NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.     

Low energy charge and high adenosine content in smooth muscle of human bladder in comparison with striated muscle

Summary This study determined the energy charge, adenosine and inosine content of human bladder smooth muscle in comparison with striated muscle of the same individual. Biopsies were obtained from 21 women who were subjected to urethrocystopexy because of urinary stress incontinence. We found that the ATP content of bladder smooth muscle was only about one-eighth of that of striated muscle. The energy charge of bladder smooth muscle was 0.78±0.13, which is low compared with striated muscle (0.92±0.02). The adenosine content of bladder smooth muscle was 6.7 times higher than striated muscle and the adenosine/ATP ratio was 1∶9 compared with 1∶450 for striated muscle. These findings were in accordance with our previous studies on uterine smooth muscle.     

Compartmentation of cardiac adenine nucleotides and formation of adenosine

Summary After prelabeling the adenine nucleotides (ATP, ADP, AMP) of isolated perfused guinea pig hearts with either¹⁴C-adenine or¹⁴C-adenosine for 35 min, labeled adenosine, inosine, hypoxanthine and cyclic 35-AMP (cAMP) were continuously released into the cardiac perfusate. Determination of the specific activities (SA) of the adenine nucleotides, cAMP, and their breakdown products (adenosine, inosine, hypoxanthine) in tissue and perfusate revealed: Under steady state conditions the SA of adenosine and cAMP in the perfusate were of the same order of magnitude and proved to be many times higher than the SA of the respective precursor adenine nucleotides. This difference was observed regardless whether adenine or adenosine was used as prelabeling substance. The SA of inosine and hypoxanthine in the perfusate were constantly lower than the SA of adenosine. Cardiac ischemia of 6 min, which resulted in a markedly increased formation of adenosine, led to a pronounced decrease in the SA of adenosine released from the heart.Our findings provide evidence that at least two different adenine nucleotide compartments of the heart serve as precursors for the formation of adenosine and cAMP, one characterized by a high, the other by a lower SA. Under normoxic conditions adenosine and cAMP released into the cardiac perfusate are derived mainly from a nucleotide fraction of high SA, which appears to be rather small. During ischemia a second compartment of much lower SA in addition contributes to the formation of adenosine.A preliminary report of part of this work appeared in Biochemistry and Pharmacology of Myocardial Hypertrophy, Hypoxia and Infarction Vol. 7 of Recent advances in studies on cardiac structure and metabolism. (P. Harris, R. J. Bing, A. Fleckenstein, eds.), pp. 171–175. München: Urban & Schwarzenberg 1976A preliminary report of part of this work appeared in Biochemistry and Pharmacology of Myocardial Hypertrophy, Hypoxia and Infarction Vol. 7 of Recent advances in studies on cardiac structure and metabolism. (P. Harris, R. J. Bing, A. Fleckenstein, eds.), pp. 171–175. München: Urban & Schwarzenberg 1976     

视神经萎缩的治疗临床研究

目的 探讨视神经萎缩的有效治疗方法。方法 对324例526例眼视神经萎缩患,用胞二磷胆碱、肌苷做球后注射。结果 临床治愈88例,显效261例,进步106眼,有效率86．9％,收到了较满意的效果。结论 胞二磷胆碱、肌苷可通过卵磷脂的合成改善视神经周围的血液循环,刺激和促进视神经纤维的生物修补,从而导致视神经功能的改善和恢复。     

超滤法提取肌苷工艺

采用超过滤膜对肌苷发酵液进行超滤，再经浓缩、结晶、干燥，得到粗苷。实验确定最佳超滤条件为：压力0．15Mpa，温度64．9℃。肌苷提取收率为85．7％，其粗苷中肌苷含量为73．2％。比离子交换法提取肌苷，收率提高15个百分点。     

Adenine pool catabolism in the ischemic, the calcium-depleted ischemic, and the substrate free anoxic isolated rat heart: Relationship to contracture development

Metabolic changes in the myocardial adenine and hypoxanthine pools of isolated rat hearts subjected to global ischemia, hypocalcemic global ischemia, and global substrate-free anoxia were compared. At timed intervals between 0 and 60 min separate aliquots of extracts of the ventricles were used to determine either tissue pH, or the components of the adenine pool and their catabolites by reverse phase high performance liquid chromatography (HPLC). The coronary perfusate draining from anoxically perfused hearts was collected over perchloric acid, neutralised and chromatographed by HPLC. The development of left ventricular resting tension (contracture) was recorded in the three groups of hearts. After 60 min ischemia the major catabolites, (AMP, inosine and hypoxanthine) comprised 70% of the total pool (11, 7 and 4 mumol/g dry wt, respectively). After the same period of anoxia 50% of the total pool, comprising adenosine, inosine, hypoxanthine and uric acid in approximately equal proportions, was recovered from the coronary perfusate. The major products remaining in the tissue were IMP and, to a lesser extent AMP (8 and 5 mumol/g dry wt, respectively). Left ventricular contracture developed at different rates in the three groups of hearts but always correlated closely with the maximum rate of adenine pool catabolism. The loss of components from the tissue and the divergence in pathway from adenosine to IMP production which occurs during anoxic perfusion should possibly be considered when assessing the biochemical events occurring in regionally ischemic heart muscle with significant residual flow.     

HPLC法检查腺苷注射液的有关物质

目的:建立腺苷注射液中有关物质的检查方法。方法:采用高效液相色谱法。色谱柱为Agilent TC C18,流动相为乙腈-0.01 mol/L磷酸二氢钾溶液(pH 5.8)(12∶88),流速为1.0 ml/min,检测波长为260 nm。已知杂质按外标法以峰面积计算含量;总杂质及其他单个杂质以自身对照法计算。结果:在该色谱条件下,腺苷与各杂质分离良好,腺苷检测质量浓度线性范围为0.3³0μg/ml,特定杂质尿苷、鸟苷、肌苷及腺嘌呤检测质量浓度线性范围均为0.0330μg/ml,特定杂质尿苷、鸟苷、肌苷及腺嘌呤检测质量浓度线性范围均为0.03³.0μg/ml(r=0.999 83.0μg/ml(r=0.999 8¹.000),检测限为0.03、0.21、1.20、0.21、0.03 ng。结论:该方法操作简单、灵敏度高,为更好地控制产品的质量提供了有效的检查方法。     

A novel, biodegradable polymer conduit delivers neurotrophins and promotes nerve regeneration.

OBJECTIVE/HYPOTHESIS: A wide variety of substances have been shown to promote neuritic extension after nerve injury. An obstacle to achieving the maximal benefit from these substances has been the difficulty in effectively delivering the substances over a protracted time course that promotes maximal, directed growth. In this study the delivery of a growth-promoting substance through a biodegradable conduit, using materials originally designed for drug delivery applications, was hypothesized to promote more robust neural regeneration than through conduits lacking the substance. The objectives of this study were to create a growth factor-loaded biodegradable nerve guidance conduit, and to assess in vivo nerve regeneration through the conduit compared with that through conduits lacking the substance. MATERIALS/METHODS: Inosine, a purine analogue thought to promote axonal extension following neural injury, was loaded into cylindrical polymer foams composed of a polylactide-co-glycolide copolymer. First, in vitro extravasation of inosine was measured over a several week period using spectrophotometry. Second, the foams were fashioned into single-channel cylindrical nerve guidance conduits via a novel, low-pressure injection molding technique. The conduits were then used to bridge 7-mm defects in the rat sciatic nerve (n = 8). Control conduits lacking inosine were implanted into another set of animals as controls (n = 12). RESULTS: In vitro spectrophotometric measurements indicated appreciable leaching of inosine from the loaded foams over a period of at least 9 weeks. In the in vivo model, after 10 weeks, a higher percentage cross sectional area composed of neural tissue existed through the inosine-loaded conduits compared with controls (mean 44%, SD 7.5% vs. 36%, SD 8.6%, respectively). A difference was also found in mean fiber diameter between the two groups, with the inosine-loaded tubes showing a statistically significantly larger diameter than controls (P < .05). CONCLUSIONS: A nerve regeneration conduit was successfully created that delivers growth promoting substances over a protracted time course. In an in vivo model, the presence of inosine, a purine analogue, yielded neural regeneration whose histological features suggest possible superior long-term motor function.     

大剂量阿托品联合三磷酸胞苷二钠救治重度有机磷中毒的临床价值

目的 探讨阿托品联合三磷酸胞苷二钠（CTP）救治重度急性有机磷中毒（AOPP）的疗效和临床价值。方法 68例重度AOPP患者分成研究组36例，对照组32例。前者采用大剂量阿托品联合CTP治疗，后者单纯使用大剂量阿托品治疗。观察两组患者机械通气时间、中间综合征（IMS）和迟发性周围神经病变（OPIDP）发生率。结果 研究组机械通气时间（291．8±73．5）h，迟发性周围神经病变2例，与对照组比较差异有统计学意义（P〈0．01）。结论 阿托品联合CTP治疗重度AOPP能有效缩短机械通气时间、降低OPIDP的发生率、有重要的临床应用价值。