Retreats: getting your money's worth

Though well-done retreats can be sound investments, those investments can be substantial. Direct expenses alone can range from $200 for an in-town luncheon to $450,000 for a week-long event.     

Presynaptic modulation of dopamine-induced locomotor activity by oxotremorine in nucleus accumbens of the rat

Summary Behavioural studies were carried out to determine whether central cholinergic mechanisms regulate dopaminergic activity by presynaptic mechanisms as suggested by recentin vitro studies. Bilateral injections of a muscarinic receptor agonist, oxotremorine (4g), into the nucleus accumbens were found to enhance dopamine-induced locomotor activity. In rats deprived of presynaptic terminals by pretreatment with intraaccumbens injections of 6-hydroxydopamine, oxotremorine did not enhance dopamine-induced locomotor activity but on the contrary produced a marked reduction of locomotor activity. Although dopamine induced locomotor activity could occur in 6-hydroxydopamine treated animals, the muscarinic regulation was dependent on the presence of the intact dopamine terminal and hence a presynaptic receptor may be involved.     

Are single fractions of radiotherapy suitable for plantar fasciitis?

The use of radiotherapy for plantar fasciitis has never been reported in Australasia and is scarcely found in the English language medical literature, but it is commonly used in Europe, especially in Germany. In Europe, treatment courses consisting of multiple small fractions have been associated with high levels of pain relief. In the present report, the use of single fractions or radiotherapy was evaluated by reviewing seven consecutive patients referred for treatment and by applying objective and subjective criteria for pain relief. One patient died of unrelated causes soon after treatment and one declined to receive radiotherapy. Four patients each received a single dose of 8 Gy resulting in complete pain relief. One patient was treated with 8 Gy and 12 weeks later was retreated achieving partial pain relief. A follow‐up interview was conducted after a mean of 15.6 months, ranging from 1.5 to 30 months. No acute or late effects occurred; however, the possibility that delayed effects may yet occur, particularly carcinogenesis, cannot be excluded. Radiotherapy for this common condition should be investigated further as it might be safer and more effective than other methods currently in use.     

Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea

OBJECTIVE: To evaluate the impact of zinc supplementation on the clinical course, stool weight, duration of diarrhoea, changes in serum zinc, and body weight gain of children with acute diarrhoea. DESIGN: Randomised double blind controlled trial. Children were assigned to receive zinc (20 mg elemental zinc per day) containing multivitamins or control group (zinc-free multivitamins) daily in three divided doses for two weeks. SETTING: A diarrhoeal disease hospital in Dhaka, Bangladesh. PATIENTS: 111 children, 3 to 24 months old, below 76% median weight for age of the National Center for Health Statistics standard with acute diarrhoea. Children with severe infection and/or oedema were excluded. MAIN OUTCOME MEASURES: Total diarrhoeal stool output, duration of diarrhoea, rate of weight gain, and changes in serum zinc levels after supplementation. RESULTS: Stool output was 28% less and duration 14% shorter in the zinc supplemented group than placebo (p = 0.06). There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter (less than 95% height for age), 239 v 326 g/kg (p < 0.04), and who had a lower initial serum zinc (< 14 mmol/l), 279 v 329 g/kg (p < 0.05); a shortening of mean time to recovery occurred (4.7 v 6.2 days, p < 0.04) in those with lower serum zinc. There was an increase in mean serum zinc in the zinc supplemented group (+2.4 v -0.3 mumol/l, p < 0.001) during two weeks of supplementation, and better mean weight gain (120 v 30 g, p < 0.03) at the time of discharge from hospital. CONCLUSIONS: Zinc supplementation is a simple, acceptable, and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished.     

Clinical measurement, statistical analysis, and risk-benefit: controversies from trials of spinal injury

BACKGROUND: The National Acute Spinal Cord Injury Studies have been a series of trials assessing the role of pharmacologic agents in the prevention of secondary neuronal damage after acute spinal cord injury. METHODS: The trials were multicenter randomized, controlled studies. RESULTS: Two trials have demonstrated the efficacy of high-dose methylprednisolone in improving neurologic and functional recovery and have shown a reassuring safety profile. CONCLUSION: This study responds to a recent commentary on these trials and examines in particular the roles of clinical measurement, statistical analysis, and risk benefit in assembling evidence for or against innovative therapies.     

催醒宁在大鼠离体灌流肝脏中的生物转化

用离体大鼠肝脏灌流方法,研究了胆碱酯酶抑制剂CXN的生物转化过程。径HPLC分离纯化及光谱分析,鉴定了CXN的六个脂溶性代谢产物的化学结构。产物Ⅰ为CXN原形,其余均为氧化产物。其中产物Ⅲ尚保留部分抑酶活力,而产物Ⅱ,Ⅴ及Ⅵ对小鼠全脑胆碱酯酶的抑酶活力明显下降。另外还观察到,代谢产物Ⅱ及Ⅴ对小鼠的急性毒性也明显减小。     

新麻醉药静松灵生物转化的研究

静松灵[2-(2,4-二甲基苯胺基)-4,5-二氢噻唑,XT]是国内合成的麻醉物,经ip给药后,从大鼠尿中分离、纯化、鉴定了四个代谢产物。MB₁即XT原形;MB₃及MA₂互为异构体,分别为2位、4位甲基氧化为羧基的产物;MA₁则4位甲基氧化为羧基,二氢噻唑环中4¹位亚甲基氧化为羰基。初步实验表明:代谢产物MB₃,MA²,MA₁的药效与毒性均远低于原形药,大鼠与小鼠对XT的转化机制相近,但也存在种属的差异。     

灰黄霉素中灰黄霉酸杂质及色泽的考查

目的:本文采用薄层色谱法考查了不同厂家灰黄霉素中灰黄霉酸杂质的存在.方法:以丙酮为溶媒,精制灰黄霉素,摸索分离条件,探讨杂质限度,考查产品色泽.结果:杂质均值为0.276%,RSD为0.168%.结论:对改进产品检验方法、提高产品质量具有一定的参考价值.     

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF^V600E models showed acquired drug resistance, one BRAF^V600E model had a complete and durable response, and a BRAF^V600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.