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Biomedical subjects

M Dreyer

Publications and source records attributed to M Dreyer.

At least 19 recordsLinked to original sources
PubMed2005

InDuo, a novel combined insulin injection and blood glucose monitoring device - effective and save as other devices, and patient preference.

BACKGROUND AND AIM: Frequent blood glucose (BG) monitoring and insulin administration are necessary in intensive insulin regimes. A new integrated system, InDuo is a compact and portable combined insulin doser and BG monitor, designed to overcome some of the limitations of current insulin therapy. The aim of the study was to compare InDuo and a non-integrated system (HumaPen Ergo and Accu-Chek Sensor Meter) for efficacy and safety, and to evaluate patients preference. MATERIALS AND METHODS: The trial design was a multicentre, randomised, 12-week, open-label, comparative, two period crossover. One hundred and ten patients with diabetes, treated with a basal bolus regime, were included. The subjects were assigned to use either InDuo or the non-integrated system. After six weeks of treatment, the subjects were transferred to the alternative system. To assess efficacy, fasting plasma glucose (FBG), 7-point blood glucose profile, serum fructosamine and HbA1c were measured. Serum fructosamine and FBG were measured at baseline and at six and 12 weeks; HbA1c was measured at baseline and week 12. Safety endpoints were number and severity of hypoglycaemic episodes, adverse events and adverse device effects. Patient preference was assessed by a comparative device questionnaire at 12 weeks. RESULTS: Analysis with an ANOVA mixed model showed no difference after each treatment between serum fructosamine or between FBG levels. HbA1c decreased during the trial from 7.5 % +/- 1.2 to 7.1 % +/- 0.8 at 12 weeks. The safety profiles were similar for both treatments for hypoglycaemic episodes. The incidence of adverse events was also similar. There were 10 adverse device effects reported: eight for the Innovo device in the InDuo, one for the InDuo device and one for the Accu-Chek Sensor Meter. The comparative device questionnaire at 12 weeks showed patients strongly preferred InDuo to HumaPen Ergo and Accu-Chek Sensor Meter (all p < 0.0001). Of those preferring InDuo, more than 60 % classified their choice as very or extremely strong. Both memory functions in InDuo(R) (i. e., for insulin dosage and for blood glucose readings) were used by more than 70 % of the patients. CONCLUSION: Treatment with the InDuo system was as effective and safe as treatment with the non-integrated system. Almost 75 % preferred using InDuo to the non-integrated HumanPen Ergo and Accu-Chek Sensor Meter.

Adult↗
PubMed2005

Efficacy and safety of insulin glulisine in patients with type 1 diabetes.

Insulin glulisine (glulisine), a human insulin analogue with a rapid-acting time-action profile, has been developed to fulfil the mealtime (bolus) insulin requirement in patients with diabetes. The aim of this multinational, multi-centre, controlled, open-label, randomized, parallel-group study was to compare the efficacy and safety of insulin glulisine (glulisine) to that of insulin lispro (lispro) in adults diagnosed with Type 1 diabetes. Of the 683 patients randomized, 672 received treatment (339 patients received glulisine, 333 patients received lispro). Over the 26-week study, a similar reduction in mean HbA1c occurred in both groups (adjusted mean change from baseline -0.14% in both groups). The basal insulin dose was relatively unchanged from baseline in the glulisine group but increased in the lispro group (glulisine: 0.12 IU vs. lispro: 1.82 IU; p = 0.0001). As a consequence, total daily insulin dose decreased in the glulisine group but increased in the lispro group (glulisine: -0.86 IU vs. lispro: 1.01 IU; p = 0.0123). There was no relevant difference between the two groups in the reporting of symptomatic hypoglycaemia (overall, nocturnal and severe). This study demonstrates that glulisine provides equivalent glycaemic control to lispro. The clinical relevance of any difference in total daily insulin dose remains to be established.

Adult↗
PubMed2005

The effects of skin temperature and testing site on blood glucose measurements taken by a modern blood glucose monitoring device.

BACKGROUND: Modern blood glucose (BG) monitoring devices (e.g., InDuo [LifeScan, Inc., Milpitas, CA]) require very low blood volumes, allowing for testing at sites other than the traditional fingertip, but the reliability of such testing has not been fully elucidated. The aim of this randomized study was to compare the effects of cold/warm skin temperature combined with alternative site (forearm) testing versus conventional fingertip measurements on fasting and postprandial conditions. MATERIALS AND METHODS: The study population consisted of 19 patients who had previously used InDuo for 6 weeks. Four simultaneous (within 1 min) BG readings (left and right forearm and fingertips) were obtained from each patient 15, 10, and 5 min before eating. Ten minutes before eating, the patient immersed one arm in cold water (15.5 degrees C) and the other in warm water (35 degrees C). At time 0 min arms were removed from water baths, and the patient was offered a standard meal (duration 15 min). Arms were again immersed in water baths, and BG was measured from the same locations 20 min after eating and at subsequent 15-min intervals for 185 min. The effects of site testing and temperature were assessed in this period by identifying maximum BG concentrations (C (max)) and time to C (max) (T (max)). RESULTS: Significantly lower Cmax values were observed for (1) cold forearm versus cold fingertip (mean Delta 28.6 mg/dL, P < 0.001), (2) warm forearm versus warm fingertip (mean Delta 12 mg/dL, P = 0.028), (3) cold fingertip versus warm fingertip (mean Delta 17.2 mg/dL, P = 0.002), and (4) cold forearm versus warm forearm (mean Delta 33.7 mg/dL, P < 0.001). Significantly longer Tmax values were reported for cold forearm versus warm forearm (mean Delta 22.4 min, P < 0.001) and cold forearm versus cold fingertip (mean Delta 20 min, P < 0.001). CONCLUSIONS: These results demonstrate that cold skin and forearm conditions significantly underestimate BG concentrations and delay T(max) compared with warm skin and fingertip measurements.

Blood Glucose↗
PubMed2003

A 75% insulin lispro/25% NPL mixture provides a longer duration of insulin activity compared with insulin lispro alone in patients with Type 1 diabetes.

AIMS: To compare a new insulin formulation, high mix (HM) [75% lispro (LP) and 25% neutral protamine lispro (NPL)], to regular human insulin (HR) and LP with respect to glucose response and pharmacokinetics following a test meal in patients with Type 1 diabetes. METHODS: After fasting overnight, patients received an intravenous insulin infusion to standardize blood glucose (BG) to 7.5 mmol/l (135 mg/dl). In a randomised, three-way crossover study, HR was injected 30 min before, and LP or HM was injected immediately before the test meal on three separate occasions. For each patient, LP and HR were administered at identical doses; the HM dose was one and one third times that of HR and LP to maintain the same dose of short or rapid-acting insulin. The insulin infusion was stopped 15 min after the insulin injection. Free insulin and BG concentrations were measured frequently for 7 h following the test meal. RESULTS: HM and LP resulted in better glycaemic control than HR during the observation period. BG concentrations during the first 4-5 h did not differ between HM and LP. However, HM exhibited prolonged insulin activity relative to LP beyond 5 h, extending the duration of action by approximately 1 h, and resulting in lower overall BG concentrations when the 0-6- and 0-7-h intervals were considered. CONCLUSIONS: Compared with LP, HM provided similar glycaemic control for up to 5 h and superior glycaemic control from 5 to 7 h following a standard test meal.

Adult↗
PubMed2001

[Acute deep venous thrombosis and PET scanning with 2-fluoro-2-deoxy-D-glucose, FDG].

UNLABELLED: A 30-year-old woman with a history of malignant non-Hodgkin lymphoma with a bulky tumour on the right thigh, primarily treated with high-dose chemotherapy and involving field radiation, developed a deep venous thrombosis (DVT) in her right leg two weeks after the end of therapy. Positron emission tomography with fluorine-18 flourodeoxyglucose (FDG PET) was performed to assess the response of the lymphoma to therapy. The PET scan showed several sites of pathological, high tracer uptake corresponding to residual lymphoma, but also intense activity in the right calf correlating to the deep veins located peripheral to the site of DVT. FDG PET performed two months later showed no pathological FDG uptake in this area. CONCLUSION: Acute DVT may cause pathological uptake of FDG and should therefore be considered a possible pitfall in the interpretation of FDG PET.

Acute Disease↗
PubMed2001

New insecticidal rocaglamide derivatives and related compounds from Aglaia oligophylla.

Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product. All isolated rocaglamide, aglain, and aglaforbesin derivatives have a characteristic methylenedioxy substituent linked to C-6 and C-7 or to C-7 and C-8, respectively. Structure elucidation of the new natural products and the determination of the absolute configuration of compound 1 by calculation of its CD spectrum with molecular dynamics simulation are described. All isolated rocaglamide derivatives exhibited strong insecticidal activity toward neonate larvae of the polyphageous pest insect Spodoptera littoralis when incorporated into an artificial diet, with LC(50) values varying between 2.15 and 6.52 ppm.

Animals↗
PubMed2001

Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes.

Besides its actions on the regulation of appetite, leptin has also been implicated in regulating reproductive and immune functions. Because leptin-deficient mice are more susceptible to lipopolysaccharide- and tumor necrosis factor-alpha-induced shock, which is associated with lower levels of interleukin 1 receptor antagonist (IL-1Ra), we investigated whether leptin is a direct regulator of IL-1Ra in human monocytes. In human moncytic cells, leptin was capable of inducing a 6- to 10-fold increase in secreted IL-1Ra in a time- and dose-dependent manner. Moreover, leptin induced the messenger RNA for IL-1Ra within 8 h and specifically activated the promoter for this gene. However, leptin had no effect on the expression or secretion of IL-1 in THP-1 cells. This effect of leptin on monocytic cells requires the presence of the functional leptin receptor OB-Rb, which we have shown to be present in human monocytes by RT-PCR and by measuring the activation of the Jak/STAT pathway. In summary, we have demonstrated that leptin is capable of inducing the expression and secretion of IL-1Ra by human monocytes, an effect that is potentially mediated through the presence of functional leptin receptors on these cells. These findings suggest that leptin may have immunomodulatory functions in vivo.

3T3 Cells↗
PubMed2000

[Intensified insulin therapy. References for general practice for increased control].

Today, intensified conventional insulin therapy (ICT) is the standard treatment for type 1 diabetes, but patients with type 2 diabetes younger than 70 also profit it. Within an international framework too, the DCCT study has confirmed the usefulness of intensified insulin therapy. Factors that have a decisive influence on the success of such treatment are the choice of a suitable insulin, its dose, site of injection, and prandial adaptation. The various possibilities of carrying out ICT are discussed.

Adult↗
PubMed2000

Association of impaired phosphatidylinositol 3-kinase activity in GLUT1-containing vesicles with malinsertion of glucose transporters into the plasma membrane of fibroblasts from a patient with severe insulin resistance and clinical features of Werner syndrome.

The purpose of this study was to examine the molecular mechanism responsible for the defective insulin-stimulated glucose transport in cultured fibroblasts from a patient (VH) with clinical features of Werner syndrome and severe insulin resistance. Thus, in cells derived from VH, the subcellular distribution, structure, functional activity, as well as plasma membrane insertion of GLUT1 glucose transporters were analyzed. Furthermore, the insulin signal transduction pathway leading to activation of phosphatidylinositol (PI) 3-kinase as well as components of GLUT1-containing membrane vesicles were characterized. In fibroblasts derived from VH, GLUT1 glucose transporters were overexpressed by 8-fold in plasma membranes (PM) and by 5-fold in high density microsomes, respectively. Exofacial photolabeling revealed that only 14% of the overexpressed PM-GLUT1 transporters were properly inserted into the plasma membrane. The complementary DNA structure of the patient's insulin receptor and the GLUT1 glucose transporter, the intrinsic activity of plasma membrane glucose transporters, the tyrosine phosphorylation, as well as the protein expression of insulin receptor substrate-1/2 and p85 alpha/beta- and p110 alpha/beta-subunits of PI 3-kinase were normal. However, insulin-stimulated association of the p85 subunit of PI 3-kinase was defective in fibroblasts derived from VH compared to those from controls, and this defect was associated with a reduced IRS-1-dependent activation of PI 3-kinase by 50.2% and 63.6% after incubation for 5 and 10 min with 100 nmol/L insulin, respectively. Furthermore, immunodetection of small GTP-binding Rab proteins in subcellular membrane fractions indicated a decreased expression of Rab4 in total cellular homogenates as well as in high density microsomes by 70% and 58%, respectively. After preparation of GLUT1-containing vesicles, Rab4 was not detected to be a component of these vesicles. Analysis of the PI 3-kinase in GLUT1-containing membrane vesicles revealed insulin-dependent targeting of the p85 subunit to the vesicles immunoadsorbed from VH and control fibroblasts. Importantly, the association of the p85 subunit as well as the p85-immunoprecipitable PI 3-kinase activity were markedly reduced in GLUT1-vesicles derived from the patient. In conclusion, impaired PI 3-kinase activity in GLUT1-containing membrane vesicles derived from fibroblasts of VH is associated with a defective docking and/or fusion process of glucose transporters with the plasma membrane and thus might contribute to the molecular defect causing insulin resistance in this patient.

Adult↗
PubMed1999

Engineering a soluble extracellular erythropoietin receptor (EPObp) in Pichia pastoris to eliminate microheterogeneity, and its complex with erythropoietin.

The extracellular ligand-binding domain (EPObp) of the human EPO receptor (EPOR) was expressed both in CHO (Chinese Hamster Ovary) cells and in Pichia pastoris. The CHO and yeast expressed receptors showed identical affinity for EPO binding. Expression levels in P. pastoris were significantly higher, favoring its use as an expression and scale-up production system. Incubation of EPO with a fourfold molar excess of receptor at high protein concentrations yielded stable EPO-EPObp complexes. Quantification of EPO and EPObp in the complex yielded a molar ratio of one EPO molecule to two receptor molecules. Residues that are responsible for EPOR glycosylation and isomerization in Pichia were identified and eliminated by site-specific mutagenesis. A thiol modification was identified and a method was developed to remove the modified species from EPObp. EPObp was complexed with erythropoietin (EPO) and purified. The complex crystallized in two crystal forms that diffracted to 2.8 and 1.9 A respectively. (Form 1 and form 2 crystals were independently obtained at AxyS Pharmaceuticals, Inc. and Amgen, Inc. respectively.) Both contained one complex per asymmetric unit with a stoichiometry of two EPObps to one EPO.

Animals↗
PubMed1998

Early results of percutaneous transluminal angioplasty (PTA) of failing below-knee bypass grafts.

OBJECTIVES: An audit of treating femoro-crural bypass stenosis in the first instance by PTA. DESIGN: Prospective clinical pilot study in consecutive patients. MATERIALS: Prior to vascular bypass grafting all patients had critical ischaemia. Sixty-four PTA procedures in 50 grafts in 49 patients were carried out. Thirteen were in situ saphenous grafts, 16 were combined venous segments, 18 were combined PTFE and vein and three were PTFE only. METHODS: Conventional cross-over or antegrade PTA, eventually combined with local thrombolytic therapy. RESULTS: The nine-month assisted patency using PTA was 72%, following surgical repair in five cases after failed PTA the secondary patency was 86%. The amputation free survival rate was 88%. In 11 cases thrombosis was treated successfully with local thrombolysis. In two cases the balloon ruptured the native artery wall below the distal anastomosis with pseudoaneurysm formation. Six limbs were amputated during follow-up. The frequency of stenosis in combined grafts was significantly higher than in in situ vein grafts. CONCLUSION: Our results are comparable with surgery. About 600 hospital beds/days were saved. This shortened the time from the diagnosis of stenosis to therapy and shortened the waiting list for vascular surgery.

Adult↗
PubMed1998

The relationship between the serum leptin concentrations of thyrotoxic patients during treatment and their total fat mass is different from that of normal subjects.

OBJECTIVE: Previous studies of leptin in thyrotoxic human subjects have been short-term and cross-sectional. We have measured serum leptin concentrations in thyrotoxic patients in order to study the influence of endogenous thyroid hormones on the relationship between serum leptin and fat mass. DESIGN PATIENTS, MEASUREMENTS: In 10 fasting thyrotoxic patients (8 females, 2 males, mean age: 51 years) we measured serum leptin (microgram/l), total thyroxine (TT4), total triiodothyronine (TT3), thyrotropin (TSH) and by Dual Energy X-ray Absorptiometry (DEXA) total fat mass (TFM, kg) at time of diagnosis (0 months, baseline) and during 12 months treatment with thiamazole. For comparison 16 fasting thiamazole-treated euthyroid patients (14 females, 2 males, mean age: 38 years) were studied after one year follow-up (26 months (15-48)) and 18 normal controls (12 females, 6 males, mean age: 39 years). RESULTS: The serum leptin concentration was 9.1 (1.3 micrograms/l (mean (SEM) in the thyrotoxic patients and increased significantly to 16.0 (1.3 micrograms/l (P < 0.0005) after 12 months treatment compared to both normal subjects and their own baseline. There was a significant correlation between serum leptin concentration and TFM in the normal control group (r = 0.79, P < 0.00009), in the thiamazole-treated euthyroid group (r = 0.85, P < 0.00003) and in the baseline thyrotoxic group (r = 0.84, P < 0.002) but the serum leptin/TFM ratio increased significantly during 12 months of antithyroid drug treatment from 0.34 (1.2 micrograms/l/kg to 0.53 (1.2 micrograms/l/kg (P < 0.03). CONCLUSION: The thiamazole-treated thyrotoxic patients increased their serum leptin concentrations during 12 months antithyroid drug treatment without a significant corresponding degree of changes in TFM as expected from normal controls. It is suggested that the metabolic state in thyrotoxic patients can influence the regulation of serum leptin concentrations without any associated changes in TFM.

Adult↗
PubMed1998

Heterologous expression of human granzyme K in Bacillus subtilis and characterization of its hydrolytic activity in vitro.

Human granzyme K, a serine protease found in secretory granules of cytotoxic T-lymphocytes, was produced in its catalytically active form by recombinant technology using Bacillus subtilis as host. The enzyme displays 40-45% identity to other members of the human granzyme group, and its closest homologue (75% identity) is the rat tryptase RNK-tryp2. The recombinant protein can be recovered in its mature form from the bacterial culture supernatant and purified by cation exchange chromatography. Initial characterization reveals a protein of approximately 28 kDa that is specifically labelled by [3H]di-isopropyl fluorophosphate. Measurements of Kcat/K(m) for single-residue thioester substrates show approximately a two-fold preference for a Lys versus Arg residue at Pl. No activity was observed on ester substrates with various other residues at the Pl position. Using oligopeptide substrates, the enzyme displays peptidolytic activity C-terminal to both Lys and Arg residues with comparable rates of hydrolysis. Likewise, substrate hydrolysis is blocked most efficiently by inhibitors that contain Lys or Arg at position Pl. The availability of the cloned enzyme will facilitate the analysis of biological roles for this novel granzyme, and differentiate its activity from that of other granzymes.

Amino Acid Sequence↗
PubMed1997

Defects of insulin and IGF-1 action at receptor and postreceptor level in a patient with type A syndrome of insulin resistance.

The action of insulin and IGF-1 in comparison to non-diabetic controls was studied in cultured fibroblasts of a patient with an inherited syndrome of insulin resistance (Type A syndrome). Insulin binding was reduced due to decreased receptor affinity, but sequence analyses revealed no alterations of splicing or primary insulin receptor (IR) structure. Most likely due to the IR affinity defect analyses of signal transduction pathways showed an impairment of insulin action on glucose uptake, total RNA synthesis and phosphorylation as well as activity of MAP-kinase. In addition inducibility of c-fos mRNA level was strongly impaired by insulin and IGF-1, but comparable to controls by PDGF indicating a postreceptor defect. In conclusion, we provide evidence that genetic syndromes of insulin resistance can be associated with both, receptor and postreceptor defects.

Cells, Cultured↗
PubMed1997

Interactions of mast cell tryptase with thrombin receptors and PAR-2.

Tryptase is a serine protease secreted by mast cells that is able to activate other cells. In the present studies we have tested whether these responses could be mediated by thrombin receptors or PAR-2, two G-protein-coupled receptors that are activated by proteolysis. When added to a peptide corresponding to the N terminus of PAR-2, tryptase cleaved the peptide at the activating site, but at higher concentrations it also cleaved downstream, as did trypsin, a known activator of PAR-2. Thrombin, factor Xa, plasmin, urokinase, plasma kallikrein, and tissue kallikrein had no effect. Tryptase also cleaved the analogous thrombin receptor peptide at the activating site but less efficiently. When added to COS-1 cells expressing either receptor, tryptase stimulated phosphoinositide hydrolysis. With PAR-2, this response was half-maximal at 1 nM tryptase and could be inhibited by the tryptase inhibitor, APC366, or by antibodies to tryptase and PAR-2. When added to human endothelial cells, which normally express PAR-2 and thrombin receptors, or keratinocytes, which express only PAR-2, tryptase caused an increase in cytosolic Ca2+. However, when added to platelets or CHRF-288 cells, which express thrombin receptors but not PAR-2, tryptase caused neither aggregation nor increased Ca2+. These results show that 1) tryptase has the potential to activate both PAR-2 and thrombin receptors; 2) for PAR-2, this potential is realized, although cleavage at secondary sites may limit activation, particularly at higher tryptase concentrations; and 3) in contrast, although tryptase clearly activates thrombin receptors in COS-1 cells, it does not appear to cleave endogenous thrombin receptors in platelets or CHRF-288 cells. These distinctions correlate with the observed differences in the rate of cleavage of the PAR-2 and thrombin receptor peptides by tryptase. Tryptase is the first protease other than trypsin that has been shown to activate human PAR-2. Its presence within mast cell granules places it in tissues where PAR-2 is expressed but trypsin is unlikely to reach.

Amino Acid Sequence↗