Extinction and reinstatement of an operant responding maintained by food in different models of obesity.

A major problem in treating obesity is the high rate of relapse to abnormal food-taking habits after maintaining an energy balanced diet. Alterations of eating behavior such as compulsive-like behavior and lack of self-control over food intake play a critical role in relapse. In this study, we used an operant paradigm of food-seeking behavior on two different diet-induced obesity models, a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity or for unhealthy food regularly consumed in our societies. A reduced operant performance and motivation for the hedonic value of palatable chocolate pellets was revealed in both obesity mouse models. However, only mice exposed to high-fat diet showed an increased compulsive-like behavior in the absence of the reinforcer further characterized by impaired operant learning, enhanced impulsivity and intensified inflexibility. We used principal component analysis to globally identify the specific behaviors responsible for the differences among diet groups. Learning impairment and inflexible behaviors contributed to a first principal component, explaining the largest proportion of the variance in the high-fat diet mice phenotype. Reinforcement, impulsion and compulsion were the main contributors to the second principal component explaining the differences in the chocolate-mixture mice behavioral phenotype. These behaviors were not exclusive of chocolate group because some high-fat individuals showed similar values on this component. These data indicate that extended access to hypercaloric diets differentially modifies operant behavior learning, behavioral flexibility, impulsive-like and compulsive-like behavior, and these effects were dependent on the exposure to each specific diet.

Ceramide levels regulated by carnitine palmitoyltransferase 1C control dendritic spine maturation and cognition.

The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C-deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock-out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning.

Behavioral characterization of a mouse model overexpressing DSCR1/ RCAN1.

DSCR1/ RCAN1 is a chromosome 21 gene found to be overexpressed in the brains of Down syndrome (DS) and postulated as a good candidate to contribute to mental disability. However, even though Rcan1 knockout mice have pronounced spatial learning and memory deficits, the possible deleterious effects of its overexpression in DS are not well understood. We have generated a transgenic mouse model overexpressing DSCR1/RCAN1 in the brain and analyzed the effect of RCAN1 overexpression on cognitive function. TgRCAN1 mice present a marked disruption of the learning process in a visuo-spatial learning task. However, no significant differences were observed in the performance of the memory phase of the test (removal session) nor in a step-down passive avoidance task, thus suggesting that once learning has been established, the animals are able to consolidate the information in the longer term.

An animal model of compulsive food-taking behaviour.

The increase in the incidence of obesity and eating disorders has promoted research aimed at understanding the aetiology of abnormal eating behaviours. Apart from metabolic factors, obesity is caused by overeating. Clinical reports have led to the suggestion that some individuals may develop addictive-like behaviours when consuming palatable foods, and compulsive eating plays a similar dominant role in obesity as compulsive drug taking does in drug addiction. The progress made in the development of treatment strategies for obesity is limited, in part, because the physiological and neurological causes and consequences of compulsive eating behaviour are not clearly understood and cannot readily be studied in human subjects. We have developed experimental approaches that reflect the functioning of the components of eating control, including compulsive food taking in rats. Rats that are given free choice between standard chow and a palatable, chocolate-containing 'Cafeteria Diet' (CD) develop distinct signs of compulsive food taking that appear at an early stage. These include the inability to adapt intake behaviour in periods of limited or bitter-tasting CD access, continued food intake during resting phases and changes in fine structure of feeding (duration, distribution and recurrence of feeding bouts). The model will help examine the neurobiological underpinnings of compulsive food seeking and food taking and provides a possibility to study the effects of novel anti-obesity compounds on compulsive eating and other components of food-taking behaviour in detail. For future use of genetic models, the possibility of a transfer to a mouse was discussed.

Hybrid approaches to repair of complex aortic aneurysmal disease.

With the endovascular revolution upon us, the management of aortic aneurysmal disease has changed dramatically. Since 1991, more than 100,000 aneurysms worldwide have been repaired using early-generation and current-generation standardized grafts and this has dramatically reduced the 30-day mortality rates associated with open aortic surgery. A new phenomenon has also arisen from this wonderful technology. The term hybrid means "of different origins" and hybrid approaches to vascular disease involve open and endovascular techniques to achieve a common goal, namely, to prevent death caused by aneurysmal rupture. This article reviews novel approaches to the repair of complex aortic aneurysms and provides several illustrative examples.

Confirmed graft flow following use of recombinant factor VIIa in coronary artery bypass grafting: a case report and literature review.

We present our experience of a unique opportunity to survey coronary artery bypass graft (CABG) patency following the administration of recombinant factor VIIa in the early postoperative period. A review of the published literature on use of this medication in cardiothoracic surgery, specifically CABG, is included.

Operative management and outcomes of traumatic lung resection.

BACKGROUND: To analyze the presentation, injury patterns, and outcomes among a large cohort of patients requiring lung resection for trauma, and to compare outcomes stratified by the extent of resection. STUDY DESIGN: Review of all adult patients undergoing lung resections in the National Trauma Data Bank. Patients were categorized by extent of lung resection; wedge resection, lobectomy, or pneumonectomy. Patient factors, injury data, and outcomes were compared between groups using univariate and multivariable analysis for the entire sample, and after excluding patients with severe associated injuries. RESULTS: There were 669 patients who had a lung resection after trauma identified for an overall prevalence of 0.08%, with 325 undergoing wedge resection (49%), 244 had a lobectomy (36%), and 100 underwent complete pneumonectomy (15%). Blunt mechanism was associated with worse outcomes in terms of prolonged hospital stay, complications, disability, and a trend toward higher mortality (38% versus 30%, p = 0.07). Patients undergoing pneumonectomy had a higher mortality (62%) and more complications (48%) compared with patients undergoing lobectomy (35% mortality, 33% complications) and wedge resection (22% and 8%, all p < 0.05). After excluding patients with severe associated injuries (head, abdomen, heart, great vessels), there were 535 patients with "isolated" lung injury. There was again a stepwise increase in mortality by extent of resection, 19% for wedge resection, 27% for lobectomy, and 53% for pneumonectomy. Extent of lung resection remained an independent predictor of mortality for both the entire sample and for patients with isolated lung injury. CONCLUSIONS: Lung resection is infrequently required for traumatic injury, but carries substantial associated morbidity and mortality. The extent of lung resection is an independent predictor of hospital mortality, even after exclusion of patients with severe associated injuries. The worst outcomes were seen after complete pneumonectomy.

Modified sternotomy to minimize infection risk in patients with prior laryngectomy and permanent tracheostomy.

Patients with prior laryngectomy and permanent tracheostomy undergoing complete sternotomy historically are at increased risk for wound infection, osteomyelitis, mediastinitis, bleeding, tracheal injury, and poor wound healing. We describe three patients who underwent cardiac surgery via low midline incision with transverse flap, providing the exposure of complete sternotomy and decreased infectious risk. Patient selection, technique, and management principles are discussed.

Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients.

OBJECTIVE: The purpose of this study was to investigate if the preoperative use of new platelet inhibitors and low-molecular-weight heparins may contribute to bleeding after cardiac surgery. DESIGN: Retrospective data review. SETTING: University teaching hospital. PARTICIPANTS: One hundred eleven patients divided in 5 groups. INTERVENTIONS: Patients were grouped according to preoperative antithrombotic regimen: group 1, control, no agents (n=55); group 2, clopidogrel (n=9); group 3, enoxaparin (n=17); group 4, any GP IIb/IIIa inhibitor (n=14); and group 5, any drug combination (n=15). Data included cumulative mediastinal chest tube drainage, allogeneic blood transfusions, total blood donor exposures, and re-exploration. MEASUREMENTS AND MAIN RESULTS: Use of any drug (groups 2-5) resulted in greater total blood transfusions and donor exposure (p=0.0003) than control, especially red cells (p=0.002) and platelets (p=0.006). A greater percentage of patients on enoxaparin required mediastinal re-exploration for nonsurgical bleeding versus control (3/17 v 0/55, p=0.001). The use of enoxaparin was associated with significantly higher chest tube output after the first 24 hours postoperatively (p=0.048). CONCLUSION: Newer antithrombotic agents were associated with greater transfusion rates and total donor exposures. Enoxaparin use was associated with greater overall blood loss and with higher incidence of mediastinal re-exploration. The relative risk-benefit ratio of reduced periprocedure morbidity versus increased bleeding complications has yet to be determined.

Contemporary results of total aortic arch replacement.

BACKGROUND AND AIM: Aneurysmal dilatation of the aortic arch is uncommon, and the complex anatomy involved imposes unique technical challenges. The results of surgical intervention reported from large centers are improving; however, the degree to which these results are reproducible by other surgeons is less clear. We therefore reviewed our recent experience with total aortic arch replacement. METHODS: Between July 1, 1997 and July 1, 2001 19 patients underwent complete aortic arch replacement, with or without concomitant procedures. We retrospectively reviewed perioperative results retrieved from the computerized database and clinical records. RESULTS: The mean age of the study population was 68 +/- 8.3 years (range 52 to 82), with women predominating (11 women, 8 men). All patients had hypertension. Patient history indicated active or past tobacco abuse in 16 patients (80%); cerebrovascular disease in 3, and peripheral vascular disease in 7 patients. Associated procedures included an elephant trunk in 12 (63%), replacement of the upper descending thoracic aorta in 5 (26%), concomitant coronary artery bypass in 5 (26%), and aortic root replacement in 3 (16%). One patient underwent replacement of the entire aorta from sinotubular ridge to iliac bifurcation in a single procedure. Brachiocephalic reconstruction with a "Y-graft" permitting early antegrade cerebral perfusion was performed in 12 patients. Retrograde cerebral perfusion was performed in ten patients (53%). Perioperatively, death occurred in two patients (11%) and stroke in two (11%). CONCLUSIONS: With cautious application, techniques developed in high-volume centers can also achieve satisfactory results when used at centers with a more modest case volume.

Comparison of open subxiphoid pericardial drainage with percutaneous catheter drainage for symptomatic pericardial effusion.

BACKGROUND: The optimal therapy for symptomatic pericardial effusions remains controversial. This paper compares outcomes after the two most commonly used techniques, percutaneous catheter drainage and operative subxiphoid pericardial drainage. METHODS: We performed a 5-year retrospective, single-institution study to analyze outcomes after either percutaneous catheter drainage or subxiphoid open pericardial drainage for symptomatic pericardial effusions. RESULTS: Symptomatic pericardial effusions in 246 patients were treated by open pericardiotomy and tube drainage (n = 150) or percutaneous catheter drainage (n = 96). Drainage duration, total drainage volume, and duration of follow-up (2.6 years) were similar in both groups. Effusions were classified malignant in 79 (32%) patients and benign in 167 (68%) patients. No direct procedural mortality occurred, but the hospital mortality was 16 patients (10.7%) in the open group and 22 (22.9%) in the percutaneous group (p = 0.01) The 5-year survival rate was 51% in the open group versus 45% in the percutaneous group, despite a greater percentage of the open group having a preoperative malignant diagnosis (35% versus 28%). Symptomatic effusions recurred in 16.5% of the percutaneous group compared with 4.6% in the open group (p = 0.002), and sclerosis did not appear to reduce recurrence rates (10.7% with sclerosis versus 15.6% without; p > 0.05). The diagnosis of malignancy was confirmed in 16 of 27 (59%) percutaneous procedures performed on patients with known malignancy. In the open group, cytologic and pathologic evaluation of the pericardial specimen revealed malignancy in 32 of 52 (62%) patients with known malignancy. CONCLUSIONS: Subxiphoid and percutaneous pericardial drainage of symptomatic pericardial effusions can be performed safely; however, death occurs from underlying disease. Open subxiphoid pericardial drainage with pericardial biopsy appears to decrease recurrence but does not improve diagnostic accuracy of malignancy over cytology alone.

Effect of hypergastrinemia on pancreatic carcinogenesis.

BACKGROUND: Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated. METHODS: Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions. RESULTS: Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%). CONCLUSION: Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.

The gastrin receptor promotes pancreatic growth in transgenic mice.

INTRODUCTION: We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors. AIMS AND METHODOLOGY: To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter. RESULTS: Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities. CONCLUSION: In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.