Interstitial lung diseases in children

Interstitial lung disease (ILD) in children (chILD) is a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and the diseases share common features of inflammatory and fibrotic changes of the lung parenchyma that impair gas exchanges. The etiologies of chILD are numerous. In this review, we chose to classify them as ILD related to exposure/environment insults, ILD related to systemic and immunological diseases, ILD related to primary lung parenchyma dysfunctions and ILD specific to infancy. A growing part of the etiologic spectrum of chILD is being attributed to molecular defects. Currently, the main genetic mutations associated with chILD are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1. Other genetic contributors include mutations in MARS, CSF2RA and CSF2RB in pulmonary alveolar proteinosis, and mutations in TMEM173 and COPA in specific auto-inflammatory forms of chILD. However, only few genotype-phenotype correlations could be identified so far. Herein, information is provided about the clinical presentation and the diagnosis approach of chILD. Despite improvements in patient management, the therapeutic strategies are still relying mostly on corticosteroids although specific therapies are emerging. Larger longitudinal cohorts of patients are being gathered through ongoing international collaborations to improve disease knowledge and targeted therapies. Thus, it is expected that children with ILD will be able to reach the adulthood transition in a better condition.     

Prediction of skin sensitization potency using machine learning approaches

The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non‐sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non‐animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave‐one‐out cross‐validation. A one‐tiered strategy modeled all three categories of response together while a two‐tiered strategy modeled sensitizer/non‐sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two‐tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one‐tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non‐animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.     

A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.     

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

冷藏ACD-EDTA抗凝血和全血细胞计数稳定性观察

目的　观察ACD EDTA抗凝血作为血细胞计数质控物或校准物的稳定性。方法　在ACD抗凝血中加入适量EDTA抗凝剂 ,冷藏保存 ,在Beckman CoulterACTdiffⅡ、SysmexK 4 5 0 0、AbbottCell Dyn 1 2 0 0和ABXMicros 6 0共 4台仪器上连续测定 1 0d ,观察白细胞 (WBC)、红细胞 (RBC)、血红蛋白 (HGB)、血细胞比容 (HCT)和血小板 (PLT)共 5项参数的变化。结果　每天新开瓶的ACD EDTA抗凝全血在 1 0d内 ,各仪器测定结果的偏倚值差异无显著性 (P >0 .0 5 )。每天新开瓶的ACD EDTA抗凝红细胞悬液在 1 0d内 ,各仪器测定WBC和PLT结果的偏倚值差异有显著性 (P <0 .0 1 )。ACD EDTA抗凝全血一次性开瓶后 ,连续测定 1 0d ,则各仪器测定WBC和PLT结果的偏倚值差异有显著性 (P <0 .0 1 )。结论　ACD EDTA抗凝血在冷藏条件下能稳定 1 0d左右 ,但在不同仪器有不同的测定值。总之 ,ACD EDTA抗凝血因其制备方便 ,相对稳定 ,可作为短期质控物或校准物使用。     

Evaluation of the immunomodulatory and DNA protective activities of the shoots of Cynodon dactylon

Ethnopharmacological relevance

Fresh juice of Cyanodon dactylon known as ‘durva’ grass is employed in India as a rejuvenator and for wound healing.

Aim of the study

To validate the traditional use of the herb through evaluation of DNA protective activity in vitro and immunomodulatory activity in vivo.

Materials and methods

Fresh juice of the grass was prepared as indicated for use in traditional medicine and standardized for solid content. Its total phenol content was estimated by Folin–Ciocalteau method. Freshly prepared juice was investigated for its effect on doxorubicin-induced DNA damage in vitro. Its immunomodulatory activity was tested on balb/c mice by the humoral antibody response which was determined by haemagglutination antibody titer and spleen cell assay.

Results

Fresh juice of Cyanodon dactylon of 1.46% (w/w) solid content had a phenolic content of 47 ± 0.33 mg/kg GAE. At doses equivalent to 50, 100 and 200 mg total solids/kg body weight the juice protected human DNA against doxorubicin-induced DNA damage as demonstrated in DNA spectral studies, where the ratio of absorbance of DNA at 260 and 280 nm in samples pretreated with the juice was 1.66, 1.53 and 1.63 respectively, while it was 1.37 for DNA treated with doxorubicin only. This indicates nucleic acid purity in the Cynodon dactylon treated samples. Oral administration of the juice at 250 and 500 mg/kg in balb/c mice increased humoral antibody response upon antigen challenge, as evidenced by a dose-dependent, statistically significant increase in antibody titer in the haemagglutination antibody assay and plaque forming cell assay.

Conclusions

The present report demonstrated the DNA protective activity and immunomodulatory property of the fresh juice of Cynodon dactylon validating the traditional use of the herb as a ‘rasayana’ in ayurvedic system of medicine.     

Pentacam眼前节成像分析系统在晶状体半脱位中的应用研究

目的 评估Pentacam眼前节成像分析系统在晶状体半脱位诊断和疗效评估中的应用价值.方法 通过测量50名(100只眼)正常人眼前房的深度,获得角膜直径4mm范围内6个对称点相对应的前房深度差异范围.对7例(9只眼)晶状体半脱位患者的Scheimpflug图像及6个对称点前房深度值和正常值范围进行对比分析.结果 Scheimpflug图像能直观显示晶状体脱位的方向,定量显示脱位的范围,通过三维前房分析系统对术后6个对称点前房深度值和正常值范围进行对比分析,可判断患者手术后的视觉效果.结论 Pentacam眼前节成像分析系统为晶状体半脱位临床诊断提供有效的证据,对术后疗效的评估具有一定的指导意义.     

ACD/Log P method description

This study describes the development of the ACD/Log P calculation method. Analysis of 14 calculation methods revealed that the most accurate calculations are obtained when correction factors are used. We evaluated the correction factors used by Hansch and Leo in CLOGP in order to simplify their method. Most of the CLOGP structural factors are included in our fragmental increments. Aliphatic and aromatic factors are replaced with additive interfragmental increments. Missing increments are estimated by two empirical equations with simple physical interpretation. The final method uses three simple equations with several types of parameters. The training set included 3601 compounds and the correlation between experimental and calculated Log P values gave R = 0.992, S = 0.21. The method was validated by comparing it with 17 other methods on various data sets of independently selected drugs and other compounds. In all cases, our method produced the best results. The weakness of this method is that it uses a large number of individual increments for aromatic interactions. Each increment represents a combination of several effects which presently cannot be separated. This revised version was published online in August 2006 with corrections to the Cover Date.     

体外测定CPDA与ACD全血在4℃以上的有效保存期

为确定血液在4℃以上的有效保存期并为战时血液保存与运输提供依据，采集10名健康献血者全血各200ml，每袋分出50ml标记为对照组，其余为实验组。将对照组置于4℃冰箱保存，于保存末期检测红细胞ATP含量为临界ATP；将实验组置于10—33℃下保存，每天测定ATP等指标，以临界ATP为指示点确定有效保存期。结果显示，在10—33℃条件下CPDA全血有效保存期为2．5-18天，ACD全血有效保存期为1—13天。结论：4℃以上保存的CPDA全血可以在有效保存期内运送到前线，使伤员得到快速有效的输血救治。