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Felix Ratjen

Publications and source records attributed to Felix Ratjen.

At least 19 recordsLinked to original sources
PubMed2026

PangyPlot: multi-scale interactive visualization of pangenome variation graphs.

SUMMARY: Pangenome variation graphs integrate multiple samples into a unified representation, mitigating the reference bias inherent to linear genomes. However, these graphs can be large and structurally complex. Existing visualization tools are each confined to a fixed scale of resolution, requiring researchers to switch between multiple tools to examine variation at different levels of detail. PangyPlot is an interactive pangenome browser designed for multi-scale exploration of reference variation graphs from full chromosome to nucleotide-level sequence segments. PangyPlot anchors navigation to linear reference coordinates, organizes variation into hierarchical bubble structures, and uses a force-directed layout engine for automatic node arrangement. AVAILABILITY AND IMPLEMENTATION: An instance preloaded with data is available at https://pangyplot.research.sickkids.ca. Source code and documentation are openly available at https://github.com/strug-hub/pangyplot under the MIT License.

Software↗
PubMed2006

Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis.

BACKGROUND: L-arginine is the common substrate for nitric oxide synthases and arginases. Increased arginase levels in the blood of patients with cystic fibrosis may result in L-arginine deficiency and thereby contribute to low airway nitric oxide formation and impaired pulmonary function. METHODS: Plasma amino acid and arginase levels were studied in ten patients with cystic fibrosis before and after 14 days of antibiotic treatment for pulmonary exacerbation. Patients were compared to ten healthy non-smoking controls. RESULTS: Systemic arginase levels measured by ELISA were significantly increased in cystic fibrosis with exacerbation compared to controls (17.3 +/- 12.0 vs. 4.3 +/- 3.4 ng/ml, p < 0.02). Arginase levels normalized with antibiotic treatment. Plasma L-arginine was significantly reduced before (p < 0.05) but not after treatment. In contrast, L-ornithine, proline, and glutamic acid, all downstream products of arginase activity, were normal before, but significantly increased after antibiotic therapy. Bioavailability of L-arginine was significantly reduced in cystic fibrosis before and after exacerbation (p < 0.05, respectively). CONCLUSION: These observations provide further evidence for a disturbed balance between the L-arginine metabolic pathways in cystic fibrosis.

Journal Article↗
PubMed2006

Diagnosing and managing infection in CF.

Acute and chronic bacterial infections of the lower respiratory tract remain one of the hallmarks of cystic fibrosis lung disease. We here review some of the controversial areas of diagnosing airway infection in CF patients including the use of techniques such as induced sputum and bronchoalveolar lavage. Treatment strategies have evolved over the years and there is ongoing discussion as to whether to treat on the basis of symptoms, positive cultures alone or continuously regardless of clinical and laboratory findings. Prophylactic antibiotic therapy with anti-staphylococcal antibiotics has been linked to a higher incidence of P. aeruginosa infection, but it is still unclear whether this side effect is limited to broader spectrum antibiotics such as cephalosporins. Early antibiotic therapy against P. aeruginosa has become an accepted treatment strategy as it not only delays the onset of chronic infection, but also leads to eradication of the organism in the majority of patients. So far no evidence exists that combination therapy is superior to inhaled therapy alone. In addition, the optimal duration of therapy type of inhaled antibiotic as well as the optimal dose has not been clarified. Studies are currently ongoing to resolve these issues.

Anti-Bacterial Agents↗
PubMed2006

What's new in CF airway inflammation: an update.

Neutrophilic airway inflammation is a characteristic feature of cystic fibrosis (CF) lung disease and present in most patients with pulmonary manifestations of the disease. Here we discuss the ongoing controversy whether the CFTR mutation itself causes a pro-inflammatory milieu in the airways or whether inflammation is always secondary to infection. Since the presence of inflammation has been shown to be a risk factor for subsequent lung function decline, noninvasive tests to monitor airway inflammation are urgently needed. Induced sputum is currently being assessed as a clinical and research tool, but unfortunately is only feasible in cooperative children. While nonspecific treatment approaches that decrease infection or improve clearance of airway secretions were found to positively affect airway inflammation, specific anti-inflammatory treatment strategies have been less successful. Since any intervention that decreases inflammation may potentially have a detrimental effect by promoting airway infection, a better understanding of the factors regulating inflammation in the CF lung will form the basis for more targeted treatment strategies in the future.

Animals↗
PubMed2006

Inhaled L-arginine improves exhaled nitric oxide and pulmonary function in patients with cystic fibrosis.

RATIONALE: Nitric oxide formation is deficient in airways of patients with cystic fibrosis (CF). Since nitric oxide has bronchodilatory effects, nitric oxide deficiency may contribute to airway obstruction in CF. OBJECTIVES: We reasoned that inhalation of l-arginine, the precursor of enzymatic nitric oxide formation, could improve airway nitric oxide formation and pulmonary function in patients with CF. MEASUREMENTS: Exhaled nitric oxide, pulmonary function, and peripheral oxygen saturation were measured before and after a single inhalation of nebulized l-arginine solution in patients with CF and in healthy subjects. A saline solution of similar osmolarity (1.7%) was used as control. RESULTS: Nebulized l-arginine not only significantly increased exhaled nitric oxide concentrations but also resulted in a sustained improvement of FEV(1) in patients with CF. Oxygen saturation also increased significantly after the inhalation of l-arginine. Nebulized saline resulted in a small but significant increase in exhaled nitric oxide but a decrease in FEV(1) in patients with CF. In control subjects inhalation of l-arginine increased exhaled nitric oxide concentrations, but FEV(1) decreased. No effect of saline on exhaled nitric oxide, pulmonary function, or oxygen saturation was observed in healthy subjects. CONCLUSIONS: These data suggest that a single inhalation of l-arginine acutely and transiently improves pulmonary function in CF through the formation of nitric oxide. Augmentation of airway nitric oxide formation by inhalation of l-arginine is a promising therapeutic approach in patients with CF.

Administration, Inhalation↗
PubMed2006

P2Y2 receptor polymorphisms and haplotypes in cystic fibrosis and their impact on Ca2+ influx.

OBJECTIVE: Activation of P2Y2 receptors in airway epithelia by ATP and UTP stimulates a Ca2+-regulated Cl- channel, which regulates Cl- secretion in cystic fibrosis (CF). We hypothesized that genetic alterations in the P2Y2 receptor may act as disease modifiers in CF and thus analyzed the coding region of this gene for polymorphisms in 146 CF patients and 64 healthy controls. We also assessed the impact of the genetic variants on Ca2+-influx of P2Y2-null cells transfected with several P2Y2 receptor haplotypes. RESULTS: We identified three frequent nonsynonymous P2Y2 receptor polymorphisms: Leu46Pro; Arg312Ser and Arg334Cys, of which only Arg312Ser was significantly more common in CF: Arg = 0.80, Ser = 0.20 (CF) vs. Arg = 0.72, Ser = 0.28 (controls), P < 0.05; for Leu46Pro, Leu = 0.92, Pro = 0.08 (CF) vs. Leu = 0.96, Pro = 0.04 (controls), P = 0.65 and for Arg334Cys, Arg = 0.79, Cys = 0.21 (CF) vs. Arg = 0.84, Cys = 0.16 (controls), P = 0.79. The most frequent haplotype was Leu46Leu/Arg312Arg/Arg334Arg (28% in CF, 31% in controls) but 6% of CF patients and none of the controls had Leu46Leu/Ser312Ser/Arg334Cys or Leu46Leu/Arg312Arg/Cys334Cys. To assess function of the receptor haplotypes, we stably transfected 1321N1 (P2Y-null) cells to similar levels of mRNA expression with Leu46Leu/Arg312Arg/Arg334Arg (wild-type), Leu46Leu/Ser312Ser/Arg334Arg and Leu46Leu/Arg312Arg/Cys334Cys and measured ATP-stimulated transient Ca2+-influx. Cells expressing the homozygous Cys334 variant had significantly increased Ca2+-influx compared to wild-type (P<0.01). The increase in Ca2+-influx was more pronounced in cells carrying the homozygous Ser312 variant than in cells with the other two genotypes (P<0.01). CONCLUSIONS: These data indicate that P2Y2 receptor gene haplotypes influence intracellular Ca2+-release. Such genetic variants might therefore represent modifiers of Cl- secretion or of response to P2Y2 agonist therapy in CF.

Adolescent↗
PubMed2006

Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis.

PURPOSE OF REVIEW: While Pseudomonas aeruginosa continues to be the major pathogen in cystic fibrosis lung disease, there is increasing evidence that antibiotic therapy initiated early after the onset of infection is an effective strategy to postpone chronic P. aeruginosa infection. There are also studies showing that early treatment can eradicate the organism in the majority of cases. RECENT FINDINGS: While comparative data for different treatment strategies are currently lacking, inhaled antibiotic therapy alone or in combination with ciprofloxacin has been shown to be efficacious. So far eradication of P. aeruginosa has not been associated with an increased risk of airway infection with other pathogens, but these studies have been performed in small cohorts. Additional information is also needed to clarify the optimal form and duration of therapy. Currently, there are two large studies ongoing to resolve some of these issues. SUMMARY: There is sufficient evidence that early antibiotic therapy against P. aeruginosa can clear the bacteria from the respiratory tract. While the negative effects of chronic P. aeruginosa infection are well documented, long-term benefits of this intervention on lung function is lacking. Observational studies suggest, however, that early intervention therapy is both beneficial and cost effective for cystic fibrosis patients.

Anti-Bacterial Agents↗
PubMed2006

Multidrug-resistant organisms in cystic fibrosis: management and infection-control issues.

Chronic infection and inflammation are the hallmarks of cystic fibrosis lung disease. As cystic fibrosis patients are living longer owing to more intense treatment, multidrug-resistant organisms are being isolated increasingly from patients' respiratory tracts. While the adverse effects of Pseudomonas aeruginosa and Burkholderia cepacia complex are well described, less is known about the clinical significance of other emerging multidrug-resistant organisms, such as methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Owing to multiple mechanisms of antimicrobial resistance, these organisms are difficult to treat and often require combination antibiotic therapy. Until more is known about their pathogenicity and effect on clinical outcomes, physicians should be aware of the potential transmissibility of these organisms and implement adequate infection control strategies.

Anti-Infective Agents↗
PubMed2005

Sequential analysis of surfactant, lung function and inflammation in cystic fibrosis patients.

BACKGROUND: In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time. METHODS: As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV1 94% of predicted) at three times over a three year period. RESULTS: There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV1, MEF(75/25%VC), and MEF(25%VC). The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period. CONCLUSION: Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.

Cross-Sectional Studies↗
PubMed2005

Increased arginase activity in cystic fibrosis airways.

RATIONALE: Airway nitric oxide concentrations are reduced in cystic fibrosis (CF). Arginases compete for L-arginine, the substrate of nitric oxide synthesis. OBJECTIVES: We hypothesized that increased arginase activity may be one factor contributing to nitric oxide deficiency in CF. MEASUREMENTS: We therefore studied sputum arginase activity, exhaled nitric oxide, and pulmonary function in patients with cystic fibrosis. RESULTS: Mean (+/- SEM) sputum arginase activity was significantly higher in patients admitted for pulmonary exacerbation compared with patients with stable disease (1.032 +/- 0.148 vs. 0.370 +/- 0.091 U/mg protein, p = 0.004). Fourteen days of intravenous antibiotic treatment resulted in significantly decreased sputum arginase activity in all patients (p = 0.0002). However, arginase activity was still significantly (p = 0.0001) higher in CF sputum after treatment for exacerbation compared with induced sputum from healthy control subjects (0.026 +/- 0.006 U/mg protein). Negative correlations were found for sputum arginase activity at admission with FEV1 (r = -0.41, p = 0.01), as well as changes in arginase activity with percent change in FEV1 during antibiotic therapy (r = -0.4, p < 0.01) in CF. Exhaled nitric oxide in CF was positively correlated to FEV1 (r = 0.34, p = 0.007), and in patients admitted for pulmonary exacerbation negatively correlated to sputum arginase activity (r = -0.45, p = 0.03). CONCLUSIONS: These data suggest that increased sputum arginase activity contributes to nitric oxide deficiency in CF lung disease and may be relevant in the pathogenesis of CF airway disease.

Adolescent↗
PubMed2005

Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis.

Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.

Adolescent↗
PubMed2005

Human adenosine 2B receptor: SNP discovery and evaluation of expression in patients with cystic fibrosis.

OBJECTIVES AND METHODS: We analyzed the adenosine 2B (A2B) receptor gene, which consists of two exons, for single nucleotide polymorphisms (SNPs) and tested the hypothesis that coding sequence polymorphisms in the gene contribute to disease state in patients with cystic fibrosis (CF). Using PCR and restriction fragment length polymorphism (RFLP) analysis, we assessed 53 American subjects of mixed ethnicity, 64 European Caucasian control subjects and 148 Caucasian patients with CF for A2B SNPs. RESULTS: We identified one SNP in the 5' untranslated region (UTR) and seven SNPs in the open reading frame. One SNP was identified in the coding region of a German patient with CF but in none of the American subjects. No other SNPs were found in CF patients. A nonsynonymous SNP was identified in exon 2 of the German controls with an allelic frequency of 11%. The US subjects were of mixed ethnicity and most frequently (10.4%) had a SNP in the 5'UTR; 7 coding SNPs occurred in <3%. All SNPs other than the Leu96Phe and Gly136Arg variants were found only in African-Americans. Of the 26 African-Americans who were genotyped, 42% were hypertensive but the study group was too small to show an association between blood pressure status and SNP expression. CONCLUSIONS: The data show that SNPs in the A2B receptor gene are much more frequent in African-Americans than in Caucasians and that German Caucasians, but not African-Americans, express Gly136Arg. None of the SNPs identified in A2B receptors are likely to be modifiers in CF.

Adult↗
PubMed2004

Pulmonary surfactant, lung function, and endobronchial inflammation in cystic fibrosis.

Cystic fibrosis (CF) lung disease is primarily a disease of the small airways. We hypothesized that even in patients with normal lung function, a reduced surfactant function would be present and favor small airway obstruction. Bronchoalveolar lavages from 76 patients with CF (5-31 years, median 11) with well-conserved lung function (FEV1 94% predicted, range 78-121) and from 10 healthy control subjects were investigated. The deviation of the biophysical surfactant performance from normal, assessed in a bubble surfactometer, was small; however, the ability of the surfactant to maintain the patency of a narrow airway (% open) was significantly reduced. Surfactant protein (SP)-C level was increased, SP-B and SP-D were unchanged, whereas SP-A was decreased. Among the patients with CF, neutrophilic inflammation was modestly related to a poorer surfactant activity, but not to lung function. SP-D was reduced in proportion to the degree of inflammation and in the presence of bacteria. These findings in a large cohort of patients with CF with normal lung function show that the endobronchial airway inflammation is linked to early perturbations of the biophysical properties and immunologic components of pulmonary surfactant and opens fields for novel therapeutic interventions.

Adolescent↗
PubMed2004

Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis.

Chronic neutrophilic inflammation leads to oxidative damage, which may play an important role in the pathogenesis of cystic fibrosis lung disease. Bronchoalveolar lavage levels of the antioxidant glutathione are diminished in patients with cystic fibrosis. Here we evaluated the effects of glutathione aerosol on lower airway glutathione levels, lung function, and oxidative status. Pulmonary deposition of a radiolabeled monodisperse aerosol generated with a Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) connected to an AKITA inhalation device (Inamed, Gauting, Germany) was determined in six patients. In 17 additional patients bronchoalveolar lavage fluid was assessed before and after 14 days of inhalation with thrice-daily doses of 300 or 450 mg of glutathione. Intrathoracic deposition was 86.3 +/- 1.4% of the emitted dose. Glutathione concentration in lavage 1 hour postinhalation was increased three- to fourfold and was still almost doubled 12 hours postinhalation. FEV(1) transiently dropped after inhalation but increased compared with pretreatment values after 14 days (p < 0.001). This improvement was not related to the lavage content of oxidized proteins and lipids, which did not change with treatment. These results show that, using a new inhalation device with high efficacy, glutathione treatment of the lower airways is feasible. Reversion of markers of oxidative injury may need longer treatment, higher doses, or different types of antioxidants.

Adolescent↗
PubMed2004

Dornase in non-CF.

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Bronchiectasis↗
PubMed2004

Microaspiration in infants with laryngomalacia.

OBJECTIVES/HYPOTHESIS: Laryngomalacia is the most common congenital laryngeal anomaly and the most frequent cause of stridor in infants. Infants with laryngomalacia may have associated respiratory symptoms other than stridor. In this study, we evaluated whether infants with laryngomalacia have episodes of microaspiration by calculating the amount of lipids present in the alveolar macrophages. STUDY DESIGN: We reviewed bronchoalveolar lavage (BAL) findings obtained in 14 infants with laryngomalacia and in 11 control children. METHODS: BAL was performed during flexible fiberoptic bronchoscopy (FFB) to diagnose persistent stridor. The presence of microaspiration was determined by evaluating the amount of lipid per single macrophage, assigning each cell a score from 0 to 4 according to the amount of lipid in the cytoplasm. RESULTS: The lipid-laden macrophage index was similar in patients and controls (31.5, range 12-177 vs. 45, range 35-106). In 5 of the 14 (36%) patients the index exceeded 100, and more than 25% of the cells were graded 3 and 4, indicating the presence of microaspiration. The lipid-laden macrophage index correlated significantly with the number and percentage of BAL neutrophils (Pearson correlation test, r = 0.83, P < .001 and r = 0.925, P < .001) as a marker of lung inflammation. CONCLUSIONS: Infants with laryngomalacia may have episodes of microaspiration. BAL performed during FFB to evaluate stridor may add helpful therapeutic information without increasing the risks of the procedure.

Bronchoalveolar Lavage Fluid↗