Endokrine Toxizität von Fluorchinolone Untersuchungen zum insulinsekretion steigerung Effekt

Fluoroquinolones, an important class of antibacterial agents, have been associated with disturbances of the glucose homeostasis, including life-threatening hypoglycemias. The hypoglycemias are due to an increased insulin secretion which is commonly explained by the ability of the fluoroquinolones to block the KATP channel activity of the pancreatic beta cells. However, in recent experiments we have found that i) fluoroquinolones enhance glucose-induced insulin secretion of perifused mouse islets but do not increase secretion in the presence of a basal glucose concentration ii) fluoroquinolones which strongly inhibit KATP channel activity in open cells are unable to significantly depolarize the plasma membrane potential of metabolically intact beta cells at the same concentration (100 µM). Supposing that an interference with mitochondrial energy metabolism was the reason for this discrepancy, the effect of gatifloxacin, ciprofloxacin and moxifloxacin on NAD(P)H- and FAD-autofluorescence, the mitochondrial membrane potential (Rhodamine 123-fluorescence), adenine nucleotide content and the cytosolic free Ca2+ concentration ([Ca2+]i) of isolated mouse pancreatic islets and beta cells were investigated in this thesis. Gatifloxacin is the fluoroquinolone which is the most associated with hypoglycemias, including several fatalities, ciprofloxacin is also implicated, while only mild to moderate hypoglycemias are reported for moxifloxacin. In the presence of a basal glucose concentration (5 mM) all three fluoroquinolones at 100 µM were unable to increase [Ca2+]i but did so at 500 µM, confirming the above-mentioned discrepancy. Also, they increased [Ca2+]i of islets from SUR1 KO mice which don’t have functional KATP channels. Thus, additional sites of action must exist. All three fluoroquinolones, most notably moxifloxacin, diminished the NAD(P)H increase and FAD decrease caused a glucose stimulus (20 mM). Also, moxifloxacin partially antagonized the mitochondrial hyperpolarization and diminished the ATP/ADP-ratio increase caused by 20 mM glucose. Apparently, fluoroquinolones interact with the mitochondrial energy metabolism of the pancreatic beta cells, thereby counteracting the consequences of their KATP channel-blocking effect.Fluorchinolone, eine wichtige Antibiotikaklasse, lösen u.a. Hyper- und Hypoglykämien aus, wobei letztere lebensbedrohlich sein können. Den Hypoglykämien liegt eine gesteigerte Insulinsekretion zugrunde, die damit erklärt wird, daß die Fluorchinolone den KATP Kanal der pankreatischen beta-Zelle blockieren. Kürzlich haben wir jedoch gefunden, i) daß die Fluorchinolone zwar die Glucose-induzierte Insulinsekretion verstärken, nicht jedoch selbst eine Sekretion auslösen, wenn die Glucosekonzentration basal ist, ii) daß Fluorchinolone, die an offenen Zellpräparationen eine Hemmung des KATP Kanals bewirken, in metabolisch intakten Zellen nicht in der Lage waren, in der gleichen Konzentration (100 µM) die Plasmamembran zu depolarisieren. In der Annnahme, daß eine Beeinflussung des mitochondrialen Metabolismus diese Diskrepanzen erklären könnte, wurden in dieser Dissertation die Effekte von Gatifloxacin, Ciprofloxacin und Moxifloxacin auf folgende Parameter untersucht: NAD(P)H- und FAD-Autofluoreszenz, das mitochondriale Membranpotential (Rhodamin 123-Fluoreszenz), Adeninnucleotid-Gehalt und die cytosolische freie Ca2+ Konzentration ([Ca2+]i) von isolierten Pankreasinseln und beta-Zellen der Maus. Gatifloxacin ist das Fluorchinolon, das am häufigsten Hypoglykämien, auch tödliche, auslöste, Ciprofloxacin ist weniger effektiv und Moxifloxacin hat bisher nur milde Verläufe bewirkt. Bei einer basalen Glucosekonzentration (5 mM) waren alle drei Fluorchinolone (100 µM) unfähig, die [Ca2+]i zu erhöhen, konnten das aber bei 500 µM, was die o. a. Diskrepanzen mechanistisch bestätigt. Da auch die [Ca2+]i von Pankreasinseln aus SUR1 KO Mäusen erhöht wurde, die keinen funktionellen KATP Kanal haben, müssen zusätzliche Wirkorte existieren. Alle drei Fluorchinolone, am stärksten jedoch Moxifloxacin, verminderten den NAD(P)H-Anstieg und den FAD-Rückgang, der von einem Glucosestimulus (20 mM) bewirkt wurde. Zudem antagonisierte Moxifloxacin partiell die mitochondriale Hyperpolarisation und verminderte den Anstieg der ATP/ADP-Ratio, die durch 20 mM Glucose ausgelöst waren. Anscheinend beeinflussen die Fluorchinolone den mitochondrialen Energiestoffwechsel der pankreatischen beta-Zellen und wirken so den Konsequenzen ihres hemmenden Effekts auf den KATP Kanal entgegen

Synthesis, Characterization And Selected Application Of Chitosan-coated Magnetic Iron Oxide Nanoparticles

In this research, we report an efficient method to prepare highly active chitosan-coated magnetic iron oxide nanoparticles by implementing co-precipitation technique which is used for wastewater treatment applications. Chitosan-coated magnetic iron oxide nanoparticles were synthesized and characterized using TEM, XRD, and XPS. A comparative study has been made between chitosan powder and chitosan coated with magnetic nanoparticles with respect to the rate of adsorption of copper from aqueous solution. It was also experimentally verified that chitosan coated magnetic iron oxide nanoparticles are much more effective in adsorption of heavy metals than chitosan powder and it takes just few minutes instead of hours. Moreover, the super paramagnetic behavior of the chitosan coated with iron oxide nanoparticles enabled the easy removal through applying an external magnetic field and hence leaving the solution free from copper

DNA integrity in diagnosis of premalignant lesions

Carcinogenesis is a dynamic process which traditional biopsying can not keep up with. Saliva as fluid in the vicinity of the tumor can offer better insights to this process. This study aimed to identify the accuracy of salivary DNA integrity index in differentiating between oral premalignant lesions and oral cancer. This phase II diagnostic test accuracy study included 93 patients divided into three groups: 30 oral cancer patients, 33 patients with oral premalignant lesions divided into 21 oral lichen planus patients and 12 patients with leukoplakia and 30 normal individuals who acted as controls. Oral rinse was collected from all participants and they all underwent conventional visual and tactile examination, and patients with oral lesions had the diagnosis confirmed by histopathological examination of tissue biopsy. DNA integrity index was determined as the ratio between ALU247 and ALU115 measured by qPCR. There was no statistically significant difference regarding ALU115, ALU247 and DNA integrity index between the three study groups. The index was significantly higher in the oral cancer group than the oral lichen planus patients, while no significant difference was found between the oral cancer and the leukoplakia cases. The DNA integrity index sensitivity, specificity, positive and negative predictive values were 73%, 45%, 55% and 65% respectively. Salivary DNA integrity index showed poor diagnostic abilities in differentiating between the oral cancer and premalignant lesions

A comparative study of microcystin-LR degradation by UV-a, solar and visible light irradiation using bare and C/N/S-modified titania

In an endeavor to tackle environmental problems, the photodegradation of microcystin- LR (MC-LR), one of the most common and toxic cyanotoxins, produced by the cyanobacteria blooms, was examined using nanostructured TiO2 photocatalysts (anatase, brookite, anatase- brookite, and C/N/S co-modified anatase-brookite) under UV-A, solar and visible light irradiation. The tailoring of TiO2 properties to hinder the electron-hole recombination and improve MC-LR adsorption on TiO2 surface was achieved by altering the preparation pH value. The highest photocatalytic efficiency was 97% and 99% with degradation rate of 0.002 mmol L-1 min-1 and 0.0007 mmol L-1 min-1 under UV and solar irradiation, respectively, using a bare TiO2 photocatalyst prepared at pH 10 with anatase to brookite ratio of ca. 1:2.5. However, the bare TiO2 samples were hardly active under visible light irradiation (<25%) due to a large band gap. Upon UV, solar and vis irradiation, the complete MC-LR degradation (100%) was obtained in the presence of C/N/S comodified TiO2 with a degradation rate constant of 0.26 min-1, 0.11 min-1 and 0.04 min-1, respectively. It was proposed that the remarkable activity of co-modified TiO2 might originate from its mixedphase composition, mesoporous structure, and non-metal co-modification

Serum magnesium levels and acute exacerbation of chronic obstructive pulmonary disease: a retrospective study

A decrease in serum Mg+ 2 is associated with airway hyper-reactivity and impaired pulmonary function. The purpose of this study was to determine if decreased serum Mg+ 2 levels in patients with chronic obstructive pulmonary disease (COPD) are associated with acute exacerbations. In a retrospective study, the charted serum Mg+ 2 levels in 100 COPD patients were examined. These included 50 patients who presented with an acute exacerbation of COPD and 50 stable patients. Chart review was sequential within both groups. Serum Mg 2+ levels in the stable COPD patients averaged 0.91±0.10 mmol/L (mean±SD) with a 95% CI of 0.88–0.94 mmol/L. Patients undergoing an exacerbation had significantly lower serum Mg+ 2 levels (0.77±0.10 mmol/L; CI, 0.74–0.79; p< 0.0001). Logistic regression of the dichotomous outcomes as a function of serum Mg+ 2 concentration demonstrated a highly significant

Solar Thermal Collector Education Using Polysun Simulations Software

There are a variety of solar thermal collectors available in the market today. These collectors are typically manufactured in diverse countries and have different performance characteristics. For homeowners and commercial solar solution providers, it is important to know how these collectors will perform to ensure maximum return on investment. Therefore, engineers and technicians need to be trained into how different collectors will perform in different locations. In this article, we demonstrate how a Swiss simulations software package called Polysun can be used to accurately determine the performance of a particular system under real operating conditions. To demonstrate the accuracy of the simulations tool, we show performance comparisons with experimental results for different types of flat plate and evacuated tube solar collectors. We also show examples of exercises that can be implemented in an undergraduate course in solar thermal systems. According to our investigations, the thermal performance predicted by Polysun was in close agreement with our experimental measurements. The outcomes of our investigations can help educators make informed decisions regarding teaching solar thermal systems to undergraduates using state-of-the art simulation and visualization tools

Stereotactic Body Radiotherapy in Bulky Hepatocellular Carcinoma with or without Portal Vein Thrombosis: A Feasibility Review in an Egyptian Cohort

Background: Hepatocellular carcinoma (HCC) complicated by portal vein thrombosis presents significant clinical challenges. This study aims to retrospectively assess the feasibility of stereotactic irradiation for treating bulky HCC, with or without vascular invasion. Method: In this retrospective analysis, the radiotherapy treatment plans and clinical follow-up data of 22 patients diagnosed with HCC, with or without portal vein thrombosis, were reviewed. These patients underwent stereotactic body radiation therapy (SBRT) between September 2019 and September 2022. Treatment involved administering 40-50 Gy in 5 fractions using SBRT with volumetric modulated arc therapy (VMAT)/4D-computed tomography. Descriptive statistics were utilized without the application of statistical tests. Results: The mean age of the patients was 65 years, with 77% being male. Portal vein thrombosis was present in 73% of the cases, and the average tumor size was 7.2 cm (range 5-12 cm). 59% of patients were classified as Child-Pugh B. The median follow-up duration was 8 months (range 3-36 months). At 3 months, tumor response assessments revealed that 59% of patients had a partial response and 41% had stable disease; by 6 months, 37% achieved complete response, 26% maintained a partial response, and 37% had stable condition. Failure patterns included intrahepatic failure in two patients (at 7 and 9 months) and extrahepatic loss in two others (at 6 and 10 months). Radiation-induced liver disease occurred in two patients at 9- and 11-weeks post-treatment, respectively. Liver cancer-specific mortality was 13.6%, while non-liver cancer-specific mortality stood at 9%. The progression-free survival rate was 82%. Conclusion: SBRT via VMAT represents a highly cost-effective, non-invasive local therapy with a favorable therapeutic ratio for treating bulky HCC cases, with or without vascular invasion