Development of pancreatic diseases during long-term follow-up after acute pancreatitis: a post-hoc analysis of a prospective multicenter cohort.

BACKGROUND AND AIM: More insight into the incidence of and factors associated with progression following a first episode of acute pancreatitis (AP) would offer opportunities for improvements in disease management and patient counseling. METHODS: A long-term post hoc analysis of a prospective cohort of patients with AP (2008-2015) was performed. Primary endpoints were recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic cancer. Cumulative incidence calculations and risk analyses were performed. RESULTS: Overall, 1184 patients with a median follow-up of 9 years (IQR: 7-11) were included. RAP and CP occurred in 301 patients (25%) and 72 patients (6%), with the highest incidences observed for alcoholic pancreatitis (40% and 22%). Pancreatic cancer was diagnosed in 14 patients (1%). Predictive factors for RAP were alcoholic and idiopathic pancreatitis (OR 2.70, 95% CI 1.51-4.82 and OR 2.06, 95% CI 1.40-3.02), and no pancreatic interventions (OR 1.82, 95% CI 1.10-3.01). Non-biliary etiology (alcohol: OR 5.24, 95% CI 1.94-14.16, idiopathic: OR 4.57, 95% CI 2.05-10.16, and other: OR 2.97, 95% CI 1.11-7.94), RAP (OR 4.93, 95% CI 2.84-8.58), prior pancreatic interventions (OR 3.10, 95% CI 1.20-8.02), smoking (OR 2.33, 95% CI 1.14-4.78), and male sex (OR 2.06, 95% CI 1.05-4.05) were independently associated with CP. CONCLUSION: Disease progression was observed in a quarter of pancreatitis patients. We identified several risk factors that may be helpful to devise personalized strategies with the intention to reduce the impact of disease progression in patients with AP.

Inter-Rater Agreement of the Classification of Intraoperative Adverse Events (ClassIntra) in Abdominal Surgery.

OBJECTIVE AND SUMMARY OF BACKGROUND DATA: Adverse events in surgical patients can occur preoperatively, intraoperatively, and postoperatively. Universally accepted classification systems are not yet available for intraoperative adverse events (iAEs). ClassIntra has recently been developed and validated as a tool for grading iAEs that occur between skin incision and skin closure irrespective of the origin, that is, surgery, anesthesia, or organizational. The aim of this study is to assess the inter-rater agreement of ClassIntra and assess its predictive value for postoperative complications in elective abdominal surgery. METHODS: This study is a secondary use of data from the LAParotomy or LAParoscopy and ADhesiolysis (LAPAD) study, with detailed data on incidence and management of intra-operative and post-operative complications. Data were collected in a cohort of elective abdominal surgeries. Two teams graded all recorded events in the LAPAD study according to ClassIntra. Cohen Kappa coefficient was calculated to determine inter-rater agreement. Uni- and multivariable linear regression was used to assess the predictive value of the ClassIntra grades for postoperative complications. RESULTS: IAEs were rated in 333 of 755 (44%) surgeries by team 1, and in 324 of 755 (43%) surgeries by team 2. Cohen kappa coefficient for ClassIntra grades was 0.87 [95% confidence interval (CI) 0.84-0.90]. Discrepancies in grading were most frequent for intraoperative bleeding and adhesions' associated injuries. At least 1 postoperative complication was observed in 278 (37%) patients. The risk of a postoperative complications increased with every increase in severity grade of ClassIntra. Intraoperative hypotension [mean difference (MD) 23.41, 95% CI 12.93-33.90] and other organ injuries (MD 18.90, 95% CI -4.22 - 42.02) were the strongest predictors for postoperative complications. CONCLUSIONS: ClassIntra has an almost perfect inter-rater agreement for the classification of iAEs. An increasing grade of ClassIntra was associated with a higher incidence of postoperative complications. Discrepancies in grading related to common complications in abdominal procedures mostly consisted of intraoperative bleeding and adhesion-related injuries. Grading of interoperative events in abdominal surgery might further improve by consensus regarding the definitions of a number of frequent events.

Oxidative Stress Predicts Post-Surgery Complications in Gastrointestinal Cancer Patients.

INTRODUCTION: An excessive perioperative inflammatory reaction can lead to more postoperative complications in patients treated for gastrointestinal cancers. It has been suggested that this inflammatory reaction leads to oxidative stress. The most important nonenzymatic antioxidants are serum free thiols. The purpose of this study was to evaluate whether high preoperative serum free thiol levels are associated with short-term clinical outcomes. METHODS: Blood samples were drawn before, at the end of, and 1 and 2 days after surgery of a consecutive series of patients with gastrointestinal cancer. Serum free thiols were detected using a colorimetric detection method using Ellman's reagent. Short-term clinical outcomes were defined as 30-day complications (Clavien-Dindo ≥2) and length of hospital stay. Logistic regression was applied to examine the association between serum free thiol levels and short-term patient outcomes. RESULTS: Eighty-one patients surgically treated for gastrointestinal cancer were included in the study. Median age was 68 (range 26-87) years, and 28% were female. Patients in the lowest tertile of preoperative serum free thiols had a threefold higher risk to develop postoperative complications (odds ratio [OR]: 3.4; 95% confidence interval [CI]:1.1-10.7) and a fourfold higher risk to have an increased length of stay in the hospital (OR 4.0; 95% CI 1.3-12.9) compared with patients in the highest tertile. CONCLUSIONS: Patients with lower preoperative serum free thiol levels, indicating a decrease in extracellular antioxidant capacity and therefore an increase in systemic oxidative stress, are more likely to develop postoperative complications and show a longer in hospital stay than patients with higher serum free thiol levels.

Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus.

BACKGROUND: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16-, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD. METHODS: Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers. RESULTS: Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM. CONCLUSIONS: Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions.

Analgesia in patients with adhesion-related chronic abdominal and pelvic pain after surgery: a systematic review.

BACKGROUND AND OBJECTIVE: Adhesions are the most common cause of chronic abdominal pain after surgery. Surgical adhesiolysis can relieve symptoms in selected patients, but many require other treatments. The aim of this study is to evaluate analgesic treatments other than abdominal surgery in chronic pain related to adhesions. DATABASE AND DATA TREATMENT: A search was conducted in PubMed, Embase, and Central. Studies with patients suffering from chronic postoperative pain related to adhesions and undergoing all types' analgesic treatment were included. The primary outcome was the number of patients who improved in pain at long-term follow-up (at least 1 year). Secondary outcomes included improvement in pain at 3 months follow-up, quality of life, and physical functioning. RESULTS: Searches identified 3022 citations. Four studies were included, one trial, one cohort study, and two case reports. The primary outcome was not reported. In a small trial (n = 18) pregabalin tended to have a benefit over placebo improving pain at 3 months. In the cohort study, 17 patients with chronic pelvic pain underwent a trial of sacral nerve stimulation. Eight patients who responded positively received an implanted device for continuous modulation, reporting sustainable improvement during follow-up (range: 6-36 months). One case report described improved pain at 6 months with trans-abdominis plane stimulation. The second report described improvement of physical function with manual therapy at long-term follow-up. CONCLUSIONS: Low level of evidence is available regarding analgesic treatments of chronic abdominal and pelvic pain related to adhesions. The benefit of pregabalin is doubtful; nerve modulation is promising in a selected group.HighlightsAdhesions are a frequent cause of chronic abdominal and pelvic pain after surgery.Many patients are not good candidates for surgery (Adhesiolysis) or have relapses of pain.There is an important knowledge gap regarding non-surgical analgesic treatment.Analgesia in adhesion-related chronic abdominal pain after surgery.

Low body weight and involuntary weight loss are associated with Raynaud's phenomenon in both men and women.

Objectives: Low body weight is an easily assessable cause of Raynaud's phenomenon (RP), and is frequently overlooked by clinicians. We aim to investigate the association of low body weight (body mass index < 18.5 kg/m2), involuntary weight loss, and nutritional restrictions with the presence of RP.Method: Participants from the Lifelines Cohort completed a validated self-administered connective tissue disease questionnaire. Subjects who reported cold-sensitive fingers and biphasic or triphasic colour changes were considered to suffer from RP. Patient characteristics, anthropometric measurements, and nutritional habits were collected. Statistical analyses was stratified for gender.Results: Altogether, 93 935 participants completed the questionnaire. The prevalence of RP was 4.2% [95% confidence interval (CI) 4.1-4.4%], and was three-fold higher in women than in men (5.7% vs 2.1%, p < 0.001). Subjects with RP had a significantly lower daily caloric intake than those without RP. Multivariate analysis, correcting for creatinine level, daily caloric intake, and other known aetiological factors associated with RP, revealed that low body weight [men: odds ratio (OR) 5.55 (95% CI 2.82-10.93); women: 3.14 (2.40-4.10)] and involuntary weight loss [men: OR 1.32 (1.17-1.48); women: 1.31 (1.20-1.44)] were significantly associated with the presence of RP. Low-fat diet was also associated with RP in women [OR 1.27 (1.15-1.44)].Conclusion: Low body weight and prior involuntary weight loss are associated with an increased risk of RP in both men and women. This study emphasizes that low body weight and weight loss are easily overlooked risk factors for RP, and should be assessed and monitored in subjects with RP.

Low-fat/high-fibre diet prehabilitation improves anastomotic healing via the microbiome: an experimental model.

BACKGROUND: Both obesity and the presence of collagenolytic bacterial strains (Enterococcus faecalis) can increase the risk of anastomotic leak. The aim of this study was to determine whether mice chronically fed a high-fat Western-type diet (WD) develop anastomotic leak in association with altered microbiota, and whether this can be mitigated by a short course of standard chow diet (SD; low fat/high fibre) before surgery. METHODS: Male C57BL/6 mice were assigned to either SD or an obesogenic WD for 6 weeks followed by preoperative antibiotics and colonic anastomosis. Microbiota were analysed longitudinally after operation and correlated with healing using an established anastomotic healing score. In reiterative experiments, mice fed a WD for 6 weeks were exposed to a SD for 2, 4 and 6 days before colonic surgery, and anastomotic healing and colonic microbiota analysed. RESULTS: Compared with SD-fed mice, WD-fed mice demonstrated an increased risk of anastomotic leak, with a bloom in the abundance of Enterococcus in lumen and expelled stool (65-90 per cent for WD versus 4-15 per cent for SD; P = 0·010 for lumen, P = 0·013 for stool). Microbiota of SD-fed mice, but not those fed WD, were restored to their preoperative composition after surgery. Anastomotic healing was significantly improved when WD-fed mice were exposed to a SD diet for 2 days before antibiotics and surgery (P < 0·001). CONCLUSION: The adverse effects of chronic feeding of a WD on the microbiota and anastomotic healing can be prevented by a short course of SD in mice. Surgical relevance Worldwide, enhanced recovery programmes have developed into standards of care that reduce major complications after surgery, such as surgical-site infections and anastomotic leak. A complementary effort termed prehabilitation includes preoperative approaches such as smoking cessation, exercise and dietary modification. This study investigated whether a short course of dietary prehabilitation in the form of a low-fat/high-fibre composition can reverse the adverse effect of a high-fat Western-type diet on anastomotic healing in mice. Intake of a Western-type diet had a major adverse effect on both the intestinal microbiome and anastomotic healing following colonic anastomosis in mice. This could be reversed when mice received a low-fat/high-fibre diet before operation. Taken together, these data suggest that dietary modifications before major surgery can improve surgical outcomes via their effects on the intestinal microbiome.

ANTECEDENTES: Tanto la obesidad como la presencia de cepas bacterianas colagenolíticas (Enterococcus faecalis) pueden aumentar el riesgo de fuga anastomótica. El objetivo de este estudio fue determinar si los ratones alimentados durante un tiempo prolongado con una dieta de tipo occidental con alto contenido en grasas (western type diet, WD) desarrollaban una fuga anastomótica en asociación con una microbiota alterada, así como determinar si una dieta estándar preoperatoria de corta duración baja en grasa/alta en fibra (standard diet, SD) podía mitigar la aparición de fuga. MÉTODOS: Ratones machos C57BL/6 obtenidos de Charles River fueron asignados aleatoriamente a una dieta chow estándar (SD) o a una dieta de tipo occidental obesogénica (WD) durante 6 semanas, seguida de la administración preoperatoria de antibióticos y la realización de una anastomosis en el colon. La microbiota se analizó longitudinalmente después de la operación y se correlacionó con la curación utilizando una puntuación de cicatrización anastomótica ya establecida. En experimentos repetidos, los ratones con una WD durante 6 semanas fueron expuestos a una SD durante 2, 4 y 6 días antes de la cirugía de colon, analizándose la cicatrización de la anastomosis y la microbiota del colon. RESULTADOS: Los ratones alimentados con WD en comparación con los alimentados con SD presentaron un mayor riesgo de fuga anastomótica con un rápido incremento en la abundancia de Enterococcus (65-90% para WD versus 4-15% para SD, P < 0,01). La microbiota de ratones alimentados con SD, pero no con WD, se restableció a su composición preoperatoria después de la operación. La cicatrización anastomótica mejoró significativamente cuando los ratones alimentados con WD fueron expuestos a una dieta SD durante 2 días antes del tratamiento antibiótico y de la cirugía (P < 0,01). CONCLUSIÓN: En ratones, los efectos adversos de una alimentación crónica con una WD sobre la microbiota y la cicatrización anastomótica se pueden prevenir mediante una SD de corta duración.

Novel de novo synthesized phosphate carrier compound ABA-PEG20k-Pi20 suppresses collagenase production in Enterococcus faecalis and prevents colonic anastomotic leak in an experimental model.

BACKGROUND: Previous work has demonstrated that anastomotic leak can be caused by collagenolytic bacteria such as Enterococcus faecalis via an effect on wound collagen. In humans, E. faecalis is the organism cultured most commonly from a leaking anastomosis, and is not routinely eliminated by standard oral or intravenous antibiotics. Novel strategies are needed to contain the virulence of this pathogen when present on anastomotic tissues. METHODS: Polyphosphorylated polymer ABA-PEG20k-Pi20 was tested in mice for its ability to prevent anastomotic leak caused by collagenolytic E. faecalis. The study design included a distal colonic resection and anastomosis followed by introduction of E. faecalis to anastomotic tissues via enema. Mice were assigned randomly to receive either ABA-PEG20-Pi20 or its unphosphorylated precursor ABA-PEG20k in their drinking water. The development of anastomotic leak was determined after the animals had been killed. RESULTS: Overnight incubation of two different E. faecalis collagenolytic strains with 2 mmol/l of ABA-PEG20k-Pi20 led to near complete inhibition of collagenase production (from 21 000 to 1000 and from 68 000 to 5000 units; P < 0·001; 6 samples per group) without suppressing bacterial growth. In mice drinking 1 per cent ABA-PEG20k-Pi20, the phosphate concentration in the distal colonic mucosa increased twofold and leak rates decreased from eight of 15 to three of 15 animals (P < 0·001). In mice drinking ABA-PEG20k-Pi20, the percentage of collagenolytic colonies among E. faecalis populations present at anastomotic tissue sites was decreased by 6-4800-fold (P = 0·008; 5 animals). CONCLUSION: These data indicate that oral intake of ABA-PEG20k-Pi20 may be an effective agent to contain the virulence of E. faecalis and may prevent anastomotic leak caused by this organism. Clinical relevance Progress in understanding the pathogenesis of anastomotic leak continues to point to intestinal bacteria as key causative agents. The presence of pathogens such as Enterococcus faecalis that predominate on anastomotic tissues despite antibiotic use, coupled with their ability to produce collagenase, appears to alter the process of healing that leads to leakage. Further antibiotic administration may seem logical, but carries the unwanted risk of eliminating the normal microbiome, which functions competitively to exclude and suppress the virulence of pathogens such as E. faecalis. Therefore, non-antibiotic strategies that can suppress the production of collagenase by E. faecalis without affecting its growth, or potentially normal beneficial microbiota, may have unique advantages. The findings of this study demonstrate that drinking a phosphate-based polymer can achieve the goal of preventing anastomotic leak by suppressing collagenase production in E. faecalis without affecting its growth.

Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction.

Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and IDO gene therapy inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline. During the first 10 days recipients received low-dose cyclosporine. Body weight, blood pressure, serum creatinine and proteinuria were measured every 2 weeks. Rats were killed after 12 weeks. IDO had a striking beneficial effect on transplant vasculopathy at week 12. It also significantly improved body weight gain; it reduced blood pressure and decreased proteinuria during the follow-up. However, it did not affect the kidney function. In addition, IDO therapy significantly decreased the number of graft-infiltrating macrophages at week 12. The messenger RNA levels of forkhead box p3 and transforming grow factor-ß were elevated in the IDO treated group at week 12. Here we show for first time a clear beneficial effect of local IDO gene therapy especially on transplant vasculopathy in a rat model of renal CTD.

[An infected necrosis of the chin]. / Geïnfecteerde necrose van de kin.

A 51-year-old man was referred by his dentist to a maxillofacial surgeon with complaints of illness and pain in the mandible, associated with a rapidly expanding area of black gingiva and mucosa surrounding the lower front teeth. Clinically and radiographically there was evidence of an infected necrosis of the chin and floor of mouth. Following debridement at the operating room, the patient was treated at the intensive care unit for septic shock leading to prolonged hospitalisation. Investigation of the bone marrow did not provide an explanation for pancytopenia or the severity of the illness. In addition, genetic investigation of thiopurine S-methyltransferase gene showed no mutations. This gene codes for an identically named protein enzyme that contributes in the metabolising of the medicine azathioprine, used daily for an autoimmune disease. A combination of the use of azathioprine, a folic acid deficiency and sepsis led to this exceptional course of illness. Therapeutic intervention consisted of surgical debridement and treatment of the bacteraemia. Afterwards several corrective surgeries were necessary to restore oral functions.

Systematic review of experimental studies on intestinal anastomosis.

BACKGROUND: The contribution of animal research to a reduction in clinical intestinal anastomotic leakage is unknown, despite numerous experimental studies. In view of the current societal call to replace, reduce and refine animal experiments, this study examined the quality of animal research related to anastomotic healing and leakage. METHODS: Animal studies on intestinal anastomotic healing were retrieved systematically from PubMed and Embase. Study objective, conclusion and animal model were recorded. Reporting quality and internal validity (reporting of randomization and blinding) were assessed. RESULTS: A total of 1342 studies were identified, with a rising publication rate. The objectives of most studies were therapeutic interventions (64·8 per cent) and identification of risk factors (27·5 per cent). Of 350 articles studying experimental therapies, 298 (85·1 per cent) reported a positive effect on anastomotic healing. On average, 44·7 per cent of relevant study characteristics were not reported, in particular details on anastomotic complications (31·6 per cent), use of antibiotics (75·7 per cent), sterile surgery (83·4 per cent) and postoperative analgesia (91·4 per cent). The proportion of studies with randomization, blinding of surgery and blinding of primary outcome assessment has increased in the past two decades but remains insufficient, being included in only 62·4, 4·9 and 8·5 per cent of publications respectively. Animal models varied widely in terms of species, method to compromise healing, intestinal segment and outcome measures used. CONCLUSION: Animal research on anastomotic leakage is of poor quality and still increasing, contrary to societal aims. Reporting and study quality must improve if results are to impact on patients.

Dutch Chronic Pancreatitis Registry (CARE): design and rationale of a nationwide prospective evaluation and follow-up.

BACKGROUND: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted. METHODS: The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years. RESULTS: A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years. DISCUSSION: The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies.

Health-related quality of life and hospital costs following esophageal resection: a prospective cohort study.

BACKGROUND: The incidence rates for adenocarcinoma of the esophagus are increasing while the prognosis has only improved slightly. There is no apparent benefit in short- and long-term survival after different surgical strategies, but surgery is associated with significant morbidity. The goal of this study is to prospectively assess the quality of life and hospital costs after esophageal resections depending on the development of complications. METHODS: Prospective data was collected from 47 patients undergoing an esophageal resection for esophageal cancer participating in the prospective LAParotomy or LAParoscopy and Adhesions (LAPAD) study (clinicaltrials.gov registration number: NCT01236625). A comparison was made between patients who developed major complications and minor or no complications regarding quality of life and hospital costs. RESULTS: Thirteen patients developed major complications while 34 patients developed only minor or no complications. Patients with major complications had a mean hospital cost of $16,369 vs $12,409 for patients without or with minor complications. We found no difference in quality of life between the two groups 6 months after surgery. CONCLUSIONS: In our cohort, major complications did not seem to have a detrimental effect on postoperative quality of life 6 months after surgery but they increased costs associated with esophageal resection.

Hepatic syndecan-1 changes associate with dyslipidemia after renal transplantation.

Syndecan-1 is a transmembrane heparan sulfate (HS) proteoglycan present on hepatocytes and involved in uptake of triglyceride-rich lipoproteins via its HS polysaccharide side chains. We hypothesized that altered hepatic syndecan-1 metabolism could be involved in dyslipidemia related to renal transplantation. In a rat renal transplantation model elevated plasma triglycerides were associated with fivefold increased expression of hepatic syndecan-1 mRNA (p < 0.01), but not protein. Expression of syndecan-1 sheddases (ADAM17, MMP9) and heparanase was significantly up-regulated after renal transplantation (all p < 0.05). Profiling of HS side chains revealed loss of hepatic HS upon renal transplantation accompanied by significant decreased functional capacity for VLDL binding (p = 0.02). In a human renal transplantation cohort (n = 510), plasma levels of shed syndecan-1 were measured. Multivariate analysis showed plasma syndecan-1 to be independently associated with triglycerides (p < 0.0001) and inversely with HDL cholesterol (p < 0.0001). Last, we show a physical association of syndecan-1 to HDL from renal transplant recipients (RTRs), but not to HDL from healthy controls. Our data suggest that after renal transplantation loss of hepatic HS together with increased syndecan-1 shedding hampers lipoprotein binding and uptake by the liver contributing to dyslipidemia. Our data open perspectives toward improvement of lipid profiles by targeted inhibition of syndecan-1 catabolism in renal transplantation.

Preoperative nomogram to predict risk of bowel injury during adhesiolysis.

BACKGROUND: Inadvertent bowel injury during adhesiolysis is a major cause of increased morbidity and mortality following abdominal surgery. Identification of risk factors predicting this complication would guide preoperative counselling and surgical decision-making. The aim of this study was to identify predictive preoperative factors for inadvertent bowel injury occurring during adhesiolysis. METHODS: All patients undergoing elective abdominal surgery between June 2008 and June 2010 were evaluated prospectively as part of the LAPAD study. Data on adhesiolysis and inadvertent organ injury were gathered by direct observation during operation. Univariable logistic regression was used to investigate factors that increased the risk of inadvertent bowel injury. Independent predictors of bowel injury were identified using multivariable logistic regression and used to create a clinical nomogram. RESULTS: Of 715 patients eligible for analysis, 48 (6.7 per cent) had inadvertent bowel injuries. In 42 patients the defect was detected during operation and in nine at a later time (3 patients had both). Bowel resection was required for almost two-thirds of the enterotomies. The number of previous laparotomies, anatomical site of the operation, presence of bowel fistula and laparotomy via a pre-existing median scar were independent predictors of bowel injury. A clinical scoring system was constructed using a nomogram incorporating these risk factors; this had a predictive discrimination, measured as the area under the receiver operating characteristic curve, of 0.85. CONCLUSION: A nomogram based on four independent factors predicted the risk of inadvertent bowel injury. REGISTRATION NUMBER: NCT01236625 (http://www.clinicaltrials.gov).

Reproducibility and predictive value of three grading systems for intraoperative adverse events in a cohort of abdominal surgery.

INTRODUCTION: Intraoperative adverse events (iAEs) are increasingly recognized for their impact on patient outcomes. The Kaafarani classification and Surgical Apgar Score (SAS) were developed to assess the intraoperative course; however, both have their drawbacks. ClassIntra was validated for iAEs of any origin. This study compares the Kaafarani and SAS to ClassIntra considering predictive value and interrater reliability in a cohort of abdominal surgery to support implementation of a classification in clinical practice. METHODS: The authors made use of the LAParotomy or LAParoscopy and ADhesiolysis (LAPAD) study database of elective abdominal surgery. Detailed descriptions on iAEs were collected in real-time by a researcher. For the current research aim, all iAEs were graded according ClassIntra, Kaafarani, and SAS (score ≤4). The predictive value was assessed using univariable and multivariable linear regression and the area under the receiver operating curve (AUROC). Two teams graded ClassIntra and Kaafarani to assess the interrater reliability using Cohen's Kappa. RESULTS: A total of 755 surgeries were included, in which 335 (44%) iAEs were graded according to ClassIntra, 228 (30%) to Kaafarani, and 130 (20%) to SAS. All classifications were significantly correlated to postoperative complications, with an AUROC of 0.67 (95% CI: 0.62-0.72), 0.64 (0.59-0.70), and 0.71 (0.56-0.76), respectively. For the secondary endpoint, the interrater reliability of ClassIntra with κ 0.87 (95% CI: 0.84-0.90) and Kaafarani 0.90 (95% CI: 0.87-0.93) was both strong. CONCLUSION: ClassIntra, Kaafarani, and SAS can be used for reporting of iAEs in abdominal surgery with good predictive value for postoperative complications, with strong reliability. ClassIntra, compared with Kaafarani and SAS, included the most iAEs and has the most comprehensive definition suitable for uniform reporting of iAEs in clinical practice and research.

Caloric restriction reduces proteinuria in male rats with established nephropathy.

Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: ad libitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria.

Variability in perfusion conditions and set-up parameters used in ex vivo human placenta models: A literature review.

The ex vivo human placenta perfusion model has proven to be clinically relevant to study transfer- and fetal exposure of various drugs. Although the method has existed for a long period, the setup of the perfusion model has not been generalized yet. This review aims to summarize the setups of ex vivo placental perfusion models used to examine drug transfer across the placenta to identify generalized properties and differences across setups. A literature search was carried out in PubMed September 26, 2022. Studies were labeled as relevant when information was reported, between 2000 and 2022, on the setups of ex vivo placental perfusion models used to study drug transfer across the placenta. The placenta perfusion process, and the data extraction, was divided into phases of preparation, control, drug, and experimental reflecting the chronological timeline of the different phases during the entire placental perfusion process. 135 studies describing an ex vivo human placental perfusion experiment were included. Among included studies, the majority (78.5%) analyzed drug perfusion in maternal to fetal direction, 18% evaluated bi-directional drug perfusion, 3% under equilibrium conditions, and one study investigated drug perfusion in fetal to maternal direction. This literature review facilitates the comparison of studies that employ similar placenta perfusion protocols for drug transfer studies and reveals significant disparities in the setup of these ex vivo placental perfusion models. Due to interlaboratory variability, perfusion studies are not readily comparable or interchangeable. Therefore, a stepwise protocol with multiple checkpoints for validating placental perfusion is needed.

Emerging role of gasotransmitters in renal transplantation.

Once patients with kidney disease progress to end-stage renal failure, transplantation is the preferred option of treatment resulting in improved quality of life and reduced mortality compared to dialysis. Although 1-year survival has improved considerably, graft and patient survival in the long term have not been concurrent, and therefore new tools to improve long-term graft and patient survival are warranted. Over the past decades, the gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) have emerged as potent cytoprotective mediators in various diseases. All three gasotransmitters are endogenously produced messenger molecules that possess vasodilatory, anti-apoptotic, anti-inflammatory and anti-oxidant properties by influencing an array of intracellular signaling processes. Although many regulatory functions of gasotransmitters have overlapping actions, differences have also been reported. In addition, crosstalk between NO, CO and H2S results in synergistic regulatory effects. Endogenous and exogenous manipulation of gasotransmitter levels modulates several processes involved in renal transplantation. This review focuses on mechanisms of gas-mediated cytoprotection and complex interactions between gasotransmitters in renal transplantation.