Kryptokokkenmeningoenzephalitis von HIV-infizierten Immigranten¶Diagnostische und therapeutische Aspekte unter Berücksichtigung der “evidence-based medicine”– Ein Überblick

Zusammenfassung Die Kryptokokkenmeningoenzephalitis ist eine der h?ufigsten Meningoenzephalitiden von AIDS-Patienten. Ihre H?ufigkeit betrug vor der Einführung der Triazol-Antibiotika wie Difluconazol 5–10% aller AIDS-Patienten, sank jedoch in den letzten Jahren. Klinisch imponieren meist unspezifische Zeichen einer meningealen Reizung, w?hrend fokale neurologische Symptome selten sind. Prognostisch entscheidend für die mit einer hohen Mortalit?t verbundenen Erkrankung sind eine rechtzeitige, hochdosierte Antimykotikatherapie, die derzeit üblicherweise mit Amphotericin B, Flucytosin und Fluconazol durchgeführt wird. Der Nachweis von Kryptokokken-Antigen im Liquor, die Darstellung von Kryptokokken im Tuschepr?parat und die üblicherweise positive Liquor-Kryptokokkenkultur best?tigen die klinische Verdachtsdiagnose. Aktuelle Entwicklungen zielen auf Optimierung der antimykotischen Therapie. In den letzten Jahren wurde die lebenslange Terti?rpr?vention mit Difluconazol oral etabliert. Mittelfristig wird die Prognose der Patienten von der zugrundeliegenden Immunsuppression bestimmt, so da? nach erfolgreicher Therapie eine moderne antivirale Kombinationstherapie zus?tzlich zur Terti?rpr?vention dringend indiziert ist. Die vorliegende übersicht thematisiert Entscheidungssituationen in der Behandlung von Patienten mit Kryptokokkenmeningoenzephalitis anhand von Prinzipien der “evidence-based medicine”.      

Cidofovir (Vistide®) in der Therapie der Progressiven multifokalen Leukoenzephalopathie (PML) bei AIDSLiteraturübersicht und Beschreibung zweier Fälle

Zusammenfassung Die Progressive Multifokale Leukoenzephalopathie (PML), eine durch das JC-Virus hervorgerufene Enzephalitis, tritt bei etwa 4%–5% aller HIV-1-infizierten Personen auf und hat mit einer mittleren postdiagnostischen überlebenszeit von 3 bis 6 Monaten eine ?u?erst schlechte Prognose. Bis heute existiert keine effektive Therapie der PML, Therapieversuche an kleineren Kollektiven mit a-Interferon, Didanosin und Arabinosid hatten nur wenig Erfolg. In einer kontrollierten Studie mit Cytarabin konnte keine Wirksamkeit dieses Medikamentes gegen die PML beobachtet werden. Erste Einzelfallbeschreibungen über eine Therapie der PML mit Cidofovir (Vistide^?), einem für die Zytomegalie-Retinitis bei AIDS-Patienten ohne renale Dysfunktion zugelassenen Nukleotid-Analogon, zeigten positive Ergebnisse. Wir berichten über zwei weitere F?lle der Behandlung einer AIDS-assoziierten PML mit Cidofovir. Von 22 in der Literatur beschriebenen F?llen einer Behandlung der AIDS-assoziierten PML mit Cidofovir – einschlie?lich der beiden hier beschriebenen F?lle – haben sich 16 Patienten unter der Therapie gebessert, 2 Patienten zeigten eine stabile Symptomatik und nur 4 Patienten verschlechterten sich weiterhin fulminant. Diese Ergebnisse deuten darauf hin, da? Cidofovir einen antiviralen Effekt auch auf das JC-Virus ausübt, der in der Therapie der PML bei Patienten mit AIDS genutzt werden sollte, da bisher kaum therapeutische Alternativen bestehen. Ob andere Faktoren für die klinische Verbesserung der 16 bisher beschriebenen F?lle unter einer Therapie mit Cidofovir mitverantwortlich sind oder ob die klinische Verbesserung ein alleiniger Effekt der Therapie mit Cidofovir ist, mu? letztlich offen bleiben und in einer randomisierten, kontrollierten Studie mit gro?er Patientenzahl gekl?rt werden.      

CAS-System MKM(R): use and results in lateral skull base surgery

BACKGROUND: Computer assisted surgery has reached an advanced stage of development and offers new possibilities in daily surgical procedures. METHODS: The MKM(R) - is a navigation system fitted with a laser-guided, autofocus-microscope for referencing purposes. The coordinates can be set using various marker systems and a special workstation is used for preoperative planning. It is possible to add landmarks and display them in the surgeon's eyepiece. The clinical integration, the time required for the use of the navigation system and the intraoperative accuracy of the system were evaluated on the basis of 136 lateral skull base procedures. RESULTS: The degree of accuracy is determined by the type, amount and positioning of markers. The adjustment of reference points should be carried out following macrosurgery in order to avoid shifting factors. For an additional increase in accuracy, an improvement in the spatial resolution of the CT scans is required, with a section thickness of 1 mm and a pixel size of 0.5mm. The bone-anchored structures of the temporal bone do not underlie shifting or extensive intraoperative swelling. Skull base surgery is, therefore, ideally suited for the application of CAS. We found that registration was accurate to less than 1 mm (0.68 mm +/- 0.17 mm) and that the MKM(R) system made an additional contribution to surgical safety by identifying important structures. CONCLUSIONS: A practical accuracy found to be approximately one millimetre suggests that the non-invasive referencing system may be effective, accurate and useful for computer assisted identification of vital structures. We expect navigation systems to improve the quality and reduce the risks of surgical intraventions.     

Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory- type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia

Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal models have shown that IL-1 contributes to mortality in sepsis, the mechanisms whereby IL-1 mediates lethal effects are not well established. A possible mechanism is that IL-1 enhances the activation and release of other inflammatory mediator systems such as coagulation, fibrinolysis, neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated this possibility by assessing the effect of intravenously injected recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in baboons. In addition, we examined the course of these inflammatory parameters in baboons after a challenge with a lethal dose of Escherichia coli and while receiving a 24-hour constant infusion of IL-1ra or placebo. Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the formation of thrombin, as evidenced by the appearance of thrombin-antithrombin III (TAT) complexes into the circulation (peak levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of fibrinolysis, assessed by circulating plasmin-alpha 2- antiplasmin complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA; peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1 alpha administration also induced the release of sPLA2 (maximal levels, 336 +/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the septic baboons, a significant reduction of the formation of thrombin (peak TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P < .005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to 17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed in the group receiving IL-1ra compared to that receiving placebo. The release of neutrophilic elastase was also significantly attenuated in IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in control and treatment groups, respectively; P < .05). The difference between sPLA2 levels in both groups, although higher in the controls (maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to activation of various other mediator systems in severe sepsis in nonhuman primates. We propose that these effects may explain the lethal actions of IL-1 in this sepsis model and suggest a similar role for IL-1 in severe human sepsis.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon- gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

Study of the three-dimensional geometry of the central conducting airways in man using computed tomographic (CT) images

Clinical research on the deposition of inhaled substances (e.g. inhaled medications, airborne contaminants, fumes) in the lungs necessitates anatomical models of the airways. Current conducting airway models lack three‐dimensional (3D) reality as little information is available in the literature on the distribution of the airways in space. This is a limitation to the assessment or predictions of the particle deposition in relation to the subject’s anatomy. Detailed information on the full topology and morphology of the airways is thus required to model the airway tree realistically. This paper presents the length, diameter, gravity, coronal and sagittal angles that together describe completely the airways in 3D space. The angle at which the airways branch out from their parent (branching angle) and the rotation angle between successive bifurcation planes are also included. These data are from the study of two sets of airways computed tomography (CT) images. One CT scan was performed on a human tracheobronchial tree cast and the other on a healthy male volunteer. The airways in the first nine generations of the cast and in the first six conducting generations of the volunteer were measured using a computer‐based algorithm. The data contribute to the knowledge of the lung anatomy. In particular, the spatial structure of the airways is shown to be strongly defined by the central airways with clear angular lobar patterns. Such patterns tend to disappear with a mean gravity, coronal and sagittal angles of 90° in each generation higher than 13–15. The mean branching angle per generation appears independent of the lobe to which the airways belong. Non‐planar geometry at bifurcation is observed with the mean (± SD) bifurcation plane rotation angle of 79 ± 41° (n = 229). This angle appears constant over the generations studied. The data are useful for improving the 3D realism of the conducting airway structure modelling as well as for studying aerosol deposition, flow and biological significance of non‐planar airway trees using analytical and computational flow dynamics modelling.     

The diagnostic reliability of the occipitomental radiograph of the paranasal sinuses. Correlation with magnetic resonance tomography]

100 conventional occipitomental radiographs of the paranasal sinuses were studied independently by five radiologists. Predictive values were determined, based on MRI as the gold standard. Sensitivity and specificity for detection of mucosal thickening in the sinuses were: maxillary sinus: 0.73/0.76, frontal sinus: 0.20/0.85, ethmoid sinus: 0.38/0.87, sphenoid sinus: 0.14/0.96. In the maxillary sinus polypoid thickening was demonstrated with a significantly higher sensitivity than that of diffuse mucosal thickening (0.82 versus 0.65, Chi-square-test, p less than 0.01). Because of the low predictive values the occipitomental view is insufficient to assessing mucosal thickening in the paranasal sinuses, with the exception of polypoid mucosal thickening in the maxillary sinus.