Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid.

BACKGROUND: Lefamulin is a pleuromutilin antibiotic under evaluation for the treatment of bacterial infections, including respiratory tract infections. Currently, there are no high-quality pharmacokinetic data on drug tissue concentrations of lefamulin available. METHODS: A single dose of intravenous lefamulin (150 mg) was given to 12 healthy men. The registered EudraCT number for this study was 2010-021938-54. Lefamulin concentrations were simultaneously measured in plasma, skeletal muscle tissue, subcutaneous adipose tissue and epithelial lining fluid (ELF) over 24 h, and corresponding pharmacokinetic parameters were calculated. Microdialysis was used to measure unbound lefamulin concentrations in skeletal muscle tissue and subcutaneous adipose tissue, which were similar to unbound lefamulin concentrations in plasma. Bronchoalveolar lavage was performed 1, 2, 4 and 8 h post-dose to determine lefamulin concentrations in ELF. RESULTS: Unbound lefamulin levels showed a 5.7-fold higher exposure in ELF compared with that in plasma, demonstrating good penetration to the target site. CONCLUSIONS: Lefamulin may be an addition to the therapeutic armamentarium for the treatment of infections. Simultaneous measurements of unbound drug concentration can guide target attainment for future therapeutic trials.

Using extended reality (XR) for medical training and real-time clinical support during deep space missions.

Medical events can affect space crew health and compromise the success of deep space missions. To successfully manage such events, crew members must be sufficiently prepared to manage certain medical conditions for which they are not technically trained. Extended Reality (XR) can provide an immersive, realistic user experience that, when integrated with augmented clinical tools (ACT), can improve training outcomes and provide real-time guidance during non-routine tasks, diagnostic, and therapeutic procedures. The goal of this study was to develop a framework to guide XR platform development using astronaut medical training and guidance as the domain for illustration. We conducted a mixed-methods study-using video conference meetings (45 subject-matter experts), Delphi panel surveys, and a web-based card sorting application-to develop a standard taxonomy of essential XR capabilities. We augmented this by identifying additional models and taxonomies from related fields. Together, this "taxonomy of taxonomies," and the essential XR capabilities identified, serve as an initial framework to structure the development of XR-based medical training and guidance for use during deep space exploration missions. We provide a schematic approach, illustrated with a use case, for how this framework and materials generated through this study might be employed.

Early immunomodulatory effects of linezolid in a human whole blood endotoxin model.

Gram-negative sepsis resulting in endotoxin triggered septic shock is one of the leading causes of death in critically ill patients. Because treatment options are limited, recent approaches focus on immunomodulatory effects of antimicrobials. Thus, we characterized the immunomodulatory effects of linezolid at mRNA and on cytokine levels in supernatants of an ex vivo model of endotoxemia. Whole blood from 10 healthy volunteers was incubated with 50 pg/ml LPS with or without 13 microg/ml linezolid (concentrations were chosen to reflect in vivo conditions) for 2 and 4 hours (h). Quantitative real-time PCR was performed from messenger RNA (mRNA) of IL-1beta;, IL-6, IL-8 or TNF-alpha;. Cytokine levels in the supernatant were measured by ELISA for IL-6, IL-8 and TNF-alpha;. Incubation of human whole blood with LPS increased mRNA levels of cytokines several thousand fold compared with baseline. The addition of linezolid significantly reduced mRNA levels of IL-1beta, IL-6, IL-8 and TNF-alpha; (p < 0.05) after 2 and 4 h. LPS stimulation also increased levels of IL-6, IL-8 and TNF-alpha between 100 and 1000-fold. However, in contrast to mRNA - except for IL-6 - no significant reduction at protein level was observed. These results indicate that immunosuppressive effects of linezolid on mRNA transcription are only partially reflected by cytokine release.

Microvascular response of striated muscle to metal debris. A comparative in vivo study with titanium and stainless steel.

Wear products of metal implants are known to induce biological events which may have profound consequences for the microcirculation of skeletal muscle. Using the skinfold chamber model and intravital microscopy we assessed microcirculatory parameters in skeletal muscle after confrontation with titanium and stainless-steel wear debris, comparing the results with those of bulk materials. Implantation of stainless-steel bulk and debris led to a distinct activation of leukocytes combined with a disruption of the microvascular endothelial integrity and massive leukocyte extravasation. While animals with bulk stainless steel showed a tendency to recuperation, stainless-steel wear debris induced such severe inflammation and massive oedema that the microcirculation broke down within 24 hours after implantation. Titanium bulk caused only a transient increase in leukocyte-endothelial cell interaction within the first 120 minutes and no significant change in macromolecular leakage, leukocyte extravasation or venular diameter. Titanium wear debris produced a markedly lower inflammatory reaction than stainless-steel bulk, indicating that a general benefit of bulk versus debris could not be claimed. Depending on its constituents, wear debris is capable of eliciting acute inflammation which may result in endothelial damage and subsequent failure of microperfusion. Our results indicate that not only the bulk properties of orthopaedic implants but also the microcirculatory implications of inevitable wear debris play a pivotal role in determining the biocompatibility of an implant.

Policy process framework: a systems approach to policy development.

This paper discusses a framework for understanding policy analysis and development. The framework presented can be used in the policy development process or post facto in policy analysis. The usefulness of the framework is that it provides a means to think about a policy and its development. It is not prescriptive, nor is it predictive about any particular policy. Policy analysis has tended to rely too heavily on technical analysis, with insufficient attention to other dimensions. This framework offers a basis for people to talk across organizations and cultures.

[Simultaneous stereograms of the fundus oculi]. / Jednoczasowe stereogramy dna oka.

Stereophotograms and stereoangiograms of the fundus in selected pathological conditions are presented. The simultaneous performance of fundus stereograms are devoid of drawbacks and faults encountered in stereoscopic pictures registered in double time. A major consistency of the half-pictures results from an identical utilization of the focal depth and an uniform illumination in one exposure. In the fluorographic examination this method is a method of choice in the registration of a spatial picture throughout the examination.

[3-Tesla MRI vs. arthroscopy for diagnostics of degenerative knee cartilage diseases: preliminary clinical results]. / 3-Tesla-MRT vs. Arthroskopie bei der Diagnostik degenerativer Knorpelschäden des Kniegelenkes : Erste klinische Ergebnisse.

BACKGROUND: The literature contains only a few studies investigating the magnetic resonance imaging (MRI) diagnostics of degenerative cartilage diseases. Studies on MRI diagnostics of the cartilage using field strengths of 3-Tesla demonstrate promising results. To assess the value of 3-Tesla MRI for decision making regarding conservative or operative treatment possibilities, this study focused on patients with degenerative cartilage diseases. METHODS: Thirty-two patients with chronic knee pain, a minimum age of 40 years, a negative history of trauma, and at least grade II degenerative cartilage disease were included. Cartilage abnormalities detected at preoperative 3-Tesla MRI (axial/koronar/sagittal PD-TSE-SPAIR, axial/sagittal 3D-T1-FFE, axial T2-FFE; Intera 3.0T, Philips Medical Systems) were classified (grades I-IV) and compared with arthroscopic findings. RESULTS: Thirty-six percent (70/192) of the examined cartilage surfaces demonstrated no agreement between MRI and arthroscopic grading. In most of these cases, grades II and III cartilage lesions were confounded with each other. Regarding the positive predictive values, the probability that a positive finding in MRI would be exactly confirmed by arthroscopy was 39-72%. In contrast, specificities and negative predictive values of different grades of cartilage diseases were 85-95%. CONCLUSIONS: Regarding the high specificities and negative predictive values, 3-Tesla MRI is a reliable method for excluding even slight cartilage degeneration. In summary, in degenerative cartilage diseases, 3-Tesla MRI is a supportive, noninvasive method for clinical decision making regarding conservative or operative treatment possibilities. However, the value of diagnostic arthroscopy for a definitive assessment of the articular surfaces and for therapeutic planning currently cannot be replaced by 3-Tesla MRI. This applies especially to treatment options in which a differentiation between grade II and III cartilage lesions is of interest.

[Quality analysis of internet information on epicondylitis radialis humeri]. / Analyse der Informationsqualität im Internet zur Epicondylitis radialis humeri.

AIM: By means of conventional internet search engines we assessed the World Wide Web for the topic "epicondylitis radialis humeri" and analysed the content of the listed pages for their quality and transparency. METHODS: Three of the most frequently used internet search engines were utilised to search the World Wide Web for the terms "tennis arm", "tennis elbow" and "epicondylitis". The first 50 listed internet addresses per search engine were scrutinised in respect to the authors' source, financier of the web page and whether commercial interests were evident. Furthermore, the medical content concerning radial epicondylitis was analysed using a 10-point score. RESULTS: After elimination of repetitive and not accessible internet pages, as well as web pages only giving links to further web-sites or chat-rooms, we were able to evaluate 137 internet sites. The average content-score of all pages was low with 2.91 +/- 3.27 SD. Web-pages, where authorship could not be identified or where commercial interests were clearly evident, had the lowest content-scores. Sites authored by or associated with orthopaedic surgeons had a significantly higher content-score (6.84 +/- 3.17 SD) in comparison to other initiators of web-pages (p < 0.0001). CONCLUSION: The facts derived from the World Wide Web when searching for information on epicondylitis radialis humeri are mostly of low professional quality and transparency. Orthopaedic surgeons need to point out this problem to patients who additionally inform themselves on the internet. If the desire for browsing the web for further information concerning musculoskeletal pathology exists, orthopaedic surgeons should tell their patients which web sites are suitable.

[Systemic spread of wear debris--an in-vivo study]. / In-vivo-Analyse zur systemischen Verteilung von metallischen Abriebpartikeln.

AIM: The aim of this study was to elucidate whether there is a systemic spread of wear debris from peripherally applied stainless steel and titanium particles into the blood and subsequently to parenchymatous organs. Furthermore, we report on histological findings at the implantation site. METHOD: In Syrian Gold hamsters we implanted 2 mm3 wear debris of stainless steel and titanium into the dorsal skin fold chamber. Over a period of 2 weeks we took blood samples and afterwards explanted the implant area, the heart, lung, liver and spleen. One half of the organs and the implant area were used for histological analysis. The other half of the organs and the blood samples were analysed by optical emission spectrometer with inductively coupled plasma and graphite furnace atomic absorption spectrophotometry for their contents of chromium, nickel and titanium. RESULTS: In the group with titanium particles, histological analysis of the implant site showed moderate phagocyted wear in granulocytes but no other pathological findings. Animals treated with stainless steel wear debris had a massive inflammatory reaction, in some cases leading to necrosis. The analysis of the blood and one half of the organs showed increased levels of chromium and, already 24 hours after implantation, raised values for nickel. The result of the hamsters treated with titanium showed significantly elevated levels of titanium ions in the organs, but not in the blood samples. Histology of the organs did not reveal pathological findings. CONCLUSION: In this study we could show a massive inflammatory reaction for stainless steel wear debris in contrast to titanium wear debris at the implantation site. The elevated blood levels of chromium and increased values of other metals in the organs suggest the haematogenic distribution of ions from the peripherally implanted wear debris.

Implications of orthopedic fretting corrosion particles on skeletal muscle microcirculation.

Particulate corrosion and wear products of metal implants are increasingly becoming topics of interest, due to the cascade of biological and biomechanical events they induce. The impairment of skeletal muscle microcirculation by fretting corrosion particles may have profound consequences. We therefore studied in vivo leukocyte-endothelial cell interaction in skeletal muscle after confrontation with characterized titanium and stainless steel fretting corrosion particles, and compared these results with those of the bulk materials. Using the hamster dorsal skinfold chamber preparation and intravital microscopy, we could demonstrate that stainless steel induces a more pronounced inflammatory answer in contrast to the implant material titanium. However, we were not able to show a general benefit of bulk vs. debris. Overall, the study suggests that not only the bulk properties of orthopaedic implants, but also the microcirculatory implications of inevitable wear debris, may play a role in determining biocompatibility and ultimately longevity of an implant. The skinfold chamber is a feasible and versatile model for observation of the dynamic process of microvascular response after foreign-body implantation, and offers much perspective.

Impact of a nickel-reduced stainless steel implant on striated muscle microcirculation: a comparative in vivo study.

The impairment of skeletal muscle microcirculation by a biomaterial may have profound consequences. With moderately good physical and corrosion characteristics, implant-quality stainless steel is particularly popular in orthopedic surgery. However, due to the presence of a considerable amount of nickel in the alloy, concern has been voiced in respect to local tissue responses. More recently a stainless steel alloy with a significant reduction of nickel has become commercially available. We, therefore, studied in vivo nutritive perfusion and leukocytic response of striated muscle to this nickel-reduced alloy, and compared these results with those of the materials conventional stainless steel and titanium. Using the hamster dorsal skinfold chamber preparation and intravital microscopy, we could demonstrate that reduction of the nickel quantity in a stainless steel implant has a positive effect on local microvascular parameters. Although the implantation of a conventional stainless steel sample led to a distinct and persistent activation of leukocytes combined with disruption of the microvascular endothelial integrity, marked leukocyte extravasation, and considerable venular dilation, animals with a nickel-reduced stainless steel implant showed only a moderate increase of these parameters, with a clear tendency of recuperation. Titanium implants merely caused a transient increase of leukocyte-endothelial cell interaction within the first 120 min, and no significant change in macromolecular leakage, leukocyte extravasation, or venular diameter. Pending biomechanical and corrosion testing, nickel-reduced stainless steel may be a viable alternative to conventional implant-quality stainless steel for biomedical applications. Concerning tolerance by the local vascular system, titanium currently remains unsurpassed.

[Striated muscle microvascular response to implants with sol-gel calcium phosphate coating. A comparative in vivo study]. / Der Einfluss von kalziumphosphatbeschichteten Implantaten auf die Mikrozirkulation des Skelettmuskels. Eine vergleichende In-vivo-Studie.

AIM: Local microvascular perfusion plays an important role in reparative processes and the pathogenesis of infection. The impairment of skeletal muscle microcirculation by a biomaterial may therefore have profound consequences. The aim of our study was to determine whether the biological acceptance of the widely utilised implant material stainless steel can be improved by a coating of sol-gel calcium phosphate. METHODS: Using the hamster dorsal skinfold chamber preparation and intravital microscopy, we quantified nutritive perfusion and leukocyte-endothelium interaction in skeletal muscle after implantation of sol-gel calcium phosphate-coated stainless steel- and commercial pure titanium implants, and compared these results to those obtained with uncoated stainless steel and titanium. RESULTS: Within the first 24 h after implantation, animals with calcium phosphate coated stainless steel showed a significantly lower inflammatory response than did those with an uncoated stainless steel implant. After 24 h the quantified microcirculatory parameters deteriorated for animals with a calcium phosphate-coated stainless steel plate, indicating that, for as yet unknown reasons, the shielding mechanism of the calcium phosphate seems to deteriorate. Although not as inert as pure titanium, we found a relatively low inflammatory response for calcium phosphate coated titanium over the whole observation period, suggesting that the coating as such is well tolerated by the skeletal muscle microcirculation. CONCLUSIONS: Our in vivo results suggest that the biological acceptance of a conventional stainless steel implant can be improved over a short term by a sol-gel coating of calcium phosphate. Concerning tolerance by the local vascular system, commercially pure titanium currently remains unsurpassed.