| Pregnancy and Infants' Outcome: Nutritional and Metabolic Implications |
Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.
- Berti, C.
- Cetin, I.
- Agostoni, C.
- Desoye, G.
- Devlieger, R.
- Emmett, P. M.
- Ensenauer, R.
- Hauner, H.
- Herrera, E.
- Hoesli, I.
- Krauss-Etschmann, S.
- Olsen, S. F.
- Schaefer-Graf, U.
- Schiessl, B.
- Symonds, M. E.
- Koletzko, B.
Keywords
- Adult
- Child Development
- Female
- Fetal Development
- *Global Health
- Humans
- Infant Nutrition Disorders/epidemiology/*prevention & control
- Infant, Newborn
- *Maternal Nutritional Physiological Phenomena
- *Models, Biological
- *Nutrition Policy
- Nutritional Status
- *Patient Compliance
- Pregnancy
- Pregnancy Complications/epidemiology/*prevention & control
- Pregnancy Outcome
- Risk
- Weight Gain
- Fetal nutrition
- fatty acids
- maternal body mass index
- maternal diabetes
- placental transport
|
10.1080/10408398.2012.745477 |
Crit Rev Food Sci Nutr |
AA |
FZB |
ARCN |
Review |
2016 |
| Do not leave the heart arrested. Non-cardioplegic continuous myocardial perfusion during complex aortic arch repair improves cardiac outcome |
OBJECTIVES: Myocardial protection with cardioplegia alone may be inadequate during complex aortic arch surgery, potentially resulting in postoperative myocardial insufficiency. We hypothesized that non-cardioplegic continuous myocardial perfusion (CMP) is feasible and safe to protect the heart while operating on the aortic arch, and improves cardiac outcome. METHODS: Between April 2010 and April 2014, 144 patients (60% male, age: 60 +/- 13 years) underwent complex aortic arch repair in our institution using prefabricated, branched aortic arch grafts. In 36 patients, the hearts were protected with a combination of cardioplegic cardiac arrest during cardiac procedures and subsequent non-cardioplegic CMP group during aortic arch repair. In 108 patients, myocardial protection was achieved by cardioplegic arrest (CA group) only. RESULTS: Preoperative risk factors were comparable in both groups. Acute aortic dissection was the indication for surgery in 42% (CMP) and 44% (CA) of patients; 22% (CMP) and 29% (CA) of patients underwent reoperations. Concomitant cardiac procedures were similar. CMP patients received a frozen elephant trunk more frequently (89 vs 66%, P = 0.0096). Cardiopulmonary bypass time (242 +/- 50 vs 264 +/- 68 min; P = 0.046), and cardiac ischaemic time (49 +/- 32 vs 149 +/- 56 min, P < 0.0001) were significantly lower in the CMP group. There were no conversions to CA in the CMP group. Aortic arch repair was not prolonged by CMP. Low cardiac output syndrome occurred less frequently in the CMP group (3 vs 22%, P = 0.0052). Thirty-day mortality was significantly lower in the CMP group (6 vs 21%, P = 0.040). There were no cardiac deaths in the CMP group (0 vs 9%, P = 0.067). Neurological outcome was comparable. Blood loss was higher in the CA group (P < 0.001). CONCLUSIONS: Routinely protecting the heart during complex aortic arch repair with non-cardioplegic CMP is a valuable new concept. The CMP technique is feasible and safe, does not prolong aortic arch repair, reduces myocardial damage and improves cardiac outcome. Further evaluation in a larger patient cohort is warranted to establish this novel technique.
- Martens, A.; Koigeldiyev, N.; Beckmann, E.; Fleissner, F.; Kaufeld, T.; Krueger, H.; Stanelle, D.; Puntigam, J.; Haverich, A.; Shrestha, M.
Keywords
- Adult
- Aged
- Aneurysm, Dissecting/*surgery
- Aorta, Thoracic/*surgery
- Aortic Aneurysm, Thoracic/*surgery
- Blood Vessel Prosthesis Implantation/*methods
- Cardiopulmonary Bypass
- Female
- *Heart Arrest, Induced
- Humans
- Male
- Middle Aged
- Perfusion/*methods
- Treatment Outcome
- Aortic arch surgery
- Beating heart
- Myocardial protection
|
10.1093/ejcts/ezv009 |
Eur J Cardiothorac Surg |
ELD |
MHH |
BREATH |
Original |
2016 |
| Comparison of C-arm Computed Tomography and Digital Subtraction Angiography in Patients with Chronic Thromboembolic Pulmonary Hypertension |
PURPOSE: To assess the feasibility and diagnostic performance of contrast-enhanced, C-arm computed tomography (CACT) of the pulmonary arteries compared to digital subtraction angiography (DSA) in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH). MATERIALS: Fifty-two patients with CTEPH underwent ECG-gated DSA and contrast-enhanced CACT. Two readers (R1, R2) independently evaluated pulmonary artery segments and their sub-segmental branching using DSA and CACT for optimal image quality. Afterwards, the diagnostic findings, i.e., intraluminal filling defects, stenosis, and occlusion, were compared. Inter-modality and inter-observer agreement was calculated, and subsequently consensus reading was done and correlated to a reference standard representing the overall consensus of both modalities. Fisher's exact test and Cohen's Kappa were applied. RESULTS: A total of 1352 pulmonary segments were evaluated, of which 1255 (92.8 %) on DSA and 1256 (92.9 %) on CACT were rated to be fully diagnostic. The main causes of the non-diagnostic image quality were motion artifacts on CACT (R1:37, R2:78) and insufficient contrast enhancement on DSA (R1:59, R2:38). Inter-observer agreement was good for DSA (kappa = 0.74) and CACT (kappa = 0.75), while inter-modality agreement was moderate (R1: kappa = 0.46, R2: kappa = 0.47). Compared to the reference standard, the inter-modality agreement for CACT was excellent (kappa = 0.96), whereas it was inferior for DSA (kappa = 0.61) due to the higher number of abnormal consensus findings read as normal on DSA. CONCLUSION: CACT of the pulmonary arteries is feasible and provides additional information to DSA. CACT has the potential to improve the diagnostic work-up of patients with CTEPH and may be particularly useful prior to surgical or interventional treatment.
- Hinrichs, J. B.; Marquardt, S.; von Falck, C.; Hoeper, M. M.; Olsson, K. M.; Wacker, F. K.; Meyer, B. C.
Keywords
- Aged
- Angiography, Digital Subtraction/*methods
- Chronic Disease
- Contrast Media
- Feasibility Studies
- Female
- Humans
- Hypertension, Pulmonary/complications/*diagnostic imaging
- Male
- Middle Aged
- Pulmonary Artery/diagnostic imaging
- Pulmonary Embolism/complications/*diagnostic imaging
- Radiographic Image Enhancement
- Reproducibility of Results
- Sensitivity and Specificity
- Tomography, X-Ray Computed/*methods
- Balloon pulmonary angioplasty
- C-arm computed tomography
- Chronic thromboembolic pulmonary hypertension
- Cone beam CT
|
10.1007/s00270-015-1090-7 |
Cardiovasc Intervent Radiol |
PH |
MHH |
BREATH |
Original |
2016 |
| Retrograde in situ versus antegrade pulmonary preservation in clinical lung transplantation: a single-centre experience |
OBJECTIVE: Experimental and clinical studies have indicated a beneficial effect of retrograde lung preservation on post-transplant results. Accordingly, we conducted a non-randomized trial. METHODS: A total of 209 consecutive recipients transplanted with low-potassium dextrane (LPD)-preserved lungs were eligible for analysis. Antegrade lung preservation (AP) was performed in 173 patients and retrograde in situ perfusion (RP) in 36 patients using low-potassium dextrane solution in all cases. The prostacycline was added to preservation solution. RESULTS: The main donor, graft and recipient characteristics did not differ significantly between groups. There was a beneficial trend toward improved oxygenation indices in the RP cohort within the initial 48 post-transplant hours. The incidence of severe primary graft dysfunction was comparable up to 48 h post-transplant and was significantly increased in the RP cohort 72 h post-transplant (2.2% AP vs 14.8% RP, P = 0.016). Fatal bronchial dehiscences occurred more often in RP recipients (5.6% RP vs 0.6% AP, P = 0.067). The occurrence of bronchial stenoses revealed a slightly improved trend in the RP group (24.9% AP vs 13.9% RP, P = 0.218). Survival (P = 0.927) and bronchiolitis obliterans syndrome-free survival (P = 0.337) were comparable between groups. CONCLUSION: In our clinical survey, this analysis does not confirm the beneficial results of retrograde lung preservation alone, as was previously observed in experimental studies.
- Gohrbandt, B.; Warnecke, G.; Fischer, S.; Simon, A. R.; Gottlieb, J.; Niehaus, A.; Bothig, D.; Haverich, A.; Strueber, M.
Keywords
- Adult
- Cohort Studies
- Female
- Follow-Up Studies
- Graft Rejection
- Graft Survival
- Humans
- Kaplan-Meier Estimate
- Lung Transplantation/adverse effects/*methods/*mortality
- Male
- Middle Aged
- Multivariate Analysis
- Organ Preservation/*methods
- Organ Preservation Solutions/*pharmacology
- Proportional Hazards Models
- Retrospective Studies
- Risk Assessment
- Statistics, Nonparametric
- Survival Analysis
- Time Factors
- Tissue Donors
- Treatment Outcome
- Airway complication
- BOS-free survival
- Lung transplantation
- Primary graft dysfunction
- Retrograde lung preservation
|
10.1093/ejcts/ezv108 |
Eur J Cardiothorac Surg |
ELD |
MHH |
BREATH |
Original |
2016 |
| Unchanged NADPH Oxidase Activity in Nox1-Nox2-Nox4 Triple Knockout Mice: What Do NADPH-Stimulated Chemiluminescence Assays Really Detect? |
NADPH oxidases of the Nox family are considered important sources of cellular reactive oxygen species (ROS) production. This conclusion is, in part, based on the ability of NADPH to elicit a chemiluminescence signal in tissue/cell homogenates or membrane preparations in the presence of enhancers such as lucigenin, luminol, or L012. However, the ability of these particular assays to specifically detect Nox activity and Nox-derived ROS has not been proven. In this study, we demonstrate that combined knockout of the three main Nox enzymes of the mouse (Nox1-Nox2-Nox4 triple knockout) had no impact on NADPH-stimulated chemiluminescence signals in the aorta, heart, and kidney homogenates. In the NADPH-stimulated membrane assays, no effect of in vivo angiotensin II pretreatment or deletion of Nox enzymes was observed. In in vitro studies in HEK293 cells, the overexpression of Nox5 or Nox4 markedly increased ROS production in intact cells, whereas overexpression of Nox5 or Nox4 had no influence on the signal in membrane assays. In contrast, overexpression of nitric oxide synthase or cytochrome P450 enzymes resulted in an increased chemiluminescence signal in isolated membranes. On the basis of these observations, we propose the hypothesis that NADPH-stimulated chemiluminescence-based membrane assays, as currently used, do not reflect Nox activity.
- Rezende, F.; Lowe, O.; Helfinger, V.; Prior, K. K.; Walter, M.; Zukunft, S.; Fleming, I.; Weissmann, N.; Brandes, R. P.; Schroder, K.
Keywords
- Angiotensin II/metabolism
- Animals
- Cell Membrane/metabolism
- Cytochrome P-450 Enzyme System/metabolism
- Enzyme Activation
- Kidney/metabolism
- Membrane Glycoproteins/deficiency/genetics/metabolism
- Mice
- Mice, Knockout
- Myocardium/metabolism
- NADH, NADPH Oxidoreductases/deficiency/genetics/metabolism
- NADP/metabolism
- NADPH Oxidase/deficiency/*genetics/*metabolism
- Nitric Oxide Synthase Type III/metabolism
- Oxidation-Reduction
- Phenotype
- Reactive Oxygen Species
- Signal Transduction
|
10.1089/ars.2015.6314 |
Antioxid Redox Signal |
General Lung and Other |
JLU |
UGMLC |
Original |
2016 |
| Moisture damage in home associates with systemic inflammation in children |
This study investigated the association between confirmed moisture damage in homes and systemic subclinical inflammation in children. Home inspections were performed in homes of 291 children at the age of 6 years. Subclinical inflammation at the age of 6 years was assessed by measuring the circulating levels of C-reactive protein (CRP) and leukocytes in peripheral blood and fractional exhaled nitric oxide (FeNO). Proinflammatory cytokines interleukin (IL)-1beta and IL-6 and tumor necrosis factor (TNF)-alpha were measured in unstimulated, and in phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG)-stimulated whole blood. Major moisture damage in the child's main living areas (living room, kitchen, or child's bedroom) and moisture damage with mold in the bathroom were associated with increased levels of CRP and stimulated production of several proinflammatory cytokines. There were no significant associations between moisture damage/visible mold and leukocyte or FeNO values. The results suggest that moisture damage or mold in home may be associated with increased systemic subclinical inflammation and proinflammatory cytokine responsiveness.
- Mustonen, K.
- Karvonen, A. M.
- Kirjavainen, P.
- Roponen, M.
- Schaub, B.
- Hyvarinen, A.
- Frey, U.
- Renz, H.
- Pfefferle, P. I.
- Genuneit, J.
- Vaarala, O.
- Pekkanen, J.
Keywords
- Air Pollution, Indoor/*adverse effects/analysis
- C-Reactive Protein/analysis
- Child
- Cytokines/blood
- Exhalation
- Female
- Fungi/*growth & development
- *Housing
- Humans
- Humidity/*adverse effects
- Inflammation/blood/*etiology
- Leukocyte Count
- Male
- Nitric Oxide/analysis
- Steam/*adverse effects/analysis
- *Children
- *Cytokines
- *Indoor
- *Inflammation
- *Moisture damage
- *Mold
|
10.1111/ina.12216 |
Indoor Air |
General Lung and Other |
LMU, UMR |
CPC-M, UGMLC |
Original |
2016 |
| [Minimally invasive chest surgery. Is palpation control still necessary with modern computed tomography?] |
BACKGROUND: A fundamental argument against minimally invasive oncological chest surgery is the risk of overlooking pulmonary nodules due to a lack of intraoperative palpation. In the literature this risk in the treatment of primary lung cancer is given as up to 8.4 % and as more than 15 % in the surgical treatment of pulmonary metastases. OBJECTIVE: The aim of this study was to evaluate if modern computed tomography (CT) is sensitive enough to replace intraoperative palpation and justify a minimally invasive approach. PATIENTS AND METHODS: The medical records from 92 patients who underwent 95 open lung resections due to pulmonary malignancies from April 2010 through September 2011 at the Medical School Hannover were retrospectively analysed. A comparison was carried out between the lesions detected preoperatively by CT and those removed during surgery and histologically confirmed as being malignant. Patients with more than five nodules suspected of being malignant in the preoperative CT scan were excluded. RESULTS: According to the final histopathological examination 125 malignant nodules were resected and 2 of these were not detected in the preoperative CT scan, which were performed in external hospitals with a slice thickness of 5 mm and 8 mm, respectively. This represents a sensitivity of 98 % for all CT scans in terms of detection of pulmonary nodules. With thin slice CT (slice thickness up to 1.5 mm) a sensitivity of 100 % was even achieved. CONCLUSION: The results demonstrate that a high sensitivity of thin slice CT for detection of lung nodules can be achieved. Based on these results the categorical reservation with respect to thoracoscopic resection of pulmonary metastases should be reconsidered in suitable patients where a minimally invasive resection is possible. The extent of lymph node dissection is not influenced by these data. Further studies with larger sample sizes are warranted to confirm these results.
- Kruger, M.; Zinne, N.; Shin, H.; Zhang, R.; Biancosino, C.; Kropivnitskaja, I.; Langer, F.; Haverich, A.; Dettmer, S.
Keywords
- Adult
- Aged
- Aged, 80 and over
- Female
- Humans
- Lung Neoplasms/diagnostic imaging/pathology/*secondary/*surgery
- Male
- Middle Aged
- Minimally Invasive Surgical Procedures/*methods
- Neoplasms, Multiple Primary/diagnostic imaging/pathology/*secondary/*surgery
- Palpation/*methods
- *Pneumonectomy
- Retrospective Studies
- Risk Factors
- Sensitivity and Specificity
- Thoracic Surgery, Video-Assisted/*methods
- Tomography, X-Ray Computed/*methods
- Computed tomography
- Computer assisted detection
- Lung cancer
- Lung metastasis
- Video assisted thorascopic surgery
|
10.1007/s00104-015-0013-0 |
Chirurg |
LC |
MHH |
BREATH |
Original |
2016 |
| Peak weight velocity in infancy is negatively associated with lung function in adolescence |
BACKGROUND: Rapid weight gain during infancy increases childhood asthma risk, which might be related to impaired lung function. This study investigated associations between peak weight velocity (PWV) during the first two years of life and spirometric lung function indices at 15 years of age. METHODS: Data from 1842 children participating in the GINIplus German birth cohort who underwent spirometry at age 15 were analysed. PWV was calculated from weight measurements obtained between birth and two years of age. Generalised additive models were fitted after adjustment for potential confounding factors (birth weight, height, and age at lung function testing). Results are presented per interquartile range increase (3.5 kg/year) in PWV. RESULTS: PWV was negatively associated with pre-bronchodilation flow rates after extensive adjustment for potential confounders including asthma: forced expiratory flow at 50% of forced vital capacity (FEF50 ) decreased by 141 ml/s (95%CI = [-225;-57]), FEF75 by 84 ml/s [-144;-24] and FEF25-75 by 118 ml/s [-192;-44]. FEV1 /FVC was also negatively associated with PWV (-0.750% [-1.273;-0.226]) whereas forced expiratory volume in 1s (FEV1 ) and forced vital capacity (FVC) were not. Similar results were found for measurements post-bronchodilation. CONCLUSION: Early life weight gain was negatively associated with flow indices in adolescence, suggesting structural changes in peripheral lungs.
- Claudia, F.
- Thiering, E.
- von Berg, A.
- Berdel, D.
- Hoffmann, B.
- Koletzko, S.
- Bauer, C. P.
- Koletzko, B.
- Heinrich, J.
- Schulz, H.
Keywords
- Adolescent
- Asthma/*epidemiology/physiopathology
- *Birth Weight
- *Child Development
- Cohort Studies
- Female
- Follow-Up Studies
- Forced Expiratory Volume
- Humans
- Infant
- Infant, Newborn
- Linear Models
- Lung/*physiopathology
- Male
- Maximal Midexpiratory Flow Rate
- Prospective Studies
- Respiratory Function Tests
- Risk Factors
- Spirometry
- Vital Capacity
- *Weight Gain
- adolescence
- asthma
- early life factor
- growth
- lung function
- weight gain
|
10.1002/ppul.23216 |
Pediatr Pulmonol |
General Lung and other |
HMGU |
CPC-M |
Original |
2016 |
| Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene |
RATIONALE: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations. METHOD: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). RESULTS: The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04). CONCLUSIONS: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.Genet Med 18 4, 333-340.
- Dupuis, A.; Keenan, K.; Ooi, C. Y.; Dorfman, R.; Sontag, M. K.; Naehrlich, L.; Castellani, C.; Strug, L. J.; Rommens, J. M.; Gonska, T.
Keywords
- Adolescent
- Adult
- Alleles
- Canada/epidemiology
- Child
- Cystic Fibrosis/*complications/diagnosis/epidemiology/*genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/*genetics
- Female
- Genetic Association Studies
- Genotype
- Humans
- Ileus/diagnosis/*epidemiology/*etiology
- Male
- *Meconium
- *Mutation
- Phenotype
- Prevalence
- Registries
- Respiratory Function Tests
- Severity of Illness Index
- Young Adult
|
10.1038/gim.2015.79 |
Genet Med |
CF |
JLU |
UGMLC |
Original |
2016 |
| Thoracic and abdominal aortic diameters in a general population: MRI-based reference values and association with age and cardiovascular risk factors |
OBJECTIVES: To generate reference values for thoracic and abdominal aortic diameters determined by magnetic resonance imaging (MRI) and analyse their association with cardiovascular risk factors in the general population. METHODS: Data from participants (n = 1759) of the Study of Health in Pomerania were used for analysis in this study. MRI measurement of thoracic and abdominal aortic diameters was performed. Parameters for calculation of reference values according to age and sex analysis were provided. Multivariable linear regression models were used for determination of aortic diameter-related risk factors, including smoking, blood pressure (BP), high-density lipoprotein cholesterol (HDL-C). RESULTS: For the ascending aorta (beta = -0.049, p < 0.001), the aortic arch (beta = -0.061, p < 0.001) and the subphrenic aorta (beta = -0.018, p = 0.004), the body surface area (BSA)-adjusted diameters were lower in men. Multivariable-adjusted models revealed significant increases in BSA-adjusted diameters with age for all six aortic segments (p < 0.001). Consistent results for all segments were observed for the positive associations of diastolic BP (beta = 0.001; 0.004) and HDL (beta = 0.035; 0.087) with BSA-adjusted aortic diameters and for an inverse association of systolic BP (beta = -0.001). CONCLUSIONS: Some BSA-adjusted median aortic diameters are smaller in men than in women. All diameters increase with age, diastolic blood pressure and HDL-C and decrease as systolic BP increases. KEY POINTS: * Median aortic diameter increases with age and diastolic blood pressure. * Median aortic diameter is larger in men than in women. * Some BSA-adjusted median aortic diameters are smaller in men than in women.
- Mensel, B.
- Hesselbarth, L.
- Wenzel, M.
- Kuhn, J. P.
- Dorr, M.
- Volzke, H.
- Lieb, W.
- Hegenscheid, K.
- Lorbeer, R.
Keywords
- Adult
- Aged
- *Aging
- Aorta, Abdominal/*anatomy & histology
- Aorta, Thoracic/*anatomy & histology
- Blood Pressure/physiology
- Body Surface Area
- Cardiovascular Diseases/*etiology/pathology
- Cholesterol, HDL/metabolism
- Cross-Sectional Studies
- Female
- Healthy Volunteers
- Humans
- Linear Models
- Magnetic Resonance Angiography
- Male
- Middle Aged
- Reference Values
- Risk Factors
- Smoking/adverse effects/pathology
- Aortic diameter
- Magnetic resonance imaging
- Population-based research
|
10.1007/s00330-015-3926-6 |
Eur Radiol |
General Lung and Other |
UKSH (Kiel) |
ARCN |
Original |
2016 |
| The molecular targets of approved treatments for pulmonary arterial hypertension |
Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)--prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
- Humbert, M.; Ghofrani, H. A.
Keywords
- Antihypertensive Agents/administration & dosage/*therapeutic use
- Drug Interactions
- Drug Therapy, Combination
- Endothelin Receptor Antagonists/administration & dosage/therapeutic use
- Humans
- Hypertension, Pulmonary/*drug therapy
- Phosphodiesterase Inhibitors/administration & dosage/therapeutic use
- Prostaglandins/administration & dosage/therapeutic use
- Pyrazoles/administration & dosage/therapeutic use
- Pyrimidines/administration & dosage/therapeutic use
- Primary Pulmonary Hypertension
|
10.1136/thoraxjnl-2015-207170 |
Thorax |
PH |
JLU |
UGMLC |
Review |
2016 |
| Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension |
Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes.
- Veith, C.; Schermuly, R. T.; Brandes, R. P.; Weissmann, N.
Keywords
- Animals
- Humans
- Hypertension, Pulmonary/*metabolism/pathology/physiopathology
- Hypoxia-Inducible Factor 1/*metabolism
- Myocytes, Smooth Muscle/*metabolism/pathology
- Oxygen/metabolism
|
10.1113/JP270689 |
J Physiol |
PH |
JLU |
UGMLC |
Review |
2016 |
| Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial |
AIMS: The impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients. METHODS AND RESULTS: Eighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 +/- 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was the change in peak VO2/kg. Secondary endpoints included changes in haemodynamics. For missing data, multiple imputation and responder analyses were performed. The study results showed a significant improvement of peak VO2/kg in the training group (difference from baseline to 15 weeks: training +3.1 +/- 2.7 mL/min/kg equals +24.3% vs. control -0.2 +/- 2.3 mL/min/kg equals +0.9%, P < 0.001). Cardiac index (CI) at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6 min walking distance, quality of life, and exercise capacity significantly improved by exercise training. CONCLUSION: Low-dose exercise training at 4-7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that exercise training may improve the right ventricular function. Further, large multicentre trials are necessary to confirm these results.
- Ehlken, N.
- Lichtblau, M.
- Klose, H.
- Weidenhammer, J.
- Fischer, C.
- Nechwatal, R.
- Uiker, S.
- Halank, M.
- Olsson, K.
- Seeger, W.
- Gall, H.
- Rosenkranz, S.
- Wilkens, H.
- Mertens, D.
- Seyfarth, H. J.
- Opitz, C.
- Ulrich, S.
- Egenlauf, B.
- Grunig, E.
Keywords
- Analysis of Variance
- Biomarkers/metabolism
- Cardiac Output/physiology
- Chronic Disease
- Exercise Test
- Exercise Therapy/*methods
- Exercise Tolerance/physiology
- Female
- Heart Rate/physiology
- Humans
- Hypertension, Pulmonary/physiopathology/*rehabilitation
- Male
- Middle Aged
- Natriuretic Peptide, Brain/metabolism
- Oxygen Consumption/physiology
- Peptide Fragments/metabolism
- Prospective Studies
- Pulmonary Wedge Pressure/physiology
- Thromboembolism/physiopathology/*rehabilitation
- Treatment Outcome
- Vascular Resistance/physiology
- Ventricular Dysfunction, Right/physiopathology/rehabilitation
- Cardiac index
- Cardiac output
- Cardiac rehabilitation
- Pulmonary hypertension
- Right heart catheterization
|
10.1093/eurheartj/ehv337 |
Eur Heart J |
PH |
JLU, MHH, Thorax |
BREATH, TLRC, UGMLC |
Original |
2016 |
| Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes |
BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce. OBJECTIVES: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD. METHODS: This cohort study used data from German National Health Insurance beneficiaries aged 40 years or younger (n = 655,815) from 2005 through 2011. Prevalent AD in the period 2005 to 2006 was defined as primary exposure, and incident RA, IBD, and T1D in the period 2007 to 2011 were defined as primary outcomes. Risk ratios were calculated with generalized linear models. Established RA, IBD, and T1D loci were explored in high-density genotyping data from 2,425 cases with AD and 5,449 controls. RESULTS: Patients with AD (n = 49,847) were at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, 1.25-2.37) and/or IBD (CD: RR, 1.34; 95% CI, 1.11-1.61; UC: RR, 1.25; 95% CI, 1.03-1.53). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, 0.53-0.998). There was no disproportionate occurrence of known RA, CD, UC, or T1D risk alleles in AD. CONCLUSIONS: AD is a risk factor for the development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors.
- Schmitt, J.
- Schwarz, K.
- Baurecht, H.
- Hotze, M.
- Folster-Holst, R.
- Rodriguez, E.
- Lee, Y. A. E.
- Franke, A.
- Degenhardt, F.
- Lieb, W.
- Gieger, C.
- Kabesch, M.
- Nothen, M. M.
- Irvine, A. D.
- McLean, W. H. I.
- Deckert, S.
- Stephan, V.
- Schwarz, P.
- Aringer, M.
- Novak, N.
- Weidinger, S.
Keywords
- Adolescent
- Adult
- Arthritis, Rheumatoid/*epidemiology
- Child
- Child, Preschool
- Dermatitis, Atopic/*epidemiology
- Diabetes Mellitus, Type 1/*epidemiology
- Female
- Germany/epidemiology
- Humans
- Incidence
- Infant
- Infant, Newborn
- Inflammatory Bowel Diseases/*epidemiology
- Male
- Odds Ratio
- Prevalence
- Risk Factors
- Young Adult
- Atopic dermatitis
- cohort study
- epidemiology
- inflammatory bowel disease
- rheumatoid arthritis
- type 1 diabetes
|
10.1016/j.jaci.2015.06.029 |
J Allergy Clin Immunol |
AA |
UKSH (Kiel) |
ARCN |
Original |
2016 |
| Evaluating acellular versus cellular perfusate composition during prolonged ex vivo lung perfusion after initial cold ischaemia for 24 hours |
Normothermic ex vivo lung perfusion (EVLP) has developed as a powerful technique to evaluate particularly marginal donor lungs prior to transplantation. In this study, acellular and cellular perfusate compositions were compared in an identical experimental setting as no consensus has been reached on a preferred technique yet. Porcine lungs underwent EVLP for 12 h on the basis of an acellular or a cellular perfusate composition after 24 h of cold ischaemia as defined organ stress. During perfusion, haemodynamic and respiratory parameters were monitored. After EVLP, the lung condition was assessed by light and transmission electron microscopy. Aerodynamic parameters did not show significant differences between groups and remained within the in vivo range during EVLP. Mean oxygenation indices were 491 +/- 39 in the acellular group and 513 +/- 53 in the cellular group. Groups only differed significantly in terms of higher pulmonary artery pressure and vascular resistance in the cellular group. Lung histology and ultrastructure were largely well preserved after prolonged EVLP and showed only minor structural alterations which were similarly present in both groups. Prolonged acellular and cellular EVLP for 12 h are both feasible with lungs prechallenged by ischaemic organ stress. Physiological and ultrastructural analysis showed no superiority of either acellular or cellular perfusate composition.
- Becker, S.; Steinmeyer, J.; Avsar, M.; Hoffler, K.; Salman, J.; Haverich, A.; Warnecke, G.; Ochs, M.; Schnapper, A.
Keywords
- Animals
- Cold Ischemia/*methods
- Disease Models, Animal
- Extracorporeal Circulation/*methods
- Female
- Flow Cytometry/methods
- Graft Rejection
- Graft Survival
- Immunohistochemistry
- Lung/*pathology
- Lung Transplantation/adverse effects/*methods
- Organ Preservation/*methods
- Organ Preservation Solutions/pharmacology
- Perfusion/methods
- Random Allocation
- Risk Assessment
- Sensitivity and Specificity
- Sus scrofa
- Swine
- Time Factors
- Tissue Donors
- acellular perfusion
- cellular perfusion
- ex vivo lung perfusion
- large animal model
- lung physiology
- lung ultrastructure
|
10.1111/tri.12649 |
Transpl Int |
ELD |
MHH |
BREATH |
Original |
2016 |
| 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) |
- Galie, N.; Humbert, M.; Vachiery, J. L.; Gibbs, S.; Lang, I.; Torbicki, A.; Simonneau, G.; Peacock, A.; Vonk Noordegraaf, A.; Beghetti, M.; Ghofrani, A.; Gomez Sanchez, M. A.; Hansmann, G.; Klepetko, W.; Lancellotti, P.; Matucci, M.; McDonagh, T.; Pierard, L. A.; Trindade, P. T.; Zompatori, M.; Hoeper, M.; Aboyans, V.; Vaz Carneiro, A.; Achenbach, S.; Agewall, S.; Allanore, Y.; Asteggiano, R.; Paolo Badano, L.; Albert Barbera, J.; Bouvaist, H.; Bueno, H.; Byrne, R. A.; Carerj, S.; Castro, G.; Erol, C.; Falk, V.; Funck-Brentano, C.; Gorenflo, M.; Granton, J.; Iung, B.; Kiely, D. G.; Kirchhof, P.; Kjellstrom, B.; Landmesser, U.; Lekakis, J.; Lionis, C.; Lip, G. Y.; Orfanos, S. E.; Park, M. H.; Piepoli, M. F.; Ponikowski, P.; Revel, M. P.; Rigau, D.; Rosenkranz, S.; Voller, H.; Luis Zamorano, J.
Keywords
- Adult
- Algorithms
- Antihypertensive Agents/therapeutic use
- Arrhythmias, Cardiac/etiology
- Balloon Embolectomy/methods
- Biomarkers/metabolism
- Cardiac Catheterization/methods
- Child
- Combined Modality Therapy/methods
- Connective Tissue Diseases/complications/diagnosis/therapy
- Cross Infection/prevention & control
- Drug Interactions
- Echocardiography/methods
- Elective Surgical Procedures/methods
- Electrocardiography
- Exercise Test/methods
- Exercise Therapy/methods
- Female
- Genetic Counseling
- Genetic Testing/methods
- HIV Infections/complications/diagnosis/therapy
- Health Status
- Heart Defects, Congenital/complications/diagnosis/therapy
- Hemangioma/complications/diagnosis/therapy
- Hemoptysis/etiology
- Humans
- Hypertension, Portal/complications/diagnosis/therapy
- Hypertension, Pulmonary/*diagnosis/etiology/*therapy
- Lung Transplantation/methods
- Magnetic Resonance Angiography/methods
- Multimodal Imaging/methods
- Patient Compliance
- Pregnancy
- Pregnancy Complications, Cardiovascular/therapy
- Referral and Consultation
- Respiratory Function Tests/methods
- Risk Assessment/methods
- Risk Factors
- Social Support
- Terminal Care/methods
- Therapies, Investigational/methods
- Thromboembolism/complications/diagnosis/therapy
- Tomography, X-Ray Computed/methods
- Travel Medicine/methods
- Treatment Outcome
- Ventricular Dysfunction, Right/complications/therapy
- Chronic thromboembolic pulmonary hypertension
- Congenital heart disease
- Connective tissue disease
- Endothelin receptor antagonists
- Guidelines
- Heart failure
- Left heart disease
- Lung disease
- Phosphodiesterase type 5 inhibitors
- Prostacyclin analogues
- Pulmonary arterial hypertension
- Pulmonary hypertension
- Respiratory failure
|
10.1093/eurheartj/ehv317 |
Eur Heart J |
PH |
MHH |
BREATH |
Original |
2016 |
| Changes in Dynamic Pelvic Floor Magnet Resonance Imaging and Patient Satisfaction after Resection Rectopexy for Obstructed Defecation Syndrome |
PURPOSE: Resection rectopexy (RR) provides good functional results and low recurrence rates for the treatment of obstructed defecation syndrome based on rectal prolapse and cul-de-sac syndrome, whereas little is known about changes in pelvic floor dynamics and patient satisfaction after surgery. MATERIALS AND METHODS: Within three years 26 consecutive female patients were prospectively included. Indications for RR (22 laparoscopic, 3 primary open and 1 converted-to-open) were rectal prolapse III degrees in 11 patients and cul-de-sac syndrome in 15 patients. Patients' quality of life (QOL), fecal behavior and defecation-associated pain were investigated before and after surgical treatment using anamnesis and clinical examination, Rand 36-idem health survey (SF-36), Cleveland-Clinic Incontinence Score (CCIS) and the visual analog scale for defecation-associated pain (VAS). Dynamic pelvic floor magnet resonance imaging (dPF-MRI) was used for the investigation of changes in pelvic floor anatomy and function before and after surgery. RESULTS: RR improved the rate of fecal incontinence (p < 0.01) and CCIS (p = 0.01). The use of laxatives (p = 0.01), the need for self-digitation (p = 0.02) and VAS (p < 0.01) were decreased, leading to improvements in QOL (overall p < 0.01). RR led to shortening of the H-line but not of the M-line under rest (p < 0.01) and during defecation (p = 0.04). A rectocele was co-incident in all patients in dPF-MRI before surgery. RR led to a reduction (p < 0.01) and declined protrusion (p = 0.03) of the rectocele. This results in a decreased rate of cul-de-sac (p < 0.01) and increased rate of complete defecation (p < 0.01) after surgery. At the 36-month follow-up no recurrence was observed. CONCLUSION: RR promises high rates of patient satisfaction and improvement in pelvic floor anatomy in select patients. KEY POINTS: * RR improves the pelvic floor anatomy of patients suffering from ODS. * RR improves the QOL of patients suffering from ODS. * An improvement in pelvic floor anatomy led to an improved QOL. * RR is an adequate treatment for select patients suffering from ODS.
- Reichert, M.; Busse, A.; Hecker, A.; Askevold, I.; Kampschulte, M.; Wusten, O.; Krombach, G. A.; Schwandner, T.; Padberg, W.
Keywords
- Adult
- Aged
- Defecation/*physiology
- Female
- Humans
- Magnetic Resonance Imaging/*methods
- Middle Aged
- *Patient Satisfaction
- Pelvic Floor/*physiopathology/*surgery
- Pelvic Floor Disorders/*physiopathology/*surgery
- Postoperative Complications/*diagnosis/*physiopathology
- Quality of Life
- Rectum/*physiopathology/*surgery
- Syndrome
|
10.1055/s-0041-105406 |
Rofo |
PLI |
JLU |
UGMLC |
Original |
2016 |
| Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis |
Alpha-1-antitrypsin deficiency (AATD) is a hereditary disorder that is characterized by a low serum level of alpha-1-antitrypsin (AAT). The loss of anti-inflammatory and antiproteolytic functions, together with pro-inflammatory effects of polymerized AAT contribute to protein degradation and increased inflammation resulting in an increased risk of developing chronic obstructive pulmonary disease (COPD) and emphysema, especially in smokers. AATD is a rare disease that is significantly underdiagnosed. According to recent data that are based on extrapolations, in many countries only 5-15% of homozygous individuals have been identified. Furthermore, the diagnostic delay typically exceeds 5 years, resulting in an average age at diagnosis of about 45 years. Although the American Thoracic Society/European Respiratory Society recommendations state that all symptomatic adults with persistent airway obstruction should be screened, these recommendations are not being followed. Potential reasons for that include missing knowledge about the disease and the appropriate tests, and the low awareness of physicians with regard to the disorder. Once the decision to initiate testing has been made, a screening test (AAT serum level or other) should be performed. Further diagnostic evaluation is based on the following techniques: polymerase chain reaction (PCR) for frequent and clinically important mutations, isoelectric focusing (IEF) with or without immunoblotting, and sequencing of the gene locus coding for AAT. Various diagnostic algorithms have been published for AATD detection (severe deficiency or carrier status). Modern laboratory approaches like the use of serum separator cards, a lateral flow assay to detect the Z-protein, and a broader availability of next-generation sequencing are recent advances, likely to alter existing algorithms.
- Greulich, T.; Vogelmeier, C. F.
Keywords
- Adult
- Delayed Diagnosis
- Humans
- Isoelectric Focusing
- Mass Screening/*methods
- Middle Aged
- Polymerase Chain Reaction
- Pulmonary Disease, Chronic Obstructive/etiology
- Pulmonary Emphysema/etiology
- Smoking/adverse effects
- alpha 1-Antitrypsin/*blood
- alpha 1-Antitrypsin Deficiency/*diagnosis/genetics/physiopathology
- Alpha-1-antitrypsin deficiency (AATD)
- awareness
- diagnosis
- screening
- test
|
10.1177/1753465815602162 |
Ther Adv Respir Dis |
General Lung and Other |
UMR |
UGMLC |
Review |
2016 |
| Circulating Dendritic Cells, Farm Exposure and Asthma at Early Age |
Farm environment has been shown to protect from childhood asthma. Underlying immunological mechanisms are not clear yet, including the role of dendritic cells (DCs). The aim was to explore whether asthma and farm exposures are associated with the proportions and functional properties of DCs from 4.5-year-old children in a subgroup of the Finnish PASTURE birth cohort study. Myeloid DCs (mDCs), plasmacytoid DCs (pDCs) and CD86 expression on mDCs ex vivo (n = 100) identified from peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. MDCs and production of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-alpha) by mDCs were analysed after 5 h in vitro stimulation with lipopolysaccharide (LPS) (n = 88). Prenatal and current farm exposures (farming, stables, hay barn and farm milk) were assessed from questionnaires. Asthma at age 6 years was defined as a doctor's diagnosis and symptoms; atopic sensitization was defined by antigen-specific IgE measurements. Asthma was positively associated with CD86 expression on mDCs ex vivo [adjusted odds ratio (aOR) 4.83, 95% confidence interval (CI) 1.51-15.4] and inversely with IL-6 production in mDCs after in vitro stimulation with LPS (aOR 0.19, 95% CI 0.04-0.82). In vitro stimulation with LPS resulted in lower percentage of mDCs in the farm PBMC cultures as compared to non-farm PBMC cultures. Our results suggest an association between childhood asthma and functional properties of DCs. Farm exposure may have immunomodulatory effects by decreasing mDC proportions.
- Kaario, H.
- Nieminen, J. K.
- Karvonen, A. M.
- Huttunen, K.
- Schroder, P. C.
- Vaarala, O.
- von Mutius, E.
- Pfefferle, P. I.
- Schaub, B.
- Pekkanen, J.
- Hirvonen, M. R.
- Roponen, M.
Keywords
- *Agriculture
- Asthma/*epidemiology/*immunology
- Child
- Child, Preschool
- Cohort Studies
- Dendritic Cells/*immunology
- Female
- Finland
- Flow Cytometry
- Humans
- Hypersensitivity/epidemiology/immunology
- Immunophenotyping
- Male
|
10.1111/sji.12389 |
Scand J Immunol |
AA |
LMU, UMR |
CPC-M, UGMLC |
Original |
2016 |
| Prolonged vasodilatory response to nanoencapsulated sildenafil in pulmonary hypertension |
Direct vasodilator delivery to the airways enables a selective therapy of pulmonary hypertension (PH). However, short-term effects of the applied medication require multiple daily inhalations. Controlled release formulations (polymeric nanomedicines) offer the potential of prolonging drug effects within the respiratory tract, thereby reducing the number of necessary inhalations. In the model of U46619-elicited PH, sildenafil and two sildenafil-loaded polymeric submicron particle formulations were evaluated for their pharmacodynamic and pharmacokinetic characteristics and acute tolerability. Lung-delivered sildenafil caused a selective dose-dependent decline of the pulmonary arterial pressure and vascular resistance. Compared to the transient pharmacodynamic effect observed for sildenafil, the same dose of nanoencapsulated sildenafil resulted in prolongation, but not augmentation, of the pulmonary vasodilatation. An extended pharmacokinetic profile was observed for nanoencapsulated sildenafil, and nanomedicines revealed no acute toxicity. The amplification of pulmonary vasodilatory response caused by nanoencapsulation of sildenafil offers an intriguing approach to ameliorate the therapy of PH. From the Clinical Editor: Pulmonary hypertension usually results in right heart failure long term. Current medical therapy includes the use of potent vasodilators such as sildenafil. In this article, the authors investigated the use of nanoencapsulated formulation for sustained delivery via inhalation route. An extended pharmacokinetic profile was seen for this nanoformulation with little side effects. It is hoped that clinical application of this would come to fruition soon.
- Beck-Broichsitter, M.; Hecker, A.; Kosanovic, D.; Schmehl, T.; Gessler, T.; Weissmann, N.; Ghofrani, H. A.; Kissel, T.; Seeger, W.; Schermuly, R. T.
Keywords
- Administration, Inhalation
- Animals
- Delayed-Action Preparations/*administration & dosage/chemistry
- Diffusion
- Hypertension, Pulmonary/*drug therapy/*physiopathology
- Nanocapsules/*chemistry/ultrastructure
- Pulmonary Circulation/*drug effects
- Rabbits
- Sildenafil Citrate/*administration & dosage/chemistry
- Treatment Outcome
- Vasodilator Agents/administration & dosage
- Controlled drug release
- Polymeric nanomedicines
- Prolonged vasodilation
- Pulmonary drug delivery
- Pulmonary hypertension
- Sildenafil
|
10.1016/j.nano.2015.08.009 |
Nanomedicine |
PH |
JLU, UMR |
UGMLC |
Original |
2016 |
| FXYD1 negatively regulates Na(+)/K(+)-ATPase activity in lung alveolar epithelial cells |
Acute respiratory distress syndrome (ARDS) is clinical syndrome characterized by decreased lung fluid reabsorption, causing alveolar edema. Defective alveolar ion transport undertaken in part by the Na(+)/K(+)-ATPase underlies this compromised fluid balance, although the molecular mechanisms at play are not understood. We describe here increased expression of FXYD1, FXYD3 and FXYD5, three regulatory subunits of the Na(+)/K(+)-ATPase, in the lungs of ARDS patients. Transforming growth factor (TGF)-beta, a pathogenic mediator of ARDS, drove increased FXYD1 expression in A549 human lung alveolar epithelial cells, suggesting that pathogenic TGF-beta signaling altered Na(+)/K(+)-ATPase activity in affected lungs. Lentivirus-mediated delivery of FXYD1 and FXYD3 allowed for overexpression of both regulatory subunits in polarized H441 cell monolayers on an air/liquid interface. FXYD1 but not FXYD3 overexpression inhibited amphotericin B-sensitive equivalent short-circuit current in Ussing chamber studies. Thus, we speculate that FXYD1 overexpression in ARDS patient lungs may limit Na(+)/K(+)-ATPase activity, and contribute to edema persistence.
- Wujak, L. A.
- Blume, A.
- Baloglu, E.
- Wygrecka, M.
- Wygowski, J.
- Herold, S.
- Mayer, K.
- Vadasz, I.
- Besuch, P.
- Mairbaurl, H.
- Seeger, W.
- Morty, R. E.
Keywords
- Adult
- Aged
- Animals
- Cell Line, Tumor
- Epithelial Cells/*metabolism
- Female
- Genetic Vectors
- Humans
- Lentivirus/genetics
- Lung/*metabolism
- Male
- Membrane Glycoproteins/*metabolism
- Membrane Proteins/genetics/*metabolism
- Mice
- Middle Aged
- Neoplasm Proteins/genetics/*metabolism
- Phosphoproteins/genetics/*metabolism
- Promoter Regions, Genetic
- Respiratory Distress Syndrome, Adult/metabolism
- Sodium/metabolism
- Sodium-Potassium-Exchanging ATPase/*metabolism
- Ards
- Edema
- Fxyd
- Ion transport
- Na(+)/K(+)-ATPase
- TGF-beta
|
10.1016/j.resp.2015.09.008 |
Respir Physiol Neurobiol |
ALI |
JLU, RKU |
TLRC, UGMLC |
Original |
2016 |
| Comparison between B.R.A.H.M.S PCT direct, a new sensitive point-of-care testing device for rapid quantification of procalcitonin in emergency department patients and established reference methods - a prospective multinational trial |
BACKGROUND: Procalcitonin (PCT) is increasingly being used for the diagnostic and prognostic work up of patients with suspected infections in the emergency department (ED). Recently, B.R.A.H.M.S PCT direct, the first high sensitive point-of-care test (POCT), has been developed for fast PCT measurement on capillary or venous blood samples. METHODS: This is a prospective, international comparison study conducted in three European EDs. Consecutive patients with suspicion of bacterial infection were included. Duplicate determination of PCT was performed in capillary (fingertip) and venous whole blood (EDTA), and compared to the reference method. The diagnostic accuracy was evaluated by correlation and concordance analyses. RESULTS: Three hundred and three patients were included over a 6-month period (60.4% male, median age 65.2 years). The correlation between capillary or venous whole blood and the reference method was excellent: r2=0.96 and 0.97, sensitivity 88.1% and 93.0%, specificity 96.5% and 96.8%, concordance 93% and 95%, respectively at a 0.25 mug/L threshold. No significant bias was observed (-0.04 and -0.02 for capillary and venous whole blood) although there were 6.8% and 5.1% outliers, respectively. B.R.A.H.M.S PCT direct had a shorter time to result as compared to the reference method (25 vs. 144 min, difference 119 min, 95% CI 110-134 min, p<0.0001). CONCLUSIONS: This study found a high diagnostic accuracy and a faster time to result of B.R.A.H.M.S PCT direct in the ED setting, allowing shortening time to therapy and a more wide-spread use of PCT.
- Kutz, A.; Hausfater, P.; Oppert, M.; Alan, M.; Grolimund, E.; Gast, C.; Alonso, C.; Wissmann, C.; Kuehn, C.; Bernard, M.; Huber, A.; Mueller, B.; Schuetz, P.
Keywords
- Adolescent
- Adult
- Aged
- Blood Chemical Analysis/*methods/standards
- Calcitonin/*blood
- Calcitonin Gene-Related Peptide
- *Emergency Service, Hospital
- Female
- Humans
- Immunochromatography/*methods
- Male
- Middle Aged
- *Point-of-Care Testing/standards
- Prospective Studies
- Protein Precursors/*blood
- Young Adult
|
10.1515/cclm-2015-0437 |
Clin Chem Lab Med |
ELD |
MHH |
BREATH |
Original |
2016 |
| NADPH oxidases-do they play a role in TRPC regulation under hypoxia? |
In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation.
- Malczyk, M.
- Veith, C.
- Schermuly, R. T.
- Gudermann, T.
- Dietrich, A.
- Sommer, N.
- Weissmann, N.
- Pak, O.
Keywords
- Animals
- Humans
- Hypoxia/*metabolism
- NADPH Oxidases/*metabolism
- Reactive Oxygen Species
- Signal Transduction
- TRPC Cation Channels/*metabolism
- Hypoxic pulmonary vasoconstriction
- NADPH oxidases
- Pulmonary hypertension
- Pulmonary vascular remodelling
- Transient receptor potential channels
|
10.1007/s00424-015-1731-3 |
Pflugers Arch |
PH |
JLU, LMU |
CPC-M, UGMLC |
Review |
2016 |
| Percutaneous dilatational tracheostomy (PDT) in trauma patients: a safe procedure |
PURPOSE: Percutaneous dilatational tracheostomy (PDT) is a standard procedure routinely performed on intensive care units. While complication rates and long-term outcomes have been studied in different patient populations, there are few studies known to these authors involving PDT in trauma patients and the complications which may result. METHODS: Between March 2007 and August 2013, all instances and peri-procedural complications during PDT occurring on the trauma intensive care unit, a unit specialized in the care of injured patients and especially polytrauma patients, were documented. PDTs were performed by a surgeon with the assistance and supervision of another, using bronchoscopic guidance performed by the respiratory medicine department. RESULTS: 289 patients were included in the study, 225 men and 64 women with a mean age of 49 +/- 21 years. Complications occurred in 37.4 % of cases. The most common complication, bleeding, occurred in 26.3 % of patients ranging from little to severe bleeding. Fracture of tracheal cartilage occurred in 6 % of PDT cases. Additional complications such as dislocation of the guidewire, hypotension, and oxygen desaturation were observed. Most complications did not require treatment. The second tracheal intercartilaginous space was successfully intubated in 82 % of cases. CONCLUSIONS: PDT is a safe procedure in trauma patients. When considering the severity of complications such as major blood loss, pneumothorax, or death, this evidence suggests that PDT is safer in trauma patients compared to other patient cohorts.
- Decker, S.; Gottlieb, J.; Cruz, D. L.; Muller, C. W.; Wilhelmi, M.; Krettek, C.; Wilhelmi, M.
Keywords
- Complications
- Multiple injured
- Percutaneous dilatational tracheotomy
- Polytrauma
- Ventilation
- Weaning
|
10.1007/s00068-015-0578-9 |
Eur J Trauma Emerg Surg |
ELD |
MHH |
BREATH |
Original |
2016 |
| Steroid Treatment Reduces Allergic Airway Inflammation and Does Not Alter the Increased Numbers of Dendritic Cells and Calcitonin Gene-Related Peptide-Expressing Neurons in Airway Sensory Ganglia |
OBJECTIVES: Our previous data demonstrated that allergic airway inflammation induces migration of dendritic cells (DC) into airway sensory jugular and nodose ganglia (jugular-nodose ganglion complex; JNC). Here we investigated the effects of steroid treatment regarding the expression and migration of DC and calcitonin gene-related peptide (CGRP)-immunoreactive neurons of vagal sensory ganglia during allergic airway inflammation. METHODS: A house dust mite (HDM) model for allergic airway inflammation was used. The mice received 0.3 mg fluticasone propionate per kilogram of body weight in the last 9 days. JNC slices were analyzed on MHC II, the neuronal marker PGP9.5, and the neuropeptide CGRP. RESULTS: Allergic airway inflammation increased the numbers of DC and CGRP-expressing neurons in the JNC significantly in comparison to the controls (DC/neurons: HDM 44.58 +/- 1.6% vs. saline 33.29 +/- 1.6%, p < 0.05; CGRP-positive neurons/total neurons: HDM 30.65 +/- 1.9% vs. saline 19.49 +/- 2.3%, p < 0.05). Steroid treatment did not have any effect on the numbers of DC and CGRP-expressing neurons in the JNC compared to HDM-treated mice. CONCLUSIONS: The present findings indicate an important role of DC and CGRP-containing neurons in the pathogenesis of allergic airway inflammation. However, steroid treatment did not have an effect on the population of DC and neurons displaying CGRP in the JNC, whereas steroid treatment was found to suppress allergic airway inflammation.
- Le, D. D.; Funck, U.; Wronski, S.; Heck, S.; Tschernig, T.; Bischoff, M.; Sester, M.; Herr, C.; Bals, R.; Welte, T.; Braun, A.; Dinh, Q. T.
Keywords
- Analysis of Variance
- Animals
- Calcitonin Gene-Related Peptide/*metabolism
- Dendritic Cells/*drug effects
- Disease Models, Animal
- Female
- Fluticasone/toxicity
- Histocompatibility Antigens Class II/metabolism
- In Vitro Techniques
- Lung/pathology
- Mice
- Mice, Inbred BALB C
- Neurons/*drug effects
- Nodose Ganglion/*pathology
- *Respiratory Hypersensitivity/chemically induced/drug therapy/pathology
- Steroids/*therapeutic use
- Ubiquitin Thiolesterase/metabolism
|
10.1159/000440622 |
Neuroimmunomodulation |
AA |
ITEM |
BREATH |
Original |
2016 |
