Polymorphic drug metabolizing CYP‐enzymes – a pathogenic factor in oral lichen planus?

Background:  Oral lichen planus (OLP) is a chronic mucosal disease with a characteristic clinical phenotype. Environmental exposures, e.g. drugs have been associated with the pathogenesis.
Objectives:  To test the hypothesis that some OLP lesions have a pharmacological pathogenesis related to polymorphisms of the cytochrome P450 enzymes (CYPs) resulting in poor or intermediate CYP metabolism.
Methods:  One hundred and twenty patients with OLP and 180 gender-matched controls without OLP were genotyped for CYP2C9 , CYP2C19 , and CYP2D6 alleles with absent or reduced function.
Results:  The prevalence of poor or intermediate metabolizers was not higher among the OLPs as compared with the controls; however, there were higher numbers of variant CYP2D6 genotypes among the OLP females ( P  < 0.05). There were no differences between the groups with regard to intake of drugs metabolized by polymorphic CYPs or drug or herbal products inhibiting CYPs. The prevalence of CYP2D6*4 alleles among the OLPs was higher [28%; 95% confidence interval (CI) 20–36%] than previously reported among Danes (19%; 95% CI 17–22%). Fifty per cent of the OLPs had a CYP2D6*4 genotype as compared with 30% in the background population ( P  = 0.0001). The CYP2D6*4 protein has sequence homology with human herpes simplex virus type 1 (HSV1) and Candida albicans , which may result in molecular mimicry.
Conclusion:  It was not possible to substantiate a pharmacological pathogenesis of OLP based on poor or intermediate CYP metabolism. However, molecular mimicry between CYP2D6, in particular CYP2D6*4, and common oral pathogens may be involved in the pathogenesis of OLP.     

Wasserdampfunabhängige Probeneinlaßsysteme für Respirationsmassenspektrometer

Zusammenfassung Bei massenspektrometrischen Atemgasuntersuchungen wirken sich Änderungen des Wasserdampfpartialdruckes während der In- und Exspirationsphase sehr störend aus, wenn die Einlaßsysteme eine unterschiedliche Leitfähigkeit für Wasserdampf und Permanentgase aufweisen. Es werden ein 2- und ein 3 stufiges Einlaßsystem beschrieben, mit denen eine quantitative Analyse auch bei schnell wechselnden Wasserdampfspannungen möglich ist.Mit Unterstützung der Montan-Union — Europäische Gemeinschaft für Kohle und Stahl — durchgeführte Forschungsarbeit.     

A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy

Summary Glomerular filtration rate (GFR, single bolus ⁵¹Cr-EDTA technique), serum creatinine, proteinuria and arterial blood pressure have been measured prospectively in 14 young onset insulin-dependent diabetics selected by of persistent proteinuria (> 0.5 g/day) secondary to diabetic nephropathy. Twelve of the 14 patients had normal serum creatinine levels. None of the patients received antihypertensive treatment. During the mean observation period of 26 months (range 23 to 33 months) GFR decreased from 107 to 87 ml/min/1.73 m² (p< 0.001), serum creatinine remained unchanged: 107 and 112/gmmol/l (NS), proteinuria increased from 1.8 to 3.3 g/day (p<0.001) and arterial blood pressure rose from 132/88 to 153/101 mmHg (p<0.001). Glomerular filtration rate decreased linearly with time (slope=–0.75, r=0.99, p<0.001) by a mean of 0.75 ml/min/month (range 0.1 to 1.5 ml/ min/month). The decrease in GFR did not correlate with sex, age at onset, duration of diabetes, arterial blood pressure, proteinuria, insulin requirement, postprandial blood glucose or the initial GFR, but numbers were small. The decline in GFR in each individual was constant, but varied considerably between patients. Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy in young insulin-dependent diabetics.     

Left Ventricular Hypertrophy in Non-insulin-dependent Diabetic Patients With and Without Diabetic Nephropathy

The aim of our cross-sectional case–control study was to evaluate putative mechanisms of the increased cardiac morbidity and mortality in NIDDM patients with or without diabetic nephropathy. Fifty-one NIDDM patients with diabetic nephropathy (38 males, age 61 ± 8 years, group 1), 53 NIDDM patients with normoalbuminuria (42 males, 61 ± 7 years, group 2), and 22 non-diabetic control subjects (15 males, 58 ± 8 years, group 3) were investigated. Previous antihypertensive treatment was withdrawn 2 weeks before the study. Left ventricular mass index (LVMI) and systolic function were determined by echocardiography. LVMI was elevated, mean ± SE, in group 1: 157 ± 6 g m⁻², and in group 2: 139 ± 7 g m⁻², as compared with group 3: 95 ± 5 g m⁻² (p < 0.001, for both), and in group 1 as compared with group 2 (p = 0.05). The prevalence of left ventricular hypertrophy (LVH) (LVMI > 131 g m⁻² in men and > 100 g m⁻² in women) was much higher in group 1: 75 % (95 % CI, 60–86), and group 2: 51 % (95 % CI, 37–65), as compared with group 3: 9 % (95 % CI, 1–29) (p < 0.001, for both), and in group 1 as compared with group 2 (p < 0.01). Shortening fraction of the left ventricle, % ± SE, was relatively reduced in group 1: 32.5 ± 1.1 %, and group 2: 33.4 ± 1.1 %, as compared with group 3: 41.2 ± 1.2 % (p < 0.01, for both). In a subgroup of 26 normoalbuminuric normotensive NIDDM patients, LVMI was higher than in 14 normotensive non-diabetic control subjects: 137 ± 10 g m⁻² vs 96 ± 7 g m⁻², respectively (p < 0.005). The prevalence of LVH was 42 % (95 % CI, 23–63) and 14 % (95 % CI, 2–43) (p = 0.07) in these two groups, respectively. In conclusion, normotensive and hypertensive NIDDM patients with and without diabetic nephropathy frequently suffer from LVH and relatively reduced systolic function which may constitute independent risk factors for fatal and non-fatal cardiac events. © 1997 John Wiley & Sons, Ltd.     

Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta

Cytosolic free Ca2+ plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic beta cell. A number of Ca2+-binding proteins have been implicated in this process. Here, we define the role of the Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1) in insulin secretion. In pancreatic beta cells, NCS-1 increases exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of NCS-1 on exocytosis is mediated through an increase in phosphatidylinositol (PI) 4-kinase beta activity and the generation of phosphoinositides, specifically PI 4-phosphate and PI 4,5-bisphosphate. In turn, PI 4,5-bisphosphate controls exocytosis through the Ca2+-dependent activator protein for secretion present in beta cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic beta cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase beta, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.     

Dose-dependent efficacy of the glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3-30)NH2 on GIP actions in humans

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH₂ is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH₂ across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A–F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A–E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH₂ at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A–F) and GIP (A–E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH₂ provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.     

Influence of selected antimicrobials on the viability, endotoxicity and lipopolysaccharide composition of Pseudomonas aeruginosa in vitro

This research focused on the influence of selected antimicrobial agents (AMAs) on the lipopolysaccharide (LPS) composition of Pseudomonas aeruginosa, a common causative agent of nosocomial infections. As LPS has been shown to play a role in attachment and virulence, the research is primarily aimed at shedding light on the response of these organisms to cleaning regimens in healthcare settings using various disinfectants. The endotoxicity and viability of the organisms following disinfection were further investigated via propagation in sublethal concentrations of the selected AMAs. The AMAs included a CIP chlorinated disinfectant, a heavy-duty alkaline detergent and a phenolic handwash solution. The effects of the antimicrobials on LPS both from intact cells and from debris were assessed by gas chromatography–mass spectrometry (GC–MS) analysis and a chromogenic Limulus amoebocyte lysate assay. Results indicated significant changes in the supramolecular structure of the O-polysaccharide when exposed to the AMAs. Adaptations occurred in both the total assessed saccharide and the lipid fractions, especially in the case of the heavy-duty alkaline detergent. Endotoxicity was found to be influenced by changes in the O-chain rather than the lipid fraction. The phenolic handwash and chlorine-based AMA treatments resulted in a slight decrease in the total amount of fatty acids in the LPS compared with saccharides, whereas the heavy-duty alkaline detergent resulted in a notable reduction in total saccharides. Microbial adaptation of the supramolecular structure of LPS may cause a reduction in membrane solubility of these organisms in an aqueous environment, thus affecting the organism's susceptibility to water-soluble AMAs as well as its ability to adhere to charged surfaces.