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Camilla Al Fayed成为Issa品牌新任总裁

  Harrods前任持有人Mohamed的女儿Camillla Al Fayed成为Issa品牌的新任总裁,而Issa品牌的设计师和创立者Daniella Helayel将继续担任品牌的创意总监。Camilla Al Fayed持有Issa品牌51%的股份,将帮助品牌实施全球扩张和发展计划。

  Camilla Al Fayed说:“我非常信任Issa这个品牌,长期以来我都非常欣赏Daniella Helayel的设计和独创性。她的成就都是通过这八年的努力达成的,我觉得她现在非常需要有一个合作伙伴,帮她实现进军全球市场的目标。”

  Issa品牌一直深受新王妃凯特和她姐姐Pippa middleton的喜爱,品牌成立于2003年,在当时的伦敦时装周上首次亮相。

  Helayel这样评价即将和Camilla的合作:“我非常开心能和Camilla一起工作,我们俩都会尽全力让Issa品牌越来越成功,而且我们对于品牌未来发展的理念和策略非常清晰。Camilla的高超零售手段必定会为Issa品牌创造成功。”

  Camilla Al Fayed说道:“我们将重整品牌的商业模式,未来我们会建立网购网站,紧接着会开设独立商店,主要选址在伦敦和巴西。未来的长期规划是将品牌建立成一个生活理念品牌,推出童装和家具系列。”

  而Mohamed Al Fayed最近刚刚收购了网购设计师折扣店Cocosa,这将意味着他从去年五月出售Harrods以后重新回归零售业。在某种程度上这次的收购也将意味着Mohamed Al Fayed将计划创立一个全新的时尚网络王国。

  Cocosa品牌前持有人为Bauer Media,成立于2008年,销售Alexander McQueen, Alice Temperley, Halston Heritage等高端品牌。

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

日期:2011年7月13日 - 来自[流行设计师]栏目
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儿童急性白血病MDM2基因的表达

【摘要】  目的 探讨MDM2基因mRNA的表达与儿童急性白血病(AL)的关系。方法 采用逆转录多聚酶链式反应技术(RT-PCR),对42例初发或复发AL患儿和13例完全缓解AL(AL-CR)患儿及15例非恶性疾病患儿骨髓单个核细胞进行MDM2 mRNA表达的检测。结果 AL组中MDM2 mRNA的表达率为57.1%,明显高于AL-CR组和对照组;完全缓解组和对照组差异无显著性。MDM2 mRNA的表达与白细胞总数及临床危险度分型有关,与性别、年龄、免疫分型无明显相关性。MDM2 mRNA表达者缓解率低。结论 儿童AL中存在MDM2 mRNA过表达,且可能与儿童AL发病有关;MDM2 mRNA表达是AL的不良预后因素;AL MDM2 mRNA表达者可以降低AL的化疗敏感性,MDM2 mRNA表达对AL有疗效判断和预后的价值。

【关键词】  急性白血病;儿童; MDM2; 逆转录多聚酶链式反应

 Expression of MDM2 gene in childhood acute leukemia

    LIU Zhuang, TAN Li-zhen, WU Xiang-qin, et al.Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021,China

    【Abstract】  Objective  To investigate the expression and significance of MDM2 gene in childhood acute leukemia (AL). Methods  The mRNA expression of MDM2 gene was examined by RT-PCR in bone marrow cells from 42 cases of incipient or relapsed childhood AL, 13 cases of complete remission AL (AL-CR) and 15 children without malignance disease as control group.Results  57.1% AL cases were positive for MDM2 mRNA, remarkably significant higher than that of control group and AL-CR group. There was no difference of MDM2 mRNA expression between AL-CR group and control group. The expression of MDM2 mRNA was connected with initial white blood cell (WBC) count and clinical risk type of AL. There was no connection between MDM2 mRNA expression and some clinical and laboratory parameters such as age, sex and immunogenic type. The remission rate in patients with high expression of MDM2 mRNA was lower. Conclusion  There is over expression of MDM2 mRNA in childhood acute leukemia, which may be related to pathogenesis of AL. The expression of MDM2 may imply higher risk and lower sensitivity of the leukemic cells to chemotherapy. The expression of MDM2 mRNA might be the index of treatment effect and poor prognosis.

    【Key words】  acute leukemia; child; MDM2; reverse transcription-polymerase chain reaction

    MDM2(murine double minute 2)基因是从自然转化的Bal B/C小鼠细胞株中发现的癌基因,它编码一种DNA结合蛋白,该蛋白与p53蛋白形成复合体,致p53失去对肿瘤活性的抑制作用,从而导致肿瘤的发生和发展,造成肿瘤对放疗、化疗的耐受,与不良预后有关[1,2] 。为探讨儿童急性白血病的MDM2过度表达的发生率及其与疾病的发生发展的关系,笔者采用逆转录多聚酶链式反应(RT-PCR)的方法对儿童急性白血病(AL)患者骨髓单个核细胞MDM2 mRNA的表达进行了检测,现报告如下。

    1  对象与方法

    1.1  研究对象   病例组:初发及复发未治AL组42例,为2004年2月~2006年11月期间在广西医科大学第一附属医院儿科住院的AL初发及复发且未经治疗患儿,均经骨髓细胞学检查确诊。其中ALL 32例(其中L1  3例、L2  27例、L3  2例),ANLL 10例(M2a 4例、M2b 1例、M3a 3例、M3b 1例、M4b 1例)。男27例,女15例;年龄2~14岁,中位年龄8岁。初发组35例,复发组7例。初发组中ALL 26例,其中B-ALL 16例,T-ALL 5例,5例未进行免疫分型,ANLL 9例。初发组中高危8例,标危27例。诊断及分型依据文献[3],各组性别、年龄等条件相似。缓解组(AL-CR组)13例,为同期住院的AL治疗后达完全缓解(CR)患儿,其中男9例,女4例;年龄3.8~14岁,中位年龄8.6岁。均经骨髓细胞学检查证实为AL-CR。 对照组15例,为同期住院的非恶性血液病(特发性血小板减少性紫癜、缺铁性贫血等),男9例,女6例;年龄3~14岁,中位年龄8.9岁。

    1.2  方法

    1.2.1  标本采集  骨髓涂片后,抽取骨髓液1~2 ml,ACD抗凝,采用Ficoll密度梯度离心分离出单个核细胞(MNC),PBS洗涤2次,-80℃保存。

    1.2.2  总RNA提取  按照Trizol试剂盒(Gibco BRL Invitrogen,USA)说明提取总RNA。用紫外分光光度计测定RNA纯度(A260/A280>1.8),同时进行RNA定量,并经甲醛琼脂糖凝胶电泳证实RNA完整。-80℃保存备用。

    1.2.3  cDNA逆转录反应  20.0μl反应体系, 总RNA 2μl(1μg/μl), oligo(dT)18 1.0μl引物1.0μl,去离子水9.0μl,混匀。70℃ 5min,冰浴冷却,离心混匀,加下列反应物:5×缓冲液4.0μl, dNTPs (10mmol/L)2.0μl, RNasin 1.0μl,混匀,37℃ 5min,然后加入M-MuLV逆转录酶 (200u/μl)1.0μl,42℃ 60min,70℃ 10min,冰浴冷却终止反应。-20℃保存待用。

    1.2.4  MDM2 cDNA的PCR反应   引物设计参考文献[4],由上海生工公司合成。MDM2有意义链引物:5′-TTATTAAAGTCTGTTGGTGCA-3′,反意义链引物:5′-TGAAGGTTTCTCTTCCTGAAG-3′,扩增产物长度336bp。内对照β-actin上游引物5′-AAGAGAGGCATCCTCACCCT-3′,β-actin下游引物5′-TACATG GCTGGGGTGTTGAA-3′,扩增产物长度218bp。反应体系40.0μl,取cDNA产物10.0μl,加dNTPs、缓冲液、MgCl2、MDM2与β-actin引物、去离子水。终浓度为:dNTPs 0.2mol/L,MgCl2 2.5mol/L,各引物浓度均为25pmol/L。94℃预反应4min,加Taq酶2.0u,进行32个PCR循环,每循环94℃ 45s、54℃ 40s、74℃ 40s,终末延伸72℃5min。

    1.2.5  PCR产物分析  2.0%琼脂糖凝胶电泳80min,在紫外光下观察,用BIO RAD公司的凝胶图像分析软件进行吸光度(A值)分析,计算MDM2 /β-actin值,以此得到MDM2基因表达水平。参照文献[4]的评定标准,以MDM2 /β-actin的比值>16%为MDM2 mRNA过表达。

    1.3  统计学处理  使用SPSS10.0软件包对实验结果进行统计学处理,对数据进行卡方检验、Fisher精确概率法。

    2  结果

    2.1  病例组和对照组MDM2 mRNA的表达  见表1。42例AL中有24例MDM2表达,表达率为57.1%,13例AL-CR及15例对照组中无MDM2 mRNA表达,MDM2 mRNA表达率在AL组与对照组、AL组与AL-CR组之间均差异有显著性(P=0.0002,P=0.0001);AL-CR组和对照组比较差异无显著性(P=1.000)。表1   MDM2 mRNA在病例组和对照组的表达                   

    2.2  AL初发组与复发组MDM2 mRNA的表达比较  35例AL初发组中MDM2 mRNA过度表达19例,表达率为54.3%,7例AL复发组中MDM2 mRNA表达5例,表达率为71.4%,两者之间差异无显著性(P=0.675)。

    2.3  MDM2 mRNA表达与化疗反应的关系  见表2。AL组中有19例患者完成了诱导缓解化疗,其中初发AL 13例、复发AL 6例。初发13例中诱导化疗后达完全缓解(CR)10例,未缓解(NR)3例,6例复发病例中,CR 2例,NR 4例。CR与NR病例的MDM2 mRNA表达水平无论是治疗前还是治疗后均差异有显著性,NR患者表达水平显著高于CR患者(P均<0.05)。CR病例缓解后与自身缓解前的MDM2 mRNA表达差异有显著性(P<0.05)。未缓解病例治疗前后MDM2 mRNA表达差异无显著性(P>0.05)。表2  儿童AL MDM2 mRNA表达与化疗反应的关系注:采用秩和检验,NR与CR组比较,▲P<0.05;与治疗前比较,●P<0.05,★P>0.05。CR:完全缓解;NR:未缓解

    2.4  AL初发组MDM2 mRNA表达水平与临床特征及临床分型的关系  见表3。WBC≥100×109/L患儿与WBC<100×109/L患儿之间、高危型患儿与标危型患儿之间均差异有显著性。在年龄≥10岁或<1岁与1~10岁患儿之间、男性与女性之间、T-ALL和B-ALL之间均差异无显著性。表3  MDM2 mRNA表达水平与儿童AL临床特征及临床分型的关系

    3  讨论

    MDM2属癌基因,具有调节细胞生长的作用,可通过与启动细胞周期的启动子直接联结,使细胞从G1期向S期转化,促进细胞增殖,MDM2转录产物MDM2蛋白还可与抑癌基因p53产物p53蛋白结合,抑制p53介导的转录活性,并将p53蛋白转运到细胞质中降解,从而抑制细胞凋亡[5,6]。许多肿瘤中有MDM2过度表达,MDM2基因过度表达时会促使肿瘤的发生发展,并且MDM2过度表达者肿瘤恶性度高,还会造成肿瘤对放疗、化疗的耐受,与不良预后有关[1,2]。

    在造血系统恶性疾病中,可有不同程度的MDM2基因扩增及mRNA的过度表达, 并且与不良预后有关。笔者曾对31例儿童非霍奇金淋巴瘤(NHL)患者MDM2 mRNA的表达状况进行了检测,发现MDM2的表达与儿童NHL的不良状况、不良预后有关[7]。樊娟等[8]采用免疫组化法观察AML患者MDM2蛋白表达情况,有75%的AML患者有不同程度的MDM2蛋白的过度表达,且发现AML各亚型中均有MDM2蛋白阳性表达的患者,提示MDM2基因的过度表达在白血病的发病中起一定的作用。蒋莎义等[9]检测儿童急性淋巴细胞性白血病, 其结果显示MDM2 mRNA表达率为 44%,不良预后患者中过表达率达到83%。本组资料中笔者采用RT-CR方法检测了42例儿童急性白血病(AL)患者的MDM2 mRNA表达状况,发现儿童AL中MDM2 mRNA表达率为57.1%,明显高于AL-CR及对照组;在高危组表达率达87.5%,明显高于标危组,而在WBC计数≥100×109/L的6例患者表达率更达100%;在完成诱导化疗的19例AL中,完全缓解与未缓解病例的MDM2 mRNA表达水平无论是治疗前还是治疗后均差异有显著性,未缓解患者表达水平显著高于完全缓解患者。提示MDM2 mRNA表达状况与儿童AL的发病、疗效、预后有一定关系, MDM2 mRNA表达的检测有助于对儿童AL细胞对化疗的敏感性及其预后的评估。

【参考文献】
  1 Juven-Gershon T, Oren M. MDM2: the ups and downs. Mol Med, 1999, 5(2):71-83.

2 Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the tumor suppresser protein. Gene, 2000,242(1-2):15-29.

3 黄绍良. 小儿血液病临床手册,第2版.北京:人民卫生出版社,2000,484-547.

4 Bueso-Ramos CE, Yang YY, Deleon E, et al. The human MDM-2 oncogene is overexpressed in leukemias. Blood, 1993, 82(9):2617-2623.

5 Haupt Y, Maya R, Kazaz A, et al. MDM2 promotes the rapid degradation of p53. Nature, 1997, 387(6630):296-299.

6 Prives C. Signaling to p53: breaking the MDM2-p53 circuit. Cell, 1998, 95(1):5-8.

7 刘壮,龙桂芳,韩蕴丽,等. MDM2的表达与儿童非霍奇金淋巴瘤关系的研究. 中华儿科杂志, 2004, 42(12):928-931.

8 樊娟, 徐功立, 徐键,等. MDM2和p53基因在急性白血病细胞中的表达及意义. 癌症, 2000, 19(8):786-788.

9 蒋莎义, 陈力军, 高飞, 等. 癌基因MDM2过度表达与儿童急性淋巴白血病的发病和预后的关系. 中华儿科杂志, 2000, 38:445.


作者单位:广西南宁,广西医科大学第一附属医院儿科 广西柳州,柳州中医院肿瘤科

日期:2009年8月24日 - 来自[2008年第7卷第8期]栏目

Diet and leukocytes

C Wayne Smith1

1 From the Section of Leukocyte Biology, Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX

2 Reprints not available. Address correspondence to CW Smith, Children's Nutrition Research Center, 1100 Bates, Room 6014, Houston, TX 77030. E-mail: cwsmith{at}bcm.tmc.edu.

See corresponding article on page 1286.

In this issue of the Journal, Erridge et al (1) cited work from several laboratories on postprandial activation of blood leukocytes. The evidence of leukocyte activation in these studies includes increases in circulating leukocytes (neutrophils, lymphocytes, and platelets), activation of the transcription factor nuclear transcription factor B (NF-B) in peripheral blood mononuclear cells, increased expression of tumor necrosis factor- (TNF-) in monocytes, and alterations in some surface adhesion molecules in neutrophils and monocytes (eg, increased surface levels of CD11B, the -subunit of one member of the ß2 integrin family). The test diets that apparently induced these changes were high in fat (eg, butter or cream), glucose, or mixed carbohydrates and fats. The mechanisms for this acute postprandial activation of inflammation are unclear. Ting et al (2) recently reported that triacylglycerol-rich lipoproteins isolated from 3.5 h postprandial blood significantly augmented TNF-–dependent activation of endothelial cells, which resulted in the expression of adhesion molecules capable of capturing monocytes under conditions of fluid shear. Erridge et al provide evidence of postprandial elevations in venous blood samples of endotoxin (lipopolysaccharide), a cell wall component derived primarily from Gram-negative bacteria. Published evidence (cited by Erridge et al) from animal models and human investigations is consistent with endotoxin release from the gut. Given the fact that leukocytes, particularly monocytes, and endothelial cells express the Toll-like receptor 4 (TLR4) complex, a key cell surface–signaling receptor for endotoxin, postprandial elevations in blood endotoxin may contribute to leukocyte and endothelial activation. Shi et al (3) raise additional considerations. They showed that the saturated free fatty acids (FFAs) lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0) stimulate macrophage activation of NF-B and expression of proinflammatory cytokines. These responses were largely dependent on the TLR4 receptor complex. Thus, postprandial activation of inflammation appears multifactorial, possibly involving several potential agonists for the TLR4 receptor complex as well as other mechanisms.

Heightened interest in the TLR4 receptor complex comes from observations that mice deficient in TLR4 are substantially protected against high-fat diet–induced vascular inflammation (4), insulin resistance, and expression of proinflammatory cytokines in adipose tissue and liver (3, 5). If high-fat meals provoke repeated surges in TLR4 agonists such as endotoxin, saturated FFAs, and other factors that induce endothelial capture of leukocytes and if tissue cells expressing the TLR4 receptor complex are activated to release proinflammatory cytokines and chemokines, the emigration of leukocytes (eg, monocytes) into tissues is not unexpected. Lumeng et al (6) and Weisberg et al (7) published evidence of the emigration of proinflammatory macrophages in adipose tissue in an animal model, and other investigators have observed macrophages in human adipose tissue, especially omental adipose tissue (8). Suganami et al (5) analyzed the potential interplay between adipocytes and macrophages by using a coculture setting in vitro. They found that coculture induced significant release of FFAs by adipocytes and significant increases in proinflammatory cytokines from macrophages. The FFAs from adipocytes were capable of activating macrophage NF-B in a TLR4-dependent manner, and mice deficient in TLR4 had significantly reduced proinflammatory cytokine production from adipose tissue. Thus, mounting evidence from animal models positions TLR4 as a critical link in the proinflammatory aspects of obesity. That this apparent link could be simply triggered by the availability of TLR4 ligands such as endotoxin was recently questioned by Tang et al (9). They proposed that, under normal conditions, many cells expressing TLR4 do not respond readily to TLR4 agonists but must be released from "constitutive suppression." They provided evidence that neutrophil elastase potentiates TLR4 responsiveness and that endogenous ligands for TLR4, such as heparan sulfate, a ubiquitous component of tissue matrix, will induce TLR4-dependent activation in the absence of exogenous agonists. They found that treatment of mice with amounts of elastase insufficient to directly activate responses greatly augmented inflammatory responses to exogenous TLR4 agonists. There may be, therefore, reason to consider diet-induced activation of neutrophils (a source of elastase) as a step in the inflammatory cascade where TLR4 is a link.

Investigation of blood leukocytes and soluble inflammatory markers in humans will certainly yield insights into diet-activated inflammatory pathways, but an important complexity that must be addressed is the diversity of leukocyte subsets. The functional significance of changes in activation signals detectedin mixed populations of leukocytes is obscured by the diversity of cell types. To date, no studies have dealt with this issue in sufficient detail. Neutrophils, lymphocytes, and platelets show postprandial increases in number, and neutrophils express activation markers. Platelets have received little attention, although they have been shown to play critical roles in many inflammatory responses (10). Several investigations have studied peripheral blood mononuclear cells, a substantial fraction of blood leukocytes that contains numerous subsets of lymphocytes and monocytes with both pro- and antiinflammatory activities. T lymphocyte subsets have been observed in adipose tissue in obese humans (11). Even studies focusing on isolated monocytes are confounded by the fact that subpopulations exist with different response capabilities and functions (12). For example, one population expresses a receptor (CCR5) that is capable of recognizing the chemokine CCL5, produced by adipose tissue in response to a high-fat diet (11). Another subpopulation of monocytes lacks this receptor. Edwards et al (13) defined 3 activation pathways for macrophages in response to different combinations of cytokines with and without TLR4-dependent signaling. Two pathways result in macrophages that produce antiinflammatory factors, and one pathway results in macrophages that produce predominately proinflammatory factors. A subset referred to as "alternatively activated" macrophages can produce high concentrations of interleukin 10, a cytokine that protects adipocytes from TNF-–induced insulin resistance (6). Studies in an animal model indicate that this population assists in counterbalancing the proinflammatory effects of a high-fat diet (14). Sorting out the effects of dietary stimuli on these various subsets of leukocytes in humans will be a substantial effort, but future studies of defined leukocyte populations can be facilitated by the ready availability of marker antibodies and isolation techniques.

ACKNOWLEDGMENTS

The author had no personal or financial conflict of interest.

REFERENCES


Related articles in AJCN:

A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation
Clett Erridge, Teresa Attina, Corinne M Spickett, and David J Webb
AJCN 2007 86: 1286-1292. [Abstract] [Full Text]  

日期:2008年12月28日 - 来自[2007年86卷第5期]栏目
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Reply to D Sluik et al

Ahmad Esmaillzadeh and Leila Azadbakht

Department of Nutrition
School of Health
Isfahan University of Medical Sciences
PO Box 81745
Isfahan
Iran
E-mail: esmaillzadeh{at}hlth.mui.ac.ir

Dear Sir:

In our recent article (1), entitled "Fruit and vegetables intakes, C-reactive protein, and the metabolic syndrome," we concluded that a higher intake of fruit and vegetables is associated with a lower risk of the metabolic syndrome; part of this association may be mediated through C-reactive protein concentrations. These findings support current dietary recommendations to increase the intake of fruit and vegetables as a primary preventive measure against cardiovascular disease.

First, we thank Sluik et al for their interest in our article. They claimed in their letter that the corrected odds ratios we derived from logistic regression models may yield inaccurate estimates of the association between fruit and vegetable intakes and the metabolic syndrome. We obtained adjusted prevalence odds ratios from logistic regression models, but because the prevalence of the metabolic syndrome in our study population was high (>10%), we used the formula suggested by Zhang and Yu (2) to correct these odds ratios. Although previous investigations have shown that the prevalence ratio is preferred over the prevalence odds ratio for evaluating associations in cross-sectional data (3, 4), inaccurate estimates with the use of the prevalence odds ratio would result when the odds ratio is >2.5 or <0.5 (2). This is not the case in our article, as shown in our Table 4. Furthermore, we corrected the simple odds ratios obtained from logistic regression, which can further attenuate the prevalence odds ratio toward the value of the prevalence ratio. However, both the prevalence odds ratio and the prevalence ratio would maintain statistical significance (if a significant association really exists) (5) and choosing either one would not affect the association between fruit and vegetable intakes and the metabolic syndrome.

ACKNOWLEDGMENTS

None of the authors declared any personal or financial conflicts of interest.

REFERENCES


日期:2008年12月28日 - 来自[2007年86卷第5期]栏目

Reply to A Molfino et al

Juan Jesús Carrero, Olof Heimbürger and Peter Stenvinkel

Division of Renal Medicine, K56
Karolinska University Hospital at Huddinge
141 86 Stockholm
Sweden
E-mail: peter.stenvinkel{at}ki.se

Bengt Lindholm

Baxter Healthcare, Inc
Stockholm
Sweden

Dear Sir:

We want to thank Molfino et al for their comments on our report about appetite loss in persons undergoing hemodialysis (1). We read with interest their recent publication (2) and agree on the importance of ghrelin in the regulation of appetite behavior in uremic patients. Indeed, the discovery of the different structural variants of ghrelin presents exciting new opportunities, especially after recent observations showing that des-acyl ghrelin may be more than just an innocent bystander.

To be able to better address the comments raised by Molfino et al, we measured total ghrelin concentrations in stored plasma samples (n = 223) from the same cohort of persons undergoing hemodialysis as previously studied (1). Confirming previous results (3), an inverse correlation ( = –0.25, P < 0.0001) between ghrelin and body mass index (BMI; in kg/m2) was observed. Because anorectic persons undergoing hemodialysis have low BMI, we compared the ratio of ghrelin to BMI in persons undergoing hemodialysis reporting good appetite (n = 124) or appetite loss (n = 99). In agreement with previous studies, we found that persons undergoing hemodialysis reporting loss of appetite had significantly higher ghrelin concentrations than did those reporting good appetite (437 ± 21 and 327 ± 18 pg/mL, respectively; P = 0.05). In our study, we used a radioimmunoassay method that analyzed the sum of ghrelin and des-acyl ghrelin, which presumably may account for >90% of total circulating ghrelin (4). Yoshimoto et al (4) reported that another radioimmunoassay kit that measures ghrelin alone did not find a correlation with renal function, and thus it seems conceivable that the accumulation of the structural variant of des-acyl ghrelin accounts for most of the observed increase in plasma ghrelin concentration in persons with chronic kidney disease, which confirms the findings of Molfino et al (2).

In our report, we hypothesized that sex-specific mechanisms are involved in the regulation of feeding behavior in persons undergoing hemodialysis, and we speculated that the regulation of leptin and ghrelin may be different in males and females. When we compared ghrelin concentrations in males and females undergoing hemodialysis who did and did not have loss of appetite, they were significantly higher in the males reporting appetite loss, but not in the females (P = 0.01; Figure 1). It is interesting that recent data have shown that inflammation may influence ghrelin concentrations (5). Thus, the higher prevalence of inflammation in anorectic males than in anorectic females in that cohort may explain at least part of the differences observed in ghrelin concentrations. In fact, whereas a significant correlation was found between ghrelin concentrations and both C-reactive protein (r = 0.16, P < 0.05) and interleukin-6 (r = 0.17, P < 0.05) in males, no such correlations were found in females, which again suggests that the associations among inflammation, appetite, and body composition should be evaluated separately in males and females. It is worth investigating whether our observations are due to the des-acyl ghrelin fraction, and that investigation may open new therapeutic perspectives in this and other populations of patients with inflammation and anorexia.


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FIGURE 1.. Comparison of the ratio of total ghrelin to BMI in males and females undergoing hemodialysis who reported loss of appetite or no loss of appetite. Differences between appetite categories were assessed with the chi-square test. This analysis comprised 124 persons undergoing hemodialysis who reported good appetite (44 F, 80 M) and 99 persons undergoing hemodialysis who reported some degree of appetite loss (52 F, 47 M). The ratio of total ghrelin to BMI was significantly (P < 0.01) higher in the men reporting loss of appetite, but not in the women.

 
However, elevated ghrelin concentrations may represent just one of many pieces in the complicated puzzle of uremic anorexia. Clearly, this condition can arise from such diverse causes as early satiety, dysfunctional hypothalamic responses, increases in cytokine concentrations, effects of medications, and decreased taste and smell of foods. Thus, uremic anorexia represents a complex and multifactorial disorder in which many hormones and transmitters play a role, including the release of neurotransmitters (eg, serotonin) and neuropeptides (eg, neuropeptide Y and orexin) and increased production or retention of uremic toxins and gut-to-brain signaling factors (eg, cholecystokinin and ghrelin) and cytokines (eg, tumor necrosis factor-, leptin, interleukin-6, adiponectin, and interleukin-1ß) (6). Although most uremic patients regain their appetite immediately upon the start of dialysis (which suggests the removal of 1 toxic factor that suppresses appetite), poor appetite is a common finding in persons undergoing dialysis. Poor appetite in persons undergoing hemodialysis is associated with higher concentrations of proinflammatory cytokines (1), which regulate the release and function of neurotransmitters affecting orexigenic and anorexigenic hypothalamic neurons. Leptin is an adipocytokine retained in uremia that is important in the control of metabolic rate and appetite.

Whereas some studies show that elevated circulating leptin concentrations in persons undergoing dialysis are associated with better nutritional status (perhaps reflecting leptin resistance, decreased transport of leptin across the uremic blood-brain barrier, or both), a recent study by Cheung et al (7) showed that uremic cachexia was attenuated in leptin receptor–deficient mice (db/db). This finding suggests that leptin plays a crucial role in the regulation of appetite and metabolic rate in uremia. The central effects of leptin are mediated via local activation of neurons, such as neuropeptide Y or agouti-related peptide and proopiomelanocortin, which triggers the release of -melanocyte–stimulating hormone and melanocortin receptor-4 (MC4-R). Because this sequence of events leads to decreased food intake and increased energy expenditure, genetic or pharmacologic blockade of MC4-R may be a future treatment for uremic anorexia. Indeed, Cheung et al (7) showed that, by central blocking of MC4-R via a genetic approach, uremic anorexia was attenuated in a mice model. Adiponectin (another adipocytokine retained in uremic patients) has mostly been seen as a protector of vascular function; among other beneficial effects, it has been reported to inhibit the expression of adhesion molecules, stabilize plaques, suppress tumor necrosis factor- production, and attenuate the proliferation of vascular smooth muscle. However, because elevated adiponectin concentrations were, unexpectedly, associated with greater mortality in large cohorts of patients with congestive heart failure (8) and chronic kidney disease (9), it is possible that this adipokine also has deleterious effects. Indeed, a recent study in mice showed that intracerebroventricular administration of adiponectin decreased body weight mainly by stimulating energy expenditure, and thus adiponectin may promote wasting (10). Because Agouti mice in that study did not respond to the energy-modulating effects of adiponectin, the melanocortin pathway may be the common target (10).

Anorexia is a multifactorial feature in persons undergoing dialysis that heralds poor prognosis. Many peripheral hormones retained in uremia (including ghrelin and adipocytokines) affect appetite via central signaling pathways, and thus it is not surprising that there is currently no effective treatment for this devastating condition. Indeed, the use of various nutritional strategies and appetite stimulants has so far been largely ineffective. However, recent studies suggested that hypothalamic MC4-R plays an important role in transducing cachexigenic signals in uremia, and thus oral antagonism of the central melanocortin system may represent a novel treatment approach.

ACKNOWLEDGMENTS

Supported by an unrestricted grant from Amgen and by a fellowship from the European Renal Association–European Dialysis and Transplantation Association (to JJC).

BL is employed by Baxter Healthcare Inc. No other author had a personal or financial conflict of interest.

REFERENCES


日期:2008年12月28日 - 来自[2007年86卷第5期]栏目
循环ads

Reply to S Voutilainen et al

Cuno SPM Uiterwaal

Julius Center for Health Sciences and Primary Care
University Medical Center
PO Box 85500
3508 GA Utrecht
Netherlands
E-mail: c.s.p.m.uiterwaal{at}umcutrecht.nl

WM Monique Verschuren

Center for Prevention and Health Services Research
National Institute of Public Health and the Environment
Bilthoven
Netherlands

Diederick E Grobbee

Julius Center for Health Sciences and Primary Care
University Medical Center
PO Box 85500
3508 GA Utrecht
Netherlands

Dear Sir:

Voutilainen et al found our results on coffee intake and the risk of hypertension (1) to be largely consistent with their findings in the Kuopio Ischaemic Heart Disease Risk Factor Study (2). The main point they raise concerns the part of our conclusions that abstinence of coffee drinking was associated with a lower risk of hypertension than was low coffee consumption. Voutilainen et al argue that the number of coffee abstainers was small; indeed, there were only 231 coffee abstainers. Second, they claim that the coffee abstainers "did not represent the general population" and thus that the observation was confounded. However, after adjustment for confounders, we found this effect of coffee to still be there. Although this observation may appear unreliable because of the small number of subjects, and, although residual confounding cannot be excluded, it is consistent with other findings (3). Therefore, we felt that Voutilainen et al did not provide sufficient reasons to overturn this part of our conclusions.

ACKNOWLEDGMENTS

CSPMU was provided an unrestricted grant by the organization on Physiological Effects of Coffee (PEC) in Paris, France. No other authors had any conflicts of interest.

REFERENCES


日期:2008年12月28日 - 来自[2007年86卷第4期]栏目
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