"Early" and "Late" Hospital readmissions in the first year after kidney transplant at a single center.

BACKGROUND: Hospital readmission (HR) after surgery is considered a quality metric. METHODS: Data on 2371 first-time adult kidney transplant (KT) recipients were collected to analyze the "early" (≤30 days) and "late" (31-365 days) HR patterns after KT at a single center over a 12-year time span (2002-2013). RESULTS: 30-day, 90-day, and 1-year HR were 31%, 41%, and 53%, respectively. Risk factors for HR included age >50, female sex, black race, BMI >30, transplant LOS >5 days, and pre-transplant time on dialysis >765 days. Indications for early (n = 749) and late (n = 508) HR were similar. Early HR (OR: 3.80, P = .007) and black race (OR: 2.38, P = .009) were associated with higher odds of 1-year graft failure while frequency (1-2, 3-4, 5+) of HR (ORs: 4.68, 8.36, 9.44, P < .001) and age > 50 (OR: 2.11, P = .007) were associated with higher odds of 1-year mortality. Transplant LOS > 5 days increased both odds of 1-year graft failure (OR: 3.51, P = .001) and mortality (OR: 2.05, P = .006). One-year graft and recipient survival were 96.7% and 94.8%, respectively. CONCLUSIONS: Hospital readmission was associated with reduced graft and patient survival; however, despite a relatively high and consistent HR rate after KT, overall 1-year graft and patient survival was high.

Morphometric data on severely and morbidly obese deceased, established on forensic and non-forensic autopsies.

With the widespread increase in the incidence of obesity, autopsies on severely and morbidly obese deceased have become common in the USA. Standard reference tables for organ weights provide little or no information on individuals with a body mass index greater than 35 kg/m(2). Although several recent reports have provided organ weights for small numbers of morbidly obese persons who died naturally from a variety of causes, these data may have been affected by comorbidities. Furthermore, they did not provide information relative to differences in organ weight based on gender, age, and race. The aim of the present study was to fill this void by developing reference tables for organ weights of severely and morbidly obese individuals. Our study was based on data from 802 forensic and medical autopsies, including 435 cases of death of natural and 367 of non-natural causes. Organ weights were compared between these groups, and reference ranges were generated. Significant variability was found in organ weights especially among deceased older than 40 years who died naturally, suggesting that comorbidities affect organ weight. Reference tables were compiled for organ weights and morphometric data based on gender, age, and race. Since obesity is a pathological condition affecting organ weight, these reference tables do not reflect normal organ weights but only weight as seen in severely and morbidly obese individuals. They should be useful to pathologists who perform forensic and non-forensic autopsies.

Effect of cell seeding on neotissue formation in a tissue engineered trachea.

BACKGROUND: Surgical management of long segment tracheal disease is limited by a paucity of donor tissue and poor performance of synthetic materials. A potential solution is the development of a tissue-engineered tracheal graft (TETG) which promises an autologous airway conduit with growth capacity. METHODS: We created a TETG by vacuum seeding bone marrow-derived mononuclear cells (BM-MNCs) on a polymeric nanofiber scaffold. First, we evaluated the role of scaffold porosity on cell seeding efficiency in vitro. We then determined the effect of cell seeding on graft performance in vivo using an ovine model. RESULTS: Seeding efficiency of normal porosity (NP) grafts was significantly increased when compared to high porosity (HP) grafts (NP: 360.3 ± 69.19 × 10(3) cells/mm(2); HP: 133.7 ± 22.73 × 10(3) cells/mm(2); p<0.004). Lambs received unseeded (n=2) or seeded (n=3) NP scaffolds as tracheal interposition grafts for 6 weeks. Three animals were terminated early owing to respiratory complications (n=2 unseeded, n=1 seeded). Seeded TETG explants demonstrated wound healing, epithelial migration, and delayed stenosis when compared to their unseeded counterparts. CONCLUSION: Vacuum seeding BM-MNCs on nanofiber scaffolds for immediate implantation as tracheal interposition grafts is a viable approach to generate TETGs, but further preclinical research is warranted before advocating this technology for clinical application.

Intraoperative Use of a Portable Large Field of View Gamma Camera and Handheld Gamma Detection Probe for Radioguided Localization and Prediction of Complete Surgical Resection of Gastrinoma: Proof of Concept.

BACKGROUND: Surgical management of Zollinger-Ellison syndrome (ZES) relies on localization and resection of all tumor foci. We describe the benefit of combined intraoperative use of a portable large field of view gamma camera (LFOVGC) and a handheld gamma detection probe (HGDP) for indium-111 ((111)In)-pentetreotide radioguided localization and confirmation of gastrinoma resection in ZES. STUDY DESIGN: Five patients (6 cases) with (111)In-pentetreotide-avid ZES were evaluated. Patients were injected with (111)In-pentetreotide for diagnostic imaging the day before surgery. Intraoperatively, an HGDP and LFOVGC were used to localize (111)In-pentetreotide-avid lesions, guide resection, assess specimens for (111)In-pentetreotide activity, and to verify lack of abnormal post-resection surgical field activity. RESULTS: Large field of view gamma camera imaging and HGDP-assisted detection were helpful for localization and guided resection of tumor and removal of (111)In-pentetreotide-avid tumor foci in all cases. In 3 of 5 patients (3 of 6 cases), these techniques led to detection and resection of additional tumor foci beyond those detected by standard surgical techniques. The (111)In-pentetreotide-positive or-negative specimens correlated with neuroendocrine tumors or benign pathology, respectively. In one patient with mild residual focal activity on post-resection portable LFOVGC imaging, thought to be artifact, had recurrence of disease in the same area 5 months after surgery. CONCLUSIONS: Real-time LFOVGC imaging and HGDP use for surgical management of gastrinoma improve success of localizing and resecting all neuroendocrine tumor-positive tumor foci, providing instantaneous navigational feedback. This approach holds potential for improving long-term patient outcomes in patients with ZES.

Hemodynamic Characterization of a Mouse Model for Investigating the Cellular and Molecular Mechanisms of Neotissue Formation in Tissue-Engineered Heart Valves.

Decellularized allograft heart valves have been used as tissue-engineered heart valve (TEHV) scaffolds with promising results; however, little is known about the cellular mechanisms underlying TEHV neotissue formation. To better understand this phenomenon, we developed a murine model of decellularized pulmonary heart valve transplantation using a hemodynamically unloaded heart transplant model. Furthermore, because the hemodynamics of blood flow through a heart valve may influence morphology and subsequent function, we describe a modified loaded heterotopic heart transplant model that led to an increase in blood flow through the pulmonary valve. We report host cell infiltration and endothelialization of implanted decellularized pulmonary valves (dPV) and provide an experimental approach for the study of TEHVs using mouse models.

Complete "in situ" avulsion of the radial artery complicating transradial coronary rotational atherectomy.

BACKGROUND: Transradial percutaneous access (TR) is promoted because of increased patient comfort and convenience as well as a lower risk of access site and cardiac complications in the literature. Increased use of the TR purports a new set of possible complications for which the vascular surgeon must be capable to recognize and manage. METHODS: A 48-year-old, devout Jehovah's Witness, woman with a history of coronary artery bypass surgery presented with a non-ST-segment elevation acute myocardial infarction. Pretransfer catheterization demonstrated a heavily calcified, 90% distal left main stenosis with an occluded left internal mammary artery graft to the left anterior descending coronary artery. To minimize the risk of bleeding requiring a blood transfusion, a coronary rotational atherectomy via a TR was performed. A nonhydrophilic, 7F sheath was used to accommodate the larger rotational atherectomy burr sizes. The coronary procedure was successful, but the sheath removal was complicated by significant resistance to pullback while the patient complained of severe pain. Post procedure she developed a hematoma with motor and neurological deficits of her hand. RESULTS: Emergent surgical exploration with fasciotomy was planned. The radial artery was explored and found to be redundant and pulseless, prompting proximal evaluation and revealing complete avulsion of the radial artery at its origin. An intraoperative arteriogram revealed that the brachial and ulnar arteries and interosseous branches were patent and filled the palmar arch and surgical ligation of the radial artery was conducted. CONCLUSION: Vascular surgeons need to be aware of potential complications related to TR which are likely to increase as this method is more widely disseminated.

A systematic review of the need for MRI for the clearance of cervical spine injury in obtunded blunt trauma patients after normal cervical spine CT.

Clearance of cervical spine injury (CSI) in the obtunded or comatose blunt trauma patient remains controversial. In patients with unreliable physical examination and no evidence of CSI on computed tomography (CT), magnetic resonance imaging of the cervical spine (CS-MRI) is the typical follow-up study. There is a growing body of evidence suggesting that CS-MRI is unnecessary with negative findings on a multi-detector CT (MDCT) scan. This review article systematically analyzes current literature to address the controversies surrounding clearance of CSI in obtunded blunt trauma patients. A literature search through MEDLINE database was conducted using all databases on the National Center for Biotechnology Information (NCBI) website (www.ncbi.nlm.nih.gov) for keywords: "cervical spine injury," "obtunded," and "MRI." The search was limited to studies published within the last 10 years and with populations of patients older than 18 years old. Eleven studies were included in the analysis yielding data on 1535 patients. CS-MRI detected abnormalities in 256 patients (16.6%). The abnormalities reported on CS-MRI resulted in prolonged rigid c-collar immobilization in 74 patients (4.9%). Eleven patients (0.7%) had unstable injury detected on CS-MRI alone that required surgical intervention. In the obtunded blunt trauma patient with unreliable clinical examination and a normal CT scan, there is still a role for CS-MRI in detecting clinically significant injuries when MRI resources are available. However, when a reliable clinical exam reveals intact gross motor function, CS-MRI may be unnecessary.

Transplantation of pulmonary valve using a mouse model of heterotopic heart transplantation.

Tissue engineered heart valves, especially decellularized valves, are starting to gain momentum in clinical use of reconstructive surgery with mixed results. However, the cellular and molecular mechanisms of the neotissue development, valve thickening, and stenosis development are not researched extensively. To answer the above questions, we developed a murine heterotopic heart valve transplantation model. A heart valve was harvested from a valve donor mouse and transplanted to a heart donor mouse. The heart with a new valve was transplanted heterotopically to a recipient mouse. The transplanted heart showed its own heartbeat, independent of the recipient's heartbeat. The blood flow was quantified using a high frequency ultrasound system with a pulsed wave Doppler. The flow through the implanted pulmonary valve showed forward flow with minimal regurgitation and the peak flow was close to 100 mm/sec. This murine model of heart valve transplantation is highly versatile, so it can be modified and adapted to provide different hemodynamic environments and/or can be used with various transgenic mice to study neotissue development in a tissue engineered heart valve.

Heparin-binding epidermal growth factor-like growth factor restores Wnt/ß-catenin signaling in intestinal stem cells exposed to ischemia/reperfusion injury.

BACKGROUND: We have previously demonstrated that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) protects the intestines from injury in several different experimental animal models. In the current study, we investigated whether the ability of HB-EGF to protect the intestines from ischemia/reperfusion (I/R) injury was related to its effects on Wnt/ß-catenin signaling in intestinal stem cells (ISC). METHODS: Lucien-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-enhanced green fluorescent protein (EGFP) transgenic (TG) mice with fluorescently labeled ISC, as well as the same mice treated with intraluminal HB-EGF or genetically engineered to overexpress HB-EGF, were exposed to segmental mesenteric artery occlusion (sMAO) to the terminal ilium. Wnt/ß-catenin signaling was evaluated using immunofluorescent staining and Western blotting. RESULTS: LGR5 expression and Wnt/ß-catenin signaling in the ISC of the terminal ilium of LGR5-EGFP TG mice was significantly reduced 24 hours after sMAO. Intraluminal administration of HB-EGF or HB-EGF overexpression in these mice led to preservation of LGR5 expression and Wnt/ß-catenin signaling. CONCLUSION: These data show that HB-EGF preserves Wnt/ß-catenin signaling in ISC after I/R injury.

Heparin-binding epidermal growth factor-like growth factor improves intestinal barrier function and reduces mortality in a murine model of peritonitis.

BACKGROUND: The morbidity and mortality associated with bacterial peritonitis remain high. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a potent intestinal cytoprotective agent. The aim of this study was to evaluate the effect of HB-EGF in a model of murine peritonitis. METHODS: HB-EGF(-/-) knockout (KO) mice and their HB-EGF(+/+) wild-type (WT) counterparts were subjected to sham operation, cecal ligation and puncture (CLP), or CLP with HB-EGF treatment (800 µg/kg IP daily). Villous length, intestinal permeability, intestinal epithelial cell (IEC) apoptosis, bacterial load in peritoneal fluid (PF) and mesenteric lymph nodes (MLN), inflammatory cytokine levels, and survival were determined. RESULTS: After exposure to CLP, HB-EGF KO mice had significantly shorter villi (1.37 ± 0.13 vs 1.96 ± 0.4 relative units; P < .03), increased intestinal permeability (17.01 ± 5.18 vs 11.50 ± 4.67 nL/min/cm2; P < .03), increased IEC apoptotic indices (0.0093 ± 0.0033 vs 0.0016 ± 0.0014; P < .01), and increased bacterial counts in PF (25,313 ± 17,558 vs 11,955 ± 6,653 colony forming units [CFU]/mL; P < .05) and MLN (19,009 ± 11,200 vs 5,948 ± 2,988 CFU/mL/g; P < .01) compared with WT mice. Administration of HB-EGF to WT and HB-EGF KO mice exposed to CLP led to significantly increased villous length and decreased intestinal permeability, IEC apoptosis and bacterial counts in MLN (P < .05). Survival of HB-EGF KO mice subjected to CLP was significantly improved with administration of HB-EGF (P < .05). CONCLUSION: HB-EGF gene KO increases susceptibility to peritonitis-induced intestinal injury, which can be reversed by administration of HB-EGF. These results support a protective role of HB-EGF in peritonitis-induced sepsis.

Heparin-binding epidermal growth factor-like growth factor promotes murine enteric nervous system development and enteric neural crest cell migration.

BACKGROUND/PURPOSE: Developmental defects of the enteric nervous system lead to a variety of disorders including Hirschprung disease. We have previously shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) exerts neuroprotective effects on injured neurons. The goals of this study were to assess the role of HB-EGF in enteric nervous system development and to evaluate the effect of HB-EGF on enteric neural crest-derived cell (ENCC) migration in the developing gastrointestinal tract of mice. MATERIALS AND METHODS: HB-EGF immunohistochemistry was used to examine HB-EGF protein expression in the hindgut of embryonic mice. Gut specimens were stained for PGP9.5 (a neuronal cell marker) to examine the extent of ENCC migration in the intestine at different embryonic stages in HB-EGF knockout (KO) and wild-type (WT) mice. Embryonic gut organ cultures were established to examine the effect of HB-EGF on ENCC migration. RESULTS: The expression of HB-EGF was limited to the endodermal epithelium of the hindgut in early gestation, but rapidly involved the hindgut mesenchyme after ENCC migrated into this region. ENCC migration was significantly delayed in HB-EGF KO compared with WT embryos, leading to defects in neural colonization of the distal gut in postnatal HB-EGF KO mice. Addition of HB-EGF to WT embryonic intestine significantly promoted ENCC migration, as demonstrated by a significant increase in the ratio of ENCC migration distance toward the distal hindgut/total colon length (78% ± 4% vs 53% ± 2%, P = .001). CONCLUSIONS: Deletion of the HB-EGF gene leads to enteric nervous system developmental defects. HB-EGF stimulates ENCC migration in the gut, supporting a potential role for administration of HB-EGF in the future for the treatment of patients with intestinal neuronal disorders.

Heparin-binding EGF-like growth factor protects pericytes from injury.

BACKGROUND: We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) promotes angiogenesis and preserves mesenteric microvascular blood flow in several models of intestinal injury. The current study was designed to evaluate the effect of HB-EGF on pericytes, since these cells function to regulate capillary blood flow and new capillary growth. MATERIALS AND METHODS: C3H/10T1/2 mouse mesenchymal cells were differentiated into pericyte-like cells in vitro using transforming growth factor-ß1 (TGF-ß1). In addition, primary pericyte cultures were established from rat brain. The effect of HB-EGF on pericyte proliferation was assessed. In addition, cells were stressed by exposure to anoxia, and apoptosis determined. In vivo, we examined the effect of HB-EGF on pericytes in a model of intestinal I/R injury based on superior mesenteric artery occlusion (SMAO) in mice. RESULTS: Differentiated C3H/10T1/2 cells (pericyte-like cells) demonstrated morphologic characteristics of pericytes, and expressed pericyte specific markers. Addition of HB-EGF led to significant cell proliferation in differentiated pericyte-like cells, even under conditions of anoxic stress. Addition of the EGF receptor inhibitor AG 1478 led to complete inhibition of the proliferative effects of HB-EGF on pericyte-like cells. In addition, HB-EGF protected pericyte-like cells from anoxia-induced apoptosis. In addition, HB-EGF promoted cell proliferation in primary pericyte cultures. In vivo, administration of HB-EGF to mice subjected to intestinal I/R injury led to protection of pericytes from injury. CONCLUSIONS: These results suggest that HB-EGF may function as a microcirculatory blood flow regulator, at least in part, via its effects on pericytes.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) preserves gut barrier function by blocking neutrophil-endothelial cell adhesion after hemorrhagic shock and resuscitation in mice.

BACKGROUND: We have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) protects the intestines from injury in several different animal models, including hemorrhagic shock and resuscitation (HS/R). The current study was designed to explore the mechanisms underlying the anti-inflammatory role of HB-EGF in preservation of gut barrier function after injury. METHODS: In vivo, HS/R was induced in wild-type and neutropenic mice, with or without administration of HB-EGF, and intestinal permeability determined by use of the everted gut sac method. In vitro, cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated human peripheral blood mononuclear cells (PMNs) were used to determine the effects of HB-EGF on HUVEC-PMN adhesion, reactive oxygen species production in PMN, adhesion molecule expression in HUVEC and PMN, and the signaling pathways involved. RESULTS: We found that administration of HB-EGF to healthy mice led to preservation of gut barrier function after HS/R. Likewise, induction of neutropenia in mice also led to preservation of gut barrier function after HS/R. Administration of HB-EGF to neutropenic mice did not lead to further improvement in gut barrier function. In vitro studies showed that HB-EGF decreased neutrophil-endothelial cell (PMN-EC) adherence by down-regulating adhesion molecule expression in EC via the phosphoinositide 3-kinase-Akt pathway, and by inhibiting adhesion molecule surface mobilization and reactive oxygen species production in PMN. CONCLUSION: These results indicate that HB-EGF preserves gut barrier function by inhibiting PMN and EC activation, thereby blocking PMN-EC adherence after HS/R in mice, and support the future use of HB-EGF in disease states manifested by hypoperfusion injury.

Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an often catastrophic disease that typically affects premature newborns. Although the exact etiology of NEC is uncertain, the disease is associated with formula feeding, bacterial colonization of the gut, hypoxia and hypoperfusion. In light of the pathogenesis of NEC, the integrity and function of the intestinal mucosa has a major defensive role against the initiation of NEC. Various forms of intestinal injury, including NEC, injure the intestinal epithelial cell (IEC) lineages, including the intestinal stem cells (ISCs), thereby disrupting the normal homeostasis needed to maintain gut barrier function. In the current study, we examined the effects of heparin-binding EGF-like growth factor (HB-EGF) administration on enterocytes, goblet cells, neuroendocrine cells and ISCs in a newborn rat model of experimental NEC. We also examined the cytoprotective effects of HB-EGF on ISCs in in vitro cell cultures and in ex vivo crypt-villous organoid cultures. We found that HB-EGF protects all IEC lineages, including ISCs, from injury. We further found that HB-EGF protects isolated ISCs from hypoxic injury in vitro, and promotes ISC activation and survival, and the expansion of crypt transit-amplifying cells, in ex vivo crypt-villous organoid cultures. The protective effects of HB-EGF were dependent on EGF receptor activation, and were mediated via the MEK1/2 and PI3K signaling pathways. These results show that the intestinal cytoprotective effects of HB-EGF are mediated, at least in part, through its ability to protect ISCs from injury.

HB-EGF protects the lungs after intestinal ischemia/reperfusion injury.

BACKGROUND: Acute respiratory distress syndrome continues to be a major source of morbidity and mortality in critically-ill patients. Heparin binding EGF-like growth factor (HB-EGF) is a biologically active protein that acts as an intestinal cytoprotective agent. We have previously demonstrated that HB-EGF protects the intestines from injury in several different animal models of intestinal injury. In the current study, we investigated the ability of HB-EGF to protect the lungs from remote organ injury after intestinal ischemia/reperfusion (I/R). METHODS: Mice were randomly assigned to one of the following groups: (1) sham-operated; (2) sham+HB-EGF (1200 microg/kg in 0.6 mL administered by intra-luminal injection at the jejuno-ileal junction immediately after identification of the superior mesenteric artery); (3) superior mesenteric artery occlusion for 45 min followed by reperfusion for 6 h (I/R); or (4) I/R+HB-EGF (1200 microg/kg in 0.6 mL) administered 15 min after vascular occlusion. The severity of acute lung injury was determined by histology, morphometric analysis and invasive pulmonary function testing. Animal survival was evaluated using Kaplan-Meier analysis. RESULTS: Mice subjected to intestinal I/R injury showed histologic and functional evidence of acute lung injury and decreased survival compared with sham-operated animals. Compared with mice treated with HB-EGF (I/R+HB-EGF), the I/R group had more severe acute lung injury, and decreased survival. CONCLUSION: Our results demonstrate that HB-EGF reduces the severity of acute lung injury after intestinal I/R in mice. These data demonstrate that HB-EGF may be a potential novel systemic anti-inflammatory agent for the prevention of the systemic inflammatory response syndrome (SIRS) after intestinal injury.