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Insulin-like Growth Factor (insulin-like + growth_factor)
Kinds of Insulin-like Growth Factor Terms modified by Insulin-like Growth Factor Selected AbstractsInsulin-like Growth Factor (IGF)-I, IGF-binding Protein-3 and Colorectal Adenomas in Japanese MenCANCER SCIENCE, Issue 11 2002Satoshi Teramukai Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0,4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (,5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia. [source] Serum Insulin-like Growth Factors, Insulin-like Growth Factor-binding Protein-3, and Risk of Lung Cancer Death: A Case-control Study Nested in the Japan Collaborative Cohort (JACC) StudyCANCER SCIENCE, Issue 12 2002Kenji Wakai To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseline from 39 140 men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs), adjusted for smoking and other covariates, were smaller with higher levels of IGF-II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI], 0.27,0.63), 0.47 (0.31,0.71), and 0.67 (0.46,0.98) for IGF-II (trend P=0.018), and 0.55 (95% CI, 0.37,0.81), 0.54 (0.36,0.82), and 0.67 (0.45,1.01) for IGFBP-3 (trend P=0.037). These peptides were not independently related to lung cancer risk when mutually adjusted. The risk was increased in the highest vs. the lowest quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08,2.81). Limiting subjects to those followed for ,3 years strengthened the negative associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally decreased. A higher level of circulating IGFBP-3 and/or IGF-II may decrease lung cancer risk. Elevated serum IGF-I may increase the risk, but this could partly be attributable to latent tumors. [source] Remote myocardium gene expression after 30 and 120 min of ischaemia in the ratEXPERIMENTAL PHYSIOLOGY, Issue 2 2006Miguel S. Guerra The aim of the present study was to investigate how early the onset of ischaemia-induced changes in gene expression is in remote myocardium, and whether these changes would be different for left and right ventricles. Wistar rats (n= 27) were randomly assigned to left coronary artery (LCA) ligation for 30 or 120 min and sham groups. Evans Blue infusion revealed antero-apical left ventricle (LV) and left intraventricular (IV) septal ischaemia (35.5 ± 0.6% of LV mass). LCA ligation induced transient LV systolic dysfunction and sustained biventricular slowing of relaxation. Regarding mRNA levels, type B natriuretic peptide (BNP) was upregulated in the LV at 30 (+370 ± 191%) and 120 min (+221 ± 112%), whilst in the right ventricle (RV) this was only significant at 120 min (+128 ± 39%). Hipoxia-inducible factor 1, and interleukin 6 overexpression positively correlated with BNP. Inducible NO synthase upregulation was present in both ventricles at 120 min (LV, +327 ± 195%; RV, +311 ± 122%), but only in the RV at 30 min (+256 ± 88%). Insulin-like growth factor 1 increased in both ventricles at 30 (RV, +59 ± 18%; LV, +567 ± 192%) and 120 min (RV, +69 ± 33%; LV, +120 ± 24%). Prepro-endothelin-1 was upregulated in the RV at 120 min (+77 ± 25%). Ca2+ -handling proteins were selectively changed in the LV at 120 min (sarcoplasmic reticulum Ca2+ ATPase, 53 ± 7%; phospholamban, +31 ± 4%; Na+,Ca2+ exchanger, 31 ± 6%), while Na+,H+ exchanger was altered only in the RV (,79 ± 5%, 30 min; +155 ± 70%, 120 min). Tumour necrosis factor-, and angiotensin converting enzyme were not significantly altered. A very rapid modulation of remote myocardium gene expression takes place during myocardial ischaemia, involving not only the LV but also the RV. These changes are different in the two ventricles and in the same direction as those observed in heart failure. [source] Identification of membrane-bound serine proteinase matriptase as processing enzyme of insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1/angiomodulin/mac25)FEBS JOURNAL, Issue 3 2006Sanjida Ahmed Insulin-like growth factor (IGF) binding protein-related protein-1 (IGFBP-rP1) modulates cellular adhesion and growth in an IGF/insulin-dependent or independent manner. It also shows tumor-suppressive activity in vivo. We recently found that a single-chain IGFB-rP1 is proteolytically cleaved to a two-chain form by a trypsin-like, endogenous serine proteinase, changing its biological activities. In this study, we attempted to identify the IGFBP-rP1-processing enzyme. Of nine human cell lines tested, seven cell lines secreted IGFBP-rP1 at high levels, and two of them, ovarian clear cell adenocarcinoma (OVISE) and gastric carcinoma (MKN-45), highly produced the cleaved IGFBP-rP1. Serine proteinase inhibitors effectively blocked the IGFBP-rP1 cleavage in the OVISE cell culture. The conditioned medium of OVISE cells did not cleave purified IGFBP-rP1, but their membrane fraction had an IGFBP-rP1-cleaving activity. The membrane fraction contained an 80-kDa gelatinolytic enzyme, which was identified as the membrane-type serine proteinase matriptase (MT-SP1) by immunoblotting. When the membrane fraction was separated by SDS/PAGE, the IGFBP-rP1-cleaving activity comigrated with matriptase. A soluble form of matriptase purified in an inhibitor-free form efficiently cleaved IGFBP-rP1 at the same site as that found in a naturally cleaved IGFBP-rP1. Furthermore, small interfering RNAs for matriptase efficiently blocked both the matriptase expression and the cleavage of IGBP-rP1 in OVISE cells. These results demonstrate that IGFBP-rP1 is processed to the two-chain form by matriptase on the cell surface. [source] Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of ,-catenin signalingJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2010Lai Wang Abstract Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt/,-catenin signaling pathway. Insulin-like growth factor 1 (IGF-1) has been described as a stabilizer of ,-catenin, and thyroid hormone is a known stimulator of IGF-1 receptor expression. The purpose of this study was to test the hypothesis that IGF-1 signaling is involved in the interaction between the thyroid hormone and the Wnt/,-catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation. The results show that IGF-1 and the IGF- receptor (IGF1R) stimulate Wnt-4 expression and ,-catenin activation in growth plate chondrocytes. The positive effects of IGF-1/IGF1R on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1. T3 activates IGF-1/IGF1R signaling and IGF-1-dependent PI3K/Akt/GSK-3, signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy. T3 -mediated Wnt-4 expression, ,-catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K/Akt signaling inhibitors LY294002 and Akti1/2. These data indicate that the interactions between thyroid hormone and ,-catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF-1/IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. While chondrocyte proliferation may be triggered by the IGF-1/IGF1R-mediated PI3K/Akt/GSK3, pathway, cell hypertrophy is likely due to activation of Wnt/,-catenin signaling, which is at least in part initiated by IGF-1 signaling or the IGF-1-activated PI3K/Akt signaling pathway. © 2010 American Society for Bone and Mineral Research [source] Effects of Liver-Derived Insulin-Like Growth Factor I on Bone Metabolism in Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002Klara Sjögren Abstract Insulin-like growth factor (IGF) I is an important regulator of both skeletal growth and adult bone metabolism. To better understand the relative importance of systemic IGF-I versus locally expressed IGF-I we have developed a transgenic mouse model with inducible specific IGF-I gene inactivation in the liver (LI-IGF-I,/,). These mice are growing normally up to 12 weeks of age but have a disturbed carbohydrate and lipid metabolism. In this study, the long-term effects of liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism were investigated. The adult (week 8,55) axial skeletal growth was decreased by 24% in the LI-IGF-I,/, mice whereas no major reduction of the adult appendicular skeletal growth was seen. The cortical cross-sectional bone area, as measured in the middiaphyseal region of the long bones, was decreased in old LI-IGF-I,/, mice. This reduction in the amount of cortical bone was caused mainly by decreased periosteal circumference and was associated with a weaker bone determined by a decrease in ultimate load. In contrast, the amount of trabecular bone was not decreased in the LI-IGF-I,/, mice. DNA microarray analysis of 30-week-old LI-IGF-I,/, and control mice indicated that only four genes were regulated in bone whereas ,40 genes were regulated in the liver, supporting the hypothesis that liver-derived IGF-I is of minor importance for adult bone metabolism. In summary, liver-derived IGF-I exerts a small but significant effect on cortical periosteal bone growth and on adult axial skeletal growth while it is not required for the maintenance of the trabecular bone in adult mice. [source] Insulin-like growth factor (IGF) binding protein-3 regulation of IGF-I is altered in an acidic extracellular environmentJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2001Kimberly E. Forsten While extracellular acidification within solid tumors is well-documented, how reduced pH impacts regulation of insulin-like growth factor-I (IGF-I) has not been studied extensively. Because IGF-I receptor binding is affected by IGF binding proteins (IGFBPs), we examined how pH impacted IGFBP-3 regulation of IGF-I. IGF-I binding in the absence of IGFBP-3 was diminished at reduced pH. Addition of IGFBP-3 reduced IGF-I cell binding at pH 7.4 but increased surface association at pH 5.8. This increase in IGF-I binding at pH 5.8 corresponded with an increase in IGFBP-3 cell association. This, however, was not due to an increase in affinity of IGFBP-3 for heparin at reduced pH although both heparinase III treatment and heparin addition reduced IGFBP-3 enhancement of IGF-I binding. An increase in IGF-I binding to IGFBP-3, though, was seen at reduced pH using a cell-free assay. We hypothesize that the enhanced binding of IGF-I at pH 5.8 is facilitated by increased association of IGFBP-3 at this pH and that the resulting cell associated IGF-I is IGFBP-3 and not IGF-IR bound. Increased internalization and nuclear association of IGF-I at pH 5.8 in the presence of IGFBP-3 was evident, yet cell proliferation was reduced by IGFBP-3 at both pH 5.8 and 7.4 indicating that IGFBP-3-cell associated IGF-I does not signal the cell to proliferate and that the resulting transfer of bound IGF-I from IGF-IR to IGFBP-3 results in diminished proliferation. Solution binding of IGF-I by IGFBP-3 is one means by which IGF-I-induced proliferation is inhibited. Our work suggests that an alternative pathway exists by which IGF-I and IGFBP-3 both associate with the cell surface and that this association inhibits IGF-I-induced proliferation. © 2001 Wiley-Liss, Inc. [source] Longevity is not influenced by prenatal programming of body sizeAGING CELL, Issue 4 2010Cheryl A. Conover Summary Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, whereas, in the adult, IGFs are associated with aging and age-related diseases. However, it is unclear as to what extent lifespan is influenced by events that occur during development. Here, we provide direct evidence that the exceptional longevity of mice with altered IGF signaling is not linked to prenatal programming of body size. Mice null for pregnancy-associated plasma protein-A (PAPP-A), an IGF-binding protein proteinase that increases local IGF bioavailability, are 60,70% the size of their wild-type littermates at birth and have extended median and maximum lifespan of 30,40%. In this study, PAPP-A,/, mice whose body size was normalized during fetal development through disruption of IgfII imprinting did not lose their longevity advantage. Adult-specific moderation of IGF signaling through PAPP-A inhibition may present a unique opportunity to improve lifespan without affecting important aspects of early life physiology. [source] Involvement of ,1,1 integrin in insulin-like growth factor-1-mediated protection of PC12 neuronal processes from tumor necrosis factor-,-induced injuryJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2006Jin Ying Wang Abstract Insulin-like growth factor 1 receptor (IGF-1R) supports neuronal survival against a wide variety of insults. This includes tumor necrosis factor-, (TNF,)-mediated neuronal damage, which represents one of the factors suspected to play a role in HIV-associated dementia (HAD). PC12 neurons engineered to express human IGF-1R (PC12/IGF-1R) maintain neuronal processes on collagen IV for several weeks. However, prolonged treatment with TNF, caused degeneration of neuronal processes, with no apparent signs of apoptosis. In this process, TNF, did not affect IGF-1-mediated phosphorylation of IRS-1, IRS-2, Akt, or Erks. In addition, PC12/IGF-1R cells were found to express predominantly ,1,1 integrin, which has high affinity to collagen IV. The treatment of PC12/IGF-1R neurons with a specific ,1,1 integrin inhibitor, obtustatin, also caused loss of neuronal processes, accompanied by a quick cell detachment and extensive apoptosis. In the presence of IGF-1, both TNF,-induced and obtustatin-induced degeneration of neuronal processes were effectively inhibited. Furthermore, TNF,-mediated neuronal degeneration correlated with decreased attachment of PC12/IGF-1R cells to collagen IV and with a reduced level of ,1,1 integrin, consistent with a role for this surface protein in the maintenance of neuronal processes. Thus the neuroprotective effects of IGF-1 are not restricted to its antiapoptotic properties but also involve an additional neuroprotective mechanism, by which IGF-1 counteracts the negative effect of TNF, on ,1,1 integrin-mediated attachment to collagen IV. © 2005 Wiley-Liss, Inc. [source] Growth hormone and insulin-like growth factor 1 levels and their relation to survival in children with bacterial sepsis and septic shockJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 4 2004N Önenli-Mungan Objectives: Despite improved supportive care, the mortality of sepsis and septic shock is still high. Multiple changes in the neuroendocrine systems, at least in part, are responsible for the high morbidity and mortality. A reduced circulating level of insulin-like growth factor and an elevated level of growth hormone are the reported characteristic findings early in the course of sepsis and septic shock in adults. The aim of this study was to evaluate the changes of growth hormone/insulin-like growth factor 1 axis in sepsis and septic shock and investigate the relationship between these hormones and survival. Methods: Fifty-one children with sepsis (S), 21 children with septic shock (SS) and 30 healthy, age- and sex-matched children (C) were enrolled in this study. Growth hormone, insulin-like growth factor 1 and cortisol levels of the sepsis and septic shock groups were obtained before administration of any inotropic agent. Results: Growth hormone levels were 32.3 ± 1.5 µIU/mL (range 4,56), 15.9 ± 0.6 µIU/mL (range 11,28) and 55.7 ± 2.7 µIU/mL (range 20,70) in S, C and SS groups, respectively. The difference between the growth hormone levels of the S and C groups, S and SS groups, and C and SS groups were significant (P < 0.001). Non-survivors (54.7 ± 1.6 µIU/mL) had significantly higher growth hormone levels than survivors (29.4 ± 1.5 µIU/mL) (P < 0.001). Insulin-like growth factor 1 levels were 38.1 ± 2.1 ng/mL (range 19,100), 122.9 ± 9.6 ng/mL (range 48,250) and 22.2 ± 1.9 ng/mL (range 10,46) in the S, C and SS groups, respectively, and the difference between the insulin-like growth factor 1 levels of the S and C, S and SS, and C and SS groups were significant (P < 0.001). Non-survivors (8.8 ± 1.1 µg/dL) had significantly lower cortisol levels than survivors (40.9 ± 2.1 µg/dL) (P < 0.001). We detected a significant difference between the levels of cortisol in non-survivors (19.7 ± 1.8 µg/dL) and survivors (33.9 ± 0.9 µg/dL) (P < 0.01). Conclusions: There were elevated levels of growth hormone with decreased levels of insulin-like growth factor 1 in children during sepsis and septic shock compared to healthy subjects. In addition, there were even higher levels of growth hormone and lower levels of insulin-like growth factor 1 in non-survivors than in survivors. We think that both growth hormone and insulin-like growth factor 1 may have potential prognostic value to serve as a marker in bacterial sepsis and septic shock in children. As there is insufficient data in the paediatric age group, more studies including large numbers of patients and additionally evaluating cytokines and insulin-like growth factor binding proteins are needed. [source] Embryotropic effect of insulin-like growth factor (IGF)-I and its receptor on development of porcine preimplantation embryos produced by in vitro fertilization and somatic cell nuclear transferMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2005Sue Kim Abstract Insulin-like growth factor (IGF)-I is a receptor-mediated autocrine/paracrine growth/survival factor for mammalian embryo development. The present study investigated the temporal expression and regulation of porcine IGF-I receptor (IGF-IR) mRNA and the role of IGF-I on development of porcine in vitro fertilized (IVF) and somatic cell nuclear transfer (SCNT) embryos. As assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), the level of IGF-IR mRNA expression was high in unfertilized oocytes, 2-cell and 4-cell embryos and gradually decreased in 8-cell embryos, morulae, and blastocysts in both IVF and SCNT series. The IVF or SCNT embryos were cultured with 0, 1, 10, 50, or 100 ng/ml IGF-I for 168 hr. Supplementing with 50 ng/ml IGF-I increased blastocyst formation and the number of cells in inner cell masses (ICMs) in both IVF and SCNT embryos. In a second experiment, more blastocysts were obtained when IVF or SCNT embryos were cultured for the first 48 hr or for the entire 168 hr with 50 ng/ml IGF-I compared to culturing without IGF-I for 48 hr or with IGF-I for the last 120 hr or without IGF-I for the entire 168 hr. Treating IVF or SCNT embryos with 50 ng/ml IGF-I significantly up-regulated IGF-IR mRNA compared to untreated control embryos. In conclusion, the present study demonstrated that IGF-IR mRNA is expressed in porcine IVF and SCNT embryos, and that IGF-I improved the developmental competence of IVF and SCNT embryos through its specific receptors. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] A Novel Drug Therapy for Recurrent Laryngeal Nerve Injury Using T-588,THE LARYNGOSCOPE, Issue 7 2007Yuko Mori MD Abstract Objectives/Hypothesis: We have previously shown that gene therapy using Insulin-like growth factor (IGF)-I, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), or a combination of these trophic factors, is a treatment option for recurrent laryngeal nerve (RLN) palsy. However, there remain some difficulties preventing this option from becoming a common clinical therapy for RLN injury. Thus, we need to develop novel treatment option that overcomes the problems of gene therapy. R(,)-1-(benzothiophen-5-yl)-2-[2-N,N-diethylamino]ethoxy]ethanol hydrochloride (T-588), a synthetic compound, is known to have neuroprotective effects on neural cells. In the present study, the possibility of new drug treatments using T-588 for RLN injury was assessed using rat models. Study Design: Animal study. Methods: Animals were administered T-588 for 4 weeks. The neuroprotective effects of T-588 administration after vagal nerve avulsion and neurofunctional recovery after recurrent laryngeal nerve crush were studied using motoneuron cell counting, evaluation of choline acetyltransferase immunoreactivity, the electrophysiologic examination, and the re-mobilization of the vocal fold. Results: T-588 administration successfully prevented motoneuron loss and ameliorated the choline acetyltransferase immunoreactivity in the ipsilateral nucleus ambiguus after vagal nerve avulsion. Significant improvements of motor nerve conduction velocity of the RLN and vocal fold movement were observed in the treatment group when compared to controls. Conclusion: These results indicate that oral administration of T-588 might be a promising therapeutic option in treating peripheral nerve injury. [source] A Synthetic Mechano Growth Factor E Peptide Enhances Myogenic Precursor Cell Transplantation SuccessAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2007P. Mills Myogenic precursor cell (MPC) transplantation is a good strategy to introduce dystrophin expression in muscles of Duchenne muscular dystrophy (DMD) patients. Insulin-like growth factor (IGF-1) promotes MPC activities, such as survival, proliferation, migration and differentiation, which could enhance the success of their transplantation. Alternative splicing of the IGF-1 mRNA produces different muscle isoforms. The mechano growth factor (MGF) is an isoform, especially expressed after a mechanical stress. A 24 amino acids peptide corresponding to the C-terminal part of the MGF E domain (MGF-Ct24E peptide) was synthesized. This peptide had been shown to enhance the proliferation and delay the terminal differentiation of C2C12 myoblasts. The present study showed that the MGF-Ct24E peptide improved human MPC transplantation by modulating their proliferation and differentiation. Indeed, intramuscular or systemic delivery of this synthetic peptide significantly promoted engraftment of human MPCs in mice. In vitro experiments demonstrated that the MGF-Ct24E peptide enhanced MPC proliferation by a different mechanism than the binding to the IGF-1 receptor. Moreover, MGF-Ct24E peptide delayed human MPC differentiation while having no outcome on survival. Those combined effects are probably responsible for the enhanced transplantation success. Thus, the MGF-Ct24E peptide is an interesting agent to increase MPC transplantation success in DMD patients. [source] Prognostic role of insulin-like growth factor receptor-1 expression in small cell lung cancerAPMIS, Issue 12 2009MYUNG HEE CHANG Insulin-like growth factor receptor-1 (IGFR-1) is a cellular membrane receptor which is overexpressed in many tumors and seems to play a critical role in anti-apoptosis. The insulin-like growth factor binding protein-3 (IGFBP-3) is known as a growth suppressor in multiple signaling pathways. The aim of this study was to determine IGFR-1 and IGFBP-3 expression in small-cell lung cancer (SCLC) and analyze the prognostic value in patients with SCLC. We analyzed IGFR-1 and IGFBP-3 expression in 194 SCLC tissues by immunohistochemical staining. Correlative analyses between IGFR-1 and IGFBP-3 expression in SCLC and clinicopathologic factors were performed. A total of 117 patients had extensive disease (ED) (60.3%) and 77 had limited disease (39.7%). With the median follow-up duration of 49.5 months (24,82 months), the median progression-free survival (PFS) and overall survival (OS) were 7.2 months [95% confidence interval (CI): 6.4,8.0 months] and 14.4 months (95% CI: 12.7,16 months), respectively. IGFR-1 expression was observed in 154 of the 190 tumor tissues, whereas there was no IGFBP-3 expression. Multivariate analysis showed that stage (p < 0.001), response rate (p < 0.001), and lactate dehydrogenase (LDH) levels (p < 0.001) were the independent prognostic factors for PFS, and age (p = 0.014), LDH level (p < 0.001), and stage (p < 0.001) for OS. The IGFR-1 positivity was not associated with PFS or OS in the entire cohort. Subgroup analysis revealed that OS was significantly longer in patients with IGFR-1-positive tissue than IGFR-1-negative tissue in SCLC-ED (p = 0.034). These results suggest that IGFR-1 expression may be useful as a prognostic marker in patients with SCLC-ED. [source] Insulin-like growth factor 1-coated sutures improve anastomotic healing in an experimental model of colitis,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 2 2010E. Rijcken Background: Exogenously applied insulin-like growth factor (rhIGF-1) may improve normal intestinal healing. This study examined the effect of rhIGF-1-coated sutures on anastomotic healing in experimental colitis. Methods: Acute colitis was induced in rats by dextran sodium sulphate (DSS). Inflammation was assessed by clinical Disease Activity Index (DAI), myeloperoxidase (MPO) measurement and histological examination. A distal colonic anastomosis was performed using sutures coated with rhIGF-1 dissolved in poly(D,L -lactide) (PDLLA) under general anaesthetic. Anastomotic healing was evaluated histologically, and by hydroxyproline measurement and bursting parameters after 1, 3 and 7 days, and compared with healthy, DSS and DSS + PDLLA controls. Results: DAI, MPO and histological inflammation scores were significantly increased in all animals treated with DSS. Bursting occurred less often within the anastomotic line on day 3 in the IGF group than in DSS controls (three versus eight of ten). On day 7, the IGF group had significantly increased histological healing scores (mean(s.e.m.) 12·5(0·7) versus 9·2(0·8) (P < 0·050)) and hydroxyproline content (4·6(0·3) versus 3·6(0·1) mg/g tissue; P < 0·050) compared with DSS controls. Conclusion: IGF-1-coated sutures improve important aspects of anastomotic healing in rats with experimental colitis. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Novel role for ,-adrenergic signalling in skeletal muscle growth, development and regenerationCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2010James G Ryall Summary 1. In adult mammals, skeletal muscle mass is maintained through a precise balance of protein synthesis and protein degradation, whereas during development cellular (not protein) turnover predominates. When protein balance is shifted towards synthesis, skeletal muscle hypertrophy ensues. In contrast, increased protein degradation leads to skeletal muscle atrophy. Insulin-like growth factor (IGF)-I is among the best documented of the growth factors and regulates skeletal muscle mass by increasing protein synthesis and decreasing protein degradation. However, an IGF-I-independent growth pathway has been identified that involves the activation of ,-adrenoceptors and subsequent skeletal muscle growth, development and hypertrophy. 2. Although the importance of ,-adrenergic signalling in the heart has been well documented and continues to receive significant attention, it is only more recently that we have started to appreciate the importance of this signalling pathway in skeletal muscle structure and function. Studies have identified an important role for ,-adrenoceptors in myogenesis and work from our laboratory has identified a novel role for ,-adrenoceptors in regulating skeletal muscle regeneration after myotoxic injury. In addition, new data suggest that ,-adrenoceptors are markedly upregulated during differentiation of C2C12 cells. 3. It is now clear that ,-adrenoceptors play an important role in regulating skeletal muscle structure and function. Importantly, a clearer understanding of the pathways regulating skeletal muscle mass may lead to the identification of novel therapeutic targets for the treatment of muscle wasting disorders, including sarcopenia, cancer cachexia and the muscular dystrophies. [source] Insulin-like growth factors, hepatocyte growth factor and transforming growth factor-, in mouse tongue myogenesisDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2003Akira Yamane Many reports have shown that tongue striated muscles have several unique characteristics not found in other skeletal muscles such as limb and trunk. Several peptide growth factors are reported to play important roles in skeletal myogenesis. In this article, the roles of insulin-like growth factors (IGF), hepatocyte growth factor (HGF) and transforming growth factor (TGF)-, in mouse tongue myogenesis were studied using an organ culture system of the mandible or tongue obtained from mouse embryos. It was found that IGF-I promotes the differentiation of tongue myoblasts. HGF plays an essential role in the migration and proliferation of tongue myogenic cells, and inhibits the differentiation of tongue myoblasts. TGF-, does not play an essential role in the proliferation of tongue myogenic cells, but does promote the early differentiation of tongue myoblasts. The role of IGF-I in the differentiation of tongue myoblasts, and that of HGF in the migration, proliferation and differentiation of tongue myogenic cells appear to be almost identical to their roles in the myogenesis of limb and cultured myogenic cell lines. However, the role of TGF-, in the proliferation and differentiation of tongue myogenic cells appears to be different from its role in the myogenesis of limb and cultured myogenic cell lines such as C2 and L6. [source] Insulin-like growth factors and pancreas beta cellsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2004T. W. Van Haeften Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signalling pathways for pancreas beta-cell development, and for type 2 diabetes. Insulin-like growth factor-I signalling has a lot in common with insulin signalling, and is involved in diverse cellular effects such as antiapoptosis, protein synthesis, cell growth and mitogenesis. Insulin-like growth factor-II can be bound by the insulin receptor A subtype and the IGF-1 receptor, which may explain its antiapoptotic effect. Various knock-out model studies indicate that absence of IGF-I or the IGF-1 receptor is critical for foetal and postnatal growth. Similarly, knock-out models of post-receptor molecules (such as IRS-2) point to the physiological role of IGFs for pancreas beta-cell development. A beta-cell-specific IGF-1 receptor knock out model indicates the importance of IGF-I for beta-cell function. The Goto-Kakizaki (GK) rat, a model for diabetes, has insufficient beta-cell development, which may be related to its defective IGF-II synthesis. As normal pancreas beta cells adapt to the prevailing insulin resistance with increasing beta-cell function, it is possible that insulin resistance interacts with IGF signalling in pancreas beta cells. [source] An ecdysteroid-inducible insulin-like growth factor-like peptide regulates adult development of the silkmoth Bombyx moriFEBS JOURNAL, Issue 5 2009Naoki Okamoto Insulin-like growth factors (IGFs) play essential roles in fetal and postnatal growth and development of mammals. They are secreted by a wide variety of tissues, with the liver being the major source of circulating IGFs, and regulate cell growth, differentiation and survival. IGFs share some biological activities with insulin but are secreted in distinct physiological and developmental contexts, having specific functions. Although recent analyses of invertebrate genomes have revealed the presence of multiple insulin family peptide genes in each genome, little is known about functional diversification of the gene products. Here we show that a novel insulin family peptide of the silkmoth Bombyx mori, which was purified and sequenced from the hemolymph, is more like IGFs than like insulin, in contrast to bombyxins, which are previously identified insulin-like peptides in B. mori. Expression analysis reveals that this IGF-like peptide is predominantly produced by the fat body, a functional equivalent of the vertebrate liver and adipocytes, and is massively released during pupa,adult development. Studies using in vitro tissue culture systems show that secretion of the peptide is stimulated by ecdysteroid and that the secreted peptide promotes the growth of adult-specific tissues. These observations suggest that this peptide is a Bombyx counterpart of vertebrate IGFs and that functionally IGF-like peptides may be more ubiquitous in the animal kingdom than previously thought. Our results also suggest that the known effects of ecdysteroid on insect adult development may be in part mediated by IGF-like peptides. [source] Insulin-like growth factors in patients with liver cystsJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 6 2004Olgica Nedi Abstract Insulin-like growth factors (IGFs) play an important role in cell growth and differentiation, and the liver is the main source of IGFs and IGF-binding proteins (IGFBPs) that appear in the circulation. The effect of liver cysts on the circulating IGF system was studied in this work. Serum concentrations of IGF-I and -II were measured by radioimmunoassay, IGFBP patterns were characterised by ligand-affinity and immunoblotting, and a lectin-binding assay was used to investigate the glyco component of IGFBP-3 complexes. IGF-I and -II concentrations in patients with cysts were significantly lower compared to those in healthy individuals (P<0.0001 and P<0.01, respectively), and the decrease was related to age but not sex. The overall mean concentrations of IGF-I and -II were not significantly different whether the cysts were caused by Echinococcus granulosus, cross-reactive pathologies, or some other factor. IGFBP profiles correlated with the amount of IGF present: patients with lower IGF-I concentrations expressed decreased IGFBP-3 and elevated IGFBP-2 levels. Increased IGFBP-3 proteolytic activity in the patients' blood was not detected by immunoblotting. In the lectin-binding assay, IGFBP-3 complexes in the circulation of patients demonstrated reactivity similar to that in healthy persons, suggesting that the overall structure of the saccharide moieties of the IGFBP-3 complexes was not significantly altered due to liver cyst formation. J. Clin. Lab. Anal. 18:299,304, 2004. © 2004 Wiley-Liss, Inc. [source] Maternal exposure to first-trimester sunshine is associated with increased birth weight in human infantsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 4 2004Karen Tustin Abstract Two alternative hypotheses have been generated to account for seasonal variation in the birth weight of human infants born in industrialized countries. First, it has been hypothesized that low ambient temperature during the second trimester of gestation decreases birth weight. Second, it has been hypothesized that exposure to bright sunshine during the first trimester increases birth weight. We tested these two hypotheses to determine which, if either, accounted for seasonal variation in birth weight of full-term infants. Birth weight data, collected over a 5-year period, were analyzed as a function of peak and trough sunshine and ambient temperature. Although there was no effect of ambient temperature during any trimester on birth weight, infants whose mothers were exposed to peak sunshine during their first trimester were born significantly heavier than infants whose mothers experienced trough levels of sunshine during the same trimester. Furthermore, infants whose mothers were exposed to trough levels of sunshine during their second and third trimesters were born significantly heavier than infants whose mothers were exposed to peak levels of sunshine during the same trimesters. We hypothesize that high levels of sunshine during early gestation may increase the level of insulin-like growth factor (IGF)-1, facilitating prenatal growth. © 2004 Wiley Periodicals, Inc. Dev Psychobiol 45: 221,230, 2004. [source] The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2009Swapnil N. Rajpathak Abstract This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic ,-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright © 2009 John Wiley & Sons, Ltd. [source] INSULIN-LIKE GROWTH FACTOR-I RECEPTOR AS A CANDIDATE FOR A NOVEL MOLECULAR TARGET IN GASTROINTESTINAL CANCERSDIGESTIVE ENDOSCOPY, Issue 4 2006Yasushi Adachi Abnormal activation of growth factor receptors and their signal pathways are required for neoplastic transformation and tumor progression. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, such as those acting against HER2/neu, epidermal growth factor receptor 1, and c-Kit. In this review, we focus on the next promising therapeutic molecular target of insulin-like growth factor (IGF)-I receptor (IGF-Ir). The IGF/IGF-Ir system is an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity in a number of neoplastic diseases, including human gastrointestinal carcinomas. Preclinical studies demonstrated that downregulation of IGF-Ir signals reversed the neoplastic phenotype and sensitized cells to antitumor treatments. We summarize a variety of ways to disrupt IGF-Ir function. Then, we introduce our strategy of adenoviruses expressing dominant negative of IGF-Ir (IGF-Ir/dn) against gastrointestinal cancers, including stomach, colon, and pancreas. IGF-Ir/dn suppresses tumorigenicity both in vitro and in vivo and increases stressor-induced apoptosis. IGF-Ir/dn expression upregulates chemotherapy-induced apoptosis and these combination therapies with chemotherapy are very effective against tumors in mice. Some drugs blocking IGF-Ir function are now entering clinical trial, thus IGF-Ir might be a candidate for a therapeutic target in several gastrointestinal malignancies. [source] Chronic cognitive sequelae after traumatic brain injury are not related to growth hormone deficiency in adultsEUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2010D. Pavlovic Objective:, The objective of the study was to asses the possible influence of hypothalamo,pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency. Design:, We performed retrospective and cross-sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 ± 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 ± 0.6 years). Serum insulin-like growth factor 1 (IGF-I), thyroxin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide-6 (GHRP-6) test. Cognitive function was assessed by using a standard neuropsychological battery. Results:, GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF-I level. Conclusions:, GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI. [source] Eccentric cardiac hypertrophy was induced by long-term intermittent hypoxia in ratsEXPERIMENTAL PHYSIOLOGY, Issue 2 2007Li-Mien Chen It is unclear whether cardiac hypertrophy and hypertrophy-related pathways will be induced by long-term intermittent hypoxia. Thirty-six Sprague,Dawley rats were randomly assigned into three groups: normoxia, and long-term intermittent hypoxia (12% O2, 8 h per day) for 4 weeks (4WLTIH) or for 8 weeks (8WLTIH). Myocardial morphology, trophic factors and signalling pathways in the three groups were determined by heart weight index, histological analysis, Western blotting and reverse transcriptase-polymerase chain reaction from the excised left ventricle. The ratio of whole heart weight to body weight, the ratio of left ventricular weight to body weight, the gross vertical cross-section of the heart and myocardial morphological changes were increased in the 4WLTIH group and were further augmented in the 8WLTIH group. In the 4WLTIH group, tumour necrosis factor-,(TNF,), insulin-like growth factor (IGF)-II, phosphorylated p38 mitogen-activated protein kinase (P38), signal transducers and activators of transcription (STAT)-1 and STAT-3 were significantly increased in the cardiac tissues. However, in the 8WLTIH group, in addition to the above factors, interleukin-6, mitogen-activated protein kinase (MEK)5 and extracellular signal-regulated kinase (ERK)5 were significantly increased compared with the normoxia group. We conclude that cardiac hypertrophy associated with TNF, and IGF-II was induced by intermittent hypoxia. The longer duration of intermittent hypoxia further activated the eccentric hypertrophy-related pathway, as well as the interleukin 6-related MEK5,ERK5 and STAT-3 pathways, which could result in the development of cardiac dilatation and pathology. [source] ,-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial culturesGLIA, Issue 9 2010Ping Ye Abstract By promoting cell proliferation, survival and maturation insulin-like growth factor (IGF)-I is essential to the normal growth and development of the central nervous system. It is clear that IGF-I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)-Akt kinases and MAP kinases signal many of IGF-I-IGF1R actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether ,-catenin, a molecule that is a downstream target of glycogen synthase kinase-3, (GSK3,) and plays a key role in the Wnt canonical signaling pathway, mediates IGF-I actions. We found that IGF-I increases ,-catenin protein abundance within an hour after IGF-I-induced phosphorylation of Akt and GSK3,. Inhibiting the PI3-Akt pathway suppressed IGF-I-induced increases in ,-catenin and cyclin D1 mRNA, while suppression of GSK3, activity simulated IGF-I actions. Knocking-down ,-catenin mRNA by RNA interference suppressed IGF-I-stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that ,-catenin is an important downstream molecule in the PI3-Akt-GSK3, pathway, and as such it mediates IGF-I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells. © 2010 Wiley-Liss, Inc. [source] Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration,HEPATOLOGY, Issue 2 2007Yongzhi Cui Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1,/, mice with a hepatocyte-specific deletion of Stat5. Concomitant loss of both Stat5 and Stat1 restored cell proliferation upon PHx but did not reverse fatty liver development. Thus the molecular underpinnings of some defects observed in the absence of Stat5 are the consequence of a deregulated activation of other signal transducers and activators of transcription (STAT) family members. Conclusion: Aberrant cytokine-Stat5 signaling in hepatocytes alters their physiology through increased activity of Stat1 and Stat3. Such cross-talk between different pathways could add to the complexity of syndromes observed in disease. (HEPATOLOGY 2007.) [source] Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liverHEPATOLOGY RESEARCH, Issue 9 2008Lisa Longato Aim:, Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression. Methods:, Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT),Frizzled (FZD) pathways, given their known roles in HCC. Results:, In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl,asparaginyl , hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC. Conclusion:, In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation. [source] Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification,INTERNATIONAL JOURNAL OF CANCER, Issue 11 2010Katherine A. Janeway Abstract Wildtype (WT) gastrointestinal stromal tumors (GISTs), lacking mutations in KIT or PDGFRA, represent 85% of GISTs in pediatric patients. Treatment options for pediatric WT GIST are limited. Recently, expression profiling of a limited number of pediatric and adult WT GISTs and more in depth study of a single pediatric WT GIST implicated the insulin-like growth factor 1 receptor (IGF1R) as a potential therapeutic target in pediatric WT GIST. We performed immunoblotting, SNP and FISH studies to determine the extent of expression, biochemical activation and genomic amplification of IGF1R in a larger number of pediatric WT GISTs. Pediatric WT GISTs expressed IGF1R strongly, whereas typical adult KIT mutant GISTs did not. IGF1R gene amplification was not detected in pediatric WT GISTs, and some KIT -mutant GISTs had IGF1R gene deletion due to monosomy 15. Despite the absence of apparent genomic activation mechanisms accounting for overexpression, clinical study of IGF1R-directed therapies in pediatric WT GIST is warranted. [source] Long term consequences of the 1944,1945 Dutch famine on the insulin-like growth factor axisINTERNATIONAL JOURNAL OF CANCER, Issue 4 2004Sjoerd G. Elias Abstract The insulin-like growth factor axis is highly responsive to nutritional status and may be involved as one of the underlying mechanisms through which caloric restriction could affect cancer risk. High levels of circulating insulin-like growth factor (IGF)-I, or IGF-I relative to IGF binding protein (IGFBP)-3 have been related to various human cancer types. In a group of 87 postmenopausal women, we found that childhood exposure to the 1944,1945 Dutch famine was associated with increased plasma levels of IGF-I and IGFBP-3, whereas IGFBP-1 and -2 levels were weakly decreased. These results are opposite to immediate responses seen under starvation and we hypothesize that this could indicate a permanent overshoot upon improvement of nutritional status after the famine. © 2003 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||