[Seasonal and Perennial Allergic Rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonsal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90% of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivitity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection,watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1ß signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1ß and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1ß in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

[Electrolyte disorders as a hallmark of monogenetic diseases]. / Elektrolytstörungen als Merkmal monogenetischer Erkrankungen.

In daily clinical practice, the term electrolyte generally refers to sodium, potassium, chloride, calcium, and magnesium ions. In addition to their many functions, such as neuronal and muscular transmission, some electrolytes also contribute to osmolality and maintenance of electrochemical gradients, which, in turn enable many transport processes. The absorption and reabsorption of electrolytes occurs via polarized cell assemblies, i.e., epithelia. Besides the intestine (absorption), the most important organ is the kidney. Here, following glomerular filtration, electrolytes are reabsorbed via trans- and paracellular mechanisms along the renal tubular system. In the past, the identification and elucidation of transport-associated monogenetic disorders has contributed tremendously to our understanding of the physiology and pathophysiology of such transport mechanisms. Sodium reabsorption mechanisms along the tubular system have been characterized by means of pharmacological compounds for a long time. However, only with the development of novel molecular genetic tools and approaches has it been possible to clarify the genetic basis of distinct diseases. As examples, we discuss here Bartter and Gitelman syndrome, and other sodium disorders such as pseudohypoaldosteronism and Liddle Syndrome. Diagnosis, clinical presentation, and therapy are briefly described. Furthermore, examples of magnesium homeostasis disorders are also presented, the molecular mechanisms and pathophysiology of which could also be characterized by the identification of different human mutations.

[Seasonal and perennial allergic rhinoconjunctivitis]. / Die saisonale und perenniale allergische Rhinokonjunktivitis.

Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90 % of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection, watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.

[Interstitial lung diseases : From imaging to treatment]. / Interstitielle Lungenerkrankungen : Vom Bild zur Therapie.

BACKGROUND: The role of radiology in the diagnosis of interstitial lung diseases (ILDs) has evolved over time, in part replacing histology. Radiology now represents a pillar of diagnostics and monitoring in ILDs. OBJECTIVE: To what extent does radiology influence diagnostics and treatment in ILDs? MATERIALS AND METHODS: A literature review was conducted, and current findings were discussed in the context of clinical data. RESULTS: Radiology plays a crucial role in the diagnosis of ILDs. Within the framework of the multidisciplinary conference, it provides specific CT patterns such as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP), or helps in identifying cystic lung diseases. Multicompartment diseases can be detected, and pulmonary hypertension or extrapulmonary involvement of the respective diseases can be suspected. Progressive pulmonary fibrosis requires radiologic assessment as one of the required criteria. Interstitial lung abnormalities are usually detected by radiological studies performed for an unrelated indication. CONCLUSION: Radiology plays an important role within the multidisciplinary conference to determine both diagnosis and treatment with antifibrotic or anti-inflammatory drugs, or a combination of both.

[Examination of calibrated item banks for the assessment of work capacity in an outpatient sample of cardiological patients]. / Überprüfung kalibrierter Itembanken zur Erfassung der beruflichen Funktionsfähigkeit an einer Stichprobe ambulanter kardiologischer Rehabilitanden.

BACKGROUND: Work capacity is a major outcome variable in cardiological rehabilitation. However, there is a lacks of capacious and economic assessment instruments for work capacity. By developing item response theory based item banks a first step to close this gap is done. The present study aims to validate the work capacity item banks for cardiovascular rehabilitation inpatients (WCIB-Cardio) in a sample of cardiovascular rehabilitation outpatients. Additionally, we examined differences between in- and outpatients with regard to their work capacity. METHODS: Data of 283 cardiovascular rehabilitation inpatients and 77 cardiovascular rehabilitation outpatients were collected in 15 rehabilitation centres. The WCIB-Cardio contains the 2 domains of "cognitive work capacity"(20 items) and "physical work capacity"(18 items). Validation of the item bank for cardiological outpatients was conducted with separate Rasch analysis for each domain. RESULTS: For the domain of cognitive work capacity 10 items showed satisfying quality criteria (Rasch reliability=0.71; overall model fit=0.07). For the domain of physical work capacity good values for Rasch-reliability (0.83) and overall -model fit (0.65) could be proven after exclusion of 3 items. Unidimensionality and a broad ability spectrum could be covered for both domains. With regard to content, outpatients evaluate themselves less burdened than inpatients for the domain of cognitive work capacity (‾X outpatient =-2.06 vs. ‾X inpatient =-2.49; p<0.07) similarly for the domain of physical work capacity (‾X outpatient =-3.68 vs. ‾X inpatient =-2.88; p<0.01). DISCUSSION: With the WCIB-Cardio II there is a precondition to develop self-report instruments of work capacity in cardiological in- and outpatients.

Physiomimetic biocompatibility evaluation of directly printed degradable porous iron implants using various cell types.

Additively manufactured (AM) degradable porous metallic biomaterials offer unique opportunities for satisfying the design requirements of an ideal bone substitute. Among the currently available biodegradable metals, iron has the highest elastic modulus, meaning that it would benefit the most from porous design. Given the successful preclinical applications of such biomaterials for the treatment of cardiovascular diseases, the moderate compatibility of AM porous iron with osteoblast-like cells, reported in earlier studies, has been surprising. This may be because, as opposed to static in vitro conditions, the biodegradation products of iron in vivo are transported away and excreted. To better mimic the in situ situations of biodegradable biomaterials after implantation, we compared the biodegradation behavior and cytocompatibility of AM porous iron under static conditions to the conditions with dynamic in situ-like fluid flow perfusion in a bioreactor. Furthermore, the compatibility of these scaffolds with four different cell types was evaluated to better understand the implications of these implants for the complex process of natural wound healing. These included endothelial cells, L929 fibroblasts, RAW264.7 macrophage-like cells, and osteoblastic MG-63 cells. The biodegradation rate of the scaffolds was significantly increased in the perfusion bioreactor as compared to static immersion. Under either condition, the compatibility with L929 cells was the best. Moreover, the compatibility with all the cell types was much enhanced under physiomimetic dynamic flow conditions as compared to static biodegradation. Our study highlights the importance of physiomimetic culture conditions and cell type selection when evaluating the cytocompatibility of degradable biomaterials in vitro. STATEMENT OF SIGNIFICANCE: Additively manufactured (AM) degradable porous metals offer unique opportunities for the treatment of large bony defects. Despite the successful preclinical applications of biodegradable iron in the cardiovascular field, the moderate compatibility of AM porous iron with osteoblast-like cells was reported. To better mimic the in vivo condition, we compared the biodegradation behavior and cytocompatibility of AM porous iron under static condition to dynamic perfusion. Furthermore, the compatibility of these scaffolds with various cell types was evaluated to better simulate the process of natural wound healing. Our study suggests that AM porous iron holds great promise for orthopedic applications, while also highlighting the importance of physio-mimetic culture conditions and cell type selection when evaluating the cytocompatibility of degradable biomaterials in vitro.

Deletion of NADPH oxidase 2 in chondrocytes exacerbates ethanol-mediated growth plate disruption in mice without major effects on bone architecture or gene expression.

BACKGROUND: Excess reactive oxygen species generated by NADPH oxidase 2 (Nox2) in response to ethanol exposure mediate aspects of skeletal toxicity including increased osteoclast differentiation and activity. Because perturbation of chondrocyte differentiation in the growth plate by ethanol could be prevented by dietary antioxidants, we hypothesized that Nox2 in the growth plate was involved in ethanol-associated reductions in longitudinal bone growth. METHODS: Nox2 conditional knockout mice were generated, where the essential catalytic subunit of Nox2, cytochrome B-245 beta chain (Cybb), is deleted in chondrocytes using a Cre-Lox model with Cre expressed from the collagen 2a1 promoter (Col2a1-Cre). Wild-type and Cre-Lox mice were fed an ethanol Lieber-DeCarli-based diet or pair-fed a control diet for 8 weeks. RESULTS: Ethanol treatment significantly reduced the number of proliferating chondrocytes in the growth plate, enhanced bone marrow adiposity, shortened femurs, reduced body length, reduced cortical bone volume, and decreased mRNA levels of a number of osteoblast and chondrocyte genes. Conditional knockout of Nox2 enzymatic activity in chondrocytes did not consistently prevent any ethanol effects. Rather, knockout mice had fewer proliferating chondrocytes than wild-type mice in both the ethanol- and control-fed animals. Additional analysis of tibia samples from Nox4 knockout mice showed that loss of Nox4 activity also reduced the number of proliferating chondrocytes and altered chondrocyte size in the growth plate. CONCLUSIONS: Although Nox enzymatic activity regulates growth plate development, ethanol-associated disruption of the growth plate morphology is independent of ethanol-mediated increases in Nox2 activity.

Retinal vascular occlusion in pregnancy: three case reports and a review of the literature.

BACKGROUND: Retinal arterial occlusive events in young patients are rare. However, because of physiological multifactorial adaptations during pregnancy, retinal vascular occlusive disease may occur spontaneously. In addition, a patent foramen ovale is a risk factor for an ischemic thromboembolic event. Since fluorescein angiography, a central tool in the evaluation of these occlusions, should be avoided during pregnancy, optical coherence tomography angiography, a novel technique, offers a good opportunity for visualizing vascular perfusion of retinal tissue. CASE PRESENTATION: Here we present a case series of three patients (Caucasian, nonsmoker) who visited our clinic owing to acute visual impairment and central scotoma. Using regular optical coherence tomography and optical coherence tomography angiography, retinal vascular occlusions were detected, thus initiating the evaluation of systemic risk factors. We report two patients (30 and 32 years old) who developed cilioretinal artery occlusion but whose etiology differed: one was of thromboembolic origin associated with patent foramen ovale, while the other was caused by hemodynamic blockade secondary to central retinal vein occlusion. In both cases, optical coherence tomography angiography revealed reperfusion of the cilioretinal artery occlusion. However, transient ischemia led to retinal atrophy after a few weeks. In the third patient (32 years old), 8 weeks after onset of scotoma, optical coherence tomography angiography revealed atrophy of the middle layers and impaired perfusion in the deep capillary plexus, and thus a paracentral acute middle maculopathy was diagnosed. All patients regained normal visual acuity and had otherwise uncomplicated pregnancies, and laboratory blood tests did not reveal any defects or alterations. CONCLUSIONS: As shown here, optical coherence tomography angiography enables risk-free imaging of retinal vessel perfusion during pregnancy. Together with regular optical coherence tomography, it allows one to predict functional outcome according to the existing retinal occlusion-related atrophy.

Nox4 promotes endothelial differentiation through chromatin remodeling.

RATIONALE: Nox4 is a constitutively active NADPH oxidase that constantly produces low levels of H2O2. Thereby, Nox4 contributes to cell homeostasis and long-term processes, such as differentiation. The high expression of Nox4 seen in endothelial cells contrasts with the low abundance of Nox4 in stem cells, which are accordingly characterized by low levels of H2O2. We hypothesize that Nox4 is a major contributor to endothelial differentiation, is induced during the process of differentiation, and facilitates homeostasis of the resulting endothelial cells. OBJECTIVE: To determine the role of No×4 in differentiation of murine inducible pluripotent stem cells (miPSC) into endothelial cells (ECs). METHODS AND RESULTS: miPSC, generated from mouse embryonic wildtype (WT) and Nox4-/- fibroblasts, were differentiated into endothelial cells (miPSC-EC) by stimulation with BMP4 and VEGF. During this process, Nox4 expression increased and knockout of Nox4 prolonged the abundance of pluripotency markers, while expression of endothelial markers was delayed in differentiating Nox4-depleted iPSCs. Eventually, angiogenic capacity of iPSC-ECs is reduced in Nox4 deficient cells, indicating that an absence of Nox4 diminishes stability of the reached phenotype. As an underlying mechanism, we identified JmjD3 as a redox target of Nox4. iPSC-ECs lacking Nox4 display a lower nuclear abundance of the histone demethylase JmjD3, resulting in an increased triple methylation of histone 3 (H3K27me3), which serves as a repressive mark for several genes involved in differentiation. CONCLUSIONS: Nox4 promotes differentiation of miPSCs into ECs by oxidation of JmjD3 and subsequent demethylation of H3K27me3, which forced endothelial differentiation and stability.

Quantitative immunohistochemical examination of the local cellular reactions following implantation of biomaterials.

Examining the biocompatibility of implant materials includes the in vivo investigation of the local tissue response following implantation in experimental animals. By contrast to qualitative and semi-quantitative approaches often used in this field, a quantitative technique would facilitate a more accurate determination and better comparability of different studies. Therefore, this study aimed at evaluating the applicability of the free image analysis software ImageJ for fast, easy and reproducible quantification of the tissue response following implantation of titanium samples in rats with subsequent immunohistochemical examination of peri-implant tissue samples for monocytes and macrophages (ED1) and MHC class II positive antigen presenting cells (OX6). The quantification of positively stained cells in the vicinity of the implant pockets was based on a grid-supported manual count carried out using two ImageJ plugins (CellCounter, Grid) and resulted in a mean coefficient of variation of 13.8% (ED1) and 19.6% (OX6) between different investigators and 10.0% (ED1) and 13.8% (OX6) for repeated counting by the same investigator. In conclusion, ImageJ was found to be suitable for morphometric evaluation of the tissue response following implantation, particularly the analysis of discrete cellular events at the tissue-biomaterial interface. The procedure which was used is described in detail, and its advantages and disadvantages are discussed.

[Multiplan correction of a 3D deformity. Options and relevance of optimizing the thoracic kyphosis in reconstructive scoliosis surgery]. / Dreidimensionale Korrekturprinzipien einer dreidimensionalen Deformität : Möglichkeiten und Relevanz der operativen Optimierung der Thorakalkyphose in der Skoliosechirurgie.

BACKGROUND: There is presently still no consensus on how to operatively treat adolescent idiopathic scoliosis (AIS), i.e. a clearly reduced thoracic kyphosis. For a long time the primary focus was mostly on correcting the coronal plane while neglecting the sagittal profile. Based on the current literature and own retrospective data a comprehensive review will be given on the optimal correction of the spine and how to avoid secondary complications. Different operative standard procedures are demonstrated with special attention to the sagittal balance and the special parameters sagittal vertical axis (SVA), lumbar lordosis (LL), thoracic kyphosis (TK), pelvic tilt (PT), sagittal slope (SSL) and pelvic incidence (PI). RESULTS: A total of 24 patients (2 groups of 12 patients) with AIS and posterior fusion with (group A) and without (group B) additional osteotomy were analyzed with respect to the impact on spinopelvic balance and health-related quality of life (HRQoL) parameters. Patients in group A had a significant reduction of TK, LL and SSL and an increase in PT whereas patients in group B showed the opposite. Correlation analysis revealed a significant dependence of HRQoL on PT. DISCUSSION: Both the results from the literature and own data confirm that operative correction of AIS needs a careful planning including sagittal spinopelvic parameters. Rigid thoracic hypokyphosis require additional osteotomy.

Cyclosporine-induced autoimmunity. Conditions for expressing disease, requirement for intact thymus, and potency estimates of autoimmune lymphocytes in drug-treated rats.

These studies explore the phenomenon of cyclosporine-induced autoimmunity in irradiated Lewis rats. We show that (a) the presence of a thymus is required, and autoimmune precursors develop in and exit from this organ to the peripheral lymphocyte pool within a 2-wk period after the initiation of cyclosporine treatment; (b) adoptive transfers of drug-induced autoimmunity to irradiated secondary recipients can be accomplished with relatively few cells of the Th subset, and these transfers of autoimmunity can be blocked by cotransfer of normal lymphoid cells; and (c) potency estimates, using popliteal lymph node assays in syngeneic and F1 recipients indicate similar levels of auto- and alloreactivity by cells from drug-induced autoimmune donors. These various findings indicate that this particular animal model may be useful for studies of the onset and control of autoimmunity, and they raise the possibility that the lack of autoimmunity in normal animals and its induction with cyclosporine may involve similar cellular mechanism as have been found to be operative in GVH reactions and specifically induced immunologic resistance to GVHD.

Rat T cell responses to superantigens. II. Allelic differences in V beta 8.2 and V beta 8.5 beta chains determine responsiveness to staphylococcal enterotoxin B and mouse mammary tumor virus-encoded products.

The previous paper in this series demonstrates that rat T cells developing de novo in the presence of mouse mammary tumor virus (Mtv) antigens in rat-->severe combined immunodeficiency (SCID) mouse xenochimeras display a distinct pattern of V beta-restricted deletion; this deletion pattern is remarkably similar to that occurring during thymic development of mouse T cells in Mtv+ strains. In addition, T cells developing in the absence of Mtv antigens in these rat-->mouse xenochimeras are tolerant of host antigens, but show strong primary proliferative responses in cultures stimulated with Mtv-7+ (Mlsa) mouse cells; like the mouse, these rat T cell responses are dominated by V beta 6 and V beta 8 T cells. Here, we continue analysis of rat T cell responses to superantigens; we show that T cells from Lewis and Fischer 344 rats expressing V beta 8.2 display an important all-or-nothing difference in their responses to Mtv-7 superantigens. This all-or-none strain difference in the response to Mtv-7 applies also to the response by V beta 8.2 and V beta 8.5 T cells to the soluble superantigen staphylococcal enterotoxin B. Because these two rat strains express different alleles of these two V beta 8 family members, this finding identifies additional, hitherto unreported residues of the T cell receptor beta chain important in T cell responses to superantigens.

[Collagen hydroxyapatite (Healos) saturated with gentamicin or levofloxacin. In vitro antimicrobial effectiveness - a pilot study]. / Mit Gentamicin oder Levofloxacin gesättigter Kollagenhydroxyapatit (Healos). Antimikrobielle In-vitro-Wirksamkeit - eine Pilotstudie.

BACKGROUND: The functions of synthetic bone graft substitutes include not only structural support to provide bone healing and osseous ingrowth but also the ability to serve as a local antibiotic delivery system to prevent or treat infections of the spine. MATERIAL AND METHODS: The impregnation and antibiotic efficiency of gentamicin and levofloxacin with Healos was investigated in vitro and compared with Healos without an antibiotic additive. These antibiotic-loaded bone graft substitutes were examined without dilution and with 10-fold and 100-fold dilution for activity against spondylodiscitis-causing bacteria on different agar plates using an agar diffusion method. RESULTS: All hydroxyapatite (HA)/collagen-saturated diluted antibiotics showed elliptical inhibition zones on the corresponding agar plates. For both antibiotics, there was a linear correlation between dilution and area of the inhibition zone. CONCLUSION: The analysis showed that the antimicrobial activity of HA/collagen-saturated antibiotics corresponded to the antimicrobial dilutions. These results should be further analyzed using in vivo studies to determine the remaining antibiotic efficiency after implantation of bone graft substitutes.

Bone tissue and plasma concentrations of linezolid and vancomycin in rabbits with prosthesis-related infection due to MRSA.

BACKGROUND: Due to its safety profile and ease of oral administration, linezolid became an alternative to vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of our study was to compare bone tissue and plasma concentrations of linezolid and vancomycin in prosthesis-related MRSA infection in a rabbit model. MATERIAL AND METHODS: During implantation of titanium cylinders into the femurs of nine rabbits, a bacterial suspension of MRSA was added to induce infection. Antibiotic treatment was started eight hours later. Antibiotic concentrations in plasma (day one, three and seven) and bone (day seven) were determined by HPLC analysis. RESULTS: At steady state the mean peak and trough plasma levels of linezolid were 29.0 microg/mL and 8.2 microg/ mL and for vancomycin 39.1 microg/mL and 28.2 microg/mL. On day seven the mean peak concentration of linezolid in plasma was 28.5 microg/mL and after six hours 26.3 microg/mL and for vancomycin 53.8 microg/mL and 29.1 microg/mL after six hours. Vancomycin showed a penetration into the infected bone (femur) of 53% of plasma concentration, into the uninfected 28%, linezolid 11% (for both six hours after administration). CONCLUSION: In conclusion, we observed a higher rate of tissue penetration for vancomycin than for linezolid into femur bone in this animal model. As linezolid offers the option for oral treatment of gram-positive organisms, results of further studies comparing vancomycin and linezolid are keenly awaited.

The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner.

The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.

AMS-100: The Next Generation Magnetic Spectrometer in Space - An International Science Platform for Physics and Astrophysics at Lagrange Point 2.

The next generation magnetic spectrometer in space, AMS-100, is designed to have a geometrical acceptance of 100 m2 sr and to be operated for at least ten years at the Sun-Earth Lagrange Point 2. Compared to existing experiments, it will improve the sensitivity for the observation of new phenomena in cosmic rays, and in particular in cosmic antimatter, by at least a factor of 1000. The magnet design is based on high temperature superconductor tapes, which allow the construction of a thin solenoid with a homogeneous magnetic field of 1 Tesla inside. The inner volume is instrumented with a silicon tracker reaching a maximum detectable rigidity of 100 TV and a calorimeter system that is 70 radiation lengths deep, equivalent to four nuclear interaction lengths, which extends the energy reach for cosmic-ray nuclei up to the PeV scale, i.e. beyond the cosmic-ray knee. Covering most of the sky continuously, AMS-100 will detect high-energy gamma rays in the calorimeter system and by pair conversion in the thin solenoid, reconstructed with excellent angular resolution in the silicon tracker.