Comb-resolved spectroscopy with immersion grating in long-wave infrared.

We have developed a dispersive spectrometer by using a compact immersion grating for direct frequency comb spectroscopy in the long-wave infrared region of 8-10 µm for the first time. A frequency resolution of 460 MHz is achieved, which is the highest reported in this wavelength region with a dispersive spectrometer. We also demonstrate individual comb mode-resolved imaging by cavity filtering and apply this to obtain spectra of both simple and complex molecular spectra. These results indicate that the immersion grating spectrometer offers the next advancement for sensitive, high-resolution spectroscopy of transient and large/complex molecules when combined with cavity enhancement and cooling techniques.

[Dyspnea in airway and pulmonary diseases]. / Dyspnoe bei Atemwegs- und Lungenerkrankungen.

The subjective perception of pulmonary dyspnea varies based on behavioral and physiological responses. Acute pulmonary dyspnea is the most common symptom of diseases of the airways and the lungs and the differential diagnosis includes harmless causes, such as lack of training as well as acute life-threatening diseases, such as thromboembolism, obstruction of the upper or lower airway, pneumonia, pulmonary hemorrhage and pneumothorax. Most cases of chronic pulmonary dyspnea result from asthma, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, pulmonary fibrosis and pleural disorders. Listening to the patient's "language of dyspnea" may already provide indications for the diagnosis. Initial testing includes chest radiography, spirometry, complete blood count and the basic metabolic panel. Measurement of brain natriuretic peptide levels may help to exclude heart failure in COPD and D-dimer testing may help rule out pulmonary embolisms. Computed tomography of the chest is the most appropriate imaging procedure for diagnosing pulmonary embolism and interstitial lung disease. To diagnose pulmonary arterial hypertension echocardiography and right heart catheterization may be necessary.

[Heart and combined heart-lung transplantation. Indications, chances and risks]. / Herz- und Herz-Lungen-Transplantation. Indikationen, Chancen, Risiken.

Orthotopic heart transplantation (HTX) is nowadays the worldwide accepted gold standard for the treatment of terminal heart failure. The main indications for HTX are non-ischemic dilatative (54%) and ischemic (37%) heart failure. In the acute phase after HTX the survival rate is approximately 90%. Good short and long-term results with survival rates ranging from 81% after 1 year to more than 50% after 11 years demonstrate that there is currently no real treatment alternative to HTX for treatment of end-stage heart failure. In the case of irreversible pulmonary hypertension in combination with end-stage heart failure or complex congenital heart syndromes, a combined heart and lung transplantation (HLTX) is necessary. Compared with HTX the short-term survival of HLTX is reduced, mostly for technical reasons. Improved long-term results after HTX and HLTX are a result of highly specialized transplantation units and effective immunosuppression. However, a major problem is the shortage of organ donors in Germany and the resulting long waiting times for patients with frequently occurring blood groups of up to 10 months for transplantation. The consequence of the latter is the ever increasing number of implanted cardiac assist devices in patients not only as a bridge to transplant but also as destination therapy.

Making sense of muscle fatigue and liver lesions.

Muscle weakness is a common complaint in clinical practice. If this symptom is combined with focal liver lesions there is a broad spectrum of differential diagnoses for the gastroenterologist to consider. Tumors of neuroendocrine origin such as small-cell lung carcinoma (SCLC) produce a wide array of peptide hormones and are common causes of paraneoplastic syndromes. We report on a 68-year-old woman who presented with progressing muscle fatigue and multiple liver lesions on ultrasonography. Hypertension, hyperglycemia, hypokalemia and metabolic alkalosis prompted consideration of underlying hypercortisolism. Further work-up demonstrated an acute ectopic ACTH syndrome as paraneoplastic manifestation of a small cell lung carcinoma. The woman deteriorated rapidly and finally died from intracranial tumor spread and septic complications. This case stresses the diagnostic and therapeutic difficulties of acute ectopic ACTH syndrome in the setting of SCLC.

Goal-oriented treatment and combination therapy for pulmonary arterial hypertension.

Combination therapy may improve outcome in patients with severe pulmonary arterial hypertension (PAH). PAH patients were treated according to a goal-oriented therapeutic strategy. Patients who did not reach the treatment goals with monotherapy received combination treatment according to a predefined strategy, including bosentan, sildenafil and inhaled iloprost. Intravenous iloprost and lung transplantation were reserved for treatment failures. End points were overall survival, transplantation-free survival, and survival free from transplantation and intravenous prostanoid treatment. Between January 2002 and December 2004, 123 consecutive patients with PAH were treated according to the novel approach. Survival at 1, 2 and 3 yrs was 93.0, 83.1 and 79.9%, respectively, which was significantly better than the survival of a historical control group, as well as the expected survival. Compared to the historical control group, the use of combination treatment also significantly improved the combined end point of death, lung transplantation and need for intravenous iloprost treatment. In conclusion, a therapeutic approach utilising combinations of bosentan, sildenafil and inhaled iloprost in conjunction with a goal-oriented treatment strategy provides acceptable long-term results in patients with severe pulmonary arterial hypertension, and reduces the need for intravenous prostaglandin treatment and lung transplantation.

Bosentan therapy for portopulmonary hypertension.

The dual endothelin receptor antagonist bosentan has been approved in several countries for pulmonary arterial hypertension, and patients with portopulmonary hypertension (PPHTN) have not specifically been excluded. However, no data have been published on the efficacy and safety of bosentan in this patient population. Here, the first clinical experiences with bosentan in patients with Child A cirrhosis and severe PPHTN are reported. In total, 11 consecutive patients with cirrhosis and severe PPHTN in New York Heart Association Functional Classes III and IV were treated for >1 yr with bosentan. After 1 yr of treatment with bosentan, all patients showed improved symptoms and exercise capacity. The 6-min walking distance increased from 310+/-102 m at baseline to 388+/-81 m at 1 yr. Cardiopulmonary exercise testing disclosed a significant increase in peak oxygen uptake, from 12.6+/-3.5 to 16.6+/-2.8 mL.min(-1).kg(-1). Pulmonary vascular resistance fell from 944+/-519 to 635+/-321 dynes.s.L(-1). The medication was well tolerated by all patients, and there was no evidence of drug-related liver injury. In conclusion, bosentan proved to be efficacious and safe in a small number of patients with portopulmonary hypertension.

Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension.

It has been proposed that targeted treatments should be combined for patients with idiopathic pulmonary arterial hypertension (IPAH) responding insufficiently to monotherapy. This study followed the clinical course of nine patients with severe IPAH, in whom the endothelin receptor antagonist bosentan caused transient clinical improvement, eventually followed by a decline in exercise tolerance, who received adjunct treatment with the phospodiesterase-5-inhibitor sildenafil. Measurements included the 6-min walk distance (6MWD) and cardiopulmonary exercise testing (CPET). The 6MWD at baseline was 346+/-66 m and improved to 403+/-80 m 3 months after introduction of bosentan treatment. However, this effect was not sustained and, after an interval of 11+/-5 months, the walk distance had declined to 277+/-80 m. At this point, sildenafil was added to bosentan. Three months later, the 6MWD had increased to 392+/-61 m and the patients remained stable throughout the median follow-up of 9 months (range 6-12). Measurement of the maximum oxygen uptake during CPET confirmed these results. The combination of bosentan and sildenafil was well tolerated by all patients. These preliminary data suggest that combining bosentan and sildenafil may be safe and effective in patients with idiopathic pulmonary arterial hypertension.

[Lung transplantation. Possibilities and limitations]. / Lungentransplantation. Möglichkeiten und Grenzen.

Lung transplantation is an option for patients with endstage pulmonary diseases without contraindications. Recent European studies showed a survival benefit for patients with cystic fibrosis, fibrosis and emphysema after lung transplantation. Early mortality has been reduced recently by surgical improvements. Life expectancy after lung transplantation has improved in recent years but is still lower than in patients with other solid organ transplantations. Quality of life is consistently improved but exercise tolerance keeps reduced in comparison to the normal population. Specific problems described in detail are frequent organ rejections and infections, airway problems and a high incidence of malignant diseases. 5-year survival after lung transplantation is in average 60%.

[Quality of life and exercise capacity in lung transplant recipients]. / Lebensqualität und körperliche Leistungsfähigkeit bei Patienten nach Lungentransplantation.

BACKGROUND: Quality of life in lung transplant recipients (LTR) is reported to be comparable with that of the general population. However, previous studies have shown that exercise capacity was reduced to 30 - 40 % of normal values. The purpose of this study was to investigate the gap between good self-reported quality of life and reduced exercise capacity in LTR, to describe possible correlations and to compare the results with those of a control group (CG). METHODS: 27 LTR 208 +/- 67 days after bilateral lund transplantation (16 male, 11 female; age: 46 +/- 10 years; body mass index: 24 +/- 3 kg x m (- 2), FEV (1) % 75 +/- 27 %) and 30 controls (17 male 13 female; age 47 +/- 15 years; BMI: 26 +/- 4 kg x m (- 2), FEV (1) % 103 +/- 15 %) performed cardiopulmonary exercise testing and were interviewed with the standardized German "Quality of life profile for chronic disease" self-rating questionnaire. RESULTS: Significant differences were shown in objective exercise related variables (peak oxygen consumption: LTR 15.1 +/- 1.8, CG 34.5 +/- 9.1 ml x min (- 1) x kg (- 1); p < 0,01); peak workload: LTR 1.0 +/- 0.2; CG 2.4 +/- 1.0 W. kg (- 1); p < 0.01); percentage of predicted workload: LTR 44 +/- 12, CG 115 +/- 33 %; p < 0.01). The rating of subjective quality of life in physical, psychological and social domains of LTR did not differ from values of the CG or of the general population (n = 1143). The quality of life in the physical domain correlated significantly with peak exercise capacity (LTR r = 0.44, p < 0.05; CG r = 0.37; p < 0.05). CONCLUSION: Patients 7 months after lung transplantation described their physical, social and psychological quality of life as equally good as the healthy control group. However, peak exercise capacity and oxygen consumption were markedly reduced. To improve physical capacity in the range of daily activities, an exercise training program should be offered to patients after lung transplantation.

The experience of the support person involved in a lung transplant programme: results of a pilot study.

UNLABELLED: In contrast to the high priority most transplant programmes give to the recipient's support system there is a paucity of studies referring to the experience of the respective support persons. This study sought to focus on the subjective burden of support persons and their unmet needs. METHOD: A questionnaire was designed for a cross-sectional study using numerical rating scales and fill-in-the-gap-items concerning subjective burden, stress symptoms, unmet needs, suggestions to improve the support person's situation. Participants were 39 relatives of adult transplant patients (22 cystic fibrosis transplant recipients, 17 recipients with other aetiologies) who had transplants 5 years ago (mean). RESULTS: The acute illness stage was rated as extremely stressful by most of the respondents. However, even during the rehabilitation period, one third described themselves as very stressed. Stress related symptoms at or post transplant were reported by 82% of respondents (more mothers than partners). Symptoms mostly referred to depressive and anxiety states. Most support persons had to tackle organizational difficulties in order to stay with the recipient and faced financial burdens not refunded by agencies. Support persons made suggestions to improve the recipient's situation and those of other support persons. Regarding the recipient their advice referred to enhanced information giving, aspects of communication and better access to psychosocial professionals. Regarding another support person they suggested to be well-informed beforehand and to remain optimistic. CONCLUSIONS: Mothers in this study seemed to be particularly vulnerable as support persons and thus deserve special attention. Few resources may be needed to achieve considerable benefit for the support person, such as arranging accommodation or identifying a team member to relate to.

Bronchial epithelial cell B7-1 and B7-2 mRNA expression after lung transplantation: a role in allograft rejection?

Obliterative bronchiolitis is commonly interpreted as chronic rejection and involves the bronchial and bronchiolar epithelium. Upregulation of major histocompatibility complex (MHC) II on bronchial epithelial cells (BEC) had been hypothesised to be an important trigger of a bronchus directed rejection response. More recently, the additional expression of the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) on antigen presenting cells were found to play an important role in the activation of T-lymphocytes in transplant rejection. The role of the expression of these molecules by BEC is unclear. BEC obtained by bronchial brushing and bronchoalveolar lavage fluid (BALF) cells from lung transplant recipients were studied and evaluated for messenger ribonucleic acid (mRNA) expression of B7-1 and B7-2 by semi-quantitative reverse transcriptase-polymerase chain reaction. Significantly elevated B7-1/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratios were found in BEC from patients examined during the first 3 months after lung transplantation. Interestingly, in a small group of patients with bronchiolitis obliterans syndrome the B7-1/GAPDH and B7-2/GAPDH ratios were significantly elevated for BEC, whereas no differences were found for the BALF cells. In summary, B7 messenger ribonucleic acid expression by bronchial epithelial cells may play a role in (chronic) lung allograft rejection.

N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.

Loss of expression of neural cell-adhesion molecule (N-CAM) is implicated in the progression of tumour metastasis. Here we show that N-CAM modulates neurite outgrowth and matrix adhesion of beta-cells from pancreatic tumours by assembling a fibroblast-growth-factor receptor-4 (FGFR-4) signalling complex, which consists of N-cadherin, FGFR-4, phospholipase C gamma (PLC-gamma), the adaptor protein FRS2, pp60(c-src), cortactin and growth-associated protein-43 (GAP-43). Dominant-negative FGFR-4, inhibitors of FGFR signalling and anti-beta(1)-integrin antibodies repress matrix adhesion induced by N-CAM. FGF ligands can replace N-CAM in promoting matrix adhesion but not neurite outgrowth. The results indicate that N-CAM stimulates beta1-integrin-mediated cell-matrix adhesion by activating FGFR signalling. This is a potential mechanism for preventing the dissemination of metastatic tumour cells.

Expression of the fibroblast activation protein during mouse embryo development.

Human Fibroblast Activation Protein (FAP), a member of the serine prolyl oligopeptidase family, is a type II cell surface glycoprotein that acts as a dual-specificity dipeptidyl-peptidase (DPP) and collagenase in vitro. Its restricted expression pattern in embryonic mesenchyme, in wound healing and in reactive stromal fibroblasts of epithelial cancers, has suggested a role for the FAP protease in extracellular matrix degradation or growth factor activation in sites of tissue remodeling. The FAP homologue in Xenopus laevis has been reported to be induced in the thyroid hormone-induced tail resorption program during tadpole metamorphosis supporting a role for FAP in tissue remodeling processes during embryonic development. However, Fap-deficient mice show no overt developmental defects and are viable. To study the expression of FAP during mouse embryogenesis, a second Fap-deficient mouse strain expressing beta-Galactosidase under the control of the Fap promoter was generated by homologous recombination (Fap-/- lacZ mice). FAP deficiency was confirmed by the absence of FAP-specific dipeptidyl-peptidase activity in detergent-soluble extracts isolated from 17.5 d.p.c. Fap-/- lacZ embryos. We report that Fap-/- lacZ mice express beta-Galactosidase at regions of active tissue remodeling during embryogenesis including somites and perichondrial mesenchyme from cartilage primordia.

[Long-term treatment of primary pulmonary hypertension with inhaled iloprost]. / Langfristige Behandlung der primären pulmonalen Hypertonie mit inhalativem Iloprost.

BACKGROUND: Continuous intravenous infusion of prostacyclin is an effective treatment for primary pulmonary hypertension. This approach, however, requires the insertion of a permanent central venous catheter with the potential risk of serious complications. Recently, administration of aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of treatment with aerosolized iloprost over a one-year period on exercise capacity and hemodynamic variables in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a cumulative daily dose of 100 to 150 micrograms for at least one year. The mean (+/- SD) walking distance in the 6-min-walk test increased from 278 +/- 96 meters at base line to 363 +/- 135 meters after 12 months (P < 0.0001). During the same period, the mean pulmonary artery pressure declined from 59 +/- 10 mmHg to 52 +/- 15 mmHg (P = 0.006), the cardiac output increased from 3.8 +/- 1.4 l/min to 4.4 +/- 1.3 l/min (P = 0.02), and the pulmonary vascular resistance declined from 1.205 +/- 467 dynes.s.cm-5 to 925 +/- 469 dynes.s.cm-5 (P = 0.0003). Treatment was generally well tolerated and except for mild coughing, minor headache and jaw pain in some patients, no side effects occurred. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation.

OBJECTIVES: We have previously demonstrated experimentally an amelioration of reperfusion injury of the lung after preservation using low potassium dextran (LPD) solution compared to Euro-Collins (EC) solution. Now we report on early graft function in 106 lung transplant recipients of LPD or EC preserved grafts. METHODS: Initial graft function was assessed by measurement of lung compliance and oxygenation index 2 h after transplantation. Length of stay on the intensive care unit and hours of mechanical ventilation were compared. Correlation of donor oxygenation, ischemic time, type of transplant, recipient age and sex as well as initial lung compliance and oxygenation with early postoperative course were calculated. RESULTS: Dynamic lung compliance was significantly (P<0.05) improved in the LPD group. PO(2)/fiO(2) was comparable in both groups (303+/-122 mmHg LPD, 282+/-118 mmHg EC). Mechanical ventilation was used for 321+/-500 h in the EC group and 189+/-365 h in the LPD group (P=0.006). Intensive care therapy was required for 17.2+/-23.7 days in the EC group and 10.4+/-16 days in the LPD group (P=0.012). Significantly higher lung function parameters were obtained in extubated recipients of LPD preserved grafts 2 weeks after TX. Thirty day graft survival was improved in the LPD group (P=0.045). In the EC group, 30 day mortality was 14.2 and 8% in the LPD group. CONCLUSIONS: A reduction of perioperative mortality and morbidity suggests that LPD solution has superior early graft function compared to lung preservation using EC solution.

Azathioprine withdrawal in stable lung and heart/lung recipients receiving cyclosporine-based immunosuppression.

BACKGROUND: Chronic rejection is the leading cause of graft failure after (heart-) lung transplantation. Therefore, many centers maintain a triple immunosuppressive cyclosporine-based regimen including azathioprine (AZA) during the long-term course after lung transplantation. However, an increased risk of malignancies has been attributed to prolonged immunosuppression, and there is evidence that less intensive immunosuppressive regimens are feasible in the long-term course after other solid organ transplantation. Therefore, we investigated the effects of AZA withdrawal in stable lung transplant recipients. METHODS: A prospective study was performed to assess the effects of AZA withdrawal in patients who received a lung transplant more than 4 years ago with stable graft function defined by absence of rejection episodes for at least 2 years and no evidence of bronchiolitis obliterans. RESULTS: A total of 24 patients qualified for the study and 7 discontinued AZA. Despite the small number of patients, termination of the study became necessary after 12 months because significantly more grafts showed deteriorating function after withdrawing AZA (4 of 7) compared to recipients continuing a triple therapy (1 of 17; P<0.05). In recipients with deteriorating graft function conventional treatment with high-dose corticosteroids and reinstitution of AZA failed to stop the development of obliterative bronchiolitis. CONCLUSIONS: Our data reinforce the importance of a potent immunosuppressive regimen for the maintenance of stable graft function after lung transplantation.