The effects of different doses of inhaled bacteriophage therapy for Pseudomonas aeruginosa pulmonary infections in mice

ObjectivesInhaled phage therapy has been revisited as a potential treatment option for respiratory infections caused by multidrug-resistant Pseudomonas aeruginosa; however, there is a distinct gap in understanding the dose–response effect. The aim of this study was to investigate the dose–response effect of Pseudomonas-targeting phage PEV31 delivered by the pulmonary route in a mouse lung infection model.MethodsNeutropenic BALB/c mice were infected with multidrug-resistant P. aeruginosa (2 × 10⁴ colony-forming units) through the intratracheal route and then treated with PEV31 at three different doses of 7.5 × 10⁴ (Group A), 5 × 10⁶ (Group B), and 5 × 10⁸ (Group C) plaque-forming units, or phosphate-buffered saline at 2 hours postinoculation. Mice (n = 5–7) were euthanized at 2 hours and 24 hours postinfection, and lungs, kidneys, spleen, liver, bronchoalveolar lavage fluid, and blood were collected for bacteria and phage enumeration.ResultsAt 24 hours postinfection, all phage-treated groups exhibited a significant reduction in pulmonary bacterial load by 1.3–1.9 log₁₀, independent of the delivered phage dose. The extent of phage replication was negatively correlated with the dose administered, with log₁₀ titre increases of 6.2, 2.7, and 9 for Groups A, B, and C, respectively. Phage-resistant bacterial subpopulations in the lung homogenate samples harvested at 24 hours postinfection increased with the treatment dose (i.e. 30%, 74%, and 91% in respective Groups A–C). However, the mutants showed increased susceptibility to ciprofloxacin, impaired twitching motility, and reduced blue-green pigment production. The expression of the inflammatory cytokines (IL-1ß and IL-6, and TNF-α) was suppressed with increasing PEV31 treatment dose.DiscussionThis study provides the dose–response effect of inhaled phage therapy that may guide dose selection for treating P. aeruginosa respiratory infections in humans.     

放射治疗中剂量梯度概念及其在临床中的应用

射线剂量场的剂量梯度可用哈密顿算子求出，剂量梯度可矢量运算方法求和，文中给出射线束的射束轴上各点剂量梯度的计算公式：当各射线束束轴相交于一点时，可由矢量和求出该点的合成剂量梯度。由此可估算出靶区剂量不均匀情况。文中提出中心零梯度假设：如果靶区中心剂量梯度为零，则靶区剂量分布均匀。文中学例证实了这一点。     

剂量分布比较中γ因子的快速计算方法

γ比较方法作为放射治疗剂量学验证中的一种手段,现在已经在科研和临床的剂量分布比较中得到广泛应用。但是,在比较三维剂量分布时,γ因子的计算量大,需要花费大量的时间。本文采用一种预先排序技术和基于图形处理器(GPU)的并行计算技术结合,实现了γ因子的快速计算。通过7对剂量分布的测试,基于GPU的γ因子的计算速度提高了几十倍,而且与CPU相比保持了相同的计算精度。实验结果表明,利用GPU的并行计算对γ比较方法进行加速是切实有效的。     

Chinese Herbal Medicine: A Safe Alternative Therapy for Urinary Tract infection in Patients with Renal Insufficiency

We have used reduced doses of Chinese herbs for estimation of urinary tract infections (UTIs) patients with stable impairment of renal function. A total of 33 adult female patients with moderately impaired renal function and symptomatic UTIs were included in this study. Urine cultures were carried out. Patients were monitored clinically and with various laboratory tests. Chinese herbal concoction divided by milligrams of creatinine per 100 ml were orally administrated for ten days. Three patients were excluded from final analysis. Most of the patients responded symptomatically to treatment. Chinese herbs eradicated the primary pathogen in 68.7% of the patients at the day 10 of treatment. Two patients relapsed (one had abbreviated courses of therapy) 6 to 8 days posttreatment. Organisms which recurred included Escherichia coli and Pseudomonas aeruginosa. Bacterial reinfections occurred 5 to 8 days posttreatment in four patients. Adverse reactions observed among the 30 patients were rare. Nausea (6.67%) and mild elevation of hepatic enzymes (3.33%) were probably drug related. Nausea disappeared when the therapy ended. Elevated hepatic enzymes resumed at the 2-week follow-up. Two patients demonstrated slight increases in serum creatinine on day 10 of treatment. One patient had a 12.5% elevation over baseline and the other had a 13.0% elevation. Serum creatinine values had improved in these two patients at 4-week follow-up. Chinese herbal medicine was effective and safe in the treatment of UTIs with renal insufficiency.     

HRT and the primary prevention of cardiovascular disease

Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy.     

放射治疗中碳纤维头颈肩架剂量影响研究

目的：探讨全碳头颈肩架对三维治疗计划（TPS）剂量分布的影响。方法：分析35例应用头颈肩架的三维适形放疗计划,比较在移除和不移除头颈肩架的情况下TPS计算的PTV内最低剂量（Dmin）、最高剂量（Dmax）、最高剂量与最低剂量之差（Dmax—Dmin）、平均剂量（Dmean）及100％等剂量曲线包绕PTV的体积百分比（P100％）,用配对t检验或Wilcoxon符号秩检验来比较组间差异,并统计TPS在2种条件下计算出的剂量偏差率。结果：移除头颈肩架组与不移除头颈肩架组间在TPS中计算的Dmin、Dmax、Dmax-Dmin、Dmean的差异有统计学意义（P=0．028,0．000,0．009,0．042）,P100％的差异无统计学意义（P=0．342）;剂量偏差率｜△Dmin｜／Dose、｜△Dmax｜／Dose、｜△Dmean｜／Dose分别为1．116％、2．058％、2．142％。结论：设计TPS时,移除头颈肩架对剂量计算与评估有偏差。     

骨盆数字化X射线摄影曝光剂量的优化研究

目的研究直接数字化X射线摄影照射剂量与成像质量的关系，确定骨盆X射线摄影的最佳摄影条件。方法以对比度一细节体模CDRAD2．0在不同照射剂量下所获取的影像的图像质量因子IQF，进行ANOVA及SNK统计学分析，确定最佳照射条件。应用X射线摄影模拟人拍摄骨盆X射线影像，按照欧共体（CEC）图像质量标准验证最佳摄影条件与常规摄影条件下照射剂量与成像质量的差别。结果不同照射剂量条件下，对比度一细节体模影像质量因子IQF有显著性差别（P=0．0001），照射剂量大于0．61mGy时，不同剂量组间IQF差异无统计学意义。对以最佳照射条件和常规照射条件所拍摄的X射线摄影模拟人影像按照CEC标准评判，两者影像质量的差异无统计学意义。结论直接数字化X射线摄影时通过增大照射剂量可以提高影像质量，但是当曝光剂量达到足够大时，再增大曝光剂量并不能显著改善图像质量，影像质量与曝光剂量间存在一个优化剂量。标准体模骨盆X射线摄影的优化剂量为0．61mGy。     

Gestational flu exposure induces changes in neurochemicals,affiliative hormones and brainstem inflammation,in addition to autism-like behaviors in mice

The prevalence of neurodevelopmental disorders such as autism is increasing, however the etiology of these disorders is unclear and thought to involve a combination of genetic, environmental and immune factors. A recent epidemiological study found that gestational viral exposure during the first trimester increases risk of autism in offspring by twofold. In mice gestational viral exposures alter behavior of offspring, but the biological mechanisms which underpin these behavioral changes are unclear. We hypothesized that gestational viral exposure induces changes in affiliative hormones, brainstem autonomic nuclei and neurotransmitters which are associated with behavioral alterations in offspring. To address this hypothesis, we exposed pregnant mice to influenza A virus (H3N2) on gestational day 9 and determined behavioral, hormonal and brainstem changes in male and female offspring. We found that gestational flu exposure induced dose-dependent alterations in social and aggressive behaviors (p ⩽ 0.05) in male and female offspring and increases in locomotor behaviors particularly in male offspring (p ⩽ 0.05). We found that flu exposure was also associated with reductions in oxytocin and serotonin (p ⩽ 0.05) levels in male and female offspring and sex-specific changes in dopamine metabolism. In addition we found changes in catecholaminergic and microglia density in brainstem tissues of male flu exposed offspring only (p ⩽ 0.05). This study demonstrates that gestational viral exposure induces behavioral changes in mice, which are associated with alterations in affiliative hormones. In addition we found sex-specific changes in locomotor behavior, which may be associated with sex-specific alterations in dopamine metabolism and brainstem inflammation. Further investigations into maternal immune responses are necessary to unravel the molecular mechanisms which underpin abnormal hormonal, immune and behavioral responses in offspring after gestational viral exposure.     

Oxytocin and enhancement of the positive valence of social affiliation memories: An autobiographical memory study

Intranasal oxytocin has been shown to alter self-perceptions of personality (e.g., more trusting, increased extraversion). To follow up these findings, we examined the acute effects of two doses of intranasal oxytocin (24 IU and 48 IU) on another form of self-referential cognition: autobiographical memory. Changes in autobiographical memory (personal memories for the past) could conceivably effect change in self-perception and consequently alter social behaviors. We predicted that oxytocin would increase the number of specific personal memories recalled, and promote the recall of positive social affiliation memories. Seventeen male participants self-administered a placebo or oxytocin (24 IU, 48 IU) using a nasal spray on three separate occasions in a placebo-controlled, double-blind, and within-subject experiment. Participants completed the Autobiographical Memory Test (AMT) 110 minutes later. Analyses revealed a quadratic dose–response curve for the effects of intranasal oxytocin on autobiographical memory recall. The 24 IU dose, relative to the 48 IU dose and placebo, increased the number of specific personal memories recalled and promoted the recall of social affiliation memories that were rated more positively. The lack of effect with the 48 IU dose could be due to saturation of the oxytocin receptors at higher doses. Changes in autobiographical memory may be one mechanism by which oxytocin alters prosocial worldviews.     

Development of a low-energy monoenergetic neutron source for applications in low-dose radiobiological and radiochemical research

The McMaster University 3 MV KN Van de Graff accelerator facility primarily dedicated to in vivo neutron activation measurements has been used to produce moderate dose rates of monoenergetic fast neutrons of energy ranging from 150 to 600 keV with a small energy spread of about 25 keV (1σ width of Gaussian) by bombarding thin lithium targets with 2.00–2.40 MeV protons. The calculated dose rate of the monoenergetic neutrons produced using thin lithium targets as functions of beam energy, target thickness, lab angle relative to beam direction, and the solid angle subtended by the sample with the target has also been reported.