[Medical Devices Law for pain therapists]. / Medizinprodukterecht für Schmerztherapeuten.

Medical Devices Law is a relatively new legal system, which has replaced the Medical Devices Regulations still well-known in Germany. German Medical Devices Law is based on European directives, which are, in turn, incorporated into national law by the Medical Devices Act. The Medical Devices Act is a framework law and covers a number of regulations that address specific topics within Medical Devices Law. In turn, in individual regulations, reference is made to guidelines, recommendations, etc. from other sources that provide detailed technical information on specific topics. Medical Devices Law is a very complex legal system, which needs to be permanently observed due to constant updating and adjustment. In the current article, the design and the structure of the system will be described, but special emphasis will be laid on important problem areas that need to be considered when applying and operating medical products, in this case by pain therapists in particular.

[Medical Devices Law for anesthesiologists]. / Medizinprodukterecht für Anästhesisten.

The Medical Devices Law is a relatively new legal system, which has replaced the still well-known medical devices regulations in Germany. The Medical Devices Law in Germany is based on European directives, which have been translated into national law with the Medical Devices Act. The Medical Devices Act is a framework of regulations and incorporates a number of decrees that address specific topics within the medical devices directives and in turn individual regulations refer to guidelines and recommendations from other sources which provide detailed technical information on specific topics. Overall, the Medical Devices Act represents a very complex legal system, which needs to be permanently observed with respect to continuous updating and adjustment. In this article the design and the structure are described but most of all the article filters significant problem areas that need to be considered when using and operating medical devices, especially for anesthesiologists.

[Critical incidents with medical products]. / Kritische Ereignisse mit Medizinprodukten.

Various vigilance systems have been established in medicine during the last two decades. The aims are the identification of critical incidents and to implement appropriate countermeasures thus decreasing the likelihood of accidents and increasing patient and user safety. The types of systems are very divergent: they are either restricted to individual departments, hospitals, specialist or occupational groups or function nationwide. The legislative provision for medical products also includes critical incident surveillance and reporting systems and focuses on the subset of events with involvement of medical products. The responsible German authority is the Federal Institute for Drugs and Medical Products which contacts manufacturers and informs users. This article describes experiences with the responsible authority. Not all users are aware that an obligation for reporting exists. A proposal is made to simplify the reporting process in order to enhance user willingness for reporting. Additionally, it is suggested that a link should be incorporated into all existing critical incident reporting systems which can forward the user to the specific reporting website.

[Anonymous critical incident reporting system. Implementation in an intensive care unit]. / Anonymes Meldesystems für kritische Ereignisse. Implementierung auf einer Intensivstation.

In 2003 an anonymous reporting system for critical incidents was implemented in the Department of Anaesthesiology and Intensive Care Medicine of the University Hospital Dresden. This reporting system was modified to an intranet-based version and extended to the intensive care unit (ICU). During the first 18 months 70 anonymous reports originating from the ICU were registered. The most common errors involved fluid management, followed by errors in airway management, cardio-vascular management, neurological problems and errors in drug administration. The main causes were lack of attention, missing check of measures, work load of nurses, experience and communication deficits. The article discusses the incidence of errors in the ICU setting and their potential effects.

[Anonymous critical incident reporting system in anaesthesiology. Results after 18 months]. / Anonymes Meldesystem kritischer Ereignisse in der Anästhesie. Ergebnisse nach 18 Monaten.

Two years ago we implemented a reporting system for critical incidents in the Department of Anaesthesiology and Intensive Care of the University Hospital Dresden. During the first 18 months 162 anonymous reports were registered. The most common errors involved airway and ventilation management, followed by errors in fluid and cardio-vascular management. The main causes were distraction, lack of experience, specific training and communication deficits. The confidence in the anonymity of the reporting system was very high. Following the analysis of the reports, several modifications were initiated, e.g. specific training programs or definition of standards. Over time, a change in the relative distribution of reported errors was observed. The article discusses the different kinds of errors and possible countermeasures. It also strengthens several aspects which are important to consider during the initial phase of a local critical incident reporting system.

[Reduction in the aggressiveness of ventilation by inhalation of perfluorohexane after therapy of oleic acid-induced respiratory failure]. / Reduktion der Aggressivität der Beatmung nach Therapie eines Olsäure-induzierten Lungenversagens durch Inhalation von Perfluorhexan.

INTRODUCTION: The application of perfluorohexane (PFH) vapor led to an improvement of oxygenation and mechanical lung function in a model of oleic acid-induced ARDS in sheep. The aim of this study was to investigate the effects of PFH on gas exchange over an extended time period and to reduce the invasiveness of ventilation. METHOD: ARDS was induced in sheep ( n=12) by injecting 0.1 ml/kg body weight oleic acid intravenously. Six sheep were treated for 30 min with 18 vol.% PFH (PFH-Tx) and followed up over a time period of 240 min while untreated sheep ( n=6) served as controls. Subsequently the F(I)O(2) was reduced to generate a p(a)O(2) between 100-140 mmHg. Gas exchange, respiratory and hemodynamic data were collected at regular intervals. Data were analysed using covariance analysis. RESULTS: PFH treatment led to an improvement in oxygenation ( p<0.01) and in mechanical lung function ( p<0.01). Furthermore, mean pulmonary artery pressure ( p<0.01) and shunt ( p<0.01) were lower in PFH-Tx. F(I)O(2) could be reduced in all PFH-treated animals ( p<0.01). CONCLUSION: Treatment of oleic acid-induced lung injury with PFH vapor improved oxygenation and mechanical lung function over a extended time period allowing a reduction in the invasiveness of ventilation.

Effector cytolotic function but not IFN-gamma production in cytotoxic T cells triggered by virus-infected target cells in vitro.

Cytolysis and interferon(IFN)-gamma production are two independent effector functions of activated cytotoxic T (Tc) cells. We have used the Tc-cell response against the flavivirus, Murray Valley encephalitis virus (MVE), to investigate the requirements for inducing these two functions with regard to antigen-concentration and CD8 coreceptor involvement. Cognate peptide-pulsed target cells triggered cytolysis by primary ex vivo MVE-immune as well as in vitro peptide-restimulated splenocytes at lower peptide concentrations than IFNgamma-production (100-fold lower in the case of primary ex vivo effectors). Little difference was observed in CD8 dependency. Importantly, neither of the effector populations were triggered to produce IFN-gamma by virus-infected target cells, although cytolysis occurred. This result raises the possibility that the levels of presentation of cognate antigen on virus-infected cells in vivo may be below the threshold required for the IFN-gamma production.

Effects of inhalation of perfluorocarbon aerosol on oxygenation and pulmonary function compared to PGI2 inhalation in a sheep model of oleic acid-induced lung injury.

OBJECTIVE: To evaluate the effects of PFC aerosol compared to PGI2 aerosol and NaCl aerosol on gas exchange and lung mechanics in oleic acid-induced acute lung injury. DESIGN: A prospective, controlled, randomised, in vivo animal laboratory study. SETTING: Research laboratory at an university hospital. SUBJECTS: Twenty one (n = 21) adult sheep of either gender weighing 26.8+/-6.4 kg. INTERVENTIONS: The animals were randomised to three groups: PFC aerosol (perfluorooctane), PFC group; prostacyclin aerosol (Flolan), PGI2 group; and NaCl aerosol (0.9% sodium chloride solution), control group. After induction of anaesthesia and placement of vascular catheters, lung injury was induced with 0.12 ml x kg(-1) oleic acid. Aerosols were continuously administered for 2 h using a jet nebuliser. Gas exchange, pulmonary mechanic, and haemodynamic parameters were obtained at regular intervals. MEASUREMENTS AND MAIN RESULTS: PFC aerosol increased oxygenation (PaO2) 15 min after the initiation of treatment up to 120 min (P < 0.05). Transpulmonary shunt improved in the PFC group (P < 0.05) while it did not change in the two other groups. PFC aerosol reduced maximum airway pressure (Pmax) (median) significantly from (median) 38 mbar to 32 mbar (P < 0.05). Static compliance improved significantly in the PFC group (P < 0.05). CONCLUSION: The inhalation of a PFC aerosol led to a significant improvement in pulmonary mechanics and gas exchange, which was not observed in the other two groups. These data suggest that a small dose of perfluorocarbon will have beneficial effects on gas exchange and respiratory mechanics. Therefore, the non-invasive aerosol application technique seems to be a reasonable alternative to administer perfluorocarbons in severe lung injury.

Immunogenicity of two peptide determinants in the cytolytic T-cell response to flavivirus infection: inverse correlation between peptide affinity for MHC class I and T-cell precursor frequency.

We used the CD8+ cytotoxic T (Tc) cell immune response against the flavivirus, Murray Valley encephalitis virus (MVE), restricted by the H-2Kk major histocompatibility complex (MHC) class I molecule, to investigate immunodominance. Split-clone limiting dilution analysis revealed almost exclusive recognition of two peptides, MVE1785 and MVE1971, derived from the viral NS3 protein. The precursor frequency of MVE-reactive Tc cells was determined by limiting dilution analysis for cytotoxic function and intracellular staining for interferon-gamma; the latter gave a 100-fold higher estimate of MVE-reactive Tc cell precursors. MHC class I cell surface stabilization assays revealed that affinity for H-2Kk as well as halflives of the peptide-H-2Kk-complexes were markedly different for the two peptides. However, a kinetic study of antigen presentation showed that both peptides are presented for recognition by Tc cells with a comparable kinetics during the latent period of virus infection. Nevertheless, the lower affinity peptide MVE1785 elicited roughly twofold more Tc cell clones than the high-affinity peptide MVE1971. While the cytolytic activity against both determinants was similar after in vitro restimulation at the peak of the primary response, the smaller pool of memory anti-MVE1971 Tc cells correlated with an impaired memory response against that determinant, suggesting that the available T-cell repertoire is a major factor influencing the establishment of T-cell memory.

Cross-reactivity in T-cell antigen recognition.

The molecular interactions between the T-cell receptor (TCR) and peptide-MHC (pMHC) have been elucidated in recent years. Nevertheless, the fact that binding of only slightly different ligands by a TCR, or ligation of the same pMHC at different developmental stages of the T cell, can have opposing consequences, continues to pose intellectual challenges. Kinetic proofreading models, which have at their core the dissociation rates of pMHC from the TCR, are best suited to account for these observations. However, T cells can be triggered by peptides with often minimal homology to the primary immunogenic peptide. This cross-reactivity of the TCR is manifest at several levels, from positive selection of immature thymocytes to homeostasis and antigen-cross- reactive immune responses of mature peripheral T cells. The implications of the high cross-reactivity of T-cell antigen recognition for self-tolerance and T-cell memory are discussed.

Antiviral cytotoxic T cells cross-reactively recognize disparate peptide determinants from related viruses but ignore more similar self- and foreign determinants.

We have investigated the reactivities of cytotoxic T (Tc) cells against the two immunodominant, H-2K(k)-restricted determinants from the FLAVIVIRUS: Murray Valley encephalitis virus (MVE), MVE(1785) (REHSGNEI) and MVE(1971) (DEGEGRVI). The respective Tc cell populations cross-reactively lysed target cells pulsed with determinants from the MVE(1785)- and MVE(1971)-corresponding positions of six other flaviviruses, despite low sequence homology in some cases. Notably, anti-MVE(1785) Tc cells recognized a determinant (TDGEERVI) that shares with the determinant used for stimulation only the carboxyl-terminal amino acid residue, one of two H-2K(k) anchor residues. These reactivity patterns were also observed in peptide-dependent IFN-gamma production and the requirements for in vitro restimulation of memory Tc cells. However, the broad cross-reactivity appeared to be limited to flavivirus-derived determinants, as none of a range of determinants from endogenous mouse-derived sequences, similar to the MVE-determinants, were recognized. Neither were cells infected with a number of unrelated viruses recognized. These results raise the paradox that virus-immune Tc cell responses, which are mostly directed against only a few "immunodominant" viral determinants, are remarkably peptide cross-reactive.

Vaporized perfluorocarbon improves oxygenation and pulmonary function in an ovine model of acute respiratory distress syndrome.

BACKGROUND: Perfluorocarbon liquids are being used experimentally and in clinical trials for the treatment of acute lung injury. Their resemblance to inhaled anesthetic agents suggests the possibility of application by vaporization. The authors' aim was to develop the technical means for perfluorocarbon vaporization and to investigate its effects on gas exchange and lung function in an ovine model of oleic acid-induced lung injury. METHODS: Two vaporizers were calibrated for perfluorohexane and connected sequentially in the inspiratory limb of a conventional anesthetic machine. Twenty sheep were ventilated in a volume controlled mode at an inspired oxygen fraction of 1.0. Lung injury was induced by intravenous injection of 0.1 ml oleic acid per kilogram body weight. Ten sheep were treated with vaporized perfluorohexane for 30 min and followed for 2 h; 10 sheep served as controls. Measurements of blood gases and respiratory and hemodynamic parameters were obtained at regular intervals. RESULTS: Vaporization of perfluorohexane significantly increased arterial oxygen tension 30 min after the end of treatment (P < 0.01). At 2 h after treatment the oxygen tension was 376+/-182 mmHg (mean +/- SD). Peak inspiratory pressures (P < 0.01) and compliance (P < 0.01) were significantly reduced from the end of the treatment interval onward. CONCLUSION: Vaporization is a new application technique for perfluorocarbon that significantly improved oxygenation and pulmonary function in oleic acid-induced lung injury.

An improved method for the detection of peptide-induced upregulation of HLA-A2 molecules on TAP-deficient T2 cells.

Peptide-induced upregulation of MHC class I on TAP-deficient T2 cells is used to monitor peptide binding to class I molecules. We present a temperature-dependent modification of the T2 assay which increases the sensitivity of peptide binding to MHC class I with several orders of magnitude.

T cell-mediated cytotoxicity against p53-protein derived peptides in bulk and limiting dilution cultures of healthy donors.

The p53 tumour suppressor gene product plays an important role in the development of most human cancers. Point mutations in the p53 gene are common in malignant states and results in over-expression of wild type and mutant determinants of the p53 protein. This process might generate MHC-I restricted epitopes for T cell recognition and p53-derived peptides have been suggested as targets for tumour-specific cytotoxic T lymphocytes (CTL). Our primary aim was to estimate the frequencies of p53-peptide reactive CTL precursors (CTLp) in peripheral blood from healthy young individuals. We selected wild type and mutated peptides derived from the p53 sequence with a binding motif for HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from healthy HLA-A2 donors were stimulated in vitro in bulk cultures as well as in limiting dilution cultures using autologous cells pulsed with p53 peptides as stimulator cells. T cell reactivity was observed towards both wild type and mutated p53 peptide epitopes with CTL precursor frequencies varying from 1:2 x 10(4) to 1:1.5 x 10(5). These results might suggest the presence of an ongoing immune response in normal individuals against cells expressing increased levels of p53 protein.

Effectiveness of a printed leaflet for enabling patients to use digoxin side-effect information.

The effectiveness of a printed leaflet designed to inform patients about digoxin was evaluated. The printed leaflet alone was compared to the verbal consultation alone and the verbal consultation in addition to the printed leaflet. The study assessed patients' decisions about the appropriate course of action to take if side-effect symptoms occurred. Patients receiving the printed leaflet alone scored higher than patients receiving the verbal consultation; however, they scored lower than patients receiving both the printed leaflet and verbal consultation together. Patients receiving both verbal and printed information scored significantly higher than those receiving verbal consultation only. The findings suggest that printed materials together with verbal consultation are essential for enabling patients to make appropriate decisions with respect to side effects. There is not enough evidence to support the use of printed materials in place of verbal consultation. Health practitioners should use printed materials as an adjunct to verbal information.