Visceral fat loss by whole-body electromyostimulation is attenuated in male and absent in female older Non-Insulin-Dependent diabetes patients.

INTRODUCTION: Type 2 diabetes and its reversal correlate with increases and decreases in visceral fat (VF). Resistance exercise reduces VF in healthy persons, but little is known in type 2 diabetes. Muscle contractions induced by whole-body electromyostimulation (WB-EMS) provide a very effective form of resistance training. We hypothesized that WB-EMS reduces VF and improves plasma glucose measures in older non-insulin dependent diabetes mellitus (NIDDM) males and females. METHODS: A four-arm age-matched case control study was done on WB-EMS twice a week in older NIDDM patients (27 males, 18 females) compared with controls (15 males, 15 females). VAT area (VAT, cm2 ), total fat mass (TFM, kg) and lean body mass (LBM, kg) were assessed by DEXA-scanning. HbA1c, fasting glucose and plasma lipoproteins were measured at baseline and after 4 months. RESULTS: Baseline control VAT was higher in males than females (140.5 ± 35.6 vs. 96.7 ± 42.3, p < .001). In NIDDM, VAT was higher with no significant sex difference (206.5 ± 65.0 vs. 186.5 ± 60.5). In controls, WBEMS reduced VAT in males and females to similar extent (-16.9% and -16.4%, p < .001 vs. baseline) and in preference to TFM (-9.2% and -3.6%) or body weight loss (-2.8 and -2.1%). In NIDDM, VF loss was attenuated in males (-7.3%, p < .01) but completely absent in females. WBEMS reduced HbA1c and cholesterol and increased HDL levels (all p < .05) only in male NIDDM CONCLUSIONS: WBEMS induced VF loss in healthy older males and females an effect strongly attenuated in male and completely absent in female NIDDM patients. This questions the effectiveness of muscle contraction-induced VF lipolysis in NIDDM. Sex differences may dictate the success of resistance training in NIDDM, a subject that needs to be addressed in future studies.

Improving postoperative outcome in rectal cancer surgery: Enhanced Recovery After Surgery in an era of increasing laparoscopic resection.

PURPOSE: The Enhanced Recovery After Surgery (ERAS) protocol reduces complications and length of stay (LOS) in colon cancer, but implementation in rectal cancer is different because of neo-adjuvant therapy and surgical differences. Laparoscopic resection may further improve outcome. The aim of this study was to evaluate the effects of introducing ERAS on postoperative outcome after rectal cancer resection in an era of increasing laparoscopic resections. MATERIALS AND METHODS: Patients who underwent elective rectal cancer surgery from 2009 till 2015 were included in this observational cohort study. In 2010, ERAS was introduced and adherence to the protocol was registered. Open and laparoscopic resections were compared. With regression analysis, predictive factors for postoperative outcome and LOS were identified. RESULTS: A total of 499 patients were included. The LOS decreased from 12.3 days in 2009 to 5.7 days in 2015 (p = 0.000). Surgical site infections were reduced from 24% in 2009 to 5% in 2015 (p = 0.013) and postoperative ileus from 39% in 2009 to 6% in 2015 (p = 0.000). Only postoperative ERAS items and laparoscopic surgery were associated with an improved postoperative outcome and shorter LOS. CONCLUSIONS: ERAS proved to be feasible, safe, and contributed to improving short-term outcome in rectal cancer resections. The benefits of laparoscopic surgery may in part be explained by reaching better ERAS adherence rates. However, the laparoscopic approach was also associated with anastomotic leakage. Despite the potential of bias, this study provides an insight in effects of ERAS and laparoscopic surgery in a non-randomized real-time setting.

Visceral Fat and Anastomotic Leakage After Colon Cancer Resection.

BACKGROUND: Visceral fat is considered a risk for postoperative complications in colon cancer surgery. However, the association with anastomotic leakage as the most worrisome complication is not clear mainly because of underpowered studies. OBJECTIVE: The purpose of this study was to analyze the effect of visceral fat as a continuous variable on anastomotic leakage in a large cohort of colon cancer resections. DESIGN: This was a retrospective, multicenter cohort study. SETTINGS: This study used data of the Dutch Surgical Colorectal Audit of the years 2011 through 2014 from 8 Dutch teaching hospitals. Visceral fat was assessed on the routine preoperative abdominal CT scan. PATIENTS: A total of 2370 patients underwent colon cancer resection with primary anastomosis. There were 2011 patients operated electively and 359 in an emergency setting. MAIN OUTCOME MEASURES: The effect of visceral fat on anastomotic leakage after multivariable analysis was measured. RESULTS: Visceral fat was associated with anastomotic leakage in the elective colon resection group (n = 2011) but not in emergency colon resections (n = 359). Significant confounding was found for type of resection, BMI, and sex. The association of male sex and BMI as previously reported risk factors for anastomotic leakage was explained by visceral fat. LIMITATIONS: The study was limited by its retrospective character and missing clinical data of known risk factors for anastomotic leakage, like smoking history and certain medication. CONCLUSIONS: The independent association of visceral fat with anastomotic leakage was confined to the elective colon cancer resection group. The previously reported associations of male sex and BMI with anastomotic leakage were explained by visceral fat. Visceral fat-associated comorbidities did not influence anastomotic leakage, suggesting that its effect on colon anastomotic healing is local rather than systemic. Future risk analysis for anastomotic leakage in colon cancer surgery should contain visceral fat values and consider subgroup differences. See Video Abstract at http://links.lww.com/DCR/B396. ADIPOSIDAD VISCERAL Y FUGA ANASTOMTICA EN CASOS DE RESECCIN DE CNCER DE COLON: ANTECEDENTES:La acumulación de grasa visceral se considera como un factor de riesgo en caso de complicaciones postoperatorias de cirugía de cáncer de colon. Sin embargo, la asociación con la fuga anastomótica como la complicación más preocupante no está clara principalmente debido a los estudios de bajo impacto disponibles.OBJETIVO:Analizar el efecto de la adiposidad visceral como una variable contínua sobre la fuga anastomótica en una gran cohorte de resecciones de cáncer de colon.DISEÑO:Estudio de cohorte multicéntrico retrospectivo.AJUSTES:Se utilizaron los datos de la Auditoría Colorrectal Quirúrgica Holandesa entre los años 2011 y 2014 en 8 hospitales de enseñanza de los Paises bajos. La grasa visceral fué evaluada por medio de la tomografía computada abdominal preoperatoria de rutina.PACIENTES:Un total de 2370 pacientes fueron sometidos a resección de cáncer de colon con anastomosis primaria. 2011 pacientes fueron operados electivamente y 359 en situación de emergencia.PRINCIPALES MEDIDAS DE RESULTADO:El efecto de la adiposidad visceral en la fuga anastomótica después del análisis multivariable.RESULTADOS:La grasa visceral se asoció con la fuga anastomótica en el grupo de resección electiva de colon (n = 2011) pero no en las resecciones de emergencia (n = 359). Se encontraron factores de confusión significativos para el tipo de resección, el índice de masa corporal y el género. La adiposidad visceral explica la asociación del género masculino y el índice de masa corporal como factores de riesgo reportados previamente en los casos de fugas anastomóticas.LIMITACIONES:Carácter retrospectivo del estudio y la falta de datos clínicos de factores de riesgo conocidos para la fuga anastomótica, como los antecedentes de tabaquismo y el consumo de ciertos medicamentos.CONCLUSIONES:La asociación independiente de la adiposidad visceral con la fuga anastomótica se limitó al grupo de resección electiva por cáncer de colon. Las asociaciones previamente reportadas de género masculino e índice de masa corporal con fuga anastomótica se explicaron por la grasa visceral. Las comorbilidades asociadas a la grasa visceral no influyeron en la fuga anastomótica, lo que sugiere que la cicatrisación anastomótica obedece más a un factor local que a un factor sistémico. Un análisis de riesgos previsibles para fugas anastomóticas en casos de resección de cáncer de colon deben involucrar los valores de la adiposidad visceral y considerar las diferencias entre subgrupos. Consulte Video Resumen en http://links.lww.com/DCR/B396. (Traducción-Dr Xavier Delgadillo).

Erythrocyte deformability and aggregation in morbidly obese women undergoing laparoscopic gastric bypass surgery and effects of oral omega-3 fatty acid supplementation.

BACKGROUND: An adequate erythrocyte function is vital for tissue oxygenation and wound healing. The erythrocyte membrane phospholipid composition plays an important role in erythrocyte function and administration of omega-3 fatty acids may provide a means to improve it. OBJECTIVE: To investigate peri-operative erythrocyte function and effects of oral omega-3 fatty acids in morbidly obese women undergoing gastric bypass surgeryMETHODS:Fifty-six morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery were randomized between a low calorie diet (LCD) during 2 weeks or oral omega-3 poly-unsaturated fatty acids (n-3 PUFAs) and a normal diet during 4 weeks. Peri-operative blood samples were analyzed with the Lorrca MaxSIS Ektacytometer for erythrocyte deformability and aggregability. RESULTS: There were no significant differences in erythrocyte function between the groups at any time point. Only erythrocyte aggregability parameters were affected by surgery. At six month follow-up, aggregation index (AI) and cholesterol, glucose and insulin were significantly improved. CONCLUSIONS: In this study, oral Omega-3 supplementation did not affect erythrocyte function compared to a LCD. Six months after surgery a significant improvement in AI and metabolic parameters was observed in both groups, contributing to a reduction in the risk at thromboembolic and cardiovascular complications.

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women.

Retinol-binding protein-4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity-induced insulin resistance and correlates inversely with insulin-stimulated glucose disposal. But its role in insulin-mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin-mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4-activated macrophages markedly increased basal lipolysis and impaired insulin-mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro-inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4-induced insulin resistance in humans.

Preoperative Cerebrospinal Fluid Cortisol and the Risk of Postoperative Delirium: A Prospective Study of Older Hip Fracture Patients.

BACKGROUND: Ageing, depression, and neurodegenerative disease are common risk factors for delirium in the elderly. These risk factors are associated with dysregulation of the hypothalamic-pituitary-adrenal axis, resulting in higher levels of cortisol under normal and stressed conditions and a slower return to baseline. OBJECTIVES: We investigated whether elevated preoperative cerebrospinal fluid (CSF) cortisol levels are associated with the onset of postoperative delirium. METHODS: In a prospective cohort study CSF samples were collected after cannulation for the introduction of spinal anesthesia of 75 patients aged 75 years and older admitted for surgical repair of acute hip fracture. Delirium was assessed with the confusion assessment method (CAM) and the Delirium Rating Scale-Revised-98 (DRS-R98). Because the CAM and DRS-R98 were available for time of admission and 5 postoperative days, we used generalized estimating equations and linear mixed modeling to examine the association between preoperative CSF cortisol levels and the onset of postoperative delirium. RESULTS: Mean age was 83.5 (SD 5.06) years, and prefracture cognitive decline was present in one-third of the patients (24 [33%]). Postoperative delirium developed in 27 (36%) patients. We found no association between preoperative CSF cortisol levels and onset or severity of postoperative delirium. CONCLUSIONS: These findings do not support the hypothesis that higher preoperative CSF cortisol levels are associated with the onset of postoperative delirium in elderly hip fracture patients.

Effects of perioperative intravenous ω-3 fatty acids in colon cancer patients: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The postoperative inflammatory response contributes to tissue healing and recovery but overwhelming inflammation is associated with postoperative complications. n-3 (ω-3) PUFAs modulate inflammatory responses and may help to prevent a proinflammatory cascade. OBJECTIVES: We aimed to investigate the effects of perioperative intravenous n-3 PUFAs on inflammatory cytokines in colon cancer surgery. METHODS: This study is a randomized, double-blind, placebo-controlled clinical trial. Forty-four patients undergoing elective colon resection for nonmetastasized cancer were randomly assigned to 2 intravenous n-3 PUFA or saline control infusions the night before and the morning after surgery. Blood was sampled at 6 perioperative time points for changes in cytokines in serum and in LPS-stimulated whole blood samples and leukocyte membrane fatty acid profiles. RESULTS: Twenty-three patients received saline and 21 patients received n-3 PUFAs. Patient and operation characteristics were equal between groups, except for open resection (saline n = 5 compared with n-3 PUFA n = 0, P = 0.056). Ex-vivo IL-6 after LPS stimulation was significantly higher in the n-3 PUFA group at the first day after surgery (P = 0.014), but not different at the second day after surgery (P = 0.467). White blood cell count was higher in the n-3 PUFA group at the fourth day after surgery (P = 0.029). There were more patients with infectious complications in the n-3 PUFA group (8 compared with 3, P = 0.036). There were no overall differences in serum IL-6, IL-10, C-reactive protein, and length of stay. The administration of n-3 PUFAs resulted in rapid increases in leukocyte membrane n-3 PUFA content. CONCLUSIONS: In the n-3 PUFA group a clear relation with serum and LPS-stimulated cytokines was not found but, unexpectedly, more infectious complications occurred. Caution is thus required with the off-label use of a perioperative intravenous n-3 PUFA emulsion as a standalone infusion in the time sequence reported in the present study in colon resections with primary anastomosis. This trial was registered at clinicaltrials.gov as NCT02231203.

Erythrocyte deformability and aggregability in patients undergoing colon cancer surgery and effects of two infusions with omega-3 fatty acids.

BACKGROUND: An adequate erythrocyte function is vital for tissue oxygenation and wound healing. The erythrocyte membrane phospholipid composition plays an important role in erythrocyte function and administration of omega-3 fatty acids may provide a means to improve it. OBJECTIVE: To investigate peri-operative erythrocyte function and effects of omega-3 fatty acidsMETHODS:Forty-four patients undergoing elective laparoscopic colon resection for non-metastasized cancer were randomized between intravenous omega-3 poly-unsaturated fatty acids (n-3 PUFAs) or placebo (saline). Peri-operative blood samples were analyzed with a Lorrca MaxSIS Ektacytometer and erythrocyte membrane phospholipids were determined with gas chromatography. RESULTS: Patient and operation characteristics were equal between groups. There was a significant increase in erythrocyte membrane eicosapentaenoic acid (EPA) but not docosahexaenoic acid (DHA) in the n-PUFA group. There were no significant differences in erythrocyte deformability but the aggregation index (AI) was significantly lower and the aggregation half time (T½) was significantly higher in the n-3 PUFA group. CONCLUSION: This study confirms rapid changes in erythrocyte membrane phospholipid composition after administration of intravenous n-3 PUFAs. Erythrocyte deformability parameters were not affected but erythrocyte aggregability was decreased in the n-3 PUFA group. Further investigation is necessary to gain more insights in the effects of n-3 PUFA and the postoperative inflammatory response on erythrocyte function.

The trajectory of C-reactive protein serum levels in older hip fracture patients with postoperative delirium.

OBJECTIVES: Important precipitating risk factors for delirium such as infections, vascular disorders, and surgery are accompanied by a systemic inflammatory response. Systemic inflammatory mediators can induce delirium in susceptible individuals. Little is known about the trajectory of systemic inflammatory markers and their role in the development and outcome of delirium. METHODS: This is a prospective cohort study of older patients undergoing acute surgery for hip fracture. Baseline characteristics were assessed preoperatively. During hospital admission, presence of delirium was assessed daily according to the Confusion Assessment Method criteria. This study compared the trajectory of serum levels of the C-reactive protein (CRP) between people with and without postoperative delirium. Blood samples were taken at baseline and at postoperative day 1 through postoperative day 5. RESULTS: Forty-one out of 121 patients developed postoperative delirium after hip fracture surgery. Longitudinal analysis of the trajectory of serum CRP levels using the Generalized Estimating Equations (GEE) method identified that higher CRP levels were associated with postoperative delirium. CRP levels were higher from postoperative day 2 through postoperative day 5. No significant differences in serum CRP levels were found when we compared patients with short (1-2 days) and more prolonged delirium (3 days or more). CONCLUSIONS: Delirium is associated with an increased systemic inflammatory response, and our results suggest that CRP plays a role in the underlying (inflammatory-vascular) pathological pathway of postoperative delirium.

Four Weeks of Preoperative Omega-3 Fatty Acids Reduce Liver Volume: a Randomised Controlled Trial.

PURPOSE: Weight loss before bariatric surgery with a low-calorie diet (LCD) has several advantages, including reduction of liver volume and an improved access to the lesser sac. Disadvantages include performing surgery in a state of undernutrition, side effects, costs and patient compliance. Omega-3 fatty acids may serve as an alternative to reduce liver steatosis. MATERIALS AND METHODS: A randomised controlled open-label trial was done to compare the effects of a LCD with Modifast (800 kcal/day) during 2 weeks with 2 g of omega-3 fatty acids a day and a normal diet (2000 kcal/day) during 4 weeks. Total liver volume (TLV) and volume of the left liver lobe (LLL), visceral fat area (VFA) and muscle area (SMA) at the L3-L4 level were measured with MRI before and after preoperative treatment. RESULTS: Sixty-two morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) were recruited. In both groups, there was a significant decrease in LLL, TLV and VFA. For LLL and TLV reduction, the LCD had a significantly larger effect (p < 0.05). Only in the LCD group was there a significant decrease in SMA with significantly more side effects and worse compliance. CONCLUSION: Both the LCD and omega-3 diet reduced LLL, TLV and VFA. The LCD outperformed the omega-3 diet in LLL and TLV reduction, but induced significant loss of SMA and had worse compliance due to more side effects. Omega-3 fatty acids may provide a safe and more patient-friendly alternative for a LCD and further research is indicated. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov (NCT02206256).

Superiority of Step-up Approach vs Open Necrosectomy in Long-term Follow-up of Patients With Necrotizing Pancreatitis.

BACKGROUND & AIMS: In a 2010 randomized trial (the PANTER trial), a surgical step-up approach for infected necrotizing pancreatitis was found to reduce the composite endpoint of death or major complications compared with open necrosectomy; 35% of patients were successfully treated with simple catheter drainage only. There is concern, however, that minimally invasive treatment increases the need for reinterventions for residual peripancreatic necrotic collections and other complications during the long term. We therefore performed a long-term follow-up study. METHODS: We reevaluated all the 73 patients (of the 88 patients randomly assigned to groups) who were still alive after the index admission, at a mean 86 months (±11 months) of follow-up. We collected data on all clinical and health care resource utilization endpoints through this follow-up period. The primary endpoint was death or major complications (the same as for the PANTER trial). We also measured exocrine insufficiency, quality of life (using the Short Form-36 and EuroQol 5 dimensions forms), and Izbicki pain scores. RESULTS: From index admission to long-term follow-up, 19 patients (44%) died or had major complications in the step-up group compared with 33 patients (73%) in the open-necrosectomy group (P = .005). Significantly lower proportions of patients in the step-up group had incisional hernias (23% vs 53%; P = .004), pancreatic exocrine insufficiency (29% vs 56%; P = .03), or endocrine insufficiency (40% vs 64%; P = .05). There were no significant differences between groups in proportions of patients requiring additional drainage procedures (11% vs 13%; P = .99) or pancreatic surgery (11% vs 5%; P = .43), or in recurrent acute pancreatitis, chronic pancreatitis, Izbicki pain scores, or medical costs. Quality of life increased during follow-up without a significant difference between groups. CONCLUSIONS: In an analysis of long-term outcomes of trial participants, we found the step-up approach for necrotizing pancreatitis to be superior to open necrosectomy, without increased risk of reinterventions.

Effects of a Carbohydrate-, Glutamine-, and Antioxidant-Enriched Oral Nutrition Supplement on Major Surgery-Induced Insulin Resistance: A Randomized Pilot Study.

BACKGROUND: Insulin resistance after surgery hampers recovery. Oxidative stress is shown to be involved in the occurrence of postoperative insulin resistance. Preoperative carbohydrate-rich oral nutrition supplements reduce but do not prevent insulin resistance. The aim of the present study was to investigate the effect of a carbohydrate-, glutamine-, and antioxidant-enriched preoperative oral nutrition supplement on postoperative insulin resistance. METHODS: A double-blind randomized controlled pilot study in 18 patients with rectal cancer, who received either the supplement (S) or the placebo (P) 15, 11, and 4 hours preoperatively, was conducted. Insulin sensitivity was studied prior to surgery and on the first postoperative day using a hyperinsulinemic euglycemic 2-step clamp. RESULTS: Hepatic insulin sensitivity (insulin-mediated suppression of glucose production) decreased significantly after surgery in both groups, with no differences between the groups. Peripheral insulin sensitivity (glucose rate of disappearance, Rd) was significantly decreased after surgery in both groups (S: 37.2 [19.1-50.9] vs 20.6 [13.9-27.9]; P: 23.8 [15.7-35.5] vs 15.3 [12.6-19.1] µmol/kg·min) but less pronounced in the supplemented group (P = .04). The percentage decrease in glucose Rd did not differ between the groups. Adipose tissue insulin sensitivity (insulin-mediated suppression of plasma free fatty acids) decreased to the same extent after surgery in both groups. CONCLUSION: Rectal cancer surgery induced profound insulin resistance, affecting glucose and fatty acid metabolism. The preoperative nutrition supplement somewhat attenuated but did not prevent postoperative peripheral insulin resistance.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development.

A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1.

BACKGROUND: Anti-angiogenic therapies, targeting VEGF, are a promising treatment for hepatocellular carcinoma (HCC). To enhance this potential therapy, identification of novel targets in this pathway is of major interest. Nitric oxide (NO) plays a crucial role in VEGF-dependent angiogenesis. NO production depends on arginine as substrate and asymmetric dimethylarginine (ADMA) as inhibitor. Dimethylarginine dimethylaminohydrolase 1 (DDAH-1) catabolizes ADMA and therefore regulates NO and VEGF expression. This study unravels additional mechanisms to improve VEGF targeting therapies. METHODS: The expression of DDAH-1 was examined in HCC specimen and non-tumorous background liver of 20 patients undergoing liver resection. Subsequently, arginine/ADMA balance, NO production, and VEGF expression were analyzed. The influence of hypoxia on DDAH-1 and angiogenesis promoting factors was evaluated in HepG2 cells and primary human hepatocytes. RESULTS: DDAH-1 expression was significantly induced in primary HCC tumors compared to non-tumorous background liver. This was associated with an increased arginine/ADMA ratio, higher NO formation, and higher VEGF expression in human HCC compared to non-tumorous liver. Hypoxia induced DDAH-1, iNOS, and VEGF expression in a time-dependent manner in HepG2 cells. CONCLUSIONS: Our results indicate that DDAH-1 expression is increased in human HCC, which is associated with an increase in the arginine/ADMA ratio and enhanced NO formation. Hypoxia may be an initiating factor for the increase in DDAH-1 expression. DDAH-1 expression is associated with promotion of angiogenesis stimulating factor VEGF. Together, our findings for the first time identified DDAH-1 as a key player in the regulation of angiogenesis in human HCC, and by understanding this mechanism, future therapeutic strategies targeting VEGF can be improved.

Enteral Glutamine Administration in Critically Ill Nonseptic Patients Does Not Trigger Arginine Synthesis.

Glutamine supplementation in specific groups of critically ill patients results in favourable clinical outcome. Enhancement of citrulline and arginine synthesis by glutamine could serve as a potential mechanism. However, while receiving optimal enteral nutrition, uptake and enteral metabolism of glutamine in critically ill patients remain unknown. Therefore we investigated the effect of a therapeutically relevant dose of L-glutamine on synthesis of L-citrulline and subsequent L-arginine in this group. Ten versus ten critically ill patients receiving full enteral nutrition, or isocaloric isonitrogenous enteral nutrition including 0.5 g/kg L-alanyl-L-glutamine, were studied using stable isotopes. A cross-over design using intravenous and enteral tracers enabled splanchnic extraction (SE) calculations. Endogenous rate of appearance and SE of glutamine citrulline and arginine was not different (SE controls versus alanyl-glutamine: glutamine 48 and 48%, citrulline 33 versus 45%, and arginine 45 versus 42%). Turnover from glutamine to citrulline and arginine was not higher in glutamine-administered patients. In critically ill nonseptic patients receiving adequate nutrition and a relevant dose of glutamine there was no extra citrulline or arginine synthesis and glutamine SE was not increased. This suggests that for arginine synthesis enhancement there is no need for an additional dose of glutamine when this population is adequately fed. This trial is registered with NTR2285.

Visceral obesity, muscle mass and outcome in rectal cancer surgery after neo-adjuvant chemo-radiation.

BACKGROUND: Preoperative chemoradiation has become a routine modality in the treatment of rectal carcinoma that may impair a patients general condition. In these patients, it is important to identify factors that influence postoperative recovery. Visceral obesity(VO) as a metabolic risk factor was studied in rectal cancer patients receiving preoperative chemoradiation. AIM: The impact of VO on post-operative outcome in rectal carcinoma surgery after preoperative chemoradiation was studied. In addition, the effect of chemoradiation on body composition was studied. METHOD: The visceral fat area(VFA), total fat area(TFA) and skeletal muscle area(SMA) were measured on cross-sectional CT-slides in 74 patients who underwent rectal cancer surgery after chemoradiation. CT-scans taken before and after chemoradiation were analysed. Associations between VFA, per- and postoperative complications were studied. A VFA of 100 cm(2) and 130 cm(2) was used to differentiate between non-VO and VO. RESULTS: Using a VO cut-off point of a VFA of 100 cm(2), the VO patients had more per-operative blood loss(471 mL vs 271 mL p = 0.020), a higher complication rate(10% vs 49% p = 0.001), more ileus(2% vs 28% p = 0.027) and a longer length of stay(9.7days vs 13days p = 0.027). When a VFA of 130 cm(2) was used, VO patients showed more complications(17% vs 55%, p = 0.001) and ileus(10% vs 32% p = 0.017). During chemoradiation the SMA increased(Mean difference: 2.2 cm(2) p = 0.024), while the VFA showed no change. CONCLUSION: It appears that VO is associated with co-morbidity and poor outcome in rectal cancer patients. Using different cutoff values for VO different associations with outcome were found. SMA increased during chemoradiation, a phenomenon that remains to be explained.

Taurine Concentrations Decrease in Critically Ill Patients With Shock Given Enteral Nutrition.

BACKGROUND: Nutrition studies in the intensive care unit (ICU) have shown that adequate enteral nutrition (EN) support has clinical benefits. However, the course of amino acid concentrations in plasma has never been investigated in patients admitted with shock receiving EN. We hypothesized that plasma concentrations, when deficit, increase during EN and that persistent deficiency is associated with poor outcome. METHODS: In 33 septic or cardiogenic shock patients receiving EN, plasma amino acid concentrations were measured during 5 days. Changes in amino acid concentrations, correlations with clinical outcome variables, and regression analyses were studied. RESULTS: On ICU admission, several plasma concentrations were deficient. Plasma concentrations of almost all amino acids increased. In contrast, taurine decreased by >50%, from 47.6 µmol/L on admission to 20.0 µmol/L at day 1, and remained low at day 5. Taurine (admission) correlated with time on mechanical ventilation (R = -0.42, P = .015). Taurine decrease within 24 hours correlated with Acute Physiology and Chronic Health Evaluation II predicted mortality (R = 0.43, P = .017) and Sequential Organ Failure Assessment score (R = 0.36, P = .05). Regression analyses confirmed correlations. CONCLUSIONS: Several amino acids were deficient in plasma on ICU admission but increased during EN. Taurine concentrations declined and were associated with longer periods of mechanical ventilation and ICU support. Fast taurine decline correlated with severity of organ failure. These findings support the role of taurine during ischemia, reperfusion, and inflammation. Taurine may be an essential candidate to enrich nutrition support for critically ill patients, although more research is required.

Risk of anastomotic leakage with nonsteroidal anti-inflammatory drugs within an enhanced recovery program.

INTRODUCTION: Anastomotic leakage is a serious complication after colorectal resection. Recent studies suggest that nonsteroidal anti-inflammatory drugs may increase the risk of anastomotic leakage. We investigated this association in our enhanced recovery population. MATERIAL AND METHODS: Patients undergoing an elective colon or rectal resection with primary anastomosis because of malignancy and treated within our enhanced recovery program were included. Univariable and multivariable logistic regression analyses were used to study risk factors for anastomotic leakage. RESULTS: Between 2006 and 2013, 856 patients were included. The anastomotic leakage rate was significantly higher in the group that received nonsteroidal anti-inflammatory drugs compared to patients who did not: 9.2 vs. 5.3%, p = 0.038. This higher rate was only seen in patients receiving diclofenac: for colonic resections, 11.8 vs. 6.0%, p = 0.016; for rectal resections, 13.1 vs. 0%, p = 0.017. Only male sex (odds ratio 2.20, p = 0.005) was also independently associated with anastomotic leakage. CONCLUSION: The results of this study are in line with other comparable studies in the literature, showing an increased risk for anastomotic leakage with diclofenac. The use of diclofenac in colorectal surgery can no longer be recommended. Alternatives for postoperative analgesia need to be explored within an enhanced recovery program.

Preoperative protein profiles in cerebrospinal fluid in elderly hip fracture patients at risk for delirium: A proteomics and validation study.

BACKGROUND: A neuroinflammatory response is suggested to play an important role in delirium, a common complication in older hospitalized patients. We examined whether hip fracture patients who develop postoperative delirium have a different proteome in cerebrospinal fluid (CSF) prior to surgery. METHODS: Patients (≥ 75 years) were admitted for hip fracture surgery. CSF was collected during spinal anaesthesia; proteins were separated using gel electrophoresis and identified with mass spectrometry. We compared the proteome of patients with and without postoperative delirium. Findings were validated in an independent, comparable cohort using immuno-assays. RESULTS: In the derivation cohort 53 patients were included, 35.8% developed postoperative delirium. We identified differences in levels of eight CSF proteins between patients with and without subsequent delirium: complement factor C3, contactin-1, fibulin-1 and I-beta-1,3-N-acetylglucosaminyltransferase were significantly lower in patients with postoperative delirium, while neural cell adhesion molecule-2, fibrinogen, zinc-α-2-glycoprotein and haptoglobin levels were significantly higher. In the validation cohort 21.2% of 52 patients developed postoperative delirium. Immuno-assays confirmed contactin-1 results although not statistically significant. Complement factor C3 was significantly higher in patients with postoperative delirium. CONCLUSION: Our results show the complexity of pathophysiological mechanisms involved in delirium and emphasizes the need of independent validation of findings. GENERAL SIGNIFICANCE: This study highlights the challenges and inconsistent findings in studies of delirium, a serious complication in older patients. We analysed proteins in CSF, the most proximal fluid to the brain. All patients were free from delirium at the time of sampling.