Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion.

PURPOSE: Perillyl alcohol (POH) displays preventive and therapeutic activity against a wide variety of tumor models, and it has been suggested that this might be associated with the ability of POH to interfere with Ras prenylation. POH also selectively induces G(1) arrest and apoptosis in Bcr/Abl-transformed hematopoietic cells. Because signaling through Ras is necessary for Bcr/Abl transformation, we examined whether POH induces its anti-leukemia effect by inhibiting Ras signaling. EXPERIMENTAL DESIGN: The ability of POH to inhibit posttranslational farnesylation and signaling from Ras as well as signaling through the Raf-Mek-Erk cascade was examined in Bcr/Abl-transformed and mock-transformed cells and related to the anti-leukemia effect of POH. RESULTS: POH does not affect Ras prenylation or Ras activity, but it blocks signaling downstream of Ras by reversing the state of activation of the Erk kinase, Mek. POH affects Mek activity only when it is added to intact cells. Treatment of either cell lysates or of purified Mek with POH has no effect on Mek activity. Inhibition of the Mek-Erk pathway seems to be related to the POH anti-leukemia effect for the following reasons: (a) the concentration of POH needed to block the Erk pathway, as well the kinetics with which POH inhibits this signaling cascade, both correlate with the anti-leukemia effect of POH; (b) both U0126 (a specific Mek inhibitor) and POH induce similar anti-leukemia effects; and (c) mock-transformed hematopoietic cells are simultaneously resistant to POH anti-leukemia effects and inhibition of the Mek-Erk pathway. CONCLUSION: Blocking Mek is sufficient to induce growth arrest and apoptosis in Bcr/Abl-transformed cells; therefore, POH represents a novel small molecule inhibitor of Mek that might be effective for treating Bcr/Abl leukemias.     

不同类型高危儿早期干预的临床研究

目的 探索早期干预对窒息、高胆、早产三类高危儿智力发育改善的效果，寻找更合适的早期干预措施。方法 将三类高危儿分为干预组及对照组，同时随机选取正常对照组进行随访。干预组采用鲍秀兰教授“0～3岁”早期干预方案训练，各组均在6个月、1岁时分别采用婴幼儿智能发育量表(CDCC)进行智力发育测评，结果用MDI、PDI表示。结果 (1)6个月龄时MDI各干预组与对照组间有显著性差异，窒息组、早产组与正常组间亦有显著性差异；高胆组与正常组间无差异；PDI窒息组中干预组与对照组之间有显著差异(P＜0．01)，高胆组、早产组均无差异(P＞0．05)。(2)1岁时MDI和PDI结果一致，干预组与对照组间比较窒息组、高胆组有显著差异，早产组无差异；窒息组、高胆组干预组与正常组比较无差异，对照组和早产组与正常组比较均有显著差异(P＜0．01)。(3)所有干预组测评分值均高于对照组，6个月与1岁之间比较有显著差异，各观察组间比较有显著性差异(P＜0．01)。结论 三类高危儿早期干预效果差异较大，干预组均较对照组分值高，早期干预有改善智力发育的作用；三类高危儿中，窒息组、高胆组效果最好，均达到或超过正常水平。所有未干预组均不及正常水平；早期干预对足月高危儿效果显著，对早产儿欠佳，远期效果尚需进一步随访观察。     

Childhood fractures are associated with decreased bone mass gain during puberty: an early marker of persistent bone fragility?

Whether peak bone mass is low among children with fractures remains uncertain. In a cohort of 125 girls followed over 8.5 years, 42 subjects reported 58 fractures. Among those, BMC gain at multiple sites and vertebral bone size at pubertal maturity were significantly decreased. Hence, childhood fractures may be markers of low peak bone mass acquisition and persistent skeletal fragility. INTRODUCTION: Fractures in childhood may result from a deficit in bone mass accrual during rapid longitudinal growth. Whether low bone mass persists beyond this period however remains unknown. MATERIALS AND METHODS: BMC at the spine, radius, hip, and femur diaphysis was prospectively measured over 8.5 years in 125 girls using DXA. Differences in bone mass and size between girls with and without fractures were analyzed using nonparametric tests. The contribution of genetic factors was evaluated by mother-daughter correlations and that of calcium intake by Cox proportional hazard models. RESULTS: Fifty-eight fractures occurred in 42 among 125 girls (cumulative incidence, 46.4%), one-half of all fractures affecting the forearm and wrist. Girls with and without fractures had similar age, height, weight. and calcium intake at all time-points. Before and during early puberty, BMC and width of the radius diaphysis was lower in the fracture compared with no-fracture group (p < 0.05), whereas aBMD and BMAD were similar in the two groups. At pubertal maturity (Tanner's stage 5, mean age +/- SD, 16.4 +/- 0.5 years), BMC at the ultradistal radius (UD Rad.), femur trochanter, and lumbar spine (LS), and LS projected bone area were all significantly lower in girls with fractures. Throughout puberty, BMC gain at these sites was also decreased in the fracture group (LS, -8.0%, p = 0.015; UD Rad., -12.0%, p = 0.004; trochanter, -8.4%, p = 0.05 versus no fractures). BMC was highly correlated between prepuberty and pubertal maturity (R = 0.54-0.81) and between mature daughters and their mothers (R = 0.32-0.46). Calcium intake was not related to fracture risk. CONCLUSIONS: Girls with fractures have decreased bone mass gain in the axial and appendicular skeleton and reduced vertebral bone size when reaching pubertal maturity. Taken together with the evidence of tracking and heritability for BMC, these observations indicate that childhood fractures may be markers for low peak bone mass and persistent bone fragility.     

前列腺癌去雄激素治疗不良反应的预防和处理

目的观察去雄激素治疗前列腺癌的不良反应,并探讨其预防和治疗。方法回顾性分析1998年7月-2006年1月112例去雄激素治疗晚期前列腺癌的临床资料。结果112例患者中,97例完成了不良反应的调查。随访3-36月,去雄激素治疗后潮热、性功能障碍、病理性骨折发生率分别为46％、75％、4％;患者潮热、精神疲乏、四肢乏力、纳差症状明显加重(P<0．05);性功能明显减退(P<0．05)。12例潮热症状严重者使用抗抑郁药博乐欣(25mg,tid)1-2周症状减轻。7例有骨转移性疼痛或严重骨质疏松患者,应用唑来膦酸4mg静脉滴注,每45d一次,骨痛症状缓解。结论去雄激素对前列腺癌患者生活质量有一定影响。博乐欣可减轻患者潮热症状,唑来膦酸可预防和治疗去雄激素相关的骨质疏松并发症。     

大鼠自体平滑肌细胞移植对心肌梗死后心功能恢复的作用

目的:研究自体平滑肌细胞移植到心肌梗死区后对心功能恢复的作用.方法:用酶消化法从SD大鼠的输精管中分离、提取自体平滑肌细胞,进行体外培养、扩增.移植组(n=12)将BrdU标记后的自体平滑肌细胞直接注射移植到左冠脉前降支结扎后2周形成的心肌梗死区瘢痕组织中;对照组(n=12)注射同等剂量的DMEM培养液.超声检查评估移植前和移植后4周的心功能状况.用免疫组化染色的方法,检测心肌瘢痕组织中是否有植入的平滑肌细胞存活以及促血管新生的情况.结果:移植的自体平滑肌细胞能在心肌梗死区内存活并形成肌样组织.与对照组比较,移植组左心室舒张末容积(LVEDV)明显减小[(0.78±0.16) vs (0.92±0.15) ml, P<0.01],左心室射血分数(LVEF)显著提高[(47.6±7.2)％ vs (29.3±6.1)％, P<0.01],心肌瘢痕组织血管新生明显[血管密度:(1.9±0.4)/(0.8 mm2) vs (0.4±0.2)/(0.8 mm2), P<0.01].结论:自体平滑肌细胞移植能防止心肌梗死后的心室腔扩大,促进梗死区血管新生,改善心功能.     

EFFECTS OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IV INHIBITOR, Ro20,1724, ON PANCREATIC EXOCRINE SECRETION IN DOG

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretin and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1–30 nmol/kg), IBMX (3–30 nmol/kg), secretin (0.01–0.1 pmol/kg) or CCK-8 (0.1–1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 μmol/ kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.     

护士配制表柔比星致自身变态反应1例

表柔比星为半合成的第2代蒽环类抗生素，为多柔比星的同分异构体，4-位置上的羟基由顺式变为逆式。这种立体结构上的细微变化提高了抗肿瘤的治疗指数，且降低了骨髓和心脏的毒性。因此，该药目前临床上广泛用于抗肿瘤的治疗。但我院1名护士在配制表柔比星时出现变态反应，现介绍如下。     

Health status,work limitations,and return-to-work trajectories in injured workers with musculoskeletal disorders

BACKGROUND: The purpose of this study was to describe the health status and work limitations in injured workers with musculoskeletal disorders at 1 month post-injury, stratified by return-to-work status, and to document their return-to-work trajectories 6 months post-injury. METHODS: A sample of 632 workers with a back or upper extremity musculoskeletal disorder, who filed a Workplace Safety and Insurance Board lost-time claim injury, participated in this prospective study. Participants were assessed at baseline (1 month post-injury) and at 6 months follow-up. RESULTS: One month post-injury, poor physical health, high levels of depressive symptoms and high work limitations are prevalent in workers, including in those with a sustained first return to work. Workers with a sustained first return to work report a better health status and fewer work limitations than those who experienced a recurrence of work absence or who never returned to work. Six months post-injury, the rate of recurrence of work absence in the trajectories of injured workers who have made at least one return to work attempt is high (38%), including the rate for workers with an initial sustained first return to work (27%). CONCLUSIONS: There are return-to-work status specific health outcomes in injured workers. A sustained first return to work is not equivalent to a complete recovery from musculoskeletal disorders.