Loss of body cell mass in Cushing's syndrome: effect of treatment

Cushing's syndrome (CS) is associated with low fat-free mass, but it is unclear whether hypercortisolism causes a loss of whole body protein. Body composition was studied prospectively in 15 patients with untreated CS (n = 14 pituitary adenoma; n = 1 adrenal adenoma), in 15 nonobese healthy controls, and in 15 weight-matched obese controls by 3 different methods: total body potassium counting (TBP), bioelectrical impedance analysis (BIA), and anthropometry. In 6 patients, body composition was studied before and within 6 months after pituitary surgery. In CS patients and weight-matched controls, body weight and total body fat were significantly higher than in nonobese controls. In CS patients, TBP was 18.4% lower than predicted, whereas in weight-matched controls TBP was 7.1% higher than predicted. As compared with nonobese and weight-matched controls, in CS patients TBP indicated a significant loss of body cell mass (BCM) of -20.2 and -21.1%, respectively. A significantly reduced arm muscle area of -21.3% compared with weight-matched controls also indicated a loss of whole body protein. In CS, however, BIA overestimated BCM when compared with TBP by +18% and agreement between BIA and TBP in the individual patient was poor (limits of agreement plus minus 27.6%), indicating the invalidity of standard BIA equations in this population. Measurements performed before and 6 months after successful pituitary surgery demonstrated a significant loss of body weight (-11%) and body fat (-33%), but BCM and muscle mass remained on a constant low level. In conclusion, this study shows that, in patients with CS, a significantly reduced BCM indicates a true protein loss. The second interesting finding is that in the early recovery after successful treatment of hypercortisolism patients lose body fat without gaining BCM or muscle mass.     

Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia

The breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MXR) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). BCRP has been detected in acute myeloid leukaemia and in breast, colon and gastric cancer but there has been no reports regarding BCRP expression in acute lymphoblastic leukaemia (ALL). We report the first results of BCRP expression in childhood ALL. Sixty-seven children (47 initial stage, 20 relapses) with ALL were analysed for BCRP gene expression by TaqMan real-time polymerase chain reaction. The expression of BCRP in mononuclear cells obtained from the bone marrow (BM) and peripheral blood (PB) of healthy donors was also investigated. There was no relationship between BCRP expression and age, sex, initial blast cell count, prednisolone response or BM response on d 15 and 33. Patients with T-lineage ALL showed a lower expression of BCRP (P = 0.044). Kaplan-Meier analysis of the relapse-free interval showed no prognostic significance of BCRP expression when different levels of BCRP expression were used as cut-off points. No significant difference in expression of BCRP mRNA was measured between initial-stage and relapsed-stage ALL or between normal MNC obtained from BM and ALL patients. The results indicate a low expression of BCRP in childhood ALL. Relationships between BCRP and clinical, molecular or in vivo resistance characteristics of the patients were not observed.     

Antineutrophil cytoplasmic autoantibody-negative antiproteinase 3 syndrome presenting as vasculitis,endocarditis, polyneuropathy and Dupuytren's contracture

Antiproteinase 3 antibodies (antiPR3) are assumed to be subtypes of antineutrophil cytoplasmic autoantibodies (ANCA), with a high specificity for active Wegener's granulomatosis and microscopic polyangiitis. Thus, antiPR3 positivity in ELISA, together with negativity in indirect immunofluorescence (IIF) is a rare finding. A 56-year-old man with Dupuytren's contracture and polyneuropathy was admitted for leukocytoclastic vasculitis. Echocardiography, performed because of fever and dyspnea, detected aortic valve endocarditis. Because of severe aortic insufficiency the valve was replaced. Blood cultures and bacteriologic investigations of the explanted valve were negative. AntiPR3 were elevated (123-163 U/ml; normal <6 U/ml), together with negativity in IIF. This case shows that antiPR3 elevation with negative ANCA may be associated with vasculitis, endocarditis, polyneuropathy and Dupuytren's contracture. A causal relationship between the clinical presentation and antiPR3 elevation is likely. In order not to miss such cases of vasculitis, combined screening by IIF and ELISA is recommended in selected cases.     

Ventricular arrhythmias before and late after aortic valve replacement

The influence of aortic valve replacement on the incidence of ventricular arrhythmias was studied by 24-hour Holter electrocardiographic monitoring in 45 patients immediately before and 14 ± 7 months after operation. Ventricular arrhythmias were graded according to the Lown criteria. Preoperative left ventricular (LV) ejection fraction (EF) was determined by angiography and postoperative LVEF by gated blood pool scintigraphy. Repetitive ventricular arrhythmias (Lown grade 4A/B) were associated with a reduced LVEF (< 55%) before and after operation. In 24 patients with preoperative normal LVEF (>- 55%) (group A), mean LVEF remained unchanged after operation (72% vs 71 %). Pre- and postoperative ventricular premature complex (VPC) frequency (45 ± 99 vs 39 ± 94 VPC/24 hours and grade (1.3 vs 1.4) were not significantly different. However, in 17 patients with preoperative impaired LVEF (< 55%) (group B, LVEF preoperatively 40 ± 8%) and marked postoperative improvement (> 10%) (LVEF postoperatively 64 ± 7%), mean VPC frequency decreased from 536 to 69 VPCs/24 hours and mean VPC grade was reduced from 3.8 to 1.5. Complex VPCs were found preoperatively in all 17 patients of group B, but in only 5 patients after operation. Four patients had a reduced LVEF preoperatively and it did not improve postoperatively (group C). Postoperative Holter monitoring detected ventricular tachycardia in all 4 patients.This study indicates that repetitive VPCs are infrequent in patients with normal LVEF before and late after aortic valve replacement. In patients with impaired LVEF and complex VPCs preoperatively, the postoperative improvement of LV function is usually accompanied by a reduction of frequent and complex VPCs.     

Dosing Accuracy of Two Disposable Insulin Pens According to New ISO 11608-1: 2012 Requirements

Objective:

The aim was to compare 2 disposable insulin pens, FlexTouch® (Novo Nordisk, insulin aspart) and SoloSTAR® (Sanofi, insulin glulisine), according to new ISO 11608-1:2012 requirements for dosing accuracy.

Methods:

Sixty pens of each type were tested at 1, 40, and 80 U doses. Following the new ISO requirements, each dose was delivered from the front, middle, and rear one-third of the pen. Statistical analysis was performed using Student’s t test.

Results:

Both pens delivered all doses within ISO limits. The difference between the average measured dose and the target dose was significantly smaller for SoloSTAR than FlexTouch at 40 U (P = .009) and 80 U (P = .008), but not at 1 U (P = .417).

Conclusion:

Both insulin pens fulfilled the dosing accuracy requirements defined by ISO 11608-1:2012 at all 3 dosage levels.     

Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer

OBJECTIVES: In managing patients with bleeding peptic ulcers, prevention of rebleeding is a particular challenge to hemostasis and fibrinolysis, both of which involve reactions that are impaired in acidic gastric environment. Therefore, such patients are expected to benefit from profound acid suppression. The present investigation aimed to establish a safe and, with regard to pH elevation, effective treatment that, based on in vitro evidence, should provide clinical benefit in this patient population. METHODS: Patients with acute bleeding peptic ulcers (Forrest Ia, Ib, IIa) after successful endoscopic hemostasis were enrolled in two pilot studies (N = 20 each). They were given an intravenous bolus injection of 80 mg of pantoprazole immediately followed by continuous infusion of either 6 mg/h or 8 mg/h pantoprazole for 72 h. Intragastric pH was measured continuously over 24 h and, if possible, for up to 48 h. RESULTS: Intragastric pH increased rapidly to values of about 6 with both treatments. For the 0-24 h period, the median pH values were 6.1 (68% range 4.5-7.4) and 6.1 (68% range 5.2-6.7) in patients receiving 6 mg/h and 8 mg/h continuous infusion, respectively; the values for the 0-48 h period were 5.9 (4.9-6.7) and 6.3 (5.5-7.0), respectively. The median percentage time that pH was > or =6 during the 0-48 h interval was 47% (68% range 28-89) for the 6 mg/h treatment group and 64% (68% range 41-84) for the 8 mg/h treatment group. Both treatment regimens with pantoprazole were well tolerated based on electrocardiographic measurements, vital signs, clinical laboratory values, and adverse events. CONCLUSIONS: Compared with the infusion with 6 mg/h pantoprazole, the continuous infusion of 8 mg/h pantoprazole showed a lower interindividual variability of the intragastric pH and a greater percentage of time that pH was >/ or =6. Thus, with regard to safety and efficacy, an initial 80-mg bolus injection, followed by 8 mg/h continuous infusion, seems to be the adequate treatment in patients with a high risk of rebleeding.     

Preserved circadian rhythm of serum insulin concentration at low plasma glucose during fasting in lean and overweight humans

Circadian rhythms in glucose metabolism are well documented. Most studies, however, evaluated such variations under conditions of continuous glucose supply, either via food intake or glucose infusion. Here we assessed in 30 subjects circadian variations in concentrations of plasma glucose, serum insulin, and C-peptide during a 72-hour fasting period to evaluate rhythms independent from glucose supply. Furthermore we assessed differences in these parameters between normal-weight (n = 20) and overweight (n = 10) subjects. Blood was sampled every 4 hours. During fasting, plasma glucose, serum insulin, and C-peptide levels gradually decreased (all P < .001). While there was no circadian variation in plasma glucose levels after the first day of fasting, serum levels of insulin were constantly higher in the morning (8.00 h) than at night (0.00 h) (P < .001), although the extent of this morning-associated rise in insulin levels decreased with the time spent fasting (P = .001). Also, morning C-peptide concentrations were higher compared to the preceding night (P < .001). The C-peptide/insulin ratio (CIR) decreased during prolonged fasting (P = .030), suggesting a decrease in hepatic insulin clearance. Moreover, CIR was significantly lower in the morning than at the night of day 1 and day 2 of fasting (P = .010 and P = .004, respectively). Compared to normal-weight subjects, overweight subjects had higher plasma glucose, as well as serum insulin and C-peptide levels (all P < .03). Data indicate preserved circadian rhythms in insulin concentrations in the presence of substantially decreased glucose levels in normal-weight and overweight subjects. This finding suggests a central nervous system contribution to the regulation of insulin secretion independent of plasma glucose levels.