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Constrictive pericarditis is a disease where loss of pericardial elasticity and restriction of filling of the cardiac chambers occurs. It is most often seen as an associated symptom of heart failure. Pericardiectomy provides effective treatment for patients with symptomatic constrictive pericarditis, although high rates of morbidity and mortality are related to the procedure. We present a case with extensive calcification, massive caseous necrosis and an important impairment of right ventricular function successfully operated in our institution.

Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic β-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, β-cell insulin secretion and glycemic control - suggesting that SWELL1-LRRC8 complex dysfunction contributes to T2D pathogenesis. Here, we show that ICl,SWELLand SWELL1 protein are reduced in adipose and β-cells in murine and human T2D. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-designed active derivatives (SN-40X) of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1-LRRC8 hexameric complex, restore SWELL1-LRRC8 protein, plasma membrane trafficking, signaling and islet insulin secretion via SWELL1-dependent mechanisms.In vivo, SN-401 and active SN-40X compounds restore glycemic control and prevents NAFLD by improving insulin-sensitivity and insulin secretion in murine T2D. These findings demonstrate that small molecule SWELL1 modulators restore SWELL1-dependent insulin-sensitivity and insulin secretion in T2D and may represent a first-in-class therapeutic approach for T2D and NAFLD.

Background This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. Methods This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. Results Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10–120 months) (P Conclusion Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.

Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.

Suitable experimental models of gallstone pancreatitis with systemic inflammation and mortality are limited. We developed a novel murine model of duct-ligation-induced acute pancreatitis associated with multiorgan dysfunction and severe mortality.Laparotomy was done on C57/BL6 mice followed by pancreatic duct (PD) ligation, bile duct (BD) ligation without PD ligation, or sham operation.Only mice with PD ligation developed acute pancreatitis and had 100% mortality. Pulmonary compliance was significantly reduced after PD ligation but not BD ligation. Bronchoalveolar lavage fluid neutrophil count and interleukin-1β concentration, and the plasma creatinine level, were significantly elevated with PD ligation but not BD ligation. Pancreatic nuclear factor κB (p65) and activator protein 1 (c-Jun) were activated within 1 h of PD ligation.PD-ligation-induced acute pancreatitis in mice is associated with systemic inflammation, acute lung injury, multiorgan dysfunction and death. The development of this novel model is an exciting and notable advance in the field.

Assessment of physical activity in morbidly obese subjects is important especially in bariatric surgery. We examined the validity of Intelligent Device for Energy Expenditure and Activity (IDEEA) for measuring physical activity and sedentary behavior in morbidly obese women. Activity types, gait counts, and speed detected by the IDEEA monitor were compared to those reported by an observer. The IDEEA monitor detected activity types and gait counts with relatively high accuracy, although slightly lower in extremely obese women than in normal weight controls. The IDEEA monitor accurately estimated gait speeds in both groups. Since gait speed predicts energy expenditure more accurately than gait counts, it is of greater clinical relevance. Reliability of the IDEEA monitor was excellent. The IDEEA monitor is a valid instrument for measuring physical activity and sedentary behavior in extremely obese women, and therefore has potential applications in bariatric surgery both in preoperative evaluation and long-term follow-up.

Background Acute lung injury is a major determinant of outcomes in acute pancreatitis. We evaluated acute lung injury and stress kinase activation in ligation-induced acute pancreatitis in mice. Methods Mice with duct ligation or sham operation were killed after 24 or 48 hours. Results In addition to acute pancreatitis, duct ligation was associated with pulmonary morphologic changes indicative of acute lung injury (alveolar septal thickening, congestion, and neutrophil infiltration). Furthermore, immunoblotting showed stress kinase activation in the pancreas and lung after ligation. Although mortality was observed in the ligated group, that is consistent with severe lung injury, it requires further evaluation. Conclusions Bile and pancreatic duct ligation in the mouse is associated with pancreatic and pulmonary stress kinase activation and acute inflammatory changes consistent with early acute pancreatitis and acute lung injury. Our findings are important as acute lung injury increases mortality in clinical acute pancreatitis and stress kinases are established proinflammatory signal transducers.

Bile-pancreatic duct ligation in rats causes acute pancreatic inflammation. We performed serial morphologic evaluation of the exocrine pancreas after duct ligation to facilitate further investigations using the model.The pancreas was excised from 74 rats after 0, 1, 3, 5, 24 or 48 hours of duct ligation or sham surgery. A pathologist evaluated 1 hematoxylin- and eosin-stained slide from each rat. Confirmatory immunostaining was performed with markers for apoptosis (activated caspase-3), proliferation (cyclin D3), neutrophils (myeloperoxidase), and macrophages (CD68).Interstitial edema and white blood cell infiltration were apparent at 24 hours and increased at 48 hours. Progressive periods of duct ligation were characterized by ductular ectasia (1 to 3 hours), acinar vacuolization (5 to 48 hours), leukocytic margination and neutrophil exocytosis (5 to 48 hours), ductule epithelium hypertrophy and proliferation (24 to 48 hours), and discernible loss of zymogen granules (48 hours).Ligation-induced acute pancreatitis in rats is a useful model to investigate early events in disease pathogenesis.

Background: This is a study of the causes of 30-day postoperative death following surgical treatment for obesity and a search for ways to decrease an already low mortality rate. Methods: Data were contributed from 1986-2004 to the International Bariatric Surgery Registry by 85 sites, representing 137 surgeons. A spread-sheet was prepared with rows for causes and columns for patients. The 251 causes contributing to 93 deaths were then marked in cells wherever a patient was noted to have one of the causes. Rows and columns were then moved into positions that provided patterns of best fit. Results: 11 patterns were found. 10 had well known initiating causes of death. Overall operative 30-day mortality was 0.24% (93 / 38,501). The most common cause of death was pulmonary embolism (32%, 30/93). 14 deaths were caused by leaks (15%, 14/93), and were equally prevalent after simple (15%, 2/14) or complex (15%, 12/79) operations. Small bowel obstruction caused 8 deaths, exclusively after complex operations. 5 of these involved the bypassed biliopancreatic limb and were defined as "bypass obstruction". Conclusions: A spread-sheet study of cause of 30-day postoperative death revealed a rapidly lethal initiating complication of Roux-en-Y gastric bypass obstruction that requires the earliest possible recognition and treatment. Bypass obstruction needs a name and code to facilitate recognition, study, prevention and early treatment. Spread-sheet pattern analysis of all available data helped identify the initiating cause of death for individual patients when multiple data elements were present.

Using a unique surgical model (the donor rat model), we showed previously that duodenal replacement of bile-pancreatic juice, obtained fresh from a donor rat, ameliorates ligation-induced acute pancreatitis. We hypothesize that bile-pancreatic juice exclusion from gut exacerbates Akt/nuclear factor-kappaB (NF-kappaB) pathway activation and induces chemokine production in ligation-induced acute pancreatitis. We compared rats with bile-pancreatic duct ligation to those with duodenal bile-pancreatic juice replacement fresh from a donor rat beginning immediately before duct ligation. Sham control rats had ducts dissected but not ligated. Rats were killed 1 or 3 hours after operation (n = 7/group). Akt activation (immunoblotting, immune-complex kinase assay, and ELISA), inhibitory protein I-kappaB (IkappaB) activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA) were measured in pancreatic homogenates. NF-kappaB was quantitated in nuclear fractions using electrophoretic mobility shift assay. Duct ligation produced significant increases in pancreatic Akt, IkappaB, and NF-kappaB activation and production of MCP-1 and RANTES. Activation of the Akt/NF-kappaB pathway and increased MCP-1 and RANTES production in response to duct ligation were significantly reduced by bile-pancreatic juice replacement (ANOVA, P < 0.05). Bile-pancreatic juice exclusion stimulates Akt/NF-kappaB pathway activation and increases chemokine production in ligation-induced acute pancreatitis.

Background The role of cholinergic pathways in the pathogenesis of bile-pancreatic duct ligation (BPDL)-induced acute pancreatitis in rats remains controversial. We hypothesized that cholinergic stimulation exacerbates acute pancreatic inflammation in the presence of duct obstruction. Methods We studied 34 rats divided into 5 groups as follows: (1) sham operation; (2) BPDL; (3) BPDL with duodenal bile-pancreatic juice (BPJ) replacement fresh from a donor rat; (4) BPDL with BPJ replacement as in 3 above, and carbachol (CCh) 5 ug/h subcutaneously; or (5) CCh 5 ug/h subcutaneously only. Rats were killed after 6 hours. Results The P value was less than .05 by analysis of variance. Pancreatic morphologic changes and zymogen fraction hyperamylasemia seen with duct ligation (2 vs. 1) were ameliorated significantly by duodenal BPJ replacement (3 vs. 2), but not when exogenous CCh was administered (4 vs. 3), whereas CCh alone showed no significant changes compared with sham (5 vs. 1). Conclusions Cholinergic stimulation and duct obstruction synergistically amplify acinar hyperstimulation and exacerbate acute pancreatitis.

Acute pancreatitis is associated with stress kinase activation and cytokine production. We hypothesize that bile-pancreatic juice exclusion activates p38(MAPK) and induces TNF-alpha production in ligation-induced acute pancreatitis. We compared rats with 1-3 h of duct ligation, duct ligation with duodenal bile-pancreatic juice replacement from a donor rat, and sham operation. Pancreatic homogenates were analyzed as follows: (a) Immunoblots using phospho-specific p38(MAPK) antibody showed increased p38(MAPK) activation after ligation that was inhibited by bile-pancreatic juice replacement. (b) Immune-complex kinase assay using ATF-2 as substrate showed increased p38(MAPK) activation after ligation that was subdued by bile-pancreatic juice replacement. (c) ELISA showed increased pancreatic TNF-alpha production after ligation that was significantly ameliorated by bile-pancreatic juice replacement.Bile-pancreatic juice exclusion from gut increases p38(MAPK) activation and TNF-alpha production in this experimental model. Our findings support our central hypothesis that bile-pancreatic juice exclusion exacerbates cell stress and acute inflammation in ligation-induced acute pancreatitis.

Bile-pancreatic duct ligation in rats excludes bile-pancreatic juice from the gut and induces acute pancreatitis. Bile-pancreatic juice exclusion from the gut results in increased plasma cholecystokinin (CCK) levels. CCK-A receptor-mediated exocrine pancreatic hyperstimulation is implicated in disease pathogenesis. In the present study, we show for the first time a progressive rise in CCK-A receptor protein expression in ligation-induced acute pancreatitis in rats. As CCK-A receptor induction could amplify CCK-mediated acinar hyperstimulation and exacerbate acinar cell stress with activation of the p38MAPK stress kinase pathway, we studied CCK-A receptor protein expression and p38MAPK activation in duct ligation-induced acute pancreatitis in rats. Compared to sham-operated controls, acute pancreatitis induced by bile-pancreatic duct ligation associates with a temporal increase in pancreatic CCK-A receptor protein expression, p38MAPK expression and activation, and NF-ĸB activation. These findings may have significance in the mechanism of disease pathogenesis in this experimental model.

Using an original model, the donor rat model, we previously showed that bile-pancreatic juice exclusion from gut exacerbates ligation-induced acute pancreatitis. Here, we examine the mechanism by which bile-pancreatic juice exclusion from gut exacerbates acute pancreatitis. In the first part of the study we test the hypothesis that Na taurocholate and trypsin are components of bile-pancreatic juice that exacerbate acute pancreatitis when excluded. Our experiments show that combined replacement of Na taurocholate and trypsin ameliorates acute pancreatitis. In the second part of the study we test the hypothesis that bile-pancreatic juice exclusion from gut exacerbates acute pancreatitis via combined CCK-A and cholinergic receptor pathways. Our experiments show that combined CCK-A and cholinergic receptor blockade significantly ameliorates acute pancreatitis while blockade of either receptor alone does not. We conclude that bile-pancreatic juice exclusion-induced exacerbation of ligation-induced acute pancreatitis involves a neurohormonal duodenal response to exclusion of trypsin and Na taurocholate resulting in acinar cell hyperstimulation via combined CCK-A and cholinergic receptor-mediated pathways.

Background Cholecystokinin-A (CCK-A) and cholinergic receptor pathways, capable of activating stress kinases p38 mitogen-activated protein kinase (p38 MAPK ) and cJUN N-terminal kinase (JNK), are implicated in the pathogenesis of ligation-induced acute pancreatitis in rats. As ligation-induced acute pancreatitis in rats is associated with CCK-A receptor induction and p38 MAPK activation, and as receptor induction could amplify acinar hyperstimulation and exacerbate cell stress, we tested the hypothesis that the cholinergic M3 receptor is induced and JNK is activated in this model. Methods Cholinergic M3 receptor expression and JNK activation was compared in rats 1, 3, or 24 hours after sham operation or duct ligation. Results Immunoblot analysis of pancreatic homogenates showed a time-dependent increase in cholinergic M3 receptor protein, total JNK, and phospho-JNK after duct ligation. Conclusions There is a rapid and progressive cholinergic M3 receptor induction and JNK activation in ligation-induced acute pancreatitis in rats. These findings may have significance in the mechanism of disease pathogenesis.

Background Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown. Methods/Results In duct ligation-induced acute pancreatitis in mice and rats, we found that (a) IL-33 concentration was increased in the pancreas; (b) mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c) plasma histamine and pancreatic substance P concentrations were increased; and (d) pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK) and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α). Also, IL-33 activated ERK in human pancreatic tissue. Significance As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation. Conclusion IL-33 is induced in acute pancreatitis, activates acinar cell proinflammatory pathways and exacerbates acute pancreatic inflammation.

Background Acinar cell inhibitors (eg, atropine) fail to ameliorate clinical and experimental acute pancreatitis. We hypothesized that amelioration of pancreatic acinar cell hyperstimulation after bile and pancreatic duct ligation is better with gut replacement of bile and pancreatic juice than with cholinergic- and cholecystokinin (CCK)-receptor blockade. Methods Using acinar cell amylase activity as an index of hyperstimulation, we studied 63 rats in two sets of experiments. Bile-pancreatic juice exclusion from gut—without (set one) and with (set two) bile and pancreatic duct obstruction— was treated with atropine and CCK-receptor antagonist L-364,718, or with enterai replacement of bile-pancreatic juice. Results In the set one experiment, acinar cell hyperstimulation after bile-pancreatic; juice exclusion was reversed by combined L-364,718 and atropine pretreatment. In set two, acinar cell hyperstimulation after bile and pancreatic duct ligation was reversed by enterai bile and pancreatic juice replacement, but not by combined L-364,718 and atropine pretreatment. Conclusions According to this experimental corollary of early gallstone impaction, prevention of acinar cell hyperstimulation after duct occlusion should be aimed at the source of the response to bile-pancreatic juice exclusion, namely, the gut, rather than at the target of the response, the pancreatic acinar cell.

Acute pancreatitis in opossums induced by ligation of the pancreatic duct was studied with and without exclusion of bile from gut and with and without exclusion of pancreatic enzymes from gut. Opossum

Acute necrotizing pancreatitis in opossums after bile and pancreatic duct ligation (BPDL) is a useful experimental corollary of gallstone-induced acute pancreatitis in humans. In experimental and human acute pancreatitis, a loss of segregation of the lysosomal enzyme cathepsin B and the zymogen proenzyme trypsinogen (colocalization) is implicated as the triggering event of disease pathogenesis, as cathepsin B can activate trypsinogen. The object of this study was to quantitate acinar cell necrosis and to study subcellular distribution of cathepsin B in BPDL-induced acute necrotizing pancreatitis in opossums. Bile and pancreatic ducts were ligated separately (no bile reflux) in four opossums, while ducts were dissected in four sham controls. Opossums were killed 24 hr after operation. Three equidistant cross-sectional portions of each opossum pancreas were submitted to histologic examination. In blinded fashion, each focus of acinar cell necrosis was photographed and quantitated with digitizing morphometry. Numerical density (foci/cm 2 ) and areal density (×10 3 μm 2 /cm 2 ) of focal acinar cell necrosis were determined. Differentially centrifuged pancreatic homogenates were assayed for cathepsin B, the lysosomal marker enzyme N-acetylglucosaminidase, and amylase. Morphometric quantitation of acinar cell necrosis confirmed development of acute necrotizing pancreatitis after 24 hr of BPDL in opossums. However, colocalization was not observed after BPDL, as evidenced by an absence of subcellular shift of cathepsin B activity (and N-acetyl-glucosaminidase activity) from the lysosome-enriched to the zymogen-enriched subcellular fraction. Amylase activity was increased in subcellular fractions after BPDL. In this experimental corollary of early gallstone-induced acute pancreatitis, colocalization is not the triggering event of acute necrotizing pancreatitis pathogenesis, as acinar cell necrosis occurs even in the absence of colocalization

We have previously shown that distal pancreatic duct ligation-induced acute pancreatitis in mice is associated with substantial mortality. We examined the cause of death in duct ligation-induced acute pancreatitis in mice by serial examination of multiple parameters in three experimental groups: distal pancreatic duct ligation (PD), bile duct ligation alone (BD), and sham operation (S). BD and S had no mortality, while PD had 94% mortality with most deaths between days 2 and 4. Characteristics of mice with acute pancreatitis included (ANOVA; p

Although migraine headache (MH) is more severe in the obese, the risk of developing MH in the obese population is controversial. The effect of surgical weight loss on morbidly obese patients with MH provides a unique opportunity to evaluate this potential association.We analyzed the data from 702 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from 2000 to 2009. We identified patients with physician-diagnosed MH taking antimigraine medication.The data are presented as the mean ± SEM, with the range in parentheses. Of the 102 patients with preoperative MH, 21 were excluded because they had12-month follow-up data and 81 were followed up for 38.6 ± 3 months (range 12-123). Of the 81 patients, 90% were women. Their body mass index was 48 ± 1 kg/m(2) (range 37-85), and their age was 40 ± 1 years (range 18-62). After surgical weight loss, clinical improvement in MH was seen in 89% of patients within 5.6 ± .9 months (range 1-36; P.01, chi-square test), with 57 reporting total resolution and 15 reporting partial resolution (9 experienced no change). Using logistic regression analysis, we showed that the improvement in MH after RYGB was independent of the improvement in migraine-associated co-morbidities, such as sleep apnea, menstrual dysfunction, depression, and anxiety. We also compared patients who developed MH after obesity onset with those who had MH before obesity. The MH after obesity onset group included 51 patients, of whom 48 showed clinical improvement (41 complete, 7 partial, and 3 no improvement). The MH before obesity group included 24 patients, of whom 18 showed clinical improvement (11 complete, 7 partial, and 6 no improvement). The MH after obesity group showed a greater rate of complete resolution of MH after RYGB than did the MH before obesity group (P.01; chi-square test).Weight loss after RYGB substantially resolves MH, especially when obesity onset precedes MH onset. It remains to be determined whether RYGB-induced endocrine alterations or a reduction in adipokine burden contribute to migraine improvement.

Background: Polycystic ovary syndrome (PCOS) is a common cause of infertility, especially in the morbidly obese. We evaluated the long-term effects of Roux-en-Y gastric bypass on PCOS and infertility. Methods: A total of 566 morbidly obese women underwent Roux-en-Y gastric bypass from 2000 to 2009. A total of 31 patients (5.5%) had a history of PCOS. Of the 31 patients, 6 were postmenopausal and 5 lost to follow-up and were excluded. Telephone interviews were conducted with the 20 eligible patients. Results: The mean age and body mass index was 32 5.8 years (range 22- 42) and 52.8 9.08 kg/m 2 (range 37-76) before surgery. All 20 patients had 2 of 3 diagnostic criteria for PCOS, including clinical or biochemical evidence of hyperandrogenism, anovulation, or polycystic ovaries. Of these, 85% had oligomenorrhea, 70% had hirsutism, and 45% had type 2 diabetes mellitus with medication. Before surgery, 8 patients conceived with or without hormonal treatment, 2 did not desire pregnancy, and 10 did not conceive. The mean follow-up was 46.7 months. After surgical weight loss, menstruation was corrected in 82%, hirsutism had resolved in 29%, and 77.8% of those with diabetes had complete remission. Of the 10 patients who did not conceive before surgery, 4 no longer desired pregnancy, and the remaining 6 patients had become pregnant within 3 years of surgery—5 without any hormonal treatment and 1 with in utero insemination. Conclusion: Surgical weight loss after Roux-en-Y gastric bypass achieves excellent amelioration of PCOS manifestations and the postoperative conception rate in infertile PCOS subjects desiring pregnancy was 100%. (Surg Obes Relat Dis 2012;8:440 - 444.) © 2012 Published by Elsevier Inc. on behalf of American Society for Metabolic and Bariatric Surgery.

Background Hyperlipidemia is a known risk factor for the development of atherosclerosis and coronary artery disease in morbidly obese individuals. The aim of our study was to review the trends in the serum lipid profiles of patients undergoing Roux-en-Y gastric bypass at our institution. Methods A retrospective 6-year analysis of data of patients undergoing Roux-en-Y gastric bypass was performed. The indicators of resolution of hyperlipidemia were reviewed for 6 months and then annually for 6 consecutive years. Hyperlipidemia was defined according to the American Heart Association and National Cholesterol Education Program Adult Treatment Panel III guidelines. The changes in the lipid profile of the patients with subnormal levels of high-density lipoprotein (HDL) cholesterol and total cholesterol/HDL cholesterol risk ratio were also examined. Results A total of 94 patients were diagnosed with hyperlipidemia, of whom 23 were receiving clinical treatment. The mean patient age was 39 ± 9 years, and the mean body mass index was 50 ± 9.6 kg/m 2 , with a female predominance. The mean baseline serum levels were as follows: total cholesterol 220 ± 42.2 mg/dL, triglycerides 212 ± 123.5 mg/dL, low-density lipoprotein cholesterol 135 ± 34.2 mg/dL, and HDL cholesterol 51 ± 12 mg/dL. The optimization of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol profiles was seen in all patients within 6 months after surgery. The HDL cholesterol levels improved more slowly, reaching desirable levels within 12 months after surgery. All patients taking lipid-lowering agents no longer required the medication at the end of the study period. Conclusion Roux-en-Y gastric bypass provides an effective remission of hyperlipidemia in morbidly obese patients, with most patients no longer requiring lipid-lowering agents within 6 months after surgery. The improvement in overall lipid profiles continued during follow-up after surgery.

We have previously demonstrated that enteral exclusion augments pancreatic p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor-alpha (TNF-alpha) production after bile-pancreatic duct ligation in rats.In the present study, we evaluated c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation, and cytokine production, in pancreata of duct-ligated rats with and without duodenal bile-pancreatic juice replacement from a donor rat. We hypothesized that enteral exclusion of bile-pancreatic juice activates stress kinases and induces cytokine production in ligation-induced acute pancreatitis.Increased JNK and ERK activation after ligation are inhibited by bile-pancreatic juice replacement. Increases in pancreatic production of IL-1beta and IL-12 after ligation are significantly subdued by replacement. In additional in vitro studies, we show that cholecystokinin- or TNF-alpha-stimulated nuclear transcription factor kappa-B activation in AR42J cells is inhibited by dominant negative ERK2.Our novel findings using our Donor Rat Model indicate that bile-pancreatic juice exclusion induces MAP kinase activation and exacerbates cell stress and inflammation in this experimental model of gallstone pancreatitis. and IAP.

Hypothesis Bile and pancreatic juice exclusion from gut activates acinar stress kinases and exacerbates gallstone pancreatitis as evidenced by the ameliorating effects of replacement therapy in an experimental model of duct ligation-induced acute pancreatitis. In the early stages of gallstone pancreatitis, bile-pancreatic juice cannot enter the gut. Enteral exclusion worsens pancreatitis by causing feedback hyperstimulation of the exocrine pancreas that activates acinar cell stress kinases. Investigations using a unique surgical model, the Donor Rat Model, showed that duodenal replacement of bile-pancreatic juice in rats with duct ligation attenuates pancreatic stress kinase activation, reduces pancreatic cytokine production, and ameliorates pancreatic morphologic changes. These findings suggest that exclusion-induced acinar hyperstimulation, in the presence of duct obstruction, exacerbates acute pancreatitis via stress kinase activation. Although acinar hyperstimulation has often been implicated in the pathogenesis of acute pancreatitis, the lack of supporting evidence remains a conspicuous void. The proposed hypothesis draws on fresh evidence to present a new paradigm that reexamines the role of exocrine pancreatic hyperstimulation in gallstone pancreatitis pathogenesis.

Weight loss after gastric bypass procedures has been well studied, but the long-term metabolic sequelae are not known. Data on bone mineral density (BMD), calcium, parathyroid hormone, and vitamin D were collected preoperatively and at yearly intervals after gastric bypass procedures. A total of 230 patients underwent preoperative BMD scans. Fifteen patients were osteopenic preoperatively, and three patients subsequently developed osteopenia postoperatively within the first year. No patient had or developed osteoporosis. At 1 year, total forearm BMD decreased by 0.55% (n = 91; P = .03) and radius BMD had increased overall by 1.85% (n = 23; P = .008); both total hip and lumbar spine BMD decreased by 9.27% (n = 22; P < .001) and 4.53% (n = 31; P < .001), respectively. By the second postoperative year, BMD in the total forearm had decreased an additional 3.62% (n = 14; P < .001), whereas radius BMD remained unchanged. Although total hip and lumbar spine BMD significantly decreased at 1 year, by year 2 both total hip and lumbar spine BMD only slightly decreased and were not significantly different from before the operation. Serum calcium decreased from 9.8 mg/dL to 9.2 during the first year (not significant [NS]) and then to 8.8 (NS) by the second year. Parathyroid hormone increased from 59.7 pg/mL (nl 10-65 pg/mL) preoperatively to 63.1 during year 1 (NS) and continued to increase to 64.7 by year 2 (NS). No difference was noted among levels of 25-hydroxy vitamin D preoperatively (25.2 ng/mL; nl 10-65 ng/mL), at 1 year (34.4), and at 2 years (35.4). Our data indicate that bone loss is highest in the first year after gastric bypass with stabilization, and that, in some cases, there is an increase in bone density after the first year.

Background Using an original model, the Donor Rat Model, we showed that bile-pancreatic juice (BPJ) exclusion from gut exacerbates ligation-induced acute pancreatitis in rats. We also showed that muscarinic cholinergic M3 and CCK-A receptor expression is induced following duct ligation. Increased receptor number potentially could exacerbate cytokine production. We hypothesize that BPJ exclusion is responsible for M3 and CCK-A receptor induction and increased interleukin-6 (IL-6) production. Methods M3 and CCK-A receptor expression and IL-6 production were compared in rat pancreata 1 to 3 hours after duct ligation with or without BPJ replacement. Results Our studies showed that BPJ replacement attenuates duct ligation–induced increases in M3 and CCK-A receptor expression and IL-6 production. Conclusions In this model, BPJ exclusion from gut induces M3 and CCK-A receptor expression and increases IL-6 production. In this experimental corollary of gallstone pancreatitis, BPJ exclusion from gut may play a key role in the mechanism of disease pathogenesis.

We present a case of an extensive gas-forming abdominal wall abscess secondary to ruptured retroperitoneal appendicitis in a diabetic patient. Computed tomography (CT) demonstrated a retroperitoneal abscess extending to the abdominal subcutaneous tissue through the superior lumbar triangle pathway, a known anatomical defect of the lumbar musculature. This case not only represents an unusual manifestation of acute appendicitis, but also alerts us to the importance of anatomical considerations in the imaging interpretation of disease extent. The applied anatomy of the lumbar triangle as a conduit of intra-abdominal and retroperitoneal processes into the abdominal wall is reviewed.

We encountered a case of pneumoperitoneum caused by a gas-forming splenic abscess in a patient with acquired immunodeficiency syndrome (AIDS). Plain abdominal films and computed tomography demonstrated a large amount of free air. Pneumoperitoneum was eventually shown to represent gas liberated from fermentation by gas-forming organisms within the splenic abscess. Gas-containing necrotic tissue from the ruptured spleen mimicked the spillage of feces from colon perforation. The authors emphasize that a ruptured abscess should be included in the differential diagnosis of acute abdomen in an immunocompromised patient.

Ligation of the common bile-pancreatic duct induces hyperamylasemia and acute pancreatitis in rats. Pancreatic morphologic changes include edema, acinar cell damage, and mild inflammation. The pathogenesis of acute pancreatitis in this model is not understood, but may involve altered secretion and intrapancreatic activation of acinar proteases. We hypothesized that trypsinogen activation, measured by the production of plasma and pancreatic trypsinogen activation peptides (TAP), occurs early in this model. We performed the following experiments: rats were prepared with (1) bile-pancreatic ducts ligated and (2) ducts dissected but not ligated (sham). Rats were killed after 6, 24, and 48 hr. Serum amylase was measured and histologic sections were analyzed for morphologic changes. TAP was measured in both serum and pancreatic tissue homogenates using a specific polyclonal. anti-TAP antibody in an enzyme-linked immunosorbant assay. After 6, 24, and 48 hr of bile-pancreatic duct ligation, hyperamylasemia and acute morphologic changes of acute pancreatitis were observed. Evidence of acinar cell destruction was not evident until 48 hr after ligation. Levels of serum and pancreatic tissue TAP were significantly elevated at both 24 and 48 hr after ligation compared to those of sham. We conclude that increased intrapancreatic trypsinogen activation occurs early in this form of experimental acute pancreatitis and that it occurs prior to evidence of acinar cell destruction. These data and observations support the possibility that intrapancreatic protease activation contributes to the pathogenesis of ligation-induced acute pancreatitis.

Bile and pancreatic duct ligation (BPDL) in rats does not induce severe acute pancreatitis but only mild inflammation, which is self-limiting and eventually leads to pancreatic atrophy. However, BPDL in opossums induces severe acute necrotizing pancreatitis which uniformly leads to death within 14 days. We compared pancreatic morphologic changes after 24 hr of BPDL in rats and opossums. Pancreatitis histology score and acinar cell ultrastructural changes were evaluated. In both species, BPDL was associated with significant increases in histology score compared to sham controls (5.0 +/- 0.3 vs 1.5 +/- 0.3 in rats, 5.3 +/- 0.4 vs 1.1 +/- 0.1 in opossums; mean +/- SEM, ANOVA, P0.05). However, there was no significant difference in histology score between rats and opossums following BPDL; histologic changes, such as white blood cell infiltration, acinar cell vacuolation, and focal acinar cell necrosis, were similar. Acinar cell ultrastructural changes after BPDL in both species included dilated endoplasmic reticulum and autophagic vacuole formation. These findings indicate that the early morphologic changes after BPDL in rats are quite similar to those seen early in the course of BPDL-induced acute necrotizing pancreatitis in opossums. As the rat is a more economical and convenient model to study than the opossum, this study supports the use of the rat model to conduct pilot studies of early events in the development of BPDL-induced acute pancreatitis. This study also suggests the potential for investigating mechanisms that may be present in the rat which protect against progressive and fatal acute necrotizing pancreatitis as observed in opossums after longer periods of BPDL.

Background: Migraine headaches (MH) are common and more severe in the morbidly obese. We analyzed the impact of RYGB on MH in the morbidly obese. Methods: We analyzed our database of 702 morbidly obese patients that underwent RYGB between 2000-09. We identified patients with physician-diagnosed MH actively on medication. Results: Data are Mean SEM (range). Out of 102 patients with preoperative MH, 21 were excluded due to short follow-up of less than 12 months, while the remaining 81 were followed-up for 38.6 3 (16-103) months. These 81 patients were 90% female and had BMI of 48 1 (37-85) kg/m and age 40 1 (18-62) years. Following significant surgical weight loss, clinical improvement of MH was seen in 89% of patients within 5.6 0.9 (1-36) months (p 0.00001; Chi-Sq test), with 57 reporting complete resolution and 15 reporting partial resolution (9 experienced no change). We then compared patients that developed MH after obesity onset (MHAO Group) to those who had MH before obesity onset (MHBO Group), where 6 patients were excluded as indeterminate. The MHAO Group had 51 patients where 48 showed clinical improvement (41 complete, 7 partial and 3 no resolution). The MHBO Group had 24 patients where 18 showed clinical improvement (11 complete, 7 partial and 6 no resolution). Interestingly, the MHAO Group showed a significantly greater rate of complete resolution of MH after RYGB compared to the MHBO Group (p 0.0057; Chi-Sq test). Conclusion: Weight loss following RYGB substantially resolves migraine headaches, especially when obesity onset precedes the development of migraine. Whether RYGB-induced endocrine alterations also contribute to improvement of migraine remains to be determined.

A 35-year-old drug abuser inadvertently injected adulterated heroin into her left femoral artery and presented with critical ischaemia of her left leg. Treatment with intravenous Iloprost, a stable prostacycline analogue, combined with Heparin, produced a dramatic improvement in her circulation within 4 h.

Introduction: Using a unique surgical model (The Donor Rat Model) we showed that duodenal replacement of BPJ, obtained fresh from a Donor Rat, ameliorates pancreatic morphologic changes, hyperamylasemia and hypercholecystokininemia in ligation-induced acute pancreatitis. We hypothesize that BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and induces proinflammatory chemokine production in ligation-induced acute pancreatitis. The cytosolic IkB/NF-kB complex dissociates when IkB is phosphorylated following Akt activation, allowing NF-kB to translocate to the nucleus and induce transcription of various inflammatory mediators including chemokines. Methods: We studied rats as follows: Diseased-controls had bile-pancreatic duct ligation. Diseased-treated rats had duodenal BPJ replacement fresh from a Donor Rat beginning immediately before duct ligation. Sham controls had ducts dissected only. Rats were killed after 1 or 3 hours (n = 7/group). Pancreatic homogenates were used to determine Akt activation (immunoblotting, immunecomplex kinase assay and ELISA), IkB activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA). NF-kB was quantitated in pancreatic nuclear fractions using EMSA. Results: Compared to sham, duct ligation was associated with marked increases in pancreatic Akt and IkB activation, NF-kB nuclear translocation, and MCP-1 and RANTES production. Akt/NF-kB pathway activation and increased MCP-1 and RANTES production after duct ligation were substantially ameliorated by BPJ replacement (ANOVA, p Conclusions: BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis. These findings support our central hypothesis that BPJ exclusion-induced acinar cell hyperstimulation exacerbates acute pancreatic inflammation in this experimental corollary of gallstone-induced acute pancreatitis. (Support: ACS Faculty Research Fellowship, NIH-K08 Award#DK062805)

Bile-pancreatic duct ligation in rats excludes bile-pancreatic juice from gut and induces acute pancreatitis. CCK-A and c:holinergic receptor-mediated exocr/ne pancreatic hyperstimulation secondat 7 to bile-pancreatic juice exclusion ~ implicated in disease pathogenesis. Stimulation of these G protein coupled receptors can activate the Akt-NFkB pathway Nuclear Transcrip~ lion Factor kappa B (NFkB) is a downstream messenger of acinar cell signal transduction via the Akt pathway and is capable o/inr Nag adnar cell cytokina production. We hypothesize that the Akt-NFkB pathway is activated in figation-induced acute pancreatitis. METHODS: We studied rats w~th 1, 3, or 24 hra ot duct ligation or sham-operation (ducts dLssected but not ligated)(n= 5 rats/group). RESULTS: Compared to sham-controls, duct ligation induced acute pancreatitis as evidenced by hyperamylasemia and pancreatic morphologic changes. Electro-mobility shift assay showed a irma-dependent incraase in NFkB in pancreatic nuclear extracts after duct ligation (transcnption factor E-box was used as control; competing cold NFkB prone excluded non-specihc binding), immunobIot analysis of pancreatic homogehates showed mcreases in phospho-Akt and phospho-lkB that were also time-dependent and parallel with NFkB activation (actin immunobiots confirmed equal loadtirg of lanes) (lkB phosphorylation permits translocatinn of NFkB from the cytosol to the nucleus). CONCLUSIONS: 'Paere is a time-dependem and parallel increase in nuclear translocation of NFkB and acuvation of Akt and IkB after duct ligationdnduced acute pancreatitis in rats. These findings are consistent wuh the h)~otbesis that the Akt-NFkB pathway is activated in duct ligation induced acute pancreatitis. In this expemnentaI corollary of gallstone-reduced acute pancreatitts, bile-pancreatic juice exclusion-induced stimulation of acinar cell G protein coupled receptors could exacerbate acute pancreatitis by increased acinar cell production of pro-inflammatory cytokines via lbe Akt-NFkB pathway (Support: Carver Collaborative Pilot Grant; N1H #lK08DK062805)

To the Editor.— Kartagener's syndrome (chronic sinopulmonary symptoms and situs inversus) was shown to be a part of the immotile-cilia syndrome (chronic sinopulmonary symptoms and male sterility) when Afzelius and coworkers demonstrated that males with the immotile-cilia syndrome had immotile (or dysmotile) respiratory cilia and spermatozoa and that 50% of cases of the immotile-cilia syndrome had situs inversus. 1,2 The immotility is attributed to an ultrastructural defect of the respiratory cilium and sperm tail. 1 The inheritance is autosomal recessive. Absence of frontal sinuses is a recognized association. 2 This is to my knowledge the second report of a case of Kartagener's syndrome with normal spermatozoa. The patient had chronic sinopulmonary symptoms, situs inversus, and absent frontal sinuses, while his spermatozoa had normal motility, ultrastructure, and fertilizing capacity. Thus, the entity can be regarded as a new subgroup of the immotile-cilia syndrome. Report of a Case.— A bachelor, aged 26