The wingless-related integration site-5a/secreted frizzled-related protein-5 system is dysregulated in human sepsis.

Sepsis and type 2 diabetes exhibit insulin resistance as a common phenotype. In type 2 diabetes we and others have recently provided evidence that alterations of the proinflammatory wingless-related integration site (wnt)-5a/anti-inflammatory secreted frizzled-related protein (sFRP)-5 system are involved in the pathogenesis of insulin resistance. The aim of the present study was to investigate whether this novel cytokine system is dysregulated in human sepsis, which may indicate a potential mechanism linking inflammation to metabolism. In this single-centre prospective observational study, critically ill adult septic patients were examined and proinflammatory wnt5a and wnt5a inhibitor sFRP5 were measured in serum samples by enzyme-linked immunosorbent assay (ELISA) at admission to the intensive care unit (ICU) and 5 days later. Sixty sepsis patients were included, and 30 healthy individuals served as controls. Wnt5a levels were found to be increased significantly in septic patients compared to healthy controls (2·21 ± 0·33 versus 0·32 ± 0·03 ng/ml, P < 0·0001). In contrast, sFRP5 was not altered significantly in septic patients (19·72 ± 3·06 versus 17·48 ± 6·38 ng/ml, P = 0·07). On admission to the ICU, wnt5a levels exhibited a significant positive correlation with the leucocyte count (rs = 0·3797, P = 0·004). Interestingly, in patients recovering from sepsis, wnt5a levels declined significantly within 5 days (2·17 ± 0·38-1·03 ± 0·28 ng/ml, P < 0·01). In contrast, if sepsis was worsening, wnt5a levels increased in the same time-period by trend (2·34 ± 0·59-3·25 ± 1·02 ng/ml, P > 0·05). sFRP5 levels did not change significantly throughout the study period. The wnt5a/sFRP5 system is altered in human sepsis and might therefore be of interest for future studies on molecular pathophysiology of this common human disease.

[Mothers with cystic fibrosis: psychosocial data about an almost unknown group]. / Mütter mit Mukoviszidose: Ergebnisse einer Befragung einer nahezu unbekannten Patientengruppe.

AIMS: To explore pregnancy and motherhood in cystic fibrosis patients from the women's perspective. METHODS: Data were assessed with a purpose designed questionnaire and the paper focuses on the following sections: "pregnancy and birth" (feedback of significant others, women's knowledge, concerns, and overall judgement), and the "first year as a mother" (overall judgement). SAMPLE: 38/73 mothers filled in the questionnaire; mean age was 33.8 y ±â€Š7.1 y and mean age of firstborn child was 6.9 y ±â€Š5.7 years. Nine women had more than one biological child. 18 mothers (47 %) were currently employed, 12 of whom with 19 to 30 hours per week and none full-time. Mean FEV1 in perc. Pred. was 66 ±â€Š19 %. RESULTS: Pregnancy in CF should be planned and prepared, and this was achieved in 28 women, while 10 pregnancies were unplanned. The feedback of significant others towards wish for child/pregnancy was more positive in those who planned. Mothers' own parents reacted least enthusiastic, irrespective of whether or not pregnancy had been planned. The feedback of CF-teams differed according to women's lung function. The women's knowledge about "pregnancy and CF" was rather poor. Their concerns predominantly referred to detrimental effects of CF medication to the unborn child. CONCLUSIONS: Motherhood is increasingly becoming an option for young women with CF. Therefore, CF-teams are well-advised to proactively engage them in a dialogue about wish for child and impact of CF on motherhood. Knowledge about pregnancy/motherhood and CF should be increased.

Perceived Impact of Motherhood on Adherence to Therapy in Mothers with Cystic Fibrosis.

AIM: To explore the stress related to motherhood and its perceived impact on adherence to therapy in women with cystic fibrosis (CF). METHODS: Cross-sectional study with a purpose-designed questionnaire. SAMPLE: 46/73 eligible women were enrolled and 38 returned the questionnaire. Mean age of mothers was 33.8 y  ±â€Š7.1 y, mean age of firstborn child was 6.9 y  ±â€Š5.7 y. Nine women had more than one biological child. 18 mothers (47%) were currently employed, 12 of whom worked 19 to 30 hours per week and none full-time. RESULTS: There were mothers who reported a detrimental effect on adherence (time constraints 38%; intentional nonadherence 42%), and mothers who reported that adherence had actually improved (29%). Both of these effects were related to daily CF therapy at home. By contrast, i. v. antibiotic therapy was less impaired by role strains, mainly due to home i. v. therapy being an alternative and/or due to intensive social support (husband, parents). Participants clearly addressed the importance of adherence and the need for adequate self-management in narrative comments. CONCLUSION: Motherhood may improve adherence to CF therapy as well as it may affect it negatively. Health caregivers are well-advised to address a possible detrimental effect, proactively.

[Pulmonary emergencies in connective tissues disorders and vasculitides]. / Pneumologische Notfälle bei Kollagenosen und Vaskulitiden.

Pulmonary emergencies in rheumatic diseases are rare, potentially life-threatening conditions that occur either as a manifestation of the disease itself or as an adverse event of immunosuppressive treatment. Diffuse alveolar hemorrhage, tracheal stenosis, acute pneumonitis and drug-induced lung injury belong to this category. The management of these emergencies requires intensive cooperation between rheumatology and pulmonology. The latter contributes its experience in the care of related conditions, specific endoscopic techniques and local interventions as well as the indispensable and life-supporting forms of assisted ventilation. The present article summarizes the current knowledge on diagnostic and therapeutic procedures including the newly available B-cell directed treatments.

[ECMO treatment in acute lung failure : Who profits?] / ECMO-Therapie beim akuten Lungenversagen : Wer profitiert?

In intensive care medicine, rapid technical developments that are often beneficial to patients are taking place. On the other hand, there are also voices that generally criticize an increasing "interventionalism". This area of tension includes other important questions regarding usefulness, quality, ethical compliance, scientific evidence, structural capacities and economy. The treatment of acute respiratory distress syndrome (ARDS) using extracorporeal membrane oxygenation (ECMO) is an example of these considerations. Although ECMO has rarely been prospectively evaluated according to scientific criteria, it is still used with an increasing tendency, not least since the documented register survival rates in ECMO patients with severe ARDS are 60%. However, the implementation of this therapy means an immense effort. The necessary centralization and certification for ECMO treatment is currently under intensive discussion. Closely related to this are considerations about which criteria represent good quality in patient care. In order to be able to guarantee high quality, a precise indication is the first step. And here indications and contraindications still need to be defined. It has not yet been sufficiently clarified which prognosis factors need to be taken into account. This article summarizes what is known about ECMO prognosis and indication criteria. In conclusion, parameters are identified that should be developed scientifically in the future.

Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes.

Immunosenescence is characterized by a quantitative decline of adequate immune responses, which renders the elderly individual particularly susceptible to bacterial, viral and fungal pathogens. Whereas changes of the aging adaptive immune system (for example, reduced immunoglobulin secretion) have been extensively characterized, alterations of the innate immune system are still poorly understood. The aim of the present study was to systematically examine mRNA expression levels of innate immune genes and proinflammatory cytokines in peripheral and intestinal leukocytes of subjects of different ages. In both, whole blood samples and in colonic biopsies most of the Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain-like receptors (NLRs) transcript levels were significantly downregulated in elderly subjects (90-99 years). Older individuals, when compared to the younger, exhibited an increased expression and/or secretion of proinflammatory cytokines by peripheral and intestinal leukocytes as well as an increased level of nuclear factor-kappaB activation in colonic biopsies. The observed downregulation of TLRs and NLRs during the aging process may contribute to the lack of effective recognition of invading pathogens or the commensal flora. This effect results in aberrant secondary immune cell activation and could significantly contribute to morbidity and mortality at advanced age.

Fatal pneumocystis jirovecii pneumonia in a case of ectopic Cushing's syndrome due to neuroendocrine carcinoma of the kidney.

Immunosuppression with subsequent opportunistic infections is a well-recognized complication of severe hypercortisolism. We report a case of fatal pneumocystis jirovecii pneumonia (formerly pneumocystis carinii pneumonia) in a case of ectopic Cushing's syndrome caused by a neuroendocrine carcinoma of the kidney. The 36-year old male patient had consulted a physician because of weight gain. Further endocrine diagnostic work-up revealed ACTH-dependent hypercortisolism of non-pituitary origin. Because of rapid clinical deterioration therapy with metyrapone was initiated. A neuroendocrine carcinoma of the right kidney with regional lymph node infiltration was identified and was suspected to be the source of the ACTH excess. Before any causal therapy could be initiated, the patient developed severe pneumocystis jirovecii pneumonia and died shortly thereafter from multiorgan failure one month after he first consulted a physician. Pneumocystosis has been reported in only a few cases of Cushing's syndrome. There seems to be a relationship between the degree of hypercortisolism and the susceptibility to opportunistic infections. Since ACTH concentrations may be excessively high in ectopic Cushing's syndrome and pneumocystosis may deteriorate as a consequence of decreasing circulating cortisol levels under adrenolytic therapy, prophylaxis against pneumocystis jirovecii infection should be considered.

Fast T1- and T2-weighted pulmonary MR-imaging in patients with bronchial carcinoma.

PURPOSE: A prospective study to evaluate the diagnostic potential and limitations of three fast MRI sequences in patients with bronchial carcinoma based on the comparison with spiral CT. MATERIAL AND METHODS: Three fast chest MRI sequences from 20 patients with central or peripheral bronchial carcinoma were evaluated by two observers for relation of tumour to adjacent structures, lymph node enlargement, additional pulmonary lesions and artefacts. The information from MR-imaging was compared with the results from spiral CT. MRI comprised a T1-3D-GRE breath-hold examination ("VIBE", TR/TE 4.5/1.9 ms, flip-angle 12 degrees , matrix 502 x 512, 2.5 mm coronal slices), a breath-hold, T2-HASTE sequence (TR/TE 2000/43 ms, matrix 192 x 256, 10 mm coronal slices) and a respiration-triggered T2-TSE sequence (TR/TE 3000-6000/120 ms, matrix 270 x 512, 6 mm transverse slices). The FOV was adapted individually (380-480 mm). RESULTS: The presence of the primary bronchial carcinoma and infiltration of thoracic structures by tumour tissue could be demonstrated by all sequences. VIBE sequence was more suitable for detecting small pulmonary nodules than the other MRI examinations, but compared to CT still 20% of these lesions were missed. Contrary to VIBE and T2-weighted TSE scans, HASTE sequence was limited in imaging mediastinal lymph nodes due to missing relevant findings in 2/20 patients. HASTE images significantly provided the lowest rate of artefacts in imaging lung parenchyma (P < 0.001 in peripheral parenchyma), but spatial resolution was limited in this sequence. Concerning the differentiation between tumour and adjacent atelectasis (n = 8), T2-weighted TSE imaging was superior to CT and VIBE in all cases and to HASTE sequence in 4/8 patients. CONCLUSION: The combination of VIBE and HASTE sequence allows for an adaequate imaging of thoracic processes in patients with bronchial carcinoma, limited only in visualizing small pulmonary nodules. To obtain more detail resolution and to differentiate tumour tissue from adjacent atelectasis, T2-TSE examination may be added in selected cases.

Symptoms and signs of an acute myocardial ischemia caused by chemotherapy with Paclitaxel (Taxol) in a patient with metastatic ovarian carcinoma.

INTRODUCTION: Paclitaxel (Taxol) is an anticancer agent used for the treatment of breast and ovarian cancer. The major side effects are bone marrow suppression, alopecia, polyneuropathy and cardiac toxicity like bradycardia, myocardial infarction, congestive heart failure and cardiac death. SETTING: Intensive care unit (ICU) of a university hospital. PATIENT: We report on a 58-years-old woman with a metastatic ovarian carcinoma who had chest pain, nausea and collapse during their first Taxol infusion. The infusion was stopped and the patient was submitted to the intensive care unit (ICU) to exclude an acute coronary syndrome. RESULTS: The electrocardiography (ECG) showed a third-degree heart block and ST elevation in II, III and avF. In the initial and in the control laboratory investigation values of cardiac enzymes (creatininkinase and Troponine T) remained normal. The control ECG after 30 minutes turned back to normal. After one day the patient was submitted back to a normal ward. CONCLUSION: Symptomatic bradyarrhythmia and clinical sign of an myocardial infarction are rare but important cardiac side effects in patients treated with Taxol. Those patients should be under intensive care unit until patients conditions improve and acute myocardial ischemia has been excluded.

In vitro and in vivo transfer and expression of human surfactant SP-A- and SP-B-associated protein cDNAs mediated by replication-deficient, recombinant adenoviral vectors.

Congenital pulmonary alveolar proteinosis (CPAP) is a fatal disease of full-term infants that is unresponsive to current medical therapy. It is now recognized that at least some forms of this disorder are associated with a deficiency of SP-B, one of the surfactant-associated proteins, as well as probable aberrations in the surfactant-associated proteins SP-A and SP-C. Given these developments, it is logical to hypothesize that CPAP may be amenable to gene therapy, in which the human SP-B cDNA, and possibly the cDNAs of the other surfactant associated proteins, are transferred to the epithelium of the lower respiratory tract. We constructed replication-deficient, recombinant adenovirus vectors in which a constitutive viral promoter drives the expression of the DNAs for the surfactant-associated proteins, SP-B (AdCMV.SP-B) and SP-A (AdCMV.SP-A). Following infection of the human lung A549 epithelial cell line with these vectors in vitro, the appropriately sized mRNAs for these cDNAs were detected, whereas cells infected with a control virus or uninfected cells produced none. Western blots demonstrated expression of these proteins, including appropriate processing of the hydrophobic protein, SP-B. Following in vivo intratracheal infection of rats with these vectors, Northern analysis of the lungs revealed appropriately sized mRNAs for these cDNAs whereas rats infected with control virus or uninfected rats show no hybridization with the human surfactant-associated protein probes. In the AdCM-V.SP-A-infected rats, Western blots confirmed the overproduction of the human SP-A protein in both the bronchoalveolar lavage and lung homogenates compared to controls. Thus, it is feasible to utilize adenovirus vectors to transfer and express the human surfactant associated protein cDNAs in vitro and in vivo, presenting a possible mode of therapy for CPAP, as well as other surfactant deficiency states such as the neonatal respiratory distress syndrome and possibly the adult respiratory distress syndrome.

Modulation of fibroblast activity in histiocytosis X by platelet-derived growth factor.

Platelet-derived growth factor (PDGF) was shown to modulate fibroblast activity in interstitial lung diseases like idiopathic pulmonary fibrosis (IPF). The role of PDGF in fibrosing mechanisms in histiocytosis X is unclear. Eight patients with histiocytosis X, five patients with idiopathic pulmonary fibrosis (IPF), and nine patients with no evidence of interstitial lung disease underwent bronchoalveolar lavage (BAL). The c-sis gene (a proto-oncogen encoding for the B-chain of PDGF) expression was measured by gene hybridization revealing an upregulated c-sis transcript in the group of histiocytosis X and patients, whereas no c-sis expression was detectable in the control group. The alveolar macrophage supernatants from histiocytosis X patients and from the control group were incubated with a human lung fibroblast cell line (WI-38). The mitosis rate was measured by tritiated thymidine incorporation and collagen production was estimated by determining the procollagen III peptide concentration in fibroblast supernatants. Tritiated thymidine uptake was increased 1.6 times in histiocytosis X compared with the control group (p < 0.01). Procollagen-III-peptide levels in fibroblast supernatants after incubation with alveolar macrophage supernatants from histiocytosis X were elevated 2.5 times compared with the control group (p < 0.01). Prior to incubation with the WI-38 cell line, the cell supernatant then was preincubated with nonpreserved anti-human PDGF (AA- and BB-chain) resulting in an 80% decrease of tritiated thymidine uptake and procollagen-III-peptide production in the group of histiocytosis X patients compared with native supernatants. No significant change in fibroblast activity was seen in the control group. Preincubation with nonpreservated Ki-T2 antibodies as pan T-lymphocyte marker did not show significant differences in both groups excluding unspecific antibody inhibition. These findings suggest increased PDGF production by alveolar macrophages in histiocytosis X patients. The PDGF is in part responsible for increased fibroblast replication and collagen production.

Mechanical thrombectomy of major and massive pulmonary embolism with use of the Amplatz thrombectomy device.

RATIONALE AND OBJECTIVES: To evaluate the feasibility of mechanical thrombectomy with the Amplatz thrombectomy device (ATD) in restoring patency of acutely thrombosed pulmonary arteries resulting from pulmonary embolism for the improvement of patient outcome. METHODS: Mechanical thrombectomy with the ATD (8F) was performed in nine consecutive patients with angiographically documented thrombus in the left or right pulmonary artery resulting from deep vein thrombosis (n = 4) or unknown cause (n = 5). RESULTS: The Miller index decreased from 18 to 11. In all patients, the majority of the thrombus in the pulmonary artery was cleared after a mean activation time of the ATD of 367 seconds. Thrombectomy was performed with the ATD alone (n = 4) or with additional long-term fibrinolysis therapy (n = 5) with infusion of recombinant tissue-type plasminogen activator. Pulmonary arterial pressure decreased from a mean of 57 mm Hg before mechanical thrombectomy to 55 mm Hg directly after the procedure and to 39 mm Hg after termination of the recombinant tissue-type plasminogen activator infusion. CONCLUSIONS: Mechanical thrombectomy with the ATD in patients with minor and major pulmonary embolism is technically feasible and safe. It is a potential alternative to drug-mediated thrombolysis and surgery. However, the incremental benefit of the ATD over conventional treatments could be shown only in a randomized controlled study.

Topical amphotericin B application in severe bronchial aspergillosis after lung transplantation: report of experiences in 3 cases.

Ulcerative tracheobronchial aspergillosis after lung transplantation (ltx) may lead to bronchial-pulmonary artery fistula that results in fatal bleeding. We report our early experience with combined systemic, aerolized and topical application of amphotericin B in 3 cases of bronchial aspergillosis after ltx. Two patients are still alive, but 1 died of bleeding from a fistula between the left upper lobe bronchus and the pulmonary artery. Aspergillosis in the second patient resolved with minimal stenosis of the left main and the left upper lobe bronchus, and the third patient developed an anastomotic stenosis that was successfully dilated.

Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseases--implications for the euthyroid sick syndrome.

OBJECTIVE: To determine whether cytokine release or activation of the hypothalamo-pituitary-adrenal (HPA) axis is predominantly involved in the development of the euthyroid sick syndrome (ESS). DESIGN: Prospective observational study. SETTING: Intensive care unit at a tertiary care medical center in Germany. PATIENTS: Nine patients with sepsis of different causes and eight patients with acute myocardial infarction. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Immediately on admission and on day 7 the following parameters were determined: total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), serum cortisol and plasma adrenocorticotropin (ACTH). On admission, concentrations of all thyroid hormones and TSH were significantly lower in septic patients compared to non-septic patients, whereas all cytokines except IL-2 were significantly elevated in the sepsis group. By contrast, there was no difference in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and T3 were still lower in the septic group, whereas IL-1 beta, sIL-2R and IL-6 were still elevated. Again, no differences were found with regard to cortisol and ACTH levels. CONCLUSIONS: Euthyroid sick syndrome occurs very early during the course of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH in septic patients suggest central suppression of TSH as well as inhibition of thyroid hormone release in ESS. The HPA axis is activated in septic patients and in non-septic patients and does not contribute to the development of ESS.

Percutaneous placement of a self-expandable stent for treatment of a malignant pulmonary artery stenosis.

Venous stent placement is widely accepted as the treatment of stenoses caused by external tumour compression to reduced clinical sequelae. We report percutaneous stent placement into a severely obstructed right pulmonary artery in a 73-year-old female patient. The underlying disease was a medistinal tumour mass of unknown aetiology. Pulmonary perfusion was successfully but temporarily restored by the intervention.

[The effect of liver cirrhosis on activation of the coagulation and fibrinolysis system and on coagulation inhibitors]. / Der Einfluss der Leberzirrhose auf die Aktivierung des Gerinnungs- und Fibrinolysesystems und auf die Gerinnungsinhibitoren.

The activation of coagulation and fibrinolysis as well as coagulation inhibitors in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis were studied. Protein C (PC) was decreased in a more pronounced manner than antithrombin III (AT III) in liver cirrhosis. Thereby, PC proved to be a highly sensible indicator of liver cell dysfunction. Decreased levels of PC activity (PC ratio activity/antigen 0.82) in decompensated liver cirrhosis suggest production of dysfunctional, undercarboxylated PC. We observed increased blood concentrations of fibrinopeptide A (FPA) (p less than 0.05) in both groups of patients compared to healthy volunteers (n = 25), while D-Dimer was increased only in patients with decompensated liver cirrhosis (p less than 0.01). Comparing both groups of patients. D-Dimer was significantly different with higher levels in decompensated liver cirrhosis (p less than 0.01). The ratio D-Dimer/FPA was significantly increased in decompensated liver cirrhosis compared to both other groups. These observations indicate that efflux from the extravascular space, e.g. ascitic fluid, contributes to the high contents of fibrin degradation products (D-Dimer) in patients with decompensated liver cirrhosis. In summary we conclude that patients with liver cirrhosis have enhanced activation of both coagulation and fibrinolysis but that the balance is not significantly displaced.

[Eosinophilia - inflammation, proliferation, reaction. Part 1: diagnostics]. / Die Eosinophilie - Inflammation, Proliferation, Reaktion.

Eosinophilia presents a challenge to differential diagnostics due to the multitude of possible causes. An initial difficulty is often to distinguish between threatening disease symptoms and relatively harmless secondary reactions. A highly dynamic clinical progression with severe impairment of the vital functions, like breathing, for example, can make swift action necessary. An example of this is known as acute eosinophile pneumonia, which can often only be controlled with the rapid use of high steroid doses. However, a peripheral blood eosinophilia must not lead to an automatic use of steroids before the most important core tests, as this can compromise further diagnostic measures. Furthermore, less dramatic courses require careful handling of an eosinophilia. Various pneumological, infectological, rheumatological or haematological / oncological disease patterns with a prolonged course can develop seriously if they are not recognised in time and treated in a targeted manner. There is no guideline for eosinophile clinical pictures in general. Already the recommendations for a structured diagnosis are scarce and are often concentrated on internist emphases.

Synergism of imatinib mesylate and everolimus in attenuation of bronchiolitis obliterans after rat LTX.

Bronchiolitis obliterans (BO) is a progressive and fatal disease after lung transplantation (LTX). Dysregulated growth factor-induced proliferation of myofibroblasts seems to be responsible for the development of BO. The aim was to confirm the efficacy of both inhibitors of receptor tyrosine kinases (RTKI) and of mammalian target of rapamycin (mTORI) after rat LTX. We used a rat model of left lung allo-transplantation (F344-to-WKY) to evaluate the effect of imatinib (RTKI; 20 mg/kg/day; postoperative day (POD) 0-100) alone or in combination with everolimus (mTORI; 2.5 mg/kg/day; POD 14-100). Non-treated animals were the reference. In non-treated rats, acute rejection (AR) peaked between POD 20 and 30 (19/19) and ended in chronic rejection (CR) on POD 60/100 (12/12). Imatinib alone did not prevent AR (6/6), but attenuated the degree of degenerated bronchioles on POD 30 (non-treated, 57%; imatinib, 4%), and increased the allografts free of CR on POD 60/100 (3/12). A combination of imatinib and everolimus significantly reduced AR, attenuated fibrotic degenerated bronchioles (5%) and vessels (non-treated, 24%; combination therapy, 11%) on POD 30, and reduced fibrotic degenerated vessels (non-treated, 97%; combination therapy, 43%) and bronchioles (non-treated, 88%; combination therapy, 34%) on POD 60/100. Fifty percent of the animals were completely free of BO and vasculopathy. In conclusion, co-application of RTKI and mTORI attenuated the development of BO and vasculopathy. Thus, imatinib might be an interesting therapeutic approach after LTX.