Jakob Usemann

EZH2 mutation in an adolescent with Weaver syndrome developing acute myeloid leukemia and secondary hemophagocytic lymphohistiocytosis

Weaver syndrome is an overgrowth syndrome characterized by pre‐ and postnatal overgrowth with distinctive craniofacial appearance. Mutations in the enhancer of zeste homolog 2 (EZH2) gene were found to cause Weaver syndrome, and have been associated with hematologic malignancies, including acute myeloid leukemia (AML). We present the first report of a patient with Weaver syndrome, who developed AML and harbored an EZH2 mutation. The clinical course of the 16‐year‐old female adolescent patient was complicated by a secondary hemophagocytic lymphohistiocytosis. Genomic DNA was isolated from bone marrow cells at AML diagnosis. Polymerase chain reactions were performed with primers covering all exons of the EZH2 gene. We found a novel heterozygous EZH2 mutation within exon 5 that caused an amino acid change from proline to leucine at position 132 (p.Pro132Leu) within the catalytic D1 domain. Analysis of a remission sample also showed this mutation, indicating a germline mutation. It remains to be elucidated whether EZH2 mutations contribute to disease severity in specific AML cases.

Relationship between computerized wheeze detection and lung function parameters in young infants.

Computerized respiratory sound analysis (CORSA) has been validated in the assessment of wheeze in infants, but it is unknown whether automatically detected wheeze is associated with impaired lung function. This study investigated the relationship between wheeze detection and conventional lung function testing (LFT) parameters.

Effects of gasoline and ethanol-gasoline exhaust exposure on human bronchial epithelial and natural killer cells in vitro

Air pollution exposure, including passenger car emissions, may cause substantial respiratory health effects and cancer death. In western countries, the majority of passenger cars are driven by gasoline fuel. Recently, new motor technologies and ethanol fuels have been introduced to the market, but potential health effects have not been thoroughly investigated. We developed and verified a coculture model composed of bronchial epithelial cells (ECs) and natural killer cells (NKs) mimicking the human airways to compare toxic effects between pure gasoline (E0) and ethanol-gasoline-blend (E85, 85% ethanol, 15% gasoline) exhaust emitted from a flexfuel gasoline car. We drove a steady state cycle, exposed ECs for 6h and added NKs. We assessed exhaust effects in ECs alone and in cocultures by RT-PCR, flow cytometry, and oxidative stress assay. We found no toxic effects after exposure to E0 or E85 compared to air controls. Comparison between E0 and E85 exposure showed a weak association for less oxidative DNA damage after E85 exposure compared to E0. Our results indicate that short-term exposure to gasoline exhaust may have no major toxic effects in ECs and NKs and that ethanol as part of fuel for gasoline cars may be favorable.

“Lung sparing growth”: is the lung not affected by malnutrition?

Malnutrition is a major cause of mortality and morbidity in developing countries [1]. It has been reported to play a role in different acute and chronic disease conditions [2–4], including respiratory diseases and lung development [5, 6]. Starting in utero, maternal malnutrition during pregnancy may influence postnatal lung function directly (e.g. through decreased alveolar number), or indirectly (e.g. through intrauterine growth retardation, prematurity or low birth weight) [7]. There is clear evidence of detrimental effects of vitamin A deficiency in pregnancy on lung function in childhood [8]. Early postnatal malnutrition was associated with several adverse pulmonary effects and lung injury in animal models, e.g. decreased lung protein and DNA synthesis in the lungs [9], whereas breastfeeding and balanced nutrition is thought to be protective [10, 11]. Furthermore, Vitamin D and C deficiency have been reported to cause deficits in lung function and structure [12, 13]. To summarise, malnutrition potentially influences respiratory health and lung function on multiple levels. “Lung sparing growth”: intriguing hypothesis to explain why the lung is not affected by severe acute malnutrition http://ow.ly/9V5d309M1ho

CHI3L1 polymorphisms, cord blood YKL-40 levels and later asthma development

BackgroundSingle nucleotide polymorphisms (SNPs) in chitinase 3-like 1 (CHI3L1), the gene encoding YKL-40, and increased serum YKL-40 levels are associated with severe forms of asthma. It has never been addressed whether SNPs in CHI3L1 and cord blood YKL-40 levels could already serve as potential biomarkers for milder forms of asthma. We assessed in an unselected population whether SNPs in CHI3L1 and cord blood YKL-40 levels at birth are associated with respiratory symptoms, lung function changes, asthma, and atopy.MethodsIn a prospective birth cohort of healthy term-born neonates (n = 260), we studied CHI3L1 polymorphisms, and measured cord blood YKL-40 levels by ELISA in (n = 170) infants. Lung function was performed at 5 weeks and 6 years. Respiratory health during the first year of life was assessed weekly by telephone interviews. Diagnosis of asthma and allergic sensitisation was assessed at 6 years (n = 142).ResultsThe SNP rs10399805 was significantly associated with asthma at 6 years. The odds ratio for asthma was 4.5 (95 % CI 1.59–12.94) per T-allele. This finding was unchanged when adjusting for cord blood YKL-40 levels. There was no significant association for cord blood YKL-40 levels and asthma. SNPs in CHI3L1 and cord blood YKL-40 were not associated with lung function measurements at 5 weeks and 6 years, respiratory symptoms in the first year, and allergic sensitisation at 6 years.ConclusionGenetic variation in CHI3L1 might be related to the development of milder forms of asthma. Larger studies are warranted to establish the role of YKL-40 in that pathway.

Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls

Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.

Interrupter technique in infancy: Higher airway resistance and lower short‐term variability in preterm versus term infants

In preschool children, measurement of airway resistance using interrupter technique (Rint) is feasible to assess the degree of bronchial obstruction. Although some studies measured Rint in infancy, values of Rint and its variability in preterm infants are unknown. In this study, Rint and its variability was measured at infancy and compared between healthy term and preterm infants.

Fresh frozen plasma transfusion – a risk factor for pulmonary hemorrhage in extremely low birth weight infants?

Abstract Aim: To evaluate risk factors for pulmonary hemorrhage (PH) in extremely low birth weight infants (ELBW) taking into consideration coagulation screens, platelet counts, transfusion of fresh frozen plasma (FFP), and platelet concentrates prior to PH. Patients and methods: A retrospective case-control study consisting of 20 ELBW infants with PH and 40 matched controls. Coagulation screens, platelet counts at birth and at onset of PH, and transfusion frequencies prior to PH were compared to case-controls at birth and 24–96 h after birth. Results: While the initial platelet counts, fibrinogen concentrations, and international normalized ratios were similar in PH infants and controls, the activated partial prothrombin time was prolonged (P=0.05). Compared to 28% of case controls (P<0.05), 55% of infants with later PH received FFP prior to PH. Platelet counts were significantly lower at onset of PH (median 81/nL; range: 37–236/nL) compared to controls (166/nL; 27–460/nL; P<0.005). Multivariate analysis indicated a lack of antenatal steroids, supplemental oxygen, and transfusion of FFP as independent risk factors for PH. Conclusion: Prolonged activated partial thromboplastin time (aPTT) might be associated with PH. PH does not primarily depend upon severe thrombocytopenia. A developmental mismatch in hemostasis by transfusion of adult donor plasma should be considered a risk factor for PH.

A big step forward in understanding global differences in respiratory health: First lung function data in African infants

Early life lung function is associated with lung function in later life (so-called tracking of lung function) and subsequent respiratory morbidity (reviewed in). To prevent later respiratory disease, it is therefore crucial to assess determinants of early lung development as they impact upon long-term respiratory morbidity and even mortality. Among others, maternal exposure during pregnancy towards air pollution or tobacco smoke has been shown to affect lung function already in newborns (reviewed in). Before pathological values of lung function and thus infants at risk for later lung diseases can be identified, reference data on lung function are needed. Since lung function differs between ethnic groups, existing normative values compiled mostly in Caucasians and high-income settings (e.g.) cannot be transferred to non-Caucasians and/or low-income countries. However, the burden of respiratory diseases is highest in those settings. In this regard, the study of Gray et al. in this issue of Respirology is a major step forward closing this gap. The authors not only present data on lung function in South African infants from lowto middle-class parents, but are the first to describe reference data in infants on forced oscillation technique at all. In addition, data on tidal volume, respiratory rate, tidal flows, exhaled nitric oxide, lung clearance index (LCI) and functional residual capacity (FRC) are presented from 448 infants aged 5–11 weeks as part of the Drakenstein Child Health study. Notably, infants were measured without the use of sedation; still the study was performed in a strikingly short period of time (between December 2012 and December 2013). Besides those factors, further strengths are the large sample of the cohort and several methodological aspects. Data collection and analysis was done by a well-trained study team under experienced surveillance, and lung function measurements were performed only in one centre. The latter is of relevance, since lung function measures such as FRC can largely differ when studied in several centres even when measurements are performed by the same investigators using similar equipment. While most of the lung function measures were comparable to those previously reported in European infants, significant differences were observed for FRC. The FRC reported by Gray et al. was notably smaller compared with that reported by Fuchs et al. (mean ± SD FRC 78 ± 17 mL vs 102 ± 16 mL), corresponding to 24% smaller end expiratory lung volume in African than European infants. How can this surprisingly large difference in FRC between study populations be explained? Differing hardware and software in this case seem rather unlikely as underlying reason, since other parameters such as tidal volumes and LCI were very similar. As mentioned by Gray et al., differences in population characteristics are more likely the cause of differing FRC values. There are numerous reports documenting differences in lung function between ethnic groups. For example, vital capacity and forced expiratory volume in 1 s has been shown to be about 14% smaller in African American than in whites. Besides ethnic differences, different exposures between study populations might also contribute to differences in lung volumes. While it is not easy to differentiate whether the differences in FRC are due to ethnicity, associated with environmental factors or both, this complex interaction should be considered when interpreting study results or determining associations with environmental factors. This is especially important as exposure towards risk factors often differs between ethnic groups and social classes. In this regard, it is relevant to note that the R values of the models for FRC were rather low in both large studies (11% and 13%, respectively). An R value of 100% indicates that all of the variation in the outcome is explained by the examined exposures, while an R of 0% means that only other exposures than those investigated predict the variation in the outcome. This low R value indicates that factors other than age, weight and birthweight are much more predictive of FRC. Further it probably reflects the high physiological variability of end expiratory lung volume in infants, which makes it more difficult to clearly define determinants of lung volume. On the other hand, this high variability could also be regarded as chance, for example to define ‘freedom of breathing’ in infants as a marker of lung development, as has been suggested for preterm infants before. Both at the individual level (coefficient of variation of three measurements) and at the population level (by e.g. comparing R values of exposed and unexposed infants), the strengths of associations could reflect a signal per se and could be used in future analyses. Taken together, the work of Gray and colleagues is a milestone in infant lung function measurements and represents the first normative data in low-income bs_bs_banner

Gasoline particle filter reduces oxidative DNA damage in bronchial epithelial cells after whole gasoline exhaust exposure in vitro

A substantial amount of traffic-related particle emissions is released by gasoline cars, since most diesel cars are now equipped with particle filters that reduce particle emissions. Little is known about adverse health effects of gasoline particles, and particularly, whether a gasoline particle filter (GPF) influences the toxicity of gasoline exhaust emissions. We drove a dynamic test cycle with a gasoline car and studied the effect of a GPF on exhaust composition and airway toxicity. We exposed human bronchial epithelial cells (ECs) for 6 hours, and compared results with and without GPF. Two hours later, primary human natural killer cells (NKs) were added to ECs to form cocultures, while some ECs were grown as monocultures. The following day, cells were analyzed for cytotoxicity, cell surface receptor expression, intracellular markers, oxidative DNA damage, gene expression, and oxidative stress. The particle amount was significantly reduced due to GPF application. While most biological endpoints did not differ, oxidative DNA damage was significantly reduced in EC monocultures exposed to GPF compared to reference exhaust. Our findings indicate that a GPF has beneficial effects on exhaust composition and airway toxicity. Further studies are needed to assess long-term effects, also in other cell types of the lung.