Open abdominal aortic repair in the current era has more complications for occlusive disease than for aneurysm repair.

BACKGROUND: Endovascular intervention has become the first-line treatment of patients with abdominal aortic aneurysms (AAAs) or aortoiliac occlusive disease (AIOD). However, open abdominal aortic repair remains a valuable treatment option for patients who are younger, those with unfavorable anatomy, and patients for whom endovascular intervention has failed. The cohort of patients undergoing open repair has become highly selected; nevertheless, updated outcomes or patient selection recommendations have been unavailable. In the present study, we explored and compared the characteristics and postoperative outcomes of patients who had undergone open abdominal aortic repair from 2009 to 2018. METHODS: Patients who had undergone open AAA (n = 9481) or AIOD (n = 9257) repair were collected from the National Surgical Quality Improvement Program database. The primary outcome was the 30-day mortality. The secondary outcomes included 30-day return to the operating room, total operative time, total hospital stay, and postoperative complications. Unmatched and matched differences between the two groups and changes over time were analyzed. Univariate and multivariate regression analyses were conducted to assess the risk factors predicting for 30-day mortality. RESULTS: After propensity matching (n = 4980), those in the AIOD group had had a higher 30-day mortality rate (5.1% vs 4.1%; P = .021), a higher incidence of wound complications (7.4% vs 5.1%; P<.0001) and an increased 30-day return to the operating room (14.2% vs 9.1%; P < .0001). More open AIOD cases (P = .02) and fewer open AAA cases (P = .04) had been treated in the second half of the decade than in the first. The factors associated with an increased odds of 30-day mortality included advanced age, American Society of Anesthesiologists score ≥III, functional dependence, blood transfusion <72 hours before surgery, weight loss in previous 6 months, and a history of chronic obstructive pulmonary disease. CONCLUSIONS: From 2009 to 2018, the number of open AAA repairs decreased and the proportion of open abdominal AIOD cases increased. Open AIOD surgery was associated with higher 30-day mortality, increased return to the operating room, and increased wound complications vs open AAA repair. Multiple risk factors increased the odds for perioperative mortality. Thus, open abdominal aortic repair should be selectively applied to patients with fewer risk factors.

Effect of Direct Oral Anticoagulants Versus Warfarin on Patency in High-Risk Bypass Patients.

BACKGROUND: The use of warfarin for anticoagulation in thromboembolic disease has been the mainstay of treatment. Direct oral anticoagulants (DOACs) have demonstrated equivalent anticoagulant effects, without increased bleeding risks or need for frequent monitoring. However, the role of DOACs remains unclear in the setting of replacing warfarin for high-risk peripheral artery disease (PAD) interventions. The purpose of this study is to evaluate the efficacy of DOACs compared to warfarin during the postoperative period in patients that underwent a lower extremity high-risk bypass (HRB). METHODS: The study is a single institution, retrospective review of all lower extremity HRBs between January 2012 and June 2021, who were previously placed on or started on anticoagulation with a DOAC or warfarin. The HRB group included all patients undergoing femoral to above or below knee bypass with an adjunct procedure, or below knee bypass with synthetic or composite vein conduit. All demographics, preoperative factors, and complications were evaluated with respect to DOAC versus warfarin. RESULTS: A total of 44 patients (28 males; average age 68.8 ± 10.9) underwent an HRB during the study period. There were no significant differences in demographics and preoperative characteristics between the 2 groups. Among patient comorbidities, coronary artery disease was found to be significantly higher in patients on DOACs (P = 0.03). The 12-month primary patency rate was 83.3% versus 57.1%, for DOAC versus warfarin respectively (P = 0.03). Multivariate analyses revealed that <30-day reinterventions contribute to 12-month patency (P = 0.02). CONCLUSIONS: Patients who underwent lower extremity HRB with postoperative DOAC appeared to exhibit higher graft patency rates than those who were placed on warfarin. Due to their low incidence of undesirable side effects and the lack of frequent monitoring, DOACs could be considered a safe alternative to warfarin in the postoperative period for patients with HRB.

Open conversion after failed endovascular aneurysm repair is increasing and its 30-day mortality is higher than that after primary open repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) has become the preferred treatment of abdominal aortic aneurysms (AAAs). Recent studies have demonstrated that cases of EVAR failure repair and subsequent open conversion have increased. The aim of the present study was to evaluate the national trend of annual cases and assess the 30-day outcomes of conversion to open repair after failed EVAR compared with primary open repair. METHODS: The National Surgical Quality Improvement Program database was queried for relevant Current Procedural Terminology and International Classification of Diseases, Ninth and Tenth Revision, codes to identify patients who had undergone conversion to open repair or primary open repair of nonruptured AAAs from 2009 to 2018. The annual trend of cases was assessed, and the perioperative outcomes of both procedures were compared. Multivariable logistic regression analyses were conducted to identify independent perioperative factors associated with mortality. RESULTS: Of the 9635 patients with nonruptured AAAs included in the present analysis, 9250 had undergone primary repair and 385 had required open conversion. During the 10-year period, the annual number of cases of open conversion had steadily increased and that of primary repair had decreased. The incidence of postoperative complications was similar between both groups, except for cardiac arrest, which had occurred more frequently in the open conversion group. The 30-day mortality was higher in the open conversion group than in the primary group (9.6% vs 3.9%; P < .0001). Open conversion was also independently associated with higher odds of death (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.8-2.4; P < .0001). When the average mortality in both groups was compared between the first and last 5 years, no difference was found (open conversion: 9.8% vs 9.5% [P = 1.00]; primary repair: 3.6% vs 4.2% [P = .19]). Other perioperative factors independently associated with mortality included increased age (OR, 1.8; 95% CI, 1.5-2.1; P < .0001), American Society of Anesthesiologists class ≥III (OR, 2.7; 95% CI, 1.1-6.6; P = .029), insulin-dependent diabetes (OR, 2.0; 95% CI, 1.2-3.3; P = .005), chronic obstructive pulmonary disease (OR, 1.4; 95% CI, 1.1-1.8; P = .006), the presence of dyspnea at rest (OR, 3.3; 95% CI, 1.8-6.1; P < .0001), and a high preoperative hematocrit (OR, 0.94; 95% CI, 0.93-0.97; P < .0001). CONCLUSIONS: Open conversion to treat nonruptured AAAs after failed EVAR was independently associated with higher mortality. Also, the annual cases of open conversion have continued to increase without any significant changes in postoperative mortality. This highlights the danger of open conversion and stresses the need for better solutions to prevent and manage EVAR failure.

Abdominal aortic aneurysm and bilateral pelvic kidneys.

A 61-year-old man presented with a 5.8-cm abdominal aortic aneurysm with bilateral pelvic kidneys incidentally discovered by computed tomography angiography. Given the complex anatomy, an open approach was favored over an endovascular approach to address the aneurysm and preserve renal function. Renal perfusion was achieved with a short clamp time of 29 minutes and intermittent boluses of cold renal perfusion solution delivered into each renal artery via a Fogarty infusion catheter. We describe a rare case of bilateral ectopic kidneys in the setting of open abdominal aortic aneurysm repair using the described technique.

Endovascular repair of right-sided iliac vein aneurysm and iliac arteriovenous fistula.

A 72-year-old man receiving anticoagulation therapy for chronic bilateral deep vein thromboses presented with acute right leg swelling. Right-sided imaging showed deep femoral vein thrombosis, chronic partial femoral vein thrombosis, and 4.8-cm distal external iliac vein dilation with possible right iliac vein stenosis. Venography confirmed common iliac vein occlusion and an aneurysm, with a fistula to the right internal iliac artery found by angiography. Aneurysm obliteration was achieved via arterial embolization with coils and an Amplatzer plug (Abbott, Chicago, IL). The patient continued with anticoagulation therapy, with patent common and external iliac arteries and a stable right external iliac vein aneurysm without arterial waveforms found on follow-up. His clinical manifestations were improved.

Intraoperative fusion imaging during transcarotid artery revascularization.

Background: Transcarotid artery revascularization (TCAR) with reverse-flow neuroprotection has emerged as an alternative to transfemoral carotid artery stenting and carotid endarterectomy. However, it requires fluoroscopic guidance, exposing the patient and surgeon to radiation. Although fusion-guided endovascular aneurysm repair has been demonstrated to significantly decrease this radiation risk, not much is known about similar outcomes for TCAR. The purpose of this study is to evaluate the outcomes at a single institution using fusion-guided imaging during TCAR compared with regional TCAR cases in the Vascular Quality Initiative (VQI) registry without fusion imaging. Methods: A retrospective analysis was conducted of data collected from all patients undergoing TCAR with fusion-guided imaging (TCAR-F) at our hospital and patients undergoing TCAR alone within the VQI database. The primary outcomes included the total operative time, dose area product, fluoroscopy time, contrast usage, and flow-reversal time. The demographics and preoperative risk factors were also assessed in both groups. Continuous outcomes were compared using the Welch t test. Categorical outcomes were compared using the Fisher exact test. Results: A total of 30 TCAR-F cases (January 2019 to May 2022) at our institution were compared against the regional VQI dataset (n = 2535). The TCAR-F cases had a lower dose area product (5.67 vs 93.1 Gy cm2; P < .0001), shorter fluoroscopy time (8.07 vs 16.4 minutes; P < .0001), and less contrast usage (13.49 vs 76.7 mL; P < .0001) compared with the regional averages of the same. The TCAR-F cases had a longer total operative time (117.3 vs 80.9 minutes; P < .0001) and flow-reversal time (14.4 vs 11.7 minutes; P = .025) compared with the regional cases. Conclusions: The results from this pilot study comparing TCAR-F patients at a single institution with VQI regional TCAR patients suggest that TCAR-F cases use less radiation and contrast compared with TCAR without fusion imaging. Fusion-guided imaging might provide radiation protection to both patients and surgeons and decrease contrast usage for the patient.

Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation.

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable CoI/CoIII catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.

Internal jugular to internal jugular vein bypass of symptomatic central vein obstruction.

INTRODUCTION: Central venous obstruction (CVO) often arises among hemodialysis patients with upper extremity access due to a varying number of risk factors. While the true incidence of CVO in hemodialysis patients is unknown, it been reported in the range of 20%-40% in dialysis patients undergoing venograms. In the non-hemodialysis population, chronic central vein obstruction has a compensatory mechanism comprised of numerous collaterals along the chest wall, neck, and mediastinum. However, the presence of an AVF or AVG ipsilateral to a central venous stenosis or occlusion can overwhelm the collateral network due to the significantly elevated blood flow. This may result in severe and debilitating upper extremity and fascial swelling. While ligation results in almost instantaneous symptomatic relief, it does not address the patient's underlying pathologic process and necessitates an additional access. As these patients continue to live longer, our strategies to manage these failing accesses are becoming increasingly complex. The goal of preserving existing access while correcting any symptoms is paramount. Previous case reports have documented various surgical options for preserving an existing access. CASE PRESENTATION: Our patient is a 49-year-old female with hypertension and end-stage renal disease, on hemodialysis through a right arm arteriovenous (AV) fistula. She had a history of multiple AV fistulae creations in the past, all of which previously thrombosed. Several years after the creation of her most recent fistula, she developed severe throbbing headaches, right arm and facial swelling, right eye lacrimation, and blurry vision. AV fistula angiogram demonstrated right brachiocephalic vein chronic occlusion and endovascular revascularization through both trans-AVF and transfemoral approaches were attempted, but unsuccessful. DISCUSSION: This case illustrates the success of the creation of an internal jugular-jugular vein bypass to maintain a right arm arteriovenous fistula, while at the same time, correcting the symptoms of a right brachiocephalic vein occlusion.

Soleal venous aneurysm in a patient with a history of pulmonary embolism.

A lower extremity venous aneurysm is an uncommon vascular disease known to increase a patient's risk of pulmonary embolism. Although most will be popliteal venous aneurysms, crural aneurysms have been rarely documented. We have presented a rare case of a soleal venous aneurysm in a patient with a history of pulmonary embolism. Risk-reducing open aneurysm resection with lateral venorrhaphy was performed.

Extended Use of Distal Embolic Protection Devices in Treatment of Distal Embolism During Lower Extremity Arterial Endovascular Interventions.

There is no consensus on the best treatment modality for acute distal embolization complications during endovascular interventions for peripheral arterial diseases. We report on 3 patients who underwent mechanical embolectomy using a distal embolic protection device (EPD). All patients showed angiographic evidence of distal embolism, which occurred during lower extremity limb salvage endovascular procedures. After embolectomy, all had complete recanalization of the involved vessel on completion angiogram, and none had any device-related complications or adverse outcomes from the embolization. This initial experience suggests that EPD can be used for both the prevention and treatment of intraoperative distal embolization during endovascular intervention of lower extremity arterial disease.

Iliac vein aneurysms associated with May-Thurner anatomy.

A 61-year-old woman with May-Thurner anatomy status post recent hysterectomy was found to have two iliac vein aneurysms on postoperative magnetic resonance imaging. Transfemoral venography showed the venous aneurysms received retrograde flow from the left internal iliac vein and the left common iliac vein (CIV) was compressed by the right common iliac artery. Both aneurysms were coil embolized and a left CIV stent was placed. Our initial experience suggests that iliac vein aneurysms may be caused by CIV compression and an endovascular approach is safe and effective to treat both lesions.

Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells.

Nitric oxide (NO) is thought to play an important role as an inhibitor of vascular cell proliferation, motility, and neointima formation. This effect is mediated, in part, via the upregulation of protein tyrosine phosphatase (PTP)1B. Conversely, studies have reported that in presumably hyperinsulinemic mice fed a high-fat diet, NO enhances vascular remodeling, whereas a deficit of NO attenuates vascular remodeling. We have reported that in differentiated cultured smooth muscle cells treated with insulin, NO induces a motogenic effect that is dependent on Src homology-2 domain PTP 2 (SHP2) upregulation. In the present study, we describe novel mechanisms relevant to the motogenic effect of NO. Treatment of cultured cells with the selective angiontensin type 1 receptor antagonist losartan, but not with the selective angiotensin type 2 receptor antagonist PD-123319, blocked the comotogenic capacity of NO and insulin. Insulin and NO increased the secretion of ANG II into the culture media by 2- and 2.5-fold (P < 0.05), respectively, whereas treatment of cells with ANG II uncovered the motogenic effect of NO (1.4-fold above control, P < 0.05) and decreased the levels of PTP1B to 45% of control (P < 0.05). Suppression of PTP1B function was sufficient to uncover the motogenic effect of NO. The capacity of insulin to suppress PTP1B activity was blocked by losartan, implicating ANG II function in mediating this effect. Both insulin and ANG II induced the upregulation of phosphatidyl inositol 3-kinase (PI3K)-δ by two- to threefold (P < 0.05), and this effect was both necessary and sufficient to uncover NO-induced motogenesis. Finally, suppression of PTP1B function potentiated, whereas overexpression of PTP1B inhibited, SHP2-induced motogenesis. These results support the hypothesis that the comotogenic effect of insulin and NO occurs via an ANG II-mediated effect involving the suppression of PTP1B and upregulation of PI3K-δ and SHP2.

Suppression of PKG by PDGF or nitric oxide in differentiated aortic smooth muscle cells: obligatory role of protein tyrosine phosphatase 1B.

Treatment of aortic smooth muscle cells with PDGF induces the upregulation of protein tyrosine phosphatase 1B (PTP1B). PTP1B, in turn, decreases the function of several growth factor receptors, thus completing a negative feedback loop. Studies have reported that PDGF induces the downregulation of PKG as part of a repertoire of dedifferentiation of vascular smooth muscle cells. Other studies have reported that chronic nitric oxide (NO) treatment also induces the downregulation of PKG. In the present study, we tested the hypothesis that the downregulation of PKG by PDGF or NO in differentiated rat aortic smooth muscle cells can be attributed to the upregulation of PTP1B. We found that treatment with PDGF or NO induced an upregulation of PTP1B levels. Overexpression of PTP1B induced a marked downregulation of PKG mRNA and protein levels, whereas the expression of dominant negative PTP1B or short interfering RNA directed against PTP1B blocked the capacity of PDGF or NO to decrease PKG levels. We conclude that the upregulation of PTP1B by PDGF or NO is both necessary and sufficient to induce the downregulation of PKG via an effect on PKG mRNA levels.

Gastrointestinal perforation in a critically ill patient with COVID-19 pneumonia.

Gastrointestinal complications in critically ill patients during the COVID-19 pandemic pose a diagnostic and treatment dilemma. We present a case of a 74-year-old male who was brought to our emergency department with worsening shortness of breath, fever, and dry cough and was found to have COVID-19 pneumonia. Early in his hospital course, he was admitted to the intensive care unit, and was found to have significant abdominal distension with large amounts of simple fluid on bedside ultrasound. Bedside paracentesis returned succus and enteric feeds, and a methylene blue test confirmed a likely gastrointestinal perforation. The patients' family refused surgical intervention and the patient underwent bedside drainage. This case represents several critical dilemmas clinicians faced during the recent surge of the COVID-19 pandemic.

Iliac venous stenting for outflow obstruction does not significantly change the quality of life of patients with severe chronic venous insufficiency.

PURPOSE: Percutaneous endovenous iliac stenting has emerged as a new modality in the treatment of advanced chronic venous insufficiency with outflow obstruction. However, the effect of this intervention on the quality of life remains unclear. We examined the impact of iliac venous stenting for outflow obstruction as compared to conservative medical management on the quality of life in severe chronic venous insufficiency patients. METHODS: Medical records of all patients with CEAP class 5 and 6 disease (N = 172) who underwent ilio-caval venography with intravascular ultrasonography (IVUS) at a single institution over a seven-year period, were reviewed for this case-control study. Quality of life evaluation was performed utilizing the Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ-20) one year after the index procedure. RESULTS: Of the 172 severe chronic venous insufficiency patients, 109 were stented and 63 patients were treated medically based on their venography and IVUS results. The indication for stenting was confirmation of IVUS determined surface area or diameter outflow stenosis of greater than 50% within the common or external iliac venous systems. Eighty patients (47%) responded with completed CIVIQ-20 questionnaires for analysis. Of these, 47 were from the stented group and 33 from the non-stented group. At least moderate persistent pain or discomfort post-procedure was reported by 20 (43%) stented group patients and 19 (58%) non-stented group patients. Scores for all the other criteria in the CIVIQ-20 were similar between the groups. The mean total CIVIQ-20 score was 45.23 and 47.13, respectively, in stented group and non-stented group patients. (p = 0.678). CONCLUSION: There was no significant difference in the quality of life reported by CEAP 5 and 6 patients who underwent iliac venous stenting versus those who were treated medically for presumed iliac outflow obstruction. Prospective studies are needed to determine the true value of iliac venous stenting based on IVUS criteria in the management advanced chronic venous insufficiency.

Counter-regulatory function of protein tyrosine phosphatase 1B in platelet-derived growth factor- or fibroblast growth factor-induced motility and proliferation of cultured smooth muscle cells and in neointima formation.

OBJECTIVE: We have previously reported that vascular injury or treatment of cultured vascular smooth muscle cells with platelet-derived growth factor-BB (PDGF-BB) or fibroblast growth factor-2 (FGF2) increases the levels of protein tyrosine phosphatase (PTP)1B. The current study was designed to test the hypothesis that PTP1B attenuates PDGF- or FGF-induced motility and proliferation of cultured cells, as well as neointima formation in injured rat carotid arteries. METHODS AND RESULTS: Treatment of cultured cells with adenovirus expressing PTP1B decreased PDGF-BB- or FGF2-induced cell motility and blocked PDGF-BB- or FGF2-induced proliferation, whereas expression of dominant negative PTP1B (C215S-PTP1B) uncovered the motogenic effect of subthreshold levels of PDGF-BB or FGF2, increased neointimal and medial cell proliferation, and induced neointimal enlargement after balloon injury. The inhibitory effect of PTP1B directed against PDGF in cultured cells was associated with dephosphorylation of the PDGFbeta receptor. CONCLUSIONS: PTP1B suppresses cell proliferation and motility in cultured smooth muscle cells treated with PDGF-BB or FGF2, and the phosphatase plays a counter-regulatory role in vascular injury-induced cell proliferation and neointima formation. Taken together with previous studies indicating increased PTP1B levels in cells treated with growth factors, the current findings are the first to report the existence of an inhibitory feedback loop involving PDGF or FGF, and PTP1B in blood vessels.

Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery.

We tested the hypothesis that hyperinsulinemia induces the suppression of protein tyrosine phosphatase 1B (PTP1B) function, leading to enhanced PDGF receptor (PDGFR) signaling and neointimal hyperplasia. Rats were implanted with insulin-releasing pellets or sham pellets. Blood glucose levels, insulin levels, food and water intake, body weights, and blood pressures were measured. Neointimal hyperplasia was assessed by computerized morphometry 14 days after carotid balloon injury. PTP1B protein expression in injured arteries was determined via Western blot analysis, whereas PTP1B activity was determined via an immunophosphatase assay. Serum insulin levels were two- to threefold greater in hyperinsulinemic rats, whereas systolic blood pressures, food and water intake, serum triglyceride levels, plasma cortisol levels, and urinary catecholamine levels were not affected. Fourteen days after injury, neointima-to-media area ratios were 0.89 +/- 0.23 and 1.35 +/- 0.22 in control and hyperinsulinemic rats, respectively (P < 0.01). PTP1B protein levels and total PTP1B activity in injured carotid arteries from the insulin-treated group were significantly decreased 7 or 14 days after injury, whereas PTP1B specific activity was decreased only 14 days after injury. These findings were associated with decreased PTP1B mRNA levels and increased PDGFR tyrosyl phosphorylation in insulin-treated rats. These observations support the hypothesis that hyperinsulinemia induces the suppression of PTP1B function, leading to enhanced PDGFR signaling and neointimal hyperplasia.

Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B.

Hyperinsulinemia plays a major role in the pathogenesis of vascular disease. Restenosis occurs at an accelerated rate in hyperinsulinemia and is dependent on increased vascular smooth muscle cell movement from media to neointima. PDGF plays a critical role in mediating neointima formation in models of vascular injury. We have reported that PDGF increases the levels of protein tyrosine phosphatase PTP1B and that PTP1B suppresses PDGF-induced motility in cultured cells and that it attenuates neointima formation in injured carotid arteries. Others have reported that insulin enhances the mitogenic and motogenic effects of PDGF in cultured smooth muscle cells and that hyperinsulinemia promotes vascular remodeling. In the present study, we tested the hypothesis that insulin amplifies PDGF-induced cell motility by suppressing the expression and function of PTP1B. We found that chronic but not acute treatment of cells with insulin enhances PDGF-induced motility in differentiated cultured primary rat aortic smooth muscle cells and that it suppresses PDGF-induced upregulation of PTP1B protein. Moreover, insulin suppresses PDGF-induced upregulation of PTP1B mRNA levels, PTP1B enzyme activity, and binding of PTP1B to the PDGF receptor-beta, and it enhances PDGF-induced PDGF receptor phosphotyrosylation. Treatment with insulin induces time-dependent upregulation of phosphatidylinositol 3-kinase (PI3-kinase)-delta and activation of Akt, an enzyme downstream of PI3-kinase. Finally, inhibition of PI3-kinase activity, or its function, by pharmacological or genetic means rescues PTP1B activity in insulin-treated cells. These observations uncover novel mechanisms that explain how insulin amplifies the motogenic capacity of the pivotal growth factor PDGF.