Philipp C. Nett

Apoptosis in hypoxic human pancreatic islets correlates with HIF-1α expression

To become insulin independent, patients with type 1 diabetes mellitus require transplantation of at least two donor pancreata because of massive β–cell loss in the early post‐transplantation period. Many studies describing the introduction of new immunosuppressive protocols have shown that this loss is due to not only immunological events but also nonimmunological factors. To test to what extent hypoxia may contribute to early graft loss, we analyzed the occurrence of apoptotic events and the expression of hypoxia‐inducible factor 1 (HIF‐1), a heterodimeric transcription factor consisting of an oxygen‐dependent α subunit and a constitutive β subunit. Histological analysis of human and rat islets revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O2). Moreover, immunoreactivity to activated caspase‐3 was observed in the core region of isolated human islets. Of note, both of these markers of apoptosis topographically overlap with HIF‐1α immunoreactivity. HIF‐1α mRNA was detected in islets from human and rat as well as in several murine β–cell lines. When exposed to hypoxia, mouse insulinoma cells (MIN6) had an increased HIF‐1α protein level, whereas its mRNA level did not alter. In conclusion, our data provide convincing evidence that reduced oxygenation is an important cause of β–cell loss and suggest that HIF‐1α protein level is an indicator for hypoxic regions undergoing apoptotic cell death. These observations suggest that gene expression under the control of HIF‐1 represents a potential therapeutic tool for improving engraftment of transplanted islets.

Laparoscopic Sleeve Gastrectomy Versus Roux-Y-Gastric Bypass for Morbid Obesity-3-Year Outcomes of the Prospective Randomized Swiss Multicenter Bypass Or Sleeve Study (SM-BOSS).

Objective: Laparoscopic sleeve gastrectomy (LSG) is performed almost as often in Europe as laparoscopic Roux-Y-Gastric Bypass (LRYGB). We present the 3-year interim results of the 5-year prospective, randomized trial comparing the 2 procedures (Swiss Multicentre Bypass Or Sleeve Study; SM-BOSS). Methods: Initially, 217 patients (LSG, n = 107; LRYGB, n = 110) were randomized to receive either LSG or LRYGB at 4 bariatric centers in Switzerland. Mean body mass index of all patients was 44 ± 11 kg/m2, mean age was 43 ± 5.3 years, and 72% of patients were female. Minimal follow-up was 3 years with a rate of 97%. Both groups were compared for weight loss, comorbidities, quality of life, and complications. Results: Excessive body mass index loss was similar between LSG and LRYGB at each time point (1 year: 72.3 ± 21.9% vs. 76.6 ± 20.9%, P = 0.139; 2 years: 74.7 ± 29.8% vs. 77.7 ± 30%, P = 0.513; 3 years: 70.9 ± 23.8% vs. 73.8 ± 23.3%, P = 0.316). At this interim 3-year time point, comorbidities were significantly reduced and comparable after both procedures except for gastro-esophageal reflux disease and dyslipidemia, which were more successfully treated by LRYGB. Quality of life increased significantly in both groups after 1, 2, and 3 years postsurgery. There was no statistically significant difference in number of complications treated by reoperation (LSG, n = 9; LRYGB, n = 16, P = 0.15) or number of complications treated conservatively. Conclusions: In this trial, LSG and LRYGB are equally efficient regarding weight loss, quality of life, and complications up to 3 years postsurgery. Improvement of comorbidities is similar except for gastro-esophageal reflux disease and dyslipidemia that appear to be more successfully treated by LRYGB.

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss in Patients With Morbid Obesity: The SM-BOSS Randomized Clinical Trial

Importance Sleeve gastrectomy is increasingly used in the treatment of morbid obesity, but its long-term outcome vs the standard Roux-en-Y gastric bypass procedure is unknown. Objective To determine whether there are differences between sleeve gastrectomy and Roux-en-Y gastric bypass in terms of weight loss, changes in comorbidities, increase in quality of life, and adverse events. Design, Setting, and Participants The Swiss Multicenter Bypass or Sleeve Study (SM-BOSS), a 2-group randomized trial, was conducted from January 2007 until November 2011 (last follow-up in March 2017). Of 3971 morbidly obese patients evaluated for bariatric surgery at 4 Swiss bariatric centers, 217 patients were enrolled and randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass with a 5-year follow-up period. Interventions Patients were randomly assigned to undergo laparoscopic sleeve gastrectomy (n = 107) or laparoscopic Roux-en-Y gastric bypass (n = 110). Main Outcomes and Measures The primary end point was weight loss, expressed as percentage excess body mass index (BMI) loss. Exploratory end points were changes in comorbidities and adverse events. Results Among the 217 patients (mean age, 45.5 years; 72% women; mean BMI, 43.9) 205 (94.5%) completed the trial. Excess BMI loss was not significantly different at 5 years: for sleeve gastrectomy, 61.1%, vs Roux-en-Y gastric bypass, 68.3% (absolute difference, −7.18%; 95% CI, −14.30% to −0.06%; P = .22 after adjustment for multiple comparisons). Gastric reflux remission was observed more frequently after Roux-en-Y gastric bypass (60.4%) than after sleeve gastrectomy (25.0%). Gastric reflux worsened (more symptoms or increase in therapy) more often after sleeve gastrectomy (31.8%) than after Roux-en-Y gastric bypass (6.3%). The number of patients with reoperations or interventions was 16/101 (15.8%) after sleeve gastrectomy and 23/104 (22.1%) after Roux-en-Y gastric bypass. Conclusions and Relevance Among patients with morbid obesity, there was no significant difference in excess BMI loss between laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass at 5 years of follow-up after surgery. Trial Registration clinicaltrials.gov Identifier: NCT00356213

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss in Patients With Morbid Obesity

Importance Sleeve gastrectomy is increasingly used in the treatment of morbid obesity, but its long-term outcome vs the standard Roux-en-Y gastric bypass procedure is unknown. Objective To determine whether there are differences between sleeve gastrectomy and Roux-en-Y gastric bypass in terms of weight loss, changes in comorbidities, increase in quality of life, and adverse events. Design, Setting, and Participants The Swiss Multicenter Bypass or Sleeve Study (SM-BOSS), a 2-group randomized trial, was conducted from January 2007 until November 2011 (last follow-up in March 2017). Of 3971 morbidly obese patients evaluated for bariatric surgery at 4 Swiss bariatric centers, 217 patients were enrolled and randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass with a 5-year follow-up period. Interventions Patients were randomly assigned to undergo laparoscopic sleeve gastrectomy (n = 107) or laparoscopic Roux-en-Y gastric bypass (n = 110). Main Outcomes and Measures The primary end point was weight loss, expressed as percentage excess body mass index (BMI) loss. Exploratory end points were changes in comorbidities and adverse events. Results Among the 217 patients (mean age, 45.5 years; 72% women; mean BMI, 43.9) 205 (94.5%) completed the trial. Excess BMI loss was not significantly different at 5 years: for sleeve gastrectomy, 61.1%, vs Roux-en-Y gastric bypass, 68.3% (absolute difference, −7.18%; 95% CI, −14.30% to −0.06%; P = .22 after adjustment for multiple comparisons). Gastric reflux remission was observed more frequently after Roux-en-Y gastric bypass (60.4%) than after sleeve gastrectomy (25.0%). Gastric reflux worsened (more symptoms or increase in therapy) more often after sleeve gastrectomy (31.8%) than after Roux-en-Y gastric bypass (6.3%). The number of patients with reoperations or interventions was 16/101 (15.8%) after sleeve gastrectomy and 23/104 (22.1%) after Roux-en-Y gastric bypass. Conclusions and Relevance Among patients with morbid obesity, there was no significant difference in excess BMI loss between laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass at 5 years of follow-up after surgery. Trial Registration clinicaltrials.gov Identifier: NCT00356213

Wernicke Encephalopathy: a Future Problem Even After Sleeve Gastrectomy? A Systematic Literature Review

Wernicke encephalopathy (WE) is a serious complication of bariatric surgery with significant morbidity and mortality. A few cases have been reported in the literature, mainly in patients after a Roux-en-Y gastric bypass. Since sleeve gastrectomy (SG) has become a more established and popular bariatric procedure, WE is expected to appear more frequently after SG. We performed a literature review on WE after SG, and 13 cases have been found to be sufficiently documented. The risk of WE needs to be considered in patients with a prolonged vomiting episode and any type of neurological symptoms, independent of the presence of any surgical complications.

Recent Developments on Endothelin Antagonists as Immunomodulatory Drugs - from Infection to Transplantation Medicine

Endothelin, a potent endogenous vasoconstrictor and mitogen that acts through the ET(A) and ET(B) receptors, has been not only implicated in the regulation of cardiovascular homeostasis but also in inflammatory responses, including that induced by infection and solid organ transplantation. Changes in capillary perfusion and leukocyte recruitment are important features of inflammation. The concentrations of ET are elevated in many forms of inflammation and are especially high in sepsis. The rise in plasma levels of ET during early stages of inflammation may initially have some positive homeostatic effects that might help to maintain vascular tone and blood pressure. However, high levels of ET compromise the appropriate matching of flow to tissue needs and contribute to the pathophysiology of microcirculatory derangements. Attempts at regulating the effects of ET by the use of pharmacological antagonists are complicated by important interactions between the ET(A) and ET(B) receptors. This review highlights findings of recent studies and patents in this area showing that the ET system, apart from being a marker of vascular and tissue injury, is directly involved in the pathophysiology of these disease processes as an immunomodulatory mediator.

Exocrine Pancreatic Insufficiency after Roux-en-Y gastric bypass

BACKGROUND Gastric resection, short bowel syndrome, and diabetes mellitus are risk factors for development of exocrine pancreatic insufficiency (EPI). Reasons are multifactorial and not completely elucidated. OBJECTIVES To determine the prevalence of EPI after distal (dRYGB) and proximal Roux-en-Y gastric bypass (pRYGB) and to assess the influence of respective limb lengths. SETTING University hospital, Switzerland. METHODS The study comprised 188 consecutive patients who underwent primary dRYGB (common channel<120 cm, biliopancreatic limb 80-100 cm) or pRYGB (alimentary limb = 155 cm, biliopancreatic limb 40-75 cm) and who were followed-up for at least 2 years. Patients with a history of gastrointestinal or hepatobiliary resection (except for cholecystectomy), postoperative pregnancy, and any revision of RYGB (gastric pouch, limb lengths) were excluded. EPI was defined by clinical symptoms in combination with fecal pancreatic elastase-1<200 μg/g stool or fecal pancreatic elastase-1>200 and<500 μg/g stool and positive dechallenge-rechallenge test with pancreatic enzyme replacement therapy. RESULTS Mean follow-up was 52.2 months (range 24-120). Seventy-nine patients (42%) underwent dRYGB, and 109 (58%) underwent pRYGB. Of those, 59 (31%) patients were diagnosed with EPI after a mean 12.5±16.3 months. There was a significant difference between dRYGB and pRYGB groups in initial body mass index (dRYGB 47.1±8.1 kg/m(2) versus pRYGB 42.7±6.1 kg/m(2); P<.01), patients in Obesity Surgery Mortality Risk Score group C (13% versus 3%; P = .02), and prevalence of EPI (48% versus 19%; P<.01). Neither overall small bowel length nor absolute or relative limb lengths were influencing factors on EPI after dRYGB. CONCLUSION Prevalence of EPI after dRYGB (48%) and pRYGB (19%) is of clinical importance. There was no significant difference in absolute or relative limb lengths between EPI and non-EPI groups after dRYGB.

Complex hernias with loss of domain in morbidly obese patients: role of laparoscopic sleeve gastrectomy in a multi-step approach

BACKGROUND Morbid obesity and its associated co-morbidities are risk factors for the development of abdominal hernias, add complexity to their repair, and increase perioperative risk. Repair of hernias with loss of domain (LoD) is further complicated by risk of abdominal compartment syndrome. A staged concept with an initial weight loss procedure might enable a reposition of the herniated viscera, improve co-morbidities for, and prohibit abdominal compartment syndrome in the subsequent repair. OBJECTIVE To evaluate a multistep treatment strategy that entails initial laparoscopic sleeve gastrectomy (LSG) followed by open repair in the treatment of complex hernias with LoD in morbidly obese patients SETTING: University hospital METHODS: Retrospective analysis of all patients (n = 15) with morbid obesity and hernias with LoD treated in a staged concept between April 2010 and December 2015 RESULTS: Median initial body mass index was 45 kg/m2. All hernias were recurrent incisional hernias with≥2 failed repairs. No major complications occurred during or after LSG. After a median of 185 days, the second stage at a median body mass index of 33.6 kg/m2 was performed. No bowel resections were needed. The only major perioperative complication was pneumonia in 2 patients (13%). Within 24 months (6-68) after the second step, there were 3 reoperations (small recurrence [7%], infected seroma [7%], and infected mesh [7%]). One patient (7%) was lost to follow-up after 2 years. CONCLUSION A 2-step approach to treat massive hernias with LoD in morbidly obese patients is safe and effective. LSG as initial weight loss procedure addresses LoD successfully without a need for further preoperative measures to condition for hernia repair.

Downregulation of Renal Endothelin-Converting Enzyme 2 Expression in Early Autoimmune Diabetes

To determine whether renal expression of endothelin-converting enzymes (ECEs) and endothelin (ET) is affected in the early stages of autoimmune diabetes mellitus and whether ETA receptors are involved, prediabetic nonobese diabetic (NOD) and control mice were treated with the ETA receptor antagonist BSF461314 (a follow-up compound of darusentan) or with placebo. Blood samples were analyzed for glucose levels, and renal gene expression of ECE-1, ECE-2, and prepro-ET-1 was determined using real-time polymerase chain reaction. Renal morphology was assessed using standard histologic techniques. ECE-1, ECE-2, and prepro-ET-1 mRNA was detected in the kidneys of NOD and control mice. Despite normal renal histology, expression of ECE-1 and prepro-ET-1 was reduced in NOD mice by approximately 50% compared with controls (P < 0.01); ECE-2 was markedly decreased by almost 90% compared with controls (P < 0.001). Treatment with BSF461314 for 6 weeks delayed the onset of diabetes (P < 0.05) and increased expression of all three genes (P < 0.05) in NOD mice only. Hyperglycemia at an early stage of autoimmune diabetes is associated with transcriptional downregulation of ECE-1, ECE-2, and prepro-ET-1 in the kidney. Blockade of ETA receptors inhibits diabetes-associated gene regulation and delays the onset of diabetes, suggesting its therapeutic potential for the treatment of autoimmune forms of diabetes.

What Causes Late Perforation of the Jejuno-Jejunal Anastomosis After Roux-en-Y Gastric Bypass Surgery?

To the Editor: Laparoscopic Roux-en-Y gastric bypass (RYGB) is a common surgical treatment for morbid obesity that is being used more and more frequently and is still widely regarded today as the gold standard in weight loss surgery. There are, however, a number of short-term and long-term sequelae that may occur after surgery. Complications related to this intervention occurring more than 30 days postoperatively and requiring readmission are defined as late complications. These select intestinal complications include small-bowel obstructions (the most frequently reported late complication), hernias, anastomotic strictures, and marginal or stomal ulceration [1]. Late perforation at the site of the jejunojejunal (JJ) anastomosis appears to be very rare. The incidence of JJ anastomotic perforation has been reported to be under 1 % in the literature [2, 3]. To our best knowledge, only ten cases have been reported following bariatric surgery, five of them in Obesity Surgery, and the reason for perforation has not always been apparent [2–7]. We would like to present an additional case of late perforation at the JJ anastomosis, which occurred 11 months after laparoscopic RYGB performed at another hospital in a patient with an initial BMI of 42 kg/m. We would appreciate hearing about similar observations made by other clinicians. A 36-year-old woman with a total excess weight loss (EWL) of 30 % was admitted to the emergency department with severe, cramping abdominal pain and severe diarrhea. Clinical examination revealed a tender abdomen. Laboratory findings were normal except for an elevated leukocyte count of 14,700/μl. Free air in the abdomen was detected by CT scan, and the patient was immediately transferred to the operating room. After initial exploratory laparoscopy, an open technique was applied because of extensive peritonitis. A 5-mm perforation was identified at the mesenteric site of the JJ anastomosis. Specimens were obtained for microbiological cultures. The perforation was excised, and primary closure was performed with interrupted absorbable sutures. Intravenous antimicrobial agents and proton pump inhibitors were administered for 14 days. The patient denied taking any ulcerogenic drugs, consuming a l coho l , and smok ing . S t rep tococcus gallolyticus , Klebsiella oxytoca, and Aeromonas hydrophila grew in culture. The postoperative course was favorable. In previous reports, potential causes of perforation have included the following: distal obstruction (increased intraluminal pressure; caused by a bezoar [6] * Dino Kröll dino.kroell@insel.ch