Obesity Is Associated with Increased Prostate Growth and Attenuated Prostate Volume Reduction by Dutasteride

Background

Although obesity has been associated with larger prostate volumes (PV), few studies have actually investigated whether obesity enhances PV growth, especially among men using 5α-reductase inhibitors.

Objective

To examine whether obesity is associated with enhanced PV growth measured by serial transrectal ultrasound (TRUS) measurements.

Design, setting, and participants

We conducted a secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, which was originally aimed at cancer risk reduction among high-risk men with a single negative prestudy biopsy.

Intervention

Per-protocol randomization to placebo or dutasteride and mandatory TRUS-guided biopsies at 2 yr and 4 yr.

Outcome measurements and statistical analysis

Percentage change in PV at 2 yr and 4 yr from baseline. We tested its association with baseline body mass index (BMI) groups of <25, 25–29.9, and ≥30 kg/m² using multivariable linear regression. Secondarily, we tested whether BMI was associated with the likelihood of having no PV reduction among men randomized to dutasteride using multivariable logistic regression.

Results and limitations

Of 8122 participants, we analyzed 71.8% and 54.5% with complete 2-yr and 4-yr PV data, respectively. In multivariable analysis, men on placebo with BMI ≥30 versus <25 kg/m² had enhanced PV growth from baseline (at 2 yr: 17.0% vs 10.7%, p < 0.001; at 4 yr: 29.4% vs 20.1%; p = 0.001). Men on dutasteride with BMI ≥30 versus <25 kg/m² had attenuated PV reduction from baseline (at 2 yr: −14.3% vs −18.5%; p = 0.002; at 4 yr: −13.2% vs −19.3%; p = 0.001) and higher likelihood of having no PV reduction (at 2 yr: odds ratio [OR]: 1.44; 95% confidence interval [CI], 1.08–1.93; p = 0.014; at 4 yr: OR: 1.62; 95% CI, 1.18–2.22; p = 0.003). We found no significant interactions between BMI and dutasteride on PV change at 2 yr and 4 yr (p interaction ≥0.36). No clinical outcomes or effects of weight change were assessed.

Conclusions

Obesity enhanced PV growth and attenuated PV reduction by dutasteride. The null interaction between obesity and dutasteride for PV change implies that the effect of obesity on dutasteride-treated men is likely a combination of dutasteride-driven PV reduction with obesity-driven PV growth rather than decreased dutasteride efficacy.

ClinicalTrials.gov identifier

NCT00056407.     

战场环境封闭强化训练慢性应激致维和军人血清IL-6、TNF-α和执行功能的变化

目的探讨战场环境封闭训练慢性应激对维和军人血清白细胞介素IL-6(interleukin-6,IL-6)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)和执行功能的影响。方法随机选择参加南苏丹维和部队的军人41名,分别在出国前和平环境封闭训练5个月和在南苏丹战场环境中封闭训练5个月后,进行执行功能测验,包括数字符号测验、数字广度测验、词语流畅以及Stroop色词测验,并同期分别采用ELLISA进行血IL-6和TNF-α的检验。结果维和军人在战场环境下封闭训练5个月后数字符号测验得分(55.71±12.47)、数字广度测验得分(12.46±3.30)及词语流畅得分(48.49±8.07)均低于出国前和平环境中的得分(分别为62.29±10.88、14.88±2.96、49.88±8.32,均P0.01),Stroop 1〔(67.76±15.85)s〕、Stroop 2〔(28.15±5.32)s〕计时长于其出国前和平环境中的计时〔(55.73±15.50)s、(23.05±3.72)s,均P=0.00〕。维和军人战场环摬封闭强训练5个月后的IL-6〔(204.61±94.98)ng/L〕和TNF-α〔(53.18±2.69)pg/mL〕水平高于其出国前和平环境封闭训练时水平〔分别为(144.19±72.40)ng/L和(45.01±3.61)pg/mL,均P0.05〕,但IL-6、TNF-α均在正常范围内。结论战场环境条件下封闭训练慢性应激可能影响维和军人执行功能及血清IL-6、和TNF-α水平。     

Nicotine contributes to the neural stem cells fate against toxicity of microglial-derived factors induced by Aβ via the Wnt/β-catenin pathway

Recent studies have demonstrated that the molecules secreted from microglias play important roles in the cell fate determination of neural stem cells (NSCs), and nicotinic acetylcholine receptor agonist treatment could reduce neuroinflammation in some neurodegenerative disease models, such as Alzheimer's disease (AD). However, it is not clear how nicotine plays a neuroprotective role in inflammation-mediated central nervous diseases, and its possible mechanisms in the process remain largely elusive. The aim of this study is to improve the survival microenvironment of NSCs co-cultured with microglias in vitro by weakening inflammation that mediated by accumulation of β-amyloid peptide (Aβ). The viability, proliferation, differentiation, apoptosis of NSCs and underlying mechanisms associated with Wnt signaling pathway were investigated. The results showed that Aβ could directly damage NSCs. Furthermore, concomitant to elevated levels of TNF-α, IL-1β derived from microglias, the NSCs had been damaged more severely with the upregulation of Axin 2, p-β-catenin and the downregulation of β-catenin, p-GSK-3β, microtubule-associated protein-2, choline acetyltransferase. However, addition of 10 μmol/L nicotine before microglias treated with Aβ was beneficial to protect the NSCs against neurotoxicity of microglial-derived factors induced by Aβ, which partially rescued proliferation, differentiation and inhibited apoptosis of NSCs via activation of Wnt/β-catenin pathway. Taken together, these data imply that low concentration nicotine attenuates NSCs injury induced by microglial-derived factors via Wnt signaling pathway. Thus, treatment with nicotinic acetylcholine receptor agonist provides a promising research field for neural stem cell fate and therapeutic intervention in neuroinflammation diseases.     

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis,neuropathology and glucocorticoid-based therapeutics

Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics.     

The effects of preweaning manganese exposure on spatial learning ability and p-CaMKIIα level in the hippocampus

BackgroundThe effects and mechanisms of preweaning Manganese (Mn) exposure on cognitive dysfunction remain unclear.ObjectiveThis study evaluated the effects of preweaning Mn exposure on spatial learning and memory as well as the protein expression of CaMKIIα and p-CaMKIIα.MethodsWe treated neonate rats with Mn²⁺ doses of 0 (control group), 10, 20 and 30 mg of Mn²⁺ per kg body weight (Mn-exposed groups) over postnatal day (PND) 1–21 by intraperitoneal injection. The ability of spatial learning and memory was tested on PND 22 using the Morris water maze (MWM), while the protein expressions of CaMKIIα and p-CaMKIIα in the hippocampus were evaluated by Western blotting. The levels of Mn in the blood and hippocampus were measured by inductively coupled plasma-mass spectrometry (ICP-MS).ResultsThe rats in Mn-exposed groups showed a significant delay in spatial learning ability on the third day of the MWM without dose-dependent differences, but there was no effect on the spatial memory ability. p-CaMKIIα, but not CaMKIIα protein expression significantly reduced in the Mn-exposed group.ConclusionThese findings suggested that the inhibition of p-CaMKIIα could be one of the mechanisms involved in the occurrence of Mn-induced cognitive impairments.     

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

PurposeTo investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model.Materials and MethodsVX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry.ResultsThe median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 μg/mL (interquartile range [IQR], 7.42–33.5 μg/mL), and its maximal plasma concentration (C_max) was 0.164 μg/mL (IQR, 0.0798–0.528 μg/mL). The intratumoral concentration and C_max of doxorubicin were similar between the groups: 4.08 μg/mL (IQR, 3.18–4.79 μg/mL) and 0.677 μg/mL (IQR, 0.315–1.23 μg/mL), respectively, in the DOX-TACE group and 1.68 μg/mL (IQR, 0.795–4.08 μg/mL) and 0.298 μg/mL (IQR, 0.241–0.64 μg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups.ConclusionsThe addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.     

缺氧诱导因子1α诱导前列腺癌LNCaP细胞上皮间质转化的体内外研究

目的:探讨在体内外环境下缺氧诱导因子1α(HIF-1α)过表达对前列腺癌细胞发生上皮间质转化(EMT)并导致肿瘤侵袭能力升高的影响。方法:对已构建的稳定表达HIF-1α的人前列腺癌LNCaP细胞(LN-CaP/HIF-1α)复苏后培养,对HIF-1α过表达进行鉴定。MTT法测定细胞增殖;检测转染前后培养液上清PSA水平;软琼脂成瘤实验比较两种细胞体外成瘤能力;将转染前后的LNCaP细胞注射免疫裸鼠皮下建立皮下肿瘤模型,观察肿瘤生长情况;收集肿瘤标本进一步行免疫组化处理。结果:免疫荧光和Western印迹证实LNCaP/HIF-1α细胞中HIF-1α过表达。同LNCaP细胞相比,转染HIF-1α的人前列腺癌LNCaP细胞培养液中PSA水平明显降低;MTT法显示其更具有增殖活性,体外成瘤能力更强。体内实验显示皮下肿瘤成瘤率提高,成瘤时间提前。肿瘤标本免疫组化提示转染组E钙粘蛋白表达下调,波形蛋白表达上调。结论:HIF-1α过表达能够封闭E钙粘蛋白,上调波形蛋白表达,提示HIF-1α过表达可能通过诱导EMT增强LNCaP细胞侵袭能力。     

TNF-α McAb对急性失血性休克大鼠肝脏的作用

目的探讨肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)在急性失血性休克大鼠肝损伤中的作用及TNF-α单克隆抗体的保护作用。方法将24只雄性SD大鼠随机均分为三组:对照组(A组)、休克+乳酸林格氏液复苏组(B组)和休克+TNF-α单克隆抗体复苏组(C组)。B和C组大鼠通过股动脉放血,制作急性失血性休克动物模型;B组用乳酸林格氏液复苏,C组用含TNF-α单克隆抗体(3mg/kg)的乳酸林格氏液复苏,而A组在同等条件下不进行失血。分别检测各组大鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、TNF-α水平和肝组织中MDA、SOD含量,并在光镜和电镜下观察各组大鼠肝组织的病理变化。结果 B、C组大鼠血清ALT、AST、TNF-α水平和肝组织中MDA含量较A组升高,SOD含量降低;C组ALT(343.63±35.61)U/L、AST(748.75±49.76)U/L、TNF-α(99.38±13.16)pg/mL、丙二醛(26.33±1.30)nmol/mgProt较B组ALT、AST、TNF-α、MDA含量降低,C组肝组织中SOD含量(510.14±47.44)U/mgProt较B组升高;在光镜、电镜下观察,C组肝组织损伤较B组减轻。结论 TNF-α可能是急性失血性休克肝损伤的重要因子之一,使用TNF-αMcAb复苏可以减轻失血性休克时大鼠肝损伤,具有一定的保护作用。     

大鼠自体原位肝移植中逆行灌注法对急性肺损伤的影响

目的探讨大鼠自体原位肝移植术中经下腔静脉逆行灌注与经门静脉顺行灌注法对急性肺损伤的影响。方法 Sprague-Dawley(SD)大鼠75只随机分成逆行灌注组、顺行灌注组、假手术组,建立大鼠自体原位肝移植逆行灌注、顺行灌注和假手术模型,各组于术后6h、12h、24h分别随机处死6只大鼠,测定肺干/湿重量比值、肺组织髓过氧化物酶(myeloperoxidase,MPO)活性、丙二醛(malondialdehyde,MDA)含量、肿瘤坏死因子(TNF)-α含量,行肺组织病理学检查。结果与假手术组比较,逆行灌注组和顺行灌注组术后肺干/湿重量比值变小,肺组织MPO活性、MDA含量、TNF-α含量增加,以术后6h与12h明显。与顺行灌注组比较,逆行灌注组术后6h、12h的肺干/湿重量比值较高,而肺组织MPO活性、MDA含量较低,差异有统计学意义(均为P<0.05);术后24h两组间在上述指标差异无统计学意义(均为P>0.05);逆行灌注组肺组织TNF-α含量在术后6h、12h、24h均显著降低,两组间差异有统计学意义(均为P<0.05)。肺组织苏木素-伊红染色:逆行灌注组、顺行灌注组均表现不同程度的肺泡结构破坏,肺泡间隔增厚,小静脉、毛细血管充血、淤血,炎症细胞浸润。其中术后6h、12h表现较重,术后24h较轻;同时显示逆行灌注组肺组织病理损伤较顺行灌注组明显减轻。结论大鼠自体原位肝移植术中用顺行灌注或逆行灌注,术后早期均存在急性肺损伤,其中术后6h和12h损伤较严重,术后24h肺损伤减轻;逆行灌注造成的急性肺损伤程度比顺行灌注要轻。     

新疆托里县哈萨克族骨关节炎患者血清IL-18与TNF-α水平变化及临床意义

目的探讨新疆托里县哈萨克族骨关节炎患者血清白细胞介素(interleukin,IL)-18与肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平变化及临床意义。方法对新疆托里县哈萨克族骨关节炎患者168例及对照组179例抽取静脉血测定血清中IL-18、TNF-α含量。结果骨关节炎患者血清中IL-18、TNF-α含量明显高于对照组(P<0.05);对照组中哈萨克族与汉族血清中IL-18、TNF-α含量的差异无统计学意义(P>0.05);骨关节炎患者血清中IL-18与TNF-α水平存在相关性(相关系数r=0.89,P=0.00);骨关节炎患者血清中IL-18、TNF-α水平与患者病程长短无关。结论血清IL-18、TNF-α与骨关节炎的关系密切,可能成为早期诊断骨关节炎的实验室指标,为早期诊断提供参考。