限食后追赶生长性肥胖与大鼠血浆葡萄糖依赖性胰岛素释放肽水平的关系

目的 探讨限食后追赶生长性肥胖与大鼠血浆葡萄糖依赖性胰岛素释放肽(GIP)水平的相关性.方法 6周龄健康雄性SD大鼠60只按随机数字表法随机分为普通饮食组(n=15,给予普通饮食)、普通饮食追赶生长组(n=15,给予同体重普通饮食组大鼠60%普通饲料限食喂养4周后饲以普通饲料)、高脂饮食组(n=15,给予高脂饮食)和高脂饮食追赶生长组(n=15,给予同体重普通饮食组大鼠60%普通饲料限食喂养4周后饲以高脂饲料),观察大鼠体重及进食量变化.分别于4、6、8周处死部分动物,检测体脂含量及血浆GIP浓度.采用配对t检验和单因素方差分析以及一元线性相关分析进行数据统计.结果 与普通饮食组相比,高脂饮食组、普通饮食追赶生长组和高脂饮食追赶生长组体脂含量[分别为(3.6±0.6)、(7.9±1.5)、(4.6±1.1)、(7.0±1.0)g;t值分别为-2.601、-2.305、-2.501,均P＜0.05]、血浆GIP水平升高[分别为(41±9)、(61±7)、(51±8)、(59±8)pmol/L;t值分别为-6.061、-3.452、-4.651,均P＜0.05].相关分析显示,体脂含量与血浆GIP水平显著相关(r2=0.9407).结论 限食后追赶生长性肥胖与大鼠血浆GIP水平高度相关,可能与追赶生长所引发的病理生理学变化有关.     

追赶生长与高尿酸血症的相关性研究

目的:研究追赶生长人群代谢状况变化,探讨追赶生长是否与高尿酸血症(hyperuricemia,HUA)相关以及是否为HUA的危险因素。方法:2014年于宜昌市夷陵区进行人群调查研究,共有6 685名居民参与。对所有研究对象进行体格检查和问卷调查,同时采集空腹及糖负荷后2 h静脉血,进行血糖、血脂、尿酸等指标检测。在剔除584名资料不全者后,对余下6 101名的数据进行分析。根据是否存在低营养后营养水平提升将受试者判定为追赶生长或非追赶生长,比较2组的代谢状况,Logistic回归分析追赶生长人群发生HUA的优势比(odds ratio, OR)。结果:与非追赶生长人群相比,追赶生长人群具有更高的体质量指数(body mass index,BMI)、收缩压、三酰甘油(triglyceride,TG)水平,更低的高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平;进一步亚组分析显示,在女性,追赶生长HUA患病比例和血尿酸水平明显高于非追赶生长(P0.001),而在男性,追赶生长与非追赶生长HUA患病比例和血尿酸水平差异无统计学意义(P0.1);经Logistic多元回归分析校正年龄、BMI、吸烟、饮酒、血压、空腹血糖、糖负荷后2 h血糖、TG等因素后,结果显示追赶生长女性发生HUA的风险较非追赶生长显著升高,OR值为1.415(P=0.022),95%可信区间(confidence interval, CI):1.272～2.795。结论:追赶生长人群较多出现代谢异常,且追赶生长与HUA相关,是HUA的独立危险因素。     

追赶生长胰岛素抵抗形成机制的新认识

追赶生长是机体一过性生长抑制后出现的快速生长现象,现已证实追赶生长与胰岛素抵抗存在高度相关性,但其形成的具体机制尚不明确.     

从追赶生长角度剖析胰岛素抵抗相关疾病高发的机制

追赶生长为胰岛素抵抗相关疾病的研究提供了新的思路.追赶生长是一个普遍存在的现象,本是生命的一种自我代偿,但与胰岛素抵抗的形成有着密切的关系.追赶生长主要是脂肪的优先和过度生长.目前在其机制、干预等方面还有许多亟待解决的问题.     

早期营养干预对宫内生长迟缓大鼠瘦素、胰岛素敏感性的影响

目的　探寻既能保证宫内生长迟缓 (IUGR )大鼠生长追赶又可避免或减轻其在成年期产生胰岛素抵抗 (IR)的早期营养干预措施。方法　用孕鼠全程饥饿法建立IUGR大鼠模型。IUGR新生雌鼠60只随机分为五组 :( 1)IUGR对照组给予常规饲料 ;( 2 )高碳水化合物组 ;( 3 )高脂肪组 ;( 4 )高蛋白质组 ;( 5 )低蛋白质组。正常新生雌鼠 12只为正常对照组。幼鼠在 3周喂乳期间母鼠分别摄食上述饲料 ,第 4周起各组幼鼠均以常规饲料饲养。各组新生鼠于第 4周、12周分别测定体重、肾周脂肪重量、血清瘦素、血糖、胰岛素并计算胰岛素敏感指数 (ISI)。结果　IUGR高蛋白质组在 4周呈现不伴肾周脂肪增加的体重追赶生长 ,在 12周肾周脂肪不增多 ,瘦素、ISI均与正常对照组比较差异无显著性 ,不出现IR。结论　生后哺乳期高蛋白饮食继后恢复正常饮食是早期营养干预IUGR的合理措施。 12周时血清瘦素水平可作为观察IUGR大鼠成年后发生IR的一个生化指标。     

塔里木盆地子午沙鼠年龄鉴定及种群年龄组成的研究

目的研究塔里木盆地子午沙鼠年龄鉴定方法及种群年龄组成.方法2003年9月,对在塔里木盆地捕获的867只子午沙鼠进行生物学测量和解剖,以胴体重为指标,经次数分配和参考体重、体长、尾长、繁殖及实验室饲养鼠数据作对比划分年龄组.结果以胴体重为指标将子午沙鼠划分为5个年龄组,胴体重、体重、体长和尾长随其生长变化明显,且成正相关,其中胴体重生长增加相对稳定,各年龄组平均胴体重加减1个标准差,和加减3个标准差均无交差现象.各年龄组体重间差别显著(P<0.000 5),Ⅰ～Ⅳ龄♀性和Ⅰ,Ⅳ龄性间体长差别显著(P<0.05),Ⅰ～Ⅴ龄间尾长差别显著(P<0.05).结论以胴体重为指标,划分子午沙鼠年龄是一种比较可靠、适用的方法.     

川芎嗪对胎儿生长受限大鼠及胎鼠血清IGF-Ⅱ浓度的影响

目的分析胎儿生长受限(FGR)大鼠及胎鼠血清胰岛素样生长因子-Ⅱ(IGF-Ⅱ)浓度及胎鼠体重、体长、体重系数的变化,并探讨川芎嗪对其产生的影响。方法利用放射免疫法测定大鼠及胎鼠血清中IGF-Ⅱ的浓度,并测定胎鼠的体重、体长,计算体重系数[胎鼠重量(g)×100/胎鼠身长(cm)]。结果①3组大鼠血清IGF-Ⅱ浓度相近;胎鼠血清FGR组IGF-Ⅱ浓度低于正常对照组(P<0.05),干预组IGF-Ⅱ浓度高于FGR组。②胎鼠体重、体长正常对照组>FGR 干预组>FGR组,各组相比均有统计学意义(P<0.05)。③胎鼠体重系数正常对照组>FGR 干预组>FGR组,正常对照组与其余两组相比有统计学意义(P<0.05)。结论①大鼠血清及胎鼠血清中IGF-Ⅱ的来源不同,不能通过胎盘屏障而互相交换。②检测母血中IGF-Ⅱ的浓度不能用来诊断FGR。③胎血IGF-Ⅱ浓度的下降可能是导致FGR的一个重要原因。④川芎嗪可有效治疗FGR。     

早产儿、小于胎龄儿体质量追赶生长及其与IGF－1的相关性

目的：探讨早产儿和小于胎龄儿（ SGA）体质量追赶生长的规律及其与IGF－1的相关性。方法选择早产SGA 13例、早产适于胎龄儿（ AGA）80例、足月SGA 23例、足月AGA 177例，记录各组体质量，计算标准差单位（SDS）和SDS的变化值（ΔSDS），并进行统计学分析。结果①足月SGA 42 d时体质量的ΔSDS值＞0，提示其出生后即出现体质量追赶生长。9个月时体质量与足月AGA无显著差异（ P＞0．05），提示已达到完全追赶生长。②早产AGA生后42 d时体质量SDS值降至最低，其后体质量SDS值出现缓慢上升，3月龄时体质量ΔSDS值＞0，提示42 d前存在持续宫外发育迟缓，42 d后出现体质量追赶生长。③早产SGA的体质量追赶生长出现最晚，生后SDS值在3月龄时降至最低，此后开始上升，到6月龄时体质量的ΔSDS值＞0，提示其宫外发育迟缓持续至3月龄，3月龄后出现体质量追赶生长，18月时体质量仍与足月AGA存在显著差异，提示尚未达到体质量完全追赶生长。④早产和SGA的IGF－13月龄时均出现显著上升，与其体质量追赶生长趋势相吻合。结论早产儿均存在宫外发育迟缓现象，体质量追赶生长开始的时间依次为足月SGA、早产AGA、早产SGA。1岁时足月SGA和早产儿AGA体质量基本达到完全追赶生长；IGF－1水平变化与追赶生长的趋势一致。     

实验条件下黄兔尾鼠生长和发育的初步观察

对人工饲养条件下黄兔尾鼠的生长、发育和行为进行了观察,测定了该鼠的体重、体长、后足长和尾长的生物学生长发育指标,显示该鼠生长发育呈逻辑斯谛增长,15日龄之前生长非常迅速,其中以体重增长最快,15日龄之后生长逐渐减慢。根据该鼠不同日龄阶段的生长发育和行为特点,将该鼠的整个生长过程分为乳鼠（0－15日龄）、幼鼠（15－25日龄）、亚成体（25－50日龄）、成体（50日龄之后）4个阶段。     

成年期追赶生长对大鼠胰岛素敏感性与应激水平的影响

目的 观察成年期追赶生长对大鼠胰岛素敏感性和应激水平的影响,并探讨其胰岛素抵抗形成的可能机制。方法 将7周龄雄性SD大鼠分为6组（共2个时间点）,即4周时间点2组：热卡限制4周组(R4),正常饮食4周组(NC4)作为R4组对照;8周时间点4组：正常饮食追赶生长组(RN4)、高脂饮食追赶生长组(RH4)、持续高脂饮食8周组（HF8）、持续正常饮食8周组(NC8)。通过先热卡限制后恢复饮食的方法建立追赶生长大鼠模型。检测大鼠高胰岛素-正糖钳夹试验过程中葡萄糖输注率和骨骼肌2-脱氧葡萄糖摄取、胰岛素刺激后的骨骼肌胰岛素信号通路、血皮质酮、骨骼肌11β-羟类固醇脱氢酶1(11β-HSD1)表达水平。结果 热卡限制4周时,R4组大鼠血皮质酮和骨骼肌11β-HSD1 mRNA表达水平明显高于NC4组(P＜0.05),骨骼肌蛋白激酶B( Akt) Ser473磷酸化和糖摄取与NC4组相比差异无统计学意义。热卡限制后恢复饮食4周时,血皮质酮和骨骼肌11β-HSD1表达水平RN4组明显高于NC8组,RH4组明显高于NC8和HF8组,而骨骼肌Akt磷酸化和糖摄取RN4组明显低于NC8组,RH4组明显低于NC8组、HF8组和RN4组（均P＜0.05）。结论正常饮食和高脂饮食追赶生长大鼠均可导致整体和骨骼肌应激水平上调及胰岛素抵抗,尤以高脂饮食追赶生长大鼠更为明显。应激和饮食状况的交互作用可能是追赶生长胰岛素抵抗形成的重要原因。     

Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver

BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth factor I for either 3 or 7 days. The amount of epidermal growth factor receptor, transforming growth factor-alpha, and epidermal growth factor mRNA was quantitated by a calibrated user-friendly RT-PCR assay (CURT-PCR), and the expression of transforming growth factor-alpha and epidermal growth factor peptides was quantitated by ELISA. RESULTS: Control liver (n=16) contained a mean (+/-SD) value of 12.7+/-7.4x10(-18) mol epidermal growth factor receptor mRNA, 3.8+/-2.0x10(-18) mol transforming growth factor-alpha mRNA and 0.8+/-0.4x10(-18) mol epidermal growth factor mRNA per microg total RNA and 9.8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein transforming growth factor-alpha. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-alpha and epidermal growth factor receptor, as well as the expression of transforming growth factor-alpha peptide. The level of epidermal growth factor receptor and transforming growth factor-alpha mRNA expression was found to correlate both in control and growth factor-treated animals, whereas the expression of epidermal growth factor receptor and epidermal growth factor showed no correlation. Marked differences were seen upon activation of the two growth factor systems, as epidermal growth factor, but not insulin-like growth factor I treatment, increased the plasma concentration of urea and decreased the concentration of insulin-like growth factor I and the liver enzymes, alanine aminotransferase and alkaline phosphatase. CONCLUSION: Our results show that epidermal growth factor and insulin-like growth factor I, which belong to two different growth factor systems, both induce a correlated upregulation of transforming growth factor-alpha and epidermal growth factor receptor mRNA in rat liver. Although marked differences were observed after treatment with either epidermal growth factor or insulin-like growth factor I on the liver as reflected in the plasma concentrations of e.g. liver enzymes, a common motif in their action involves an upregulation of the expression of the epidermal growth factor system.     

Conversion of CSF monomeric growth hormone to large growth hormone with exposure to serum

We have found a dissociation between CSF and serum growth hormone heterogeneity in a patient with suprasellar extension of a growth hormone-secreting pituitary tumour. When CSF was studied using gel chromatography, virtually all the growth hormone eluted as monomeric growth hormone with only 2.4% eluting before albumin as large growth hormone ('big, big' growth hormone). In contrast, the large component comprised 15.4% of the total immunoreactivity in simultaneously obtained serum. When the CSF specimen was incubated with growth hormone-poor serum, the elution pattern changed remarkably with 16% of the total immunoreactivity eluting as large growth hormone causing it to resemble the serum elution pattern. We also measured growth hormone heterogeneity in the inferior petrosal vein (a site very close to pituitary venous drainage) during inferior petrosal venography in 3 patients. As the growth hormone concentration increased, the percentage eluting as monomeric growth hormone increased, whereas that eluting as large growth hormone decreased. When the growth hormone concentration fell towards baseline, the percentage of growth hormone eluting as monomeric growth hormone fell while that eluting as large growth hormone increased. Thus, our studies suggest that large growth hormone results from binding of monomeric growth hormone to serum proteins or aggregation of monomeric growth hormone in the presence of protein. Our studies also show that when blood is sampled at a site close to the pituitary, the growth hormone is released primarily as monomeric growth hormone.     

Control of Bone Growth by Fibroblast Growth Factors

Fibroblast growth factors (FGFs) and their receptors (FGFRs) negatively regulate longitudinal bone growth. Activating FGFR3 mutations impair growth, causing human skeletal dysplasias, whereas inactivating mutations stimulate growth. Systemic administration of FGF-2 to mice stimulates bone growth at low doses but inhibits growth at high doses. In organ culture, FGF-2 inhibits growth by decreasing growth plate chondrocyte proliferation, hypertrophy and cartilage matrix synthesis. Local FGF-2 infusion accelerates ossification of growth plate cartilage. Thus, FGFs may regulate both growth plate chondrogenesis and ossification.     

Over expression of transforming growth factor-alpha and epidermal growth factor receptor in human hepatic cirrhosis tissues

BACKGROUND/AIMS: Transforming growth factor-alpha has 30% amino acid homology to epidermal growth factor and binds with the same membrane-bound receptor, epidermal growth factor receptor. The purpose of this study was to investigate the expression of transforming growth factor-alpha and epidermal growth factor receptor in human hepatic cirrhosis tissues. METHODOLOGY: Expression of transforming growth factor-alpha and epidermal growth factor receptor was evaluated by immunohistochemistry stain in sixty-three hepatic cirrhosis specimens and five normal liver specimens. RESULTS: The transforming growth factor-alpha and epidermal growth factor receptor expression rates were 84.1% (53/63) and 52.4% (33/63), respectively. These positive granules were brown and most common in cytoplasm or cell membrane of hepatocytes. There was prominently positive correlation between transforming growth factor-alpha and epidermal growth factor receptor (P<0.05, gamma=0.32). In five normal liver tissues, transforming growth factor-alpha and epidermal growth factor receptor were not detectable in hepatocytes and bile ducts. CONCLUSIONS: Hepatic cirrhosis might be under the autocrine regulation of transforming growth factor-alpha and its receptor, epidermal growth factor receptor. Increasing expression of transforming growth factor-alpha and epidermal growth factor receptor might be one of the important events in hepatic cirrhosis pathogenesis. Furthermore, transforming growth factor-alpha might play a role in morphogenesis and regeneration of intrahepatic bile ducts.     

Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with Type 1 (insulin-dependent) diabetes mellitus

Summary Serum levels of insulin-like growth factor I are reduced in patients with Type 1 (insulin-dependent) diabetes mellitus. To evaluate the role of the hepatic growth hormone receptor in the decreased serum concentrations of insulin-like growth factor I, serum levels of the high affinity growth hormone-binding protein, which is qualitatively and quantitatively related to the hepatic growth hormone receptor, and of insulin-like growth factor I were measured in 70 children and adolescents with Type 1 diabetes and 105 healthy control children. Analysis of variance revealed a significant negative effect of Type 1 diabetes on serum levels of the growth hormone-binding protein and of insulin-like growth factor I. In the diabetic patients, serum levels of the growth hormone-binding protein were positively related to body mass index and to insulin dose per kg body weight, and were not influenced by pubertal stage, gender, or plasma levels of haemoglobin A_1c. Serum levels of insulin-like growth factor I increased during early puberty reaching peak levels at midpuberty and decreasing thereafter. No relationship was found between serum levels of growth hormone-binding protein and of insulin-like growth factor I. Our data suggest that decreased liver somatogenic receptor levels, as reflected by the concentrations of circulating growth hormone-binding protein, play a minor role in the suppressed concentrations of circulating insulin-like growth factor I. Post-growth hormone receptor defects or changes in the insulin-like growth factor binding proteins probably contribute more to the lower serum levels of insulin-like growth factor I.     

Platelet-derived growth factors

Blood platelets are a rich source of growth factors, including platelet-derived growth factor, platelet-derived endothelial cell growth factor, and transforming growth factor beta. Platelet-derived growth factor stimulates the growth of mesenchymal cells such as fibroblasts and vascular smooth muscle cells, whereas platelet-derived endothelial cell growth factor is a mitogen for vascular endothelial cells. Transforming growth factor beta is a bifunctional regulator of cellular growth, but acts as a potent inhibitor for most cell types. Most of the growth regulatory substances in platelets have been reported to reside in platelet alpha-granules, but platelet-derived endothelial cell growth factor appears to be present in platelet cytoplasm. These growth factors may act at sites of injury as wound hormones. Moreover, they play important roles for some pathological conditions such as atherosclerosis, myelofibrosis, connective tissue diseases, and neoplastic disorders.     

Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer

BACKGROUND & AIMS: Epidermal growth factor receptor is frequently implicated in epithelial cancers and is, therefore, being considered as a potential target for therapy. Recently, we reported the isolation and characterization of epidermal growth factor receptor-related protein, a negative regulator of epidermal growth factor receptor. To discern whether epidermal growth factor receptor-related protein could be an effective therapeutic agent for colorectal cancer, we generated epidermal growth factor receptor-related protein fusion protein and studied its effect on the growth of colon cancer cells in vivo and in vitro. We also studied whether epidermal growth factor receptor-related protein expression is altered in colorectal cancer. METHODS: A 55-kilodalton epidermal growth factor receptor-related protein fusion protein with V5 and His tags was generated in a drosophila expression system and subsequently purified by a His antibody affinity column. Rabbit polyclonal antibodies against epidermal growth factor receptor-related protein were used to examine the expression of epidermal growth factor receptor-related protein. RESULTS: Epidermal growth factor receptor-related protein expression was found to be high in benign human colonic epithelium but low in adenocarcinoma. Exposure of the colon cancer cell lines HCT-116 and Caco-2 to purified recombinant epidermal growth factor receptor-related protein caused a marked inhibition of proliferation, as well as attenuation of basal and ligand-induced stimulation of epidermal growth factor receptor phosphorylation. Epidermal growth factor receptor-related protein-induced inhibition of proliferation of colon cancer cells was prevented by epidermal growth factor receptor-related protein antibodies. Reduced epidermal growth factor receptor phosphorylation was partly due to sequestration of epidermal growth factor receptor ligands by epidermal growth factor receptor-related protein, resulting in the formation of inactive heterodimers with epidermal growth factor receptor. Intratumoral or subcutaneous (away from the tumor site) injections of purified epidermal growth factor receptor-related protein caused regression of palpable colon cancer xenograft tumors in some severely compromised immunodeficient mice and arrested tumor growth in others. CONCLUSIONS: We propose that epidermal growth factor receptor-related protein inhibits cellular growth by attenuating epidermal growth factor receptor signaling processes and is an effective therapeutic agent for colorectal cancer.     

生长激素缺乏但持续增高:垂体柄中断合并垂体多激素缺乏一例报告及文献复习

报道一例垂体柄中断合并垂体多激素缺乏、包括经低血糖刺激试验发现生长激素缺乏、但表现为持续增高的病例.结合文献复习发现,此种非生长激素依赖的身高生长一般有垂体其他激素尤其是促性腺激素缺乏、骨骺未闭合为基础条件.     

Systemic and local regulation of the growth plate

The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.     

Sex steroids and growth factors differentially regulate the growth and differentiation of cultured human endometrial stromal cells

We have studied the interaction between growth factors and sex steroids in regulating human endometrial stromal cell growth and differentiation using an in vitro serum-free cell culture model system. None of the growth factors [epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin, insulin-like growth factor-I (IGF-I), IGF-II, or platelet-derived growth factor] stimulated the growth of human endometrial stromal cells grown in progestin-free medium. However, the growth of progestin-treated cultures was dramatically increased by EGF, bFGF, or platelet-derived growth factor, but not by insulin, IGF-I, or IGF-II. Estrogen could not substitute for progesterone in this protocol, and coadministration of estrogen with progestin did not enhance the response over that to progesterone alone. In contrast to their positive effects on growth, only EGF, not bFGF, stimulated stromal cell differentiation, as measured by an increase in PRL, laminin, and fibronectin production; moreover, stimulation of differentiation was dependent upon the presence of progestin in the culture medium. Thus, human endometrial stromal cell growth is 1) regulated by a discrete set of growth factors, only a subset of which regulates stromal cell differentiation; and 2) regulation of stromal cell growth and stromal cell differentiation by growth factors is progestin dependent. Our results provide direct evidence for interaction between growth factors and sex steroids in the regulation of stromal cell growth and differentiation in vitro and suggest that growth factors may be absolutely required in conjunction with progesterone for the decidual response in vivo.