Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

AIMS: To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development. METHODS: We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years. RESULTS: Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration). CONCLUSIONS: After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the ß-cell protective properties of DXM.

What do physicians read (and ignore) in electronic progress notes?

OBJECTIVE: Several studies have documented the preference for physicians to attend to the impression and plan section of a clinical document. However, it is not clear how much attention other sections of a document receive. The goal of this study was to identify how physicians distribute their visual attention while reading electronic notes. METHODS: We used an eye-tracking device to assess the visual attention patterns of ten hospitalists as they read three electronic notes. The assessment included time spent reading specific sections of a note as well as rates of reading. This visual analysis was compared with the content of simulated verbal handoffs for each note and debriefing interviews. RESULTS: Study participants spent the most time in the "Impression and Plan" section of electronic notes and read this section very slowly. Sections such as the "Medication Profile", "Vital Signs" and "Laboratory Results" received less attention and were read very quickly even if they contained more content than the impression and plan. Only 9% of the content of physicians' verbal handoff was found outside of the "Impression and Plan." CONCLUSION: Physicians in this study directed very little attention to medication lists, vital signs or laboratory results compared with the impression and plan section of electronic notes. Optimizing the design of electronic notes may include rethinking the amount and format of imported patient data as this data appears to largely be ignored.

Nasogastric vs. intravenous rehydration in children with gastroenteritis and refusal to drink: a randomized controlled trial.

BACKGROUND: Nasogastric rehydration therapy (NGRT) is the recommended therapy in moderately dehydrated children with gastroenteritis and refusal to drink, since it is supposed to be as effective if not better than intravenous rehydration therapy (IVRT). However, in clinical practice IVRT is often favored. We conducted a clinical trial to determine whether IVRT is not inferior to NGRT. PATIENTS AND METHODS: Children 3 months to 6 years of age with moderate dehydration and refusal to drink secondary to gastroenteritis were recruited. After clinical assessment of the degree of dehydration, patients were assigned randomly to receive either IVRT or NGRT over 6 h on the hospital ward. RESULTS: Recruitment did not yield the estimated number of patients. Mainly, non-enrollment was due to failure to obtain parental consent because IVRT was expected. 97 patients were enrolled in the study, 46 were randomized to NGRT and 51 to IVRT. There was no difference between IVRT and NGRT groups concerning length of hospital stay (2.2±1.1 days vs. 2.4±1.1 days), success of rehydration (78 vs. 76%) and adverse events. DISCUSSION: Since we had to terminate the study ahead of schedule due to a low recruiting rate, our results are not reliable. However, data from the literature shows that the widespread described superiority of NGRT over IVRT is seriously influenced by studies from developing countries questioning the applicability of the results to a setting available in high-income countries nowadays. CONCLUSION: Our study demonstrates the difficulties performing such a study in a high-income country to come to an objective and clearly evident final conclusion.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

[Infantile hemangioma. Successful treatment with propranolol]. / Infantiles Hämangiom. Erfolgreiche Behandlung mit Propranolol.

We report on an infant, aged four months, suffering from a severe hemangioma of the left labium majus. We induced systemic treatment with propranolol in off-label-use over a period of 5 1/2 months. A few weeks after onset of the treatment, the size and color of hemangioma was obviously reduced; finally there was an almost complete regression. This result underlines the role of propranolol in treatment of problematic hemangioma.

Diagnostic difficulties in glucokinase hyperinsulinism.

Glucokinase hyperinsulinism is a rare variant of congenital hyperinsulinism caused by activating mutations in the glucokinase gene and has been reported so far to be a result of overactivity of glucokinase within the pancreatic beta-cell. Here we report on a new patient with difficulties to diagnose persistent hyperinsulinism and discuss diagnostic procedures of this as well as the other reported individuals. After neonatal hypoglycemia, the patient was reevaluated at the age of 3 years for developmental delay. Morning glucose after overnight fast was 2.5-3.6 mmol/l. Fasting tests revealed supressed insulin secretion at the end of fasting (1.4-14.5 pmol/l). In addition, diagnostic data of the patients reported so far were reviewed. A novel heterozygous missense mutation in exon 10 c.1354G>C (p.Val452Leu) was found and functional studies confirmed the activating mutation. There was no single consistent diagnostic criterion found for our patient and glucokinase hyperinsulinism individuals in general. Often at the time of hypoglycemia low insulin levels were found. Therefore insulin concentrations at hypoglycemia, or during fasting test as well as reactive hypoglycemia after an oral glucose tolerance test were not conclusive for all patients. A glucose lowering effect in extra-pancreatic tissues independent from hyperinsulinism that results in diagnostic difficulties may contribute to underestimation of glucokinase hyperinsulinism. Mutational analysis of the GCK-gene should be performed in all individuals with unclear episodes of hypoglycemia even without documented hyperinsulinism during hypoglycemia. Delay of diagnosis might result in mental handicap of the affected individuals.

The effectiveness of an AIDS education campaign on a college campus.

This paper reports on an AIDS education campaign at a California college campus. A pretest-posttest design was used to determine whether the AIDS-related attitudes of students, faculty, and staff were affected by an AIDS Awareness Week. The results showed that the awareness week was successful in exposing the campus community to AIDS information. It was only marginally effective in changing AIDS-related attitudes because pretest attitudes were already at desirable levels, only a fraction of the campus community attended the highly motivating events of the campaign, and faculty did not actively support the goals of the campaign.

Autogenous dermal graft coverage of submerged roots in the dog.

Dermal grafts were compared with conventional supraperiosteal recipient beds grafted with split-thickness skin for covering submerged vital roots in six dogs. Several potential advantages of this new technique are suggested.

A study of freeze-dried (lyophilized) dentin used as an apical barrier in adult monkey teeth.

Thirty-two fully formed vital teeth of four adult cynomolgus monkeys were endodontically prepared to simulate conditions of an open apex. The apical 2 to 5 mm. of 24 teeth were filled with freeze-dried dentin. The eight remaining teeth received no implant material and served as controls. All the teeth were obturated with gutta-percha. The monkeys were sacrificed at 6, 13, 23, and 27 week periods, and the specimens were prepared for histologic examination. The early specimens showed acute inflammation apically; later specimens showed osseous healing. Some experimental teeth had partial cementum bridging against the implant material. Freeze-dried dentin was found to be a biocompatible material which can be used effectively as a substitute barrier against which gutta-percha can be condensed in mechanically prepared open-apexed monkey teeth.