A novel transgenic mouse model of CBS-deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment

Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) and serine to cystathionine, which is then hydrolyzed to cysteine by cystathionine gamma-lyase. Inactivation of CBS results in CBS-deficient homocystinuria more commonly referred to as classical homocystinuria, which, if untreated, results in mental retardation, thromboembolic complications, and a range of connective tissue disorders. The molecular mechanisms that underlie the pathology of this disease are poorly understood. We report here the generation of a new mouse model of classical homocystinuria in which the mouse cbs gene is inactivated and that exhibits low-level expression of the human CBS transgene under the control of the human CBS promoter. This mouse model, designated “human only” (HO), exhibits severe elevations in both plasma and tissue levels of Hcy, methionine, S-adenosylmethionine, and S-adenosylhomocysteine and a concomitant decrease in plasma and hepatic levels of cysteine. HO mice exhibit mild hepatopathy but, in contrast to previous models of classical homocystinuria, do not incur hepatic steatosis, fibrosis, or neonatal death with approximately 90% of HO mice living for at least 6 months. Tail bleeding determinations indicate that HO mice are in a hypercoagulative state that is significantly ameliorated by betaine treatment in a manner that recapitulates the disease as it occurs in humans. Our findings indicate that this mouse model will be a valuable tool in the study of pathogenesis in classical homocystinuria and the rational design of novel treatments.     

Value of carbon dioxide wedged venography and transvenous liver biopsy in the definitive diagnosis of Abernethy malformation

We report a 25-year-old man who presented with congenital absence of the portal vein, or Abernethy malformation, a rare congenital disorder in which the mesenteric and splenic venous drainages bypass the liver and directly drain into the inferior vena cava through an extrahepatic portosystemic shunt. Magnetic resonance imaging, which showed multiple nodular lesions in both liver lobes that were associated with an absence of intrahepatic portal venous branches, strongly suggested the diagnosis of the Abernethy malformation. Carbon dioxide wedged venography and transvenous liver biopsy, which were performed in the same session by a right jugular approach, confirmed these findings. This technique can be considered a valuable alternative diagnostic tool to catheter arteriography and percutaneous transhepatic liver biopsy.     

Improved postoperative outcomes associated with preoperative statin therapy

Statin therapy is well established for prevention of cardiovascular disease. Statins may also reduce postoperative mortality and morbidity via a pleiotropic (non-lipid-lowering) effect. The authors conducted a meta-analysis to determine the influence of statin treatment on adverse postoperative outcomes in patients undergoing cardiac, vascular, or noncardiovascular surgery. Two independent authors abstracted data from 12 retrospective and 3 prospective trials (n = 223,010 patients). A meta-analysis was performed to evaluate the overall effect of preoperative statin therapy on postoperative outcomes. Preoperative statin therapy was associated with 38% and 59% reduction in the risk of mortality after cardiac (1.9% vs. 3.1%; P = 0.0001) and vascular (1.7% vs. 6.1%; P = 0.0001) surgery, respectively. When including noncardiac surgery, a 44% reduction in mortality (2.2% vs. 3.2%; P = 0.0001) was observed. Preoperative statin therapy may reduce postoperative mortality in patients undergoing surgical procedures. However, the statin associated effects on postoperative cardiovascular morbidity are too variable to draw any conclusion.     

Duodenogastric and gastroesophageal bile reflux

This study reviews current data regarding duodenogastric and gastroesophageal bile reflux-pathophysiology, clinical presentation, methods of diagnosis (namely, 24-hour intraluminal bile monitoring) and therapeutic management. Duodenogastric reflux (DGR) consists of retrograde passage of alkaline duodenal contents into the stomach; it may occur due to antroduodenal motility disorder (primary DGR) or may arise following surgical alteration of gastoduodenal anatomy or because of biliary pathology (secondary DGR). Pathologic DGR may generate symptoms of epigastric pain, nausea, and bilious vomiting. In patients with concomitant gastroesophageal reflux, the backwash of duodenal content into the lower esophagus can cause mixed (alkaline and acid) reflux esophagitis, and lead, in turn, to esophageal mucosal damage such as Barrett's metaplasia and adenocarcinoma. The treatment of DGR is difficult, non-specific, and relatively ineffective in controlling symptoms. Proton pump inhibitors decrease the upstream effects of DGR on the esophagus by decreasing the volume of secretions; promotility agents diminish gastric exposure to duodenal secretions by improving gastric emptying. In patients with severe reflux resistant to medical therapy, a duodenal diversion operation such as the duodenal switch procedure may be indicated.     

Familial adenomatous polyposis predisposes to pathologic exposure of the stomach to bilirubin

BACKGROUND: The role of duodenogastric reflux in the genesis of gastric polyps in familial adenomatous polyposis (FAP), although suggested by scintigraphy scanning studies, remains unclear. METHODS: Twenty-four hour intragastric bilirubin monitoring with the Bilitec optoelectronic device was carried out in 25 FAP patients, of whom 19 had gastric polyps (fundic gland in 13, adenomatous in 2, and both histologic types in 4) on endoscopic examination. Gastric exposure to bilirubin was expressed as the percentage of total recording time that absorbance exceeded the threshold of 0.25 and was calculated in reference to values obtained from 25 healthy volunteers. Helicobacter pylori status of the stomach was checked as well. RESULTS: Gastric exposure to bilirubin was pathologic in 14 (56%) patients. Gastric exposure to bilirubin was of longer duration in FAP patients than in healthy volunteers (mean+/-SEM: 19%+/-4% vs 6%+/-2%) (P<.005). It increased from healthy volunteers (6%+/-2%) to FAP patients without gastric polyps (10%+/-3%), and to FAP patients with gastric polyps (22%+/-5%) (P<.004). Bilirubin exposure times were similar in FAP patients with fundic gland polyps only and in those having either adenomatous polyps only or both types of polyps (24%+/-7% vs 17%+/-4%). No patient with pathologic gastric exposure to bilirubin as well as none having gastric polyps, had H. pylori in the antrum. CONCLUSIONS: This study shows that gastric exposure to bilirubin is of longer duration in FAP patients than in healthy volunteers, and in FAP patients with gastric polyps than in those without polyps. This study supports the existence of a direct correlation between pathologic duodenogastric reflux (DGR), the absence of H. pylori in the antrum, and the presence of gastric polyps in FAP patients.     

Cats as a risk for transmission of antimicrobial drug-resistant Salmonella

To determine whether cats were a risk for transmission of Salmonella to humans, we evaluated the excretion of Salmonella by pet cats. Rectal-swab specimens were taken from 278 healthy house cats, from 58 cats that died of disease, and from 35 group-housed cats. Group-housed cats were kept in one room with three cat trays and a common water and feed tray. Eighteen (51.4%) of 35 group-housed cats, 5 (8.6%) of 58 diseased cats (5/58), and 1 (0.36%) of 278 healthy house cats excreted Salmonella. Salmonella isolates were of serotypes Typhimurium, Enteritidis, Bovismorbificans and 4:i:-. Acquired antimicrobial resistance was found in serotype Typhimurium (resistance to ampicillin, chloramphenicol, and tetracycline; to ampicillin; and to chloramphenicol) and 4:i:- strains (resistance to ampicillin, chloramphenicol, sulfonamides, trimethoprim, and sulfamethoxazole/trimethoprim). Cats that excrete Salmonella can pose a public health hazard to people who are highly susceptible to Salmonella, such as children, the elderly, and immunocompromised persons.