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The influence of ageing on experimental gastric ulcer healing
April 1995
BLEEDING GIANT GASTRO-DUODENAL ULCERS: CLINICAL OUTCOME. R. Pecha, M. Carroll, R. Camp, W. Trudeau. Division of Gastroenterology, University of California at Davis, Sacramento, CA Introduction: Giant ulcers > 2.5 cm are reported to have higher complication rates including a 40 % mortality. They are also commonly associated with NSAID use, chronic renal failure, and age > 50. Methods: 194 consecutive patients ages 22 -73 years presenting with upper gastrointestinal bleeds due to ulcer disease underwent endoscopy. Those patients with ulcers measuring > 2.5 cm were enrolled. Endoscopic biopsies were obtained on all gastric ulcers and each patient was evaluated forHelicobacterpylori. Follow-up endoscopy was performed in 8 to 12 weeks. Treatment included acid suppression in all patients and anti-H. priori medications when appropriate. Resuhs: Giant ulcers were documented in 20 out of 194 bleeding ulcers. 9 of 20 (45%) were duodenal ulcers; 11 of 20 (55%) were gastric ulcers. 7 (35%) giant ulcers were associated with NSAID use; 8 (40%) were associated with H. pylori (4 gastric ulcers, 4 duodenal ulcers). 2 cases of adenocarcinoma were also documented. Two cases resulted in perforation and were successfully treated with surgical management. Four giant ulcers were associated with methamphetamine use. There were no deaths documented among the group. Conclusions: Giant ulcers accounted for 10% &all patients presenting with gastrointestinal bleeding at our institution. Gastrointestinal bleeding is a frequent complication of giant gastro-duodenal ulcers and is the common presenting feature. 35% of giant ulcers were associated with NSAID use. Methamphetamine use is a frequent cause of giant ulcers (20%). There were no deaths in the study group. Summary: Giant ulcers can be managed successfully with aggressive medical therapy to minimize complications. Evaluation of all patients for NSAIDs, H. pylori status, and methamphetamine use may reveal a cause for giant ulcers.
THE INFLUENCE OF AGEING ON EXPERIMENTAL GASTRIC ULCER HEALING. A.G. Pennev. F.J. Andrews, P.E. O'Brien. Dopt of Surgery, Mmash Medical School, Alfred Hospital, Melbourne, 3181, Australia.
Gastric ulcer disease is a more serious disorder in the eldedy than in younger individuals with an increase in the incidence, size and complications with age. Ddayed healing of gaatric alters is also a cxnraou probkm in the elderly taking NSAID therapy for arthritis. The aim of this study was to investigate the effec~ of asein8 and NSAlDs on the healing of experimental gastric ulcers. METHODS : Ulcers were induced by serosal application of acetic acid in 2-3 month old (immature), 11-12 month old (mature) and 23-24 month old (aged) male S p ~ D a w l e y rats. Groups of animals from all a8¢ groups were treated with 1 mg/kg ~ i n or 20% Tween 80 control, se. Rats were injected daily f~" 2 weeks, stasting three days aRur ulcur induction whan the ulcer hcalin8 process b~ins. Ulcers were assessed by (1) nmcroscopic m c a s ~ t of ulcer size (nunz) and expressed as a % healed from the original size and (2) by qaamitativ¢ hiatol~cal m~sammms of the alcer healing cemponents, umeosal regeneration and wound co~mctiou. RESULTS : lmmature and mature rats developed ulcers of similar size when examined three days after induction (28.3+1.2 and 27.3+1.7 mm2 ~ i y ) but aged rats had a smaller ulcer (16.8+1.8 ram2). All groups showed equivalent healing over the next two weeks with % of ulcer healed 81.6-~_2A %, 83.8+4.6 % and 77.5+10. 1%, respectively. No differences in the length of the dismptiou of the mmmlaris mucosa (an index of commction in hen) was observed betwem the groups. However the aged animals showed a decrease in the % of regenerated mucosa (ioummre control; 68.3+5.6*/,, mature cot~ml; 74.8+8.6%, aged control; 50.8_.+5.2). Indometh~in treatmeat for two weeks significantly delayed alter hcalin8 to the same extent in immature, mature and abed rats (29.1+8.8 %, 35.1+17.5 % and 38.3+14.5 % respectively). Quantitative histological analysis showed that haimnetha¢in sisnificantly delayed nammal regeneration in all three age groups (imnmture indumctlu~in; 30.0!-5.2%, mature indomethacin; 13.3+2.8%, aged indumethacin; 25.7_-¢4.8). indome~in sisnifr.an ~ delayed ulcer coutraction in both immature and mature rats but had no ~ in aged animals (inunature ¢outrol; 4.5_+0.2nun, immature indumetha¢in; 5.6-!0.4mm, mature camtrol; 4.1_+0.3nun, mature 5.9-£-0.3mm, aged co~rol; 4.4+0.5, aged indumedtacin; 5._0-~0.6). CONCLUSION : There was no clear differencebctwean natural or NSAlDinduced delayed ulcer healing with ageing.
Esophageal, Gastric, and Duodenal Disorders
A189
HEIGHTENED CYTOKINE EXPRESSION AND INFLAMMATORY RESPONSE I N VIVO TO cagA + Helicobaeter pylari STRAINS. R.M. Peel~, G.G. Miller, ICT. Tham, G.I. Perez-Perez, X.M. Zhao, J.C. Atherton, M.J. Blaser. Departments of Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, TN.
Helieobacter pylori strains that possess cagA, which encodes a high molecular weight protein, are highly associated with peptic ulcer disease. To test the hypothesis that cagA+ strains elicit a greater pro-inflammatory cytokine response in the gastric mucosa than eagA" strains, gastric biopsies were obtained from 42 patients and studied by histology, culture, enzymelinked immunosorbent assay (ELI SA), and reverse transcription-polymerase chain reaction (RT-PCR). Of 42 patients, 30 (71%) were infected with H. pylori based upon both serology and histology or culture (termed tissuepositive), 10 (24%) were negative by serology, histology and culture and 2 (5%) were positive by serology only. 22 (73%) of 30 tissue-positive persons harbored cagA+ strains as determined by RT-PCR. Of 15 H. pylori-infected patients with peptic ulceration, 14 (92%) were infected with cagA+ strains compared with 8 (36%) of 22 persons with gastritis alone (p=O.02, Fisher's exact test). Persons infected with cagA + strains had significantly more inflammation and damage in the gastric antrum and corpus compared to persons infected with cagA strains or uninfected persons, for each of the following parameters: roononuclear and polymorphonuclear cell infiltrates, erosions, epithelial cell surface degeneration and mucin depletion. IL-8 concentrations were significantly higher in the gastric antral roucosa of persons infected with cagA + strains (median 161 pg IL-8/mg protein) compared with those infected with cagA strains (median 50 pg IL-8/mg protein, p=0.032, Mann-Whitney U test) or with uninfected persons (median 56.7 pg lL-8/mg protein, p=O.04, Matin-Whitney U test). Gastric antral and body inflammation score also was significantly associated with IL-8 production; persons with moderate to severe acute or chronic inflammation had significantly higher levels of IL-8 protein compared with persons with little or no acute (antrum, p=0.002; body, p=0.003) or chronic (antrum, p<0.O01; body, p=0.02) inflammation. Finally, patients with peptic ulcer disease, compared with persons who had gastritis alone, demonstrated significantly higher concentrations of IL-8 in rite gastric antrum (p=0.O02), but there were no significant differences in IL-8 in the gastric body. These data demonstrate that infection with eagA +H. pylori strains is significantly associated with inflammation of the gastric mucosa, especiaUy the antrum, increased IL-8 synthesis, and the presence of peptic ulceration.
@ PHYSIOLOGICAL EFFECTS OF VIDEO-ASSISTED TRANS-ORAL STAPLING FOR ZENKER'S DIVERTICULUM: A PROSPECTIVE CLINICAL STUDY. A. Peracchia, L. Bonavina, S. Name, S. Bona, M. Pagani, M. Ventuti,. Department of General Surgery and Surgical Ontology, University of Milan. Milan. Italy (Supported by C.NR, Grant n. 94.02830 CT 04) Resistance to flow through the upper esophageal sphincter (LIES) as a result of incomplete sphincter opening is the major pathogenctic factor in Zenker's divefficulum. All operations designed to cure dysphagia should include a cricopharyngeal myotomy to treat the undedying motility disorder. We investigated the physiological effects of a new procedure, the video-assisted trans-oral diverticulostomy, on the pharyngo-esophageal segment. Between November 1993 and May 1994, ten patients with a median age of 60 years (41-73), were manometrically studied before and after operation. Informed consent was obtained from all patients. The length of the pouch, measured by flexible endoscopy, varied between 3 and 7 era. Under general anesthesia, the hypopharynx was entered using a modified Weerda diverticaloscope (Karl Store,Germany). A wide angle 0 ° forward=viewing telescope (Karl Sturz, Germany) was insetted. The septum between the esophagus and the diverticulum was identified. A linear stapler device (Endo GIA 30, USSC,USA) with the distal end of the anvil sawed off, was placed across the common wall. A second caflddgn was applied to complete division of the septum in 7 patients. LIES basal pressure, residual pressure and length were measured before and after operation. The Student's t test was used to compare means. No postoperative morbility and mortality was recorded. All patients had symptomatic relinf at follow-up ot"6 to 12 months. A residual radiologic spur was evident in 7 of the 10 fits. The manometric effects of the operation are shown in the table below : Pre Post p
Pharyngeal pressure(mmHg)
39.3+20.7
41.9~_15.3
ns
UES basal pressure (mmHg)
44.0~24.4
23.4+8.6
0.04
LIES residual pressure(mmHg)
3.5+4.0
2.0"~2.4
as
LIESlength (cm)
2.8+!.3
1.9£_1.0
ns
We conclude that video-assisted trans-oral stapling is a simple and safe procedure in Zenker's diverticulum. The findings of the present study show a significant defrease of LIES pressure after the operation, indicating that an effective cricopharyngealmyotmny can be performed through this approach.
BLEEDING GIANT GASTRO-DUODENAL ULCERS: CLINICAL OUTCOME. R. Pecha, M. Carroll, R. Camp, W. Trudeau. Division of Gastroenterology, University of California at Davis, Sacramento, CA Introduction: Giant ulcers > 2.5 cm are reported to have higher complication rates including a 40 % mortality. They are also commonly associated with NSAID use, chronic renal failure, and age > 50. Methods: 194 consecutive patients ages 22 -73 years presenting with upper gastrointestinal bleeds due to ulcer disease underwent endoscopy. Those patients with ulcers measuring > 2.5 cm were enrolled. Endoscopic biopsies were obtained on all gastric ulcers and each patient was evaluated forHelicobacterpylori. Follow-up endoscopy was performed in 8 to 12 weeks. Treatment included acid suppression in all patients and anti-H. priori medications when appropriate. Resuhs: Giant ulcers were documented in 20 out of 194 bleeding ulcers. 9 of 20 (45%) were duodenal ulcers; 11 of 20 (55%) were gastric ulcers. 7 (35%) giant ulcers were associated with NSAID use; 8 (40%) were associated with H. pylori (4 gastric ulcers, 4 duodenal ulcers). 2 cases of adenocarcinoma were also documented. Two cases resulted in perforation and were successfully treated with surgical management. Four giant ulcers were associated with methamphetamine use. There were no deaths documented among the group. Conclusions: Giant ulcers accounted for 10% &all patients presenting with gastrointestinal bleeding at our institution. Gastrointestinal bleeding is a frequent complication of giant gastro-duodenal ulcers and is the common presenting feature. 35% of giant ulcers were associated with NSAID use. Methamphetamine use is a frequent cause of giant ulcers (20%). There were no deaths in the study group. Summary: Giant ulcers can be managed successfully with aggressive medical therapy to minimize complications. Evaluation of all patients for NSAIDs, H. pylori status, and methamphetamine use may reveal a cause for giant ulcers.
THE INFLUENCE OF AGEING ON EXPERIMENTAL GASTRIC ULCER HEALING. A.G. Pennev. F.J. Andrews, P.E. O'Brien. Dopt of Surgery, Mmash Medical School, Alfred Hospital, Melbourne, 3181, Australia.
Gastric ulcer disease is a more serious disorder in the eldedy than in younger individuals with an increase in the incidence, size and complications with age. Ddayed healing of gaatric alters is also a cxnraou probkm in the elderly taking NSAID therapy for arthritis. The aim of this study was to investigate the effec~ of asein8 and NSAlDs on the healing of experimental gastric ulcers. METHODS : Ulcers were induced by serosal application of acetic acid in 2-3 month old (immature), 11-12 month old (mature) and 23-24 month old (aged) male S p ~ D a w l e y rats. Groups of animals from all a8¢ groups were treated with 1 mg/kg ~ i n or 20% Tween 80 control, se. Rats were injected daily f~" 2 weeks, stasting three days aRur ulcur induction whan the ulcer hcalin8 process b~ins. Ulcers were assessed by (1) nmcroscopic m c a s ~ t of ulcer size (nunz) and expressed as a % healed from the original size and (2) by qaamitativ¢ hiatol~cal m~sammms of the alcer healing cemponents, umeosal regeneration and wound co~mctiou. RESULTS : lmmature and mature rats developed ulcers of similar size when examined three days after induction (28.3+1.2 and 27.3+1.7 mm2 ~ i y ) but aged rats had a smaller ulcer (16.8+1.8 ram2). All groups showed equivalent healing over the next two weeks with % of ulcer healed 81.6-~_2A %, 83.8+4.6 % and 77.5+10. 1%, respectively. No differences in the length of the dismptiou of the mmmlaris mucosa (an index of commction in hen) was observed betwem the groups. However the aged animals showed a decrease in the % of regenerated mucosa (ioummre control; 68.3+5.6*/,, mature cot~ml; 74.8+8.6%, aged control; 50.8_.+5.2). Indometh~in treatmeat for two weeks significantly delayed alter hcalin8 to the same extent in immature, mature and abed rats (29.1+8.8 %, 35.1+17.5 % and 38.3+14.5 % respectively). Quantitative histological analysis showed that haimnetha¢in sisnificantly delayed nammal regeneration in all three age groups (imnmture indumctlu~in; 30.0!-5.2%, mature indomethacin; 13.3+2.8%, aged indumethacin; 25.7_-¢4.8). indome~in sisnifr.an ~ delayed ulcer coutraction in both immature and mature rats but had no ~ in aged animals (inunature ¢outrol; 4.5_+0.2nun, immature indumetha¢in; 5.6-!0.4mm, mature camtrol; 4.1_+0.3nun, mature 5.9-£-0.3mm, aged co~rol; 4.4+0.5, aged indumedtacin; 5._0-~0.6). CONCLUSION : There was no clear differencebctwean natural or NSAlDinduced delayed ulcer healing with ageing.
Esophageal, Gastric, and Duodenal Disorders
A189
HEIGHTENED CYTOKINE EXPRESSION AND INFLAMMATORY RESPONSE I N VIVO TO cagA + Helicobaeter pylari STRAINS. R.M. Peel~, G.G. Miller, ICT. Tham, G.I. Perez-Perez, X.M. Zhao, J.C. Atherton, M.J. Blaser. Departments of Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, TN.
Helieobacter pylori strains that possess cagA, which encodes a high molecular weight protein, are highly associated with peptic ulcer disease. To test the hypothesis that cagA+ strains elicit a greater pro-inflammatory cytokine response in the gastric mucosa than eagA" strains, gastric biopsies were obtained from 42 patients and studied by histology, culture, enzymelinked immunosorbent assay (ELI SA), and reverse transcription-polymerase chain reaction (RT-PCR). Of 42 patients, 30 (71%) were infected with H. pylori based upon both serology and histology or culture (termed tissuepositive), 10 (24%) were negative by serology, histology and culture and 2 (5%) were positive by serology only. 22 (73%) of 30 tissue-positive persons harbored cagA+ strains as determined by RT-PCR. Of 15 H. pylori-infected patients with peptic ulceration, 14 (92%) were infected with cagA+ strains compared with 8 (36%) of 22 persons with gastritis alone (p=O.02, Fisher's exact test). Persons infected with cagA + strains had significantly more inflammation and damage in the gastric antrum and corpus compared to persons infected with cagA strains or uninfected persons, for each of the following parameters: roononuclear and polymorphonuclear cell infiltrates, erosions, epithelial cell surface degeneration and mucin depletion. IL-8 concentrations were significantly higher in the gastric antral roucosa of persons infected with cagA + strains (median 161 pg IL-8/mg protein) compared with those infected with cagA strains (median 50 pg IL-8/mg protein, p=0.032, Mann-Whitney U test) or with uninfected persons (median 56.7 pg lL-8/mg protein, p=O.04, Matin-Whitney U test). Gastric antral and body inflammation score also was significantly associated with IL-8 production; persons with moderate to severe acute or chronic inflammation had significantly higher levels of IL-8 protein compared with persons with little or no acute (antrum, p=0.002; body, p=0.003) or chronic (antrum, p<0.O01; body, p=0.02) inflammation. Finally, patients with peptic ulcer disease, compared with persons who had gastritis alone, demonstrated significantly higher concentrations of IL-8 in rite gastric antrum (p=0.O02), but there were no significant differences in IL-8 in the gastric body. These data demonstrate that infection with eagA +H. pylori strains is significantly associated with inflammation of the gastric mucosa, especiaUy the antrum, increased IL-8 synthesis, and the presence of peptic ulceration.
@ PHYSIOLOGICAL EFFECTS OF VIDEO-ASSISTED TRANS-ORAL STAPLING FOR ZENKER'S DIVERTICULUM: A PROSPECTIVE CLINICAL STUDY. A. Peracchia, L. Bonavina, S. Name, S. Bona, M. Pagani, M. Ventuti,. Department of General Surgery and Surgical Ontology, University of Milan. Milan. Italy (Supported by C.NR, Grant n. 94.02830 CT 04) Resistance to flow through the upper esophageal sphincter (LIES) as a result of incomplete sphincter opening is the major pathogenctic factor in Zenker's divefficulum. All operations designed to cure dysphagia should include a cricopharyngeal myotomy to treat the undedying motility disorder. We investigated the physiological effects of a new procedure, the video-assisted trans-oral diverticulostomy, on the pharyngo-esophageal segment. Between November 1993 and May 1994, ten patients with a median age of 60 years (41-73), were manometrically studied before and after operation. Informed consent was obtained from all patients. The length of the pouch, measured by flexible endoscopy, varied between 3 and 7 era. Under general anesthesia, the hypopharynx was entered using a modified Weerda diverticaloscope (Karl Store,Germany). A wide angle 0 ° forward=viewing telescope (Karl Sturz, Germany) was insetted. The septum between the esophagus and the diverticulum was identified. A linear stapler device (Endo GIA 30, USSC,USA) with the distal end of the anvil sawed off, was placed across the common wall. A second caflddgn was applied to complete division of the septum in 7 patients. LIES basal pressure, residual pressure and length were measured before and after operation. The Student's t test was used to compare means. No postoperative morbility and mortality was recorded. All patients had symptomatic relinf at follow-up ot"6 to 12 months. A residual radiologic spur was evident in 7 of the 10 fits. The manometric effects of the operation are shown in the table below : Pre Post p
Pharyngeal pressure(mmHg)
39.3+20.7
41.9~_15.3
ns
UES basal pressure (mmHg)
44.0~24.4
23.4+8.6
0.04
LIES residual pressure(mmHg)
3.5+4.0
2.0"~2.4
as
LIESlength (cm)
2.8+!.3
1.9£_1.0
ns
We conclude that video-assisted trans-oral stapling is a simple and safe procedure in Zenker's diverticulum. The findings of the present study show a significant defrease of LIES pressure after the operation, indicating that an effective cricopharyngealmyotmny can be performed through this approach.