Anti-inflammatory effects of tobramycin and a copper–tobramycin complex with superoxide dismutase-like activity

Background and Purpose

Airway inflammation in cystic fibrosis (CF) patients is characterized by accumulations of neutrophils in the airway and T cells in bronchial tissue, with activation of platelets in the circulation. CF patients are routinely treated with systemic or inhaled tobramycin for airway infection with Pseudomonas aeruginosa. Clinical trials have indicated an anti-inflammatory effect of tobramycin beyond its bactericidal activity. Here, we investigate the anti-inflammatory properties of tobramycin in vitro and consider if these relate to the ability of tobramycin to bind copper, which is elevated in blood and sputum in CF.

Experimental Approach

A copper–tobramycin complex was synthesized. The effect of tobramycin and copper–tobramycin on neutrophil activation and migration of T cells and neutrophils across human lung microvascular endothelial cells in response to thrombin-activated platelets were investigated in vitro. Tobramycin uptake was detected by immunocytochemistry. Intracellular reactive oxygen species were detected using the fluorescent indicator, 2′,7′-dichlorofluorescein diacetate (DCFDA). Neutrophil superoxide, hydrogen peroxide and neutrophil elastase activity were measured using specific substrates. Copper was measured using atomic absorption spectroscopy.

Key Results

Tobramycin and copper–tobramycin were taken up by endothelial cells via a heparan sulphate-dependent mechanism and significantly inhibited T-cell and neutrophil transendothelial migration respectively. Copper–tobramycin has intracellular and extracellular superoxide dismutase-like activity. Neutrophil elastase inhibition by α1-antitrypsin is enhanced in the presence of copper–tobramycin. Tobramycin and copper–tobramycin are equally effective anti-pseudomonal antibiotics.

Conclusions and Implications

Anti-inflammatory effects of tobramycin in vivo may relate to the spontaneous formation of a copper–tobramycin complex, implying that copper–tobramycin may be more effective therapy.     

Safety of the long-term use of proton pump inhibitors

The proton pump inhibitors (PPIs) as a class are remarkably safe and effective for persons with peptic ulcer disorders. Serious adverse events are extremely rare for PPIs, with case reports of interstitial nephritis with omeprazole, hepatitis with omeprazole and lansoprazole, and disputed visual disturbances with pantoprazole and omeprazole. PPI use is associated with the development of fundic gland polyps (FGP); stopping PPIs is associated with regression of FGP. In the absence of Helicobacter pylori infec...     

The subcellular particulate NADPH-dependent O2.(-)-generating oxidase from human blood monocytes: comparison to the neutrophil system

Highly purified preparations of normal human monocytes obtained from peripheral blood were shown to contain a subcellular particulate O2.(-)- generating oxidase system. This O2.(-)-generating activity was present in particulate preparations from monocytes that had been previously stimulated with phorbol myristate acetate but was low or absent in control preparations from unstimulated monocytes or stimulated monocytes from a patient with chronic granulomatous disease. In the stimulated preparations from normal monocytes, O2.(-)-generation was linearly proportional to cell protein concentration, insensitive to inhibition by azide, and dependent on NADPH as substrate. These characteristics are similar to the O2.(-)-generating oxidase system from human neutrophils. A significant difference in the apparent Km for NADPH was shown between preparations from stimulated monocytes and neutrophils (monocyte 83 +/- 16 microM, neutrophil 31 +/- 5 microM, mean +/- SE). Additionally, affinity of the stimulated monocyte particulate preparation for NADH was unmeasurably low.     

New endoscopic instruments for paranasal sinus surgery.

BACKGROUND: Minimally invasive endoscopic and microscopic procedures represent state of the art paranasal sinus surgery techniques in both diagnostic and surgical fields. To combine favorable aspects of both techniques, we evaluated the clinical applicability and effectiveness of multifunctional microendoscopes, providing multiple features to ensure highest accuracy and surveillance when performing crucial steps in paranasal sinus surgery. METHODS: The study included both anatomic experiments on cadaveric heads and clinical tests on patients undergoing routine paranasal surgery. The systems applicability was evaluated in procedures approaching the frontal and sphenoid sinus. Three different endoscopes, 2 straight and the other 1 with a 90 degrees angle, were tested. They integrate canals for flushing and suction and a working canal for either drilling or obtaining biopsies with a miniaturized forceps. For stereotactic feedback, the applicability in combination with a computer-navigation system was evaluated. RESULTS: Anatomic tests were performed to optimize illumination and to test drilling features and forceps biopsies. In all cases, the frontal sinus ostium and the sphenoid sinus anterior wall was easily identified and enlarged by drilling under visual and stereotactic control. Continuous suction and irrigation ensured a constant visual surveillance by removing drilling debris and blood. Best suited for multifunctional endoscopic surgery were drill heads with a cylinder shape, for placing bore holes along the Z axis, and spherical drill heads, for furbishing and enlarging drill holes. CONCLUSION: These new instruments have proven their applicability in paranasal sinus surgery. Multifunctional endoscopic procedures were deemed best suited for maneuvers requiring highest precision, such as the surgery of the frontal and sphenoid sinus.     

Regional infusion of urokinase into occluded lower-extremity bypass grafts: long-term clinical results

The initial outcome, long-term patency rate, and rate of limb salvage were studied in patients after regional urokinase infusion for treatment of thrombosed lower-extremity grafts. Seventy-one infusions were performed in 53 patients. Complete clot lysis occurred in 75% of grafts, with establishment of antegrade blood flow in 66%. Variables that favorably influenced clot lysis and the reestablishment of antegrade blood flow through the graft were a short duration of occlusion and a suprainguinal graft position. The median duration of patency after infusion and adjunctive therapy was 162 days, with 75% limb salvage at 301 days. No statistically significant variables that influenced the length of patency were identified. These long-term patency results are inferior to the reported results in suprainguinal grafts after reoperation. They appear similar to reported results for occluded infrainguinal grafts treated with thrombectomy and patch grafting.     

Increased safety in robotic paranasal sinus and skull base surgery with redundant navigation and automated registration

We present an advanced version of our robotic setup for paranasal sinus surgery that was developed at the Department of Otorhinolaryngology, Head and Neck Surgery in Erlangen, Germany. The system was interconnected with a redundant navigation system for increasing intraoperative safety while performing telemanipulatory as well as fully automated maneuvers.In contrast to the previous "all in one" version, we built a modular three component setup. The basic feature of the computer navigation system is the "CAPPA ENT" station. The system references by automatically detecting a referencing frame mounted on a non-invasive upper jaw mouthpiece. Software components of both systems, navigation and robotics were combined on one user interface. Accuracy as well as clinical applicability studies were carried out. For better surveillance and increased safety, we decided to evaluate the robots reproducibility errors and overall stereotactic accuracy by means of redundant navigational control on a phantom model for paranasal sinus and skull base surgery. Multiple measurements from 14 CT-markers were taken representing different surgical approaches.A modular setup was designed and was deemed feasible in its size and weight dimensions as well as its maneuvrability for application in a routine operating room environment. The navigational feedback is integrated in real time in the robots user interface. In case of blocked visibility to the Dynamic Referencing Frame the robot powers down and activates the force torque sensor, thus softening all articulating joints. We found only adequate accuracies in pinpointing a specific CT-marker both in telemanipulatory and fully automated maneuvers. No significant offsets were observed evaluating accuracies for different surgical approaches.By using redundant navigation feedback, we were able to add another safety feature, the "loss of control" function, which shuts down any robotic action. However, no increase of the absolute accuracy was observed by adding this feature. We conclude that redundant navigational control does not make the robot more accurate, but it adds a potent safety feature to the system.     

Ein elektronisches Verfahren zur statistischen Auswertung von Elektromyogrammen mit Hilfe von Dauer- und Intervallhistogrammen

Zusammenfassung Ein relativ wenig aufwendiges Verfahren zur Gewinnung der statistischen Verteilung von Potentialdauern (Dauerhistogramm) aus längeren elektromyographischen Registrierungen wird beschrieben. Dabei wird die verwendete Amplitudenschwelle so gelegt, daß im interessierenden Zeitbereich das gleichzeitig registrierte Intervallhistogramm (statistische Verteilung der Intervalle) keine nennenswerten Anteile aufweist. Damit ist sichergestellt, daß im statistischen Mittel die Dauern von Potentialspitzen gemessen werden, welche über einem durch schnelle Störspannungsschwankungen verschiedener Ursache hervorgerufenen Spannungspegel liegen. Es zeigt sich, daß das Verfahren auch bei stärkeren Überlagerungen (Interferenzmuster) brauchbare Aussagen beim Vergleich zwischen klinisch gesunder und geschädigter Motorik, insbesondere im Dauerhistogramm liefert.

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Summary A relatively simple method for obtaining the statistical distribution of the duration of spikes (duration histogram) from protracted electromyographic records is described. A criterion for differentiating spike-like oscillations from background noise and rapid oscillations of different origin (interference pattern) was established empirically through the additional use of the interval histogram.The results demonstrate that especially on the basis of duration histogram parathetic motoric systems could be distinguished from those which function normally.

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Herrn Prof. Dr. W. D. Keidel zum 50. Geburtstag gewidmet.