Conservative management of distal leg necrosis in lung transplant recipients.

Critical limb ischemia (CLI) with distal leg necrosis in lung transplant recipients (LTR) is associated with a high risk for systemic infection and sepsis. Optimal management of CLI has not been defined so far in LTR. In immunocompetent individuals with leg necrosis, surgical amputation would be indicated and standard care. We report on the outcome of four conservatively managed LTR with distal leg necrosis due to peripheral arterial disease (PAD) with medial calcification of the distal limb vessels. Time interval from lung transplantation to CLI ranged from four years (n = 1) to more than a decade (n = 3). In all cases a multimodal therapy with heparin, acetylsalicylic acid, iloprost and antibiotic therapy was performed, in addition to a trial of catheter-based revascularization. Surgical amputation of necrosis was not undertaken due to fear of wound healing difficulties under long-term immunosuppression and impaired tissue perfusion. Intensive wound care and selective debridement were performed. Two patients developed progressive gangrene followed by auto-amputation during a follow-up of 43 and 49 months with continued ambulation and two patients died of unrelated causes 9 and 12 months after diagnosis of CLI. In conclusion, we report a conservative treatment strategy for distal leg necrosis in LTR without surgical amputation and recommend this approach based on our experience.

[Non-cystic fibrosis bronchiectasis: diagnosis and treatment]. / Non-CF-Bronchiektasen: Diagnostik und Therapie.

Bronchiectasis is the term used for irreversibly dilated airways. Exact epidemiological information on the frequency of bronchiectasis is not available, but the morphological findings are increasingly detected and the associated syndrome is more frequently diagnosed due to improved imaging techniques and increased awareness among chest physicians. The workup of these patients includes a wide panel of investigations guided by patient history and clinical presentation. Despite thorough evaluation the aetiology frequently remains unclear. Chronic infection with Pseudomonas aeruginosa is associated with a severe course of the disease and its detection has impacts on the therapeutic management. Chest physiotherapy, mucoactive substances and antibiotics are the mainstay of therapy. In this review the evaluation of bronchiectasis and the recent therapeutic insights for non-cystic fibrosis bronchiectasis are discussed.

[Role of pretherapeutic biomarkers in lung cancer with special regards to bronchoscopic procedures]. / Prätherapeutische Biomarker des Lungenkarzinoms unter besonderer Berücksichtigung der Bronchoskopie.

Molecular biomarkers are becoming increasingly significant in the workup of lung carcinoma patients. They assist in diagnosis, selecting the most adequate therapy and determining prognosis. Obtaining blood based biomarkers or volatile markers in exhaled breath may provide a less invasive method in the future. For the time being, bronchoscopy is still the method of choice to obtain specimen and assess tissue based biomarkers. The techniques how specimen are collected and processed for analysis are of paramount importance.

[Pulmonary hypertension: microRNAs in pathogenesis, diagnosis and therapy]. / Pulmonale Hypertonie: mikroRNAs in Pathogenese, Diagnostik und Therapie.

Whereas pulmonary arterial hypertension is an orphan disease, the term pulmonary hypertension includes several common entities and is of major clinical significance. The pathophysiological triad of vasoconstriction, microthrombosis and vascular remodeling is found in most forms of pulmonary hypertension, independently of the underlying etiology. In this review, novel aspects in the pathogenesis of the remodeling, in particular microRNAs, will be discussed. MicroRNAs are small RNA fragments which bind specifically to the mRNA of a target gene thus decreasing its stability or inhibiting further translation ("gene silencing"). Of major interest is the association between microRNAs and the expression of bone morphogenetic protein receptor type II which has been found to be dysregulated on pulmonary endothelial and vascular smooth muscle cells in several forms of pulmonary hypertension. The specific inhibition of microRNAs by antagomiRs makes microRNAs a potential therapeutic target. Moreover, microRNAs are being validated in serum as biomarkers for diagnosis, severity and prognosis of pulmonary hypertension.

[A 76-year-old female patient with deep venous thrombosis and cervical lymphadenopathy]. / 76-jährige Patientin mit tiefer Beinvenenthrombose und zervikaler Lymphadenopathie.

We report the case of a 76-year-old female patient presenting with deep venous thrombosis and upper cervical lymphadenopathy. A computed tomography (CT) scan showed multiple hepatic lesions with a high suspicion of metastatic disease from an unknown primary tumor. The differential diagnosis of lymphadenopathy and hepatic lesions includes malignant tumors and various infectious diseases. The diagnostic process, however, revealed lymph node tuberculosis with multiple hepatic granulomas despite a repeatedly negative interferon-γ release assay. A combined antituberculosis therapy led to complete clinical remission.

[The medical emergency department in a Swiss regional hospital: the important role of generalists]. / Die medizinische Notfallstation in der Schweiz am Beispiel des Spitals Lachen: Die entscheidende Rolle der Generalisten.

Patients not having a general practitioner will more likely use the emergency departments (ED) of hospitals for primary care. Crowding of the ED due to patients with minor health problems is a growing burden. The present work was aimed to analyze data of ED consultations at a Swiss regional hospital. Leading diagnoses of ED consultations covered a broad spectrum of internal medicine. The majority of patients seen in the ED are «walk-in¼ patients with minor problems that after initial evaluation and treatment in the ED could be managed as outpatients. Pediatric patients made a considerable part of the workload. Elderly patients (>65 years) were hospitalized more often.

Effects of a novel tyrosine kinase inhibitor in rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: Biologicals have revolutionised the treatment of rheumatoid arthritis (RA). However, progressive joint destruction can still be observed in many patients and the search for novel molecular therapies targeting specific signalling pathways is ongoing. In the present study, we investigated the effects of GW282974, a novel compound directed against tyrosine kinase activity with respect to the potential suppression of inflammation and destruction. METHODS: Synovial tissue specimens were obtained from RA patients undergoing surgical joint replacement. Rheumatoid arthritis synovial fibroblasts (RASFs) were stimulated with cytokines and GW282974 was added in different concentrations. Gene expression was checked by TaqMan PCR, using 18S as housekeeping gene. Protein analysis was quantified by ELISA. Cell growth and proliferation was measured using the "ViaLight" proliferation assay. RESULTS: EGF had no effect on the gene expression profile of RASFs when used as single stimulatory agent. In combination with pro-inflammatory mediators however, EGF showed a synergistic effect. The expression of matrix metalloproteinases, inflammatory cytokines and cyclooxygenase-2 on mRNA levels was strongly increased, whereas the addition of GW282974 abrogated these effects in a dose-dependent manner. These data could be confirmed on protein/lipid levels analysing the supernatants of RASFs by ELISA. Similarly, cell growth and proliferation of RASFs were inhibited by GW282974 in a dose- and time-dependent manner. By contrast, no cytotoxic effects were seen within the concentrations used. DISCUSSION: GW282974 appears to interfere with the inflammatory and the destructive pathways in RASFs and might therefore be used as novel therapeutic strategy for the treatment of RA.

Synovial fibroblasts: key players in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that primarily affects the joints and ultimately leads to their destruction. The involvement of immune cells is a general hallmark of autoimmune-related disorders. In this regard, macrophages, T cells and their respective cytokines play a pivotal role in RA. However, the notion that RA is a primarily T-cell-dependent disease has been strongly challenged during recent years. Rather, it has been understood that resident, fibroblast-like cells contribute significantly to the perpetuation of disease, and that they may even play a role in its initiation. These rheumatoid arthritis synovial fibroblasts (RASFs) constitute a quite unique cell type that distinguishes RA from other inflammatory conditions of the joints. A number of studies have demonstrated that RASFs show alterations in morphology and behaviour, including molecular changes in signalling cascades, apoptosis responses and in the expression of adhesion molecules as well as matrix-degrading enzymes. These changes appear to reflect a stable activation of RASFs, which occurs independently of continuous exogenous stimulation. As a consequence, RASFs are no longer considered passive bystanders but active players in the complex intercellular network of RA.

The release of microparticles by apoptotic cells and their effects on macrophages.

Microparticles are small membrane vesicles released from the cell membrane by exogenous budding. To elucidate the interactions of microparticles with macrophages, the effect of microparticles released from Jurkat T cells on RAW 264.7 cells was determined. Microparticles were isolated by differential centrifugation, using FACS analysis with annexin V and cell surface markers for identification. Various inducers of apoptosis increased the release of microparticles from Jurkat cells up to 5-fold. The released microparticles were then cultured with RAW 264.7 cells. As shown by confocal microscopy and FACS analysis, RAW 264.7 macrophages cleared microparticles by phagocytosis. In addition, microparticles induced apoptosis in RAW 264.7 cells in a dose-dependent manner with up to a 5-fold increase of annexin V positive cells and 9-fold increase in caspase 3 activity. Cell proliferation as determined by the MTT test was also reduced. Furthermore, microparticles stimulated the release of microparticles from macrophages. These effects were specific for macrophages, since no apoptosis was observed in NIH 3T3 and L929 cells. These findings indicate that microparticles can induce macrophages to undergo apoptosis, in turn resulting in a further increase of microparticles. The release of microparticles from apoptotic cells may therefore represent a novel amplification loop of cell death.