Superficial fibromas with CTNNB1 mutation.

Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be indicators of an underlying syndrome. Among the best-known entities of superficial fibromas is Gardner fibroma, a plaque-like benign tumor, which is associated with APC germline mutations and occurs in patients with familial adenomatosis polyposis (Gardner syndrome). Affected patients also have an increased risk to develop desmoid fibromatosis (DTF), a locally aggressive neoplasm of the deep soft tissue highly prone to local recurrences. Although a minority of DTFs occur in the syndromic context and harbor APC germline mutations, most frequently their underlying molecular aberration is a sporadic mutation in Exon 3 of the CTNNB1 gene. Up to date, a non-syndromic equivalent to Gardner fibroma carrying a CTNNB1 mutation has not been defined. Here, we present two cases of (sub-)cutaneous tumors with a hypocellular and collagen-rich Gardner fibroma-like appearance and pathogenic, somatic CTNNB1 mutations. We aim to differentiate these tumors from other fibromas according to their histological appearance, immunohistochemical staining profile and underlying somatic CTNNB1 mutations. Furthermore, we distinguish them from locally aggressive desmoid fibromatosis regarding their biological behavior, prognosis and indicated therapeutic strategies. Consequently, we call them CTNNB1-mutated superficial fibromas as a sporadic counterpart lesion to syndromic Gardner fibromas.

Use of glucagon-like peptide-1 receptor agonists among individuals on basal insulin requiring treatment intensification.

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA1c goals. For these people, treatment intensification options are relatively limited and include the addition of short-acting prandial insulin or a glucagon-like peptide-1 receptor agonist. Glucagon-like peptide-1 receptor agonists vary in their effects, with short- and long-acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon-like peptide-1 receptor agonists and prandial insulin to be effective in reducing HbA1c concentrations; however, recipients of glucagon-like peptide-1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon-like peptide-1 receptor agonist and basal insulin, fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long-term glycaemic control.

Improved glycaemic control and treatment satisfaction with a simple wearable 3-day insulin delivery device among people with Type 2 diabetes.

AIM: To evaluate the PAQ® (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. METHOD: Adults with Type 2 diabetes with HbA1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single-arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA1c , seven-point self-monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. RESULTS: A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m2 , Type 2 diabetes duration 17 ± 8 years, HbA1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA1c -16 ± 9 mmol/mol (95% CI -20, -12) or -1.5 ± 0.9% (95% CI -1.8, -1.1) P<0.0001], and at all seven self-monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia. CONCLUSIONS: Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy. (ClinicalTrials.gov identifiers: NCT02158078 & NCT02419859).

Not only age but also tactile perception influences the preference for cosmetic creams applied to the forearm.

OBJECTIVE: We aimed to examine whether and how age as well as tactile sensitivity and perception had an impact on how women liked richer and lighter creams. Furthermore, the question arose if age and tactile perception had an influence on the ability to distinguish between the creams and how the ability to distinguish between creams influenced the liking of these creams. METHODS: A total of 299 female participants were invited to rate how much they liked four different cosmetic creams applied to their forearms. The creams were based on the same base formula but differed with respect to the texture. In order to arouse the impression of more lightness (quasi-light) or more richness (quasi-rich), polyethylene particles of different sizes were added to the base formula. First of all, the participants were tested for their tactile sensitivity and perception. Tactile sensitivity was tested by Von Frey filaments, tactile spatial perception by the tactile Landolt ring test and the ability to discriminate surface structures by a sandpaper test. Furthermore, the participants rated the creams with respect to the acceptance, the subjective skin feeling after application and performed paired-comparison tests. Analyses of variance and regression analyses were applied to the data. RESULTS: In general, participants liked quasi-rich creams less than quasi-light creams. However, older women compared to younger women and women with lower tactile performance in comparison with women with higher tactile performance revealed a weaker influence of cream type-specific acceptance ratings. Further results revealed that young participants perceived the quasi-light creams (with particles of ~50 µm diameter) as soft and quasi-rich creams (with particles of ~100 µm and ~165 µm diameter), as coarse. In contrast, this subjective skin feeling after application in participants at age 50 and older did not differ much. CONCLUSION: Age and tactile perceptual abilities have additive effects on the acceptance of creams with different textures when applied to the forearm.

[Gastrointestinal stromal tumors of the stomach and precursor lesions]. / Gastrointestinale Stromatumoren des Magens und ihre Vorstufen.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract although they are much less frequent than epithelial tumors. In more than 60% of cases they occur in the stomach. Especially small lesions measuring ≤1 cm in diameter, so-called microscopic GIST can occur multifocally, frequently in the proximal stomach wall and sometimes as an incidental finding in a gastrectomy specimen resected for gastric cancer. The multicentricity of GIST alone is not proof of a metastatic behavior or a syndromal or hereditary disease. Multiple sporadic synchronous and metachronous GIST are characterized by different primary mutations mostly in the KIT or PDGFRA genes and are often less aggressive. It is speculative whether a field effect is responsible or whether still unknown GIST-promoting factors may facilitate the development of several independent lesions. If KIT or PDGFRA mutations are lacking, a succinate dehydrogenase (SDH) deficient GIST has to be considered, either hereditary as Carney-Stratakis syndrome or syndromal as part of a Carney triad.

Observation and Structure Determination of an Oxide Quasicrystal Approximant.

We report on the first observation of an approximant structure to the recently discovered two-dimensional oxide quasicrystal. Using scanning tunneling microscopy, low-energy electron diffraction, and surface x-ray diffraction in combination with ab initio calculations, the atomic structure and the bonding scheme are determined. The oxide approximant follows a 3^{2}.4.3.4 Archimedean tiling. Ti atoms reside at the corners of each tiling element and are threefold coordinated to oxygen atoms. Ba atoms separate the TiO_{3} clusters, leading to a fundamental edge length of the tiling 6.7 Å.

Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment.

AIMS: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety. METHODS: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed. RESULTS: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. CONCLUSIONS: Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.

A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin.

AIM: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. METHODS: A 26-week, multi-country (Canada, Mexico, Romania, South Africa and the USA), randomized, double-blind, placebo-controlled study compared exenatide twice-daily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA(1c) 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2-week, single-blind, lead-in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA(1c) change at endpoint (Week 26 or last-observation-carried-forward). RESULTS: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA(1c) significantly more than placebo [-0.84% (s.e. 0.20) vs. -0.10% (0.23), treatment difference -0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, -1.4 (s.e. 0.6) kg vs. placebo, -0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA(1c) and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. CONCLUSIONS: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA(1c) without associated hypoglycaemia.

Impact of a change in antibiotic prophylaxis on total antibiotic use in a surgical intensive care unit.

OBJECTIVE: The aim of this study was to evaluate the impact of reducing the length of antibiotic prophylaxis for cerebro spinal shunts on total antibiotic use and key resistant pathogens. METHODS: In January 2004, the use of antibiotic prophylaxis was reduced to a single shot dose with cefuroxime in an intensive care unit (ICU). Prior to this intervention, prophylaxis with second-generation cephalosporins was administered during the entire period of external cerebro spinal fluid (CSF) drainage. The effect on the antibiotic use density (AD: DDD [defined daily doses] per 1,000 patient-days[pd]) was calculated prior to (January 2002-December 2003) and following implementation of the intervention(January 2004-December 2006) by segmented regression analysis of an interrupted time series. Resistance proportions(RP) and resistance densities (RD), defined as resistant pathogen/1,000 pd of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis or E. faecium, third-generation-resistant (3GC) Escherichia coli and Klebsiella pneumoniae, and imipenem-resistant Pseudomonus aeruginosa, were compared by the Fisher's exact test before and after the intervention. RESULTS: Total antibiotic use by 147 DDD/1,000 pd decreased after the intervention when pre-operative prophylaxis was changed into single shot prophylaxis, from an estimated mean of 1,036 DDD/1,000 pd before the intervention to 887DDD/1,000 pd post-intervention. This decrease was primarily due to a significant reduction in the amount of cefuroxime used for prophylaxis. The reduction in total antibiotic consumption was sustainable, and it did not increase again during the next 36 months. The RR and RD of third-generation cephalosporin-resistant E. coli increased after January 2004, whereas the percentage of MRSA significantly decreased. CONCLUSION: Change to single shot prophylaxis along with an ongoing antibiotic stewardship program resulted in a cut-back in total antibiotic use amounting to as much as 15%. It would therefore appear that targeting interventions aimed at reducing antibiotic prophylaxis in surgical ICUs may be very worthwhile.

[Reservoirs of Pseudomonas aeruginosa in the intensive care unit. The role of tap water as a source of infection]. / Reservoire von Pseudomonas aeruginosa auf der Intensivstation. Die Bedeutung des Wassers als Infektionsquelle.

In spite of significant changes in the spectrum of organisms causing nocosomial infections in intensive care units (ICUs), Pseudomonas aeruginosa has held a nearly unchanged position as an important pathogen. Today, the organism is isolated as the second most frequent organism causing ventilator-associated pneumonia, and the third or fourth most frequent pathogen causing septicemia, urinary tract infections, and surgical wound infections. In the past, horizontal transmissions were regarded as the most relevant route of strain acquisition. However, during the last 10 years, a significant proportion of P. aeruginosa isolates were demonstrated to stem from ICU water sites. Studies using molecular typing techniques have shown that up to 50% (in one study 92%) of nosocomial P. aeruginosa acquisitions may result from transmission through tap water. Additional proof of concept of waterborne infection comes from the reports of three recent studies that infection rates may be lowered significantly by eliminating colonized tap water sources or interrupting transmission chains from water sites.

Intranasal mupirocin prophylaxis in elective surgery. A review of published studies.

BACKGROUND: Mupirocin is a natural antibiotic from Pseudomonas fluorescens which is available as a 2% ointment. The drug has been used mainly for topical treatment of the nasal vestibulum in patients carrying methicillin-resistant Staphylococcus aureus (MRSA). However, mupirocin is also active against methicillin-sensitive S. aureus. Nasal colonization with S. aureus has been identified as a significant risk factor for surgical site infection (SSI). METHODS: Randomized trials and sequential cohort studies investigating mupirocin nasal treatment for prophylaxis of SSI in elective surgery in comparison with placebo or no treatment were found by Medline review and additional manual search. Evaluable studies were analyzed regarding the influence of mupirocin on the rate of all SSIs and, specifically, of SSIs due to S. aureus. The effect in cardiosurgical patients was analyzed in detail. RESULTS: Four randomized and seven sequential open cohort studies were analyzed. Study design and mupirocin application schemes varied considerably. Three out of 5 studies carried out in cardiac surgery patients showed a significant reduction in sternotomy site infections. However, all three studies were open sequential cohort studies. By contrast, the only prospective, randomized, double-blind study in cardiosurgical patients showed no benefit of mupirocin. In other surgical disciplines, results were inconclusive or negative. Two studies specifically addressing the prevention of SSIs due to MRSA showed a significant effect of mupirocin on postsurgical infections due to this organism. CONCLUSIONS: Because of the heterogeneity of the studies and the variability of results, no recommendation can be given for the general use of mupirocin in elective surgical patients. Specifically, because of the negative result of a recently published high-quality study, no recommendation can be made for the use of mupirocin in cardiosurgical patients. By contrast, eradication of MRSA before surgery appears to lower SSI rates due to MRSA and is therefore recommended.

Body fluid identification using a targeted mRNA massively parallel sequencing approach - results of a EUROFORGEN/EDNAP collaborative exercise.

In a previous study we presented an assay for targeted mRNA sequencing for the identification of human body fluids, optimised for the Illumina MiSeq/FGx MPS platform. This assay, together with an additional in-house designed assay for the Ion Torrent PGM/S5 platform, was the basis for a collaborative exercise within 17 EUROFORGEN and EDNAP laboratories, in order to test the efficacy of targeted mRNA sequencing to identify body fluids. The task was to analyse the supplied dried body fluid stains and, optionally, participants' own bona fide or mock casework samples of human origin, according to specified protocols. The provided primer pools for the Illumina MiSeq/FGx and the Ion Torrent PGM/S5 platforms included 33 and 29 body fluid specific targets, respectively, to identify blood, saliva, semen, vaginal secretion, menstrual blood and skin. The results demonstrated moderate to high count values in the body fluid or tissue of interest with little to no counts in non-target body fluids. There was some inter-laboratory variability in read counts, but overall the results of the laboratories were comparable in that highly expressed markers showed high read counts and less expressed markers showed lower counts. We performed a partial least squares (PLS) analysis on the data, where blood, menstrual blood, saliva and semen markers and samples clustered well. The results of this collaborative mRNA massively parallel sequencing (MPS) exercise support targeted mRNA sequencing as a reliable body fluid identification method that could be added to the repertoire of forensic MPS panels.

Efficacy of the combination of fluticasone propionate and salmeterol in patients with moderate persistent asthma within a "real-life" setting.

There are only few data on the effectiveness of recommended drug therapies in asthma under "real-life" conditions without targeted intervention. The study aimed at analyzing the efficacy of the fixed combination of the inhaled corticosteroid fluticasone propionate and the long-acting beta2-agonist salmeterol (FS) for maintenance treatment of moderate persistent asthma (GINA stage 3) within an observational design, mimicking "real-life" as closely as possible. The fixed combination was compared with other forms of treatment that were in accordance with treatment guidelines (pooled comparison (PC) group). Patients kept a diary during a 12-month observation period and routine visits were taken for surveillance. Among 596 patients, 371 patients belonged to the FS and 225 patients to the PC group. The proportion of symptom-free days (SFD) was higher in the FS than PC group (median, 76 vs 67%; p=0.002). Furthermore, the change in asthma control score (p<0.0001) and the percent increase in FEV1 (p<0.05) after 12 months were greater. There was a lower percentage of patients with hospital stays (p<0.05). The proportions of episode-free or sick-leave days and the number of routine or emergency visits did not significantly differ between groups. Direct costs of treatment per SFD were lower in the FS than PC group (median, 3.78 vs 4.41 Euro; p<0.05). We conclude that in a setup close to clinical practice treatment of patients with moderate persistent asthma with the fixed combination of fluticasone propionate and salmeterol has beneficial effects compared to other forms of therapy and can improve cost-efficiency.

Understanding surface reactivity of Si electrodes in Li-ion batteries by in operando scanning electrochemical microscopy.

In operando SECM is employed to monitor the evolution of the electrically insulating character of a Si electrode surface during (de-)lithiation. The solid-electrolyte interface (SEI) formed on Si electrodes is shown to be intrinsically electrically insulating. However, volume changes upon (de-)lithiation lead to the loss of the protecting character of the initially formed SEI.

Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group.

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group.

BACKGROUND: Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested. OBJECTIVES: To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM. METHODS: A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal. RESULTS: Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups. CONCLUSIONS: Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM.

Use of insulin lispro in continuous subcutaneous insulin infusion treatment. Results of a multicenter trial. German Humalog-CSII Study Group.

OBJECTIVE: Insulin lispro is an analog of human insulin with a faster onset and a shorter duration of action than regular human insulin. Efficacy and tolerability of insulin lispro in continuous subcutaneous insulin infusion (CSII) treatment were assessed in an open randomized crossover trial comparing insulin lispro and regular human insulin, both applied with insulin pumps. RESEARCH DESIGN AND METHODS: A total of 113 type 1 patients (60 male, 53 female, age [mean +/- SD] 37 +/- 12 years, duration of diabetes 19 +/- 9 years) participated in this open, randomized crossover study. Both insulins were applied for 4 months each with the appropriate intervals between the prandial insulin bolus and the meal (human insulin: 30 min; lispro: 0 min). Observation parameters were HbA1c, daily and postprandial blood glucose profiles, adverse events, rate of hypoglycemic and hyperglycemic events, number of catheter obstructions, and treatment satisfaction as assessed with an international validated questionnaire. RESULTS: The patients were well controlled with a mean HBA1c of 7.24 +/- 1.0% at baseline. HbA1c decreased in both treatment periods, but it was better during insulin lispro treatment (insulin lispro: 6.8 +/- 0.9%, regular human insulin: 6.9 +/- 1.0%, Friedman's rank-sum test: P < 0.02). In addition, the 1-h and 2-h postprandial rises in blood glucose were significantly lower (P < 0.001 for each meal) with insulin lispro, resulting in smoother daily glucose profiles as compared with regular human insulin. No significant differences were reported for the rate of hypoglycemia (mean +/- SD [median]: insulin lispro 12.4 +/- 13.9 [8], regular human insulin 11.0 +/- 11.2 [8]), for the rate of catheter obstructions (42 events in each treatment arm), and for the number and type of adverse events. No severe case of ketoacidosis was seen during insulin lispro treatment, whereas one case was reported during therapy with regular human insulin. Treatment satisfaction was better when patients were treated with insulin lispro. CONCLUSIONS: Insulin lispro is a suitable and very convenient pump insulin that may result in an improvement of long-term glucose control during CSII treatment. Its safety profile does not differ from that of regular human insulin.

XMCD studies of thin Co films on BaTiO3.

Different layer thicknesses of cobalt ranging from 2.6 Å (1.5 ML) up to 55 Å (30.5 ML) deposited on ferroelectric BaTiO3 have been studied regarding their magnetic behavior. The layers have been characterized using XMCD spectroscopy at remanent magnetization. After careful data analysis the magnetic moments of the cobalt could be determined using the sum rule formalism. There is a sudden and abrupt onset in magnetism starting at thicknesses of 9 Å (5 ML) of cobalt for measurements at 120 K and of 10 Å (5.5 ML) if measured at room temperature. Initial island growth and subsequent coalescence of Co on BaTiO3 is suggested to explain the sudden onset. In that context, no magnetically dead layers are observed.

Synergistic stimulatory effect of glucagon-like peptide-1 (7-36) amide and glucose-dependent insulin-releasing polypeptide on the endocrine rat pancreas.

The interaction of glucagon-like peptide-1 (7-36)amide (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP) on insulin release from the perfused rat pancreas was studied. The GLP-1 stimulated (0.5 nmol/l), glucose-induced (6.7 mmol/l) insulin secretory answer was enhanced by GIP (0.1, 1.0 and 10.0 nmol/l) to the arterial perfusate. This effect was maximal at 1 nmol/l GIP and smaller but still significant at 0.1 nmol/l GIP. The high GIP concentration of 10 nmol/l GIP did not further increase insulin secretion compared to the stimulation by 1 nmol/l GIP. Our data demonstrate an additive synergistic effect of GLP-1 and GIP on the glucose-induced insulin release. This supports the concept of an action "in concert' of gastrointestinal incretin hormones postprandially released on the endocrine pancreas to guarantee adequate insulin answers after meals.

Kinetics and dose dependence of macrophage colony-stimulating factor-induced proliferation and activation of murine mononuclear phagocytes in situ: differences between lungs, liver, and spleen.

Alveolar macrophages (AM) play an important role in antimicrobial defense mechanisms of the lung. It therefore seems reasonable to use macrophage colony-stimulating factor (M-CSF) to enhance local resistance mechanisms. However, little is known about the in vivo activity of M-CSF on macrophages in various organs. We determined the effect of a single subcutaneous dose of M-CSF (10, 50, 100, and 500 ng, respectively) on the number and functional status of AM as well as of macrophages in liver and spleen of mice. Organs were investigated immunohistochemically on days 1 and 3 after injection using monoclonal antibodies specific for F4/80, Ia antigen, and MAC-1. We found a significant increase in the number of F4/80+ AM, Kupffer cells, and splenic macrophages reaching its maximum 24 h after injection of low doses (10 and 50 ng per mouse, respectively) of M-CSF and decreasing to a level seen in untreated mice at 72 h after M-CSF in liver and spleen, whereas at a dose of 50 ng per mouse the number of AM remained high. In contrast, the numbers of AM, Kupffer cells, and splenic macrophages did not increase significantly when high doses were used (500 ng). The expression of Ia antigen and MAC-1 was increased on macrophages in the spleen but not on AM or Kupffer cells. TNF-alpha was elevated in bronchoalveolar (BAL) fluid after 3 h and IL-6 at 6, 12, and 24 h after M-CSF injection in dose-dependent manner. Nitric oxide production was not increased after injection of M-CSF. Our results point to regional differences in the response of macrophages to M-CSF. These may caused by differences in the M-CSF-induced production of TNF-alpha and IL-6. These findings may be important for the therapeutic use of M-CSF in microbial infections.