Transjugular intrahepatic portosystemic shunt versus H-graft portacaval shunt in the management of bleeding varices: a cost-benefit analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is popular in treating portal hypertension because of its perceived efficacy and cost benefits, although it has never been compared with surgical shunting in a cost-benefit analysis. This study was undertaken to determine the cost benefit of TIPS versus small-diameter prosthetic H-graft portacaval shunt (HGPCS). METHODS: Cost of care was determined in 80 patients prospectively randomized to receive TIPS or HGPCS as definitive treatment for bleeding varices, beginning with shunt placement and including subsequent admissions for complications or follow-up related to shunting. RESULTS: Patients were similar in age, gender, severity of illness/liver dysfunction, and urgency of shunting. After TIPS or HGPCS, variceal rehemorrhage (8 versus O, respectively; p = 0.03), shunt occlusion (13 versus 4; p = 0.03), shunt revision (16 versus 4; p < 0.005), and shunt failure (18 versus 10; p = 0.10) were compared; all were more common after TIPS. Through the index admission, TIPS cost $48,188 +/- $43,355 whereas HGPCS cost $61,552 +/- $47,615. With follow-up, TIPS cost $69,276 +/- $52,712 and HGPCS cost $66,034 +/- $49,118. CONCLUSIONS: Early cost of TIPS was less than, though not different from, cost of HGPCS. With follow-up, costs after TIPS mounted. The initially lower cost of TIPS is offset by higher rates of subsequent occlusion and rehemorrhage.

Evidence of gender bias in patients undergoing flexible sigmoidoscopy.

Some studies have revealed gender bias against women in various aspects of medical care. There is no substantial evidence of gender bias in patients undergoing cancer evaluations, specifically colorectal cancer screening and diagnosis of colorectal complaints. This study was designed to examine the role of gender bias related to patients undergoing flexible sigmoidoscopy. At the University of South Florida, we conducted a retrospective study of 1910 patients at three distinct flexible sigmoidoscopy clinics over several years, through 1992. The proportions of male and female patients who underwent the procedure for indications of either screening for colorectal cancer or the diagnosis of colorectal complaints were determined. These proportions were compared with the respective male and female patient proportion from the total number of currently active patients at each site who were eligible to have the procedure for an appropriate indication. At all three sites, a significantly smaller proportion of women (p < 0.01) underwent the procedure than expected. This was true for both screening and diagnostic indications. Conversely, at all sites significantly more men (p < 0.01) underwent the procedure for both indications. The results of this study suggest gender bias against women for patients undergoing flexible sigmoidoscopy for both screening and diagnosis. This bias may adversely affect the lethality of colorectal cancer in women. It is important to determine if such biases are influenced by the physician's recommendation or mainly due to patient attitudes.

Endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy.

Endoscopic retrograde cholangiopancreatography (ERCP) is a useful adjunct to laparoscopic cholecystectomy. Preoperative ERCP is indicated if there is a high degree of suspicion for common duct stones, when severe gallstone-induced pancreatitis is present, or when there is uncertainty regarding the diagnosis. The best indicators of common duct stones preoperatively are an elevated bilirubin, a dilated common bile duct (CBD) on sonography, or stones visualized in the CBD on sonography. Mild gallstone pancreatitis and transient mild elevations in liver enzymes are not predictive of CBD stones and are not indications for ERCP. Postoperative ERCP is highly effective in clearing CBD stones. It has the advantage of being more readily available as compared to laparoscopic CBD exploration, and preserves all the advantages of the laparoscopic approach. Post-operative ERCP is indicated for retained CBD stones, evaluation and therapy of biliary injuries, and persistent biliary symptoms or abnormal liver enzymes and bilirubin. ERCP is the procedure of choice for the evaluation of laparoscopic biliary injuries. Major biliary injuries will generally require surgical therapy. Bile duct strictures are sometimes amenable to endoscopic therapy with dilation and stents. Biliary leaks are readily treatable with endoscopic therapy. Small cystic duct stump leaks and leaks from a duct of Lushka close within a few days with nasobiliary drainage. Larger leaks may require more prolonged drainage with stents and early supplemental percutaneous drainage of an accompanying biloma. Bilious ascites should be treated with nasobiliary drainage using low suction to be prevent contamination of the peritoneal cavity with intestinal flora, and simultaneous percutaneous ascites drainage. Biliary leaks, unless associated with major bile duct injuries, rarely require surgical therapy.

Leukocyte-derived growth factor links the PDGF and CXC chemokine families of peptides.

Leukocytes produce many biological mediators that orchestrate the subsequent cellular events during wound healing. We have identified a novel cytokine, leukocyte-derived growth factor (LDGF), which is mitogenic for connective tissue cells. Sequence analysis of the LDGF peptide revealed that it is a precursor of other known peptides including platelet basic protein (PBP), connective tissue activating peptide III (CTAP-III), and neutrophil activating peptide 2 (NAP-2). None of these shorter peptides are active as mitogens for fibroblasts. LDGF appears to stimulate fibroblast growth by stimulation of tyrosine kinase activity of the PDGF receptors. One of the truncated products of LDGF, NAP-2, is a potent neutrophil chemoattractant. Peptides larger than NAP-2, such as PBP and CTAP-III, are not active as neutrophil chemoattractants. Collectively, these findings demonstrate that the LDGF peptide must remain intact in order to retain its fibroblast mitogenic activity. If the LDGF peptide is processed to release the carboxyl terminal half to generate NAP-2, a peptide with proinflammatory activity is generated. These results indicate that the multiple peptides produced from the LDGF-PBP gene posses divergent biological activities that could regulate different phases of the repair process.

Massive GI hemorrhage from an ileal duplication cyst in an adult.

We describe an unusual case of a 32-yr-old man who presented with massive GI hemorrhage as an initial manifestation of an ileal duplication cyst. The lesion was first revealed by visceral angiography during investigation of the bleeding source. At laparotomy, a large ileal duplication containing full-thickness gastric-type mucosa was identified. Ulceration of the ileal mucosa adjacent to the communicating orifice was found to be the source of bleeding. Duplications of the alimentary tract are rare congenital malformations. Patients usually present in infancy and childhood, although delayed complications can present in adulthood. This entity should be considered among other lesions that can cause massive GI hemorrhage not diagnosable by endoscopy.

The role of ERCP in patients after laparoscopic cholecystectomy.

OBJECTIVES: The goal of this study was to evaluate the feasibility of endoscopic management of complications encountered in patients undergoing laparoscopic cholecystectomy. Special attention was given to establishing the optimal timing, success rate, and complications of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) after laparoscopic cholecystectomy. METHODS: Fifty-six consecutive patients referred from two major medical centers were evaluated with ERCP after laparoscopic cholecystectomy. The patient population included 22 men and 34 women 16-87 yr of age. Indications included common bile duct stones seen on operative cholangiography or ultrasound, persistently elevated liver enzymes and abdominal pain, evidence of biliary injury, and other, All endoscopic procedures were carried out by experienced endoscopists using standard ERCP techniques and equipment. Endoscopic papillotomy was performed with 2- to 2.5-cm cutting wire papillotomes and all biliary stones were removed with 8.5- to 14-mm balloons. Small biliary leaks were first treated with 3-7 days of nasobiliary drainage, and if persistent with 10-Fr internal stents for 1 month. One patient with a biliary stricture was dilated with placement of progressively larger biliary stents over 9-month period. RESULTS: ERCP was performed within 6 h to 2 yr after laparoscopic cholecystectomy (LC). In 12 patients, it was performed within the first 24 h after LC. A cholangiogram was obtained in all patients. No complications were encountered. Thirty patients underwent therapeutic endoscopy. Common bile duct stones were found and were successfully removed from 23 patients. One patient required an emergent ERCP and sphincterotomy for gallstone pancreatitis 3 days after LC. Fourteen patients had common bile duct injuries, cystic duct stump leaks, or leakage from ducts of Luschka (one patient). All leaks were successfully treated with temporary stenting. Six patients with bile duct transection or complete obstruction by clips required surgical therapy. One patient with a common bile duct stricture was managed with endoscopic stents alone. Two patients had unsuspected malignancies, one each with ampullary and pancreatic carcinoma. Fourteen patients had a normal ERCP. CONCLUSIONS: Diagnostic and therapeutic ERCP can be done within 24 h of LC with safety and a high degree of success. Delay in removal of CBD stones may lead to complications. Cystic duct stump leaks are easily corrected with nasobiliary drainage, and some post-LC strictures may be amenable to therapy with biliary stents. Finally, malignancy must be excluded in patients with unexplained recurrent symptoms.

Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils.

Human peripheral blood monocytes and neutrophils secrete TGF-beta. Activation of monocytes with LPS stimulates the secretion of TGF-beta; however, the production of TGF-beta by neutrophils was not altered by treatment with LPS. The secreted TGF-beta appears to be in a fully active form since acid treatment of the conditioned medium does not increase the amount of TGF-beta activity. TGF-beta 1 transcripts were detected at similar levels in both activated and nonactivated monocytes and neutrophils, suggesting that the increase in TGF-beta secretion after activation of monocytes is regulated by a posttranscriptional mechanism. Western blot analysis with anti-N-terminal TGF-beta 1 peptide antibodies indicate the leukocyte-derived TGF-beta is beta 1. In addition, TGF-beta 1 transcripts were detected in rat peritoneal macrophages and in a differentiating human hematopoietic tumor cell line (HEL). The ability of inflammatory cells such as monocytes and neutrophils to produce TGF-beta may play an important role in the function of these cells in wound repair, in the immune response, and in the pathogenesis of fibrotic diseases.

Human peripheral blood monocytes secrete a unique form of PDGF.

PDGF isolated from platelets and forms of PDGF produced by cells transformed with the v-sis gene (PDGF B chain) or U-20S osteosarcoma cells which express the PDGF A chain gene are known to be processed as disulfide-linked dimers of approximately 30 kd. Western blot analysis with anti human PDGF antibody of the PDGF-like factor synthesized and secreted by human blood monocytes (MDGF) on SDS gels indicates that it lacks interchain disulfide bridges and behaves as a 16-kd monomer under nonreducing conditions. Additionally, MDGF exhibits different sensitivities to either formic acid or CNBr cleavage compared to PDGF A or B chain molecules indicating it may have a different primary structure. These data suggest that MDGF represents a unique form of PDGF which lacks interchain disulfide bridges and may represent a new member of the PDGF family of growth factors.

Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats.

Subcutaneous implantation of Hunt-Schilling wound chambers in rats induces a wound repair response causing the chamber first to fill with fluid and subsequently with connective tissue. The presence of a type I collagen gel encouraged a more rapid dispersion of cells throughout the chamber but had no effect on the rate of new collagen deposition. Addition of platelet-derived growth factor (PDGF; 50 ng/chamber) to the collagen-filled chambers caused an earlier influx of connective tissue cells, a marked increase in DNA synthesis, and a greater collagen deposition in the chamber during the first 2 wk after implantation. After 3 wk, however, the levels of collagen were similar in PDGF-supplemented and control chambers. Diabetic animals exhibited a decreased rate of repair which was restored to normal by addition of PDGF to the wound chamber. Combinations of PDGF and insulin caused an even more rapid increase in collagen deposition. These results suggest that the levels of various growth factors, particularly PDGF, may be limiting at wound sites and that supplementation of wounds with these factors can accelerate the rate of new tissue formation.

Chemoattractants in fibrotic disorders.

Fibrosis represents an excessive deposition of connective tissue which impedes the normal functions of an organ or tissue. The mechanisms leading to this increased deposition of connective tissue may be similar to those occurring in normal wound repair. We have previously shown that the repair process involves the migration of connective tissue cells to the site of injury and their subsequent proliferation. One of the principal factors controlling these events appears to be the platelet-derived growth factor (PDGF). PDGF acts as a potent chemoattractant and mitogen for connective tissue cells but not other cell types. In addition to PDGF, factors produced by monocytes and tissue macrophages also act as chemoattractants for connective tissue cells. These observations suggest that such activities may be abundant in areas of inflammation. In normal repair these factors would be present for a relatively short period of time, whereas in fibrosis the chronic inflammatory response could maintain a constant or repeated release of such factors. This would recruit additional connective tissue cells to the area of inflammation, changing the cellular composition of the affected organ or tissue, resulting in an expansive and permanent nodule of connective tissue.

Inhibitors of endocytosis perturb phospholipid metabolism in rabbit neutrophils and other cells.

Dansylcadaverine, amantadine, and rimantadine, which have been shown to inhibit the endocytosis of alpha 2-macroglobulin, epidermal growth factor, and vesicular stomatitis virus [Schlegel, R., Dickson, R. B., Willingham, M. C. & Pastan, I. (1982) Proc. Natl. Acad. Sci. USA 79, 2291-2295], were found to decrease phosphatidylcholine synthesis, chemotaxis, and internalization of a formylated peptide but to stimulate the incorporation of inositol into phosphatidylinositol in rabbit neutrophils. Dansylcadaverine decreased phosphatidylcholine synthesis by both the CDP-choline and transmethylation pathways and also inhibited the synthesis of phosphatidylethanolamine by the CDP-ethanolamine pathway. Dansylcadaverine had no effect on the phosphocholine, CDP-choline, or S-adenosyl-L-homocysteine pools but increased 2-fold the S-adenosyl-L-methionine pool. These results suggest that dansylcadaverine in some manner inhibited the condensation of CDP-choline with diacylglycerol to form phosphatidylcholine. Dansylcadaverine also inhibited phosphatidylcholine synthesis in human neutrophils, human fibroblasts, chicken embryo fibroblasts, rat hepatocytes, osteosarcoma cells, and neuroblastoma cells. It did not stimulate phosphatidylinositol synthesis in chicken embryo fibroblasts.

Adherence and regulation of leukotaxis.

PMNs upon stimulation by a chemoattractant adhere to a substratum and then in amoeboid fashion migrate toward the source of the attractant. We have studied molecular events in both adherence and migration and have arrived at the following conclusions: 1) PMNs, like other motile cells such as highly metastatic tumor cells, can use laminin to attach to Type IV basement membrane collagen. PMNs may use this anchoring mechanism in their emigration from the vasculature. 2) Attached cells may be stimulated to migrate as a result of the chemo-attractant-induced inactivation of lipomodulin, a natural inhibitor of phospholipase A2, an enzyme that may be essential for chemotaxis. 3) The substrate for this enzyme is generated by both the CDP-choline and transmethylation pathways. These pathways may be regulated by another enzyme, transglutaminase (TGase). 4) Natural substrates of TGase, such as uteroglobin, inhibit leukocyte chemotaxis, again suggesting a regulatory role for TGase in chemotaxis. 5) Tumor cells also produce inhibitors of chemotaxis. In addition to protecting the tumor from the host's phagocytes, these inhibitors may be related to normal modulators of cell motility. Therefore, determination of their mode of action could increase our understanding of this type of cell behavior.

Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin.

Specific antibodies to collagen type IV, laminin, and fibronectin were used to localise these proteins by indirect immunofluorescence in frozen sections of normal and fibrotic liver. In normal livers distinct staining was found in basement membranes of blood and lymph vessels, of bile ducts and ductules and around nerve axons. Positive reactions for type IV collagen and fibronectin were also observed in the perisinusoidal space, while hepatocytes and most of the interstitial matrix of portal fields remained unstained. Liver specimens obtained from patients with alcoholic liver disease (fatty liver, hepatitis or cirrhosis) and chronic active hepatitis showed a more intense reaction with the antibodies in the perisnusoidal space including now distinct staining for laminin. These patterns were particularly prominent at borders between fibrotic septa and remnants of parenchyma or pseudolobules. Strong reactions were also found for type IV collagen and fibronectin in the periportal interstitium and in large fibrotic areas. The findings support previous electron-microscopical and chemical evidence for increased basement membrane production in human liver fibrosis and demonstrate that this may involve different proteins and occur at different anatomical sites.