Anaesthetic-surgical guide in the treatment of ascending aorta and surgery of the ascending aorta and aortic arch. Consensus document of the Spanish Society of Cardiovascular and Endovascular Surgery and the Sociedad of Anaesthesiology, Resuscitation and Pain Therapy.

Aortic pathology is always a challenge for the clinician, and must be diagnosed and treated by a multidisciplinary team due to the technical and technological complexity of the resources used. Ongoing efforts to implement a systematic, protocolized approach involving "Aortic teams" made up of cardiologists, cardiac surgeons, vascular surgeons, anaesthesiologists and radiologists, among others are now leading to improved outcomes. The aim of this consensus document drawn up by the Aortic working groups of the Spanish Society of Anaesthesiology, Resuscitation and Pain Therapy (SEDAR) and the Spanish Society of Thoracic and Cardiovascular Surgery (SECTCV) is to disseminate a set of working protocols. The latest consensus document of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society for Vascular Surgery (ESVS) define the concept of "AORTIC TEAM"(1). The aortic team should be closely involved from diagnosis to treatment and finally follow-up, and should be formed of cardiac and vascular surgeons working together with anaesthesiologists, cardiologists, radiologists and geneticists. Treatment of aortic pathologies should be centralised in large centres, because this is the only way to effectively understand the natural course of the disease, provide the entire range of treatment options under one umbrella and treat potential complications. A streamlined emergent care pathway (24/7 availability), adequate transportation and transfer capabilities, as well as rapid activation of the multidisciplinary team must be available. In light of the complexity and constant evolution of therapeutic options, we present this first version of the Anaesthesiology and surgical guidelines for surgery of the ascending aorta and aortic arch. Some questions will no doubt remain unanswered, and future versions will include new techniques that, though implemented in some centres, are still not widely recommended.

Anaesthetic-surgical guide in the treatment of ascending aorta and surgery of the ascending aorta and aortic arch. Consensus document of the Spanish Society of Cardiovascular and Endovascular Surgery and the Sociedad of Anaesthesiology, Resuscitation and Pain Therapy. / Guía anestésico-quirúrgica en el tratamiento de la cirugía de aorta ascendente y del arco aórtico. Documento de consenso de la Sociedad Española de Cirugía Cardiovascular y Endovascular y la Sociedad Española de Anestesiología, Reanimación y Terapeútica del Dolor.

Aortic pathology is always a challenge for the clinician, and must be diagnosed and treated by a multidisciplinary team due to the technical and technological complexity of the resources used. Ongoing efforts to implement a systematic, protocolized approach involving "Aortic teams" made up of cardiologists, cardiac surgeons, vascular surgeons, anaesthesiologists and radiologists, among others are now leading to improved outcomes. The aim of this consensus document drawn up by the Aortic working groups of the Spanish Society of Anaesthesiology, Resuscitation and Pain Therapy (SEDAR) and the Spanish Society of Thoracic and Cardiovascular Surgery (SECTCV) is to disseminate a set of working protocols. The latest consensus document of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society for Vascular Surgery (ESVS) define the concept of "AORTIC TEAM"(1). The aortic team should be closely involved from diagnosis to treatment and finally follow-up, and should be formed of cardiac and vascular surgeons working together with anaesthesiologists, cardiologists, radiologists and geneticists. Treatment of aortic pathologies should be centralised in large centres, because this is the only way to effectively understand the natural course of the disease, provide the entire range of treatment options under one umbrella and treat potential complications. A streamlined emergent care pathway (24/7 availability), adequate transportation and transfer capabilities, as well as rapid activation of the multidisciplinary team must be available. In light of the complexity and constant evolution of therapeutic options, we present this first version of the Anaesthesiology and surgical guidelines for surgery of the ascending aorta and aortic arch. Some questions will no doubt remain unanswered, and future versions will include new techniques that, though implemented in some centres, are still not widely recommended.

RETRACTED: Anesthesic and surgical guideline for the treatment of the thoraco-abdominal aorta. Consensus Document of the Spanish Societies of Anesthesia and Cardiovascular Surgery. / Guía anestésico-quirúrgica en el tratamiento de la patología de aorta toracoabdominal. Documento de Consenso de la Sociedad Española de Cirugía Cardiovascular Endovascular y la Sociedad Española de Anestesiología, Reanimación y Terapeútica del Dolor.

Este artículo ha sido retirado por indicación del Editor Jefe de la revista, después de constatar que parte de su contenido había sido plagiado, sin mencionar la fuente original: European Heart Journal (2014) 35, 2873 926.: https://academic.oup.com/eurheartj/article/35/41/2873/407693#89325738 El autor de correspondencia ha sido informado de la decisión y está de acuerdo con la retirada del artículo. El Comité Editorial lamenta las molestias que esta decisión pueda ocasionar. Puede consultar la política de Elsevier sobre la retirada de artículos en https://www.elsevier.com/about/our-business/policies/article-withdrawal

Guidelines for enhanced recovery after cardiac surgery. Consensus document of Spanish Societies of Anesthesia (SEDAR), Cardiovascular Surgery (SECCE) and Perfusionists (AEP). / Vía clínica de recuperación intensificada en cirugía cardiaca. Documento de consenso de la Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR), la Sociedad Española de Cirugía Cardiovascular y Endovascular (SECCE) y la Asociación Española de Perfusionistas (AEP).

The ERAS guidelines are intended to identify, disseminate and promote the implementation of the best, scientific evidence-based actions to decrease variability in clinical practice. The implementation of these practices in the global clinical process will promote better outcomes and the shortening of hospital and critical care unit stays, thereby resulting in a reduction in costs and in greater efficiency. After completing a systematic review at each of the points of the perioperative process in cardiac surgery, recommendations have been developed based on the best scientific evidence currently available with the consensus of the scientific societies involved.

Optimisation of metabolic criteria in the prognostic assessment in patients with lymphoma. A multicentre study. / Optimización de los criterios metabólicos en la valoración pronóstica de los pacientes con linfoma. Estudio multicéntrico.

OBJECTIVE: To compare sensitivity, specificity and predictive value of Deauville score (DS) vs. ΔSUVmax in interim-treatment PET (iPET) and end-treatment PET (ePET), in patients with diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and follicular lymphoma (FL). METHOD: Retrospective longitudinal multicentre study including 138 patients (46 DLBCL, 46 HL, 46 FL), on whom 3 18F-FDG PET/CT were performed: baseline, iPET, and ePET. Visual (DS) and semi-quantitative (ΔSUVmax) parameters were determined for iPET and ePET. Predictive value was determined in relation to disease-free interval. RESULTS: Statistical analysis. iPET for DLBCL, HL, and FL: 1) sensitivity of DS: 76.92/83.33/61.53%; specificity: 78.78/85/81.81%; 2) sensitivity of ΔSUVmax: 53.84/83.33/61.53%; specificity: 87.87/87.50/78.78%. ePET for DLBCL, HL and FL: 1) sensitivity of DS: 61.53/83.33/69.23%; specificity: 90.90/85/87.87%; 2) sensitivity of ΔSUVmax: 69.23/83.33/69.23%; specificity: 90.90/87.50/84.84%. Predictive assessment. iPET study: in DLBCL, DS resulted in 10.3% recurrence of negative iPET, and 17.1% in ΔSUVmax at disease-free interval; in HL, both parameters showed a 2.8% recurrence of negative iPET; in FL, DS resulted in 15.6% recurrence of negative iPET, and 16.1% in ΔSUVmax, with no statistical significance. ePET study: in DLBCL, DS resulted in 14.3% recurrence of negative ePET, and 11.8% in ΔSUVmax at disease-free interval; in HL and FL, both methods showed 2.8 and 12.5% recurrence in negative ePET, respectively. CONCLUSION: DS and ΔSUVmax did not show significant differences in DLBCL, HL and FL. Their predictive value also did not show significant differences in HL and FL. In DLBCL, DS was higher in iPET, and ΔSUVmax in ePET.

Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells.

BACKGROUND: In addition to the mutational status of KRAS, the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG) might function as bona fide biomarkers of cetuximab (Ctx) sensitivity for most EGFR-driven carcinomas. METHODS: Lentivirus-delivered small hairpin RNAs were employed to specifically reduce AREG or EREG gene expression in wild-type KRAS A431 squamous cell carcinoma cells. Colony-forming assays were used to monitor the impact of AREG and EREG knockdown on Ctx efficacy. Amphiregulin and EREG protein expression levels were assessed by quantitative ELISA in parental A431 cells and in pooled populations of A431 cells adapted to grow in the presence of Ctx. A phosphoproteomic platform was used to measure the relative level of phosphorylation of 42 distinct receptor tyrosine kinases before and after the acquisition of resistance to Ctx. RESULTS: Stable gene silencing of either ligand was found to notably reduce the expression of the other ligand. Parental A431 cells with normal expression levels of AREG/EREG exhibited significantly increased growth inhibition in response to Ctx, compared with derivatives that are engineered to produce minimal AREG/EREG. The parental A431 cells acutely treated with Ctx exhibited reduced basal expression levels of AREG/EREG. Pooled populations of Ctx-resistant A431 cells expressed significantly lower levels of AREG/EREG and were insensitive to the downregulatory effects of Ctx. Phosphoproteomic screen identified a remarkable hyperactivation of FGFR3 in Ctx-resistant A431 cells, which gained sensitivity to the cytotoxic and apoptotic effects of the FGFR3 TK inhibitor PD173074. The A431 parental cells acutely treated with Ctx rapidly activated FGFR3 and their concomitant exposure to Ctx and PD173074 resulted in synergistic apoptosis. CONCLUSION: Cross-suppression of AREG/EREG expression may explain the tight co-expression of AREG and EREG, as well as their tendency to be more highly expressed than other EGFR ligands to determine Ctx efficacy. The positive selection for Ctx-resistant tumour cells exhibiting AREG/EREG cross-suppression may have an important role in the emergence of Ctx resistance. As de-repression of FGFR3 activity rapidly replaces the loss of EGFR-ligand signalling in terms of cell proliferation and survival, combinations of Ctx and FGFR3-targeted drugs may be a valuable strategy to enhance the efficacy of single Ctx while preventing or delaying acquired resistance to Ctx.

Endovascular treatment for pseudoaneurysms after surgical correction of aortic coarctation.

Late complications after surgical repair of aortic coarctation are not uncommon. Among these complications pseudoaneurysms are the most frequent complications, occurring between 3 and 38%. Reoperation in these patients is associated with high morbidity and mortality. In the last decade, endovascular techniques emerged as an alternative to conventional surgery with excellent results. We report the case of two patients who presented with pseudoaneurysms after surgical correction for aortic coarctation, which were treated by endovascular means.

Primary stenting immediatly after surgery in occluded anastomoses of aortoaortic tube graft: a case report.

The conventional elective open procedures for abdominal aortic aneurysm repair are reliable and yield durable results. The aortoaortic tube graft has the lowest morbidity incidence when compared with different techniques. Albeit infrequent, thrombosis can be present in the first 30 days. Its treatment consists in thrombectomy and anastomosis evaluation, but with an increase in morbidity, especially in patients with urgent reintervention. This is a case report of a patient with aortoaortic tube graft, who present critical left limb ischemia immediately after surgical procedure. Angiography showed complete occlusion of left common iliac artery, affecting the distal graft anastomosis. The occlusion was resolved with endovascular treatment, and a noncovered, self-expanding, nitinol stent was deployed (primary stenting) covering the distal bypass anastomosis, with no complications and complete lower limb perfusion recovery. One month later, the patient was still asymptomatic, with distal pulse palpable and ankle-brachial index 1.

[Epidural anesthesia for coronary revascularization in the conscious patient]. / Revascularización coronaria en el paciente despierto bajo anestesia epidural.

Thoracic epidural anesthesia has been widely used to complement general anesthesia in coronary artery bypass grafting. The main advantages of the combination are excellent pain control and a less pronounced stress response to surgery. The invasiveness of surgery to treat ischemic heart disease has been attenuated thanks to the use of the mini-sternotomy and coronary anastomosis without extracorporeal circulation. In 4 patients, coronary artery revascularization was carried out via a mini-sternotomy, grafting the anterior descending artery to the left internal thoracic artery under high thoracic epidural anesthesia (block of segments T1-T8) with a perfusion of 0.75% ropivacaine and fentanyl in a conscious patient. There were no hemodynamic or respiratory complications during surgery. The mean duration of stay in the intensive care unit was less than 18 hours and the mean hospital stay was less than 5 days. Postoperative coronary arteriograms demonstrated the patency of all grafts and all patients were asymptomatic at 1 month. Our initial experience suggests that the use of only high thoracic epidural anesthesia is feasible in coronary revascularization in selected, cooperative patients who require a single coronary bypass graft.

[Cell saver devices in coronary revascularization surgery without extracorporeal circulation reduce transfusion requirements]. / El Recuperador Celular (Cell Saver) en cirugía de revascularización coronaria sin circulación extracorpóea reduce necesidades transfusionales.

OBJECTIVES: To analyze the effectiveness of a cell saver device in reducing transfusion requirements in patients undergoing off-pump coronary artery bypass surgery. PATIENTS AND METHODS: Fifty-six consecutive ASA class 4-5 patients who underwent coronary surgery without extracorporeal circulation in our cardiac surgery department between June 2004 and January 2005 were included in this retrospective study; the series comprised 28 patients who received conventional management (control group) without use of the cell saver device and 28 who received cell saver treatment. Variables analyzed were preoperative and discharge hemoglobin levels and hematocrit values, age, weight, height, ejection fraction, packed red blood cells transfused, exitus, and adverse events. RESULTS: The groups were similar with respect to preoperative characteristics. Fewer patients in the cell saver group required transfusions (6 vs 18 in the control group; relative risk 0.33, 95% confidence interval, 0.16-0.71). The mean amount of packed red cells transfused was greater in the control group than in the cell saver group (2.5 L vs 1.2 L, P = 0.03). No deaths or adverse events occurred in either group. CONCLUSIONS: The routine use of a cell saver device during off-pump coronary artery bypass surgery reduces the need for postoperative transfusions and is not associated with adverse events. Cell saver devices should be used routinely, especially in situations where the ability to provide blood transfusions may be compromised.

Cloning, expression and purification of human epidermal growth factor using different expression systems.

Epidermal growth factor (EGF) is a protein that belongs to the family of growth factors that bind the ErbB receptors, which play a prominent role in the development of carcinomas. We had demonstrated that potato carboxypeptidase inhibitor (PCI) acts as an EGF antagonist. Because of the low affinity of PCI for the epidermal growth factor receptor, it was decided to design EGF mutants with PCI abilities. In order to achieve this we have first cloned, expressed and purified the native protein, EGF. Different expression systems with different locations of the recombinant protein were designed and a purification protocol was designed with those which allowed expression of EGF. Finally, the sample needed folding. Differences in the amount of EGF obtained and its activity were observed depending on the expression system used.

Thoracoabdominal aortic aneurysm repair in cardiac transplant recipients.

We present here two cases of asymptomatic thoracoabdominal aortic aneurysms that were successfully operated on in heart transplant patients 8 and 23 months after transplantation. Thoracoabdominal aortic aneurysm was present prior to transplantation in one patient. In the other patient only the abdominal aortic aneurysm was found before transplantation. Indications for transplantation were ischemic and valvular cardiomyopathy. Surgical aortic aneurysm repair was performed with the standard technique. Both patients were discharged from the hospital. The possible contributing factors to the development and enlargement of aortic aneurysms and perioperative assessment are also discussed. Radiologic surveillance is warranted in any heart transplant recipient with abdominal or thoracoabdominal aortic aneurysms because of the more rapid aneurysm expansion.

Human pancreatic ribonuclease 1: expression and distribution in pancreatic adenocarcinoma.

BACKGROUND: Human pancreatic ribonuclease (RNase 1) is a pancreatic enzyme that is present at high levels in the serum of most patients with pancreatic adenocarcinoma. For this reason, the authors studied its patterns of expression at the single-cell level in pancreatic adenocarcinoma tissues by immunohistochemical analysis and in situ hybridization (ISH). METHODS: Immunohistochemical analysis with polyclonal antibodies against RNase 1 and by ISH with digoxigenin-labeled RNase 1 probe were used to detect RNase 1 in the neoplastic cells of ductal type pancreatic adenocarcinomas. RESULTS: Fifteen of 18 carcinoma samples were positive for RNase 1, demonstrating that the expression of ribonuclease that the authors observed previously in human pancreatic adenocarcinoma cell lines was not an artifact of cell culture. The authors also found RNase 1 in some of the metaplastic ducts and atrophic islets in 4 of 6 chronic pancreatitis samples, and they observed RNase 1 immunostaining in hyperplastic ducts adjacent to one of the well-differentiated adenocarcinomas. CONCLUSIONS: The expression levels of RNase 1 by tumor cells from pancreatic adenocarcinomas are consistent with the high RNase 1 levels found in the serum of most patients with pancreatic adenocarcinoma. This expression of RNase 1, which is an acinar protein, demonstrates that the patterns of gene expression in pancreatic adenocarcinoma are distinct from those of normal pancreatic duct cells. Conversely, RNase 1 expression levels in altered ductal cells from some chronic pancreatitis tissues and hyperplastic ducts from carcinoma tissues suggest that abnormal expression levels may be an early event in pancreatic tumorigenesis.

Ribonucleases expressed by human pancreatic adenocarcinoma cell lines.

Human ribonucleases have been considered as a possible tumor marker for pancreatic cancer, and elevated serum levels of ribonuclease activity in patients with pancreatic cancer have been reported by many authors. The reason for this elevation is unknown. In this study, we demonstrate that human pancreatic adenocarcinoma cell lines synthesize and secrete different ribonucleases. We isolated and characterized human pancreatic, or secretory, ribonuclease (RNase 1) from the conditioned media of the human pancreatic adenocarcinoma cell lines Capan-1, MDAPanc-3, IBF-CP3 and Panc-1, and the ampullary adenocarcinoma cell line MDAAmp-7, which represent a wide range of differentiation stages. Only one of these cell lines, Panc-1, produces significant amounts of nonsecretory ribonuclease. We then established a purification procedure for both secretory and nonsecretory ribonucleases, consisting of concentration of the supernatant by tangential filtration, anion-exchange and cation-exchange liquid chromatography and C4 RP-HPLC. Ribonuclease activity fractions were monitored using both the spectrophotometric and negative-staining zymogram techniques. The results of N-terminal sequence analysis, kinetic analysis and endoglycosidase digestion studies indicate that the main ribonuclease secreted by all the cell lines is the secretory-type ribonuclease and that it is composed of several differently N-glycosylated forms. Northern blot analyses confirm that some of the cell lines express secretory ribonuclease mRNA. The mRNA levels produced by Panc-1 and MDAPanc-28 are too low to be detected. Similar levels of expression of nonsecretory ribonuclease are found by Northern blot analysis in all the cell lines except Panc-1, which expresses higher levels. Here, we describe, for the first time, that several human pancreatic cancer cell lines with different degrees of differentiation express and secrete ribonucleases. This fact indicates that one origin of the elevated serum RNase levels in patients with pancreatic cancer are tumor cells. Analysis of the oligosaccharide moiety of the RNase 1 secreted by Capan-1 shows that it is highly glycosylated and its N-glycan chains are significantly different from that of the RNase 1 produced by normal pancreas. These results renew the possibility of using human serum RNase 1 determination as a tumor marker.

Eighteen-year follow up after Hancock II bioprosthesis insertion.

BACKGROUND AND AIM OF THE STUDY: The long-term (18 years) results after aortic (AVR), mitral (MVR) and double (aortic/mitral, DVR) valve replacement with Hancock II bioprosthesis were investigated. METHODS: Between 1978 and 1996, 279 Hancock II bioprostheses were implanted in 269 patients (166 males, 113 females; mean age 61.8+/-13.3 years). There were 135 AVR (48.4%), 122 MVR (43.8%) and 22 DVR (7.8%). Preoperatively, 208 patients (77.3%) were in NYHA functional class III/IV, 53 (19.7%) had previous cardiac surgery, and 19 (7.1%) underwent concomitant coronary artery bypass. Follow up (mean seven years) was 96% complete, with a total of 1,857 patient-years. RESULTS: There were 20 early (7.3%), and 78 (29.0%) late deaths. At the last follow up, 68.3% of patients were in NYHA functional class I/II. The actuarial survival rate of patients at 10 and 18 years after discharge was 67.7+/-5.0% and 44.7+/-8.8% after AVR and 64.5+/-5.6% and 32.7+/-11.5% after MVR, respectively; survival after DVR was 74.0+/-11.2% at 12 years. At 10 and 18 years, actuarial freedom from thromboembolism was 83.5+/-4.5% and 73.1+/-10.5% after AVR and 82.1+/-4.3% and 73.2+/-7.3% after MVR; it was 78.4+/-15.0% after DVR at 12 years. At these times, actuarial freedom from hemorrhage was 88.7+/-3.8% and 83.5+/-6.2% after AVR and 79.0+/-4.9% and 32.6+/-23.3% after MVR; freedom after DVR was 36.2+/-26.6%. Probability of freedom from endocarditis at 10 and >15 years was 93.4+/-3.5% and 85.9+/-7.8% after AVR and 97.0+/-2.1% and 97.0+/-2.1% for MVR, respectively; freedom at 10 years after DVR was 75.0+/-21.6%. Freedom from structural deterioration at 10 and 18 years was 77.9+/-5.3% and 18.7+/-14.6% after AVR and 78.3+/-6.0% and 32.1+/-10.2% after MVR; freedom at 10 and 12 years after DVR was 64.0+/-17.5% and 32.0+/-24.2%. A low incidence of structural valve deterioration was found in AVR patients aged >65 years (p = 0.0478). Hemorrhage and paravalvular leak were more frequent in MVR (p = 0.0296 and 0.0309, respectively). No difference was seen in thromboembolism after anticoagulation for one or three months after AVR. Actuarial freedom from explantation at 10 and 18 years was 73.1+/-5.9% and 15.9+/-13.5% after AVR and 77.1+/-6.1% and 37.3+/-9.7% after MVR; freedom at 10 and 12 years after DVR was 72.0+/-17.8% and 24.0+/-20.4%. CONCLUSION: Over an 18-year follow up, the Hancock II bioprosthesis has shown satisfactory results, with a low incidence of valve-related complications, especially in elderly patients in the aortic position.

The three-dimensional structure of human RNase 4, unliganded and complexed with d(Up), reveals the basis for its uridine selectivity.

The RNase 4 family is unique among RNase enzymes, displaying the highest level of sequence similarity and encompassing the shortest polypeptide chain. It is the only one showing high specificity. The human representative is an intracellular and plasma enzyme, first isolated from colon adenocarcinoma cell line HT-29. The crystal structures of human recombinant RNase 4, unliganded and in complex with d(Up), have been determined, revealing in the unique active site an explanation for the uridine specificity. Arg101, at a position not involved in catalysis in the other RNase enzymes, penetrates the enzyme moiety shaping the recognition pocket, a flip that is mediated by the interaction with the (shorter chain) C-terminal carboxylate group, providing an anchoring point for the O4 atom of the substrate uridine. The bulky Phe42 side-chain forces Asp80 to be in the chi1=-72.49 degrees rotamer, accepting a hydrogen bond from Thr44, further converting the latter into a hydrogen bond acceptor. This favours an interaction with the -NH-donor group of uridine at position 3 over that with the =N-acceptor of cytidine. The two chemical groups that distinguish uracyl from cytosine are used by the enzyme to discriminate between these two bases.

Potato carboxypeptidase inhibitor, a T-knot protein, is an epidermal growth factor antagonist that inhibits tumor cell growth.

Epidermal growth factor (EGF) and its receptor (EGFR) are involved in many aspects of the development of carcinomas, including tumor cell growth, vascularization, invasiveness, and metastasis. Because EGFR has been found to be overexpressed in many tumors of epithelial origin, it is a potential target for antitumor therapy. Here we report that potato carboxypeptidase inhibitor (PCI), a 39-amino acid protease inhibitor with three disulfide bridges, is an antagonist of human EGF. It competed with EGF for binding to EGFR and inhibited EGFR activation and cell proliferation induced by this growth factor. PCI suppressed the growth of several human pancreatic adenocarcinoma cell lines, both in vitro and in nude mice. PCI has a special disulfide scaffold called a T-knot that is also present in several growth factors including EGF and transforming growth factor alpha. PCI shows structural similarities with these factors, a fact that can explain the antagonistic effect of the former. This is the first reported example of an antagonistic analogue of human EGF.