Identifying potentially avoidable femoral to popliteal expanded polytetrafluoroethylene bypass for claudication using cross-site blinded peer review.

OBJECTIVE: The surgical treatment of claudication can be associated with significant morbidity and costs. There are growing concerns that some patients proceed to interventions without first attempting evidence-based nonoperative management. We used a direct, cross-site, blinded expert review to evaluate the appropriateness of the surgical treatment of claudication. METHODS: We enlisted practicing vascular surgeons to perform retrospective clinical assessments of lower extremity bypass procedures in a statewide clinical registry. Cases were limited to elective, open, infrainguinal bypasses performed for claudication using prosthetic grafts. Reviewing surgeons were randomly assigned 10 cases from a sample of 139 anonymized bypass operations and instructed to evaluate procedural appropriateness based on their expert opinion and evidence-based guidelines for preoperative treatment, namely, antiplatelet, statin, cilostazol, exercise, and smoking cessation therapy as documented in the medical record. Ninety-day episode payments were estimated from a distinct but similar cohort of patients undergoing lower extremity bypass for claudication. RESULTS: Of 325 total reviews, surgeons stated they would not have recommended bypass in 134 reviews (41%) and deemed bypass inappropriate in 122 reviews (38%). The most common reason for inappropriateness was lack of preoperative medical and lifestyle therapy, which was present in 63% of reviews where bypass was deemed appropriate and 39% of reviews where bypass was deemed inappropriate (P < .001). Surgeons stated they would have recommended additional preoperative therapy in 65% of reviews where bypass was deemed inappropriate and 35% of reviews where bypass was deemed appropriate (P < .001). The mean total episode payments in a similar cohort of 1458 patients undergoing elective open lower extremity bypass for claudication were $31,301 ± $21,219. Extrapolating to the 325 reviews, the 134 reviews in which surgeons would not have recommended bypass were associated with potentially avoidable estimated total payments of $4,194,334, and the 122 reviews in which bypass was deemed inappropriate were associated with potentially avoidable estimated total payments of $3,818,722. CONCLUSIONS: In this cross-site expert peer review study, 40% of lower extremity bypasses were deemed premature and, therefore, potentially avoidable, primarily owing to a lack of medical and lifestyle management before surgery. Reviews deemed inappropriate were associated with approximately $4 million in potentially avoidable costs. This approach could inform performance feedback among surgeons to help align clinical practice with evidence-based recommendations for the treatment of claudication.

Gastrin and Gastric Cancer.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin's actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor-induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.

Coastal clustering of HEV; Cornwall, UK.

BACKGROUND AND AIMS: Autochthonous hepatitis E virus (HEV) infection is a porcine zoonosis and increasingly recognized in developed countries. In most cases the route of infection is uncertain. A previous study showed that HEV was associated geographically with pig farms and coastal areas. AIM: The aim of the present research was to study the geographical, environmental and social factors in autochthonous HEV infection. METHODS: Cases of HEV genotype 3 infection and controls were identified from 2047 consecutive patients attending a rapid-access hepatology clinic. For each case/control the following were recorded: distance from home to nearest pig farm, distance from home to coast, rainfall levels during the 8 weeks before presentation, and socioeconomic status. RESULTS: A total of 36 acute hepatitis E cases, 170 age/sex-matched controls and 53 hepatitis controls were identified. The geographical spread of hepatitis E cases was not even when compared with both control groups. Cases were more likely to live within 2000 m of the coast (odds ratio=2.32, 95% confidence interval=1.08-5.19, P=0.03). There was no regional difference in the incidence of cases and controls between west and central Cornwall. There was no difference between cases and controls in terms of distance from the nearest pig farm, socioeconomic status or rainfall during the 8 weeks before disease presentation. CONCLUSION: Cases of HEV infection in Cornwall are associated with coastal residence. The reason for this observation is uncertain, but might be related to recreational exposure to beach areas exposed to HEV-contaminated 'run-off' from pig farms. This hypothesis merits further study.

Analysis of sphingosine-1-phosphate signaling mutants reveals endodermal requirements for the growth but not dorsoventral patterning of jaw skeletal precursors.

Development of the head skeleton involves reciprocal interactions between cranial neural crest cells (CNCCs) and the surrounding pharyngeal endoderm and ectoderm. Whereas elegant experiments in avians have shown a prominent role for the endoderm in facial skeleton development, the relative functions of the endoderm in growth versus regional identity of skeletal precursors have remained unclear. Here we describe novel craniofacial defects in zebrafish harboring mutations in the Sphingosine-1-phospate (S1P) type 2 receptor (s1pr2) or the S1P transporter Spinster 2 (spns2), and we show that S1P signaling functions in the endoderm for the proper growth and positioning of the jaw skeleton. Surprisingly, analysis of s1pr2 and spns2 mutants, as well as sox32 mutants that completely lack endoderm, reveals that the dorsal-ventral (DV) patterning of jaw skeletal precursors is largely unaffected even in the absence of endoderm. Instead, we observe reductions in the ectodermal expression of Fibroblast growth factor 8a (Fgf8a), and transgenic misexpression of Shha restores fgf8a expression and partially rescues the growth and differentiation of jaw skeletal precursors. Hence, we propose that the S1P-dependent anterior foregut endoderm functions primarily through Shh to regulate the growth but not DV patterning of zebrafish jaw precursors.

The spinster homolog, two of hearts, is required for sphingosine 1-phosphate signaling in zebrafish.

The bioactive lipid sphingosine 1-phosphate (S1P) and its G protein-coupled receptors play critical roles in cardiovascular, immunological, and neural development and function. Despite its importance, many questions remain about S1P signaling, including how S1P, which is synthesized intracellularly, is released from cells. Mutations in the zebrafish gene encoding the S1P receptor Miles Apart (Mil)/S1P(2) disrupt the formation of the primitive heart tube. We find that mutations of another zebrafish locus, two of hearts (toh), cause phenotypes that are morphologically indistinguishable from those seen in mil/s1p2 mutants. Positional cloning of toh reveals that it encodes a member of the Spinster-like family of putative transmembrane transporters. The biological functions of these proteins are poorly understood, although phenotypes of the Drosophila spinster and zebrafish not really started mutants suggest that these proteins may play a role in lipid trafficking. Through gain- and loss-of-function analyses, we show that toh is required for signaling by S1P(2). Further evidence indicates that Toh is involved in the trafficking or cellular release of S1P.

Lipid receptors in cardiovascular development.

To most people, concerns over the link between lipids and cardiovascular health most likely end with monitoring their daily consumption of dietary fats. However, it has become increasingly clear that, in addition to effects on adult cardiovascular physiology, lipids also play key roles in the formation of a functioning cardiovascular system. The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), have come to the forefront as developmental and physiological regulators of the cardiovascular system. In this review, we discuss the function of the G protein-coupled receptors responsible for transducing LPA and S1P signals during development of the vertebrate cardiovascular system, focusing first on their role in angiogenesis and then on their function during embryonic development.