Increased metabolic rate and insulin sensitivity in male mice lacking the carcino-embryonic antigen-related cell adhesion molecule 2.

AIMS/HYPOTHESIS: The carcino-embryonic antigen-related cell adhesion molecule (CEACAM)2 is produced in many feeding control centres in the brain, but not in peripheral insulin-targeted tissues. Global Ceacam2 null mutation causes insulin resistance and obesity resulting from hyperphagia and hypometabolism in female Ceacam2 homozygous null mutant mice (Cc2 [also known as Ceacam2](-/-)) mice. Because male mice are not obese, the current study examined their metabolic phenotype. METHODS: The phenotype of male Cc2(-/-) mice was characterised by body fat composition, indirect calorimetry, hyperinsulinaemic-euglycaemic clamp analysis and direct recording of sympathetic nerve activity. RESULTS: Despite hyperphagia, total fat mass was reduced, owing to the hypermetabolic state in male Cc2(-/-) mice. In contrast to females, male mice also exhibited insulin sensitivity with elevated ß-oxidation in skeletal muscle, which is likely to offset the effects of increased food intake. Males and females had increased brown adipogenesis. However, only males had increased activation of sympathetic tone regulation of adipose tissue and increased spontaneous activity. The mechanisms underlying sexual dimorphism in energy balance with the loss of Ceacam2 remain unknown. CONCLUSIONS/INTERPRETATION: These studies identified a novel role for CEACAM2 in the regulation of metabolic rate and insulin sensitivity via effects on brown adipogenesis, sympathetic nervous outflow to brown adipose tissue, spontaneous activity and energy expenditure in skeletal muscle.

Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1.

Type 2 diabetes is associated with normal-to-higher bone mineral density (BMD) and increased rate of fracture. Hyperinsulinemia and hyperglycemia may affect bone mass and quality in the diabetic skeleton. In order to dissect the effect of hyperinsulinemia from the hyperglycemic impact on bone homeostasis, we have analyzed L-SACC1 mice, a murine model of impaired insulin clearance in liver causing hyperinsulinemia and insulin resistance without fasting hyperglycemia. Adult L-SACC1 mice exhibit significantly higher trabecular and cortical bone mass, attenuated bone formation as measured by dynamic histomorphometry, and reduced number of osteoclasts. Serum levels of bone formation (BALP) and bone resorption markers (TRAP5b and CTX) are decreased by approximately 50%. The L-SACC1 mutation in the liver affects myeloid cell lineage allocation in the bone marrow: the (CD3(-)CD11b(-)CD45R(-)) population of osteoclast progenitors is decreased by 40% and the number of (CD3(-)CD11b(-)CD45R(+)) B-cell progenitors is increased by 60%. L-SACC1 osteoclasts express lower levels of c-fos and RANK and their differentiation is impaired. In vitro analysis corroborated a negative effect of insulin on osteoclast recruitment, maturation and the expression levels of c-fos and RANK transcripts. Although bone formation is decreased in L-SACC1 mice, the differentiation potential and expression of the osteoblast-specific gene markers in L-SACC1-derived mesenchymal stem cells (MSC) remain unchanged as compared to the WT. Interestingly, however, MSC from L-SACC1 mice exhibit increased PPARgamma2 and decreased IGF-1 transcript levels. These data suggest that high bone mass in L-SACC1 animals results, at least in part, from a negative regulatory effect of insulin on bone resorption and formation, which leads to decreased bone turnover. Because low bone turnover contributes to decreased bone quality and an increased incidence of fractures, studies on L-SACC1 mice may advance our understanding of altered bone homeostasis in type 2 diabetes.

Role of self-expandable metal stents in the palliation of malignant duodenal obstruction.

BACKGROUND: Palliative surgical intervention for malignant duodenal obstruction is often associated with a significant morbidity. Endoscopic enteral stenting offers a suitable alternative, that is safe, effective, and less invasive. This study reports our experience with the use of self-expanding metal stents in the palliation of malignant gastric duodenal obstruction. METHODS: A retrospective review of all patients who underwent duodenal stenting from November 1998 to February 2001 was performed. All the patients had symptomatic gastric outlet and duodenal obstruction with nausea, vomiting, and decreased oral intake. All of them underwent enteral stenting with self-expandable metal Wallstents 20 or 22 mm in diameter and 6 or 9 cm long. RESULTS: For this study, 33 patients (19 men and 14 women) with a mean age of 62 years (range, 37-81 years) were identified, 32 of whom had successful duodenal stent placement (6 were performed as outpatient surgery). The malignancies were pancreatic 18 (54%), gastric 4 (12%), duodenal 3 (9%), metastatic 6 (18%), and cholangiocarcinoma 2 (6%) disorders. The site of obstruction was pyloric (n = 5; 15%), pyloroduodenal (n = 3; 9%), duodenal bulb (n = 11; 33%), second portion of duodenum (n = 9; 27%), second and third portion of duodenum (n = 3; 9%), C-loop (n = 1; 3%), and anastomotic (n = 1; 3%). A total of 29 patients (91%) had good clinical outcomes, with relief of obstructive symptoms, Two of three patients with no symptomatic relief underwent gastrojejunostomy. One patient refused further treatment. No immediate stent-related complications were noted. During the follow-up period, 20 patients died (none as a result stent-related causes) due to progression of cancer. Median survival was 102 days. Four patients had recurrent obstruction (2 tumor ingrowths, 1 overgrowth, and 1 distally migrated stent) at a mean interval of 82 days. All four had successful restenting without complications. CONCLUSION: Self-expandable metal stents placed endoscopically provide a safe, less invasive palliative treatment option with good clinical outcome in the management of malignant gastric outlet-duodenal obstruction.

Clinical outcome of simultaneous self-expandable metal stents for palliation of malignant biliary and duodenal obstruction.

BACKGROUND: Previous studies have shown that self-expanding metal stents are an effective method for palliation of malignant biliary or duodenal obstruction. We present our experience with the use of simultaneous self-expandable metal stents for palliation of malignant biliary and duodenal obstruction. METHODS: We performed a retrospective review of all patients undergoing simultaneous biliary and duodenal self-expandable metal stent placement between November 98 and May 2001. All the patients had documented evidence of biliary obstruction and symptomatic duodenal obstruction. The patients received endoscopic biliary stenting with biliary Ultraflex or Wallstents, and endoscopic duodenal stenting using enteral Wallstents. They were followed until their death. RESULTS: We identified 18 patients (11 men and 7 women) whose mean age was 65 years, (range, 46-85 years). Malignancies included pancreatic 14 (78%), biliary 2 (11%), lymphoma 1 (5%), and metastatic 1 (5%) disorders. Ten patients previously had plastic biliary stents placed for past malignant biliary obstruction (4 patients had recurrent biliary obstruction). All the patients had evidence of duodenal obstruction. Combined metal stenting was successful in 17 patients. One procedure failed due to a tortuous duodenal stricture. All the patients had effective palliation of biliary obstruction, as evidenced by a decrease in the level of total bilirubin and alkaline phosphatase. Of the 17 patients with successful duodenal stenting, 16 had a good clinical outcome, with relief of obstructive symptoms. No immediate stent-related complications were noted. During the follow-up period, 12 patients died of progression of the underlying malignancy. None of the deaths were stent related. Median survival time was 78 days. Two patients had recurrent biliary obstruction from tumor ingrowth at 45 and 68 days, respectively. Both underwent restenting: one by endoscopic retrograde cholangiopancreatography (ERCP) and the other by percutaneous transhepatic cholangiography (PTC). Two other patients had recurrent duodenal obstruction, respectively, 36 and 45 days after the initial stenting. One obstruction was secondary to tumor ingrowth, and the other was caused by distal stent migration. Both patients had successful duodenal restenting. CONCLUSION: Combined self-expandable metal stenting for simultaneous palliation of malignant biliary and duodenal obstruction may provide a safe and less invasive alternative to surgical palliation with an acceptable clinical outcome. Simultaneous self-expandable metal stents should be considered as a treatment option for patients who are poor candidates for surgery.

Serum lipase, C-reactive protein, and interleukin-6 levels in ERCP-induced pancreatitis.

BACKGROUND: C-reactive protein (CRP) and interleukin-6 (IL-6) are elevated in acute pancreatitis. Limited studies have evaluated their role in ERCP-induced pancreatitis. The aim of this study was to assess the role of serum lipase, CRP, and IL-6 in ERCP-induced pancreatitis. METHODS: Eighty-five patients (62 women, 23 men; mean age 43 years; range 16-85 years) who underwent ERCP were entered in a prospective trial. ERCP-induced pancreatitis was classified as mild, moderate, or severe. Serum levels of lipase, CRP, and IL-6 were measured before ERCP and at 12 to 24 hours and 36 to 48 hours after ERCP. RESULTS: Mild, moderate, and severe pancreatitis occurred, respectively, in 9, 7, and 4 patients after ERCP. There were significant differences in levels of CRP and IL-6 but not lipase for patients with mild versus moderate and moderate versus severe pancreatitis. The mean CRP levels (mg/dL) at 12 to 24 hours were 0.98 +/- 0.24 in mild pancreatitis, 3.89 +/- 0.32 in moderate pancreatitis, and 12.0 +/- 1.60 in severe pancreatitis. The levels, respectively, at 36 to 48 hours were 1.60 +/- 0.31, 7.60 +/- 0.74, and 25.0 +/- 2.9. The mean IL-6 levels (pg/mL) at 12 to 24 hours were 16.6 +/- 2.06 in mild pancreatitis, 73.0 +/- 15.60 in moderate pancreatitis, and 235.5 +/- 26.31 in severe pancreatitis. The levels at 36 to 48 hours were, respectively, 18.92 +/- 3.28, 100.17 +/- 11.56, and 438.2 +/- 71.50. CONCLUSIONS: Serum CRP and IL-6 levels may be useful early markers for predicting the severity of ERCP-induced pancreatitis.

Biliary tract calculi in primary sclerosing cholangitis.

UNLABELLED: By conventional criteria the diagnosis of primary sclerosing cholangitis (PSC) is excluded if biliary tract calculi are present. OBJECTIVE: To compare patients with sclerosing cholangitis with and without calculi. METHODS: Retrospective review between 8/91 and 9/93 identified 63 patients with sclerosing cholangitis alone (Group A) and 22 patients with sclerosing cholangitis and biliary tract calculi (Group B). The mean follow-up was 13.6 months. Clinical features reviewed were age, sex, associated inflammatory disease (IBD), and clinical presentation. Cholangiographic features compared were site and extent of disease. Endoscopic stone extraction was reviewed for success and complications. RESULTS: Both groups had the following features in common: 1) mean age (45.9 vs 46.3 yr), 2) prevalence of IBD (68.3 vs 72.7%), 3) extent of bile duct strictures (intrahepatic: 28.5% vs 27.2%; extrahepatic: 12.7% vs 13.6%; both: 58.7% vs 54.5%). There were proportionately more women in Group B (45.5% vs 33.3%). Symptomatic presentation (pain, pruritus, jaundice, and cholangitis) was seen more often in Group B: 86.4% compared with Group A: 39.7% (specifically cholangitis was seen in 22.7% vs 4.7%). Among Group B, calculi developed subsequent (mean 40.2 months) after the diagnosis of sclerosing cholangitis in 77.3% of patients. The distribution of calculi was cholelithiasis: 7 (31.8%); choledocholithiasis: 9 (40.9%); and both: 6 (27.2%). Of the patients with choledocholithiasis alone, 78% had undergone previous cholecystectomy. Endoscopic stone extraction was successful in 13 (86.6%) of the patients with choledocholithiasis. Complications included mild pancreatitis in one patient and bleeding from sphincterotomy site in another patient which responded to sclerotherapy. In follow-up, only one patient had recurrent calculi and underwent successful stone extraction. CONCLUSION: We suggest that biliary tract calculi are a part of the spectrum of otherwise typical PSC and therefore their presence should not necessarily exclude the diagnosis.

Long-term follow-up of consequences of percutaneous endoscopic gastrostomy (PEG) tubes in nursing home patients.

PEG (percutaneous endoscopic gastrostomy) tubes are frequently placed in nursing home patients. The aim of this study was to assess retrospectively the long-term changes in functional and nutritional statuses, tube-related complications, and factors influencing survival in 46 nursing home residents, mean age 73.6 years (range 19-96). Functional status was evaluated by a standard rehabilitation medicine scale. Nutritional status was evaluated by serum albumin and cholesterol concentrations and by weight. PEG-related complications requiring hospitalization or emergency room or clinic evaluations were noted. Additionally, changes in resuscitation status were noted. The predominant indication for PEG placement was dementia (52%). At PEG placement, 48% of patients had total functional impairment. Regardless of the severity of impairment, no patient's functional status improved after PEG. Nutritional status did not improve significantly. Mortality approached 50% and 60% at 12 and 18 months, respectively, and was significantly related to age, resuscitation status, and serum albumin concentration. All patients under 40 years of age at PEG survived, in contrast to 41.3% of patients over 40 years of age (P < 0.001). Sixty-three percent of patients who were "full code" at PEG placement survived, in contrast to 10% of "no code" patients (P < 0.001). Albumin > or = 3.5 g/dl at PEG or thereafter was associated with improved survival (P < 0.001) as compared to albumin < 3.5 g/dl. PEG-related complications occurred in 34.7% of patients, and the first occurred four months after PEG. We conclude that realistic expectations of what PEG can accomplish be a factor in the decision to place a PEG tube in nursing home patients.

Infectious complications of endoscopic procedures in bone marrow transplant recipients.

The prevalence of clinically relevant bacteremia after endoscopic procedures in bone marrow transplant recipients was assessed retrospectively. Bacteremia, within 24 hr of procedure, was defined as positive blood cultures, while hypotension and temperature greater than 38 degrees C were taken as possible indicators of bacteremia. Sixty-seven procedures were performed in 53 endoscopic sessions (upper endoscopy 37, flexible sigmoidoscopy 7, upper endoscopy + flexible sigmoidoscopy 8, colonoscopy 1). Twenty-five endoscopic sessions were performed in patients receiving broad-spectrum antibiotics and 28 sessions in patients not receiving antibiotics. Both groups were comparable with respect to patient characteristics, procedures performed, and immune status. No patient in either group developed hypotension. One patient developed fever after flexible sigmoidoscopy; no source of fever was identified. We conclude that: (1) there were no episodes of clinically relevant bacteremia attributable to endoscopic procedures, and (2) not all bone marrow transplant recipients require routine antibiotic prophylaxis prior to endoscopic procedures.