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。     

Reactivity of hydroxybenzoic acids in the hydrogen-isotope exchange reaction.

The hydrogen-isotope exchange reaction (T-for-H exchange reaction) between tritiated water vapor (HTO vapor) and 3-hydroxy-4-methoxybenzoic acid (and it's analog; 4-hydroxy-3-methoxybenzoic acid) were observed at 50 and 70 degrees C in a gas-solid system to reveal the reactivity of a functional group in an aromatic compound having two substituents in the aromatic ring. Further, it was shown that (a) the reactivity of the compounds used in this work follows the Hammett's rule, and (b) the reactivity of trisubstituted aromatic compound could be analyzed by applying the additive property of the Hammett's rule even if the compound contains a substituent at the ortho-position.     

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.     

围产儿与儿童胸腺的病理改变

The most outstanding pathological changes of perinatal babies and children, based on the review of the autopsy files in the 1st Affiliated Hospital of West China University of Medical Sciences, are lymphocytic depletion, and reticuloepithelial cell swelling and/or fusiform malformation in the cortex, while in the medulla apoptosis is more prominent. We suppose that these alterations are due to immaturity of cortical thymocytes, and in the diseased condition, they are easily affected by extraordinary factors, especially the influence of corticosterone inducing acute severe necrosis, so the number of lymphocytes are obviously diminished. But, in the medulla, as intact mature lymphocytes exist, physiological phenomenon such as apoptosis is rather prominent in it. While in the medulla, Hassall's corpuscles have various characteristic changes, such as cornification, calcification, fusion, cystic change and disintegration. Besides, we observed a new alteration in the thymus defined as vacuolization. All the above pathological changes reached the peak in the 28- day group; there after, they might become either worse or better according to the condition of the disease and growth of the body. However, these are still problems to be further studied separately.     

Managing the premenstrual syndrome

The definition, classification, proposed etiologies, diagnosis, and treatment of the premenstrual syndrome (PMS) are discussed, and guidelines for the clinical management of PMS are presented. PMS encompasses a cluster of physical and psychosocial symptoms that recur during each menstrual cycle. Proposed etiologies for the syndrome include a hormonal imbalance between estrogen and progesterone, pyridoxine hydrochloride deficiency, hypoglycemia, excess prostaglandin production, and increased aldosterone concentrations in the luteal phase of the menstrual cycle. Diagnosis of PMS is usually based on a patient's history of recurrent symptoms accompanied by a seven-day, symptom-free period in the first half of the menstrual cycle. Management of PMS is complicated by the difficulty in diagnosing the syndrome and its unclear etiology. If possible, conservative nonpharmacologic treatment should be tried initially; suggested measures include modifications in diet, exercise, substance use, stress factors, rest patterns, and social support. Pharmacologic treatment should be considered when conservative therapies are ineffective or when PMS symptoms are more severe. Although most therapies are empirical, treatment with progesterone, pyridoxine, bromocriptine, or diuretics might prove beneficial. Once the decision is made to initiate drug therapy, the treatment regimen should be individualized and based on the patient's PMS symptom complex. The clinical management of PMS is complicated by the lack of well-designed clinical investigations of proposed treatments. Future research should be directed toward evaluating the efficacy of proposed therapeutic regimens.