PubMed Health⌕ Search

Biomedical subjects

N Kaiser

Publications and source records attributed to N Kaiser.

At least 19 recordsLinked to original sources
PubMed2006

Deposition and spectral performance of an inhomogeneous broadband wide-angular antireflective coating.

Gradient index coatings and optical filters are a challenge for fabrication. In a round-robin experiment, basically the same hybrid antireflection coating for the visible spectral region, combining homogeneous refractive index layers of pure materials and linear gradient refractive index layers of material mixtures, has been deposited. The experiment involved three different deposition techniques: electron-beam evaporation, ion-beam sputtering, and radio frequency magnetron sputtering. The material combinations used by these techniques were Nb(2)O(5)/SiO(2), TiO(2)/SiO(2), and Ta(2)O(5)/SiO(2), respectively. The spectral performances of samples coated on one side and on both sides have been compared to the corresponding theoretical spectra of the designed profile. Also, the reproducibility of results for each process is verified. Finally, it is shown that ion-beam sputtering gave the best results in terms of deviation from the theoretical performance and reproducibility.

Journal Article↗
PubMed2005

Mitochondrial regulation of insulin production in rat pancreatic islets.

AIMS/HYPOTHESIS: The study was designed to identify the key metabolic signals of glucose-stimulated proinsulin gene transcription and translation, focusing on the mechanism of succinate stimulation of insulin production. METHODS: Wistar rat islets were incubated in 3.3 mmol/l glucose with and without esters of different mitochondrial metabolites or with 16.7 mmol/l glucose. Proinsulin biosynthesis was analysed by tritiated leucine incorporation into newly synthesised proinsulin. Preproinsulin gene transcription was evaluated following transduction with adenoviral vectors expressing the luciferase reporter gene under the control of the rat I preproinsulin promoter. Steady-state preproinsulin mRNA was determined using relative quantitative PCR. The mitochondrial membrane potential was measured by microspectrofluorimetry using rhodamine-123. RESULTS: Succinic acid monomethyl ester, but not other mitochondrial metabolites, stimulated preproinsulin gene transcription and translation. Similarly to glucose, succinate increased specific preproinsulin gene transcription and biosynthesis. The inhibitor of succinate dehydrogenase (SDH), 3-nitropropionate, abolished glucose- and succinate-stimulated mitochondrial membrane hyperpolarisation and proinsulin biosynthesis, indicating that stimulation of proinsulin translation depends on SDH activity. Partial inhibition of SDH activity by exposure to fumaric acid monomethyl ester abolished the stimulation of preproinsulin gene transcription, but only partially inhibited the stimulation of proinsulin biosynthesis by glucose and succinate, suggesting that SDH activity is particularly important for the transcriptional response to glucose. CONCLUSIONS/INTERPRETATION: Succinate is a key metabolic mediator of glucose-stimulated preproinsulin gene transcription and translation. Moreover, succinate stimulation of insulin production depends on its metabolism via SDH. The differential effect of fumarate on preproinsulin gene transcription and translation suggests that these processes have different sensitivities to metabolic signals.

Animals↗
PubMed2005

Delayed autoregulation of glucose transport in vascular endothelial cells.

AIMS/HYPOTHESIS: We aimed to characterise the development of autoregulation of glucose transport in vascular endothelial cells and its relationship to 12-lipoxygenase (12-LO) expression. METHODS: Bovine aortic endothelial cells were exposed to 5.5 and 23.0 mmol/l glucose for up to 48 h. The rates of glucose transport, GLUT-1 and 12-LO expression and of 12-hydroxyeicosatetraenoic acid (12-HETE) production were determined. RESULTS: We showed high glucose-dependent downregulation of glucose transport and transporter in vascular endothelial cells within 36-48 h. A similar time-dependent increase in the expression of 12-LO and the generation of its product 12-HETE was also observed. This downregulatory process was prevented when lipoxygenase activity was inhibited. CONCLUSIONS/INTERPRETATION: Vascular endothelial cells, which were previously thought to be "glucose-blind", do in fact downregulate GLUT-1 expression and the rate of glucose transport in response to extended exposure to high glucose concentrations. This slow development of glucose-induced downregulation in vascular endothelial cells is related to the slower basal rate of glucose transport in these cells and the slow induction of 12-LO. These data are interesting in view of current hypotheses that attribute vascular endothelial cell dysfunction in diabetes to the lack of a glucose-induced autoregulatory response.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2005

A retrospective study of SSRI treatment in adolescent anorexia nervosa: insufficient evidence for efficacy.

Although selective-serotonin-reuptake-inhibitors (SSRI) have been of limited efficacy in the treatment of eating disorder psychopathology and comorbid symptoms of malnourished patients with anorexia nervosa (AN), there is recent data suggesting that SSRI may play a role in preventing relapse among weight-restored patients. Though some previous studies included patients in late adolescence, the vast majority of investigated subjects have been adults. The aim of our retrospective study was to assess the effects of SSRI treatment in partially weight-restored children and adolescents with AN. Thirty two females with AN (mean 14.5+/-1.4 years) were investigated three times during inpatient treatment and at 3- and 6-month follow-up for BMI, eating disorder psychopathology, depressive symptomology, and obsessive-compulsive symptomology. Medication history during inpatient and outpatient treatment was reconstructed at the 6-month follow-up. Nineteen patients received SSRI treatment, while 13 subjects were non-medicated. In comparison to the non-SSRI group, the SSRI group had similar BMI and obsessive-compulsive scores, but higher levels of core eating disorder psychopathology and depressive symptoms at the start of medication. Rates of re-admissions were similar in both groups (SSRI group: 36%, non-SSRI group: 31%, Phi: p=0.72). Repeated measures ANOVA revealed no significant group with time interactions for BMI-SDS (p=0.84), core eating disorder symptoms (ANIS, p=0.79), depression (DIKJ, p=0.75), and obsessive-compulsive (CY-BOCS, p=0.40) scores indicating minimal or no effects of SSRI medication on the course of these variables. In conclusion, our results challenge the efficacy of SSRI medication in the treatment of eating disorder psychopathology as well as depressive and obsessive-compulsive comorbidity in adolescent AN. Clinicians should be chary in prescribing SSRI in adolescent AN unless randomized controlled trials have proofed the benefit of these drugs.

Adolescent↗
PubMed2005

Improvement of metabolic state in an animal model of nutrition-dependent type 2 diabetes following treatment with S 23521, a new glucagon-like peptide 1 (GLP-1) analogue.

Glucagon-like peptide 1 (GLP-1) analogues are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analogue, S 23521 ([a8-des R36] GLP-1-[7-37]-NH2), on the metabolic state and beta-cell function, proliferation and survival in the Psammomys obesus model of diet-induced type 2 diabetes. Animals with marked hyperglycaemia after 6 days of high-energy diet were given twice-daily s.c. injection of 100 microg/kg S 23521 for 15 days. Food intake was significantly decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycaemia was noted in controls, as opposed to maintenance of pre-treatment glucose levels in the S 23521 group. Prevention of diabetes progression was associated with reduced mortality. In addition, the treated group had higher serum insulin, insulinogenic index and leptin, whereas plasma triglyceride and non-esterified fatty acid levels were decreased. S 23521 had pronounced effect on pancreatic insulin, which was 5-fold higher than the markedly depleted insulin reserve of control animals. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; beta-cell apoptosis was approximately 70% reduced, without a change in beta-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative beta-cell volume. Overall, S 23521 prevented the progression of diabetes in P. obesus with marked improvement of the metabolic profile, including increased pancreatic insulin reserve, beta-cell viability and mass. These effects are probably due to actions of S 23521 both directly on islets and via reduced food intake, and emphasize the feasibility of preventing blood glucose deterioration over time in type 2 diabetes.

Animals↗
PubMed2003

5-Fluorouracil in vesicular phospholipid gels for anticancer treatment: entrapment and release properties.

Vesicular phospholipid gels (VPG), i.e. highly concentrated liposomal dispersions, are suitable for entrapping substances such as anticancer drugs with particular high encapsulation efficiencies (EE). We prepared different formulations of VPG with 30% (w/w) lipid containing 5-fluorouracil (5-FU) by high pressure homogenization and analysed their EE and drug release. Using mixtures of hydrogenated soy phosphatidylcholine and cholesterol with molar ratios ranging from 55/45 to 75/25, a decreasing amount of cholesterol correlated with an increasing EE, which is probably due to a reduced amount of smaller vesicles and number of lamellae. Using a 5-FU solution of pH 8.6 for VPG preparation, an EE of approximately 40% was found after redispersion of the gel to a liposomal dispersion and separation of free drug from liposomal drug by size exclusion chromatography. The reduced EE for preparations with lower pH values was attributed to a fast initial drug release due to the increased drug lipophilicity below the pK(a) value of 8. After redispersion of a VPG of pH 8.0, an initially faster release of about a third of the entrapped drug was found during the first 20 min, followed by stable entrapment over many hours. The rapid initial release may be due to the portion of liposomes smaller than 40 nm in diameter, determined by photon correlation spectroscopy. Cryo electron microscopic pictures show a lentil-like shape of these small liposomes. The membrane defects on the edges are probably the reason for the very high initial drug release rate. The half-life time of the release of 5-FU from intact FU-VPG at both pH 7.4 and 8.0 was found to be in the order of 4-5 h and the kinetics are typical for matrix-controlled drug diffusion. The in vitro data of 5-FU loaded VPG suggest their applicability as implants with controlled release properties or, after redispersion, as intravenously injected liposomal formulations.

Antimetabolites, Antineoplastic↗
PubMed2003

Chiral dynamics of deeply bound pionic atoms.

We present and discuss a systematic calculation, based on two-loop chiral perturbation theory, of the pion-nuclear s-wave optical potential. A proper treatment of the explicit energy dependence of the off-shell pion self-energy together with (electromagnetic) gauge invariance of the Klein-Gordon equation turns out to be crucial. Accurate data for the binding energies and widths of the 1s and 2p levels in pionic 205Pb and 207Pb are well reproduced without need for a notorious "missing repulsion" in the pion-nuclear s-wave optical potential. The connection with the in-medium change of the pion decay constant is clarified.

Journal Article↗
PubMed2001

Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function.

Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on beta-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five- to ninefold increase of beta-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted beta-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C2-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved beta-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of beta-cells and impaired insulin secretion. The deleterious effect of palmitate on beta-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect beta-cell apoptosis, yet it promotes beta-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving beta-cell function.

Animals↗
PubMed2001

Defective stimulus-secretion coupling in islets of Psammomys obesus, an animal model for type 2 diabetes.

Psammomys obesus is a model of type 2 diabetes that displays resistance to insulin and deranged beta-cell response to glucose. We examined the major signaling pathways for insulin release in P. obesus islets. Islets from hyperglycemic animals utilized twice as much glucose as islets from normoglycemic diabetes-prone or diabetes-resistant controls but exhibited similar rates of glucose oxidation. Fractional oxidation of glucose was constant in control islets over a range of concentrations, whereas islets from hyperglycemic P. obesus showed a decline at high glucose. The mitochondrial substrates alpha-ketoisocaproate and monomethyl succinate had no effect on insulin secretion in P. obesus islets. Basal insulin release in islets from diabetes-resistant P. obesus was unaffected by glucagon-like peptide 1 (GLP-1) or forskolin, whereas that of islets of the diabetic line was augmented by the drugs. GLP-1 and forskolin potentiated the insulin response to maximal (11.1 mmol/l) glucose in islets from all groups. The phorbol ester phorbol myristic acid (PMA) potentiated basal insulin release in islets from prediabetic animals, but not those from hyperglycemic or diabetes-resistant P. obesus. At the maximal stimulatory glucose concentration, PMA potentiated insulin response in islets from normoglycemic prediabetic and diabetes-resistant P. obesus but had no effect on islets from hyperglycemic P. obesus. Maintenance of islets from hyperglycemic P. obesus for 18 h in low (3.3 mmol/l) glucose in the presence of diazoxide (375 pmol/l) dramatically improved the insulin response to glucose and restored the responsiveness to PMA. Immunohistochemical analysis indicated that hyperglycemia was associated with reduced expression of alpha-protein kinase C (PKC) and diminished translocation of lambda-PKC. In summary, we found that 1) P. obesus islets have low oxidative capacity, probably resulting in limited ability to generate ATP to initiate and drive the insulin secretion; 2) insulin response potentiated by cyclic AMP-dependent protein kinase is intact in P. obesus islets, and increased sensitivity to GLP-1 or forskolin in the diabetic line may be secondary to increased sensitivity to glucose; and 3) islets of hyperglycemic P. obesus display reduced expression of alpha-PKC and diminished translocation of lambda-PKC associated with impaired response to PMA. We conclude that low beta-cell oxidative capacity coupled with impaired PKC-dependent signaling may contribute to the animals' poor adaptation to a high-energy diet.

Animals↗
PubMed2001

beta-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes.

Deficient insulin secretion and relative hyperproinsulinemia are characteristic features of type 2 diabetes. The gerbil Psammomys obesus appears to be an ideal natural model of the human disease because it shows increased tendency to develop diet-induced diabetes, which is associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores and an increased proportion of insulin precursor molecules in the blood and islets. Although the proinsulin translational efficacy was found to be increased in hyperglycemic animals, insulin mRNA levels were not augmented and exhibited a gradual decrease with disease progression. The development of hyperglycemia was associated with a transient increase in beta-cell proliferative activity, as opposed to a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that glucotoxicity is responsible in part for these in vivo changes was investigated in vitro in primary islet cultures. Islets from diabetes-prone P. obesus cultured at high glucose concentrations displayed changes in beta-cell function that mimic those observed in diabetic animals. These changes include deficient insulin secretion, depleted insulin content, an increased proportion of insulin precursor molecules, a progressive increase of DNA fragmentation, and a transient proliferative response. Furthermore, insulin mRNA was not increased by short-term exposure of P. obesus islets to elevated glucose in vitro. It is proposed that beta-cell glucotoxicity in P. obesus results from the inability of proinsulin biosynthesis to keep pace with chronic insulin hypersecretion. The resulting depletion of the insulin stores may be related to deficient glucose-regulated insulin gene transcription, possibly due to defective PDX-1 (pancreatic duodenal homeobox factor-1) expression in the adult P. obesus. An additional glucotoxic effect involves the loss of beta-cell mass in hyperglycemic P. obesus as a result of progressive beta-cell death without an adequate increase in the rate of beta-cell proliferation.

Animals↗
PubMed2001

Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets.

In autoimmune type 1 diabetes, Fas-to-Fas-ligand (FasL) interaction may represent one of the essential pro-apoptotic pathways leading to a loss of pancreatic beta-cells. In the advanced stages of type 2 diabetes, a decline in beta-cell mass is also observed, but its mechanism is not known. Human islets normally express FasL but not the Fas receptor. We observed upregulation of Fas in beta-cells of type 2 diabetic patients relative to nondiabetic control subjects. In vitro exposure of islets from nondiabetic organ donors to high glucose levels induced Fas expression, caspase-8 and -3 activation, and beta-cell apoptosis. The effect of glucose was blocked by an antagonistic anti-Fas antibody, indicating that glucose-induced apoptosis is due to interaction between the constitutively expressed FasL and the upregulated Fas. These results support a new role for glucose in regulating Fas expression in human beta-cells. Upregulation of the Fas receptor by elevated glucose levels may contribute to beta-cell destruction by the constitutively expressed FasL independent of an autoimmune reaction, thus providing a link between type 1 and type 2 diabetes.

Adolescent↗
PubMed2001

IPF1/PDX1 deficiency and beta-cell dysfunction in Psammomys obesus, an animal With type 2 diabetes.

The homeodomain transcription factor IPF1/PDX1 is required in beta-cells for efficient expression of insulin, glucose transporter 2, and prohormone convertases 1/3 and 2. Psammomys obesus, a model of diet-responsive type 2 diabetes, shows markedly depleted insulin stores when given a high-energy (HE) diet. Despite hyperglycemia, insulin mRNA levels initially remained unchanged and then decreased gradually to 15% of the basal level by 3 weeks. Moreover, insulin gene expression was not increased when isolated P. obesus islets were exposed to elevated glucose concentrations. Consistent with these observations, no functional Ipf1/Pdx1 gene product was detected in islets of newborn or adult P. obesus using immunostaining, Western blot, DNA binding, and reverse transcriptase-polymerase chain reaction analyses. Other beta-cell transcription factors (e.g., ISL-1, Nkx2.2, and Nkx6.1) were expressed in P. obesus islets, and the DNA binding activity of the insulin transcription factors RIPE3b1-Act and IEF1 was intact. Ipf1/Pdx1 gene transfer to isolated P. obesus islets normalized the defect in glucose-stimulated insulin gene expression and prevented the rapid depletion of insulin content after exposure to high glucose. Taken together, these results suggest that the inability of P. obesus islets to adapt to dietary overload, with depletion of insulin content as a consequence, results from IPF1/PDX1 deficiency. However, because not all animals become hyperglycemic on HE diet, additional factors may be important for the development of diabetes in this animal model.

Adenoviridae↗
PubMed2000

Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine.

Decreased cellular GSH content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Oxidative stress has been suggested to play a causative role in the development of impaired insulin action on adipose tissue and skeletal muscle. In this study we undertook to investigate the potential of GSH depletion to induce insulin resistance, by utilizing the GSH synthesis inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). GSH depletion (20-80% in various tissues), was achieved in vivo by treating rats for 20 days with BSO, and in vitro (80%) by treating 3T3-L1 adipocytes with BSO for 18 h. No demonstrable change in the GSH/GSSG ratio was observed following BSO treatment. GSH depletion was progressively associated with abnormal glucose tolerance test, which could not be attributed to impaired insulin secretion. Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. However, insulin-stimulated glucose uptake was unaffected by GSH depletion. In accordance, normal adipose tissue insulin sensitivity was observed in BSO-treated rats in vivo, as demonstrated by normal inhibition of circulating non-esterified fatty acid levels by endogenous insulin secretion. In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. This suggests that alternative oxidation-borne factors mediate the induction of peripheral insulin resistance by oxidative stress.

3T3 Cells↗
PubMed2000

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.

Insulin gene expression is restricted to islet beta cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by 'loss-of-function' studies. We used a 'gain-of-function' approach to test whether PDX-1 could endow a non-islet tissue with pancreatic beta-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a beta-cell phenotype, may provide a valuable approach for generating 'self' surrogate beta cells, suitable for replacing impaired islet-cell function in diabetics.

Adenoviridae↗
PubMed2000

[Does modification of documentation result in a reduction of medication to involuntary patients?].

OBJECTIVE: The effects of modification of documentation on the administration of psychotropic medication to involuntary patients in hospital were investigated. METHODS: The charts of 414 inpatients on the acute-ward were reviewed two months before and two months after a new form for documentation of rationales for medication administration to involuntary patients was instituted. A follow-up was carried out for a two-month period a year later. RESULTS: The percentage of patients who received medication involuntarily, 70% of whom were schizophrenic, fell by over half, from 12% to 5%, after additional standardized documentation for the use of such medications was instituted. The number of medications administered to involuntary patients fell from 80 to 21, a reduction of 74%. The effects were stable over the course of one year. CONCLUSIONS: Modification of documentation seems to reduce the use of medication with involuntary patients.

Acute Disease↗