[Acute respiratory distress syndrome]. / "Acute respiratory distress syndrome": Diagnostik und Therapie ­ State of the Art.

Acute respiratory distress syndrome (ARDS) is an intensive medical care syndrome, which has a persistently high prevalence as well as high mortality and morbidity. Since the initial description of the syndrome in 1968, the pathophysiology with inflammation after potential triggers, the diagnostics of underlying diseases and causes, the importance of differentiated invasive ventilation and intensive medical care procedures and prognosis are far better researched and understood. The 2012 Berlin ARDS definition takes these advances into account with the aim of bedside identification of patients with ARDS. Avoiding invasive mechanical ventilation when possible, lung protective invasive ventilation when it becomes necessary with adequate positive end-expiratory pressure (PEEP) and reducing barotrauma and atelectatic trauma, managing patient fluid load and positioning treatment remain the most important mechanistic procedures. Causal treatment, apart from treatment of underlying infections, is still not available. Survivors of ARDS very often face relevant long-term sequelae.

[Noninvasive ventilation in acute respiratory insufficiency]. / Nichtinvasive Beatmung zur Behandlung akuter respiratorischer Insuffizienz.

The use of noninvasive ventilation reduces ventilator-associated complications. Thus, the outcome of patients suffering from acute hypercapnic respiratory insufficiency as well as cardiogenic lung edema can be improved. For the use of noninvasive ventilation to be successful and safe, its correct application is pivotal.

[Interventional radiological therapies in lung oncology]. / Interventionell-radiologische Therapien in der pneumologischen Onkologie.

Interventional radiological procedures for the treatment of primary and secondary pulmonary malignancies have become increasingly important. In addition to thermally ablative treatment, selective chemoembolisation by a vascular access allows localised therapy. These treatments are considered to be palliative for patients in a reduced general condition which does not allow systemic chemotherapy. In functionally inoperable patients especially the ablative procedures are potentially curative alternatives to surgery. This article provides an overview of the currently used interventional radiological procedures in lung oncology and assesses their importance. Further studies are needed to show whether interventional radiological procedures, which are promising due to their favourable risk-benefit ratio, may represent an alternative to radiotherapy or be effective in multimodal approaches.

Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells.

BACKGROUND: Interleukin (IL)-31 is a novel Th2 T-cell cytokine that induces pruritus and dermatitis in transgenic mice. While enhanced mRNA expression of this cytokine is detected in skin samples of inflammatory skin diseases, the regulation of IL-31 expression is poorly understood. OBJECTIVES: To assess the effects of ultraviolet (UV) B radiation and H2O2 on IL-31 mRNA and protein expression in skin and different peripheral blood mononuclear cells (PBMCs). METHODS: The effects of UVB radiation and H2O2, as a prototypic reactive oxygen species, on IL-31 mRNA and protein expression were analysed in various inflammation-related cells and murine skin tissue. RESULTSTreatment of cells with UVB radiation and H2 O2 strongly induced IL-31 mRNA and protein expression in human PBMCs and in the skin of SKH-1 mice. Following exposure to UVB or H2O2, we observed increased expression of IL-31 mRNA in T cells, monocytes, macrophages, and immature and especially mature dendritic cells. H2O2 treatment but not UVB radiation led to a moderate upregulation of IL-31 mRNA expression in epidermal keratinocytes and dermal fibroblasts. Pretreatment of T lymphocytes with the MAPK p38 inhibitor SB203580 or the MEK1 inhibitor U0126 reduced the stimulatory effect of H2O2. These experiments suggest that p38 is involved in the regulation of IL-31 expression in human skin. CONCLUSIONS: Our studies reveal that UVB and reactive oxygen species stimulate the expression of IL-31 in PBMCs and skin, especially in T cells, monocytes and monocyte-derived dendritic cells.

[Pulmonary necrotizing sarcoid granulomatosis in a patient with primary biliary cirrhosis]. / Nekrotisierende sarkoidale Granulomatose der Lunge bei einer Patientin mit primärer biliärer Leberzirrhose.

HISTORY AND ADMISSION FINDINGS: A 53-year-old woman presented with recurrent episodes of cough and non-specific pulmonary symptoms. For many years she had been known to have primary biliary cirrhosis. INVESTIGATIONS: The chest X-ray showed multiple pulmonary nodules. Microbiological examination did not detect any pathogen and transbronchial biopsy of the pulmonary nodules failed to provide a diagnosis. Histology of a surgical lung biopsy showed interstitial inflammation, vasculitis and non-caseating granulomas. TREATMENT AND COURSE: The findings indicated necrotizing sarcoid granulomatosis. During oral corticoid therapy the pulmonary nodules regressed within a few weeks. The patient has remained free of pulmonary symptoms. CONCLUSION: Pulmonary necrotizing sarcoid granulomatosis is a rare condition to consider in the differential diagnosis of pulmonary nodules. Because of the histological findings and its benign course it resembles sarcoidosis.

Identification and characterization of gonococcal iron transport systems as potential vaccine antigens.

Gonorrhea is the second most commonly reported infectious disease in the USA, and incidence has been increasing in recent years. Antibiotic resistance among clinical isolates has reached a critical point at which the CDC currently recommends only a single class of antibiotic for treatment. These developments have hastened the search for a vaccine to protect against gonococcal infections. Vaccine efforts have been thwarted by the ability of the gonococcus to antigenically vary most surface structures. The transferrin-iron transport system is not subject to high-frequency phase or antigenic variation and is expressed by all pathogenic Neisseria. Vaccine formulations comprised of epitopes of the transferrin-binding proteins complexed with inactivated cholera toxin generated antibodies with potentially protective characteristics. These antigens, and others predicted from genome sequence data, could be developed into a vaccine that protects against neisserial infections.

ANALYSIS OF BAROREFLEX FUNCTION BY MEANS OF MATHEMATICAL MODEL.

Re-evaluation of all functions of baroreflex by means of a simple mathematical model of circulation was the aim of the present study. The following states are modelled: 1. Rest. 2. Immediately after baroreceptor denervation. 3. Several days after denervation. 4. Physical exercise before denervation. 5. Physical exercise several days after denervation. Despite the same cardiac contractility and the same vasodilatation in working muscles as before denervation the cardiac output is by one third lower after baroreceptor denervation. In conclusion, a model simulation revealed the common regulation of blood pressure and blood volume by baroreflex and kidneys as a primary function of baroreflex.

Gonococcal genes encoding transferrin-binding proteins A and B are arranged in a bicistronic operon but are subject to differential expression.

Neisseria gonorrhoeae is capable of utilizing host iron-binding proteins, such as transferrin, lactoferrin, and hemoglobin, as the sole source of iron. The receptor involved in transferrin iron acquisition is composed of two distinct transferrin-binding proteins, TbpA and TbpB. The genes that encode these proteins are linked on the chromosome in the order tbpB-tbpA but are separated by an inverted repeat of unknown function. In this study, we sought to understand the transcriptional organization and regulation of the tbp genes, using a combination of lacZ transcriptional fusion analysis and reverse transcriptase PCR (RT-PCR). First, we demonstrated that tbpB and tbpA are cotranscribed and coregulated from the common upstream promoter that precedes tbpB. Using beta-galactosidase activity as a surrogate for tbp-specific transcription, we found that tbpB-specific transcripts were more prevalent than tbpA-specific transcripts after 2 h of growth under iron stress conditions. We confirmed the results obtained by fusion analysis by using RT-PCR applied to native RNA isolated from wild-type gonococci. Three different varieties of RT-PCR were employed: relative, competitive, and real time quantitative. The results of all analyses indicated that tbpB-specific transcripts were approximately twofold more prevalent than tbpA-specific transcripts at steady state. In iron-stressed cultures, the ratio of tbpB- to tbpA-specific message was approximately 2; however, in iron-replete cultures, this ratio dropped to 1. Using these techniques, we also quantitated the effects of iron, external pH, and presence of ligand on tbp mRNA levels.

Identification of discrete domains within gonococcal transferrin-binding protein A that are necessary for ligand binding and iron uptake functions.

The availability of free iron in vivo is strictly limited, in part by the iron-binding protein transferrin. The pathogenic Neisseria spp. can sequester iron from this protein, dependent upon two iron-repressible, transferrin-binding proteins (TbpA and TbpB). TbpA is a TonB-dependent, integral, outer membrane protein that may form a beta-barrel exposing multiple surface loops, some of which are likely to contain ligand-binding motifs. In this study we propose a topological model of gonococcal TbpA and then test some of the hypotheses set forth by the model by individually deleting three putative loops (designated loops 4, 5, and 8). Each mutant TbpA could be expressed without toxicity and was surface exposed as assessed by immunoblotting, transferrin binding, and protease accessibility. Deletion of loop 4 or loop 5 abolished transferrin binding to whole cells in solid- and liquid-phase assays, while deletion of loop 8 decreased the affinity of the receptor for transferrin without affecting the copy number. Strains expressing any of the three mutated TbpAs were incapable of growth on transferrin as a sole iron source. These data implicate putative loops 4 and 5 as critical determinants for receptor function and transferrin-iron uptake by gonococcal TbpA. The phenotype of the DeltaL8TbpA mutant suggests that high-affinity ligand interaction is required for transferrin-iron internalization.

Antigenic and sequence diversity in gonococcal transferrin-binding protein A.

Neisseria gonorrhoeae is a gram-negative pathogen that is capable of satisfying its iron requirement with human iron-binding proteins such as transferrin and lactoferrin. Transferrin-iron utilization involves specific binding of human transferrin at the cell surface to what is believed to be a complex of two iron-regulated, transferrin-binding proteins, TbpA and TbpB. The genes encoding these proteins have been cloned and sequenced from a number of pathogenic, gram-negative bacteria. In the current study, we sequenced four additional tbpA genes from other N. gonorrhoeae strains to begin to assess the sequence diversity among gonococci. We compared these sequences to those from other pathogenic bacteria to identify conserved regions that might be important for the structure and function of these receptors. We generated polyclonal mouse sera against synthetic peptides deduced from the TbpA sequence from gonococcal strain FA19. Most of these synthetic peptides were predicted to correspond to surface-exposed regions of TbpA. We found that, while most reacted with denatured TbpA in Western blots, only one antipeptide serum reacted with native TbpA in the context of intact gonococci, consistent with surface exposure of the peptide to which this serum was raised. In addition, we evaluated a panel of gonococcal strains for antigenic diversity using these antipeptide sera.

Identification and functional characterization of the Neisseria gonorrhoeae lbpB gene product.

We cloned lbpB, encoding a predicted 80-kDa lipoprotein, upstream of lbpA. A nonpolar mutant (LbpB- LbpA+) had normal lactoferrin (LF) binding and grew normally with LF as an iron source, whereas LbpB- LbpA- and LbpB+ LbpA- strains had reduced binding of LF and did not grow with LF as an iron source. LbpB bound LF directly in an affinity purification, suggesting that LbpB might play a still-uncharacterized role in the LF iron utilization.

The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers.

Iron, an essential nutrient for most microorganisms, is sequestered by the host to decrease the concentration of iron available to bacterial pathogens. Neisseria gonorrhoeae, the causative agent of gonorrhoea, can acquire iron by direct interaction with human iron-binding proteins, including the serum glycoprotein, transferrin. Iron internalization from host transferrin requires the expression of a bacterial receptor, which specifically recognizes the human form of transferrin. Two gonococcal transferrin-binding proteins have been implicated in transferrin receptor function, TbpA and TbpB. We constructed a gonococcal transferrin receptor mutant without the introduction of additional antibiotic resistance markers and tested its ability to cause experimental urethritis in human male volunteers. The transferrin receptor mutant was incapable of initiating urethritis, although the same inoculum size of the wild-type parent strain, FA1090, causes urethritis in >90% of inoculated volunteers. To our knowledge, this is the first experimental demonstration that a bacterial iron acquisition system is an essential virulence factor for human infection.

Characterization of the diversity and the transferrin-binding domain of gonococcal transferrin-binding protein 2.

The molecular weight heterogeneities of Tbp1 and Tbp2 among a panel of 45 gonococcal isolates were assessed. The tbpB genes from four of these strains were sequenced to characterize the Tbp2 sequence diversity among gonococci. By expressing truncated versions of gonococcal Tbp2, we delimited the extent of Tbp2 necessary for transferrin binding in a Western blot.

Energy-dependent changes in the gonococcal transferrin receptor.

The pathogenic Neisseria spp. are capable of iron utilization from host iron-binding proteins including transferrin and lactoferrin. Transferrin iron utilization is an energy-dependent, receptor-mediated event in which two identified transferrin-binding proteins participate. One of these proteins, TbpA, is homologous to the TonB-dependent family of outer membrane receptors that are required for high-affinity uptake of vitamin B12 and ferric siderophores. The 'TonB box' is a conserved domain near the amino-terminus of these proteins that has been implicated in interaction with TonB. Interaction between a periplasmic domain of TonB and the TonB box allows energy transduction to occur from the cytoplasmic membrane to the energy-dependent receptor in the outer membrane. We created a TonB box mutant of gonococcal TbpA and demonstrated that its binding and protease accessibility characteristics were indistinguishable from those of gonococcal Ton system mutants. The protease exposure of the second transferrin-binding protein, TbpB, was affected by the energization of TbpA, consistent with an interaction between these proteins. TbpB expressed by the de-energized mutants was readily accessible to protease, similar to TbpB expressed in the absence of TbpA. The de-energized mutants exhibited a marked decrease in transferrin diffusion rate, suggesting that receptor energization was necessary for ligand release. We propose a model to explain the observed Ton-dependent changes in the binding parameters and exposures of TbpA and TbpB.

Binding and surface exposure characteristics of the gonococcal transferrin receptor are dependent on both transferrin-binding proteins.

Neisseria gonorrhoeae is capable of iron utilization from human transferrin in a receptor-mediated event. Transferrin-binding protein 1 (Tbp1) and Tbp2 have been implicated in transferrin receptor function, but their specific roles in transferrin binding and transferrin iron utilization have not yet been defined. We utilized specific gonococcal mutants lacking Tbp1 or Tbp2 to assess the relative transferrin-binding properties of each protein independently of the other. The apparent affinities of the wild-type transferrin receptor and of Tbp1 and Tbp2 individually were much higher than previously estimated for the gonococcal receptor and similar to the estimates for the mammalian transferrin receptor. The binding parameters of both of the mutants were distinct from those of the parent, which expressed two transferrin-binding sites. Tbp2 discriminated between ferrated transferrin and apotransferrin, while Tbp1 did not. Results of transferrin-binding affinity purification, and protease accessibility experiments were consistent with the hypothesis that Tbp1 and Tbp2 interact in the wild-type strain, although both proteins were capable of binding to transferrin independently when separated in the mutants. The presence of Tbp1 partially protected Tbp2 from trypsin proteolysis, and Tbp2 also protected Tbp1 from trypsin exposure. Addition of transferrin to wild-type but not mutant cells protected Tbp1 from trypsin but increased the trypsin susceptibility of Tbp2. These observations indicate that Tbp1 and Tbp2 function together in the wild-type strain to evoke binding conformations that are distinct from those expressed by the mutants lacking either protein.