 2 diabetes admitted to a tertiary teaching hospital and treated with BBI between November 2008 and May 2010. Data from the BBI treatment group were compared with retrospective data from 96 patients treated with SSI between June 2001 and May 2006. Main outcome measures: Mean daily BGL; independent effect of insulin regimen on mean daily BGL. Results: Mean baseline BGL was not significantly different in patients receiving BBI and SSI (mean ± SD, 11.3 ± 4.1 v 10.6 ± 4.3 mmol/L; P = 0.23). After the first full day of therapy, mean daily BGL for patients receiving BBI was 1.6 ± 3.7 mmol/L lower than baseline BGL, and it remained 1.6–2.4 mmol/L lower than baseline throughout the study (P < 0.001). In contrast, there was no significant change in BGL for patients receiving SSI. Random effects regression analysis indicated that BBI was associated with a significantly lower mean daily BGL than SSI, independent of other variables (P < 0.001). The incidence of hypoglycaemia (BGL < 4 mmol/L) was significantly greater in patients receiving BBI than SSI (3.3% v 1.4%; P < 0.001), but there was no significant difference for severe hypoglycaemia (BGL < 2.8 mmol/L) (0.3 v 0.5%; P = 0.3). Conclusions: Under routine clinical conditions, BBI is effective and safe across a range of patients and appears to be superior to SSI. Clinical improvements reflected those seen in a strict formal study setting. Refereed/Peer-reviewed

Objective. The aim of the study was to assess the effect of long-term prednisolone on fasting and postglucose load glucose concentration in patients with inflammatory rheumatological disease. We hypothesized that prednisolone would predominantly increase post-glucose load glucose concentration and that fasting glucose would have poor sensitivity as a screening test for diabetes in patients receiving chronic prednisolone therapy. Methods. In a cross-sectional study of subjects with inflammatory rheumatological disease but without known diabetes, 60 subjects [age = 70 (±10) years, 62% female] who were receiving chronic (>6 months) prednisolone [6.5 (±2.1) mg/day] (Group 1) and 58 controls [age = 70 (±11) years, 62% female] who had not received oral glucocorticoids for at least 6 months (Group 2) underwent an oral glucose tolerance test. Results. Fasting glucose was significantly lower [5.0 (±0.1) vs 5.3 (±0.1) mmol/l, P = 0.02) and post-glucose load glucose concentration significantly higher [8.0 (±0.4) vs 6.8 (±0.3) mmol/l, P = 0.02] in Group 1 than in Group 2. In a multiple regression analysis, glucocorticoid use (P = 0.004) and log CRP (P = 0.02) were independently associated with fasting glucose, while waist circumference (P = 0.01), but not glucocorticoid use, was independently associated with post-glucose load glucose concentration. A fasting glucose 55.6 mmol/l had 33 and 83% sensitivity for diabetes in Groups 1 and 2, respectively. Conclusion. There is discordance between a reduced fasting and increased post-glucose load glucose concentration in rheumatological patients on long-term prednisolone. Therefore fasting glucose has poor sensitivity to screen for diabetes in prednisolone-treated patients. Treatment of prednisolone-induced hyperglycaemia should be directed at the postprandial period. Trial registration. Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/, ACTRN

CONTEXT: Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide. OBJECTIVE: To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours. PATIENTS: We report two patients with aggressive pituitary tumours treated with temozolomide, one who responded to temozolomide and the other who did not. MGMT expression was assessed in a further 88 archived pituitary tumour samples. DESIGN: MGMT expression was assessed by immunohistochemistry. MGMT promoter methylation was studied by methylation-specific polymerase chain reaction (MSP), sequencing of MGMT was performed and loss of heterozygosity (LOH) analysis undertaken. RESULTS: Low MGMT expression and MGMT promoter methylation were found in the pituitary tumour of the patient who responded to temozolomide. Conversely, high MGMT expression was seen in the patient demonstrating a poor response to temozolomide. Eleven out of 88 archived tumour samples (13%) had low MGMT expression. Prolactinomas were more likely to have low MGMT expression compared with other pituitary tumour subtypes (P < 0.001). There was no significant difference in MGMT expression between invasive and noninvasive tumours, or between recurrent and nonrecurrent tumours. A significant inverse correlation was found between MGMT expression and promoter methylation (P = 0.012). CONCLUSION: MGMT expression as assessed by immunohistochemistry may predict response to temozolomide therapy in patients with aggressive pituitary tumours. MGMT promoter methylation is likely to explain low MGMT expression in some, but not all, pituitary tumours.

Context: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. Objective: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. Design: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). Setting: The studies were performed at a clinical research facility. Patients and Intervention: In study 1, six subjects (age 69 ± 4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3 ± 0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71 ± 3 yr) treated with long-term GCs (prednisone dose 5.4 ± 0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). Main Outcome Measure: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. Results: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P = 0.03) and 31% (P = 0.02), and increased leucine incorporation into protein by 10% (P = 0.13) and 19% (P = 0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. Conclusion: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.

How protein metabolism is perturbed during chronic glucocorticoid excess is poorly understood. The aims were to investigate the impact of chronic glucocorticoid excess and restoration of eucortisolemia in Cushing's syndrome (CS) on whole body protein metabolism. Eighteen subjects with CS and 18 normal subjects (NS) underwent assessment of body composition using DEXA and whole body protein turnover with a 3-h constant infusion of l-[13C]leucine, allowing calculation of rates of leucine appearance (leucine Ra), leucine oxidation (Lox), and leucine incorporation into protein (LIP). Ten subjects with CS were restudied after restoration of eucortisolemia. Percentage FM was greater (43.9 ± 1.6 vs. 33.8 ± 2.4%, P = 0.002) and LBM lower (52.7 ± 1.6 vs. 62.1 ± 2.3%, P = 0.002) in CS. LBM was significantly correlated ( r2 > 0.44, P < 0.005) to leuceine Ra, Lox, and LIP in both groups. After correcting for LBM, leucine Ra (133 ± 5 vs. 116 ± 5 μmol/min, P = 0.02) and Lox (29 ± 1 vs. 24 ± 1 μmol/min, P = 0.01) were greater in CS. FM significantly correlated ( r2 = 0.23, P < 0.05) with leucine Ra and LIP, but not Lox in CS. In multiple regression, LBM was an independent determinant of all three indexes of leucine turnover, FM of leucine Ra, and LIP and CS of Lox. Following restoration of eucortisolemia, Lox was reduced (Δ−7.5 ± 2.6 μmol/min, P = 0.02) and LIP increased (Δ+15.2 ± 6.2 μmol/min, P = 0.04). In summary, whole body protein metabolism in CS is influenced by changes in body composition and glucocorticoid excess per se, which increases protein oxidation. Enhanced protein oxidation is a likely explanation for the reduced protein mass in CS. Successful treatment of CS reduces protein oxidation and increases protein synthesis to prevent ongoing protein loss.

ObjectiveThrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects.Design and methodsThree studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency.ResultsIn healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (PPP400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86–199) to 256 (133–516) ng/ml, (PConclusionsTSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

SummaryObjective Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. Design An open interventional and cross-sectional study was undertaken. Patients and measurements Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. Results Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone. Conclusions Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone.

Paradigms for managing acromegaly have undergone major changes in the past two decades. This has been brought about by combining surgical, pharmacological and radiotherapeutic approaches that provide tight biochemical control to reduce mortality to that of the general population. The biochemical targets for treatment are a growth hormone of

Summary Objective A comparison of the severity and distribution of perturbations in body composition and their relationship to energy metabolism in glucocorticoid excess and GH deficiency (GHD) has not been undertaken before. The aim of this study was to investigate the impact of Cushing's syndrome (CS) and GHD on whole and regional body composition and energy metabolism. Design Cross-sectional study design. Patients Eighteen subjects with CS (12 women, aged = 41·5 ± 3·0 years, 24-h urinary free cortisol = 1601 ± 361 nmol/day, normal

Medical therapy plays an important role in the management of acromegaly. Dopamine agonists and somatostatin analogs are two classes of drugs approved for this purpose worldwide. Pegvisomant, a growth hormone receptor antagonist, has recently been evaluated in clinical trials. Somatostatin analogs have been the mainstay of medical treatment during the last 10 yr with their acceptability enhanced by the development of depot preparations. Somatostatin analogs improve symptoms and signs of acromegaly in the majority, normalize IGF- 1 in up to 60%, and result in tumor shrinkage in up to half of patients. Dopamine agonists have modest efficacy and limited tolerability. They are more effective in mixed GH/prolactin-secreting tumors. Newer agonists with D2 receptor specificity have fewer side effects but are less efficacious than somatostatin analogs. The addition of a dopamine agonist to somatostatin analog therapy can result in greater biochemical control than with individual agents. Pegvisomant is the most effective drug treatment for acromegaly, but it is likely to have a major adjuvant role as its mechanism of action is not directed at the tumor. The availability of more effective and better tolerated drug therapies offers greater flexibility and individualization of therapy that will lead to improved patient care and disease control.

Aims To determine if diabetic lipaemia is caused by loss of function mutations in the lipoprotein lipase gene, LPL. Methods We conducted a case–control study over 2 years in two tertiary care hospitals in South Australia. Six patients with a history of diabetic lipaemia and 12 control subjects, with previous diabetic ketoacidosis and peak triglyceride concentrations < 2.4 mmol/l were included. Participants were well at the time of study investigations. Results Only one patient with lipaemia had a loss of function mutation in LPL and no functional mutations in APOC2 or GPIHBP1 were identified. The mean lipoprotein lipase concentration was lower in patients with diabetic lipaemia than in control subjects (306 vs 484 μg/l, P = 0.04). The mean fasting C-peptide concentration was higher in patients with diabetic lipaemia than in control subjects (771 vs 50 pmol/l; P = 0.001). Conclusions Lipoprotein lipase deficiency in patients with a history of diabetic lipaemia was predominantly quantitative, rather than secondary to mutations in LPL, APOC2 or GPIHBP1. The majority of patients with severe hypertriglyceridaemia in diabetic ketoacidosis may have ketosis-prone Type 2, rather than Type 1, diabetes.

Diabetic lipaemia, severe hypertriglyceridaemia associated with diabetic ketoacidosis, is a well recognised, but rare condition. Why this occurs in some patients and not others is unknown. We report a case of extreme lipaemia in a 20-year-old woman with type 1 diabetes who presented to hospital with diabetic ketoacidosis (DKA). At admission the patient's blood was grossly lipaemic and plasma lipid analyses showed triglyceride and cholesterol concentrations of 379 mmol/L and 52 mmol/L, respectively. She had no peripheral stigmata of chronic hyperlipidaemia and 1 year previously her plasma triglyceride and total cholesterol concentrations were 2.5 mmol/L and 4.4 mmol/L respectively. She was treated with insulin and the hypertriglyceridaemia resolved over several days. Because of the marked hypertriglyceridaemia, lipoprotein lipase (LPL) genetic testing was performed. Sequencing of the LPL gene revealed that she was heterozygous for the common S447X LPL variant and heterozygous for a novel missense mutation in exon five (I225N). Ile225 is highly conserved among species and this mutation is predicted to impair function of the mature LPL protein. We conclude that heterozygosity for LPL mutations may predispose to transient severe hypertriglyceridaemia, when combined with insulin deficiency.

Measurement of plasma cortisol by immunoassay after ACTH₁₋₂₄ stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol.We investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH₁₋₂₄ stimulation test to define HPA status in pituitary patients.This was a case control study conducted in a clinical research facility.We studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined.Participants underwent 1 μg ACTH(1-24) intravenous and 250 μg ACTH₁₋₂₄ intramuscular ACTH₁₋₂₄ stimulation tests.Concordance of ACTH₁₋₂₄-stimulated total and free plasma cortisol with previous HPA assessment.Total cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH₁₋₂₄-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 μg and 30 and 60 minutes after 250 μg ACTH₁₋₂₄ were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol.Categorization of HPA status by immunoassay and LCMS after ACTH₁₋₂₄ stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.

Purpose To evaluate the efficacy of the Wallstent endoprosthesis in the treatment of ureteral strictures. Patients and Methods Wallstents with diameters of 10 mm were placed across five malignant and six benign ureteral strictures in eight patients. All patients were believed to have poor surgical options, and their strictures were being maintained with catheter drainage. Ten lesions involved ureteroenteric anastomoses, and one malignancy involved the midureter. Results Three stents (two patients) across malignant disease remained patent until the time of patient death (3–5 months); the remaining two stents (one patient) became occluded within 1 month. Only one of six stents placed for benign disease remained patent at 11 months. All occlusions in benign strictures resulted from ingrowth of hyperplastic urothelium and granulation tissue. Complete obstruction was usually present only focally within the stent. The malignant occlusions were caused by tumor ingrowth and granulation tissue. No major complications were directly related to the stents, but two infections occurred. Conclusion Wallstent endoprostheses are ineffective in providing long-term relief in patients with benign ureteroenteric strictures. Further evaluation of their role in malignant strictures is needed.

The objective was to determine the safety of laparoscopic cholecystectomy for patients 65 years of age and older with symptomatic uncomplicated chronic gallbladder disease by comparing the mortality rate with open cholecystectomy. Connecticut Hospital Information Management Exchange and the Connecticut Society of American Board of Surgeons established a Connecticut Laparoscopic Registry made up of 33 acute care hospitals. A cohort longitudinal retrospective statewide registry collected data mortality rates on all 2865 elderly patients undergoing open (OC) or closed (LC) cholecystectomy for uncomplicated chronic cholecystitis. A database was established and continuously monitored from October 1, 1988, to December 31, 1992. Seven hundred sixty-one patients over 65 years of age underwent open cholecystectomy for uncomplicated chronic cholecystectomy during fiscal year 1989, with a mortality rate of 1.4%. The mortality rate of a similar cohort of patients who underwent laparoscopic cholecystectomy during fiscal years 1991 and 1992 was 0.3% and 0.6%, respectively. The mortality rate was further broken down into age subsets 65-69, 70-79, and 80+. The prelaparoscopic era (FY 1989) age subsets were compared with those of the laparoscopic era (FY 1991 and 1992). A statistically significant reduction (p = 0.01) in mortality rate was noted in the 70-79 age group following laparoscopic surgery. Laparoscopic cholecystectomy in the elderly for the treatment of symptomatic, uncomplicated chronic cholecystitis is as safe if not safer than open cholecystectomy as measured by mortality rate.

Endogenous glucocorticoid excess (Cushing's syndrome) predominantly increases postprandial glucose concentration. The pattern of hyperglycemia induced by prednisolone has not been well characterized.Our objective was to define the circadian effect of prednisolone on glucose concentration to optimize management of prednisolone-induced hyperglycemia.This was a cross-sectional study in a teaching hospital.Participants included 60 consecutive consenting subjects with chronic obstructive pulmonary disease admitted to hospital: 13 without known diabetes admitted for other indications and not treated with glucocorticoids (group 1), 40 without known diabetes admitted with an exacerbation of chronic obstructive pulmonary disease and treated with prednisolone (group 2, prednisolone = 30 ± 6 mg/d), and seven with known diabetes treated with prednisolone (group 3, prednisolone = 26 ± 9 mg/d).Interstitial glucose concentration was assessed during continuous glucose monitoring.Significantly more subjects in group 2 [21 of 40 (53%), P = 0.02] and group 3 [seven of seven (100%), P = 0.003] recorded a glucose of at least 200 mg/dl (≥11.1 mmol/liter) during continuous glucose monitoring than in group 1 [one of 13 (8%)]. The mean glucose concentration between 2400-1200 h for group 3 (142 ± 36 mg/dl) was significantly greater than in the other two groups (P0.005), whereas mean glucose concentrations between 2400-1200 h in group 1 (108 ± 16 mg/dl) and group 2 (112 ± 22 mg/dl) were not significantly different. In contrast, the mean glucose concentrations between 1200-2400 h for group 2 (142 ± 25 mg/dl) and group 3 (189 ± 32 mg/dl) were both significantly greater than group 1 (117 ± 14 mg/dl, P0.05 for both comparisons).Prednisolone predominantly causes hyperglycemia in the afternoon and evening. Treatment of prednisolone-induced hyperglycemia should be targeted at this time period.

Chemotherapy for primary or metastatic hepatic malignancy is limited by poor tumor response and dose-related systemic toxicity. As an alternative to chemotherapy infusion by vein or by the hepatic artery, the authors have developed a percutaneous technique of isolated liver perfusion that allows the regional delivery of high-dose chemotherapy to the liver with little systemic toxicity. After placement of a hepatic artery infusion catheter, an 18-F double-balloon catheter is placed into the inferior vena cava through the opposite femoral vein. Balloons are inflated above and below the hepatic veins, thus isolating hepatic venous outflow. The effluent passes through fenestrations in the catheter and is pumped through charcoal hemoperfusion filters where the drug is removed. The filtered blood is returned to the patient through the internal jugular vein. Fifteen treatments have been conducted in eight patients in a phase I dose-escalation study with use of 5-fluorouracil (5-FU). While it is premature to assess tumor response to isolated liver perfusion, the data demonstrate that the procedure is safe and is tolerated by patients. Pharmacokinetic studies show a 5-FU extraction of up to 85%, with minimal drug leakage into the systemic circulation. This technique shows potential for improving liver tumor response while decreasing systemic toxicity.

Context: High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. Objective: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. Design and Setting: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. Patients and Intervention: Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 ± 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. Main Outcome Measure: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. Results: Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. Conclusion: Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.

Objective Although growth hormone (GH)-induced changes in fat and protein metabolism are likely to underlie changes in body composition, the relationship has not been clearly defined. The aim was to study the effects of dose and time course on substrate metabolism and relate to body compositional changes during GH treatment. Design In an open randomised-controlled study, 16 GH-deficient adults were randomised to treatment with GH 3 μg/kg/d (low dose, n = 6) or 6 μg/kg/d (higher dose, n = 10) for 12 weeks. Changes in whole body protein metabolism, estimated using the leucine turnover technique, and resting energy expenditure (REE) were assessed after short-term GH (two weeks) and longer-term GH (12 weeks). Changes in lean body mass (LBM) and fat mass (FM) over 12 weeks were assessed by DXA. Results The maximal changes in leucine oxidation (Lox) (−3.9 ± 1.1 versus +0.8 ± 1.8 μmol/min, p = 0.03) and REE (+132 ± 36 versus −28 ± 41 kcal/d, p = 0.01) were significantly greater in the higher, than the low dose group. FM fell (−1.4 ± 0.4 kg, p = 0.005) and LBM increased (+2.2 ± 0.7 kg, p = 0.01) significantly in the higher dose group only. The acute reduction in Lox at two weeks in the higher dose group was no longer significant after 12 weeks. The change in Lox after two ( r = −0.53, p = 0.035), but not 12, weeks was significantly correlated with the change in LBM. Conclusions GH-induced changes in protein metabolism were influenced by the dose and duration of GH treatment. Suppression of protein oxidation occured soon after initiation of GH in the higher dose group and predicted a later gain in LBM. Early assessment of whole body protein metabolism may allow prediction of the anabolic potential of GH.

We describe two young men with cystic pituitary enlargement on magnetic resonance imaging (MRI) causing hypopituitarism. The first patient presented acutely unwell with headache and vomiting associated with anterior and posterior pituitary dysfunction. The second patient presented with hypopituitarism after a long history of hypogonadism. In both cases yellow/brown fluid was found at surgery and histological examination revealed inflammatory infiltrate with foamy histiocytes, lymphocytes and multinucleated giant cells containing cholesterol clefts. Full recovery of pituitary function occurred after surgery in the first but not the second patient. The first case is the first documented case of xanthomatous hypophysitis with recovery of pituitary function following surgery. The cases differed in duration of disease, as indicated by the long history of symptoms, the histological finding of marked fibrosis and the lack of recovery of pituitary function in the second. Xanthomatous pituitary lesions categorized in the literature as xanthomatous hypophysitis, xanthogranulomatous hypophysitis and xanthogranuloma of the sellar region have overlapping histological features. Our two cases revealed histological features that do not fit completely into any of the categories but share features of all three. These findings suggest that the various xanthomatous lesions of the sellar region may be a spectrum of a common inflammatory process rather than distinct pathological entities.

We compared a rapid high resolution magnetic resonance imaging (MRI) technique to contrast urethrography for the detection of urethral diverticula in women.During a 19-month interval 13 patients with clinically suspected urethral diverticula were evaluated with MRI and contrast urethrography. All patients were referred by a urologist, and had clinical signs and symptoms suggesting the presence of a urethral diverticulum. Double balloon urethrography was performed in 12 patients and voiding cystourethrography was done in 1. MRI was performed using a fast spin echo T2-weighted pulse sequence and a dedicated pelvic multicoil. Following a sagittal localizer sequence 3 mm. thick axial sections were obtained from the bladder base through the entire urethra. Total imaging time was 15 minutes.In 7 patients MRI and urethrography were negative for urethral diverticula, and in 3 cystourethroscopy was negative. In 1 patient MRI revealed a vaginal inclusion cyst confirmed by surgery. Three patients had no other studies or procedures performed. In 6 patients MRI was positive for urethral diverticula, including 4 in whom the diverticulum was confirmed at surgery, 1 who declined surgery and 1 who was lost to followup. Of the 4 patients (75%) with a surgically confirmed diverticulum double balloon urethrogram was negative in 3.MRI is a valuable noninvasive technique for determining the presence of urethral diverticula as well as detecting other abnormalities. In our study MRI had a higher sensitivity for detecting diverticula and a much higher negative predictive rate.

Three aids in the diagnosis and management of urethral diverticula are described. First, the technique of double-balloon urethrography has been modified. Diluted contrast medium is used to inflate the intravesical and external balloons so that improved delineation of the anatomy of the diverticular pouches is obtained with undiluted contrast medium. Second, for identification and irrigation with antibiotic solution of the nondraining pouches of compound diverticula, an angiographic catheter is placed in the most distal pouch using fluoroscopically guided manipulation, and then this catheter is replaced with a pigtail-shaped nephrostomy drainage catheter. Third, a 7 F Foley catheter balloon is placed in thin-walled and friable diverticular pouches to facilitate dissection.

The influence of intravenous plus oral glucose administration on splanchnic glucose handling was examined in healthy young individuals by combining the hepatic vein catheterization technique with the double glucose tracer method. After 1 h of steady state hyperglycaemia (11.7 mM) induced by intravenous glucose alone (hyperglycaemic clamp technique), subjects ingested 89 +/- 1 g of glucose, and the hyperglycaemic plateau was maintained for the subsequent 4 h by adjusting the exogenous glucose infusion rate. Over the 4-h absorptive period, only 51 +/- 4 g of oral glucose (i.e. 58 +/- 4% of the ingested load) appeared in the systemic circulation, while 193 +/- 15 g (1.072 +/- 0.83 mol) of glucose had to be infused exogenously to sustain the hyperglycaemia. Endogenous glucose production was suppressed by over 60%. Net splanchnic glucose balance switched from a positive value (i.e. net uptake) of 5.06 +/- 2.56 mumol min-1 kg-1 with intravenous glucose alone (0-60 min) to a negative one (i.e. net output) of 12.50 +/- 2.44 mumol min-1 kg-1 during 4 h (60-300 min) of intravenous + oral glucose. The mean rate of splanchnic glucose uptake was estimated to be 6.39 +/- 4.67 mumol min-1 kg-1 with intravenous glucose alone, and 8.83 +/- 4.28 mumol min-1 kg-1 with intravenous + oral glucose. In either case, the large majority (80-90%) of the glucose appearing in the systemic circulation was disposed of by extrasplanchnic tissues. These results indicate that pre-existing hyperglycaemia and/or hyperinsulinaemia inhibit gastrointestinal glucose absorption, and that oral glucose administration does not result in a major redistribution of intravenous glucose between splanchnic and extrasplanchnic tissues.

Background A variety of studies have noted seasonal variation in blood lipid levels. Although the mechanism for this phenomenon is not clear, such variation could result in larger numbers of people being diagnosed as having hypercholesterolemia during the winter. Methods We conducted a longitudinal study of seasonal variation in lipid levels in 517 healthy volunteers from a health maintenance organization serving central Massachusetts. Data collected during a 12-month period for each individual included baseline demographics and quarterly anthropometric, blood lipid, dietary, physical activity, light exposure, and behavioral information. Data were analyzed using sinusoidal regression modeling techniques. Results The average total cholesterol level was 222 mg/dL (5.75 mmol/L) in men and 213 mg/dL (5.52 mmol/L) in women. Amplitude of seasonal variation was 3.9 mg/dL (0.10 mmol/L) in men, with a peak in December, and 5.4 mg/dL (0.14 mmol/L) in women, with a peak in January. Seasonal amplitude was greater in hypercholesterolemic participants. Seasonal changes in plasma volume explained a substantial proportion of the observed variation. Overall, 22% more participants had total cholesterol levels of 240 mg/dL or greater (≥6.22 mmol/L) in the winter than in the summer. Conclusions This study confirms seasonal variation in blood lipid levels and suggests greater amplitude in seasonal variability in women and hypercholesterolemic individuals, with changes in plasma volume accounting for much of the variation. A relative plasma hypervolemia during the summer seems to be linked to increases in temperature and/or physical activity. These findings have implications for lipid screening guidelines. Further research is needed to better understand the effects of a relative winter hemoconcentration.

Acute lobar nephronia (ALN) refers to a renal mass caused by acute focal infection without liquefaction. The radiological findings in 12 patients with 13 episodes of ALN are described. A characteristic combination of uroradiological findings is (a) a relatively sonolucent mass which disrupts corticomedullary definition on ultrasonography; (b) a solid-appearing mass on other uroradiological studies; and (c) a positive gallium image in the region of the mass, which may be associated with increased activity elsewhere in the same or opposite kidney. The angiographic finding of significant venous narrowing within the mass associated with only minor arteriographic abnormalities is characteristic of ALN as well.

Five patients with acute focal bacterial nephritis and hematuria had sonographic and CT findings atypical for renal infection. Sonographically, each presented with an echogenic focus in the renal parenchyma. Noncontrast CT images showed an area of increased density in the corresponding segment of the kidney in three patients, mixed high and low density in one patient, and low density alone in the remaining patient. It is proposed that these appearances result from the presence of hemorrhage at different stages, associated with focal infection. Venous compromise is suggested as the etiology.

Duodenal tumors are rare but duodenal inflammatory disease occurs frequently. In most cases it can be accurately diagnosed without angiography but in the occasional case that presents a diagnostic problem, angiography is required. Seven cases of duodenal inflammatory disease are reviewed. Careful attention to the shape and direction of vascular displacement and to separate evaluation of pancreatic and duodenal arteries accurately distinguished duodenal from pancreatic disease. This distinction can significantly influence subsequent therapy.