Randomized clinical trial of mast cell inhibition in patients with a medium-sized abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is thought to develop as a result of inflammatory processes in the aortic wall. In particular, mast cells are believed to play a central role. The AORTA trial was undertaken to investigate whether the mast cell inhibitor, pemirolast, could retard the growth of medium-sized AAAs. In preclinical and clinical trials, pemirolast has been shown to inhibit antigen-induced allergic reactions. METHODS: Inclusion criteria for the trial were patients with an AAA of 39-49 mm in diameter on ultrasound imaging. Among exclusion criteria were previous aortic surgery, diabetes mellitus, and severe concomitant disease with a life expectancy of less than 2 years. Included patients were treated with 10, 25 or 40 mg pemirolast, or matching placebo for 52 weeks. The primary endpoint was change in aortic diameter as measured from leading edge adventitia at the anterior wall to leading edge adventitia at the posterior wall in systole. All ultrasound scans were read in a central imaging laboratory. RESULTS: Some 326 patients (mean age 70·8 years; 88·0 per cent men) were included in the trial. The overall mean growth rate was 2·42 mm during the 12-month study. There was no statistically significant difference in growth between patients receiving placebo and those in the three dose groups of pemirolast. Similarly, there were no differences in adverse events. CONCLUSION: Treatment with pemirolast did not retard the growth of medium-sized AAAs. REGISTRATION NUMBER: NCT01354184 (https://www.clinicaltrials.gov).

Recurrent inguinal hernia: randomized multicenter trial comparing laparoscopic and Lichtenstein repair.

BACKGROUND: The optimal treatment for recurrent inguinal hernia is of concern due to the high frequency of recurrence. METHODS: This randomized multicenter study compared the short- and long-term results for recurrent inguinal hernia repair by either the laparoscopic transabdominal preperitoneal patch (TAPP) procedure or the Lichtenstein technique. RESULTS: A total of 147 patients underwent surgery (73 TAPP and 74 Lichtenstein). The operating time was 65 min (range, 23-165 min) for the TAPP group and 64 min (range, 25-135 min) for the Lichtenstein group. Patients who underwent TAPP reported significantly less postoperative pain and shorter sick leave (8 vs 16 days). The recurrence rate 5 years after surgery was 19% for the TAPP group and 18% for the Lichtenstein group. CONCLUSION: The short-term advantage for patients who undergo the laparoscopic technique is less postoperative pain and shorter sick leave. In the long term, no differences were observed in the chronic pain or recurrence rate.

Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.

OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.

Postoperative convalescence after inguinal hernia surgery: prospective randomized multicenter study of laparoscopic versus shouldice inguinal hernia repair in 1042 patients.

Interest in inguinal hernia surgery has increased significantly with the introduction of new operating techniques during the past decade. This multicenter study compared short-term results in patients treated by the laparoscopic transabdominal preperitoneal patch technique (TAPP; n = 518) and the Shouldice technique (n = 524). We evaluated demographics, operative data, complications, hospital stay, postoperative pain, use of cs, functional status, sick leave, and complaints up to 3 months postoperatively. The median operating time was shorter in the Shouldice group (55 vs. 65 min), but there were no significant differences in complication rates, and major complications were rare. The hospital stay was 1 day or less in over 98% of cases in both groups, but more operations were performed on outpatient basis in the Shouldice group. In the TAPP group postoperative pain and analgesic consumption were less, postoperative functional status was better, and sick leave was shorter (10 vs. 14 days). These results show that the two methods are equally safe and have few major complications. The TAPP operation is associated with less postoperative pain, better postoperative functional status, and shorter sick leave, but at the price of a longer operating time.

Improved survival of patients with papillary thyroid cancer after surgical microdissection.

A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer.

Formation of healing tissue and angiogenesis in repair of connective tissue stimulated by epidermal growth factor.

Epidermal growth factor (EGF) has been shown to stimulate connective tissue repair in the perforated mesentery of rats. The aim of the present investigation was to study the effect of EGF on the formation of healing tissue and angiogenesis in such repair. After laparotomy standardised perforations were made in the centre of the mesenteric "windows" with a scalpel. The rats were given intraperitoneal injections of either 10 micrograms EGF dissolved in phosphate-buffered saline (PBS), or PBS alone, twice daily for four consecutive days beginning on the day of operation. In the first experiment, healing tissue formation and angiogenesis was quantified morphometrically in perpendicularly cut mesenteric windows on days 1 to 10 after operation. Treatment with EGF caused the formation of significantly more healing tissue on days 2 to 7, but no stimulation of angiogenesis. In the second experiment, angiogenesis was quantified morphometrically on days 14 and 21. Mesenteric windows were spread out on objective slides after the capillary bed had been visualised by perfusion of carbon ink. Perforation caused a significant increase of microvascular density in the centre of the mesenteric windows on days 14 and 21. Treatment with EGF did not stimulate angiogenesis at any observation point. In conclusion, treatment with EGF significantly increased the formation of healing tissue in connective tissue repair in the perforated mesentery of rats, but did not affect angiogenesis.

Nerve involvement in fluid transport in the inflamed rat jejunum.

Net fluid transport was measured in denervated jejunal segments of rats infected with larvae of Nippostrongylus brasiliensis. On days 6-9 after nematode inoculation, when the jejunal segment exhibited macroscopic and microscopic signs of inflammation, net fluid absorption was noticeably attenuated compared with control, and in eight of 26 experiments a net fluid secretion was seen. To determine whether enteric nerves participated in the response, intravenous hexamethonium (10 mg/kg body weight) was given or lidocaine (1% solution) was placed on the serosa of the intestinal segment. Both drugs significantly reduced fluid secretion or increased fluid absorption. The effect was more pronounced the lower the rate of fluid absorption or the higher the rate of fluid secretion. The inflammatory response influenced intestinal fluid transport partly via activation of the enteric nervous system. It was estimated that 50-60% of the change in fluid transport caused by the parasite could be ascribed to activation of intramural nervous reflexes. The effect of hexamethonium indicates that a cholinergic synapse is present in the secretory nervous reflux activated by inflammation. Experiments were also performed on animals on days 11-14 after infection when the nematodes had been expelled from the animal. A large net fluid absorption was then recorded.

Effect of epidermal growth factor on cell proliferation in normal and wounded connective tissue.

Epidermal growth factor has been previously shown to stimulate connective tissue repair in the perforated rat mesentery. The mechanism by which epidermal growth factor accelerates closure of mesenteric perforations has not been established, but epidermal growth factor may stimulate mitosis, contraction, migration, or angiogenesis. In the present investigation, the effect of epidermal growth factor on connective tissue cell proliferation was studied during the initial phase of repair of mesenteric perforations and in unwounded mesentery. Laparotomies were performed on Sprague-Dawley rats, and standardized perforations were made with a scalpel in the center of the mesenteric "windows," leaving every second window as an internal control. Twice daily for 4 consecutive days, beginning on the day of surgery, the animals received by intraperitoneal injection either 10 microg of epidermal growth factor dissolved in phosphate-buffered saline solution or phosphate-buffered saline solution alone. Cell proliferation was measured by either mitotic index of fibroblasts and mesothelial cells or DNA content of individual fibroblast cell nuclei in the wound area or in unperforated control windows. Laparotomy alone was found to enhance proliferation during the early postoperative period, as shown by increased numbers of S + G2 fibroblasts and a greater mitotic index. Epidermal growth factor treatment increased the mitotic index in perforated windows on the third postoperative day, compared with controls treated with phosphate-buffered saline solution, but did not significantly increase either the number of S + G2 fibroblasts or the mitotic index in unwounded tissue. Also, the proliferative response after epidermal growth factor treatment was significantly higher in wounded tissue. This study shows that epidermal growth factor stimulates proliferation of connective tissue cells in wounded but not unwounded tissue, and such enhancement of fibroblast proliferation might be of importance in epidermal growth factor-stimulated connective tissue repair.

Epidermal growth factor accelerates connective tissue wound healing in the perforated rat mesentery.

Epidermal growth factor (EGF) has been reported to stimulate healing of wounds in skin, cornea, and gastric mucosa. In the present study, we further investigate the effect of endogenous and exogenous EGF in healing of connective tissue wounds using the rat perforated mesentery model. Healing of mesenteric perforations is accomplished by the connective tissue fibroblasts since there are no interfering variables such as interactions of epithelial cells, desiccation, or foreign materials such as sutures or subcutaneous implants. We performed laparotomy in 114 adult male Sprague-Dawley rats and made 20 standardized perforations in the mesentery of each rat with a scalpel. Rats were randomly assigned to five groups. Group I received no treatment after surgery; Group II received intraperitoneal injections of phosphate-buffered saline (PBS) after surgery and then twice daily for the following 3 days; Group III received 10 micrograms of EGF in the PBS injections according to the same regimen as Group II; Group IV had sham exploration of the submandibular salivary glands; and Group V animals had excision of the submandibular glands 3 days before laparotomy to deprive the main source of EGF in rat. On Days 4 through 10 after surgery rats were sacrificed and the percentage of perforations in each rat which were closed was determined. The curves for the time course of wound closure for Groups IV and V were not different indicating that endogenous submandibular EGF does not play a role in healing of mesenteric wounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed gastric ulcer healing after extirpation of submandibular glands is sex-dependent.

This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.

The rat urinary bladder: vasoactivity and macromolecular leakage in a new model.

An in vivo model of the rat urinary bladder microcirculation has been developed and microcirculatory responses to agents which produce vasoconstriction, vasodilation, and macromolecular leakage have been characterized. The urinary bladder of anesthetized female Sprague-Dawley rats is exteriorized and positioned in a tissue bath with a single stay suture which does not penetrate the lumen of the bladder. All blood vessels and nerves from the animal remain intact. The tissue bath is filled with Krebs solution which is monitored and maintained at a temperature of 36 +/- 0.5 degrees and a pH of 7.4 +/- 0.5. In vivo television microscopy is used to monitor vascular diameter and flow changes and isothiocyanate-tagged bovine serum albumin fluorescence is used as an index of macromolecular leakage. Norepinephrine (10(-6) M) caused a statistically significant decrease in vascular diameters of both arterioles and venules while sodium nitroprusside (10(-7) M) significantly increased arteriolar and venular diameters, histamine (10(-4) M) caused no change in venular diameters but did induce a significant macromolecular leak from those vessels. Compound 48/80 (1 and 10 micrograms/ml) induced a significant dose-dependent macromolecular leakage from venules. However, only with the 10 micrograms/ml dose was there visually detectable mast cell degranulation. It is concluded that this rat urinary bladder model provides a stable, reproducible model of a smooth muscle microcirculatory bed in a controlled environment, which responds similarly to other microcirculations.

Effect of high-dose omeprazole administration on histamine storage and formation in canine gastric mucosa.

The effect of a high dose of omeprazole on the plasma gastrin response to feeding and gastric mucosal histamine formation and storage in the dog has been studied. Tissue from the oxyntic gland area was obtained by introduction of an endoscope through a gastric fistula, and biopsies were taken before, after 4 weeks of oral administration of omeprazole and 1 month after withdrawal of the drug. Omeprazole administration increased the basal plasma concentration of gastrin and induced a substantial increase in the feeding response. Histidine-decarboxylase activity was significantly increased after 4 weeks of omeprazole administration, whereas no effect was found on histamine content and mucosal mast cell density. One month after drug withdrawal, the enzyme activity had returned to pretreatment levels.

Histamine storage and formation in canine gastric mucosa--effect of pentagastrin stimulation.

Histamine storage and formation in the dog gastric mucosa were studied during basal conditions and after pentagastrin stimulation. Histamine formation (histidine decarboxylase activity), histamine content as well as the density of mast cells of the oxyntic gland mucosa were evenly distributed. Histamine content of the mucosa was significantly correlated to the density of mucosal mast cells. In the basal secretory state, histamine formation and histamine content of the oxyntic gland mucosa were of the same magnitude as in the antral mucosa. Pentagastrin stimulation induced a small but significant decrease in histamine content of the oxyntic gland mucosa and a subsequent acceleration in the rate of amine formation. Neither histamine content nor histidine decarboxylase activity of the antral mucosa was affected by pentagastrin infusion.

Histamine and mucosal mast cells in gluten enteropathy.

Coeliac disease is a malabsorptive disorder caused by intolerance to gluten and is characterized by a remodelling of the intestinal mucosa including villus atrophy, crypt hyperplasia and net increase of mucosal volume. Changes of the number of mucosal mast cells (MMCs) in coeliac mucosa has recently been reported, suggesting that the mast cell activity could have a pathogenetic role in gluten enteropathy. MMCs located solely in the lamina propria are the main repository for small-gut mucosal histamine. A consecutive prospective study was designed to study the histamine content, MMC numbers, and the relative volume of lamina propria in intestinal biopsies from adult patients suffering from unexplained diarrhea and/or malnutrition. Histamine was measured by a HPLC-method, the number of MMC was counted after long toluidine-blue staining, and the relative volumes of lamina propria and epithelium were estimated morphometrically. The findings were correlated to the histopathological appearance of the mucosa. As compared to controls the histamine content increased by 80% and MMC numbers by about 60% in the coeliac mucosa. There was also a correlation between MMC numbers and histamine content for both normal and coeliac mucosae (r = 0.81). The morphometric estimation of the relative volumes of epithelium and lamina propria revealed that the lamina-propria compartment was increased by approximately 40% in coeliac mucosa. Taking the changes in compartmental volumes of the remodelled coeliac mucosa into account, our results suggest that the histamine content and MMC population were significantly increased. MMC and MMC-associated histamine may therefore be involved in the pathogenesis of gluten enteropathy.

Turnover of different mast cell pools of histamine in the rat.

The uptake and elimination of radiolabelled histamine was studied in the rat duodenum, where histamine is stored in a specific population of mucosal mast cells (MMC), and in the tongue, where histamine is stored in the classic connective tissue mast cell (CTMC). The specific activity of histamine was measured after one i.v. injection of its precursor, 3H-histidine. Decarboxylation of histidine and uptake of histamine occurred in both tissues. The initial specific activity of histamine was very low in the tongue but 5 times higher in the duodenum, while the endogenous duodenal histamine content was 1/6 of that in the tongue. The elimination rate of labelled histamine in the two mast cell pools was very slow. In the tongue, there was no statistically significant decrease in specific activity during the observation period of 16 days. In the duodenum, there was an exponential decrease of prelabelled histamine with an apparent half-life of 9 days. However, part of this decay of radioactivity may be accounted for by increase in the mucosal histamine pool size and MMC death. The results indicate that the rate of histamine elimination from mast cells of both types is very slow, corresponding with previous results obtained from CTMC of the peritoneal cavity.

Turnover of histamine in mucosal and connective tissue mast cells of the rat.

Mast cells constitute a heterogenous cell system. The specific type of mucosal mast cell (MMC) of the gut differs with respect to a number of properties from the classical connective tissue mast cell ( CTMC ) found in, e.g. skin, tongue and the peritoneal cavity. This report summarizes recent findings concerning turnover rates of amines and heparin in the two cell types. The elimination rate of radioactively prelabelled histamine, 5-hydroxytryptamine (5-HT) and heparin from peritoneal CTMC was compared with the elimination of radiolabelled histamine from tongue, where histamine is stored in CTMC and duodenum where it is stored in MMC. The elimination of histamine from peritoneal CTMC was slow (t 1/2 = 23 days) and did not differ significantly from that of 5-HT (t 1/2 = 25 days) and heparin (t 1/2 = 35 days) suggesting a low degree of secretory activity in the normal rat. The elimination rate of histamine from the tongue was also very slow. The specific radioactivity of histamine in duodenum was decreasing more rapidly. This was explained by a dilution of the radioactivity since the histamine content increased during the experimental period, and also by MMC death. The results are compatible with the assumption that CTMC and MMC are secretory cells, but with low activity until recruited by adequate, immunological or other stimuli.