Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture

Tamoxifen increases the risk of human endometrial cancer and is a potent carcinogen in rat liver, in which it produces DNA adducts and cytogenetic damage. Nevertheless its prophylactic use against breast cancer in healthy women is under investigation in several large trials. To investigate whether rat hepatocarcinogenicity predicts human hepatocarcinogenicity we used genetically engineered bacterial and mammalian target cells to investigate how alpha-hydroxy-tamoxifen, a major phase I metabolite of tamoxifen, is further metabolised by rat and human phase II enzymes, sulfotransferases, to mutagenic and DNA- adduct-forming species. We expressed rat hydroxysteroid sulfotransferase a, a liver-specific enzyme, and corresponding human sulfotransferase in bacteria (Salmonella typhimurium) and in a mammalian cell line (Chinese hamster V79 cells) and tested alpha- hydroxytamoxifen for DNA adduct formation and mutagenicity in these systems, using unmodified cells as controls. In cells that expressed rat hydroxysteroid sulfotransferase, alpha-hydroxytamoxifen was mutagenic and formed the same pattern of DNA adducts as that found in the liver of tamoxifen-treated rats. Alpha-hydroxytamoxifen was not activated, or was at least 20 times less active in cells expressing human hydroxysteroid sulfotransferase. All the other six known human xenobiotic-metabolising sulfotransferases were also expressed in S. typhimurium. None activated alpha-hydroxytamoxifen to a mutagen. These results suggest that the risk of DNA adduct formation, and cancer, in the human liver is low and explain why tamoxifen is a powerful carcinogen to the rat liver, and why standard short-term tests fail to detect its mutagenicity.      

Smoking-associated bulky DNA adducts in bronchial tissue related to CYP1A1 MspI and GSTM1 genotypes in lung patients

Relationships between smoking status and levels of bulky DNA adducts were investigated in bronchial tissue of lung patients in relation to their GSTM1 and CYP1A1 MspI genotypes. A total of 150 Hungarian patients undergoing pulmonary surgery were included in the study, 124 with lung malignancies and 26 with non-malignant lung conditions. There were significant relationships between smoking status and bulky DNA adduct levels, as determined by 32P-post-labelling analysis, in macroscopically normal bronchial tissues. There was a highly significant difference in the adduct levels of a combined group consisting of current smokers and short-term ex-smokers (< or = 1 year abstinence) compared with life-time non-smokers and long-term ex- smokers (> 1 year abstinence) (P = 0.0001). The apparent half-life was estimated to be 1.7 years for bulky DNA adducts in the bronchial tissue from ex-smokers. There were no statistically significant correlations between (i) daily cigarette dose and DNA adduct levels in current smokers, (ii) DNA adduct level and histological type of lung cancer, or (iii) GSTM1 and CYP1A1 MspI genotypes and DNA adduct levels after adjustment for either smoking status or malignancy. By multiple logistic regression analysis, smoking and GSTM1 null genotype were found to be risk factors for squamous cell carcinoma. However, bulky DNA adduct levels in bronchial tissue did not appear to be a statistically-significant risk factor for the major histological types of lung cancer.      

Metaphyseal growth arrest lines in psychosocial short stature

Metaphyseal growth arrest lines are seen in children who experience significant physical stress such as infection or malnutrition over a sufficient period of time. These lines have not been reported previously in children with psychosocial short stature (PSS). Two boys and a girl with PSS with metaphyseal growth arrest lines on skeletal radiographs at the time of maximal stress in their homes are described. All three had reversible growth hormone insufficiency during admission, which is pathognomic for PSS. Multiple growth arrest lines in the distal end of the radius or vertebrae should alert clinicians to an alternative diagnosis in a child with growth hormone insufficiency. This may provide a clue to the diagnosis of occult PSS.     

Low dose intravenous dexamethasone (4 mg and 10 mg) significantly prolongs the analgesic duration of single-shot interscalene block after arthroscopic shoulder surgery: a prospective randomized placebo-controlled study

Background

Although intravenous dexamethasone prolongs the analgesic duration of interscalene brachial plexus block, it is uncertain whether this effect can be observed using lower doses of dexamethasone. This study evaluated the impact of intravenous dexamethasone (4 mg and 10 mg) on the analgesic duration of single-shot interscalene block after arthroscopic shoulder surgery. We hypothesized that both doses would prolong the analgesic duration compared with placebo.

Methods

This was a prospective double-blind randomized placebo-controlled study in patients undergoing elective arthroscopic shoulder surgery under regional anesthesia with a single-shot interscalene block (0.5% ropivacaine 20 mL). Patients received dexamethasone 4 mg (D4), dexamethasone 10 mg (D10), or a placebo (normal saline [NS]) intravenously at the time of block completion. The primary outcome was the duration of analgesia, defined as the time from the onset of sensory blockade to the first analgesic request. The primary outcome was first analyzed with a Kruskal-Wallis test and then with a Mann-Whitney test for pairwise between-group comparison.

Results

Sixty-nine patients completed the study. The median [interquartile range] duration of analgesia was significantly different between the three groups (D4, 19.7 [16.9-23.3] hr; D10, 19.1 [11.5-22.8] hr; and NS, 11.8 [9.3-14.0] hr; P = 0.001). This difference was statistically significant for D4 and D10 compared with placebo (median difference [MD], 7.8 hr; 95% confidence interval [CI], 4.6 to 11.1 hr; P < 0.001; and MD, 7.4 hr; 95% CI, 4.2 to 10.5 hr; P = 0.001, respectively) but not for D4 compared with D10 (MD, 0.5 hr; 95% CI, ?2.8 to 3.7 hr; P = 0.38).

Conclusions

Low doses of intravenous dexamethasone (4 mg and 10 mg) significantly prolong the analgesic duration of interscalene block. This trial was registered at ClinicalTrials.gov (NCT02412657).

     

胰岛素在严重烧伤大鼠急性肺损伤中的保护作用

目的:观察胰岛素对严重烧伤所致的急性肺损伤的保护效应。方法:实验于2006-01/08在解放军第四军医大学西京医院全军烧伤中心实验室完成。取成年雄性SD大鼠36只,随机分成3组,每组12只:①烫伤 胰岛素组:水浴锅94℃,20s,制备30%总体表面积全层皮肤烫伤模型,伤后即刻腹腔注射生理盐水40mL/kg,并皮下注射胰岛素3U/kg。②烫伤组:造模和腹腔注射同烫伤 胰岛素组,皮下注射等体积生理盐水。③假烫组:用室温水浴模拟烫伤过程,伤后不给予补液。烫伤24h后,收集动脉血测定超氧化物歧化酶活性,收集支气管肺泡灌洗液测定蛋白含量,取肺组织进行苏木精-伊红染色观察病理变化,并测定髓过氧化物酶活性,同时电镜观察胸主动脉血管内皮细胞变化情况。结果:36只大鼠进入结果分析。①肺病理变化:烫伤 胰岛素组肺脏渗出和水肿较烫伤组明显减轻。②肺泡灌洗液中蛋白的质量浓度:烫伤组和烫伤 胰岛素组高于假烫组[(702.9±169.5),(486.5±149.2),(240.5±140.7)mg/L,P<0.05],烫伤 胰岛素组低于烫伤组(P<0.05)。③肺脏髓过氧化物酶活性:烫伤 胰岛素组低于烫伤组[(36.01±8.17),(59.51±12.50)nkat/g,P<0.05],与假烫组比较差异不显著。④血清超氧化物歧化酶活性:烫伤组和烫伤 胰岛素组低于假烫组[(2.27±0.18),(2.63±0.19),(2.81±0.21)mkat/L,P<0.01,0.05],烫伤 胰岛素组高于烫伤组(P<0.01)。⑤电镜下可见烫伤 胰岛素组内皮细胞损伤较烫伤组轻。结论:严重烧伤早期外源性胰岛素干预后可减轻急性肺损伤,具有明显的肺脏保护作用,这种作用可能与胰岛素的内皮细胞保护效应有关。     

兔颧弓骨折骨缺损植骨临界值的确定

目的:在新西兰白兔颧弓上制备不同的骨折骨缺损,以求得兔颧弓骨折骨缺损植骨临界值。方法:实验于2005-06/2006-12在首都医科大学动物实验室完成。①新西兰大白兔36只,采用随机数字表法分成1mm骨缺损组、3mm骨缺损组、5mm骨缺损组和7mm骨缺损组4组,每组9只。在兔一侧颧弓分别制备1,3,5,7mm骨折骨缺损。②于4,8,12周通过大体解剖学、X射线片、病理学观察骨折骨缺损愈合情况。结果:36只兔均进入结果分析。1mm骨缺损4周即骨愈合。3mm骨折骨缺损在术后8周大体观见骨折断端无动度,缺损界线模糊,X射线片显示缺损有较明显外骨痂,骨折局部骨桥连接,骨折线模糊,病理见骨折两断端间充满致密纤维结缔组织,出现少量淡红色骨基质,未见骨性桥接骨痂。12周大体观察见缺损完全愈合,骨密度完全一致,骨折线消失;X射线片显示骨折断端有骨痂连接;病理出现部分骨桥连接。5mm,7mm骨折骨缺损在术后4,12周内经大体观察、X射线片影像、病理检查均未见骨桥,呈现骨不连特征。结论:兔颧弓12周临界骨折骨缺损为5mm,即骨折骨缺损等于或大于5mm,则骨缺损必须植骨,否则骨不连。5mm亦可以作为颌骨临界骨折骨缺损值的参考。     

Intramural Distributions of GAGs and Collagen vs. Opening Angle of the Intact Porcine Aortic Wall

The heterogeneity and contribution of collagen and elastin to residual stresses have been thoroughly studied, but more recently, glycosaminoglycans (GAGs) also emerged as potential regulators. In this study, the opening angle of aortic rings (an indicator of circumferential residual stresses) and the mural distributions of sulfated GAGs (sGAG), collagen, and elastin were quantified in the ascending, aortic arch and descending thoracic regions of 5- to 6-month-old pigs. The opening angle correlated positively with the aortic ring’s mean radius and thickness, with good and moderate correlations respectively. The correlations between the sGAG, collagen, elastin, and collagen:sGAG ratio and the opening angle were evaluated to identify aortic compositional factors that could play roles in regulating circumferential residual stresses. The total collagen:sGAG ratio displayed the strongest correlation with the opening angle (r = ? 0.715, p < 0.001), followed by the total sGAG content which demonstrated a good correlation (r = 0.623, p < 0.001). Additionally, the intramural gradients of collagen, sGAG and collagen:sGAG correlated moderately with the opening angle. We propose that, in addition to the individual role sGAG play through their content and intramural gradient, the interaction between collagen and sGAG should be considered when evaluating circumferential residual stresses in the aorta.