Academic detailing to improve laboratory testing among outpatient medication users

PURPOSE: To determine whether group academic detailing with performance feedback increases recommended laboratory monitoring among outpatients dispensed medications. METHODS: Thirty-eight primary care practices in 3 states were randomized to group academic detailing with physician-level performance feedback (intervention) or a control group. Adjusted differences in creatinine and potassium testing between intervention and control group patients with a new or continuing dispensing for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), diuretics, or digoxin were evaluated using generalized estimating equation approaches. RESULTS: Monitoring among patients with an initial ACE/ARB and diuretic dispensing significantly improved with the intervention [odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.08-1.38; and OR = 1.25, 95% CI: 1.08-1.44, respectively). The intervention also significantly improved monitoring among patients with a continuing dispensing for an ACE/ARB (OR = 1.39, 95% CI: 1.11-1.74) or a diuretic (OR = 1.28, 95% CI: 1.02-1.60). Adjusted differences in testing rates between study arms were modest (ranging from 2.5% to 4.9%). No significant differences in monitoring by study arm were detected among patients dispensed digoxin. CONCLUSIONS: The impact of a group academic detailing program with feedback on recommended laboratory monitoring among medication users was modest. Yet, given the numbers of outpatients dispensed medications for which laboratory monitoring is recommended, group academic detailing may offer 1 method by which outpatient medication safety can be significantly improved.     

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke.Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension,¹ match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis,² and protect against ischemia.^3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids.⁵ In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke,⁶ and this association could be related to modifications in SEH activity, and thus epoxide catabolism.⁷ An alternative strategy that has been used to increase EETs systemically is SEH inhibition.¹We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.⁸ Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO) without decreasing blood pressure.⁸ Although blood pressure is an important variable in controlling infarct size in the SHRSP, the cerebrovasculature is also a key determinant of increased sensitivity to cerebral ischemia and thus infarct size.^9,10 Our study provided preliminary evidence that AUDA protection in the SHRSP involved changes in vascular structure.⁸ More recently, a report suggested that administration of AUDA-butyl ester protects against cerebral ischemic reperfusion injury in normotensive mice by mechanisms that may involve neural protection rather than vascular protection.¹¹ As a result, the contribution of vascular and neural protection to the cerebral protective effects of SEH inhibition during states of hypertension and normotension are unclear and require further investigation. The present study tested the hypothesis that SEH inhibition provides cerebral protection via different mechanisms in normotensive WKY and hypertensive SHRSP rats.     

The therapeutic effect of hysterosalpingography in couples with unexplained subfertility: a post-hoc analysis of a prospective multi-centre cohort study

Research question

Hysterosalpingography (HSG) with an oil-based contrast has been shown to increase ongoing pregnancy rates compared with HSG with water-based contrast, but it remains unclear if an effect of HSG occurs compared with no HSG.

A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium

Objective

To evaluate the feasibility of combining low-dose fractionated whole abdominal radiation (LDF-WAR) with weekly full-dose cisplatin (FD-CDDP) for patients with stage III/IV endometrial carcinoma.

Methods

Patients with optimally debulked stage III/IV carcinoma of the endometrium (without extra-abdominal disease) were eligible for the study. Postoperatively, patients received the institutional standard systemic chemotherapy and vaginal brachytherapy. Patients then underwent experimental six weekly cycles of FD-CDDP (40 mg/m², maximum 70 mg IV) followed by LDF-WAR 6-8 hours after initiation of chemotherapy. In a conservative design, 6 patients were accrued to two sequential cohorts of LDF-WAR, at 0.5 Gy/fraction [Fx] (total 3 Gy) and 0.75 Gy/Fx (total 4.5 Gy). Toxicities and laboratory studies were evaluated at each visit.

Results

Twelve patients were enrolled from January 2005 to June 2009 with median follow-up of 13.5 months (range: 5-27 months). Seventy-five percent of enrolled patients had uterine papillary serous histology. Eleven patients at least partially completed therapy (range: 2-6 cycles of FD-CDDP/LDF-WAR) with one additional patient opting out at the higher dose level. Combination therapy overall was well tolerated. Three patients in each cohort experienced grade 3 acute hematologic events with one recorded grade 4 toxicity in the second cohort. Of patients receiving any of the experimental treatment, five have experienced recurrences. Three of these patients were in cohort one and received 0.5 Gy/Fx LDF-WAR.

Conclusion

Combination therapy with LDF-WAR as a novel chemopotentiator to FD-CDDP is a feasible adjuvant regimen in optimally debulked patients with stage III/IV endometrial carcinoma. Further investigation is warranted to determine treatment efficacy.     

Tumour suppressor HLJ1: A potential diagnostic,preventive and therapeutic target in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.     

Development and Implementation of National Practice Guidelines: A Prospect for Continuous Quality Improvement in Physiotherapy: Introduction to the method of guideline development

The development of national practice guidelines (NPGs) is an issue of much concern in healthcare policies world-wide to guarantee and to improve the quality and efficiency of care. The development and implementation of NPGs constitutes an important part of the quality of care policy of the Royal Dutch Physiotherapy Association (KNGF). This interest is due to pressure from society (policy-makers, healthcare managers, financiers and patients) on physiotherapists to ensure quality of care and to justify our position in the healthcare system. The development of NPGs can also be seen as a logical step in the process of professionalisation and quality assurance by physiotherapists.An NPG is described as a systematically developed statement, drafted by experts and directed at one aspect of the treatment of a health problem belonging to the domain of the profession. NPGs are based on the different stages of the physiotherapy care process, the available clinical evidence and expert consensus. Priority is given to a cost-effective approach and multidisciplinary consensus on diagnosis, treatment and primary or secondary prevention. Recommendations are based on the results of new or recorded systematic reviews or meta-analysis.NPGs are important state-of-the-art documents, which can guide professionals in their daily practice and make explicit to other relevant people what professionals can do in a certain situation or with a specific condition, and why they do it. NPGs have important functions, including supporting physiotherapists in their decision-making process; they are a frame of reference for orientation and educational purposes, they provide criteria for self-evaluation and peer review, and can initiate changes in established practice patterns.This paper describes the process and development of NPGs for physiotherapists in the Netherlands. In a companion paper the method and strategies for the implementation of NPGs and the need for evaluation of their outcome will be discussed.     

组织浓度的意义

过去几十年至今,人们普遍以组织药物浓度来推测抗生素的活性和MIC,将组织匀浆液中测得的药物浓度与相应血浆中的药物浓度的比值来指导药物的临床应用。然而从药动学和药效学角度看这种方法并不合理,并最终可能对病人产生潜在危害。全组织药物浓度通常是通过测定碾碎或溶解后的匀浆组织的药物浓度而得到,这种测定方法忽略了组织的内部结构(如间质液、细胞及亚细胞结构等),药物不一定是均匀分布于组织中,并且,组织匀浆的药物浓度不能完全反映药物的有效活性。所以全组织药物浓度不能真实反应抗生素在感染部位的浓度。比如:多数细菌的感染部位在细胞外,故细胞外药物浓度才是关注的焦点。对于主要分布于胞外的药物,组织碾碎后使细胞内外液混合,则测得的药物浓度会低于实际感染部位的浓度;相反,对于主要分布于胞内的药物,测得的全组织浓度会大大高于细胞外浓度。对于胞内菌感染也可得相应结论。给药后抗生素会分布到全身不同部位,大多数药动学可以用二室或三室模型模拟。由于室间不能瞬间达到平衡,所以各室的药-时曲线也可能出现很大差异。在某时刻采集全组织样本就可获得该时间点组织浓度与血药浓度的比值。为了减少干扰,应在同一病人上采集达稳态的样品,但这并不可行且存在伦理学问...     

建立胫骨癌痛模型的理论与实践

目的:骨癌痛动物模型已有报道,但还没有可接受的与人类骨癌痛相一致的模型。综述胫骨癌痛模型的研究进展及相关治疗前景。资料来源:应用计算机检索Medline1996-01/2006-03相关胫骨、癌痛和治疗的文献,检索词“tibial,cancerpain,therapy”,并限定文献语言种类为English。同时检索万方数据库1996-01/2006-05文献,检索词为“胫骨癌痛”,并限定语言种类为中文。资料选择:对资料进行初审,选取包括胫骨、癌痛和治疗的文献,开始查找全文。纳入标准:①胫骨和癌痛。②癌痛和治疗。排除标准:综述文献、重复研究、Meta分析类文章。资料提炼:共收集到51篇关于胫骨、癌痛和治疗的文献,纳入30篇关于胫骨和癌痛,癌痛和治疗的文献。资料综合:①目前认为,胫骨癌痛动物模型的疼痛表现与临床上所见的骨转移症状相似,可视为转移性骨癌痛模型。②恶性肿瘤骨损害的特征性变化是溶骨性骨吸收和恶性肿瘤疼痛本身,随骨质破坏的加剧,疼痛逐渐增强,移动或轻触可以引发急性痛,在到达极度痛之前,常因运动、负重或自发地间断发生突破痛,其发生的程度和频率与骨质破坏和溶骨活性成正相关。③目前从胫骨癌痛的实验研究中发现可供选择的药物主要有阿片类药、5-羟色胺受体阻断剂、抗惊厥药物加巴喷丁、环氧化酶2抑制剂表皮生长因子阻断剂。结论:利用动物胫骨癌痛模型来研究人类骨癌痛是可行的,但其研究有待进一步深入。从胫骨癌痛的实验研究中发现有许多药物可供选择,这展示了药物治疗骨癌痛的应用前景。