Characterization data of reference materials used for phase II of the priority program DFG SPP 2005 "Opus Fluidum Futurum - Rheology of reactive, multiscale, multiphase construction materials".

A thorough characterization of base materials is the prerequisite for further research. In this paper, the characterization data of the reference materials (CEM I 42.5 R, limestone powder, calcined clay and a mixture of these three components) used in the second funding phase of the priority program 2005 of the German Research Foundation (DFG SPP 2005) are presented under the aspects of chemical and mineralogical composition as well as physical and chemical properties. The data were collected based on tests performed by up to eleven research groups involved in this cooperative program.

Characterization data of reference industrial polycarboxylate superplasticizers used within Priority Program DFG SPP 2005 "Opus Fluidum Futurum - Rheology of reactive, multiscale, multiphase construction materials".

Two industrial polycarboxylate superplasticizer samples have been selected to be used within the Priority Program 2005 of the German Research Foundation (DFG SPP 2005). The PCE polymers were characterized via Size Exclusion Chromatography (SEC) to determine their molar masses (Mw, Mn ), the polydispersity index (PDI) and the conversion rate which indicates the incorporation of the macromonomer into the polymer. The anionic charge amount of the PCE samples was assessed via charge titration employing a cationic polymer. Furthermore, the cement dispersing properties of the PCE polymers were captured via 'mini slump' tests so as to assess their ability to fluidize CEM I 42.5 R and CEM III/A 42.5 N samples, respectively. Also, interaction between the PCEs and the surface of the cements was investigated via adsorption and zeta potential measurements of aqueous cement suspensions. The results shall be used for the ongoing research within the Priority Program.

Characterization data of reference cement CEM III/A 42.5N used for priority program DFG SPP 2005 "Opus Fluidum Futurum - Rheology of reactive, multiscale, multiphase construction materials".

Two types of cements were selected as the reference cement in the priority program 2005 of the German Research Foundation (DFG SPP 2005). A thorough characterization of CEM I 42.5 R has been made in a recent publication [1]. In this paper, the characterization data of the other reference cement CEM III/A 42.5 N are presented from the aspects of chemical and mineralogical compositions as well as physical and chemical properties. The characterization data of the slag, which is the second main constituent of this specific cement besides the clinker, are presented independently. For all data received, the mean values and the corresponding errors were calculated. The data shall be used for the ongoing research within the priority program. Also, researchers from outside this priority program can benefit from these data if the same materials are used.

Characterization data of reference cement CEM I 42.5 R used for priority program DFG SPP 2005 "Opus Fluidum Futurum - Rheology of reactive, multiscale, multiphase construction materials".

A thorough characterization of starting materials is the precondition for further research, especially for cement, which contains various phases and presents quite a complex material for fundamental scientific investigation. In the paper at hand, the characterization data of the reference cement CEM I 42.5 R used within the priority program 2005 of the German Research Foundation (DFG SPP 2005) are presented from the aspects of chemical and mineralogical compositions as well as physical and chemical properties. The data were collected based on tests conducted by nine research groups involved in this cooperative program. For all data received, the mean values and the corresponding errors were calculated. The results shall be used for the ongoing research within the priority program.

Rumen microbial responses to supplemental nitrate. I. Yeast growth and protozoal chemotaxis in vitro as affected by nitrate and nitrite concentrations.

Nitrates have been fed to ruminants, including dairy cows, as an electron sink to mitigate CH4 emissions. In the NO3- reduction process, NO2- can accumulate, which could directly inhibit methanogens and some bacteria. However, little information is available on eukaryotic microbes in the rumen. Protozoa were hypothesized to enhance nitrate reductase but also have more circling swimming behavior, and the yeast Saccharomyces cerevisiae was hypothesized to lessen NO2- accumulation. In the first experiment, a culture of S. cerevisiae strain 1026 was evaluated under 3 growth phases: aerobic, anoxic, or transition to anoxic culture. Each phase was evaluated with a control or 1 of 3 isonitrogenous doses, including NO3-, NO2-, or NH4+ replacing peptone in the medium. Gas head phase, NO3-, or NH4+ did not influence culture growth, but increasing NO2- concentration increasingly inhibited yeast growth. In experiment 2, rumen fluid was harvested and incubated for 3 h in 2 concentrations of NO3-, NO2-, or sodium nitroprusside before assessing chemotaxis of protozoa toward glucose or peptides. Increasing NO2- concentration decreased chemotaxis by isotrichids toward glucose or peptides and decreased chemotaxis by entodiniomorphids but only toward peptides. Live yeast culture was inhibited dose-responsively by NO2- and does not seem to be a viable mechanism to prevent NO2- accumulation in the rumen, whereas a role for protozoal nitrate reductase and NO2- influencing signal transduction requires further research.

Rumen microbial responses to supplemental nitrate. II. Potential interactions with live yeast culture on the prokaryotic community and methanogenesis in continuous culture.

Nitrates have been fed to ruminants, including dairy cows, as an electron sink to mitigate CH4 emissions. In the NO3- reduction process, NO2- can accumulate, which could directly inhibit methanogens and possibly other microbes in the rumen. Saccharomyces cerevisiae yeast was hypothesized to decrease NO2- through direct reduction or indirectly by stimulating the bacterium Selenomonas ruminantium, which is among the ruminal bacteria most well characterized to reduce both NO3- and NO2-. Ruminal fluid was incubated in continuous cultures fed diets without or with NaNO3 (1.5% of diet dry matter; i.e., 1.09% NO3-) and without or with live yeast culture (LYC) fed at a recommended 0.010 g/d (scaled from cattle to fermentor intakes) in a 2 × 2 factorial arrangement of treatments. Treatments with LYC had increased NDF digestibility and acetate:propionate by increasing acetate molar proportion but tended to decrease total VFA production. The main effect of NO3- increased acetate:propionate by increasing acetate molar proportion; NO3- also decreased molar proportions of isobutyrate and butyrate. Both NO3- and LYC shifted bacterial community composition (based on relative sequence abundance of 16S rRNA genes). An interaction occurred such that NO3- decreased valerate molar proportion only when no LYC was added. Nitrate decreased daily CH4 emissions by 29%. However, treatment × time interactions were present for both CH4 and H2 emission from the headspace; CH4 was decreased by the main effect of NO3- until 6 h postfeeding, but NO3- and LYC decreased H2 emission up to 4 h postfeeding. As expected, NO3- decreased methane emissions in continuous cultures; however, contrary to expectations, LYC did not attenuate NO2- accumulation.

Investigation of ammonium lactate supplementation on fermentation end products and bacterial assimilation of nitrogen in dual-flow continuous culture.

Supplements investigated throughout the present study are produced by fermenting lactose that is present in whey to lactate, yielding products differing in ammonium relative to lactate concentrations and in physical form (liquid or dry). Trials 1 and 2 investigated Lacto-Whey (LW; Fermented Nutrition Corp., Luxemburg, WI) and GlucoBoost (GB; Fermented Nutrition Corp.), respectively, using dual-flow continuous culture systems (n = 4), each with a 4 × 4 Latin square design. A greater proportion of nonprotein nitrogen was present in GB than in LW. In trial 1, the treatment with LW was isonitrogenously dosed against soybean meal (SBM) as a control (no LW) and factorialized with either a wheat- or corn-based concentrate (55% inclusion rate, dry matter basis). We hypothesized that LW would increase propionate production and that the combination of +LW with wheat would increase bacterial assimilation of NH3-N into cellular N. No differences were observed for total volatile fatty acid (VFA) production per day. However, treatment × time interactions revealed that +LW increased lactate concentration at 0, 0.5, and 1 h and tended to increase molar percentage of propionate at 1 and 1.5 h postfeeding, documenting the immediate availability of lactate converted to propionate in the +LW treatments. The main effect of corn increased the proportion of bacterial N derived from NH3-N. Trial 2 was designed to investigate GB; isonitrogenous treatments included an SBM control, crystal GB, liquid GB (LGB), and LGB with yeast culture, which were dosed twice daily. We hypothesized that GB would increase propionate production and bacterial assimilation of NH3-N; the combination of LGB and yeast culture was expected to have a positive additive effect, yielding the greatest VFA production and bacterial NH3-N assimilation. No differences were observed for total VFA production; however, LGB decreased molar percentage of acetate and increased propionate and butyrate molar percentages. There were no differences in non-NH3-N flow or microbial N flow. Under the conditions of our studies, lactate in LW and GB was fermented extensively to propionate, and microbial protein synthesis in these treatments was comparable with that in SBM controls.

Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion.

AIMS: To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin-sensitive tissues in humans in vivo. METHODS: Euglycaemic-hyperinsulinaemic clamp experiments were performed in healthy volunteers. Human insulin was administered i.v. at 6 pmol/kg/min and insulin detemir at 60 pmol/kg/min, achieving a comparable steady-state pharmacodynamic action. In addition, insulin detemir was doubled to 120 pmol/kg/min. Minimally invasive open-flow microperfusion (OFM) sampling methodology was combined with inulin calibration to quantify human insulin and insulin detemir in the interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissue. RESULTS: The human insulin concentration in the ISF was ∼115 pmol/l or ∼30% of the serum concentration, whereas the insulin detemir concentration in the ISF was ∼680 pmol/l or ∼2% of the serum concentration. The molar insulin detemir interstitial concentration was five to six times higher than the human insulin interstitial concentration and metabolic clearance of insulin detemir from serum was substantially reduced compared with human insulin. CONCLUSIONS: OFM proved useful for target tissue measurements of human insulin and the analogue insulin detemir. Our tissue data confirm a highly effective retention of insulin detemir in the vascular compartment. The higher insulin detemir relative to human insulin tissue concentrations at comparable pharmacodynamics, however, indicate that the lower potency of insulin detemir in humans is attributable to a reduced effect in peripheral insulin-sensitive tissues and is consistent with the reduced in vitro receptor affinity.

Assessing the ruminal action of the isopropyl ester of 2-hydroxy-4-(methylthio) butanoic acid in continuous and batch cultures of mixed ruminal microbes.

In dairy rations, Met is often a limiting amino acid that is provided by rumen-undegradable protein and rumen-protected sources of Met. A Met precursor, 2-hydroxy-4-(methylthio) butanoic acid (HMB) has undergone considerable study for ruminal and postruminal metabolism, whereas its isopropyl ester (HMBi) has been evaluated primarily with respect to its supply of metabolizable Met rather than as a preformed source of Met for microbial metabolism. A control and 3 isomolar Met treatments-0.097% dl-Met, 0.048% dl-Met plus 0.055% HMBi (Met + HMBi treatment), and 0.11% HMBi-were pulse-dosed every 8h into continuous cultures simultaneously with feeding. Treatment had no effect on digestibilities of acid-detergent fiber or true organic matter. Digestibilities of neutral detergent fiber and hemicellulose were linearly decreased with increasing HMBi inclusion. Concentration of NH3-N tended to decrease linearly and quadratically, and NH3-N flow tended to decrease linearly, with increasing HMBi inclusion; in contrast, the proportion of bacterial N derived from NH3-N increased linearly. Peptide N increased linearly and tended to be affected quadratically (highest for the HMBi treatment). Acetate and propionate production both decreased with increasing HMBi, but acetate declined more such that acetate:propionate increased linearly. Isobutyrate production decreased, but isovalerate and valerate increased with increasing HMBi inclusion. Relative changes in population abundance were not detected by denaturing gradient gel electrophoresis. In the second study, which was done in batch culture, Met treatments consisted of control, 0.097% l-Met, 0.097% l-Met, 0.125% dl-HMBi, 0.098% dl-HMB, 0.250% dl-HMBi (2× HMBi), 0.049% dl-Met + 0.063% dl-HMBi (Met + HMBi), and 0.098% dl-HMB + 0.039% isopropanol. All of these Met treatments were unlabeled (i.e., at natural abundance of (13)C) but simultaneously dosed with equivalent dosages of [1-(13)C]-l-Met. All 8 treatments were inoculated with faunated or partially defaunated inocula. Protozoal abundance had minor effect on measurements. The unlabeled l-Met treatment had the lowest (13)C enrichment of Met in the microbial pellet followed by Met + HMBi and then d-Met or dl-HMB, which were lower than remaining treatments. The percentage of the [1-(13)C]-l-Met dose recovered in microbial Met was lowest for the l-Met treatment; intermediate for d-Met, dl-HMB (with or without isopropanol), and Met + HMBi treatments; and highest for HMBi, 2× HMBi, and control. Results suggest that racemization of d-Met lags behind l-Met. The similar conversions of the HMBi and 2× HMBi treatments compared with the control suggests a low degradation of HMBi to provide unlabeled Met to dilute the [1-(13)C]-l-Met dose for protein synthesis. The lack of treatment by time interaction suggests that these initial responses carried through during the 24h of incubation. The proportion of HMBi available to ruminal microbes can influence microbial metabolism, potentially through formation of l-Met.

A toolbox to improve algorithms for insulin-dosing decision support.

BACKGROUND: Standardized insulin order sets for subcutaneous basal-bolus insulin therapy are recommended by clinical guidelines for the inpatient management of diabetes. The algorithm based GlucoTab system electronically assists health care personnel by supporting clinical workflow and providing insulin-dose suggestions. OBJECTIVE: To develop a toolbox for improving clinical decision-support algorithms. METHODS: The toolbox has three main components. 1) Data preparation: Data from several heterogeneous sources is extracted, cleaned and stored in a uniform data format. 2) Simulation: The effects of algorithm modifications are estimated by simulating treatment workflows based on real data from clinical trials. 3) ANALYSIS: Algorithm performance is measured, analyzed and simulated by using data from three clinical trials with a total of 166 patients. RESULTS: Use of the toolbox led to algorithm improvements as well as the detection of potential individualized subgroup-specific algorithms. CONCLUSION: These results are a first step towards individualized algorithm modifications for specific patient subgroups.

Eukaryotic inhibitors or activators elicit responses to chemosensory compounds by ruminal isotrichid and entodiniomorphid protozoa.

Our objectives were to evaluate potential signaling pathways regulating rumen protozoal chemotaxis using eukaryotic inhibitors potentially coordinated with phagocytosis as assessed by fluorescent bead uptake kinetics. Wortmannin (inhibitor of phosphoinositide 3-kinase), insulin, genistein (purported inhibitor of a receptor tyrosine kinase), U73122 (inhibitor of phospholipase C), and sodium nitroprusside (Snp, nitric oxide generator, activating protein kinase G) were preincubated with mixed ruminal protozoa for 3h before assessing uptake of fluorescent beads and chemosensory behavior to glucose, peptides, and their combination; peptides were also combined with guanosine triphosphate (GTP; a chemorepellent). Entodiniomorphids were chemoattracted to both glucose and peptides, but chemoattraction to glucose was increased by Snp and wortmannin without effect on chemoattraction to peptides. Rate of fluorescent bead uptake by an Entodinium caudatum culture decreased when beads were added simultaneously with feeding and incubated with wortmannin (statistical interaction). Wortmannin also decreased the proportion of mixed entodiniomorphids consuming beads. Isotrichid protozoa exhibited greater chemotaxis to glucose but, compared with entodiniomorphids, were chemorepelled to peptides. Wortmannin increased chemotaxis by entodiniomorphids but decreased chemotaxis to glucose by isotrichids. Motility assays documented that Snp and wortmannin decreased net swimming speed (distance among 2 points per second) but not total swimming speed (including turns) by entodiniomorphids. Wortmannin decreased both net and total swimming behavior in isotrichids. Results mechanistically explain the isotrichid migratory ecology to rapidly take up newly ingested sugars and subsequent sedimentation back to the ventral reticulorumen. In contrast, entodiniomorphids apparently integrate cellular motility with feeding behavior to consume small particulates and thereby stay associated and pass with the degradable fraction of rumen particulates. These results extend findings from aerobic ciliate models to explain how rumen protozoa have adapted physiology for their specific ecological niches.

Efficacy, usability and sequence of operations of a workflow-integrated algorithm for basal-bolus insulin therapy in hospitalized type 2 diabetes patients.

AIMS: To evaluate glycaemic control and usability of a workflow-integrated algorithm for basal-bolus insulin therapy in a proof-of-concept study to develop a decision support system in hospitalized patients with type 2 diabetes. METHODS: In this ward-controlled study, 74 type 2 diabetes patients (24 female, age 68 ± 11 years, HbA1c 8.7 ± 2.4% and body mass index 30 ± 7) were assigned to either algorithm-based treatment with a basal-bolus insulin therapy or to standard glycaemic management. Algorithm performance was assessed by continuous glucose monitoring and staff's adherence to algorithm-calculated insulin dose. RESULTS: Average blood glucose levels (mmol/l) in the algorithm group were significantly reduced from 11.3 ± 3.6 (baseline) to 8.2 ± 1.8 (last 24 h) over a period of 7.5 ± 4.6 days (p < 0.001). The algorithm group had a significantly higher percentage of glucose levels in the ranges from 5.6 to 7.8 mmol/l (target range) and 3.9 to 10.0 mmol/l compared with the standard group (33 vs. 23% and 73 vs. 53%, both p < 0.001). Physicians' adherence to the algorithm-calculated total daily insulin dose was 95% and nurses' adherence to inject the algorithm-calculated basal and bolus insulin doses was high (98 and 93%, respectively). In the algorithm group, significantly more glucose values <3.9 mmol/l were detected in the afternoon relative to other times (p < 0.05), a finding mainly related to pronounced morning glucose excursions and requirements for corrective bolus insulin at lunch. CONCLUSIONS: The workflow-integrated algorithm for basal-bolus therapy was effective in establishing glycaemic control and was well accepted by medical staff. Our findings support the implementation of the algorithm in an electronic decision support system.

Influence of water vapour and carbon dioxide on free lime during storage at 80 °C, studied by Raman spectroscopy.

Micro-Raman spectroscopy has been used to follow the reaction of free lime (CaO) exposed for 24h to moist air at 80 °C under conditions of different relative humidities (10-80% RH). X-ray diffraction and SEM imaging were applied as complementary techniques. The conversion of lime to calcium hydroxide and its subsequent carbonation to various calcium carbonate polymorphs was found to strongly depend on the relative humidity. At low RH (10-20%), only Raman spectroscopy revealed the formation of early amorphous CaCO3 which in the XRD patterns was detected only at ≥40% RH. However, XRD analysis could identify the crystalline polymorphs formed at higher relative humidities. Thus, between 20 and 60% RH, all three CaCO3 polymorphs (calcite, aragonite and vaterite) were observed via XRD whereas at high relative humidity (80%), calcite was the predominant reaction product. The results demonstrate the usefulness of Raman spectroscopy in the study of minor cement constituents and their reaction products on air, especially of amorphous character.

Assessment of different techniques for subcutaneous glucose monitoring in Type 1 diabetic patients during 'real-life' glucose excursions.

AIMS: To compare the accuracy of two marketed subcutaneous glucose monitoring devices (Guardian RT, GRT; GlucoDay S, GDS) and standard microdialysis (CMA60; MD) in Type 1 diabetic patients. METHODS: Seven male Type diabetic patients were investigated over a period of 26 h simulating real-life meal glucose excursions. Catheters of the three systems were inserted into subcutaneous adipose tissue of the abdominal region. For MD, interstitial fluid was sampled at 30- to 60-min intervals for offline glucose determination. Reference samples were taken at 15- to 60-min intervals. All three systems were prospectively calibrated to reference. Median differences, median absolute relative differences (MARD), median absolute differences (MAD), Bland-Altman plot and Clark Error Grid were used to determine accuracy. RESULTS: Bland-Altman analysis indicated a mean glucose difference (2 standard deviations) between reference and interstitial glucose of -10.5 (41.8) % for GRT, 20.2 (55.9) % for GDS and 6.5 (35.2) % for MD, respectively. Overall MAD (interquartile range) was 1.07 (0.39; 2.04) mmol/l for GRT, 1.59 (0.54; 3.08) mmol/l for GDS and 0.76 (0.26; 1.58) mmol/l for MD. Overall MARD was 15.0 (5.6; 23.4) % (GRT), 19.7 (6.1; 37.6) % (GDS) and 8.7 (4.1; 18.3) % (MD), respectively. Total sensor failure occurred in two subjects using GRT and one subject using GDS. CONCLUSIONS: The three investigated technologies had comparable performance. Whereas GRT underestimated actual blood glucose, GDS and MD overestimated blood glucose. Considerable deviations during daily life meal glucose excursions from reference glucose were observed for all three investigated technologies. Present technologies may require further improvement until individual data can lead to direct and automated generation of therapeutic advice in diabetes management.

A novel automated discontinuous venous blood monitoring system for ex vivo glucose determination in humans.

Intensive insulin therapy reduces mortality and morbidity in critically ill patients but imposes great demands on medical staff who must take frequent blood samples for the determination of glucose levels. A solution to this resourcing problem would be provided by an automated blood monitoring system. The aim of the present clinical study was to evaluate such a system comprising an automatic blood sampling unit linked to a glucose biosensor. Our approach was to determine the correlation and system error of the sampling unit alone and of the combined system with respect to reference levels over 12h in humans. Two venous cannulae were inserted to connect the automatic and reference systems to the subjects. Blood samples were taken at 15 and 30 min intervals. The median Pearson coefficient of correlation between manually and automatically withdrawn blood samples was 0.982 for the sampling unit alone and 0.950 for the complete system. The biosensor had a linear range up to 20 mmoll(-1) and a 95% response time of <2 min. Clark Error Grid analysis showed that 96.93% of the data (228 data pairs) was in zone A and 3.07% in zone B. Insulin Titration Error Grid analysis suggested an acceptable treatment in 99.56% of cases. Implementation of a "Keep Vein Open" saline infusion into the automated blood sampling system reduced blood withdrawal failures through occluded catheters fourfold. In summary, automated blood sampling from a peripheral vein coupled with automatic glucose determination is a promising alternative to frequent manual blood sampling.

Insulin glulisine, insulin lispro and regular human insulin show comparable end-organ metabolic effects: an exploratory study.

AIMS: To compare the end-organ metabolic effects of insulin glulisine (glulisine), insulin lispro (lispro) and regular human insulin (RHI) in patients with type 1 diabetes mellitus. METHODS: Eighteen patients with type 1 diabetes mellitus (mean age 36.9 +/- 8.6 years, BMI 23.6 +/- 2.8 kg/m(2), haemoglobin A(1c) 7.4 +/- 0.9%) were randomized in this single-centre, double-blind, three-period cross-over, standard Latin-square, euglycaemic glucose clamp trial. Patients received sequential, primed stepwise intravenous infusions of glulisine, lispro or RHI (infusion rates were increased in a stepwise manner from an initial rate of 0.33 [180 min] to 0.66 [180 min] and 1.00 [180 min] mU/kg/min). The primary variables were the suppression of endogenous glucose production (S(EGP)) and glucose uptake (GU). RESULTS: Mean basal endogenous glucose production (EGP) was 1.88, 2.12 and 2.12 mg/kg/min for glulisine, lispro and RHI respectively. Mean (+/-s.e.) maximum absolute S(EGP) (adjusted for basal EGP) was -1.64 +/- 0.06, -1.72 +/- 0.05 and -1.56 +/- 0.05 mg/kg/min respectively. Mean (+/-s.e.) maximum absolute increase in GU (adjusted for basal GU) was 6.46 +/- 0.26, 6.23 +/- 0.24 and 6.72 +/- 0.24 mg/kg/min respectively. There were no clinically relevant differences between the three insulin treatments with respect to serum insulin, free fatty acid (FFA), glycerol or lactate levels. No serious adverse events and no episodes of severe hypoglycaemia were reported. CONCLUSIONS: This study shows that glulisine, lispro and RHI have similar effects on S(EGP), GU, FFA, glycerol and lactate levels, providing evidence for similar end-organ metabolic effects.

Proportional dose-response relationship and lower within-patient variability of insulin detemir and NPH insulin in subjects with type 1 diabetes mellitus.

AIMS: This study was conducted to evaluate the dose ratio of insulin detemir and neutral protamine Hagedorn (NPH) insulin over a range of therapeutically relevant subcutaneous doses. METHODS: The study was a randomized, double-blind, crossover 24-h-iso-glycemic clamp trial in 12 C-peptide-negative type 1 diabetic patients. Each subject received, by an incomplete block design selection, two of three possible doses of insulin detemir (0.15, 0.3, 0.6 U/kg) and NPH insulin (0.15, 0.3, 0.6 IU/kg), respectively. A detailed assessment of endogenous glucose production (EGP) and glucose uptake was performed, by use of stable isotopic labeled glucose tracer (D-[6,6- (2)H (2)] glucose). RESULTS: Dose proportionality was observed within the tested dose range. Regarding unit dose ratio, 0.68 U insulin detemir equals 1 IU NPH insulin (95% CI [0.35; 1.30]). There was no statistically significant difference in effect on the area under the curve (AUC) of glucose infusion rate (GIR) (AUC (GIR)) and the maximal GIR (GIR (max)) values, when comparing U (insulin detemir) to IU (NPH insulin). The pharmacodynamic within-subject profile was lower with insulin detemir in regard to AUC (GIR 0-24 h), GIR (max) and duration of action ( P<0.05). There was a tendency for a greater reduction of EGP with insulin detemir than with NPH insulin in regard to the area over the curve (AOC) of EGP in 24 hours (AOC (EGP 0-24 h)) ( P=0.07) and minimal EPG (EGP (min)) ( P=0.02). CONCLUSIONS: These data show that insulin detemir is dose-proportional to NPH insulin in type 1 diabetic patients at clinically relevant doses. The data indicate that insulin detemir has a lower degree of within-subject variability.

Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus.

BACKGROUND: Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. OBJECTIVES: To assess the effects of long-term treatment with long-acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. MAIN RESULTS: Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. AUTHORS' CONCLUSIONS: Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir.

[Monitoring of glucose concentration in critical patients, comparing arterial blood glucose concentrations and interstitial glucose concentration measured by microdialysis technique]. / Monitorování glykemie u kriticky nemocných pacientu: srovnání arteriálních a intersticiálníh hladin glukózy merených pomocí mikrodialýzy tukové tkáne.

INTRODUCTION: Recent studies have shown that normalization of blood glucose in critically ill patients by intensive insulin therapy significantly decreases their mortality and morbidity. The aim of our study was to compare interstitial glucose concentrations in subcutaneous adipose tissue (measured by microdialysis technique) and arterial blood glucose concentrations to test the suitability of subcutaneous adipose tissue for long-term placement of biosensors for glucose measurement in critically ill patients. PATIENTS AND METHODS: 20 patients (16 men and 4 women) after cardiac surgery hospitalized at postoperative intensive care unit were included into the study. Mean age was 68 +/- 10 years, BMI was 28.3 +/- 3.9 year. Only patients with glycemia higher than 6.7 mmol/l at a time of admission to the ICU were included. Samples for measurement of interstitial glucose concentrations were collected in 60 minutes intervals during 48 hours using microdialysis of the subcutaneous adipose tissue. Perfusion fluid was 5% mannitol, perfusion rate was 1 microl/min. Arterial blood glucose concentration was measured in 60 minutes intervals, absolute concentrations of interstitial glucose were calculated using ionic reference technique. RESULTS: Mean arterial glucose concentration during the study was 6.7 +/- 0.56 mmol/l, absolute concentration of glucose in interstitial fluid was 3.55 +/- 0.58 mmol/l. Mean correlation coefficient between arterial and interstitial concentrations was 0.77 +/- 0.15. CONCLUSION: Our study demonstrated good correlation between interstitial glucose concentrations in subcutaneous adipose tissue and arterial blood glucose concentrations in post-cardiac surgery patients. Further studies are needed to evaluate this relationship in patients with more severely disturbed perfusion of subcutaneous adipose tissue.

Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

BACKGROUND: Short acting insulin analogue use for diabetic patients is still controversial, as reflected in many scientific debates. OBJECTIVES: To assess the effects of short acting insulin analogues versus regular human insulin. SEARCH STRATEGY: The Cochrane Library (Issue 3, 2005), MEDLINE, EMBASE until September 2005. SELECTION CRITERIA: Randomised controlled trials with an intervention duration of at least 4 weeks. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was done independently by two reviewers. MAIN RESULTS: Altogether 8274 participants took part in 49 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was -0.1% (95% CI: -0.2 to -0.1) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was 0.0% (95% CI: -0.1 to 0.0). In subgroup analyses of different types of interventions in type 1 diabetic patients, the WMD in HbA1c was -0.2% (95% CI: -0.3 to -0.1) in favour of insulin analogue in studies using continuous subcutaneous insulin injections (CSII), whereas for conventional intensified insulin therapy (IIT) studies the WMD in HbA1c was -0.1% (95% CI: -0.1 to 0.0). The WMD of the overall mean hypoglycaemic episodes per patient per month was -0.2 (95% CI: -1.1 to 0.7) and -0.2 (95% CI: -0.5 to 0.1) for analogues in comparison to regular insulin in patients with type 1 diabetes and type 2 diabetes, respectively. For studies in type 1 diabetes patients the incidence of severe hypoglycaemia ranged from 0 to 247.3 (median 21.8) episodes per 100 person-years for insulin analogues and from 0 to 544 (median 46.1) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.3) episodes per 100 person-years for insulin analogues and from 0 to 50.4 (median 1.4) for regular insulin. No study was designed to investigate possible long term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications. AUTHORS' CONCLUSIONS: Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues. For safety purposes, we need a long-term follow-up of large numbers of patients and well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.