Thoracic Stent Grafts Induce Persistent Aortic Remodeling in Aortic Coarctation.

BACKGROUND: This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation. METHODS: This is a retrospective study of 30 adult patients who underwent thoracic stent graft placement for aortic coarctation at our institution. Average age was 46.5 years, with 53.3% of patients presented with no prior treatment or repair for coarctation. Indications for repair included gradient ≥20 mm Hg with anatomic evidence of coarctation on imaging with left ventricular hypertrophy, pseudoaneurysm, aneurysm, refractory hypertension, or claudication. Stent grafts used for repair included MDT (Medtronic, Santa Rosa, CA) and GORE TAG (W. L. Gore & Associates, Flagstaff, AZ). RESULTS: Patients were observed for a median of 979 days, with one death during the study. All patients had complete resolution of symptoms with no recurrences. Thoracic endovascular aortic repair significantly reduced the gradient across the coarctation (P < 0.0001). Aortic coarctation diameter significantly increased at 30 days postoperatively and continued to increase up to 5 years posttreatment. At 3+ years, aortic remodeling was observed at the coarctation site and surrounding regions. At 30 days, systolic, diastolic, and mean arterial pressure were all reduced. Systolic and diastolic blood pressure and mean arterial pressure continued to significantly improve 1-year posttreatment. CONCLUSIONS: Stent grafts are a safe and effective treatment for aortic coarctation. We observed a clinically significant improvement in blood pressure and longitudinal aortic remodeling of the coarctation segment and the entire aorta that persisted more than more than 3 years.

Utilization of coronary computed tomography angiography and computed tomography-derived fractional flow reserve in a critical limb-threatening ischemia cohort.

Objective: Patients with peripheral arterial disease (PAD) have a significant risk of myocardial infarction and death secondary to concomitant coronary artery disease (CAD). This is particularly true in patients with critical limb-threatening ischemia (CLTI) who exceed a 20% mortality rate at 6 months despite standard treatment with risk factor modification. Although systematic preoperative coronary testing is not recommended for patients with PAD without cardiac symptoms, the clinical manifestations of CAD are often muted in patients with CLTI due to poor mobility and activity intolerance. Thus, the true incidence and impact of "silent" CAD in a CLTI cohort is unknown. This study aims to determine the prevalence of ischemia-producing coronary artery stenosis in a CLTI cohort using coronary computed tomography angiography (cCTA) and computed tomography (CT)-derived fractional flow reserve (FFRCT), a noninvasive imaging modality that has shown significant correlation to cardiac catheterization in the detection of clinically relevant coronary ischemia. Methods: Patients presenting with newly diagnosed CLTI at our institution from May 2020 to April 2021 were screened for underlying CAD. Included subjects had no known history of CAD, no cardiac symptoms, and no anginal equivalent complaints at presentation. Patients underwent cCTA and FFRCT evaluation and were classified by the anatomic location and severity of CAD. Significant coronary ischemia was defined as FFRCT ≤0.80 distal to a >30% coronary stenosis, and severe coronary ischemia was documented at FFRCT ≤0.75, consistent with established guidelines. Results: A total of 170 patients with CLTI were screened; 65 patients (38.2%) had no coronary symptoms and met all inclusion/exclusion criteria. Twenty-four patients (31.2%) completed cCTA and FFRCT evaluation. Forty-one patients have yet to complete testing secondary to socioeconomic factors (insurance denial, transportation inaccessibility, testing availability, etc). The mean age of included subjects was 65.4 ± 7.0 years, and 15 (62.5%) were male. Patients presented with ischemic rest pain (n = 7; 29.1%), minor tissue loss (n = 14; 58.3%) or major tissue loss (n = 3; 12.5%). Significant (≥50%) coronary artery stenosis was noted on cCTA in 19 of 24 patients (79%). Significant left main coronary artery stenosis was identified in two patients (10%). When analyzed with FFRCT, 17 patients (71%) had hemodynamically significant coronary ischemia (FFRCT ≤0.8), and 54% (n = 13) had lesion-specific severe coronary ischemia (FFRCT ≤0.75). The mean FFRCT in patients with coronary ischemia was 0.70 ± 0.07. Multi-vessel disease pattern was present in 53% (n = 9) of patients with significant coronary stenosis. Conclusions: The use of cCTA-derived fractional flow reserve demonstrates a significant percentage of patients with CLTI have silent (asymptomatic) coronary ischemia. More than one-half of these patients have lesion-specific severe ischemia, which may be associated with increased mortality when treated solely with risk factor modification. cCTA and FFRCT diagnosis of significant coronary ischemia has the potential to improve cardiac care, perioperative morbidity, and long-term survival curves of patients with CLTI. Systemic improvements in access to care will be needed to allow for broad application of these imaging assessments should they prove universally valuable. Additional study is required to determine the benefit of selective coronary revascularization in patients with CLTI.

Disparities in Outcomes Between Sexes in Type B Aortic Dissection Patients Treated with TEVAR.

BACKGROUND: To evaluate differences in presentation and outcomes between sexes in patients who underwent thoracic endovascular aortic repair for type B aortic dissection (TBAD). METHODS: Between January 1, 2012 and January 1, 2017 186 patients underwent thoracic endovascular aortic repair for TBAD at a single institution. Men (n = 112) and women (n = 74) were compared based on presenting demographics, comorbidities, and postoperative complications. Primary outcomes were survival and need for reintervention. RESULTS: Women were older (P = 0.04) and had a lower body mass index (P = 0.03). More women (F) presented with continued pain or refractory hypertension (51.0% F, 30.0% M), while more men (M) presented with acute complicated dissections (19.0% F, 39.0% M) (P = 0.008). At presentation, women had statistically higher relative rates of chronic obstructive pulmonary disease (P = 0.05), hyperlipidemia (P = 0.03), and smoking (P = 0.03). Significantly more women were on Medicare without Medicaid (55.0% F, 34.0% M), while men had private insurance (35.0% F, 13.0% M) (P = 0.005). There was no significant difference in blood pressure control at presentation, discharge, or at 30 days. When normalized by body surface area, women had larger ascending aortic diameters (19.2(3.10)F, 17.5(2.40)M, P = 0.0002), as well as proportionally larger true lumens at the left subclavian artery (14.9(2.90)F, 13.4(2.50)M, P = 0.0002), carina (12.6(5.80)F, 9.90(4.80)M, P = 0.0009), and celiac (10.5(4.50)F, 8.50(4.10)M, P = 0.006) levels, and at the largest point of dissection (11.6(6.50)F, 9.60(4.80)M, P = 0.04), as well as proportionately smaller false lumens at the carina (5.90(5.60)F, 9.30(6.10)M, P = 0.003). Despite not being statistically significant, women had lower rates of stroke (6.80% F, 8.00% M, P = 0.7) and acute kidney injury (5.40% F, 11.6% M, P = 0.2), as well fewer days in the intensive care unit (ICU) (3.20(4.30)F, 4.60(6.60)M, P = 0.2) and an overall shorter length of stay (6.80(6.70)F, 8.00(8.20)M, P = 0.5). Kaplan-Meier estimates for survival for women versus men were 96.0% vs. 92.0%, 90.0% vs. 79.0%, and 70.0% vs. 69.0% at 30 days, 1 year, and 3 years, respectively (P = 0.042). Kaplan-Meier estimates for freedom from reintervention for women versus men were 89.0% vs. 90.0%, 58.0% vs. 72.0%, and 48.0% vs. 58.0% at 30 days, 1 year, and 3 years, respectively (P = 0.13). CONCLUSIONS: Women present with TBAD at an older age, have more comorbidities, lower socioeconomic status, and have larger ascending aortic diameters for their size. Despite having less severe dissections as evidenced by smaller false lumens and wider true lumens, it does not appear that this correlates with improved outcomes for women when compared to men. It appears that this is one of the few, if not only, aortic pathologies that result in comparable outcomes between sexes.

Endovascular aortic repair in an asymptomatic COVID-19-positive patient with a symptomatic inflammatory abdominal aortic aneurysm.

In this report, we present the case of a COVID-19-positive patient whose symptomatic inflammatory abdominal aortic aneurysm was successfully treated with endovascular aortic repair at our institution. We discuss the reasoning behind the type of therapy used and the various lessons learned. Based on our experience with this patient, we recommend an endovascular approach for similar COVID-19 patients and suggest a prophylactic dose of enoxaparin (Lovenox; 40 mg daily) postoperatively for 14 days.

Clinical Experience with the Gore Hybrid Vascular Graft in Complex Revascularizations Demonstrates Safety and Efficacy.

BACKGROUND: Arterial revascularizations can present significant challenges when vessels are disadvantaged and advances in technology present the surgeon with innovative opportunities. A number of studies have used the GORE® Hybrid Vascular Graft (GHVG), and we have been using this device in arterial revascularizations since it came to market. The aim of this study is therefore to present a large single-center experience using the GHVG. This series presents patients with complex revascularizations in multiple vascular beds. METHODS: We retrospectively analyzed a single-center series of 43 patients who received a total of 56 GHVGs in complex revascularization procedures at Houston Methodist Hospital from March 2012 to April 2017. We excluded 5 patients (7 grafts in total) because of loss of follow-up. An additional 8 patients were excluded from the analysis (11 grafts in total) secondary to mortalities unrelated to their grafts (7 patients died during index hospitalization and 1 patient died shortly after discharge). RESULTS: Our results demonstrated an 18-month primary patency, assisted primary patency, and secondary patency of 82, 86, and 96%, respectively. These complex revascularizations included a total of 56 devices placed. GHVGs were placed in the external iliac artery (27/56), renal artery (12/56), common femoral artery (6/56), superficial femoral artery (4/56), common iliac artery (3/56), grafts (3/56), profunda femoris artery (1/56), and the superior mesenteric artery (1/56). Early mortality in patients (7/8) was because of the nature of their disease and not related to the surgical intervention. CONCLUSIONS: The GHVG has the ability to create a sutureless anastomosis in a disadvantaged vessel or to promote a potentially better outcome by either avoiding prolonged ischemia to visceral branches or avoiding extensive abdominal or retroperitoneal exposure in an iliofemoral bypass. These results demonstrate the value of the GHVG in complex revascularizations not amenable to traditional open surgical bypass. LEVEL OF EVIDENCE: IV.

Cocaine use is associated with worse outcomes in patients treated with thoracic endovascular repair for type B aortic dissection.

OBJECTIVE: To describe and compare the clinical and anatomical characteristics and outcomes of patients with and without known cocaine use who underwent thoracic endovascular repair for type B aortic dissections. METHODS: Between January 2012 and January 2017, 186 patients underwent thoracic endovascular repair for type B aortic dissection at our institution. Clinical data and anatomical characteristics were collected under an institutional review board-approved protocol. Survival, reintervention, complications, and characteristics of dissection were compared between patients with cocaine use (C+; n = 14) and those with no known cocaine use (C-; n = 172). RESULTS: Cocaine users were more likely to be young African American males who smoked. They tended to present with more extensive dissections as evidenced by larger false lumen diameters. They also had higher rates of endoleaks and more reinterventions. CONCLUSIONS: These results suggest that special care should be taken to provide close follow-up for these patients.

Retrograde type A dissection after thoracic endovascular aortic repair for type B aortic dissection.

BACKGROUND: The purpose of this study was to evaluate clinical, anatomic, and procedural characteristics of patients who developed retrograde type A dissection (RTAD) after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD). METHODS: Between January 2012 and January 2017, there were 186 patients who underwent TEVAR for TBAD at a multidisciplinary aortic center. Patients who developed RTAD after TEVAR (n = 15) were compared with those who did not (no-RTAD group, n = 171). Primary outcomes were survival and need for reintervention. RESULTS: The incidence of RTAD in our sample was 8% (n = 15). Kaplan-Meier estimates found that no-RTAD patients had better survival (P = .04). Survival rates at 30 days, 1 year, and 3 years were 93%, 60%, and 60% for RTAD patients and 94%, 87%, and 80% for no-RTAD patients. One RTAD was diagnosed intraoperatively, 5 were diagnosed within 30 days of the index procedure, 6 were diagnosed within 1 year, and 3 were diagnosed after 1 year. Reintervention for RTAD was undertaken in 10 of 15 patients, with a 50% survival rate after reintervention. Partial or complete false lumen thrombosis was more frequently present in RTAD patients (P = .03). RTAD patients more frequently presented with renal ischemia (P = .04). Most RTAD patients (93%, RTAD patients; 64%, no-RTAD patients; P = .02) had a proximal landing zone in zone 0, 1, or 2. Aortic diameter was more frequently ≥40 mm in the RTAD group (47%, RTAD patients; 21%, no-RTAD patients; P = .05). Patients with RTAD had stent grafts placed in the renovisceral arteries for complicated dissections, and this approached significance (P = .05). Three RTAD patients had a type II arch (20%) compared with 53 no-RTAD patients (31%; P = .6), but a comparison of type II arch with type I or type III found no statistical significance (P = .6). No correlations were found between ratio of descending to ascending diameters, average aortic sizing, graft size, or bare-metal struts at proximal attachment zone and development of RTAD. We found no statistically significant differences in demographics, genetic disease, comorbidities, or previous repairs. CONCLUSIONS: The development of RTAD after TEVAR for TBAD does not appear to be correlated with any easily identifiable demographic feature but appears to be correlated with proximal landing zones in zone 1 and 2 and an ascending diameter >4 cm. Furthermore, the presence of partial or complete false lumen thrombosis as well as more complicated presentation with renal ischemia was significantly more frequent in patients with RTAD. TBAD patients should be observed long term, as type A dissections in our patients occurred even after 1 year.

Advanced Techniques for Treating Juxtarenal and Pararenal Abdominal Aortic Aneurysms: Chimneys, Periscopes, Sandwiches and Other Methods.

The complex aortic anatomy of patients who present with juxtarenal and pararenal abdominal aortic aneurysms requires advanced techniques to ensure adequate coverage and complete exclusion of the aneurysm. Parallel stent grafting is one option for endovascular repair of complex aneurysms. Using chimneys, periscopes, or snorkels, it is possible to extend the length of the proximal seal zone and maintain perfusion to branch vessels. Because readily available stent grafts and covered stents are used, this technique is highly adaptable to each patient's unique anatomical challenges. However, the complexity of these procedures requires careful preoperative planning, excellent intraoperative imaging capabilities, a thorough understanding of technique, and anticipation of potential procedural pitfalls and complications. We present our experience with chimney/snorkel and sandwich techniques as a reliable and effective treatment strategy for complex aortic aneurysm repair.

Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome.

A 15-month-old male infant diagnosed with Williams Syndrome (WS) was admitted with severe hypercalcemia and nephrocalcinosis. Intravenous hydration and furosemide failed to yield an appreciable and sustainable fall in serum calcium, while the injection of pamidronate achieved a significant decrease in serum calcium in a short period of time. This bisphosphonate could be considered as a second-line treatment for refractory hypercalcemia in WS.

Short-term and midterm survival of ruptured abdominal aortic aneurysms in the contemporary endovascular era.

OBJECTIVE: Endovascular aneurysm repair (EVAR) has been shown to reduce mortality in the emergent repair of ruptured abdominal aortic aneurysms (AAAs). However, long-term survival data for this group of patients are lacking with contemporary endovascular endografts. The purpose of this study was to evaluate both 30-day mortality rates and 1-year survival in patients undergoing emergent EVAR in a 43-facility hospital system with a quaternary referral center with an established ruptured aneurysm protocol. METHODS: Retrospective analysis of patients captured prospectively in an Institutional Review Board-approved registry for patients treated emergently for AAA were reviewed between 2012 and 2017 was conducted. Primary outcome measures were 30-day mortality and 1-year survival for the entire group as well as for symptomatic and ruptured aneurysms. Data were analyzed using logistic regression survival curves, and a log-rank test was performed to compare survival between open and endovascular repair. Patients were evaluated on an intent-to-treat basis, and outcomes were evaluated in a multivariate model. RESULTS: A total of 249 patients were referred as part of the protocol. Of these, 102 (41%) were treated emergently. Kaplan-Meier estimates of 30-day and 1-year survival were 64% and 53% for all patients, 58% and 46% for ruptured patients, and 86% and 81% for symptomatic patients. EVAR resulted in improved 30-day survival (64% vs 31%; odds ratio, 4.0; P = .03) and 1-year survival (40% vs 23%; odds ratio, 2.3; P = .4) over open repair. Significant predictors for 30-day mortality included hypotension (P = .0003), blood transfusion (P < .0001), length of stay (P = .0005), extravasation (P = .01), preoperative cardiopulmonary resuscitation (P = .04), open repair (P = .007), aortouni-iliac reconstruction (P = .008), and abdominal compartment syndrome (P = .007). Significant predictors for 1-year mortality included advanced age (P = .04), hypotension (P = .01), blood transfusion (P = .006), extravasation (P = .03), reintubation (P = .03), and abdominal compartment syndrome (P = .03). There were no differences in outcomes based on race, gender, or outside transfer. Peripheral arterial disease (P = .04), hypertension (P = .04), coronary artery disease (P = .03), and familial history of aneurysms (P = .05) were related to increased 30-day mortality. Peripheral arterial disease (P = .06) and coronary artery disease (P = .07) were nearly significant, with increased 1-year mortality. CONCLUSIONS: EVAR is associated with improved survival compared with open repair in patients requiring emergent AAA repair. However, in the first year, there is a significant risk of death based on initial presentation as well as underlying comorbidities. To improve long-term survival, aggressive medical management and medical surveillance are warranted.

Ethnic disparities in outcomes of patients with complicated type B aortic dissection.

OBJECTIVE: The objective of this study was to evaluate the difference in outcomes after endovascular intervention in patients with complicated type B aortic dissection (TBAD) based on ethnicity and blood pressure control. METHODS: Between 2012 and 2016, there were 126 patients who underwent endovascular procedures for complicated TBAD at a single-institution quaternary referral center. Patients self-identified as African American (n = 53), white (n = 70), and Asian (n = 3). African American and white patients were compared on a number of variables, including age, ethnicity, insurance type, blood pressure, comorbidities, number of previous interventions, and number of antihypertension medications they were taking before intervention. Primary outcomes were survival and need for reintervention. RESULTS: Kaplan-Meier estimates for survival for African Americans vs whites were 94% vs 89%, 91% vs 83%, 89% vs 79%, and 89% vs 76% at 30 days, 1 year, 3 years, and 5 years, respectively (P = .05). African Americans were younger overall (52.5 ± 11 years) vs whites (63.7 ± 14.7 years; P < .0001). African Americans required a significantly greater number of reinterventions (P = .007). They also had higher rates of chronic kidney disease (P = .01), smoking (P = .03), and cocaine use (P = .02) and were more likely to be on Medicaid (P = .02). Hypertension was poorly controlled in both groups, with the percentage of patients with uncontrolled hypertension (systolic >140 mm Hg) preoperatively, postoperatively, and 30 days after intervention at 32%, 32%, and 39%. There was no significant difference between the cohorts in uncontrolled hypertension preoperatively (P = .39) or postoperatively (P = .63). However, more African Americans had uncontrolled hypertension at 30 days (African Americans, 49%; whites, 31%; odds ratio, 2.1; P = .09). African Americans were taking a greater number of antihypertension medications at presentation than whites (P = .01) and specifically had higher use rates of beta blockers (P = .02), diuretics (P = .02), and angiotensin-converting enzyme inhibitors (P = .04). CONCLUSIONS: African Americans with TBAD present at a younger age than their white counterparts do and have a survival advantage up to at least 5 years. However, African Americans have a higher rate of reintervention that is probably associated with poor blood pressure control despite taking more antihypertension medications both before and after the repair. It appears that optimal medical therapy is difficult to achieve in all groups. More aggressive medical management is needed, particularly more so in African Americans, which may in turn decrease the number of interventions and potentially improve long-term survival.

A multidisciplinary approach to giant soft tissue sarcoma of the chest wall: A case report.

INTRODUCTION: Soft tissue sarcomas of the chest wall are exceptionally rare entities that present as painless slow growing masses. Resection is often precarious due to involvement of vital structures, and patients are left with large chest wall defects postoperatively requiring extensive reconstruction. PRESENTATION OF CASE: We present a case report of a 29 year-old man who presented with a giant soft tissue sarcoma of the chest that had been growing slowly for one year prior to presentation. The patient had a biopsy that was positive for sarcoma, and PET CT demonstrated a large lobulated mass in the left chest wall with an SUV of 6.7. He received 50Gy of radiation therapy; however, the mass continued to grow in size. He subsequently underwent an en-bloc resection of the mass with latissimus and serratus muscle primary reconstruction. Final pathology showed a 27cm high-grade fibrosarcoma with prominent myxoid component. To our knowledge, this is the largest soft tissue sarcoma of the chest wall reported in the literature. Postoperatively, the patient received 6 cycles of adjuvant chemotherapy. DISCUSSION: Surgery is the mainstay of treatment, and chemotherapy and radiation are used in specific circumstances. Risk of recurrence is dependent on many factors, including histologic subtype, grade, and size of tumor. Long term surveillance with physical exam and imaging is recommended. CONCLUSION: We feel that the multidisciplinary approach is crucial for optimal management of large soft tissue sarcomas. We recommend this approach to all patients with chest wall sarcomas.

Intestinal alkaline phosphatase prevents antibiotic-induced susceptibility to enteric pathogens.

OBJECTIVE: To determine the efficacy of oral supplementation of the gut enzyme intestinal alkaline phosphatase (IAP) in preventing antibiotic-associated infections from Salmonella enterica serovar Typhimurium (S. Typhimurium) and Clostridium difficile. BACKGROUND: The intestinal microbiota plays a pivotal role in human health and well-being. Antibiotics inherently cause dysbiosis, an imbalance in the number and composition of intestinal commensal bacteria, which leads to susceptibility to opportunistic bacterial infections. Previously, we have shown that IAP preserves the normal homeostasis of intestinal microbiota and that oral supplementation with calf IAP (cIAP) rapidly restores the normal gut flora. We hypothesized that oral IAP supplementation would protect against antibiotic-associated bacterial infections. METHODS: C57BL/6 mice were treated with antibiotic(s) ± cIAP in the drinking water, followed by oral gavage of S. Typhimurium or C. difficile. Mice were observed for clinical conditions and mortality. After a defined period of time, mice were killed and investigated for hematological, inflammatory, and histological changes. RESULTS: We observed that oral supplementation with cIAP during antibiotic treatment protects mice from infections with S. Typhimurium as well as with C. difficile. Animals given IAP maintained their weight, had reduced clinical severity and gut inflammation, and showed improved survival. CONCLUSIONS: Oral IAP supplementation protected mice from antibiotic-associated bacterial infections. We postulate that oral IAP supplementation could represent a novel therapy to protect against antibiotic-associated diarrhea (AAD), C. difficile-associated disease (CDAD), and other enteric infections in humans.

Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate.

Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP. To study the anti-inflammatory effect of IAP, UDP or other proinflammatory ligands (LPS, flagellin, Pam3Cys, or TNF-α) in the presence or absence of IAP were applied to cell cultures, and IL-8 was measured. UDP caused dose-dependent increase in IL-8 release by immune cells and two gut epithelial cell lines, and IAP treatment abrogated IL-8 release. Costimulation with UDP and other inflammatory ligands resulted in a synergistic increase in IL-8 release, which was prevented by IAP treatment. In vivo, UDP in the presence or absence of IAP was instilled into a small intestinal loop model in wild-type and IAP-knockout mice. Luminal contents were applied to cell culture, and cytokine levels were measured in culture supernatant and intestinal tissue. UDP-treated luminal contents induced more inflammation on target cells, with a greater inflammatory response to contents from IAP-KO mice treated with UDP than from WT mice. Additionally, UDP treatment increased TNF-α levels in intestinal tissue of IAP-KO mice, and cotreatment with IAP reduced inflammation to control levels. Taken together, these studies show that IAP prevents inflammation caused by UDP alone and in combination with other ligands, and the anti-inflammatory effect of IAP against UDP persists in mouse small intestine. The benefits of IAP in intestinal disease may be partly due to inhibition of the proinflammatory activity of UDP.

Local peritoneal irrigation with intestinal alkaline phosphatase is protective against peritonitis in mice.

BACKGROUND: The brush-border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and detoxifies different toll-like receptor ligands. This study aimed to determine the therapeutic effects of locally administered calf IAP (cIAP) in a cecal ligation and puncture (CLP) model of polymicrobial sepsis. METHODS: C57BL/6 mice underwent CLP followed by intraperitoneal injection of cIAP or normal saline. Blood leukocyte counts, levels of cytokines and liver enzymes, and lung myeloperoxidase activity were determined. Peritoneal lavage fluid (PLF) was assayed for neutrophil infiltration and both aerobic and anaerobic bacterial counts. RESULTS: After intraperitoneal injection, cIAP activity in PLF decreased 50% within 15 min with minimal activity evident at 4 h. Compared with irrigation with normal saline, cIAP irrigation increased the 7-day survival rate in mice undergoing CLP, with maximal effects seen at 25 units of cIAP (0% vs. 46% survival rate, respectively; p < 0.001). cIAP treatment reduced lung inflammation, liver damage and levels of tumor necrosis factor alpha and interleukin-6. CONCLUSIONS: Peritoneal irrigation with cIAP significantly enhances survival in a mouse model of peritonitis, likely through reduction of local inflammation and remote organ damage. We suggest that intraperitoneal cIAP irrigation could be a novel therapy for intra-abdominal sepsis.

Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis.

BACKGROUND: The brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott-Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation. METHODS: The wildtype (WT) and IAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation. RESULTS: Microscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52±3.8 versus 28.8±6.6, respectively, P<0.0001). cIAP treatment attenuated the disease in both groups (KO=30.7±6.01, WT=18.7±5.0, P<0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3±0.52 versus 6.2±0.34, respectively, P<0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment. CONCLUSIONS: Endogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD.