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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2009.10.012 Byline: Luca Weltert, Stefano D'Alessandro, Saverio Nardella, Fabiana Girola, Alessandro Bellisario, Daniele Maselli, Ruggero De Paulis Abbreviations: ANOVA, analysis of variance; CABG, coronary artery bypass grafting; Hb, hemoglobin; HRE, human erythropoietin Abstract: Human recombinant erythropoietin has been used to obtain a rapid increase in red blood cells before surgery. Previously, the shortest preparatory interval has been 4 days, but at the European Hospital only 2.4 days on average separate hospitalization and surgery. We therefore proposed a randomized blind trial to test the efficacy of high-dose erythropoietin for very short-term administration. Author Affiliation: Cardiac Surgery Department, European Hospital, Rome, Italy Article History: Received 30 April 2009; Revised 9 September 2009; Accepted 4 October 2009 Article Note: (footnote) Disclosures: None.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2005.12.049 Byline: Christopher J. Robinson (a), Donna D. Johnson (a), Eugene Y. Chang (a), D. Michael Armstrong (a), Wei Wang (b) Abstract: The purpose of this study was to determine if maternal serum concentrations of placenta growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 receptor (s-Flt1) are more abnormal in patients with severe preeclampsia compared with mild preeclampsia. Author Affiliation: (a) Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (b) Departments of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, Charleston, SC Article History: Received 14 September 2005; Revised 13 December 2005; Accepted 22 December 2005 Article Note: (footnote) Supported by National Institutes of Health National Institute of Child Health and Human Development grant number: 5 R03 HD 41031-02, Institutional Review Board Project # HR 9983. Presented at the Twenty-fifth Society of Maternal Fetal Medicine Meeting, Reno, NV, February 7-12, 2005.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.10.035 Byline: Mitsuhiro Kawata, Shinichi Takamoto, Kazuo Kitahori, Hiroyuki Tsukihara, Tetsuro Morota, Minoru Ono, Noboru Motomura, Arata Murakami, Yoshihiro Suematsu Abbreviations: CPB, cardiopulmonary bypass; CSF, cerebrospinal fluid; EPO, erythropoietin; HDS, Histopathologic Damage Score; NDS, Neurologic Deficit Score; TUNEL, deoxyuridine-5'-triphosphate biotin nick end labeling Abstract: Current data suggest that erythropoietin protects the brain and the spinal cord from ischemic and traumatic injury. In this study, we determined whether erythropoietin protects the central nervous system during prolonged hypothermic circulatory arrest in an experimental canine model. Author Affiliation: Department of Cardiothoracic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Article History: Received 27 May 2005; Revised 29 September 2005; Accepted 3 October 2005 Article Note: (footnote) The Pharmaceutical Division of Kirin Brewery Co Ltd supplied the epoetin alpha genetic recombination.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.11.037 Byline: Francis Juthier (a)(b), Andre Vincentelli (a)(b), Julien Gaudric (a)(b), Delphine Corseaux (a), Olivier Fouquet (a)(b), Christine Calet (a)(b), Thierry Le Tourneau (a), Valerie Soenen (c), Christophe Zawadzki (a)(c), Olivier Fabre (a)(b), Sophie Susen (a)(c), Alain Prat (a)(b), Brigitte Jude (a)(c) Abbreviations: BM, bone marrow; G-CSF, granulocyte colony-stimulating factor; VWF, Von Willebrand Factor Abstract: Autologous recellularization of decellularized heart valve scaffolds is a promising challenge in the field of tissue-engineered heart valves and could be boosted by bone marrow progenitor cell mobilization. The aim of this study was to examine the spontaneous in vivo recolonization potential of xenogeneic decellularized heart valves in a lamb model and the effects of granulocyte colony-stimulating factor mobilization of bone marrow cells on this process. Author Affiliation: (a) Institut National de la Sante et de la Recherche Medicale (Inserm) ERI-9, Faculte de Medecine, Lille, France (b) Centre Hospitalier Regional Universitaire de Lille, Clinique de Chirurgie Cardiovasculaire, Lille, France (c) Institut d'Hematologie-Transfusion, Lille, France Article History: Received 5 August 2005; Revised 20 November 2005; Accepted 28 November 2005 Article Note: (footnote) Supported in part by grants from the French Fond National pour la Science, Ministere de la Recherche, Action Concertee Incitative 2002-Grant 02TS 050 and from Conseil Regional Nord Pas de Calais 2003-OBJ2-2004/1-4-1, no. 157.

The authors have investigated the effect of acute hypoxia on placental vascular endothelial growth factor system in vivo and in vitro in acute birth asphyxia. Results demonstrate that vascular endothelial growth factor system is up-regulated in response to placental hypoxia.

Byline: Bassem N. Mora, Carlos H.R. Boasquevisque, Mariano Boglione, Jon M. Ritter, Ronald K. Scheule, Nelson S. Yew, Lisa Debruyne, Lihui Qin, Jonathan S. Bromberg, G.Alexander Patterson Abstract: Background: The aim of the current work was to study the feasibility of functional gene transfer using the gene encoding for transforming growth factor-[beta]1, a known immunosuppressive cytokine, on rat lung allograft function in the setting of acute rejection. Methods: The rat left lung transplant technique was used in all experiments, with Brown Norway donor rats and Fischer recipient rats. After harvest, left lungs were transfected ex vivo with either sense or antisense transforming growth factor-[beta]1 constructs complexed to cationic lipids, then implanted into recipients. On postoperative days 2, 5, and 7, animals were put to death, arterial oxygenation measured, and acute rejection graded histologically. Results: On postoperative day 2, there were no differences in acute rejection or lung function between animals treated with transforming growth factor-[beta]1 and control animals. On postoperative day 5, oxygenation was significantly improved in grafts transfected with the transforming growth factor-[beta]1 sense construct compared with antisense controls (arterial oxygen tension = 411 [+ or -] 198 vs 103 [+ or -] 85 mm Hg, respectively; P = .002). Acute rejection scores from lung allografts were also significantly improved, corresponding to decreases in both vascular and airway rejection (vascular rejection scores: 2.0 [+ or -] 0.5 vs 2.8 [+ or -] 0.6; P = .04; airway rejection scores: 1.3 [+ or -] 0.7 vs 2.3 [+ or -] 0.8, respectively; P = .02). The amelioration of acute rejection was temporary and decreased by postoperative day 7. Conclusions: The feasibility of using gene transfer techniques to introduce novel functional genes in the setting of lung transplantation is demonstrated. In this model of rat lung allograft rejection, gene transfer of transforming growth factor-[beta]1 resulted in temporary but significant improvements in lung allograft function and acute rejection pathology. (J Thorac Cardiovasc Surg 2000;119:913-20) Author Affiliation: From the Division of Cardiothoracic Surgery, Department of Surgery,.sup.a and Department of Pathology,.sup.b Washington University School of Medicine, St Louis, Mo; Genzyme Corporation,.sup.c Framingham, Mass; and Department of Surgery,.sup.d University of Michigan, Ann Arbor, Mich Article History: Received 19 March 1999; Revised 4 May 1999; Revised 30 December 1999; Accepted 24 January 2000 Article Note: (footnote) [star] Supported by National Institutes of Health grants 1 R01 HL-41281 (to G.A.P.) and 1F32HL09751-01 (to B.N.M.). C.H.R.B. was supported by the Federal University of Rio de Janeiro-University Hospital Clementino Fraga Filho, Brazil., [star][star] Read at the Seventy-ninth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La, April 18-21, 1999., a Address for reprints: G. Alexander Patterson, MD, Professor of Surgery, Division of Cardiothoracic Surgery, One Barnes-Jewish Hospital Plaza, Suite 3108 Queeny Tower, St Louis, MO 63110.

Byline: Victor Chu, Jin-qiang Kuang, Amy McGinna, Adel Giaid, Stephen Korkola, Ray C.-J. Chiu Abstract: Background: Angiogenesis is the proposed mechanism of transmyocardial revascularization. We evaluated mechanical transmyocardial revascularization in a chronically ischemic porcine model by measuring myocardial angiogenic response. Methods: Ameroid constrictors were implanted 6 weeks before mechanical transmyocardial revascularization. Group I (n = 5) and group II (n = 3) animals received 30 punctures with an 18-gauge needle and samples were harvested at 1 and 4 weeks, respectively, after the operation. Group III (n = 5) had sternotomy only and served as the control group. Myocardial samples were immunohistochemically stained for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor [beta] (TGF-[beta]) using specific antibodies. Growth factor expression was quantified by means of computer-assisted morphometry. Vascular density was assessed by immunohistochemical stain for VEGF and factor VIII. Results: Compared with group III, increased angiogenic factor levels were found in group I (VEGF 0.47 [+ or -] 0.03 mm.sup.2 vs 0.05 [+ or -] 0.05 mm.sup.2, P = .000; bFGF 0.67 [+ or -] 0.14 mm.sup.2 vs 0.03 [+ or -] 0.03 mm.sup.2, P = .000; TGF-[beta] 1.40 [+ or -] 0.18 mm.sup.2 vs 0.09 [+ or -] 0.06 mm.sup.2, P = 0.000), and in group II (VEGF 0.34 [+ or -] 0.06 mm.sup.2 vs 0.05 [+ or -] 0.05 mm.sup.2, P = .003; bFGF 0.06 [+ or -] 0.02 mm.sup.2 vs 0.03 [+ or -] 0.03 mm.sup.2, P = .135; TGF-[beta] 0.28 [+ or -] 0.09 mm.sup.2 vs 0.09 [+ or -] 0.06 mm.sup.2, P = .042). Vascular densities after mechanical transmyocardial revascularization were also increased (group I, VEGF stain 8.1 [+ or -] 0.6 vs 1.1 [+ or -] 0.5, P = .000; factor VIII stain 5.1 [+ or -] 2.7 vs 0.4 [+ or -] 0.3, P = .018; group II, VEGF stain 1.9 [+ or -] 0.5 vs 1.1 [+ or -] 0.5, P = 0.107; factor VIII stain 2.3 [+ or -] 0.4 vs 0.4 [+ or -] 0.3, P = .004). Conclusions: Mechanical transmyocardial revascularization is associated with increased angiogenic factor expression and concomitant neovascularization at up to 4 weeks. These changes are indistinguishable from those of laser transmyocardial revascularization. Myocardial perfusion studies are needed to establish the functional significance of these angiogenic changes. (J Thorac Cardiovasc Surg 1999; 118:849-56) Author Affiliation: From the Division of Cardiothoracic Surgery.sup.a and the Department of Pathology, McGill University,.sup.b Montreal, Quebec, Canada Article History: Received 19 March 1999; Revised 4 May 1999; Revised 8 July 1999; Accepted 13 July 1999 Article Note: (footnote) [star] Read at the Seventy-ninth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La, April 18-21, 1999., [star][star] Address for reprints: Ray C.-J. Chiu, MD, Room C9.169, Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada (E-mail: mdiu@musica.mcgill.ca )., a 0022-5223/99 $8.00 + 0 12/6/101413

Byline: Misako Mishima, Tetsu Yano, Haruko Jimbo, Naomi Yano, Yutaka Morita, Hiroyuki Yoshikawa, Andrew V. Schally, Yuji Taketani Keywords: Somatostatin; somatostatin analog; endometrial cancer; growth factors; nude mice Abstract: Objective: Our purpose was to investigate the effect of the somatostatin analog RC-160 on the growth of the HEC-1 human endometrial cancer cell line in vivo and in vitro. Study Design: Nude mice bearing subcutaneous implanted HEC-1 tumors were treated for 25 days with RC-160 (100 [mu]g/d) delivered by osmotic minipumps. In cultured HEC-1 cells radioreceptor assay of somatostatin was performed, and the expression of messenger ribonucleic acid for somatostatin receptor subtypes (somatostatin receptors 1-5) was analyzed by reverse transcription-polymerase chain reaction. The effects of RC-160 on epidermal growth factor-stimulated cell proliferation and tyrosine phosphorylation of epidermal growth factor receptor were examined by colorimetric assay and Western blotting, respectively. Results: The treatment with RC-160 resulted in a significant decrease in tumor volume, tumor weight, and serum insulin-like growth factor I levels compared with those values in control animals. The presence of high-affinity somatostatin binding sites and the expression of somatostatin receptor 2 and somatostatin receptor 3 messenger ribonucleic acid were demonstrated in HEC-1 cells by radioreceptor assay and reverse transcription-polymerase chain reaction, respectively. Epidermal growth factor-stimulated proliferation of HEC-1 cells was inhibited by RC-160 in a dose-dependent manner. Western blotting revealed that epidermal growth factor-induced tyrosine phosphorylation of epidermal growth factor receptor was inhibited by RC-160, which suggests that the direct inhibitory effect of RC-160 on HEC-1 cell growth might be mediated in part by interference with epidermal growth factor receptor phosphorylation. Conclusion: These results indicate that somatostatin analog RC-160 inhibits the growth of HEC-1 human endometrial cancer cells, thus implying its potential clinical utility in treating endometrial cancer. (Am J Obstet Gynecol 1999;181:583-90.) Author Affiliation: Tokyo, Japan, and New Orleans, Louisiana Article History: Received 4 December 1998; Revised 3 May 1999; Accepted 21 May 1999 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo,a the Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center,b and the Department of Medicine, Tulane University School of Medicine.c , [star][star] Reprint requests: Tetsu Yano, MD, PhD, Assistant Professor, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongou, Bunkyo-ku, Tokyo, 113-8655 Japan., a 6/1/100251

Byline: Michael A. Frolich, Sanjay Datta, Stephen B. Corn Keywords: Platelets; thrombopoietin; pregnancy; preeclampsia; HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome; pregnancy-induced hypertension Abstract: OBJECTIVE: In normal pregnancy and pregnancies complicated by preeclampsia it has been demonstrated that there is increased activation of platelets and the clotting and fibrinolytic system. We measured plasma levels of thrombopoietin, a major regulator of platelet production in these conditions. STUDY DESIGN: We compared the thrombopoietin plasma levels of healthy term pregnant patients (n = 21) with those of healthy nonpregnant controls (n = 17), as well as patients with severe preeclampsia (n = 8) and the hemolysis, elevated liver enzymes, low platelets syndrome (n = 6). RESULTS: Thrombopoietin levels in normal pregnant patients and pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome were statistically significantly higher than thrombopoietin levels in nonpregnant controls. Data were analyzed with the Kruskal-Wallis one-way analysis of variance by ranks. CONCLUSIONS: This study is the first to report thrombopoietin levels in pregnancy. Thrombopoietin levels are significantly greater in pregnant patients and in pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome compared with nonpregnant controls. (Am J Obstet Gynecol 1998;179:100-4.) Author Affiliation: Boston, Massachusetts Article History: Received 25 July 1997; Revised 16 December 1997; Accepted 19 December 1997 Article Note: (footnote) [star] From the Departments of Obstetric Anesthesiologya and Anesthesiology,b Brigham and Women's Hospital and Children's Hospital, Harvard Medical School., [star][star] Reprint requests: Michael A. Frolich, MD, Department of Anesthesiology, PO Box 100254, Gainesville, FL 32610-0254., a 0002-9378/98 $5.00 + 0 6/1/88330

Byline: Ron Brauner, Masaki Nonoyama, Hillel Laks, Davis C. Drinkwater, Sharon McCaffery, Thomas Drake, Arnold J. Berk, Luyi Sen, Lily Wu Abstract: Background: Intracoronary transfer and expression of recombinant genes in the intact heart is now feasible. In the transplant setting, local modulation of host immune responses by a genetically modified allograft may offer an attractive alternative to systemic immunosuppression. Methods: We tested the efficacy and in vivo effect of intracoronary transfer of two immunosuppressive cytokine genes. First-generation E1-deleted adenoviral vectors expressing the Epstein-Barr virus interleukin-10 (AdSvIL10) or human transforming growth factor -- [beta].sub.1 (AdCMVTGF-[beta]) were used. Rabbit cardiac allografts were transduced during cold preservation by slow (1 ml/min) intracoronary infusion of 10.sup.10 pfu/gm diluted viral vectors and then implanted heterotopically. Controls included E1-deleted adenovirus (Ad5dl434) and AdCMVLacZ. Beating allografts were collected on day 4 for analysis of gene transfer efficacy and distribution. Additional grafts were used for evaluation of alloreactivity (n = 34). Results: Mean allograft viral uptake was 81% (up to 91%). Polymerase chain reactions and reverse transcription-polymerase chain reactions confirmed the presence and expression of both genes in the grafts. [beta]-Galactosidase staining in AdCMVLacZ-infected grafts demonstrated efficient gene expression, which was highest (100%) in subepicardial regions. More homogeneous transmyocardial distribution of the transgene (in 25% to 40% of cells) could be achieved by pulsatile slow delivery. Allograft survival was 6.9 [+ or -] 0.9 days in controls (n = 12), 11.1 [+ or -] 1.7 days in AdCMVTGF-[beta]-infected grafts (n = 11, p < 10), and 11.2 [+ or -] 3 days in AdSvIL10-infected grafts (n = 11, p < 10). Histologic scores (blinded) showed significantly (p < 0.005) higher regression coefficients for rejection in controls compared with both cytokine-transduced groups. Perioperative administration of cyclosporine A (INN: ciclosporin) to recipients had no effect on survival of AdCMVTGF-[beta]-infected grafts but reduced survival of AdSvIL10-infected grafts. Conclusions: Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts is efficient and effectively prolongs graft survival. Vectors that would induce long-term expression of such genes may make this approach clinically applicable. (J Thorac Cardiovasc Surg 1997;114:923-33) Article History: Received 11 March 1997; Revised 22 April 1997; Revised 7 May 1997; Accepted 7 May 1997 Article Note: (footnote) [star] Address for reprints: Hillel Laks, MD, Division of Cardiothoracic Surgery, UCLA Medical Center, 62-182A Center for the Health Sciences, 10833 Le Conte Ave., Los Angeles, CA 90095., [star][star] 0022-5223/97 $5.00 + 0 12/1/83237

Byline: Ron Brauner, Lily Wu, Hillel Laks, Masaki Nonoyama, Frank Scholl, Oleg Shvarts, Arnold Berk, Davis C. Drinkwater, Jing-Liang Wang Abstract: Objective:Allograft-targeted immunosuppressive gene therapy may inhibit recipient immune activation and provide an alternative to systemic immunosuppression. We studied the optimal technique and efficacy of intracoronary gene transfer of viral interleukin-10 and human transforming growth factor-[beta].sub.1 in a rabbit model of heterotopic heart transplantation. Methods: Replication-defective adenoviral vectors were constructed, expressing viral interleukin-10 (AdSvIL10) or transforming growth factor-[beta].sub.1 (AdCMVTGF-[beta].sub.1). Intracoronary delivery of vectors was accomplished ex vivo by either bolus injection or slow infusion. The allografts were implanted heterotopically in recipient rabbits and collected 4 days after the operation. Vector dose was 4 x 10.sup.9 to 6 x 10.sup.10 pfu/gm of donor heart. Transfer was confirmed by DNA amplification for both genes. Gene product expression in tissue was quantified by immunoassay and visualized by immunohistochemical staining. Results: Allograft viral uptake was only 9.9% [+ or -] 2.4% with bolus injection, but increased to 80.5% [+ or -] 6.8% at 1 ml/min infusion rate (p = 5 x 10.sup.-14). Uptake ratio was not affected by vector quantity or slower infusion rates. Transforming growth factor-[beta].sub.1 was consistently detected in allografts infected with AdCMVTGF-[beta].sub.1, but not with control adenovirus or AdSvIL10. Expression was proportional to infused vector quantity and reached 10 ng/gm of allograft at infused 10.sup.10 pfu/gm. Transforming growth factor-[beta].sub.1 was also detected in recipient's serum at less than 1 ng/ml. Viral interleukin-10 was detected in minor amounts only ( Article History: Received 3 July 1996; Revised 19 September 1996; Revised 21 October 1996; Accepted 13 December 1996 Article Note: (footnote) [star] Read at the Twenty-second Annual Meeting of The Western Thoracic Surgical Association, Maui, Hawaii, June 26-29, 1996., [star][star] Address for reprints: Hillel Laks, MD, Division of Cardiothoracic Surgery, UCLA Medical Center, 62-182A Center for the Health Sciences, 10833 Le Conte Ave., Los Angeles, CA 90095., a 12/6/79880

Byline: Thomas F. Rowe, Lisa A. King, Paul C. MacDonald, M.Linette Casey Keywords: Tissue inhibitor of metalloproteinase-1; tissue inhibitor of metalloproteinase-2; human amnion; mesenchymal cells and epithelial cells Abstract: OBJECTIVE: This study was conducted to define the cellular site of expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 in human amnion by an evaluation of the levels of messenger ribonucleic acids in separated amnion epithelial and mesenchymal cells and to ascertain whether amnion epithelial and mesenchymal cells maintained in culture continue to express tissue inhibitor of metalloproteinase messenger ribonucleic acids. STUDY DESIGN: Human placentas and fetal membranes were obtained immediately after delivery. Amnion tissue was separated from chorion laeve and either frozen immediately (-80[degrees] C) or processed by differential enzymatic treatment to separate the epithelial and mesenchymal cells, which were frozen (-80[degrees] C) or else plated and maintained in monolayer culture. The levels of tissue inhibitor of metalloproteinase types 1 and 2 messenger ribonucleic acid were evaluated by Northern analyses of total ribonucleic acid extracted from amnion tissue, freshly separated epithelial and mesenchymal cells, and epithelial and mesenchymal cells in monolayer culture. RESULTS: Tissue inhibitor of metalloproteinase types 1 and 2 messenger ribonucleic acids were detected by Northern analysis in freshly isolated amnion tissues from midtrimester and term pregnancies. The major species of tissue inhibitor of metalloproteinase-1 messenger ribonucleic acid was 0.9 kb in length; a minor species of approximately 3.5 kb also was present. Tissue inhibitor of metalloproteinase-2 messenger ribonucleic acids of 3.5 and 1.0 kb and of similar intensity were also detected. The levels of type 1 messenger ribonucleic acid were not different in amnion tissues obtained at term or during the midtrimester of pregnancy. The levels of tissue inhibitor of metalloproteinase type 2 messenger ribonucleic acids in amnion tissue most commonly were greater at term than in tissues obtained during the midtrimester. The level of type 1 messenger ribonucleic acid in mesenchymal cells was appreciably greater than that in epithelial cells, and this difference was maintained during culture of these cells. The level of type 2 messenger ribonucleic acid was similar in both cell types and was maintained during culture. The levels of type 1 or 2 messenger ribonucleic acids were not affected by treatment of amnion epithelial or mesenchymal cells in culture with a variety of test agents, including steroid hormones, cytokines, and growth factors. CONCLUSION: The amnion mesenchymal cells are the primary source of tissue inhibitor of metalloproteinase-1 in human amnion, whereas both cell types have the potential to produce tissue inhibitor of metalloproteinase-2. (Am J Obstet Gynecol 1997;176:915-21.) Author Affiliation: Dallas, Texas Article History: Received 5 November 1996; Revised 27 December 1996; Accepted 31 December 1996 Article Note: (footnote) [star] From the Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center., [star][star] Supported in part by United States Public Health Service grant No. 5-P50-HD11149. T.F.R. and L.A.K. were postdoctoral trainees supported in part by National Research Service Award grant No. 5-T32-HD07190-16., a Reprint requests: M. Linette Casey, PhD, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9051., aa 0002-9378/97 $5.00 + 0 6/1/80126

Byline: Linda C. Giudice, Natalie A. Martina, Ruth Ann Crystal, Salli Tazuke, Maurice Druzin Keywords: Insulin-like growth factor; insulin-like growth factor binding protein; preeclampsia Abstract: OBJECTIVES: Preeclampsia is characterized by maternal hypertension, proteinuria, edema, and shallow placental invasion. Insulin-like growth factor binding protein-1, abundant in maternal decidua, is believed to play a role in limiting trophoblast invasiveness. In this study we addressed the hypothesis that this binding protein is aberrantly expressed in preeclampsia. We also investigated circulating levels of insulin-like growth factor-I and insulin-like growth factor-II in subjects with severe preeclampsia compared with controls. STUDY DESIGN: Insulin-like growth factor binding protein-1 was investigated by immunohistochemistry at the maternal-fetal interface of eight pregnancies complicated by severe preeclampsia and six controls between 21 and 34 weeks of gestation. Cell types were identified with use of cell-specific markers. Circulating levels of insulin-like growth factor binding protein-1, insulin-like growth factor-I, and insulin-like growth factor-II in 16 patients with severe preeclampsia and 29 controls at the same gestational age were determined by an immunoradiometric assay and correlated with clinical parameters. Data were analyzed by t test and Pearson's method. RESULTS: Insulin-like growth factor binding protein-1 was highly expressed on syncytiotrophoblasts, cytotrophoblasts, and decidual cells but not on placental fibroblasts. Immunostaining was greater at the maternal-fetal interface in severe preeclamptic patients compared with controls. Circulating insulin-like growth factor binding protein-1 levels in subjects with severe preeclampsia were 428.3 [+ or -] 85.9 ng/ml compared with 76.6 [+ or -] 11.8 in controls (p = 0.0007). Circulating insulin-like growth factor-I levels were 80.9 [+ or -] 17.2 ng/ml compared with 179.4 [+ or -] 28.2 ng/ml in controls (p = 0.0001). In contrast, insulin-like growth factor-II levels were not significantly different in the two groups. In subjects with severe preeclampsia insulin-like growth factor binding protein-1 levels correlated with diastolic blood pressure (r = 0.498, p = 0.049) and aspartate transcarbamylase (0.621, p = 0.010). CONCLUSIONS: The abundance of insulin-like growth factor binding protein-1 at the maternal-fetal interface in severely preeclamptic pregnancies suggests that the binding protein may participate in the pathogenesis of the shallow placental invasion observed in this disorder. Low circulating insulin-like growth factor-I and elevated insulin-like growth factor binding protein-1 levels may contribute to restricted placental and therefore fetal growth. (Am J Obstet Gynecol 1997;176:751-8.) Author Affiliation: Stanford, California Article Note: (footnote) [star] From the Divisions of Reproductive Endocrinologyaand Maternal-Fetal Medicine,bDepartment of Obstetrics and Gynecology, Stanford University Medical Center., [star][star] Supported by National Institutes of Health grant No. HD 25220 (L.C.G.) and by the Walter and Ida Berry Fellowship (S.T.)., a Reprint requests: Linda C. Giudice, MD, PhD, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Stanford University Medical Center, 300 Pasteur Dr., East Pavilion, Room HH-333, Stanford, CA 94305-5317., aa 0002-9738/-1900 $5.00 + 0 6/6/80797

Byline: Johan Verhaeghe, Ruth Loos, Robert Vlietinck, Erik Van Herckb, Rita van Breea, Anne-Marie De Schuttera Keywords: Insulin in twin fetuses; insulin-like growth factors in twin fetuses; univariate genetic analysis Abstract: OBJECTIVE: Our purpose was to examine the regulation of fetal serum concentrations of insulin (C-peptide), insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein-1, which are growth-regulating factors in the fetus, in monozygotic and dizygotic twin pairs. STUDY DESIGN: Cord serum samples were collected from 110 twin pairs and compared with 178 nonsibling singleton pairs with the same gestational age. Five twin pairs were excluded from the statistical analyses because of severe intrauterine growth restriction and placental abnormalities in one. Zygosity was assigned by histologic examination of the placenta and by a questionnaire sent to the mother when the twins were [greater than or equal to]6 months old. Analyses included the calculation of correlation coefficients, between-pair variation, and univariate genetic analysis. RESULTS: Cord serum C-peptide concentrations were highly correlated in monozygotic (r = 0.94) and dizygotic twins (r = 0.79) but not in singleton pairs (r = -0.05); the between-pair variation was also smaller in twins than in singletons. Genetic analysis demonstrated a large contribution of the common environment to the variance in C-peptide concentrations (80%) and a smaller genetic contribution (12%). Insulin-like growth factor-I concentrations were better correlated in monozygotic (r = 0.82) than in dizygotic twins (r = 0.42), with a smaller between-pair variation in the former group (22% [+ or -] 4% vs 51% [+ or -] 5%). Univariate genetic analysis indicated that insulin-like growth factor-I levels were regulated predominantly by genetic mechanisms (93% in boys and 77% in girls). The regulation of insulin-like growth factor-II was more complex, with a gender-specific genetic contribution (50% for both sexes combined, 63% for girls but only 5% for boys). Insulin-like growth factor binding protein-1 was regulated by genetic mechanisms (41%) and the common environment (32%) but also by the specific or unique environment of each fetus (27%). In all five twins with intrauterine growth restriction of one member, insulin-like growth factor binding protein-1 concentrations were markedly higher in the growth-restricted fetus. CONCLUSIONS: Insulin secretion in twin fetuses is determined primarily by their common, probably maternal, environment, whereas insulin-like growth factor-I production is predominantly genetically regulated. Insulin-like growth factor-II and insulin-like growth factor binding protein-1 are regulated by both genetic and environmental factors. Of these growth-regulating factors, insulin-like growth factor binding protein-1 appears to be the best marker of intrauterine growth restriction in the individual case. (Am J Obstet Gynecol 1996;175:1180-8.) Author Affiliation: Leuven, Belgium Article History: Received 2 January 1996; Revised 9 April 1996; Accepted 23 April 1996 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecology,a the Laboratorium voor Experimentele Geneeskunde en Endocrinologie, b and the Center for Human Genetics, c Katholieke Universiteit Leuven. , [star][star] Supported by a grant for Fundamental Clinical Research No. G. 3C06.93 and research grant No. 3.0157.95 from the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek (J.V.)., a Reprint requests: J. Verhaeghe, MD, Department of Obstetrics and Gynecology, U.Z. Gasthuisberg, 49 Herestraat, 3000 Leuven, Belgium., aa 0002-9378/96 $5.00 + 0 6/1/74403

Byline: Christianne J.M. de Groot, Timothy J. O'Brien, Robert N. Taylor Keywords: Preeclampsia; placentation; CA 125; insulin-like growth factor binding protein-1 Abstract: OBJECTIVE: Reduced trophoblastic migration into the decidua during the first half of pregnancy is a fundamental abnormality in preeclampsia. CA 125 and insulin-like growth factor binding protein-1 are major endometrial proteins whose primary sources are decidual epithelial and stromal cells, respectively. We hypothesized that reduced trophoblastic invasion in pregnancies destined for preeclampsia would affect the maternal vascular deportation of these decidual proteins. STUDY DESIGN: CA 125 and insulin-like growth factor binding protein-1 concentrations were analyzed by radioimmunoassays of plasma from preeclamptic and matched control patients in a longitudinal, nested case-control study. RESULTS: CA 125 concentrations did not differ with respect to pregnancy outcome or trimester. Midtrimester plasma insulin-like growth factor binding protein-1 concentrations were significantly lower in women who later had preeclampsia compared with normal pregnant controls. CONCLUSION: These findings provide biochemical evidence that abnormalities of trophoblastic invasion affect the maternal vascular deportation of a decidual stromal protein. Lower circulating concentrations of insulin-like growth factor binding protein-1 in women destined to have preeclampsia were observed 12 to 26 weeks before the onset of clinical signs of this syndrome. (Am J Obstet Gynecol 1996;175:24-9.) Author Affiliation: San Francisco, California, and Little Rock, Arkansas Article History: Received 25 August 1995; Revised 15 January 1996; Accepted 30 January 1996 Article Note: (footnote) [star] From the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco,a and the Departments of Biochemistry and Obstetrics and Gynecology, University of Arkansas for Medical Sciences.b , [star][star] Supported by Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences (C.J.M.dG.), and National Institutes of Health grants HD30367 (R.N.T.) and CA40406 (T.J.O'B.)., a Reprint requests: Robert N. Taylor, MD, PhD, W.M. Keck Laboratory of Reproductive and Developmental Molecular Biology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine M-1489, San Francisco, CA 94143-0132., aa 0002-9378/96 $5.00 + 0 6/1/72476

Byline: Jung Gu Kim, Jin Yong Lee Keywords: Insulin-like growth factor binding protein; osteoporosis; natural postmenopause Abstract: OBJECTIVE: The objective of this study was to evaluate the relationship between serum insulin-like growth factor binding protein profiles and bone mineral density measurements and biochemical markers of bone turnover in postmenopausal women. STUDY DESIGN: Sera from 37 normal healthy postmenopausal women and 14 postmenopausal women with osteoporosis were analyzed for insulin-like growth factor binding proteins and osteocalcin by Western ligand blotting and radioimmunoassay, respectively. Bone mineral density measurements were performed by dual-energy x-ray absorptiometry. Urinary calcium and creatinine excretion were also determined. The data were analyzed statistically by analysis of variance and the least-squares method. RESULTS: The serum insulin-like growth factor binding protein-2 ratio (Insulin-like growth factor binding protein-2 intensity/total insulin-like growth factor binding protein intensity) in postmenopausal women with osteoporosis was significantly higher (p < 0.02) than that in normal healthy postmenopausal women, but the serum insulin-like growth factor binding protein-3 ratio in women with osteoporosis was significantly lower (p < 0.01). The serum insulin-like growth factor binding protein-2 ratio correlated negatively with the bone mineral density of the lumbar spine (p < 0.0001), femoral neck (p < 0.05), trochanter (p < 0.01), and Ward's triangle (p < 0.05), but there was a significant positive correlation between the serum insulin-like growth factor binding protein-3 ratio and the bone mineral density of the lumbar spine (p < 0.001) and trochanter (p < 0.05). No correlations between serum insulin-like growth factor binding protein levels or serum ratios and biochemical markers of bone turnover were noted. CONCLUSION: The measurement of serum insulin-like growth factor binding protein profiles might be useful in identifying postmenopausal women at risk for osteoporosis. (AM J OBSTET GYNECOL 1996;174:1511-7.) Author Affiliation: Seoul, Korea Article History: Received 6 March 1995; Revised 30 August 1995; Accepted 13 October 1995 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecology, College of Medicine, Seoul National University., [star][star] Supported by grant No. 06-93-003 from the Research Fund of Seoul National University, College of Medicine., a Reprint requests: Jung Gu Kim, MD, PhD., Department of Obstetrics and Gynecology, Seoul National University Hospital, 28 Yeungun-dong Chongno-Ku, Seoul 110-744, Korea., aa 0002-9378/96 $5.00 + 0 6/1/69797

Byline: K. Anwer, M. Monga, B.M. Sanborn Keywords: Epidermal growth factor; human myometrium; calcium; oxytocin; phosphoinositide turnover; tyrosine kinase; prostaglandins Abstract: OBJECTIVES: The objectives of this study were to determine whether epidermal growth factor increases intracellular calcium and phosphoinositide turnover in human myometrial cells by a tyrosine kinase - mediated mechanism, to evaluate an obligatory role for arachidonic acid metabolites in these actions, and to compare the actions of epidermal growth factor and oxytocin. STUDY DESIGN: Intracellular calcium and phosphoinositide turnover were measured in a myometrial cell line after stimulation with epidermal growth factor (0.1 to 100 nmol/L) or oxytocin (20 nmol/L). The effects of nifedipine, thapsigargin, genestein and tyrphostin, the guanosine triphosphate binding protein antagonist GPA-7, indomethacin, and nordihydroguaiaretic acid were determined. Data were analyzed by analysis of variance and Duncan's multiple-range test. RESULTS: Epidermal growth factor stimulated phosphoinositide turnover and increased intracellular calcium in a dose-dependent manner (median effective concentration 2.6 nmol/L). In contrast to oxytocin, the effects of epidermal growth factor were inhibited by tyrosine kinase inhibitors but not by GPA-7. Indomethacin and nordihydroguaiaretic acid did not inhibit the epidermal growth factor - stimulated increase in intracellular calcium. CONCLUSIONS: The acute epidermal growth factor - stimulated increase in intracellular calcium in this myometrial cell line is primarily derived from release of calcium from intracellular stores, and it involves the activation of a tyrosine kinase, presumably the epidermal growth factor receptor. Arachidonic acid metabolites are not obligatory intermediates. Oxytocin increases phosphoinositide turnover and intracellular calcium by a distinctly different pathway. (AM J OBSTET GYNECOL 1996;174:676-81.) Author Affiliation: Houston, Texas Article History: Received 27 February 1995; Revised 25 May 1995; Accepted 5 June 1995 Article Note: (footnote) [star] From the Departments of Biochemistry and Molecular Biologya and Obstetrics, Gynecology, and Reproductive Sciences, b University of Texas Houston Medical School. , [star][star] Supported by National Institutes of Health grant No. HD09618 (B.M.S.). M.M. is a Burrough-Wellcome fellow of the American Gynecological and Obstetrical Society., a Reprint requests: Barbara M. Sanborn, PhD, Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, P.O. Box 20708, Houston, TX 77225., aa 0002-9378/96 $5.00 + 0 6/1/66803

Gross cystic disease is a common benign breast disease that is associated with a twofold to fourfold increase in breast cancer risk. Both diseases are hormonally induced and may share a common biochemical environment conducive to abnormal proliferative responses. A large collection of breast cyst fluid samples was analyzed for growth factors associated with cell proliferation: epidermal growth factor (EGF), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), platelet-derived growth factor (PDGF), transforming growth factor-[alpha] (TGF-[alpha]), and transforming growth factor-[beta] (TGF-[beta]). The data demonstrate that significant amounts of proliferative growth factors are present in breast cyst fluid of all cyst subtypes. The presence of IGF-II, PDGF, and TGF-[beta] in breast cyst fluid was confirmed for the first time. EGF, PDGF, and TGF-[beta] concentrations in breast cyst fluid were several times greater than reported for serum; IGF-I and IGF-II concentrations were several times lower. In the first 100 samples tested, no TGF-[alpha] was detected. Only EGF and IGF-II levels demonstrated a consistent correlation with apocrine type 1 cysts. These results demonstrated that effective concentrations of proliferative growth factors are in breast cyst fluid and suggest that adjacent breast tissue may be a probable source of synthesis. Growth factor profiles of breast cyst fluid may indicate the presence in breast tissue of a hormonal and proliferative environment permissive to subsequent cancer growth.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1067/mob.2000.105389 Byline: Jonathan D. Goldstein, David J. Garry, Dev Maulik Keywords: Erythropoietin; hematocrit; preeclampsia Abstract: Objective: Our purpose was to evaluate and compare erythropoietin levels as related to obstetric conditions, including acute and chronic bleeding, preeclampsia, and multiple gestations. Study Design: During April 1999 all women in the labor and delivery unit with delivery expected to occur within 24 to 72 hours of admission had erythropoietin and hematocrit values obtained. First-trimester hematocrit values, obstetric problems, medications, and history of vaginal bleeding were obtained from patient interview, examination, and the prenatal record. Statistics were analyzed by the Student t test and I.sup.2. Results: During a 1-month period, 302 consecutive women were divided into 5 groups on the basis of obstetric events. Group 1 consisted of women with normal, uncomplicated term singleton gestations (n = 230); group 2, women with acute vaginal bleeding (n = 10); group 3, women with chronic vaginal bleeding (n = 29); group 4, women with multiple gestations (n = 13); and group 5, women with preeclampsia (n = 16). The mean erythropoietin level in group 1 (20.2 [+ or -] 10.3 mU/mL) was significantly different from values in the other 4 groups (group 2, 74.2 [+ or -] 29.2 mU/mL; group 3, 65.0 [+ or -] 33.0 mU/mL; group 4, 34.8 [+ or -] 16.8 mU/mL; group 5, 43.4 [+ or -] 11.4 mU/mL; P < .001). The admission hematocrit for group 1 (0.369 [+ or -] 0.029) was significantly greater than for groups 2 and 3 (group 2, 0.323 [+ or -] 0.024; group 3, 0.321 [+ or -] 0.023; P < .001) and significantly lower than for group 5 (0.384 [+ or -] 0.022; P < .05). Conclusion: The maternal serum erythropoietin level varies depending on the events occurring during gestation. Acute and chronic bleeding, multiple gestations, and preeclampsia are all associated with various serum erythropoietin levels. (Am J Obstet Gynecol 2000;182:1055-7.) Author Affiliation: Department of Obstetrics and Gynecology, Winthrop-University Hospital. Mineola, New York Article Note: (footnote) [star] Reprint requests: David J. Garry, DO, Department of Obstetrics and Gynecology, Winthrop-University Hospital, 259 First St, Mineola, NY 11501.

Byline: Allahyar Jazayeri, John C.M. Tsibris, William N. Spellacy Keywords: Erythropoietin; smoking; fetal growth restriction; pregnancy Abstract: Objective: Our goal was to determine whether maternal smoking was associated with elevated umbilical cord erythropoietin, a marker for chronic hypoxia. Study Design: Plasma erythropoietin levels were measured in umbilical cord plasma of 222 newborns. There were 48 mothers who smoked and 174 nonsmokers. Results: When all pregnancies were included, mean cord plasma erythropoietin levels were significantly higher in the smokers (78.0 [+ or -] 15.3 mIU/ml) compared with the nonsmoking group (35.2 [+ or -] 4.0 mIU/ml; p < 0.005). Regression analysis showed a significant positive correlation between the number of cigarettes smoked per day and cord plasma erythropoietin levels (r = 0.26, p < 0.0001). Smoking was associated with a significantly elevated risk (relative risk = 2.6, 95% confidence interval 1.7 to 10.9, p < 0.005) of fetal growth restriction. When pregnancies with fetal growth restriction were excluded from the analysis, the difference between the two groups remained significant (smokers 81.3 [+ or -] 18.6, n = 38; nonsmokers 24.3 [+ or -] 1.4, n = 164; p < 0.03). Conclusions: These results illustrate that smoking during pregnancy is associated with fetal growth restriction and significantly elevated umbilical cord erythropoietin levels. (Am J Obstet Gynecol 1998;178: 433-5.) Author Affiliation: Tampa, Florida Article History: Received 29 July 1997; Revised 23 September 1997; Accepted 9 October 1997 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecology, University of South Florida., [star][star] Reprint requests: William N. Spellacy, MD, Department of Obstetrics and Gynecology, Harbourside Medical Tower, Suite 500, 4 Columbia Dr., Tampa, FL 33606., a 6/1/86763

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.05.045 Byline: Faraz Kerendi (a), Michael E. Halkos (a), Hajime Kin (a), Joel S. Corvera (a), Daniel J. Brat (b), Mary B. Wagner (c), Jakob Vinten-Johansen (a), Zhi-Qing Zhao (a), Joseph M. Forbess (a), Kirk R. Kanter (a), Mary E. Kelley (d), Paul M. Kirshbom (a) Abstract: Prolonged deep hypothermic circulatory arrest is known to cause neurological injury. Hypoxia inducible factor, a transcription factor that mediates adaptive changes during hypoxia, is neuroprotective in models of ischemic brain injury, in part by upregulating erythropoietin. This study tested the hypothesis that upregulation of hypoxia inducible factor and erythropoietin by preconditioning with hypoxia or the hypoxia-mimetic agents deferoxamine and cobalt chloride would be neuroprotective in a piglet model of deep hypothermic circulatory arrest. Author Affiliation: (a) Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Ga (b) Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Ga (c) Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga (d) Department of Biostatistics, Emory University School of Medicine, Atlanta, Ga Article History: Received 10 March 2005; Revised 1 May 2005; Accepted 5 May 2005 Article Note: (footnote) This study was funded in part by an Emory Egleston Children's Research Center Seed Grant (P.M.K.) and a Thoracic Surgery Foundation for Research and Education Career Development Award (P.M.K.).