Restricted Versus Liberal Versus Goal-Directed Fluid Therapy for Non-vascular Abdominal Surgery: A Network Meta-Analysis and Systematic Review.

Optimal perioperative fluid management is crucial, with over- or under-replacement associated with complications. There are many strategies for fluid therapy, including liberal fluid therapy (LFT), restrictive fluid therapy (RFT) and goal-directed fluid therapy (GDT), without a clear consensus as to which is better. We aimed to find out which is the more effective fluid therapy option in adult surgical patients undergoing non-vascular abdominal surgery in the perioperative period. This study is a systematic review and network meta-analysis (NMA) with node-splitting analysis of inconsistency, sensitivity analysis and meta-regression. We conducted a literature search of Pubmed, Cochrane Library, EMBASE, Google Scholar and Web of Science. Only studies comparing restrictive, liberal and goal-directed fluid therapy during the perioperative phase in major non-cardiac surgery in adult patients will be included. Trials on paediatric patients, obstetric patients and cardiac surgery were excluded. Trials that focused on goal-directed therapy monitoring with pulmonary artery catheters and venous oxygen saturation (SvO2), as well as those examining purely biochemical and laboratory end points, were excluded. A total of 102 randomised controlled trials (RCTs) and 78 studies (12,100 patients) were included. NMA concluded that goal-directed fluid therapy utilising FloTrac was the most effective intervention in reducing the length of stay (LOS) (surface under cumulative ranking curve (SUCRA) = 91%, odds ratio (OR) = -2.4, 95% credible intervals (CrI) = -3.9 to -0.85) and wound complications (SUCRA = 86%, OR = 0.41, 95% CrI = 0.24 to 0.69). Goal-directed fluid therapy utilising pulse pressure variation was the most effective in reducing the complication rate (SUCRA = 80%, OR = 0.25, 95% CrI = 0.047 to 1.2), renal complications (SUCRA = 93%, OR = 0.23, 95% CrI = 0.045 to 1.0), respiratory complications (SUCRA = 74%, OR = 0.42, 95% CrI = 0.053 to 3.6) and cardiac complications (SUCRA = 97%, OR = 0.067, 95% CrI = 0.0058 to 0.57). Liberal fluid therapy was the most effective in reducing the mortality rate (SUCRA = 81%, OR = 0.40, 95% CrI = 0.12 to 1.5). Goal-directed therapy utilising oesophageal Doppler was the most effective in reducing anastomotic leak (SUCRA = 79%, OR = 0.45, 95% CrI = 0.12 to 1.5). There was no publication bias, but moderate to substantial heterogeneity was found in all networks. In preventing different complications, except mortality, goal-directed fluid therapy was consistently more highly ranked and effective than standard (SFT), liberal or restricted fluid therapy. The evidence grade was low quality to very low quality for all the results, except those for wound complications and anastomotic leak.

The competing influence of surface roughness, hydrophobicity, and electrostatics on protein dynamics on a self-assembled monolayer.

Surface morphology, in addition to hydrophobic and electrostatic effects, can alter how proteins interact with solid surfaces. Understanding the heterogeneous dynamics of protein adsorption on surfaces with varying roughness is experimentally challenging. In this work, we use single-molecule fluorescence microscopy to study the adsorption of α-lactalbumin protein on the glass substrate covered with a self-assembled monolayer (SAM) with varying surface concentrations. Two distinct interaction mechanisms are observed: localized adsorption/desorption and continuous-time random walk (CTRW). We investigate the origin of these two populations by simultaneous single-molecule imaging of substrates with both bare glass and SAM-covered regions. SAM-covered areas of substrates are found to promote CTRW, whereas glass surfaces promote localized motion. Contact angle measurements and atomic force microscopy imaging show that increasing SAM concentration results in both increasing hydrophobicity and surface roughness. These properties lead to two opposing effects: increasing hydrophobicity promotes longer protein flights, but increasing surface roughness suppresses protein dynamics resulting in shorter residence times. Our studies suggest that controlling hydrophobicity and roughness, in addition to electrostatics, as independent parameters could provide a means to tune desirable or undesirable protein interactions with surfaces.

Untying the Gordian KNOT: Unbiased Single Particle Tracking Using Point Clouds and Adaptive Motion Analysis.

Achieving mechanistic understanding of transport in complex environments such as inside cells or at polymer interfaces is challenging. We need better ways to image transport in 3-D and better single particle tracking algorithms to determine transport that are not systemically biased toward any classical motion model. Here we present an unbiased single particle tracking algorithm: Knowing Nothing Outside Tracking (KNOT). KNOT uses point clouds provided by iterative deconvolution to educate individual particle localizations and link particle positions between frames to achieve 2-D and 3-D tracking. Information from prior point clouds fuels an independent adaptive motion model for each particle to avoid global models that could introduce biases. KNOT competes with or surpasses other 2-D methods from the 2012 particle tracking challenge while accurately tracking adsorption dynamics of proteins on polymer surfaces and early endosome transport in live cells in 3-D. We apply KNOT to study 3-D endosome transport to reveal new physical insight into locally directed and diffusive transport in live cells. Our analysis demonstrates better accuracy in classifying local motion and its direction compared to previous methods, revealing intricate intracellular transport heterogeneities.

Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.

Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center's transplant electronic database. Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 ± 1.2 years; mean Model for End-Stage Liver Disease score, 35 ± 1) with HRS1 (serum creatinine, 3.37 ± 0.13 mg/dL) at liver transplant were enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialysis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients (75.8%) at a mean time of 13 ± 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine levels (3.81 ± 0.34 versus 3.23 ± 0.14 mg/dL, P = 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42 days] versus 10 days (95% CI, 10-18 days), P = 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days) versus 10 days (95% CI, 6-14 days), P = 0.01], and increased posttransplant mortality (P = 0.0045) in comparison with those whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6% increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1 should receive a timely liver transplant to improve their outcome.

Prevalence and risk factors for musculoskeletal injuries related to endoscopy.

BACKGROUND: There are limited data regarding work-related injury among endoscopists. OBJECTIVE: To define the prevalence of endoscopy-related musculoskeletal injuries and their impact on clinical practice and to identify physician and practice characteristics associated with their development. DESIGN: Survey. SETTING: Electronic survey of active members of the American Society for Gastrointestinal Endoscopy with registered e-mail addresses. PARTICIPANTS: Physicians who currently or ever performed endoscopy and responded to the survey between February 2013 and November 2013. INTERVENTION: A 25-question, self-administered, electronic survey. MAIN OUTCOME MEASUREMENTS: Prevalence, location, and ramifications of work-related injuries and endoscopist characteristics and workload parameters associated with endoscopy-related injury. RESULTS: The survey was completed by 684 endoscopists. Of those, 362 (53%) experienced a musculoskeletal injury perceived definitely (n = 204) or possibly (n = 158) related to endoscopy. Factors associated with a higher rate of endoscopy-related injury included higher procedure volume (>20 cases/week; P < .001), greater number of hours per week spent performing endoscopy (>16 hours/week; P < .001), and total number of years performing endoscopy (P = .004). The most common sites of injury were neck and/or upper back (29%) and thumb (28%). Only 55% of injured endoscopists used practice modifications in response to injuries. Specific treatments included medications (57%), steroid injection (27%), physiotherapy (45%), rest (34%), splinting (23%), and surgery (13%). LIMITATIONS: Self-reported data of endoscopy-related injury. CONCLUSION: Among endoscopists there is a high prevalence of injuries definitely or potentially related to endoscopy. Higher procedure volume, more time doing endoscopy per week, and cumulative years performing endoscopy are associated with more work-related injuries.

Performance of endoscopic ultrasound in staging rectal adenocarcinoma appropriate for primary surgical resection.

BACKGROUND & AIMS: Endoscopic ultrasound (EUS) often is used to stage rectal cancer and thereby guide treatment. Prior assessments of its accuracy have been limited by small sets of data collected from tumors of varying stages. We aimed to characterize the diagnostic performance of EUS analysis of rectal cancer, paying particular attention to determining whether patients should undergo primary surgical resection. METHODS: We performed a retrospective observational study using procedural databases and electronic medical records from 4 academic tertiary-care hospitals, collecting data on EUS analyses from 2000 through 2012. Data were analyzed from 86 patients with rectal cancer initially staged as T2N0 by EUS. The negative predictive value (NPV) was calculated by comparing initial stages determined by EUS with those determined by pathology analysis of surgical samples. Logistic regression models were used to assess variation in diagnostic performance with case attributes. RESULTS: EUS excluded advanced tumor depth with an NPV of 0.837 (95% confidence interval [CI], 0.742-0.908), nodal metastasis with an NPV of 0.872 (95% CI, 0.783-0.934), and both together with an NPV of 0.767 (95% CI, 0.664-0.852) compared with pathology analysis. Incorrect staging by EUS affected treatment decision making for 20 of 86 patients (23.3%). Patient age at time of the procedure correlated with the NPV for metastasis to lymph node, but no other patient features were associated significantly with diagnostic performance. CONCLUSIONS: Based on a multicenter retrospective study, EUS staging of rectal cancer as T2N0 excludes advanced tumor depth and nodal metastasis, respectively, with an approximate NPV of 85%, similar to that of other modalities. EUS has an error rate of approximately 23% in identifying disease appropriate for surgical resection, which is lower than previously reported.

Multicenter experience with performance of ERCP in patients with an indwelling duodenal stent.

Endoscopic retrograde cholangiopancreatography (ERCP) in patients with a preexisting duodenal stent covering the papilla is particularly challenging. The aim of this study was to describe a multicenter experience of performing ERCP in patients with biliary obstruction in whom the papilla was obscured by a preexisting duodenal stent. A total of 38 patients with preexisting duodenal stents obscuring the papilla underwent ERCP. Endoscopic biliary cannulation was successful in 13 patients (34.2 %). In 12 of these 13 patients (92.3 %), endoscopic therapy was performed during the same procedure and achieved clinical success with relief of jaundice in all cases (100 %). The most commonly utilized procedure in patients in whom ERCP failed was EUS-guided biliary drainage (EGBD; n = 13 /22, 59.1 %), followed by percutaneous transhepatic biliary drainage (n = 9 /22, 40.9 %). Three patients in whom ERCP failed either did not consent to further intervention or were transferred to other centers. Thus, ERCP was technically challenging in our cohort of patients with preexisting duodenal stents, but was nonetheless successful in about one third of cases. Overall, when performed by experts, endoscopic biliary drainage (via ERCP or EGBD) can be successfully achieved in the majority of patients with indwelling duodenal stents.

Endoscopic approach to the patient with motility disorders of the bile duct and sphincter of Oddi.

Since its original description by Oddi in 1887, the sphincter of Oddi has been the subject of much study. Furthermore, the clinical syndrome of sphincter of Oddi dysfunction (SOD) and its therapy are controversial areas. Nevertheless, SOD is commonly diagnosed and treated by physicians. This article reviews the epidemiology, clinical manifestations, and current diagnostic and therapeutic modalities of SOD.

Does leaving a main pancreatic duct stent in place reduce the incidence of precut biliary sphincterotomy-associated pancreatitis? A randomized, prospective study.

BACKGROUND: Pancreatitis is the most common major complication of ERCP and precut endoscopic sphincterotomy (ES). Prophylactic pancreatic duct (PD) stent placement has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP) in high-risk settings. OBJECTIVE: To determine whether leaving a main PD stent in place after precut ES would reduce the incidence and severity of PEP. DESIGN: Single-center, randomized, prospective study. SETTING: Tertiary care ERCP referral center. PATIENTS: Consecutive patients who underwent ERCP with a clear indication for biliary access and standard biliary ES whereby free cannulation of the bile duct was not possible and precut ES was undertaken. INTERVENTIONS: When free bile duct cannulation for ES was not possible and selective PD cannulation was achieved, a PD stent was placed. Using the PD stent as a guide, we used a needle-knife sphincterotome to perform precut ES. The patients were then randomized to either leaving the PD stent in place for 7 to 10 days (stent group) or immediate removal after the procedure (stent removed group). The remaining patients who did not undergo selective PD cannulation and stent placement were not randomized (no stent group) and had a free-hand needle-knife ES performed. MAIN OUTCOME MEASUREMENTS: Patients were prospectively followed for the development of complications. Standardized criteria were used to diagnose and grade the severity of PEP. RESULTS: A total of 151 patients were enrolled. The groups were similar with regard to patient demographics and patient and procedure risk factors for PEP. The overall incidence of PEP was 13.2% (20/151). It occurred in 4.3% (2/46), 21.3% (10/47), and 13.8% (8/58) of patients in the stent, stent removed, and no stent groups, respectively. The stent group had a significantly lower frequency and severity of PEP compared with the stent removed group (4.3% vs 21.3%; P = .027 for frequency and 0% vs 12.8%; P = .026 for moderate and severe pancreatitis). LIMITATIONS: Single center. Randomization scheme not optimal. CONCLUSIONS: These data suggest that placing and maintaining a PD stent for needle-knife precut ES reduces the frequency and severity of postprocedure pancreatitis.

Pancreatic stent migration into the portal vein causing portal vein thrombosis: a rare complication of a prophylactic pancreatic stent.

This report describes the first case of a novel complication of prophylactic pancreatic stents used to reduce the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis, whereby the stent migrated into the portal vein resulting in portal vein thrombosis. We review the literature and discuss the potential mechanisms that caused this complication. The approach and prompt treatment that resulted in a favorable clinical outcome are described.

Prevalence and predictors of MRSA, ESBL, and VRE colonization in the ambulatory IBD population.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients may be at increased risk of acquiring antibiotic-resistant organisms (ARO). We sought to determine the prevalence of colonization of methicillin-resistant Staphylococcus aureus (MRSA), Enterobacteriaceae containing extended spectrum beta-lactamases (ESBL), and vancomycin-resistant enterococi (VRE) among ambulatory IBD patients. METHODS: We recruited consecutive IBD patients from clinics (n=306) and 3 groups of non-IBD controls from our colon cancer screening program (n=67), the family medicine clinic (n=190); and the emergency department (n=428) from the same medical center in Toronto. We obtained nasal and rectal swabs for MRSA, ESBL, and VRE and ascertained risk factors for colonization. RESULTS: Compared to non-IBD controls, IBD patients had similar prevalence of colonization with MRSA (1.5% vs. 1.6%), VRE (0% vs. 0%), and ESBL (9.0 vs. 11.1%). Antibiotic use in the prior 3 months was a risk factor for MRSA (OR, 3.07; 95% CI: 1.10-8.54), particularly metronidazole. Moreover, gastric acid suppression was associated with increased risk of MRSA colonization (adjusted OR, 7.12; 95% CI: 1.07-47.4). Predictive risk factors for ESBL included hospitalization in the past 12 months (OR, 2.04, 95% CI: 1.05-3.95); treatment with antibiotics it the past 3 months (OR, 2.66; 95% CI: 1.37-5.18), particularly prior treatment with vancomycin or cephalosporins. CONCLUSIONS: Ambulatory IBD patients have similar prevalence of MRSA, ESBL and VRE compared to non-IBD controls. This finding suggests that the increased MRSA and VRE prevalence observed in hospitalized IBD patients is acquired in-hospital rather than in the outpatient setting.

Comparison of endoscopic and surgical resection of intramucosal carcinoma in Barrett's esophagus.

The optimal management of intramucosal carcinoma in Barrett's esophagus continues to be controversial. To date, there has not been a lot of research directly comparing endoscopic versus surgical management of intramucosal carcinoma. Previous studies have shown that both modalities to have excellent outcomes. The reviewed article is a matched retrospective cohort study from two high-volume centers, which shows both modalities to be effective, but an associated higher morbidity rate and risk for procedure-related mortality in the surgical group, and higher recurrence rate in the endoscopic therapy group. The study is discussed in the context of the current state of knowledge regarding Barrett's esophagus and intramucosal carcinoma, in particular outcomes and limitations of the present study.

Hepatorenal syndrome: do the vasoconstrictors work?

The development of hepatorenal syndrome (HRS) is related to many changes associated with advanced cirrhosis. Because vasoconstrictors correct systemic and splanchnic hemodynamic abnormalities, they are effective treatments for HRS, although only in approximately 40% of HRS patients. Emerging data show that combination treatment with vasoconstrictors and TIPS may yield better outcomes than either alone. All HRS patients should be assessed for liver transplantation. Reversing HRS before transplantation is associated with better long-term survival. Combined liver­ kidney transplantation is indicated for those with irreversible kidney injury. Otherwise, there is some merit in performing a liver transplant first and only considering a kidney transplant later.

Increased risk of vancomycin-resistant enterococcus (VRE) infection among patients hospitalized for inflammatory bowel disease in the United States.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) infection has become an increasingly common hospital-acquired infection in U.S. hospitals. Patients with inflammatory bowel disease (IBD) frequently require hospitalization and therefore may be at increased risk of nosocomial infections. METHODS: We used the Nationwide Inpatient Sample (NIS) to identify admissions for IBD (n = 116,842) between 1998 and 2004. We compared the prevalence of VRE in this group to that of non-IBD gastrointestinal (GI) inpatients and general inpatients and assessed for associations between VRE and hospital mortality, length of stay, and total charges. RESULTS: The crude VRE prevalence was 2.1/10,000 in hospitalized IBD patients, 1.3/10,000 in non-IBD GI patients, and 0.9/10,000 in general inpatients. After adjustment for confounders, IBD inpatients were at increased risk of VRE compared to the non-IBD GI (adjusted odds ratio [aOR] 1.65; 95% confidence interval [CI]: 1.03-2.64) and general inpatient (aOR 2.37; 95% CI: 1.31-4.27) groups. Among IBD patients, there was a higher prevalence of VRE infection in those who had surgery (4.4/10,000 versus 1.7/10,000; P < 0.04) and total parenteral nutrition (6.9/10,000 versus 1.8/10,000; P < 0.003). VRE infection was not associated with an increase in mortality (0% versus 0.7%, P = 0.8); however, it was associated with 3-fold higher total hospital charges ($63,517 versus $21,918 USD; P < 0.0001) and increased average length of stay in hospital (16.1 versus 6.1 days; P < 0.0001). CONCLUSIONS: Hospitalized IBD patients have increased susceptibility to VRE that is associated with increased economic burden. This study reinforces the importance of measures to prevent nosocomial infection, particularly in the vulnerable IBD population.

Medical management of ascites.

INTRODUCTION: Ascites is a common complication of advanced cirrhosis that has a significant negative impact on survival. This review updates the reader on the medical management of ascites. AREAS COVERED: This review explores the pathophysiology of ascites formation in cirrhosis; the current mainstays of medical management (treating the underlying cause of cirrhosis, avoiding nephrotoxic agents, sodium restriction, and combination diuretic therapy); potential novel agents, such as vasoconstrictors and vaptans; and albumin infusions. The literature research covers all aspects of medical management of ascites from the English literature, concentrating on publications from the past 10 years. It provides a thorough understanding of how the correction of pathophysiology of ascites formation helps to improve ascites; knowledge on the monitoring of patients with cirrhosis and ascites receiving medical management, and on prophylaxis against potentially life-threatening complication such as spontaneous bacterial peritonitis; and potential new treatments for ascites. EXPERT OPINION: Management of patients with cirrhosis and ascites requires careful attention to fluid and electrolyte balance and avoidance of complications. Recognition of refractory ascites allows for the use of second-line treatments. All patients with cirrhosis and ascites should be considered for liver transplantation.

Caspases from apoptotic myocytes degrade extracellular matrix: a novel remodeling paradigm.

Induction of smooth muscle cell apoptosis is critical to the reversal of severe structural remodeling in hypertensive pulmonary arteries during disease regression. This process involves coordinated resorption of pathologically deposited extracellular matrix, including elastin, and occurs in the presence of serine elastase and matrix metalloproteinase inhibitors. Here, we show that apoptotic smooth muscle cells exhibit extensive degradation of elastin coincident with cell surface immunolocalization and release of caspases. We further document that recombinant caspase-2, -3, and -7 are potently elastolytic. These enzymes are present in an active form on apoptotic cell surfaces and caspase inhibitors attenuate their elastolytic activity. Our results reveal a previously undescribed function for apoptotic cells and a novel paradigm whereby removal of cells is coordinated with degradation of excess extracellular matrix during remodeling in development and disease.

Apolipoprotein D and platelet-derived growth factor-BB synergism mediates vascular smooth muscle cell migration.

We identified apolipoprotein (apo)D in a search for proteins upregulated in a posttranscriptional manner similar to fibronectin in motile smooth muscle cells (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound migration assay (P<0.01). Confocal microscopy revealed prominent perinuclear and trailing edge expression of apoD in migrating SMCs but not in the confluent monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor (PDGF)-BB increased apoD protein expression (P<0.05). Moreover, PDGF-BB-stimulated migration of human pulmonary artery SMCs was suppressed by knock-down of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10% fetal bovine serum promoted random migration by 62% compared with vector-transfected cells (P<0.01). Overexpression of apoD or addition of exogenous apoD to a rat aortic SMC line (A10) stimulated their migration in response to a subthreshold dose of PDGF-BB (P<0.05). This was unrelated to increased phosphorylation of ERK1/2 or of phospholipase C-gamma1, but correlated with enhanced Rac1 activation. This study shows that apoD can be expressed or taken up by SMCs and can regulate their motility in response to growth factors.

Apolipoprotein D inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferated by preventing translocation of phosphorylated extracellular signal regulated kinase 1/2 to the nucleus.

OBJECTIVE: Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease. METHODS AND RESULTS: Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery. However, an increase in apoD mRNA was seen in quiescent relative to proliferating fetal lamb aortic VSMCs, and in the rat aortic VSMC line (A10), we demonstrated uptake of apoD from serum. Stable transfection of apoD in A10 cells in the absence of serum did not influence VSMC proliferation assessed by [3H]-thymidine incorporation. ApoD, administered at a dose of 100 ng/mL, completely inhibited basal as well as platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation (P<0.01) but had no effect on fibroblast growth factor-induced VSMC proliferation. ApoD did not suppress PDGF-BB or fibroblast growth factor-2-induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 but selectively inhibited PDGF-BB-mediated ERK1/2 nuclear translocation. CONCLUSIONS: Our data suggest that apoD selectively modulates the proliferative response of VSMC to growth factors by a mechanism related to nuclear translocation of ERK1/2.