Urotensin II receptor knockout mice on an ApoE knockout background fed a high-fat diet exhibit an enhanced hyperlipidemic and atherosclerotic phenotype.

RATIONALE: Expression of the vasoactive peptide Urotensin II (UII) is elevated in a number of cardiovascular diseases. OBJECTIVE: Here, we sought to determine the effect of UII receptor (UT) gene deletion in a mouse model of atherosclerosis. METHODS AND RESULTS: UT knockout (KO) mice were crossed with ApoE KO mice to generate UT/ApoE double knockout (DKO) mice. Mice were placed on a high-fat Western-type diet for 12 weeks. We evaluated the degree of atherosclerosis and hepatic steatosis by histology. In addition, serum glucose, insulin, and lipids were determined. DKO mice exhibited significantly increased atherosclerosis compared to ApoE KO mice (P<0.05). This was associated with a significant increase in serum insulin and lipids (P<0.001) but a decrease in hepatic steatosis (P<0.001). UT gene deletion led to a significant increase in systolic pressure and pulse pressure. RT-PCR and immunoblot analyses showed significant reductions in hepatic scavenger receptors, nuclear receptors, and acyl-CoA:cholesterol acyltransferase (ACAT1) expression in DKO mice. UII induced a significant increase in intracellular cholesteryl ester formation in primary mouse hepatocytes, which was blocked by the MEK inhibitor, PD98059. Hepatocytes of UTKO mice showed a significant reduction in lipoprotein uptake compared to wild-type mice. CONCLUSIONS: We propose that UT gene deletion in an ApoE-deficient background promotes downregulation of ACAT1, which in turn attenuates hepatic lipoprotein receptor-mediated uptake and lipid transporter expression. As the liver is the main organ for uptake of lipoprotein-derived lipids, DKO leads to an increase in hyperlipidemia, with a concomitant decrease in hepatic steatosis, and consequently increased atherosclerotic lesion formation. Furthermore, the hypertension associated with UT gene deletion is likely to contribute to the increased atherosclerotic burden.

Long-term pathologic consequences of acute irritant-induced asthma.

BACKGROUND: Acute irritant-induced asthma (IrIa) or reactive airways dysfunction syndrome is caused by exposure to a high concentration of an agent. The long-term pathologic consequences of IrIa remain thus far unknown. OBJECTIVE: The aim of our study was to investigate the chronic airway inflammation and remodeling that occur in association with IrIa. METHODS: Ten subjects with a history of IrIa (mean interval of 10.9 years, minimum of 4 years, since the inhalational accident) underwent bronchoscopy followed by bronchoalveolar lavage and bronchial biopsies. Immunologic and morphologic data from patients with IrIa were compared with those of patients with mild to moderate asthma as well as healthy controls. RESULTS: Bronchoalveolar lavage fluid analysis showed increased eosinophil and neutrophil counts in 30% and 60% of subjects with IrIa, respectively. In the supernatant of bronchoalveolar lavage, we found a significant increase in the majority of mediators compared with healthy subjects and a significant increase in eosinophilic cationic protein, IL-8, basic fibroblast growth factor, and matrix metalloproteinase 1 compared with control patients with asthma. Evaluation of basement membrane thickness (subepithelial fibrosis) demonstrated a significant increase in patients with IrIa compared with healthy subjects and subjects with asthma. Basement membrane thickness also significantly correlated with the PC(20) value. The epithelial cell detachment showed an elevated although not significant trend compared with subjects with asthma and control subjects. Immunocytochemical analysis demonstrated increases in the number of eosinophil cationic protein and TGF-beta1-positive cells compared with healthy controls. CONCLUSION: This study provides evidence of a significant eosinophilic and neutrophilic inflammation as well as remodeling in IrIa many years after an inhalational accident.

Th-17 cell-related cytokines' potential role in the pathogenesis of severe asthma.

Severe asthma represents a distinct, poorly-understood phenotype of asthma that has higher morbidity, mortality and a disproportionate need for health care support. Studies have indicated the presence of a specific inflammatory response in severe asthmatics, including the paucity of expression of classical Th-2 type cytokines. Following antigenic stimulation, naive CD4+ T cells proliferate and differentiate into various effector subsets such as Th-1 and Th-2 cells. A third subset of CD4+ T cells has recently been identified and designated as Th-17 cells, which produce IL-17A and F, IL-6, and TNF-alpha. In severe asthma, there may be a predominant Th-17 phenotype. These cells may promote the release of neutrophil chemotactic factors and induce the expression of GR-beta, which is responsible for corticosteroid hyporesponsiveness in immune and structural cells. If the role of Th-17 cytokines is confirmed, it might provide a new option in controlling this refractory subtype of asthma.

Laparoscopic management of a complicated case of Wilkie's syndrome: A case report.

INTRODUCTION: Superior mesenteric artery (SMA) syndrome also known as Wilkie's syndrome is a rare condition caused by the entrapment of the third part of the duodenum between the aorta and the SMA. The incidence of Wilkie's syndrome range between 0.013% and 0.3%. The normal angle between the aorta and SMA has been described to range between 38° and 65°, whereas in Wilkie's syndrome this angle is reduced to less than 20° causing gastric outlet obstruction. CASE PRESENTATION: We report a case of a previously diagnosed 43 year-old male with SMA syndrome, whom had been conservatively managed for 5-years for recurrent admissions with symptoms of gastric outlet obstruction. During his last admission, CT abdomen demonstrated gastric pneumatosis and portal venous gas requiring urgent surgical intervention. Duodenojejunostomy was successfully performed using laparoscopic technique. DISCUSSION: SMA syndrome is thought to occur secondary to the rapid and excessive weight loss leading to the reduction of the mesenteric fat around the aorta and SMA, thereby reducing the normal angle between the two arteries. Conservative medical management is usually the first line of treatment in uncomplicated cases. Surgical management is usually reserved only after failed conservative management or complicated cases, at which time either an open or laparoscopic surgical approach is undertaking. CONCLUSION: Surgical intervention is the mainstay in complicated cases of SMA syndrome and in refractory cases to conservative management. Advantages of laparoscopic approach over open surgery include rapid recovery time, reduced post-operative pain and shorter hospital stay.

Urotensin-II receptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease.

It is now well established that urotensin-II (UII) levels are increased in several cardiovascular diseases. We previously demonstrated that UII and the UII receptor (UT) protein levels are significantly increased in the hearts of both humans and rats with congestive heart failure (CHF). We have also recently demonstrated that UII blockade, with a selective UII antagonist, improves heart function in a rat model of ischemic CHF. Here, we evaluated the attenuation of cardiac remodeling associated with UII antagonism in the same rat model of ischemic CHF. Animals were administered a specific UT receptor antagonist, SB-611812 (30 mg/kg/day, gavage), or vehicle 30 min prior to coronary artery ligation followed by daily treatment for 8 weeks. Myocardial interstitial fibrosis was analyzed by Masson's trichrome and picrosirius red staining. RT-PCR analysis was utilized for mRNA expression studies. We used Western blotting to assess levels of collagen types I and III. Mitogenic activity of UII on cultured neonatal cardiac fibroblasts was also evaluated. Following coronary ligation, SB-611812 significantly attenuated both myocardial and endocardial interstitial fibrosis, and reduced collagen type I:III ratio (P<0.01). UII induced proliferation of cardiac fibroblasts and this mitogenic effect was significantly inhibited with 1 microM of SB-611218 (P<0.05). We demonstrate here that selective blockade of UT reduces diastolic dysfunction by decreasing myocardial fibrosis post-coronary ligation in vivo, and inhibits UII-mediated fibroblast proliferation in vitro.

A complicated case of amyand's hernia involving a perforated appendix and its management using minimally invasive laparoscopic surgery: A case report.

INTRODUCTION: Amyand's hernia is a rare condition of inguinal hernia in which the appendix is incarcerated within the hernia sac through the internal ring. Complications include acute appendicitis and perforated appendicitis, which are rare in incidence, accounting for about 0.1% of cases.1 These complications prove a diagnostic challenge due to their vague clinical presentation and atypical laboratory and radiological findings. Until recently, open appendectomy was the mainstay of treatment. Laparoscopic surgery offers a less invasive approach to confirming a diagnosis and serving as a therapeutic tool in equivocal cases. CASE PRESENTATION: We report a case of a previously healthy 20-year-old male presenting with atypical signs and symptoms, as well as blood investigation results, and radiological findings of a perforated appendix within an Amyand's hernia. The patient was successfully managed using a minimally invasive laparoscopic appendectomy approach. DISCUSSION: Until recently, open appendectomy was considered the mainstay in the management of complicated Amyand's hernia. Laparoscopic surgery provides a new avenue for dealing with diagnostic uncertainty with advantages including faster recovery time, reduced hospital stay, and better quality of life. CONCLUSION: This case report highlights the concealing effects of an Amyand's hernia on a perforated appendix, the considerations required when an equivocal diagnosis present and the safe use of the minimally invasive laparoscopic surgery in the treatment of this rare condition.

ATLANTIC-DIP: excessive gestational weight gain and pregnancy outcomes in women with gestational or pregestational diabetes mellitus.

CONTEXT: Women who have diabetes mellitus during pregnancy are at higher risk of adverse outcomes. Excessive gestational weight gain (GWG) is also emerging as a risk factor for maternofetal complications, and in 2009, the Institute of Medicine published recommendations for appropriate GWG. It is unclear whether excessive GWG confers additional risk to women with diabetes in pregnancy and whether Institute of Medicine recommendations are applicable to this population. OBJECTIVE: The objective of this study was to examine whether excessive GWG in pregnancies complicated by diabetes mellitus is associated with higher adverse obstetric outcomes. DESIGN: This was an observational study. SETTING: The study was conducted at five antenatal centers along the Irish Atlantic seaboard. PARTICIPANTS: 802 women with diabetes in pregnancy participated in the study. MAIN OUTCOME MEASURE: Maternal outcomes examined included preeclampsia, gestational hypertension, and cesarean delivery. Fetal outcomes included large for gestational age (LGA), macrosomia, and small for gestational age. RESULTS: Excessive GWG was noted in 59% of women. In all women, excessive GWG resulted in higher odds for LGA [adjusted odds ratio (aOR) 2.01, 95% confidence intervals 1.24-3.25 in GDM; aOR 3.97, CI 1.85-8.53 in pregestational diabetes mellitus (PGDM)] and macrosomia (aOR 2.17, CI 1.32-3.55 in GDM; aOR 3.58, CI 1.77-7.24 in PGDM). Excessive GWG was also associated with an increased odds for gestational hypertension (aOR 1.72, CI 1.04-2.85) in women with GDM, and treatment with insulin further increased the odds for LGA (aOR 2.80, CI 1.23-6.38) and macrosomia (aOR 5.63, CI 2.16-14.69) in this group. CONCLUSION: We show that in the already high-risk settings of both GDM and PGDM, excessive GWG confers an additive risk for LGA birth weight, macrosomia, and gestational hypertension.

Remodeling in asthma.

Airway remodeling refers to the structural changes that occur in both the large and the small airways of miscellaneous diseases, including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, enlargement of glands, neovascularization, and epithelial alterations. Although controversial, airway remodeling is commonly attributed to the underlying chronic inflammatory process. These remodeling changes contribute to thickening of airway walls and consequently lead to airway narrowing, bronchial hyperresponsiveness, airway edema, and mucous hypersecretion. Airway remodeling is associated with poorer clinical outcome among patients with asthma. Early diagnosis and prevention of airway remodeling has the potential to decrease disease severity, to improve control, and to prevent disease expression. In this article, we briefly provide an update on the characteristic features of airway remodeling observed in asthma and their clinical consequences.

Targeted overexpression of the human urotensin receptor transgene in smooth muscle cells: effect of UT antagonism in ApoE knockout mice fed with Western diet.

Urotensin II (UII) and its receptor UT are upregulated in the pathological setting of various cardiovascular diseases including atherosclerosis. However, their exact role in atherosclerosis remains to be determined. In the present study we used four strains of mice; wild-type (WT), UT(+) (a transgenic strain expressing human UT driven by the alpha-smooth muscle-specific, SM22, promoter), ApoE knockout (ko), and UT(+)/ApoE ko. All animals were fed high fat diet for 12 weeks. Western blot analysis revealed a significant increase in aortic UT expression in UT(+) relative to WT mice (P<0.05). Aortas of ApoE ko mice expressed comparable UT protein level to that of UT(+). Immunohistochemistry revealed the presence of strong expression of UT and UII proteins in the atheroma of UT(+), ApoE ko and UT(+)/ApoE ko mice, particularly in foam cells. Serum cholesterol and triglyceride levels were significantly increased in ApoE ko and in UT(+)/ApoE ko but not in UT(+) mice when compared to WT mice (P<0.0001). Analysis of aortas showed a significant increase in atherosclerotic lesion in the UT(+), ApoE ko and UT(+)/ApoE ko compared to WT mice (P<0.05). Oral administration of the UT receptor antagonist SB-657510A (30 microg/Kg/day gavage) for 10 weeks in a group of ApoE ko mice fed on high fat diet resulted in a significant reduction of lesion (P<0.001). SB-657510A also significantly reduced ACAT-1 protein expression in the atherosclerotic lesion of ApoE ko mice (P<0.05). The present findings demonstrate an important role for UT in the pathogenesis of atherosclerosis. The use of UT receptor antagonists may provide a beneficial tool in the management of this debilitating disease process.