[Differential Diagnosis of Pulmonary Hypertension Using the Example of Collagenosis-associated PAH in the Context of Chronic Lung and Left Heart Disease]. / Differenzialdiagnostik der pulmonalen Hypertonie am Beispiel der Kollagenose assoziierten PAH im Kontext chronischer Lungen- und Linksherzerkrankungen.

Pulmonary hypertension (PH) can be diagnosed in the context of connective tissue diseases (CTD) as well as in elderly patients with multiple comorbidities. A correct clinical differential diagnosis and classification is essential before adequate therapeutic decisions can be made. Differential diagnosis of PH in CTD comprises associated pulmonary arterial hypertension (APAH), group 2 or 3 PH (PH arising from left heart or chronic lung disease), chronic thromboembolic PH (PH) and group 5 (e. g. in the context of terminal renal insufficiency). This is also true of elderly patients in whom the decision has to be made if the increasing number of coincident diseases lead to PH or have to be interpreted as comorbidities. In this manuscript, the differential diagnosis of PH is elucidated, focusing on CTD, in the context of left heart disease and chronic lung disease. Furthermore, criteria are presented facilitating an objective approach in this context.

[Current Aspects of Definition and Diagnosis of Pulmonary Hypertension]. / Aktuelle Definition und Diagnostik der pulmonalen Hypertonie.

At the 6th World Symposium on Pulmonary Hypertension (WSPH), which took place from February 27 until March 1, 2018 in Nice, scientific progress over the past 5 years in the field of pulmonary hypertension (PH) was presented by 13 working groups. The results of the discussion were published as proceedings towards the end of 2018. One of the major changes suggested by the WSPH was the lowering of the diagnostic threshold for PH from ≥ 25 to > 20 mmHg mean pulmonary arterial pressure, measured by right heart catheterization at rest. In addition, the pulmonary vascular resistance was introduced into the definition of PH, which underlines the importance of cardiac output determination at the diagnostic right heart catheterization.In this article, we discuss the rationale and possible consequences of a changed PH definition in the context of the current literature. Further, we provide a current overview on non-invasive and invasive methods for diagnosis, differential diagnosis, and prognosis of PH, including exercise tests.

[Expert Workshop COPD: Lungs and Heart - Quite Often Ill Together]. / Expertentreffen COPD: Lunge und Herz ­ ziemlich oft gemeinsam krank!

When caring for patients with respiratory diseases, always think of the heart! This is especially important for COPD patients, but also for a variety of other disorders of the respiratory system. At the workshop "Luftschlösser", held once more at Wiesbaden, Germany in February 2019 the many and important interactions of the lungs and the heart as well as the therapeutic implications were discussed. Based on pathophysiology, the psycho-social consequences of dyspnea, the leading symptom in patients with lung and heart disease became apparent. A particularly demanding diagnostic and therapeutic situation occurs in patients suffering simultaneously of lung and heart disease. It has been shown how frequently the diagnosis myocardial infarction is missed in COPD patients - and vice versa. Surprisingly, this is also the case in asthmatics with coronary heart disease or heart failure, a fact not readily known in clinical practice. In patients with emphysema and no apparent heart disease, hyperinflation leads to significantly restricted heart function. Reducing hyperinflation by inhaling broncholytics thus improves heart function. Biomarkers are increasingly being used for diagnostic purposes. Their role is being investigated in the large German COPD cohort COSYCONET. Lung patients suffering from more severe heart diseases pose a challenge for therapy in intensive care, especially when ventilated, and weaning from the ventilator is prolonged. Lung vessel diseases are "classic" examples of the intimate interaction of the lungs and the heart. In pulmonary arterial hypertension as well as in chronic thrombo-embolic pulmonary hypertension the lag time between the first symptoms and the definite diagnosis is often unacceptably long. For both diseases of the lung vessels therapeutic options have improved significantly over the last years. Pulmonologists should take care of this increasingly important patient group. Sleep-related breathing disorders and heart function are closely intertwined. Both conditions need special attention after the results of the SERVE-HF trial have been published. But there is no doubt that obstructive sleep apnea represents an independent and important risk factor for cardiovascular disease and needs to be treated according to existing guidelines.This workshop demonstrated impressively the multiple interactions of the respiratory system with cardiac function, resulting diagnostic and therapeutic problems, and means to overcome these problems. Guidelines for respiratory diseases should appropriately address cardiac comorbidity.

[Heart or lung? : Diagnostics and management of unclear exertional dyspnea]. / Herz oder Lunge? : Diagnostik und Management der unklaren Belastungsdyspnoe.

Exertional dyspnea is a nonspecific symptom with a variety of underlying causes. It can be challenging to differentiate a beginning cardiac disease from a pulmonary disease or from deconditioning alone. In the presence of obesity, the overall assessment is even more difficult. Rare diseases, such as pulmonary hypertension with dyspnea on exertion as the cardinal symptom are usually diagnosed late in the course of disease. The starting point of a successful evaluation is a thorough patient history. The combination of symptoms, clinical signs and findings leads to a preferred differential diagnosis. Readily available basic findings, such as physical examination, electrocardiogram (ECG), spirometry and laboratory tests help with the diagnosis. For unexplained causes, extended diagnostics such as echocardiography, blood gas analysis and finally special examinations are available. Cardiopulmonary exercise testing (CPET) and exercise echocardiography as well as right heart catheterization at rest and during exercise in the hands of experienced physicians allow an exact differentiation.

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Post deposition annealing of epitaxial Ce(1-x)Pr(x)O(2-δ) films grown on Si(111).

In this work the structural and morphological changes of Ce1-xPrxO2-δ (x = 0.20, 0.35 and 0.75) films grown on Si(111) due to post deposition annealing are investigated by low energy electron diffraction combined with a spot profile analysis. The surface of the oxide films exhibit mosaics with large terraces separated by monoatomic steps. It is shown that the Ce/Pr ratio and post deposition annealing temperature can be used to tune the mosaic spread, terrace size and step height of the grains. The morphological changes are accompanied by a phase transition from a fluorite type lattice to a bixbyite structure. Furthermore, at high PDA temperatures a silicate formation via a polycrystalline intermediate state is observed.

[Riociguat: stimulator of soluble guanylate-cyclase. New mode of action for the treatment of pulmonary arterial and non operable chronic thromboembolic pulmonary hypertension]. / Riociguat: Stimulation der löslichen Guanylatzyklase. Neuer Wirkmechanismus zur Behandlung der pulmonal-arteriellen und der nicht operablen chronisch thromboembolischen pulmonalen Hypertonie.

Riociguat is the first clinically available soluble Guanylate-cyclase stimulator (sGC) and representative of a completely new class of drugs. Riociguat is approved for pulmonary arterial hypertension (PAH) and non-operable or recurrent/persistent chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, Riociguat is currently under investigation for a wider spectrum of diseases. This article focusses on its mode of action and clinical trial data. Finally, based on these data, the status of approval, as well as the costs a proposal is given how Riociguat can be integrated in the current treatment of PAH and CTEPH.

[Dyspnoea in Patients with Pulmonary Hypertension (PH) - a Survey in Spezialized German PH Centres]. / Dyspnoe bei Patienten mit Pulmonaler Hypertonie (PH) - Ergebnisse einer Befragung in deutschen PH-Zentren.

Dyspnoea is the predominant symptom in patients with pulmonary hypertension (PH) at diagnosis. However, since dyspnoea is nonspecific and often occurs in a number of common diseases, the presence of PH can easily be underdiagnosed.In addition, this symptom underlies a high variability in the subjective perception, therefore further diagnostic procedures are often delayed by the patients.A survey of the incidence and severity of dyspnoea in 372 patients with PAH was conducted by questionnaire in German centres. Age, sex distribution and the range of comorbidities corresponded to the findings of national and international registries.Approximately 99 % of patients reported the presence of dyspnoea on exertion, even at low loads.Remarkably, in 13 % of patients dyspnoea occurs as a paroxysmal symptom, which may lead to the differential diagnosis of bronchial asthma. In addition, the patients who were being followed in specialized PH centres reported an increase in dyspnoea during the last year.The results of the survey on the incidence of dyspnoea in patients with PAH are consistent with the findings of international studies.

Prognostic impact of renal function in precapillary pulmonary hypertension.

BACKGROUND: Impairment of renal function is associated with adverse outcome in various diseases. Patients with pulmonary hypertension (PH) show diminished cardiac function and organ perfusion. The aim of this study was to investigate the associations between renal function and both haemodynamic parameters and long-term survival in patients with PH. METHODS: Blood was collected from 64 patients with PH (Dana Point class 1, 3 and 4) during right heart catheterization, and plasma was prepared. Creatinine, blood urea nitrogen (BUN), cystatin C, neutrophil-gelatinase-associated lipocalin (NGAL), fibroblast growth factor 23 (FGF-23) and α-Klotho levels were determined, and glomerular filtration rate (GFR) was estimated (eGFR). Parameters were evaluated using c-statistics and dichotomized for survival analysis based on receiver operating characteristic curves. RESULTS: The median follow-up time was 9.92 years with all-cause mortality as the primary end-point. Elevated BUN, cystatin C and creatinine levels were associated with decreased survival, with hazard ratios (HRs) of 3.237, 4.514 and 2.006, respectively, and equivalent performance according to c-statistics. Estimating GFR by CKD-EPI, MDRD and Cockcroft-Gault formulas resulted in HRs of 2.942, 2.694 and 3.306, respectively. Amongst these formulas, eGFR (Cockcroft-Gault) had the highest c-statistics of 0.674. There was a correlation between BUN and both cardiac index (τ = -0.39) and pulmonary vascular resistance index (τ = 0.249), whereas eGFR (CKD-EPI) was correlated with cardiac index (τ = 0.225). No correlations between either BUN or eGFR and right atrial pressure (RAP) were observed. NGAL, FGF-23 and α-Klotho had no prognostic impact or association with haemodynamic parameters. CONCLUSION: Comparison of markers of renal function for prognosis in PH demonstrated superiority of creatinine, cystatin C and BUN over NGAL, FGF-23 and α-Klotho. Minor decreases in eGFR influence long-term prognosis, and measurement of cystatin C levels might be useful to detect renal impairment in patients with a normal serum concentration of creatinine. Renal function in patients with PH is linked to cardiac index rather than RAP.

Albinism in phylogenetically and geographically distinct populations of Astyanax cavefish arises through the same loss-of-function Oca2 allele.

The Mexican tetra, Astyanax mexicanus, comprises 29 populations of cave-adapted fish distributed across a vast karst region in northeastern Mexico. These populations have a complex evolutionary history, having descended from 'old' and 'young' ancestral surface-dwelling stocks that invaded the region ∼6.7 and ∼2.8 MYa, respectively. This study investigates a set of captive, pigmented Astyanax cavefish collected from the Micos cave locality in 1970, in which albinism appeared over the past two decades. We combined novel coloration analyses, coding sequence comparisons and mRNA expression level studies to investigate the origin of albinism in captive-bred Micos cavefish. We discovered that albino Micos cavefish harbor two copies of a loss-of-function ocular and cutaneous albinism type II (Oca2) allele previously identified in the geographically distant Pachón cave population. This result suggests that phylogenetically young Micos cavefish and phylogenetically old Pachón cave fish inherited this Oca2 allele from the ancestral surface-dwelling taxon. This likely resulted from the presence of the loss-of-function Oca2 haplotype in the 'young' ancestral surface-dwelling stock that colonized the Micos cave and also introgressed into the ancient Pachón cave population. The appearance of albinism in captive Micos cavefish, caused by the same loss-of-function allele present in Pachón cavefish, implies that geographically and phylogenetically distinct cave populations can evolve the same troglomorphic phenotype from standing genetic variation present in the ancestral taxon.

Structural transitions of epitaxial ceria films on Si(111).

The structural changes of a (111) oriented CeO2 film grown on a Si(111) substrate covered with a hex-Pr2O3(0001) interface layer due to post deposition annealing are investigated. X-ray photoelectron spectroscopy measurements revealing the near surface stoichiometry show that the film reduces continuously upon extended heat treatment. The film is not homogeneously reduced since several coexisting crystalline ceria phases are stabilized due to subsequent annealing at different temperatures as revealed by high resolution low energy electron diffraction and X-ray diffraction. The electron diffraction measurements show that after annealing at 660 °C the ι-phase (Ce7O12) is formed at the surface which exhibits a (√7 × âˆš7)R19.1° structure. Furthermore, a (√27 × âˆš27)R30° surface structure with a stoichiometry close to Ce2O3 is stabilized after annealing at 860 °C which cannot be attributed to any bulk phase of ceria stable at room temperature. In addition, it is shown that the fully reduced ceria (Ce2O3) film exhibits a bixbyite structure. Polycrystalline silicate (CeSi(x)O(y)) and crystalline silicide (CeSi1.67) are formed at 850 °C and detected at the surface after annealing above 900 °C.

Breathing pattern and chest wall volumes during exercise in patients with cystic fibrosis, pulmonary fibrosis and COPD before and after lung transplantation.

BACKGROUND: Pulmonary fibrosis (PF), cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often cause chronic respiratory failure (CRF). METHODS: In order to investigate if there are different patterns of adaptation of the ventilatory pump in CRF, in three groups of lung transplant candidates with PF (n=9, forced expiratory volume in 1 s (FEV(1))=37+/-3% predicted, forced vital capacity (FVC)=32+/-2% predicted), CF (n=9, FEV(1)=22+/-3% predicted, FVC=30+/-3% predicted) and COPD (n=21, FEV(1)=21+/-1% predicted, FVC=46+/-2% predicted), 10 healthy controls and 16 transplanted patients, total and compartmental chest wall volumes were measured by opto-electronic plethysmography during rest and exercise. RESULTS: Three different breathing patterns were found during CRF in PF, CF and COPD. Patients with COPD were characterised by a reduced duty cycle at rest and maximal exercise (34+/-1%, p<0.001), while patients with PF and CF showed an increased breathing frequency (49+/-6 and 34+/-2/min, respectively) and decreased tidal volume (0.75+/-0.10 and 0.79+/-0.07 litres) (p<0.05). During exercise, end-expiratory chest wall and rib cage volumes increased significantly in patients with COPD and CF but not in those with PF. End-inspiratory volumes did not increase in CF and PF. The breathing pattern of transplanted patients was similar to that of healthy controls. CONCLUSIONS: There are three distinct patterns of CRF in patients with PF, CF and COPD adopted by the ventilatory pump to cope with the underlying lung disease that may explain why patients with PF and CF are prone to respiratory failure earlier than patients with COPD. After lung transplantation the chronic adaptations of the ventilatory pattern to advanced lung diseases are reversible and indicate that the main contributing factor is the lung itself rather than systemic effects of the disease.

Genes, modules and the evolution of cave fish.

Cave fish provide a model system for exploring the genetic basis of regressive evolution. A proposal that regressive evolution (for example, eye loss) may result from pleiotropy, by selection on constructive traits (for example, improved taste) has received considerable recent interest as it contradicts the theory that regressive evolution results from neutral evolution. In this study, these theories are reviewed by placing the classical and molecular genetic studies of cave fish in a common framework. Sequence data and the wide range of intermediate sized eyes in hybrids between surface and cave fish suggest that currently there is no strong evidence supporting the notion that structural eye genes have been afflicted by destructive mutations. The hedgehog genes, which are suggested to reduce the primordial eye cup size in cavefish by expanded expression, are also not mutated. The as yet unidentified 'eye genes' revealed by crossing experiments seem primarily responsible for eye regression and determine eye development through hedgehog. Hybrids between different eye-reduced cave populations developing large 'back to surface eyes' support this. In such eyes, hh expression is restored by complementary restitution because of the recombination of 'eye genes', which were subjected to different destructive mutations in separately evolving cave fish populations. All regressive and constructive cave fish traits can be considered to result from genetic modules, each showing a comparable pattern of expression. The constructive and regressive modules are shown to inherit independently from each other, which does not support the view that eye regression is a spin off effect of the improvement of beneficial traits through pleiotropy.

Impaired detection of Mycobacterium tuberculosis immunity in patients using high levels of immunosuppressive drugs.

We have previously shown, in renal transplant recipients on maintenance immunosuppression, that a whole-blood assay was superior in detecting immunity towards purified protein derivative (PPD) compared with skin testing. As blood tests may have limitations during high-dose immunosuppression therapy, the present study was aimed at characterising the effect of high immunosuppressive drug levels on PPD-specific T-cell immunity. PPD-reactive CD4 T-cells from 13 renal transplant recipients were longitudinally quantified by the induction of cytokines using flow cytometry. To further address the effect of high and low maintenance immunosuppression, drug effects were studied in vitro and in 49 age-matched lung transplant recipients and 49 renal transplant recipients. Maintenance immunosuppression after renal transplantation did not affect PPD-specific T-cell detection (median T-cell frequencies 0.55% before and 0.46% >12 months after transplantation), whereas specific T-cell frequencies were significantly lower 3 months after transplantation (0.15%; p = 0.0002). Likewise, high-level maintenance immunosuppression after lung transplantation was associated with a significantly lower prevalence in PPD-specific T-cell reactivity compared with renal transplant recipients (16.7% versus 52.1%; p = 0.0005). In line with the observations made in vivo, calcineurin inhibitors analysed in vitro led to a dose-dependent decrease in antigen-specific T-cell reactivity. The flow cytometric assay is not adversely affected by low drug doses. In contrast, decreased levels of PPD-specific T-cells early after transplantation and low prevalence of PPD-reactivity in lung transplant recipients suggest a reduced sensitivity of in vitro testing during high-level immunosuppression.

Risk factors for chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by nonresolving pulmonary thromboemboli that can be treated by surgical pulmonary endarterectomy (PEA). The authors of the present study sought to confirm known and to identify novel CTEPH risk factors in a controlled retrospective cohort study of prevalent CTEPH cases collected in three European centres offering PEA. Data from CTEPH patients were compared with nonthromboembolic pre-capillary pulmonary arterial hypertension cohorts at the participating institutions. The study population comprised 687 patients assessed at the time of diagnosis between 1996 and 2007. Ventriculo-atrial shunts and infected pacemakers (odds ratio (OR) 76.40, 95% confidence interval (CI) 7.67-10,351), splenectomy (OR 17.87, 95% CI 1.56-2,438), previous venous thromboembolism (VTE; OR 4.52, 95% CI 2.35-9.12), recurrent VTE (OR 14.49, 95% CI 5.40-43.08), blood groups other than 0 (2.09, 95% CI 1.12-3.94), and lupus anticoagulant/antiphospholipid antibodies (OR 4.20, 95% CI 1.56-12.21) were more often associated with CTEPH. Thyroid replacement therapy (OR 6.10, 95% CI 2.73-15.05) and a history of malignancy (OR 3.76, 95% CI 1.47-10.43) emerged as novel CTEPH risk factors. In conclusion, the European database study confirmed previous knowledge of chronic thromboembolic pulmonary hypertension risk factors, and identified thyroid replacement therapy and a history of malignancy as new medical conditions associated with chronic thromboembolic pulmonary hypertension.

Marine lava cave fauna: composition, biogeography, and origins.

An assemblage of endemic cavernicolous marine invertebrates, including taxa found on both sides of the Atlantic Ocean of great phylogenetic age or with affinities to deep sea organisms, inhabits the Jameos del Agua cave, a sea waterflooded Holocene lava tube cave on Lanzarote in the Canary Islands. This marine cave contains both relicts from Tethyan times, such as an apparently new crustacean family belonging to what had been the monotypic class Remipedia, and relicts of groups that are now common only in the deep sea as well as species that occur outside the cave.

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Clinical classification and initial diagnosis of pulmonary hypertension: recommendations of the Cologne Consensus Conference 2016]. / Klinische Klassifikation der pulmonalen Hypertonie und initiale Diagnostik: Empfehlungen der Kölner Konsensus Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed information about the clinical classification and diagnosis of pulmonary hypertension, and furthermore provide novel recommendations for risk stratification and follow-up assessments. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the clinical classification and initial diagnosis of PH. This article summarizes the results and recommendations of this working group.