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1.
Acta Chir Belg ; 115(6): 397-403, 2015.
Article in English | MEDLINE | ID: mdl-26763837

ABSTRACT

INTRODUCTION: Mechanical bowel obstruction (MBO) remains one of the most common abdominal surgical emergencies. The aetiology of MBO depends on the population demographics and period of time in which a given population was studied. We are presenting the results of an analysis covering 145 years of observations based on patients operated in our department. METHODS: The single centre retrospective analysis included 1825 patients with MBO. They were divided into 4 groups depending on the years in which they were treated : group 1 (1868-1898), group 2 (1956-1970), group 3 (1987-1999), group 4 (2000-2013). The analysis covered the sex distribution, the mean age of patients versus the life expectancy and changes in MBO aetiology in every period. RESULTS: We noticed an increase in the mean age and the growing divergence between life expectancy. Additionally, an increasing percentage of women were observed. There were also significant changes in the aetiology. An increase in MBO caused by cancer was observed. The rate of strangulated hernias doubled in the second period of time, and then it gradually decreased. Intestinal volvulus was common in the first period and became one of the rarest causes of MBO in the subsequent periods. MBO due to adhesions remained at the same level. It became, however, the most common cause in the last period. CONCLUSIONS: Within nearly 150 years significant changes occurred in the demographics and aetiology of MBO. Currently, the most common cause is peritoneal adhesions after previous surgeries. Although our results represent a single centre experience, they may reflect changing patterns in MBO in the Polish population over time.


Subject(s)
Intestinal Obstruction/epidemiology , Intestinal Obstruction/pathology , Adult , Age Factors , Female , Hernia, Abdominal/complications , Humans , Intestinal Neoplasms/complications , Male , Middle Aged , Retrospective Studies , Risk Factors , Time Factors , Tissue Adhesions/complications
2.
J Physiol Pharmacol ; 61(4): 409-18, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20814068

ABSTRACT

Mixed reflux of the gastroduodenal contents induces the esophageal mucosal damage and inflammation progressing chronic esophagitis and premalignant Barrett's esophagus (BE). The role of cyclooxygenase-2 (COX-2) and chronic inflammation in the progression of BE toward adenocarcinoma of the esophagus has not been extensively studied in experimental models of BE in animals and in human subjects. We evaluated the expression of COX-2 in rat model of BE and examined the usefulness of COX-2 expression in determining the risk of malignant transformation in patients with BE treated with argon plasma coagulation (APC) that allows for effective ablation of metaplastic mucosa (group A) without or with proton pump inhibitors (PPI). In addition, the group B of patients was subjected to laparoscopic Nissen's fundoplication and group K that served as control, received PPI treatment only. Expression of COX-2 was evaluated in fresh-frozen biopsy specimens obtained from the distal esophagus in all 60 patients before and 12 months after treatment. In experimental studies, eighty rats were surgically prepared with esophagogastroduodenal anastomosis (EGDA) resulting in chronic esophagitis. At 4 months, the esophageal damage in EGDA rats was evaluated by macroscopic and histological index score, the plasma IL-1beta and TNF-alpha levels was determined by ELISA and the mucosal expression of COX-2 mRNA and COX-2 protein were assessed by RT-PCR and Western Blot, respectively. Chronic esophagitis was developed in all EGDA animals followed by the rise in the plasma TNF-alpha and IL-1beta levels. Histology revealed extensive esophageal ulcerations with development of columnar epithelium, formation of mucus glands in squamous epithelium, intestinal metaplasia distant to anastomosis consisting of goblet cells, infiltration of inflammatory cells including plasma cells and lymphocytes. COX-2 mRNA was absent in the esophageal mucosa of sham-control animals but strongly upregulated in metaplastic Barrett's epithelium. In BE patients, the overexpression of COX-2 was documented in patients with dysplasia. After APC (group A) or Nissen's fundoplication (group B), the expression of COX-2 mRNA was markedly reduced and these effects were positively correlated with histopathological findings. Controls failed to show significant alterations in COX-2 expression. We conclude that 1) EGDA rats serve as the suitable model of the chronic esophagitis by the gastrointestinal refluxate resembling many features of those observed in human Barrett's esophagus, as confirmed by severe morphology changes, excessive release of proinflammatory cytokines TNF-alpha and IL-1beta and overexpression of COX-2, and 2) the significant correlation of the degree of COX-2 overexpression with histopathological findings indicates the usefulness of this inducible biomarker as a valuable indicator of the risk of malignant transformation in patients with BE.


Subject(s)
Barrett Esophagus/enzymology , Barrett Esophagus/physiopathology , Cyclooxygenase 2/physiology , Disease Models, Animal , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Adenocarcinoma/physiopathology , Adult , Aged , Animals , Barrett Esophagus/pathology , Biomarkers/metabolism , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Esophageal Neoplasms/enzymology , Esophageal Neoplasms/pathology , Esophageal Neoplasms/physiopathology , Female , Humans , Male , Middle Aged , Rats , Rats, Wistar
3.
Adv Med Sci ; 51: 98-102, 2006.
Article in English | MEDLINE | ID: mdl-17357285

ABSTRACT

PURPOSE: Opinions about early endoscopic sphincterotomy and time of laparoscopic cholecystectomy in acute biliary pancreatitis are still controversial. Some authors reserved this procedure only for cases in which the stones were visualized during ERCP or patients had clinical symptoms of acute cholangitis. The aim was the assessment of the dynamic of changes of proinflammatory cytokines and white blood cells in time in patients with acute biliary pancreatitis after performed endoscopic sphincterotomy and laparoscopic cholecystectomy. MATERIAL AND METHODS: We enrolled 43 consecutive patients with clinically diagnosed mild forms of acute biliary pancreatitis. All were treated by early endoscopic sphincterotomy and laparoscopic cholecystectomy performed during the first 48 hours after admission. The course of the disease was monitored by measurement of the level of proinflammatory cytokines. RESULTS: Marked decrease of the level of proinflammatory interleukins within 24 hours after endoscopic sphincterotomy was observed. Mean values of IL-6 and IL-8 were statistically lower immidiately after this procedure (p < 0.001). Subsequent decrease was achieved after laparoscopic cholecystectomy. The mean values of TNF-alpha and IL-12p40 were relatively constant throughout the study period. CONCLUSION: All patients suffering from mild acute biliary pancreatitis should be treated by using minimally invasive procedures. However, such a only treatment should be reserved for experienced centers.


Subject(s)
Biliary Tract Diseases/surgery , Minimally Invasive Surgical Procedures/methods , Pancreatitis/surgery , Acute Disease , Biliary Tract Diseases/blood , Biliary Tract Diseases/complications , Cholecystectomy, Laparoscopic/methods , Humans , Interleukin-12 Subunit p40/blood , Interleukin-6/blood , Interleukin-8/blood , Leukocyte Count , Pancreatitis/blood , Pancreatitis/etiology , Sphincterotomy, Endoscopic/methods , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/blood
4.
Adv Med Sci ; 51: 103-4, 2006.
Article in English | MEDLINE | ID: mdl-17357286

ABSTRACT

PURPOSE: The proper timing of endoscopic sphincterotomy and laparoscopic cholecystectomy in acute biliary pancreatitis is still a subject of controversies. The following rapid report presents preliminary data concerning treatment of patients with severe form of necrotizing biliary pancreatitis (SNBP) with the sequence of minimal invasive procedures (endoscopic sphincterotomy and laparoscopic cholecystectomy) performed in the first 48 hours after admission. MATERIAL AND METHODS: Twelve patients with SNBP were included in the study. The described above procedures were performed in all of the patients within 48 hours. We evaluated clinical outcome, complications, time of stay in hospital and also some morphological (white blood cells) and liver parameters (AST, ALT, bilirubin, ALP and GGT) of these patients in the course of the disease. RESULTS: Two patients died. Two other ones has local complications. We did not observe major complications after ERCP with ES and after laparoscopic cholecystectomy. Additionally, the lavage of the abdominal cavity was performed and drainage was established during laparoscopic cholecystectomy. Conversion in our group occurred in 1 person. Later complications in the course of the disease were caused by the its progression and not related to the performed procedures. CONCLUSIONS: The results are very incurable, however, performing these types of procedures in the experienced centers deserves to be taken into account.


Subject(s)
Biliary Tract Diseases/surgery , Cholecystectomy, Laparoscopic/methods , Pancreatitis, Acute Necrotizing/surgery , Sphincterotomy, Endoscopic/methods , Adult , Aged , Aged, 80 and over , Biliary Tract Diseases/complications , Female , Humans , Male , Middle Aged , Pancreatitis, Acute Necrotizing/etiology , Severity of Illness Index , Treatment Outcome
5.
Scand J Gastroenterol ; 36(11): 1148-54, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11686213

ABSTRACT

BACKGROUND: Leptin, a protein product of obese gene expressed primarily by adipocytes, provides feedback information on the size of energy stores to central OB receptors controlling the food intake, energy expenditure and body weight homeostasis. It has recently been detected in the rat stomach, especially after cholecystokinin (CCK) administration and in human stomach infected with Helicobacter pylori, but its role in gastric secretory functions in humans has not been revealed. This study was designed to determine the involvement of leptin in the control of basal, CCK- and meal-induced gastric H+ secretion and plasma gastrin and CCK levels in humans before and after an eradication of H. pylori. METHODS: Two groups (A and B) of subjects were used; group A (n = 7), for comparison of the effects of CCK and leptin on basal gastric H+ and plasma hormone (leptin, gastrin and CCK) levels, and group B (n = 6), for studies on the involvement of leptin in gastric secretory and plasma hormonal responses to vagal stimulation and gastric peptone meal before and after H. pylori eradication. RESULTS: In H. pylori-positive subjects, CCK (12-200 pmol kg(-1) h(-1)) given i.v. caused a dose-dependent increase of gastric H+ accompanied by a dose-dependent rise in plasma CCK and leptin levels. In contrast, leptin administered i.v. in graded doses (5-80 pmol kg(-1) h(-1)) resulted in a gradual inhibition of basal gastric H+ secretion and in adose-dependent increment in plasma leptin accompanied by an increase in plasma gastrin without alteration of plasma CCK level. Following eradication of H. pylori by 1-week triple therapy in group B patients, the infusion of CCK produced a significantly smaller increase in gastric H+ secretion and significantly smaller rise in plasma leptin as compared to those before the eradication. Cephalic phase stimulation of gastric secretion induced by modified sham-feeding in group B H. pylori-positive subjects increased gastric H+ secretion to about 40% of pentagastrin maximum without affecting plasma leptin, gastrin, or CCK level, while gastric peptone meal resulted in the increase in gastric H+ response reaching about 70% of pentagastrin maximum accompanied by a marked rise in plasma leptin, gastrin and CCK. The treatment with a standard dose of leptin (20 pmol kg(-1) h(-1)) failed to affect sham-feeding-induced gastric H+ secretion but reduced significantly the peptone meal-stimulated H+ secretion, while raising plasma gastrin in response to this meal. Plasma CCK under basal conditions and after sham-feeding was not affected, but plasma CCK response to gastric meal was significantly reduced by leptin infusion. Eradication of H. pylori did not affect basal or sham-feeding-induced H+ secretion but resulted in a significant fall in gastric meal-induced H+ and plasma leptin, gastrin and CCK levels. CONCLUSIONS: 1) The gastric meal and CCK enhance the release of leptin in H. pylori-positive patients and this leptin is capable of inhibiting basal and meal-stimulated gastric H+ secretion, while raising plasma gastrin and reducing the plasma CCK levels, and 2) the eradication of H. pylori reduces the postprandial gastric H+ and plasmagastrin responses as well as the release of leptin in response to CCK and meal.


Subject(s)
Gastric Acid/metabolism , Helicobacter Infections/physiopathology , Helicobacter pylori , Leptin/physiology , Adult , Cholecystokinin/metabolism , Cholecystokinin/pharmacology , Cholecystokinin/physiology , Eating/physiology , Gastrins/metabolism , Humans , Leptin/metabolism , Leptin/pharmacology , Male
6.
Przegl Lek ; 58(1): 45-50, 2001.
Article in Polish | MEDLINE | ID: mdl-11450156

ABSTRACT

The epidemiology, symptomatology and complications of the inguinal hernia were presented. Indications for operative treatment were discussed according to contemporary approach to currently used techniques, particularly laparoscopy. The anatomy of the groin seen from the inside as during laparoscopy was described. Different techniques of laparoscopic herniorrhaphy with particular attention to TAPP method were discussed. Drawbacks, advantages and complications of those techniques were given.


Subject(s)
Hernia, Inguinal/surgery , Laparoscopy , Hernia, Inguinal/complications , Hernia, Inguinal/diagnosis , Humans , Laparoscopy/adverse effects , Surgical Mesh , Treatment Outcome
7.
Scand J Gastroenterol ; 36(1): 23-31, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11218236

ABSTRACT

BACKGROUND: Epidermal growth factor (EGF) and TGF-alpha play a central role in maintaining gastric mucosal integrity. Little is known about the regulative role of the four other widely expressed epidermal growth factor receptor ligands, heparin-binding EGF, amphiregulin, betacellulin and cripto in the gastric mucosa. METHODS: Nineteen patients with Helicobacter pylori-positive gastritis and 32 healthy controls were investigated. Mucosal mRNA expression of EGF receptor ligands was determined by quantitative PCR before and after H. pylori eradication. PCR products were analyzed by soft laser scanning densitometry. Moreover, the effect of chronic active gastritis on EGF receptor expression was assessed by [125I] EGF receptor autoradiography. Immunohistochemistry was performed for TGF-alpha to localize growth factor expression. RESULTS: Antral and oxyntic biopsies showed strong mRNA expressions for TGF-alpha, amphiregulin and heparin binding EGF, but not for EGF, cripto and betacellulin. mRNA expression was significantly reduced down to 50% in H. pylori infection, significantly lower compared to normal gastric mucosa, and increased after eradication therapy. Moreover, chronic gastritis was associated with decreased antral EGF receptor binding compared to healthy controls, possibly reflecting reduced autoinduction. Immunohistochemical analyses localized TGF-alpha in the cytoplasma of gastric epithelial cells and revealed its increased expression after H. pylori eradication. CONCLUSIONS: The data presented suggest that amphiregulin, heparin binding EGF and TGF-alpha are important EGF receptor ligands in the gastric mucosa. H. pylori infection apparently suppresses their mRNA as well as receptor expression that is reversed by H. pylori eradication. This deficiency of the gastroprotective EGF system may contribute to the gastric pathogenicity of H. pylori infection.


Subject(s)
ErbB Receptors/biosynthesis , Gastric Mucosa/metabolism , Gastritis/metabolism , Growth Substances/biosynthesis , Helicobacter Infections/metabolism , Helicobacter pylori , Intercellular Signaling Peptides and Proteins , Membrane Glycoproteins , Adult , Amphiregulin , Betacellulin , EGF Family of Proteins , Epidermal Growth Factor/biosynthesis , Female , GPI-Linked Proteins , Gastric Mucosa/microbiology , Gastritis/microbiology , Glycoproteins/biosynthesis , Heparin-binding EGF-like Growth Factor , Humans , Male , Neoplasm Proteins/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor alpha/biosynthesis
8.
Aliment Pharmacol Ther ; 14(10): 1311-8, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11012476

ABSTRACT

BACKGROUND: There is accumulating evidence for the role of Helicobacter pylori in the development of gastric cancer as well as of lymphomas that arise in mucosa-associated lymphoid tissue (MALT). We reported recently that gastric cancer patients show high prevalence of cagA-positive H. pylori and express gastrin and gastrin receptors enabling them to stimulate tumour growth in autocrine fashion. AIMS: Since the H. pylori infection is considered to be more strongly associated with MALT lymphoma than with gastric cancer, we decided to determine the gastrin and its receptors' mRNA expression and gastrin content in this tumour as well as the release of this hormone both into plasma and gastric lumen. Twenty MALT lymphoma patients were compared with 100 age- and gender-matched controls with similar dyspeptic symptoms. RESULTS: The overall H. pylori seropositivity in MALT lymphoma was about 90% and CagA positivity was 70%, compared to 56% and 33%, respectively, in controls. The serum gastrin in MALT lymphoma was about sixfold higher than in controls while gastric luminal gastrin in these patients was over 70 times higher than in controls. Gastrin content in tumour was about 10-fold higher than in antral mucosa. Gastrin and gastrin-receptor (CCKB-receptor) mRNA were detected by reverse transcriptase-polymerase chain reaction in cancer tissue whilst in the fundic and antral mucosa, only enhanced expression of CCKB-receptor mRNA and gastrin mRNA was detected, respectively. Histamine stimulation in MALT lymphoma induced acid secretion that was only about 30% of control value due to atrophic gastritis. This study confirms an important role of CagA-positive H. pylori in the pathogenesis of MALT lymphoma and shows that this lymphoma is capable of synthesizing and releasing potent growth promoting gastrin, possibly due to the action on G-cells of H. pylori-originated Nalpha-methyl histamine and cytokines (tumour necrosis factor alpha and interleukin-8). CONCLUSIONS: Gastric MALT lymphoma is closely linked to CagA-positive H. pylori infection. Gastrin and its receptors may be implicated in the pathogenesis of gastric lymphoma.


Subject(s)
Antigens, Bacterial , Gastrins/metabolism , Helicobacter Infections/complications , Helicobacter pylori , Lymphoma, B-Cell, Marginal Zone/complications , Stomach Neoplasms/complications , Adult , Aged , Bacterial Proteins/metabolism , Cytokines/metabolism , Female , Gastric Acid/metabolism , Gastric Mucosa/pathology , Gastrins/blood , Histamine/administration & dosage , Humans , Interleukin-8/metabolism , Lymphoma, B-Cell, Marginal Zone/pathology , Male , Middle Aged , Radioimmunoassay , Receptors, Cholecystokinin/drug effects , Receptors, Cholecystokinin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/pathology
9.
Arzneimittelforschung ; 47(4A): 560-4, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9205765

ABSTRACT

This is a phase III, randomized, double-blind, clinical trial with two parallel groups of 50 patients to assess the efficacy of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) 800 mg and ranitidine 300 mg as a single evening dose in the treatment of benign gastric peptic ulcer. Prior to treatment, an endoscopy was performed to detect ulcer lesions and to discard malignancies. Clinical and endoscopic examinations were performed at 6, 9 and 12 weeks. Healing rates were significant for both treatments at week 6, while at week 12 there was statistical significance for ebrotidine as compared to ranitidine (96% vs 88% in the intention-to-treat analysis and 98% vs 87.5% in the per protocol analysis). Decrease in ulcer diameter was significant for both treatments at week 6, and for ebrotidine versus ranitidine at weeks 9 and 12. The overall improvement of symptoms was higher with ebrotidine, which was already significant at week 6. Safety was considered to be excellent, since no significant adverse events were reported for the patients included in the study.


Subject(s)
Benzenesulfonates/therapeutic use , Histamine H2 Antagonists/therapeutic use , Ranitidine/therapeutic use , Stomach Ulcer/drug therapy , Thiazoles/therapeutic use , Adult , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged
10.
Wiad Lek ; 50 Suppl 1 Pt 1: 235-8, 1997.
Article in Polish | MEDLINE | ID: mdl-9446361

ABSTRACT

At our Department in cases of suspected choledocholithiasis according to such criteria as jaundice, ultrasound or biochemical profile we perform ERCP. According to this in 94 (7.67% of 1226 patients scheduled for LC) were preoperatively submitted to ERCP. In 34 no CBD stones were found. In 19 stones were successfully removed. In 41 patients we were not able to extract stones and they were scheduled for open cholecystectomy. 40 patients 3 days to one year after LC were referred to ERCP because of suspected CBD obstruction. 17 had CBD stones, which were successfully removed. In 11 cases obstruction was caused by pancreatitis in another 20 no pathology in the billard tree was seen. Concluding we may say that in a hospital were ERCP is performed routinely LC can be performed in patients with CBD stones.


Subject(s)
Cholangiopancreatography, Endoscopic Retrograde/methods , Cholecystectomy, Laparoscopic , Gallstones/diagnosis , Gallstones/surgery , Humans
11.
Wiad Lek ; 50 Suppl 1 Pt 1: 97-101, 1997.
Article in Polish | MEDLINE | ID: mdl-9446412

ABSTRACT

We present own material of 291 colonoscopic polypectomies performed between 1991 and 1996. In this group 15 (5.1%) polyps contained malignancy (14 adenocarcinoma, 1 lymphoma). Analysis of this material supported well known fact of higher malignant potential of large polyps and of adenoma villosum. In all but one cases of cancers located in polyps histological examination confirmed free margin of electro-resection. There were no local recurrences during follow-up lasting 2 month to 5.5 years. Patient with lymphoma malignum (large polyp over 4 cm in diameter) underwent typical chemotherapy and is now, one year after polypectomy disease-free. In this group colonoscopy is repeated every 3 months during first two years and every 6 months later. In cases of cancer-free margin of electro-ablation colonoscopic polypectomy seems adequate treatment of malignant large bowel polyps.


Subject(s)
Colonic Polyps/surgery , Endoscopy/methods , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adenoma, Villous/pathology , Adenoma, Villous/surgery , Colonic Polyps/pathology , Colonoscopy , Disease-Free Survival , Electrosurgery , Follow-Up Studies , Humans , Lymphoma/pathology , Lymphoma/surgery , Treatment Outcome
12.
Wiad Lek ; 50 Suppl 1 Pt 2: 369-73, 1997.
Article in Polish | MEDLINE | ID: mdl-9424905

ABSTRACT

Introduction of endoscopy and endoscopic hemostasis had substantial impact on the treatment of diseases of stomach and duodenum complicated by bleeding. We compared two 4-years' periods analysing etiology of bleeding and influence of endoscopic haemostasis on outcome of patients with upper gastrointestinal haemorrhage. Number of patients in both groups were comparable. Ratio of bleeding related to gastric and duodenal ulcer didn't change substantially. Number of patients with haemorrhagic gastritis decreased somehow while those with bleeding oesophageal varies increased. Number of patients submitted to emergency operation for bleeding ulcer decreased significantly. Mortality was lower in the second period of time only in patients with haemorrhage requiring transfusion of 4-7 units of blood.


Subject(s)
Gastrointestinal Hemorrhage/prevention & control , Gastroscopy , Hemostatic Techniques , Emergencies , Esophageal and Gastric Varices/epidemiology , Esophageal and Gastric Varices/etiology , Gastritis/epidemiology , Gastritis/etiology , Gastritis/prevention & control , Gastrointestinal Hemorrhage/epidemiology , Gastrointestinal Hemorrhage/etiology , Humans , Incidence , Peptic Ulcer/complications , Peptic Ulcer Hemorrhage/epidemiology , Peptic Ulcer Hemorrhage/etiology , Peptic Ulcer Hemorrhage/prevention & control , Retrospective Studies
13.
Hepatogastroenterology ; 33(6): 271-4, 1986 Dec.
Article in English | MEDLINE | ID: mdl-3804186

ABSTRACT

The distribution of the mucosal PGE2-generating capacity was bioassayed in the duodenum of 17 patients with duodenal ulcer (age range 20-58 years), and in 17 subjects (age range 21-57 years) who did not suffer from this disease. The age of the subjects within both groups was precisely matched in pairs. In contrast to the "young" controls or the "young" patients (under 37) or the "old" patients (over 37) the "old" control group of subjects showed an age-dependent increase in the mucosal PGE2 generation. It is concluded that with increasing age the mucosal PGE2 plays an increasingly important role in the protection against duodenal ulcers.


Subject(s)
Duodenal Ulcer/metabolism , Duodenum/metabolism , Intestinal Mucosa/metabolism , Prostaglandins E/biosynthesis , Adult , Humans , Middle Aged
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