Iliac artery-enteric fistulas following failed pancreatic transplant.

Arterial-enteric fistulas occur from a multitude of causes, especially following surgical manipulation of vasculature. The development of an iliac artery-enteric fistula (IEF) occurs rarely in patients with failed pancreatic transplants. IEFs warrant urgent intervention due to the high mortality from hemorrhagic and septic shock. The diagnosis can be delayed by a lack of suspicion, the low sensitivity of diagnostic tests, and the nonspecific signs of fistulas on computed tomography. The management of IEFs is adapted from guidelines for arterial-enteric fistulas of other causes, with little consensus on ideal vascular reconstruction and postoperative antimicrobial management. The outcomes are limited to the short-term results from case reports and case series. We report two cases of IEFs in patients with a history of simultaneous pancreatic kidney transplant. Our patients underwent successful resolution of gastrointestinal bleeding and sepsis, with definitive management of fistula resection and interposition iliac artery bypass. The index of suspicion for IEFs should be high, and they should be considered as a source of anemia or gastrointestinal bleeding of an unknown source in patients with failed pancreatic transplant. Definitive management should be pursued in patients who can tolerate fistula resection, allograft explant, and arterial reconstruction.

Female gender increases risk of stroke and readmission after carotid endarterectomy and carotid artery stenting.

OBJECTIVE: Carotid endarterectomy (CEA) has historically demonstrated a higher rate of perioperative adverse events for female patients. However, recent evidence suggests similar outcomes for CEA between genders. In contrast, fewer studies have examined gender in carotid artery stenting (CAS). Using contemporary data from the American College of Surgeons National Surgical Quality Improvement Program database, we aim to determine if gender impacts differences in postoperative complications in patients who undergo CEA or CAS. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2017 using Current Procedural Terminology and International Classification of Diseases codes for retrospective review. Patients with carotid intervention (CEA or CAS) were stratified into asymptomatic vs symptomatic cohorts to determine the effect of gender on 30-day postoperative outcomes. Symptomatic patients were defined as those with perioperative transient cerebral ischemic attack or stenosis of carotid artery with cerebral infarction. Descriptive statistics were calculated. Risk-adjusted odds of 30-day postoperative outcomes were calculated using multivariate regression analysis with fixed effects for age, race, and comorbidities. RESULTS: There were 106,568 patients with CEA or CAS (104,412 CEA and 2156 CAS). The average age was 70.9 years, and female patients accounted for 39.9% of the population. For asymptomatic patients that underwent CEA or CAS, female gender was associated with significantly higher rates of cerebrovascular accident (CVA)/stroke (13%; P = .005), readmission (10%; P = .004), bleeding complication (32%; P = .001), and urinary tract infection (54%; P = .001), as well as less infection (26%; P = .001). In the symptomatic cohort, female gender was associated with significantly higher rates of CVA/stroke (32%; P = .034), bleeding complication (203%; P = .001), and urinary tract infection (70%; P = .011), whereas female gender was associated with a lower rate of pneumonia (39%; P = .039). Subset analysis found that, compared with male patients, female patients <75 years old have an increased rate of CVA/stroke (21%; P = .001) and readmission (15%; P < .001), whereas female patients ≥75 years old did not. In asymptomatic and symptomatic patients that underwent CEA, female gender was associated with significantly higher rates of CVA/stroke (13%; P = .006 and 31%; P = .044, respectively), but this finding was not present in patients undergoing CAS. CONCLUSIONS: In patients undergoing carotid intervention, female gender was associated with significantly increased rates of postoperative CVA/stroke in the asymptomatic and symptomatic cohorts as well as readmission in the asymptomatic cohort. Female gender was associated with higher rates of CVA/stroke following CEA, but not CAS. We recommend that randomized control trials ensure adequate representation of female patients to better understand gender-based disparities in carotid intervention.

Medical therapy does not confer stroke prevention for all patients: identification of high-risk patients with asymptomatic carotid stenosis is still needed.

BACKGROUND: Recent advances in best medical therapy (BMT) has been associated with reduced risk of stroke similar to that observed following surgical carotid revascularization (CR). Thus, it remains uncertain which subset(s) of patients would benefit from prophylactic CR+BMT for asymptomatic carotid stenosis (ACS) over BMT alone. The purpose of this study was to analyze the contemporary experience in the management of >70% ACS in an academic institution, to compare the short- and long-term outcomes of BMT alone against CR+BMT, and to identify risk factors for the development of future cerebrovascular events. METHODS: A retrospective review of all patients with severe ACS between January 2005 and December 2012 at Loyola University Medical Center and its affiliated Edward Hines Jr. Veterans Administration Hospital was conducted. Baseline patient characteristics, medications, and follow-up data were collected from electronic medical records, and treatment outcomes were compared. The random forest method was performed to select potential important variables for the development of late stroke. The recursive partitioning regression analysis (RPRA) was performed to identify the patient subgroup at increased risk of future stroke. RESULTS: Of 409 patients identified; 247 were treated with CR and 162 with BMT. Between these groups with CR+BMT and BMT alone, the mean age was 69.1±8.2 versus 75.5±9.0, respectively (P<0.01). Mean follow-up was 60.7±37.5 months. Early (30-day) outcomes of stroke, acute myocardial infarction or mortality did not differ between the treatment modalities (2.0% CR vs. 0.6% BMT, P=0.41). Probability of freedom from ipsilateral stroke, and any stroke at 1- and 5-year follow-up were also comparable between CR+BMT and BMT alone. However, random forest method and RPRA demonstrated that patients with history of diabetes and remote stroke treated with BMT alone were at a high risk for future stroke (36.4% in total, 7.2% per year). The diabetics with contralateral carotid stenosis >50% who are active smokers are at the highest risk for stroke after CR (20.0% in total, 4.0% per year). CONCLUSIONS: Prophylactic CR+BMT does not provide overall late stroke prevention compared with BMT alone. Diabetics with a history of stroke, in particular, are at an increased risk of stroke despite BMT. Timely CR+BMT for high-risk patients is still indicated.

Delineating the durability outcome differences after saphenous ablation with laser versus radiofrequency.

OBJECTIVE: The mechanism of delivering thermal energy to the vein wall differs between endovenous laser ablation (EVLA) and radiofrequency ablation (RFA). Different mechanisms of ablation may have different effects on the durability of these procedures typically performed for saphenous vein insufficiency. Whether there is a difference in long-term durability outcomes between these two techniques remains uncertain. This study aimed to delineate the durability outcome differences in terms of recurrence rate and pattern. METHODS: A retrospective review identified 270 consecutive patients who underwent saphenous ablation using EVLA or RFA between July 2013 and October 2016. The primary end points were clinical symptom recurrence and anatomic recurrence of reflux. RESULTS: Overall, 343 limbs were included in the study; 246 limbs (183 patients) underwent EVLA and 97 limbs (87 patients) underwent RFA. The mean follow-up time was 112 days for EVLA (range, 2-1153 days) and 106 days for RFA (range, 3-735 days; P = .786). No significant differences were observed between the groups with respect to demographic data, Clinical, Etiological, Anatomical, Pathophysiological classification, or ratio of great saphenous vein to small saphenous vein treated. The mean time to recurrence of symptoms was 219 days longer with EVLA (n = 8; mean, 774 days; range, 187-1042 days) than RFA (n = 4; mean 555 days; range, 341-616 days). Kaplan-Meier estimates for 1- and 3-year freedom from clinical recurrence were 100% and 96% for EVLA and 97% and 93% for RFA, respectively. There was no difference between the two groups (log rank, P = .0666). In cases with recurrent reflux documented on duplex (four in the EVLA group and three in the RFA group), the thigh segment was the most frequently involved site (75% in EVLA, 67% in RFA). Same site recanalization was significantly less frequent in EVLA (0.82% in EVLA vs 2.06% in RFA; P = .0388). New areas of reflux developed at a similar rate between the groups, in 0.82% of EVLA limbs in the anterior accessory saphenous vein and the calf great saphenous vein, and in 1.03% of RFA limbs in the anterior accessory saphenous vein (P = .8436). CONCLUSIONS: The results of our study suggest that the outcomes of EVLA and RFA performed for saphenous vein insufficiency may differ in the long term. The clinical recurrence rates are similar, but the anatomic recurrence patterns may differ, with more frequent treated site recurrence in the RFA group.

Long-Term Hemodynamic Effects After Carotid Artery Revascularization.

OBJECTIVE: The baroreceptor at the carotid body plays an important role in hemodynamic autoregulation. Manipulation of the baroreceptor during carotid endarterectomy (CEA) or radial force from carotid artery angioplasty and/or stenting (CAS) may cause both intraoperative and postoperative hemodynamic instability. The purpose of this study is to evaluate the long-term effects of CEA and CAS on blood pressure (BP), heart rate (HR), and subsequent changes on antihypertensive medications. METHODS: A retrospective chart review was performed to identify patients who underwent CEA or CAS between 2009 and 2015 at a single tertiary care institution. Baseline demographics and comorbidities were recorded. Operative details of the carotid artery endarterectomy and the use of balloon angioplasty during the CAS were analyzed. Hemodynamic parameters such as BP, HR, and antihypertensive medication requirement were evaluated at 3, 6, 12, 24, and 36 months. RESULTS: A total of 289 patients were identified. The average age was 70.6 years old, and males constituted 64.0%. All patients had moderate (>50%) to severe (>70%) carotid stenosis. Of those, 111 (40.5%) patients were symptomatic. Systolic BP (mm Hg) of CAS and CEA were similar over the entire follow-up period. Heart rate (beats/min) remained stable postoperatively. A reduced number of antihypertensive medications was observed in the CAS cohort during the first postoperative year when compared to the preoperative baseline: 2.03 at preop, 1.77 ( P < .01) at 3 months, 1.78 ( P = .02) at 6 months, 1.77 ( P = .02) at 12 months, 1.86 ( P = .09) at 24 months, and 2.03 ( P = =.50) at 36 months. Logistic regression analysis identified that CAS (odds ratio [OR]: 2.52, confidence interval [CI]: 1.09-5.83) and multiple (>2) antihypertensive medication use at baseline (OR: 5.89, CI: 2.62-13.26) were predictors for a reduction in the number of antihypertensive medications following carotid revascularization. CONCLUSION: Surgical intervention for carotid stenosis poses a risk of postoperative hemodynamic dysregulation. Although postoperative BP and HR remained relatively stable after both CAS and CEA, the number of postoperative antihypertensive medications was reduced in the CAS cohort for the first postoperative year when compared to baseline. Patients with multiple antihypertensive agents undergoing CAS should have close postoperative BP monitoring and should be monitored for a possible reduction in their antihypertensive medication regimen.

Through-knee amputation is a feasible alternative to above-knee amputation.

OBJECTIVE: Through-knee amputation (TKA) is a rare amputation performed in <2% of all major lower extremity amputations in the United States. Despite biomechanical benefits and improved rehabilitation compared with above-knee amputation (AKA), TKA has largely been abandoned by vascular surgeons because of concerns for poor wound healing. The purpose of this study was to evaluate surgical outcomes of TKA. METHODS: The American College of Surgeons National Surgical Quality Improvement Program between 2005 and 2012 was queried using Current Procedural Terminology codes indicating AKA and TKA. Baseline characteristics were reviewed, and logistic regression analysis was performed to identify predictors of 30-day mortality. Propensity score matching was used to balance comorbidities between AKA and TKA. Operative variables and postoperative complications were compared between the groups. RESULTS: A total of 7469 AKA and 251 TKA patients were identified among 15,932 major lower extremity amputations. Baseline characteristics were examined. White race, chronic obstructive pulmonary disease, dyspnea, emergent operation, steroid use, myocardial infarction, congestive heart failure, high American Society of Anesthesiologists score, old age, preoperative sepsis or septic shock, and dialysis dependency were associated with increased 30-day mortality. Independent lifestyle and smoking (within 1 year) were protective against early death. Baseline comorbidities were not statistically significant after 1:1 propensity score matching. Operative outcomes were similar in both groups (AKA vs TKA). Wound infection (7.2% vs 11.2%; P = .16), dehiscence rate (1.2% vs 0.8%; P = 1.0), and 30-day mortality (9.6% vs 11.2%; P = .66) were comparable. Other outcome parameters, including cardiopulmonary and genitourinary complications, were similar except for a higher likelihood of return to the operating room in the TKA group (27.9% vs 12.4%; P < .01). Postoperative mortality was not associated with TKA (P = .77) or reoperation (P = .42), but it was associated with the patients' physiologic conditions (dyspnea, sepsis, emergent operation, high American Society of Anesthesiologists score, and dependent lifestyle). Predictors of reoperation were contaminated wound (hazard ratio [HR], 2.19; confidence interval [CI], 1.17-3.23; P = .015), sepsis or septic shock (HR, 2.63; CI, 1.37-5.05; P = .004), chronic obstructive pulmonary disease (HR, 2.81; CI, 1.23-6.42; P = .014), and wound infection (HR, 4.91; CI, 2.06-11.70; P < .001). Presence of peripheral vascular disease was not associated with post-TKA reoperation (P = .073). CONCLUSIONS: TKA demonstrated similar postoperative morbidity and mortality compared with AKA. Wound infection and risk of dehiscence were equivalent. TKA did demonstrate a higher rate of reoperation; however, neither TKA nor reoperation predicted postoperative mortality. Patients in stable physiologic condition without active infection can safely undergo elective TKA to maximize rehabilitation potential.

Iliac Stent Migration during Thoracic Endovascular Aortic Aneurysm Repair Resulting in Functional Coarctation.

Iliac arterial disease, unfavorable anatomy, and prior stenting all pose challenges to access in endovascular abdominal aortic repair (EVAR) and thoracic aortic repair (TEVAR). Iliac access injury during T/EVAR may lead to rupture, dissection, thrombosis, or distal ischemia. Some have advocated iliac stent prior to T/EVAR in patients with suboptimal iliac access. The rate of complication and iliac stent migration during subsequent T/EVAR is undocumented. This case report describes a unique instance of self-expanding iliac stent migration during TEVAR which pinched the thoracic aortic endograft causing functional aortic coarctation.

Period frequency of iliofemoral venous occlusive disease by Doppler ultrasound and corresponding treatment in a tertiary care facility.

BACKGROUND: Patients with iliofemoral deep venous thrombosis (DVT) are at highest risk for the postthrombotic morbidity including all aspects of the postthrombotic syndrome. Invasive therapies such as catheter-directed thrombolysis (CDT) and/or mechanical thrombectomy with or without angioplasty and stenting and in some cases open operative thrombectomy improves venous patency, venous valve function, and quality of life in patients with acute iliofemoral DVT. What is the current frequency of acute iliofemoral DVT and how aggressively is it being treated? We hypothesize that the 10-year period frequency of iliofemoral DVT among acute DVT cases is greater than previously reported. Further, we hypothesize that thrombus removal to treat acute iliofemoral DVT is little utilized in current practice. METHODS: Indiana University (IU) vascular laboratory records from January 1, 1998 to December 31, 2008 were searched by CPT code for venous Doppler ultrasound study (n=7240). A random sample based on the IU medical record number of lower extremity Doppler studies was then selected (n=1020) for retrospective chart review. Corresponding clinical information was gathered from the patients' electronic medical record. RESULTS: Acute DVT occurred in 6.8%, and chronic DVT in 8.8% of patients studied (25.7% inpatient, 61.7% female; median age, 56.0 years [range, 4-91 years, 1.1% less than 16 years]). History of previous DVT (33.3%) and cancer (30.4%) were the most common risk factors in patients with acute DVT. Iliofemoral DVT defined as having an iliac or common femoral vein component was identified in 49.3% of acute DVT and in 36.0% of chronic DVT. CDT was utilized in 14.3% and mechanical thrombectomy in 4.8% of acute iliofemoral DVT, and was never used with distal DVT. Warfarin anticoagulation+unfractionated heparin or low-molecular-weight heparin overlap was the most common treatment for acute iliofemoral DVT (100.0%). In 2008, the referral base of our laboratory increased significantly. Acute DVT occurred significantly less often during the 1-year period 2008 (5.3%) than the 10-year period 1998-2007 (7.6%), but iliofemoral+common femoral DVT as a component of acute DVT did not differ significantly. CONCLUSIONS: Iliofemoral DVT may be more frequent than previously reported and represents a significant portion of acute DVT. Current recommendations of acute thrombus removal for the treatment of iliofemoral DVT is underutilized suggesting that perhaps greater education of clinicians and patients regarding invasive therapy for iliofemoral DVT is required.

Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury.

Toll-like receptors (TLRs) play a key role in innate immune defenses. After activation by foreign pathogens or host-derived molecules, TLRs signal via overlapping or distinct signaling cascades and eventually induce numerous genes involved in a variety of cellular responses. A growing body of evidence suggests that TLR signaling also plays an important role in cardiac ischemia/reperfusion injury. We review our current understanding of the TLR signaling pathways and their roles in the pathophysiology of cardiac ischemia/reperfusion injury, as well as discuss several mechanisms for TLR activation and regulation.

TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia.

Mesenchymal stem cells (MSCs) may improve myocardial function after I/R injury via paracrine effects, including the release of growth factors. Genetic modification of MSCs is an appealing method to enhance MSC paracrine action. Ablation of TNF receptor 1 (TNFR1), but not TNFR2, increases MSC growth factor production. In this study, therefore, we hypothesized that 1) preischemic infusion of MSCs derived from TNFR1 knockout (TNFR1KO) mice will further improve myocardial functional recovery and that 2) TNFR2KO and TNFR1/2KO will abolish MSC-mediated protection in the heart after I/R injury. Mesenchymal stem cells were harvested from adult C57BL/6J (wild-type 1 [WT1]), B6129SF2 (WT2), TNFR1KO, TNFR2KO, and TNFR1/2KO mice. Mesenchymal stem cells were cultured and adopted for experiments after passage 3. Isolated hearts from adult male Sprague-Dawley rats were subjected to 25 min of ischemia and 40 min of reperfusion (Langendorff model), during which time myocardial function was continuously monitored. Before ischemia, 1 mL of vehicle or 1 x 10(6) MSCs/mL from WT1, WT2, TNFR1KO, TNFR2KO, or TNFR1/2KO was infused into the hearts (n = 4-6 per group). Treatment of C57BL/6J mice with MSC before ischemia significantly increased cardiac function. TNFR1 knockout MSCs demonstrated greater cardioprotection when compared with WT MSCs after I/R, as exhibited by improved left ventricular developed pressure and +/-dp/dt. However, infusion of MSCs from TNFR2KO and TNFR1/2KO mice either offered no benefit or decreased MSC-mediated cardiac functional recovery in response to I/R when compared with WT MSCs. TNFR1 signaling may damage MSC paracrine effects and decrease MSC-mediated cardioprotection, whereas TNFR2 likely mediates beneficial effects in MSCs.

Angiopoietin-1 in the treatment of ischemia and sepsis.

Angiogenic factors have been the focus of a great deal of research for the treatment of ischemic diseases. Described just more than 10 years ago, angiopoietin 1 (Ang-1) has shown promising results in I/R models. Angiopoietin 1 is essential for both embryonic vasculogenesis and adult angiogenesis. Because of its role in maturation of vessels, it seems well suited to complement the angiogenic factor vascular endothelial growth factor (VEGF), which has been shown to induce vascular budding but in isolation produces nonfunctional vessels. This review will focus on (1) Ang-1 and its receptor, Tie-2, and the resultant intracellular signaling cascade; (2) the complex relationship of Ang-1 and VEGF; (3) the results of Ang-1 in I/R and sepsis models; (4) the results of combination (Ang-1 and VEGF) therapies in I/R and sepsis models; and (5) delivery mechanisms for angiogenic factors to ischemic heart.

Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia.

BACKGROUND: Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Our lab has recently shown that gender differences exist in mesenchymal stem cell (MSC) paracrine function. Estrogen is implicated in the cardioprotection found in females. It remains unknown whether 17beta-estradiol (E2) affects MSC paracrine function and whether E2-treated MSCs may better protect injured cardiac tissue. We hypothesize that E2-exposed MSCs infused into hearts prior to ischemia may demonstrate increased vascular endothelial growth factor (VEGF) production and greater protection of myocardial function compared to untreated MSCs. MATERIALS AND METHODS: Untreated and E2-treated MSCs were isolated, cultured, and plated and supernatants were harvested for VEGF assay (enzyme-linked immunosorbent assay). Adult male Sprague-Dawley rat hearts (n = 13) were isolated and perfused via Langendorff model and subjected to 15 min equilibration, 25 min warm global ischemia, and 40 min reperfusion. Hearts were randomly assigned to perfusate vehicle, untreated male MSC, or E2-treated male MSC. Transcoronary delivery of 1 million MSCs was performed immediately prior to ischemia in experimental hearts. RESULTS: E2-treated MSCs provoked significantly more VEGF production than untreated MSCs (933.2 +/- 64.9 versus 595.8 +/- 10.7 pg/mL). Postischemic recovery of left ventricular developed pressure was significantly greater in hearts infused with E2-treated MSCs (66.9 +/- 3.3%) than untreated MSCs (48.7 +/- 3.7%) and vehicle (28.9 +/- 4.6%) at end reperfusion. There was also greater recovery of the end diastolic pressure with E2-treated MSCs than untreated MSCs and vehicle. CONCLUSIONS: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.

Are neonatal stem cells as effective as adult stem cells in providing ischemic protection?

BACKGROUND: Bone marrow stem cells (BMSCs) may be a novel treatment modality for organ ischemia, possibly through beneficial paracrine mechanisms. However, stem cells from older hosts exhibit decreased function during stress. We therefore hypothesized that (1) BMSCs derived from neonatal hosts would provide protection to ischemic myocardium, and (2) neonatal stem cells would enhance postischemic myocardial recovery above that seen with adult stem cell therapy. MATERIALS AND METHODS: Female adult Sprague Dawley rat hearts were subjected to an ischemia/reperfusion protocol via Langendorff isolated heart preparation (15 min equilibration, 25 min ischemia, and 60 min reperfusion). BMSCs were harvested from adult and neonatal mice and cultured through several passages under normal conditions (37 degrees C, 5% CO(2)/air). Immediately prior to ischemia, 1 million adult or neonatal BMSCs were infused into the coronary circulation. Cardiac functional parameters were continuously recorded. RESULTS: Pretreatment with adult BMSCs significantly increased postischemic myocardial recovery as noted by improved left ventricular developed pressure, end diastolic pressure, contractility, and rate of relaxation. Neonatal stem cells, however, did not cause any noticeable improvement in myocardial functional parameters following ischemia. CONCLUSION: Neonatal and adult BMSCs are distinctly different in the degree of beneficial tissue protection that they can provide. The data herein suggests that a critical age exists as to when stem cells become fully activated to provide their beneficial protective properties. Defining the genes that initiate these protective properties may allow for genetic amplification of beneficial signals, and the generation of "super stem cells" that provide maximum protection to ischemic tissues.

beta-Blockers in sepsis: reexamining the evidence.

Sepsis remains the leading cause for noncardiac intensive care unit deaths in the United States. Despite recent advances in the treatment of this devastating condition, mortality and morbidity remain unacceptably high. Sepsis is characterized by a multitude of pathophysiological changes that include inflammation, metabolic derangements, hemodynamic alterations, and multiorgan dysfunction. Unfortunately, several studies of treatment modalities aimed at correcting one or more of the underlying derangements have led to disappointing results. New treatment modalities are needed. beta-Receptor blockers have long been used for a variety of conditions such as coronary artery disease, congestive heart failure, and arterial hypertension. Recent data suggest that beta-blocker effects on metabolism, glucose homeostasis, cytokine expression, and myocardial function may be beneficial in the setting of sepsis. Although treating a potentially hypotensive condition with a drug with antihypertensive properties may initially seem counterintuitive, the metabolic and immunomodulatory properties of beta-blockers may be of benefit. It is the purpose of this review to discuss the effects of beta-blockers on the following: (1) metabolism, (2) glucose regulation, (3) the inflammatory response, (4) cardiac function, and (5) mortality in sepsis.

Mechanisms of sex differences in TNFR2-mediated cardioprotection.

BACKGROUND: TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males. METHODS AND RESULTS: Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females. CONCLUSIONS: Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.

VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function.

Bone marrow mesenchymal stem cells (MSCs) may be a novel treatment modality for organ ischemia, possibly through the release of beneficial paracrine factors. However, an age threshold likely exists as to when MSCs gain their beneficial protective properties. We hypothesized that 1) VEGF would be a crucial stem cell paracrine mediator in providing postischemic myocardial protection and 2) small-interfering (si)RNA ablation of VEGF in adult MSCs (aMSCs) would equalize the differences observed between aMSC- and neonatal stem cell (nMSC)-mediated cardioprotection. Female adult Sprague-Dawley rat hearts were subjected to ischemia-reperfusion injury via Langendorff-isolated heart preparation (15 min equilibration, 25 min ischemia, and 60 min reperfusion). MSCs were harvested from adult and 2.5-wk-old neonatal mice and cultured under normal conditions. VEGF was knocked down in both cell lines by VEGF siRNA. Immediately before ischemia, one million aMSCs or nMSCs with or without VEGF knockdown were infused into the coronary circulation. The cardiac functional parameters were recorded. VEGF in cell supernatants was measured via ELISA. aMSCs produced significantly more VEGF than nMSCs and were noted to increase postischemic myocardial recovery compared with nMSCs. The knockdown of VEGF significantly decreased VEGF production in both cell lines, and the pretreatment of these cells impaired stem cell-mediated myocardial function. The knockdown of VEGF in adult stem cells equalized the myocardial functional differences observed between adult and neonatal stem cells. Therefore, VEGF is a critical paracrine mediator in facilitating postischemic myocardial recovery and likely plays a role in mediating the observed age threshold during stem cell therapy.

Stem cells as a potential future treatment of pediatric intestinal disorders.

All surgical disciplines encounter planned and unplanned ischemic events that may ultimately lead to cellular dysfunction and death. Stem cell therapy has shown promise for the treatment of a variety of ischemic and inflammatory disorders where tissue damage has occurred. As stem cells have proven beneficial in many disease processes, important opportunities in the future treatment of gastrointestinal disorders may exist. Therefore, this article will serve to review the different types of stem cells that may be applicable to the treatment of gastrointestinal disorders, review the mechanisms suggesting that stem cells may work for these conditions, discuss current practices for harvesting and purifying stem cells, and provide a concise summary of a few of the pediatric intestinal disorders that could be treated with cellular therapy.

Selective estrogen receptor-alpha and estrogen receptor-beta agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism.

Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-alpha or ER-beta, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-alpha agonist propylpyrazole triol (PPT) and/or the selective ER-beta agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings (n = 3-10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10(-8)M - 10(-5)M) and hypoxia (Po(2) 35-45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10(-8)M - 10(-4)M) and sodium nitroprusside (10(-9)M - 10(-5)M). PPT or DPN (10(-9)M - 5 x 10(-5)M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) (10(-4)M). Selective ER-alpha activation (PPT, 5 x 10(-5)M) rapidly (<20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by l-NAME. In contrast, selective ER-beta activation (DPN, 5 x 10(-5)M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). l-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER-alpha and ER-beta decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-alpha primarily modulating phenylephrine-induced vasoconstriction, and ER-beta inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-alpha and ER-beta.