Lending a hand: The utility of hand-assisted laparoscopic surgery in diverticulitis with fistula.

BACKGROUND: Current guidelines recommend elective colectomy for the management of diverticulitis-associated fistulas. These cases present considerable operative challenges, and surgical approaches and fistula tract management vary widely. Hand-assisted laparoscopic surgery offers the benefits of minimally invasive surgery while maintaining the tactile advantages of open surgery. This study aims to evaluate outcomes of hand-assisted laparoscopic surgery colectomy for diverticulitis-associated fistulas, fistula tract, and urinary catheter management. METHODS: A retrospective review of patients with diverticulitis-associated fistula who underwent elective hand-assisted laparoscopic surgery colectomy between January 2, 2008, and September 8, 2022, was performed. Patients with Crohn disease or who underwent emergency surgery were excluded. RESULTS: Seventy patients were included; the mean patient age was 64.1 ± 14.8 years, and the mean body mass index was 30.9 ± 9.1 kg/m2. Colovesical fistulas were most common (n = 48; 68.6%), followed by colovaginal fistulas (n = 22; 31.4%). The median operative time was 186 minutes. Conversion to an open approach occurred in 4 cases (5.7%). The fistula tract remnant was left without intervention in 35 patients (50%), and omental coverage occurred in 23 cases (32.9%). The median duration of the urinary catheter was 3 days (range = 1-63). There were no postoperative urine leaks. Three patients (4.3%) were readmitted in ≤30 days. There were no 30-day mortalities. CONCLUSION: The challenges of colectomy for diverticulitis-associated fistulas can be mitigated using the hand-assisted laparoscopic surgery technique. We found a low conversion-to-open rate, falling below rates reported for laparoscopic colectomy. There were no cases of postoperative urine leak, suggesting that no intervention or omental coverage is a safe approach to fistula tract management.

Impact of Auricular Neurostimulation in Patients Undergoing Colorectal Surgery with an Enhanced Recovery Protocol: A Pilot Randomized, Controlled Trial.

BACKGROUND: Narcotics are the cornerstone of postoperative pain control, but the opioid epidemic and the negative physiological and psychological effects of narcotics implore physicians to utilize nonpharmacological methods of pain control. OBJECTIVE: This pilot study investigated a novel neurostimulation device for postoperative analgesia. We hypothesized that active neurostimulation would decrease postoperative narcotic requirements. DESIGN: This was a placebo-controlled, double-blinded trial. SETTINGS: This trial was conducted at an academic medical center and a Veterans Affairs hospital. PATIENTS: This trial included adult patients who underwent elective bowel resection between December 2016 and April 2018. INTERVENTIONS: Patients were randomly assigned to receive an active or inactive (sham) device, which was applied to the right ear before surgery and continued for 5 days. MAIN OUTCOME MEASURES: The primary outcome was total opioid consumption. The secondary outcomes included pain, nausea, anxiety, return of bowel function, complications, 30-day readmissions, and opioid consumption at 2 weeks and 30 days. RESULTS: A total of 57 patients participated and 5 withdrew; 52 patients were included in the analysis. Twenty-eight patients received an active device and 24 received an inactive device. There was no difference in total narcotic consumption between active and inactive devices (90.79 ± 54.93 vs 90.30 ± 43.03 oral morphine equivalents/day). Subgroup analyses demonstrated a benefit for patients after open surgery (p = 0.0278). When patients were stratified by decade, those aged 60 to 70 and >70 years derived a benefit from active devices in comparison with those aged 30 to 40, 40 to 50, and 50 to 60 years old (p = 0.01092). No serious adverse events were related to this study. LIMITATIONS: This study was limited by the small sample sizes. CONCLUSIONS: No difference in opioid use was found with auricular neurostimulation. However, this pilot study suggests that older patients and those with larger abdominal incisions may benefit from auricular neurostimulation. Further investigation in these high-risk patients is warranted. See Video Abstract at http://links.lww.com/DCR/B452.ClinicalTrials.gov identifier: NCT02892513. IMPACTO DE LA NEUROESTIMULACIN AURICULAR EN PACIENTES SOMETIDOS A CIRUGA COLORRECTAL CON UN PROTOCOLO DE RECUPERACIN MEJORADA UN ENSAYO PILOTO ALEATORIZADO Y CONTROLADO: ANTECEDENTES:Los narcóticos son la piedra angular del control del dolor postoperatorio, pero la epidemia de opioides y los efectos fisiológicos y psicológicos negativos de los narcóticos incentivan a los médicos a que utilicen métodos no farmacológicos de control del dolor.OBJETIVO:Este estudio piloto investigó un nuevo dispositivo de neuroestimulación para analgesia postoperatoria. Hipotetizamos que la neuroestimulación activa disminuiría los requerimientos narcóticos postoperatorios.DISEÑO:Este fue un ensayo doble ciego controlado con placebo.ESCENARIO:Esto se llevó a cabo en un centro médico académico y en un hospital de Asuntos de Veteranos (Veterans Affairs hospital).PACIENTES:Este ensayo incluyó pacientes adultos que se sometieron a resección intestinal electiva entre diciembre de 2016 y abril de 2018.INTERVENCIONES:Los pacientes fueron asignados al azar para recibir un dispositivo activo o inactivo (falso), que se aplicó al oído derecho antes de la cirugía y se mantuvo durante 5 días.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el consumo total de opioides; los resultados secundarios incluyeron dolor, náusea, ansiedad, retorno de la función intestinal, complicaciones, reingresos a 30 días y consumo de opioides a 2 semanas y a 30 días.RESULTADOS:Participaron un total de 57 pacientes y 5 se retiraron; Se incluyeron 52 pacientes en el análisis. Veintiocho pacientes recibieron un dispositivo activo y 24 recibieron un dispositivo inactivo. No hubo diferencias en el consumo total de narcóticos entre los dispositivos activos e inactivos (90.79 ± 54.93 vs 90.30 ± 43.03 equivalentes de morfina oral [OME] / día). Los análisis de subgrupos demostraron un beneficio para los pacientes después de cirugía abierta (p = 0.0278). Cuando los pacientes se estratificaron por década, aquellos de 60-70 y > 70 años obtuvieron un beneficio de los dispositivos activos en comparación con los de 30-40, 40-50 y 50-60 años (p = 0.01092). No hubo eventos adversos graves relacionados con este estudio.LIMITACIONES:Este estudio estuvo limitado por los pequeños tamaños de muestra.CONCLUSIONES:No se encontró diferencia en el uso de opioides con la neuroestimulación auricular. Sin embargo, este estudio piloto sugiere que los pacientes mayores y aquellos con incisiones abdominales más grandes pueden beneficiarse de la neuroestimulación auricular. Está justificada la investigación adicional en estos pacientes de alto riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B452. (Traducción-Dr. Jorge Silva Velazco).

Pouch Volvulus in Patients Having Undergone Restorative Proctocolectomy for Ulcerative Colitis: A Case Series.

BACKGROUND: Restorative proctocolectomy with IPAA improves quality of life in patients with medically refractory ulcerative colitis. Although bowel obstruction is common, pouch volvulus is rare and described only in case reports. Diagnosis can be challenging, resulting in delayed care and heightened morbidity. OBJECTIVE: The purpose of this study was to delineate the symptoms and successful management strategies used in patients with IPAA volvulus that result in pouch salvage. DESIGN: This study was a case series. SETTINGS: The study was conducted at a tertiary referral center for ulcerative colitis in Milwaukee, Wisconsin. PATIENTS: Patients included those with volvulus of the IPAA. MAIN OUTCOME MEASURES: Over the study period (2010-2015), 6 patients were diagnosed with IPAA volvulus. The primary outcomes were symptom manifestation, diagnostic practices, and treatment of pouch volvulus. RESULTS: Six patients with ulcerative colitis were identified with pouch volvulus. The majority (n = 4) underwent a laparoscopic pouch creation and had early symptom manifestation after surgery. Complications preceding volvulus included pouch ulceration (n = 5) and pouchitis (n = 4). The most common presenting symptoms of volvulus were abdominal pain (n = 4) and obstipation (n = 4). Multiple imaging modalities were used, but volvulus was most frequently identified by CT scan. Management was primarily operative (n = 5), composed of excision of the pouch (n = 3), pouch-pexy (n = 1), and detorsion with defect closure (n = 1). Both operative and nonoperative treatment with endoscopic detorsion resulted in low morbidity and improved patient symptoms. LIMITATIONS: This single-institution study is limited by its retrospective design and small number of patients. CONCLUSIONS: IPAA volvulus is a rare and challenging cause of bowel obstruction in ulcerative colitis. Heralding signs and symptoms, such as pouch ulceration and acute obstipation, should initiate a workup for a twisting pouch. Diagnosis, which is multimodal, must occur early to avert necrosis and allow for preservation of a well-functioning pouch. See Video Abstract at http://links.lww.com/DCR/A561.

Aortic Graft Infection Secondary to Iatrogenic Transcolonic Graft Malposition.

Aortic graft infections are a rare but devastating complication of aortic revascularization. Often infections occur due to contamination at the time of surgery. Iatrogenic misplacement of the limbs of an aortobifemoral graft is exceedingly rare, and principles of evaluation and treatment are not well defined. We report 2 cases of aortobifemoral bypass graft malposition through the colon. CASE REPORT: Case 1 is a 54-year-old male who underwent aortobifemoral bypass grafting for acute limb ischemia. He had previously undergone a partial sigmoid colectomy for diverticulitis. Approximately 6 months after vascular surgery, he presented with an occult graft infection. Preoperative imaging and intraoperative findings were consistent with graft placement through the sigmoid colon. Case 2 is a 60-year-old male who underwent aortobifemoral bypass grafting due to a nonhealing wound after toe amputation. His postoperative course was complicated by pneumonia, bacteremia thought to be secondary to the pneumonia, general malaise, and persistent fevers. Approximately 10 weeks after the vascular surgery, he presented with imaging and intraoperative findings of graft malposition through the cecum. CONCLUSIONS: Aortic graft infection is usually caused by surgical contamination and presents as an indolent infection. Case 1 presented as such; Case 2 presented more acutely. Both grafts were iatrogenically misplaced through the colon at the index operation. The patients underwent extra-anatomic bypass and graft explantation and subsequently recovered.

PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure.

Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide (mtH2O2). Excessive mtH2O2 production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses mtH2O2 production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)-catalase (H2O2 scavenger) or L-NAME (NG-nitro-l-arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H2O2-mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by mtH2O2-mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the mtH2O2-mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from mtH2O2-mediated dilation, increasing NO bioavailability, and reducing levels of mtH2O2 Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H2O2 to flow-mediated dilation.

Radiation-induced changes in intestinal and tissue-nonspecific alkaline phosphatase: implications for recovery after radiation therapy.

BACKGROUND: Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. METHODS: WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. RESULTS: Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. CONCLUSIONS: Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome.

Wnt/ß-Catenin Signaling Activation beyond Robust Nuclear ß-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

INTRODUCTION: Wnt/ß-catenin signaling activation has been reported only during the late steps of Barrett's esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear ß-catenin. However, ß-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/ß-catenin signaling in nondysplastic BE. METHODS: Esophageal tissues from healthy and BE patients without dysplasia were analyzed for Wnt target gene expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Esophageal squamous (EPC1-& EPC2-hTERT), BE metaplastic (CP-A), and adenocarcinoma (OE33) cell lines were characterized for Wnt activation by qRT-PCR, Western blot, and luciferase assay. Wnt activity regulation was examined by using recombinant Wnt3a and Dickkopf-1 (Dkk1) as well as Dkk1 short interfering RNA. RESULTS: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa. Elevated levels of dephosphorylated ß-catenin were detected in nondysplastic BE. Nuclear active ß-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated ß-catenin signaling activation was abolished by Dkk1 in CP-A cells. TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells. Dysplastic and esophageal adenocarcinoma tissues demonstrated further Dkk1 and AXIN2 overexpression. CONCLUSIONS: Despite the absence of robust nuclear accumulation, ß-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates ß-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells.

Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1ß with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1ß-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1ß activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.

Endothelial-mesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1ß and TGF-ß2.

Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1ß and transforming growth factor-ß2 (TGF-ß2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1ß and TGF-ß2 gene silencing in OE33 cells. Recombinant IL-1ß and TGF-ß2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression.

The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels.

Increased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 µm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10(-6) mol/l), or the angiotensin-converting enzyme inhibitor captopril (10(-5) mol/l) prevented the pressure-induced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension.

Consequences of gastrointestinal surgery on drug absorption.

Gastrointestinal (GI) surgery associated with resection or bypass can affect the absorption and kinetics of certain drugs. The goal of this article is 3-fold: (1) highlight the physiologic changes associated with selected GI surgeries (specifically gastric, small intestine, and colon), (2) review the implications for drug and nutrient absorption, and (3) suggest modifications of the pharmacologic agents, dosing regimens, and routes of delivery. Few large trials are available to use as references, but there is a wealth of individual reports and small series. Understanding the predictable challenges of drug administration in these patients will improve care.

Surgical outcomes in the elderly with inflammatory bowel disease are similar to those in the younger population.

BACKGROUND: Inflammatory bowel disease (IBD) has a bimodal distribution with approximately 15 % of patients manifesting after age 65. Previous reports suggest an increased risk of surgical complications in the elderly. AIM: To compare surgical outcomes in elderly IBD patients (≥ 65 years at the time of surgery) to matched younger IBD cohorts. METHODS: This was a retrospective cohort study at a single academic center of patients who underwent surgery for IBD. Forty-two elderly patients (≥ 65 years) were matched at least 1:1 (median 1:5) to patients in each of three control groups [18-35 years (n = 71); 36-49 years (n = 62); 50-64 years (n = 58)] according to gender, disease type/location, and type of surgery. Postoperative complications were compared. Patient characteristics were used in multivariate risk models. Analysis was performed using ordinary logistic regression. RESULTS: Twenty ileal or ileocolonic resections, 12 partial or total colectomies, four stricturoplasties, and six laparoscopic partial or total colectomies were performed in the elderly group. The post-operative complication rate was not statistically different between the elderly and younger cohorts (38 % vs. 39 % vs. 40 % vs. 48 % in the 18-35, 36-49, 50-64, and ≥ 65 years groups, respectively, p = 0.26). The only significant risk factors for complication were Charlson comorbidity index (p = 0.0002), preoperative hemoglobin (p = 0.0065), total parenteral nutrition use (p = 0.024), and failed medical therapy (as the indication for surgery) (p = <0.0001). CONCLUSIONS: The surgical complication rate among elderly and younger IBD patients was similar. Advanced age by itself should not be considered a risk factor for adverse operative outcome.

EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway.

AIM: To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC). METHODS: HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [(3)H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFκB subunit. KEY FINDING: Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFκB caspase 3 activity in HIMEC. SIGNIFICANCE: HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation.

Animal models for medical countermeasures to radiation exposure.

Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.

Modulatory effect of curcumin on survival of irradiated human intestinal microvascular endothelial cells: role of Akt/mTOR and NF-{kappa}B.

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.

Chlorhexidine-Alcohol versus Povidone-Iodine for Surgical-Site Antisepsis.

BACKGROUND: Since the patient's skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine-alcohol is more protective against infection than is povidone-iodine. METHODS: We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine-alcohol scrub or povidone-iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS: A total of 849 subjects (409 in the chlorhexidine-alcohol group and 440 in the povidone-iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections (4.2% vs. 8.6%, P=0.008) and deep incisional infections (1% vs. 3%, P=0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS: Preoperative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery. (ClinicalTrials.gov number, NCT00290290.)

Impact of autonomic dysfunction on inflammatory bowel disease.

UNLABELLED: Functional symptoms are common in patients with inflammatory bowel disease (IBD). The autonomic nervous system has been proposed to be involved in the pathogenesis of IBD. Autonomic dysfunction (AD) is associated with systemic manifestations and altered gut motility that may contributed to functional symptoms. AIM: To examine the impact of clinically manifest AD on patients with IBD. METHODS: This was a retrospective case-control study from a single tertiary referral IBD center. The cases comprised 43 IBD patients with AD diagnosed using a standardized battery of tests. Three disease-matched controls were selected for each case. We performed multivariate regression to compare health-related quality of life (SIBDQ), disease activity scores, and healthcare utilization. RESULTS: Female sex (83.7% vs. 53.5%, P<0.001) and psychiatric comorbidity (41.9% vs. 10.9%, P<0.001) were more common among IBD patients with AD than IBD controls. Small bowel transit times were significantly longer in cases (92.7 min) compared with controls (62.9 min, P=0.02). On multivariate analysis, AD was associated with a 7-point lower adjusted SIBDQ score compared with IBD controls [odds ratio (OR)-7.50; 95% confidence interval (CI), -12.0--3.03]. AD was also significantly associated with having more than 3 annual gastroenterology office visits (OR 2.84; 95% CI, 1.09-7.35), and 1 or more IBD-related medical hospitalizations (OR 2.49; 95% CI, 1.09-5.71). CONCLUSIONS: Clinically manifest AD is associated with lower quality of life and higher healthcare utilization in IBD patients. They may represent a cohort at risk for worse outcomes.

Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC).

The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-kappaB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD.

Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin.

Endothelial activation and surface expression of cell adhesion molecules (CAMs) is critical for binding and recruitment of circulating leukocytes in tissues during the inflammatory response. Endothelial CAM expression plays a critical role in the intestinal microvasculature in inflammatory bowel disease (IBD), as blockade of leukocyte alpha4-integrin binding by gut endothelial CAM ligands has therapeutic benefit in IBD. Mechanisms underlying expression of vascular cell adhesion molecule (VCAM)-1, a ligand for alpha4-integrin in primary cultures of human intestinal microvascular endothelial cells (HIMEC) has not been defined. We investigated the effect of curcumin, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK) inhibitors on VCAM-1 expression and function in HIMEC. CAM expression was assessed and HIMEC-leukocyte adhesion was visualized under static and flow conditions. Western blotting and in vitro kinase assays were used to assess Akt and MAPK activation. Nuclear factor-kappaB (NF-kappaB) activation and nuclear translocation of its p65 subunit were determined. Tumor necrosis factor (TNF)-alpha/lipopolysaccharide (LPS)-induced VCAM-1 expression in HIMEC was suppressed by Akt small-interfering RNA, curcumin, and inhibitors of NF-kappaB (SN-50), p38 MAPK (SB-203580) and PI 3-kinase/Akt (LY-294002). VCAM-1 induction was partially suppressed by p44/42 MAPK (PD-098059) but unaffected by c-Jun NH2-terminal kinase (SP-600125) inhibition. Curcumin inhibited Akt/MAPK/NF-kappaB activity and prevented nuclear translocation of the p65 NF-kappaB subunit following TNF-alpha/LPS. At physiological shear stress, curcumin attenuated leukocyte adhesion to TNF-alpha/LPS-activated HIMEC monolayers. In conclusion, curcumin inhibited the expression of VCAM-1 in HIMECs through blockade of Akt, p38 MAPK, and NF-kappaB. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.