Application of computational toxicological approaches in human health risk assessment. I. A tiered surrogate approach

Hazard identification and dose–response assessment for chemicals of concern found in various environmental media are typically based on epidemiological and/or animal toxicity data. However, human health risk assessments are often requested for many compounds found at contaminated sites throughout the US that have limited or no available toxicity information from either humans or animals. To address this issue, recent efforts have focused on expanding the use of structure–activity relationships (SAR) approaches to identify appropriate surrogates and/or predict toxicological phenotype(s) and associated adverse effect levels. A tiered surrogate approach (i.e., decision tree) based on three main types of surrogates (structural, metabolic, and toxicity-like) has been developed. To select the final surrogate chemical and its surrogate toxicity value(s), a weight-of-evidence approach based on the proposed decision tree is applied. In addition, a case study with actual toxicity data serves as the evaluation to support our tiered surrogate approach. Future work will include case studies demonstrating the utility of the surrogate approach under different scenarios for data-poor chemicals. In conclusion, our surrogate approach provides a reasonable starting point for identifying potential toxic effects, target organs, and/or modes-of-action, and for selecting surrogate chemicals from which to derive either reference or risk values.     

On the use of sample entropy to analyze human postural sway data

We analyze the irregularity of human postural sway data during quiet standing using the sample entropy (SampEn) algorithm. By considering recent methodological developments, we show that the SampEn parameter is able to characterize the irregularity of the center of pressure fluctuations through the analysis of the velocity variable. We present a practical method to select the input parameters of the SampEn algorithm. We show that the computed SampEn successfully discriminates two sensory conditions (eyes-open and eyes-closed) in a group of healthy young adults. We also perform surrogate data tests to investigate the nature of the underlying dynamics of our experimental data. Finally, the results of the proposed approach are compared to those obtained with the multiscale entropy algorithm.     

细胞图像分析预测食管上皮增生转归的研究

目的　探讨食管癌前期病变细胞核的染色质特征与癌变的关系,并对其癌变进行早期预测。方法　标本取自1983 年林县河顺乡食管细胞学普查。鳞状上皮重度增生93 例,轻度增生122例。所有标本均为食管拉网涂片,巴氏染色。图像输入设备是Axiomat 图像分析系统,由VAX4000500计算机控制,idl 软件。每一样本随机选择100 以上保存完好的鳞状上皮中层细胞,用100 ×物镜进行细胞核的测量。结果　从100 多个染色质形态、光密度和纹理的特征中,选出15 个有意义的特征进行判断。93 例重度增生3 年、5 年和9 年后癌变的病例作为高分辨率细胞分析样本,细胞图像分析判断为癌变的分别为18 例、12 例和6 例,判断正确率分别为75 .0 % (18/24) 、85 .7 % (12/14) 和85 .7 % (6/7) ;122 例轻度增生3 年、5 年和9 年后癌变的病例,细胞图像分析判断为癌变的分别为15 例、10 例和10 例,判断正确率分别为93 .8 % (15/16) 、76 .9 % (10/13) 和83 .3 % (10/12) 。结论　利用高分辨率细胞图像分析系统提取细胞核的特征能够区别癌变组和非癌变组,并可对癌前病变进行癌变的早期预测,在肿瘤预防研究中可以作为代用终期生物学指标之一。     

Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations?

AIMS: Measurement of change in carotid intima-media thickness (CIMT) has been proposed as an alternative for the occurrence of cardiovascular (CV) events in the assessment of therapeutic interventions. Nevertheless, criticism has been voiced based on observations indicating a weak relation between CIMT and coronary atherosclerosis as well as on the virtual absence of data showing that progression of CIMT indeed predicts coronary artery disease (CAD) and stroke. METHODS AND RESULTS: We set out to review the evidence on these issues by performing a literature search on these topics. Of the 34 studies on the relation of CIMT with coronary atherosclerosis, as assessed by angiography (n=33) or intravascular ultrasound (n=1), 30 showed a modest positive relationship; the magnitude of which was similar to that found in autopsy studies. Of all studies on CIMT and future CV events (n=18), 17 showed graded positive relationships. At present, only one study has provided evidence on the relation of change in CIMT and future CV events, showing an increased risk with CIMT progression. The paucity of data on progression and future CV risk is partly attributable to time windows required to complete these studies. CONCLUSION: The modest relation between CIMT and coronary atherosclerosis most likely reflects variability in atherosclerosis development between the vascular beds rather than limitations of CIMT measurements. Additional data on the relation between change in CIMT and future CV events is required and currently is in progress.     

分泌带有PGL-I末端三糖内影像的单克隆抗独特型抗体杂交瘤的建立

用抗-PGL-Ⅰ末端三糖的单克隆抗体E_(10)F_1(MAb_1)免疫BALB/c鼠,取脾细胞与SP2/O骨髓瘤细胞融合,建立了两株分泌抗PGL-Ⅰ末端三糖的抗独特型抗体杂交瘤,命名为F_7B_7和F_7B_9。对F_7B_7做了鉴定,得以下结果:①F_7B_7能与E_(10)F_1发生特异反应;②交叉ELISA中和试验呈阳性反应:抗三糖阳性血清与含在半合成抗原NT-O-BSA中的三糖结合时受F_7B_7的抑制,其抑制程度呈剂量依赖关系;抗三糖阳性血清与F_7B_7的结合受NT-O-BSA的抑制,其抑制程度也呈剂量依赖关系。以上结果提示:杂交瘤F_7B_7是能分泌带有PGL-Ⅰ上三糖内影像的单克隆抗独特型抗体。对F_7B_7为替代抗原,作麻风病患者的血清学诊断的可能性和优越性进行了讨论。     

代孕技术的伦理争议与合理规范

代孕技术作为人类辅助生殖技术之一,在积极服务于不孕不育人群的同时,也引发了社会对伦理道德和现有法律之间的激烈争议。通过介绍我国代孕技术应用和立法现状,借鉴国外有关代孕技术在法律实践方面的经验,从法学、医学、社会学等角度进行理论分析,论证代孕技术在我国合法化的可行性,并从代孕技术实施条件、代孕子女归属和代孕母亲法律地位等方面,提出构建我国代孕技术立法规范化的设想。     

Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels

AIM: To study the response to infliximab in pediatric inflammatory bowel disease (IBD), as reflected in fecal calprotectin levels. METHODS: Thirty-six pediatric patients with IBD [23 Crohn’s disease (CD), 13 ulcerative colitis (UC); median age 14 years] were treated with infliximab. Fecal calprotectin was measured at baseline, and 2 and 6 wk after therapy, and compared to blood inflammatory markers. Maintenance medication was unaltered until the third infusion but glucocorticoids were tapered off if the pat...     

Association Between Quality of Cheap and Unrecorded Alcohol Products and Public Health Consequences in Poland

Background: The research aimed to study the quality of cheap alcohol products in Poland. These included unrecorded alcohols (i.e., home‐produced or illegally imported), estimated to constitute more than 25% of total consumption and fruit wines. Methods: A sample of alcohol products (n = 52) was collected from local markets and chemical analyses were conducted. The parameters studied were alcoholic strength, volatiles (methanol, acetaldehyde, and higher alcohols), ethyl carbamate, inorganic elements, and food additives including preservatives, colors, and sweeteners. The compositions of the beverages were then toxicologically evaluated using international standards. Results: With the exception of 1 fortified wine, the unrecorded alcohols were home‐produced fruit‐derived spirits (moonshine) and spirits imported from other countries. We did not detect any nonbeverage surrogate alcohol. The unrecorded spirits contained, on average, 45% vol of alcohol. However, some products with considerably higher alcoholic strengths were found (up to 85% vol) with no labeling of the content on the bottles. These products may cause more pronounced detrimental health effects (e.g., liver cirrhosis, injuries, some forms of malignant neoplasms, alcohol use disorders, and cardiovascular disease) than will commercial beverages, especially as the consumer may be unaware of the alcohol content consumed. Fruit wines containing between 9.5 and 12.2% vol alcohol showed problems in terms of their additive content and their labeling (e.g., sulfites, sorbic acid, saccharin, and artificial colors) and should be subjected to stricter control. Regarding the other components investigated, the suspected human carcinogens, acetaldehyde and ethyl carbamate, were found at levels relevant to public health concerns. While acetaldehyde is a typical constituent of fermented beverages, ethyl carbamate was found only in home‐produced unrecorded alcohols derived from stone fruits with levels significantly above international guidelines. Conclusions: The contamination of unrecorded alcohols with ethyl carbamate should be analyzed in a larger sample that also should include legal alcoholic beverages. Furthermore, the impacts of unrecorded alcohol on the health of people with lower socioeconomic status should be studied in detail. Overall, given the extent of the alcohol‐attributable disease burden in Poland, the highest priority should be given to the problem of ethanol and its very high content in unrecorded alcohol products.     

Cardiovascular and Renal Surrogate Markers in the Clinical Management of Hypertension

Introduction  Surrogate markers represent a significant contribution to early diagnosis, longitudinal prognoses, and outcome prediction in cases of hypertension. They often enable detection of disease and disease potential when the disease is still subclinical and are useful noninvasive tools for designing and evaluating therapeutic programs. Surrogate markers are increasingly employed as predictive endpoints for treatment. Methods  Key studies supporting the importance of surrogate markers as diagnostic and prognostic predictors of cardiovascular and renal clinical outcomes in hypertension, as well as what is known about the effects of renin-angiotensin-aldosterone system-blocking agents on these biomarkers were reviewed. Results  Clinical data supporting the use of surrogate markers for heart failure, such as brain natriuretic peptide (BNP) and N-terminal prohormone BNP; markers for renal function, such as urinary albumin to creatinine ratio (UACR), urinary albumin excretion rates (UAER), and creatinine, reflecting glomerular filtration; and markers of cardiac remodeling, such as left ventricular hypertrophy and calculations of left ventricular mass index (LVMI), were reviewed for their utility in improving prognosis and treatment efficacy. Finally, hypertension treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and potentially direct renin inhibitors can significantly improve outcomes predicted by surrogate markers. Conclusions  BNP, UACR, UAER, and LVMI, among others, have been increasingly established as valid surrogate markers with significant value for hypertension prognosis and therapy. The benefits of using surrogate markers to gauge the effectiveness of hypertension therapy in reducing renal and cardiac complications can be seen in improved morbidity and mortality.