Complementary and alternative therapies in prostate cancer

Complementary and alternative therapies are used with increasing frequency in men with prostate cancer. However, little is known about the efficacy of such therapies for this cancer. While epidemiological data support the association between intake of certain micronutrients with development of prostate cancer, there exist limited prospective data that support the chemopreventative or therapeutic value of such nutritional agents in prostate cancer. To date, one of the most studied treatments has been PC-SPES, a combination of eight herbal therapies with activity against prostate cancer. Studies in cell lines of human prostate cancer demonstrate significant dose-dependent decreases in cellular viability after exposure to extracts of this agent. Clinical studies suggested that PC-SPES could reduce prostate specific antigen levels in patients with either androgen-dependent or androgen-independent prostate cancer. Toxicity was mild, although there was a low risk of thromboembolic events with such treatment. Manufacture of PC-SPES was recently halted, after revelations that the herbal combination was contaminated with warfarin, which led to a recall by the manufacturer. Subsequent analyses also revealed the presence of diethylstilbestrol (DES) and indomethacin in some lots of PC-SPES. Available data regarding other alternative therapies are reviewed as well.     

CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer's disease

Aging represents the greatest risk for development of Alzheimer's disease (AD), and changes in peripheral immune cell phenotypes have been found to be associated with aging. Using flow cytometry, we measured the relative expression levels of CD45 isoforms, a marker of nai;ve versus memory CD4+ T cell status, on isolated CD4+ T lymphocytes from patients with a clinical diagnosis of probable Alzheimer's disease, normal elderly, cognitively abnormal elderly, and patients with clinically diagnosed other forms of dementia. Data show significantly lower levels of CD45RA, and an increase in the CD45RO/CD45RA ratio, on CD4+ T cells in patients diagnosed with probable Alzheimer's disease (n=46) and in cognitively abnormal individuals (n=37) compared to age-matched normal participants (n=90). Patients diagnosed with other forms of dementia (n=19) did not significantly differ from normal individuals. Both CD45RA and the CD45RO/CD45RA ratio had higher positive and negative predictive values and were more sensitive biomarkers of probable AD than the apolipoprotein E epsilon 4 allele, and had greater predictive ability for probable AD by regression analyses. Additionally, a testing strategy employing apolipoprotein E genotyping and CD45RA or the CD45RO/CD45RA ratio revealed increased sensitivity, positive and negative predictive values, and predictive ability over the apolipoprotein E epsilon 4 allele. These data show altered peripheral immunity in AD patients, and raise the possibility that a testing strategy using CD45 isoform alteration on CD4+ T cells and apolipoprotein E genotype may be clinically valuable for diagnosing probable AD.     

Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner.

Mixed lineage leukemia (MLL) rearrangements occur in 80% of infants and 5% of older children with acute lymphoblastic leukemia (ALL). These cases have a poor prognosis with current therapy. The FLT3 kinase is overexpressed and constitutively activated in MLL-rearranged ALL cells. The FLT3 inhibitor CEP-701 selectively kills these cells, but is unlikely to be curative if used as monotherapy. To identify potentially synergistic combination strategies, we studied CEP-701 and six standard chemotherapeutic agents in three sequences of exposure (S1: chemotherapy followed by CEP-701, S2: simultaneous exposure to both; and S3: CEP-701 followed by chemotherapy) using MLL-rearranged ALL cell lines and patient bone marrow samples. MTT cytotoxicity and annexin V binding apoptosis assays were used to assess antileukemic effects. Combination indices (CI) were calculated for each combination (CI<0.9 - synergistic; CI 0.9-1.1 - additive; CI>1.1 - antagonistic). A striking pattern of sequence-dependent synergy was observed: S1 was markedly synergistic (mean CI=0.59+/-0.10), S2 was additive (mean CI=0.99+/-0.09) and S3 was antagonistic (mean CI=1.23+/-0.10). The sequence dependence is attributable to the effect of CEP-701 on cell cycle kinetics, and is mediated specifically by FLT3 inhibition, as these effects are not seen in control cells without activated FLT3.     

模型指导的微阵列显示阿尔茨海默病的retromer复合体

一般而言，尽管基因表达谱非常适合寻找与阿尔茨海默病（AD）相关的致病分子，但是当像微阵列这样的技术用于大脑疾病时，具有独特的分析方面的难题。针对上述难题，本研究首先建立1个时空模型，提前预测AD的潜在分子机制如何从解剖和时间上发挥作用。然后以模型为指导建立内嗅皮质和齿状回的基因表达谱，资料来源于AD患者和大年龄跨度健康对照者的脑组织。在许多基因的表达差异中，retromer转运分子的VPS35与AD的时空模型非常一致。免疫印迹法检测证实了该异常，即AD选择性敏感脑区的VPS35表达水平下调。VPS35是retromer转运复合体的核心分子，进一步的分析显示，该转运体的另一分子VPS26在AD中的表达也下调。使用小干扰RNAs或表达载体的细胞培养研究显示，VPS35调节Aβ肽水平，证实了retromer转运复合体与AD相关。结合最近的各种研究，对本试验结果进行回顾提示，AD中的retromer复合体表达下调可调节Aβ肽的局部水平。     

Location of incisal edge position for esthetic restorative dentistry

Restorative dentistry means just that--changing the position and morphology of teeth (when indicated) to restore the patient to a functional and esthetic occlusion. The first step considers the mandibular incisal edge position. Following that choice, the maxillary anterior teeth are evaluated for position against the lips and with the rest of the dentition, particularly the mandibular incisors and canines. When the three major determinants of incisal edge position (occlusion, phonetics, and esthetics) are used to place the anterior teeth where they will function best, all cases have the potential for a more enduring esthetic success.     

Intimate partner and nonpartner violence against pregnant women in rural Haiti

OBJECTIVE: To examine the association between violence experienced by pregnant Haitian women in the previous 6 months and pregnancy-related symptom distress. METHODS: A total of 200 women seeking prenatal care at community health dispensaries in the Artibonite Valley were interviewed. RESULTS: Over 4 in 10 women (44.0%) reported that they had experienced violence in the 6 months prior to interview; 77.8% of these women reported that the violence was perpetrated by an intimate partner. Those who experienced intimate partner violence reported significantly greater pregnancy-related symptom distress (beta=0.23, P=0.001). No significant differences between violence perpetrated by family members or others and reporting of symptoms were observed (beta=0.06, P=0.38). CONCLUSION: The findings indicate the need to integrate violence screening, resources, and primary prevention into prenatal care in rural Haiti.     

听性稳态反应应用于婴幼儿听力评估的现状

刺激速率为70～110 Hz的听性稳态反应(auditory steady-state response, ASSR)(亦称为80 Hz)最近倍受听力学工作者特别是小儿听力学工作者的关注,设备制造商也正在推销其产品.本文回顾了ASSR的技术、应用基础,并总结了其应用于婴幼儿听力评估的现状.文中斜体字为基本原则.详细的ASSR方法学、正常值以及一些ASSR研究结果请参阅Picton(2003)的综述.ASSR并不是一个新发现的听觉反应,1960年Geisler就从人类头颅上记录到了该反应;以后研究者又记录到了短声、正弦调制波以及方波调制波所诱发的反应.Galambos等在1981年发表的有关40 Hz事件相关电位将ASSR引入听力领域.不同刺激速率的ASSR的产生部位是不同的,40 Hz的ASSR产生于皮层和脑干,而80 Hz的ASSR主要来源于脑干,而且很有可能它就是ABR的波Ⅴ,只是与ABR的刺激和记录方法不同而已.ASSR的重要特征之一就是在频域内分析的方法,通过计算位相相关性或刺激速率值处的信噪比,再根据统计学分析来判定反应的引出与否,这种客观性使ASSR显著优于ABR.ASSR的刺激信号最早是象ABR一样的短纯音信号,以后主要用调幅调制声,有时也加入10%～20%的调频调制,目前大多数设备都采用这一信号,最近一种新ASSR设备的缺省设置是5～8 ms的短音.ASSR的另一个重要特征是能够同时记录多个刺激声信号所产生的反应,这种多频刺激的方法能够同时记录双耳八个频率(每耳四个频率)的反应.研究证明只要各个信号的频率相距一个倍频程以上,强度在75 dB SPL以下,多个刺激声之间的干扰就很小或没有.不对称型的听力图、不同频率所产生的反应幅度的不同以及多频刺激方式所导致的各个频率反应幅度整体的下降延长了这种方法的测试时间,使其不如理想中的那么省时,但仍比单一刺激方式快2～3倍.80 Hz ASSR通常采用的是正弦调幅调制纯音,因为其特有的频率特异性而被认为是优于短纯音ABR的一个方面,但是声信号的频率特异性只是其中的一方面,还应考虑到耳蜗基底膜的部位特异性以及神经反应的特异性.研究证明ASSR的频率特异性与短纯音ABR是非常接近的.ASSR技术以飞快的速度发展,十年前还没有商用的设备,五年前只有两家,而目前至少有六种不同的设备.随着设备的增加,各个设备之间标准化的问题突显出来.有些设备有很浑厚的研究背景,而有些则没有,使用者应该根据设备的性能及临床资料而加以选择.关于80 Hz ASSR与行为听力测试相关性的研究很多,多为感音神经性聋成人或较大儿童,结果表明至少在该人群中ASSR的阈值能够很好地预测行为听力阈值.许多ABR与ASSR的比较研究声称ASSR比ABR能够更好地评估残余听力,也就是当受试者听力损失很重、ABR不能引出时,仍能够引出ASSR.尽管这一现象客观存在,但是还有一些其他需要考虑的影响因素,如:①所比较的信号在某一特定频率上的能量是不相等的,众所周知短声的能量分布频率范围很宽,其最大输出强度较ASSR信号小;②ASSR在高强度会有伪迹或非听性反应;③ASSR的长时强声刺激会导致耳蜗损害.因此需慎重对待这一问题.目前还没有关于传导性聋或混合性聋气导ASSR的研究,模拟传导性聋的研究表明气导ASSR阈值远高于行为听阈,而且ASSR骨气导差过大.骨导ASSR的研究显示听力正常婴幼儿各个频率的ASSR的阈值与成人显著不同.正常听力婴幼儿的短纯音ABR阈值以及诊断标准已经确立,而ASSR在这一方面的研究则显得不足,而且不同研究所采用的刺激(单频与多频)及记录(不同信噪比、噪声标准以及记录时间)方法不同,使这一形势更加恶化.综合不同调幅调制纯音ASSR的研究结果,正常听力婴幼儿在500、1 000、2 000及4 000 Hz的平均阈值分别为41、43、35和32 dB HL,如果转换为dB SPL则与短纯音ABR非常相似.如果以均值的90%～95%为可信区间,取二倍标准差,则诊断标准在500 Hz为60 dB HL,1 000、2 000及4 000 Hz为50 dB HL.关于感音神经性聋儿童ASSR的研究有很多,这种研究比较理想的方法应该将婴幼儿的ASSR阈值与行为听阈或短纯音ABR阈值相比较.遗憾的是多数研究都是短声ABR与ASSR的比较.总结以上工作发现,首先样本数量还很少,其次多数有方法学的缺陷,加之不同研究所采用的刺激和记录方法不同,临床资料就更加减少.最后还没有不同类型听力损失的婴幼儿ASSR的研究.总而言之,尽管ASSR在婴幼儿听力评估方面很有前途,但目前单独以此作为听力诊断的电生理方法还为时过早,还必须结合短纯音ABR,因为只有短纯音ABR才具有充足的基础、临床研究和明确的诊断标准,因而也是目前婴幼儿听力诊断电生理方法的金标准.根据上述回顾,ASSR在婴幼儿听力诊断的现状总结如下:①新的刺激及记录方法通常都没有经过同行审阅的临床科研为依据,特别是缺乏听力障碍婴幼儿的数据;②不同设备采用不同的刺激和记录方法,且缺少专业人员的评估;③不同的方法或设备层出不穷,缺乏标准化;④刺激声信号的校准问题以及ASSR与行为听力之间的关系问题还没有解决,各种设备采用不同的刺激和记录方法更加恶化了这一状况;⑤极重度聋者的ABR和ASSR的关系还有待于进一步研究;⑥听力损失儿童的ASSR与行为听力测试的关系的研究还很少,而且现有的大多数研究没有能够将ASSR与听力诊断的金标准--行为听力和/或短纯音ABR进行比较;⑦六个月以下婴幼儿的ASSR 研究还很少;⑧传导性聋或混合性聋成人和婴幼儿的研究还很少;⑨成人的骨导ASSR研究很少,还没有婴幼儿骨导ASSR的研究报道,也没有病理状态下成人或婴幼儿的骨导ASSR研究(极重度聋除外).如果上述问题得不到解决,ASSR技术就不能称为成熟.因为对于一个结果,无法准确地判定该阈值是正常还是升高.短纯音ABR的研究虽然尚需完善,但它已有非常多的研究背景和临床数据,能够提供气导和骨导听阈,是当前婴幼儿(特别是6个月以下儿童)听阈确定的首选方法.因此目前ASSR还需与短纯音ABR或行为听力测试结合使用. 80 Hz ASSR除了用于阈值的评估外,也可以用于阈上功能的评估,如单词识别或助听器效果的预估.结果 表明在正常或异常听力成人以言语调制声为信号,其识别阈与ASSR有显著相关性,它反映了较低水平的听觉处理能力.