reflux episodes in GERD patients was associated with a TLESR representing 51% of the acid exposure time. By cout~cast, a low LESp, responsible fur 20% of reflux episodes, represented 38% of the acid exposure time. At night, 53% of 60 reflux episodes ni GERD patients ',','as associated with a TLESR representing 26% of the acid exposure time A low LESp occurred in 36% of reflux episodes representing 71% of the acid exposure time. Postprandiafly, of 190 reflux episodes 75% occurred during a TLESRs representing 53% of acid exposure time whereas a low LESp occurring in 17% of reflux episodes caused 38% of the acid exposure time, Upright, 65% of 94 reflux episodes scored was associated with a TLESR representing 54% of the acid exposure time. A low- LESp accounted for 19% of reflux episodes representing 36% of the acid exposure time Acid exposure time per TLESR, hence, was significantly shorter than the acid exposure time per period v,~th a low LESp during 24 hour (54 s vs 164 s; P<0.O05), at night (43 s vs 335 s; P<O 03), postprandially (49 s vs 140 s; P<0.O01), and upright (42 s vs 141 s; P<0 04). Concklsion: Tile role of TLESRs as the most important mechanism underlying gastroesophageal reflux in GERD patients is overestimated considering ou[y their number not taking into account the acid exposure time

M2084

Esophageal Shortening Aassociated to Acid-lnduced Esophagitis is Rreversible Xin Zhang, Jan Tack, Jozef Janssens, Daniel Sifiim

It has been recendy shown that intraesophageal acid perfusion provokes, both in opossum and human, an niflarumation related esophageal shortening. This finding suggested a causal relationship between gastroesophageal reflux and fbnnation of hiatal hernias It could be speculated that succe~ive episodes of esophageal inflammation during the infancy could provoke progressive irreversible esophageal shortening and hiatal hernias The aim of this study was to examnie the reversibility of acute inflammation-induced esophageal shortening. Methods: Esophageal length was measured manometrical/y in 5 adult cats under ketamine sedation, before 24 hours and 1 month after induction of acute esophagiti~ with acid perfusion (1 mL/min, 0.1N HCI, 80 toni). Esophageal length was defined as the distance between the distal margni of the tipper esophageal sphincter and the proximal margin of the lower esophageal sphmcter identified using a slow pulI through technique The presence and degree of esophagitia was evaluated endoscopycalty. Resuhs: Studies performed 24hs after acid perfusion showed a severe esophagitls (grade Ill), reduction or abolition of esophageal penstahic contractions and significant reduction of LES pressure. The mean esophageal length was 17 _+ 0 2 cm bdbre acid perfusion and 15s 7 cm 24hs after acid perfusion (p<O.05). After one month, four cats had endoscopic normal mucosa, normal peristalsis and LESP. One cat developed esophageal stenosis Tile esophageal length was 17.2-+ 0.8 cm (p>0.05 vs control). Conclusions: Esophagitis induced esophageal shortening is reversible after a single inflammatory- event. Ongoing studies on the effect of repetitive esophagitis challenges will further clarify the relationship between gastroesophageal reflux, esophageal shortening and hiatal hernias.

cm20

19

18 �84

t 7 �84

16

14

13 e ~ s I month

M2085

Regional Variations in Postprandial Gastric pH and Their Relationship to Acid Reflux in Healthy Volunteers Katsuhiko lwakiri, Garry Nind Dou Wu Zou, Daniel Sifrim Rachel Rigda, John Dent Rmhard H Holloway

A recent study (GE 2001;121:775) has suggested that there is a small p~x:ket of relatively less buffered gastric acid iust below the gastroesophageal j'anction that persists for up to 15-rain after a meal and that may serve as a reservoir for post-prandial acid gastroesophageal reflux (GER). This study, however, was limited to measurement at a single time-point and the position relative to tfm lower esophageal sphincter (LES) was not determined Aims To monitor esophageal and gastric pH at rnuhiple sites continuously before and after a meal in order to examine more closely the profile of intragasrtic pH and its relationship to acid reflux. Methods, We studied 15 H pylorimegative healthy" volunteers. Esophageal motility" was recorded using a multilumen asaembly with a sleeve sensor. A side-hole at the back of the sleeve ,,;'as used m standardise the position of the sleeve across the LES Esophageal pH was monitored at 2 sites, I and 6cm above the LES and gastric pH was monitored at 4 sites 1, 6, 11 aud 16 cm below tile LES Recordings were perfPrmed for 1 h before and 3 h after a standard mixed-nutrient solLsolid meal (3000kj, 50% fiat) Results. Fasting gastric pH ranged between 15 and 18 and did not differ among sites. Immediately alter the meal, gastric pH rose to between 53 and 6.6 and did not differ among sites. Subsequentiy, however, gastric pH at the most proximal site fell more rapidly such that during the first hour median pH (3.5) was signiticantly lower than at the other sites (4.3-5.2, p<0.001). Alter this time, however, pH did p.ot dif{;:r among the gastric sites. The distal esophageal

pH electrode recorded 211 post-prandial acid reflux episodes (pH drop >1 pH unit) and the proximal electrode 68 episodes. During reflux episodes, esophageal pH at either site did not correlate significantly with that at the most proximal gastric site (distal esoph r =0.011, p = 0 124, proximal esoph r=0.019, p=0.258), or with gastric pH at the other sites. Gastric pH at the onset of reflux tended to be higher than minimum esophageal pH during reflux. Conclusions. (i) The region of the stomach immediately below' the LES acidifies more rapidly after meals than more distal regions but this difference is no longer apparent alter the first hour. This region may serve as a reservoir for acid refluxate in the early post- prandial period. (it) Gastric pH electrodes may not sample accurately the gastric refluxate.

M2086

Oxidative DNA Damage and its Repair Enzyme Expression in Chronic Esophagitis Induced by Gastrojejunal Reflux in Rats Kazuhiko Uchiyama, Yuji Naito, Tomohisa Takagi, Masaaki Kuroda, Yutaka Isozaki, Kazuhiro Katada, Norimasa Yoshida, Toshikazu Yoshlkawa

BACKGROUND: Although detail mechanisms remain to be determined, recent studies show that oxdative stress has been suggested to contribute the mucosal damage of reflux esophagitis The aim of the present study is to establish an animal model for chronic esophagitis in rats and to investigate the contribntion of oxidative stress for mucosal damage and repair in reflux esophagitis METHODS: With male Wistar rats, esophagogastrojejunaI anastomosis was accomplished by anastomosing the jejunum to the gastroesophageal junction under diethyl-ether inhalation anesthesia. The operated animals were sacrificed at 2, 4, 8, 12, 24, 48 weeks after operation. Esophageal injury was evaluated by macroscopic and microscopic findings and the expression of intlammation-associated genes were quantified by real time PCR Oxidative stress was evaluated as immunoreactive 4-hydroxynonenal (4-HNE) and 8- hydroxydeoxyguanosine (8-OHdG) in the esophageal mucosa, and as the expression of oxoguanine DNA glycosylase (OGG1), a DNA repair enzyme. RESULTS: Ninety percent ot tile animal survived after surge D- and no died before the termination of the experiment Erosions and ulcers began to develop in the lower end of esophagus at 2 week after surgery At 4 and 8 weeks after surgery, severe esophagnic changes, such as 'white cobblestone appearance', ulcer, and mucosal friability were observed. HistoIogical study- showed thickness of esophageal mucosa, hyperplasia of the epidermis and basal cells, ulcer formation, and marked infiltration of inflammatory cells. The mRNA expression of niducible nitric oxide synthase, cyclooxygenase-2, and CINC-I was markedly enhanced in the esophagus after surgeD'. In addition, immuno-postive cells for 4-HNE and 8-OhdG and tile expression of OGG1 were increased in time dependent manner. CONCLUSIONS: MLxed reflux of gasuic and duodenal contents lead to the formation of chronic esophagitis in rats. With this model, it was suggested that oxidative DNA damage contnbutes to the development of mucosal injury in mixed chronic esophagitis.

M2087

Short, Spontaneous, Anamnestic Arousals are the Most Common Sleep Abnormality Associated with Nocturnal Esophageal Acid Exposure Roy Dekel, Colleen Green, Isaac Malagon, Stuart Quau, George Stephen, Ronnie Fass

Background: Gastmesophageal reflux disease (GERD) has been suggested to disrupt sleep However, the underlying mechanism has not been well studied. Aim: To determine whether spontaneous arousals from sleep are associated with acid reflux events. Methods: Patients with symptoms of GERD , at least trice weekly, were enrolled. Patients were evaluated by tile GERD Symptom Checklist questionnaire. Subsequently, patients underwent an endos- copy and 24-hour pH testing, k polysomnogram was completed during the pH test with recordings of body posture, electroencephalography, EOG, chin EMG, airflow, thoracic and abdominal excursions, leg movements, snoring, single-lead ECG and oxygen satm'ation Patients wore two pH recording devices. One stored the pH test data for later analysis and the other transmitted pH recordings onto the polysomnographic display. Arousals were classified as related to apnea, periodic leg movement, snoring, or in the absence of these, as spontaneous. The number per hour of each type of arousal was calculated for: 1) the time period when esophageal pH < 4 CLow pH Arousal Index') and 2) the time period when esophageal pH was > 4 ("Normal pH Arousal Index"). Results: Nine patients (4M, mean age 43_+ 6) were included. Two patients did not have nocturnal esophageal acid exposure. During the pH test, the percent total and supine time pH < 4 were 4.3-+ 0.9 and 3.7_+0.96, respectively, A total of 14 episodes of acid reflux (mean 1.9_+0.46) that lasted 1-29 minutes (mean duration 14.2 _+ 2.6 ram) were documented during patients sleep. None ot tile patients woke up during the night due to acid reflux. The vast nmjority of patients' arousals were spontaneous (mean 62 -+ 6, range 42-86). The spontaneous Low pH Arousal index was significantly higher than the spontaneous "Normal pH Arousal Index' (27.5 _+ 7.0 vs. 16.4"+4.5, p<0.05). On an average, spontaneous arousals were twice as common during acid reflux episodes as compared to the rest of the night. There was no significant difl?rence in the fi'equency of other causes fbr arousals between acid reflux and non-acid reflux periods. Conclusions: Short, spontaneous, anamnestic arousals are commonly associated with gastroesophageal reflux These arousals may iead to ti'agmented sleep with the overalI perception of poor sleep the next morning.

M2088

Mechanisms of Gastroesophageal Reflux in Japan: The Rate of Acid Reflux during Transient Lower Esophageal Sphincter Relaxation (TLESR) is very Low, Compared with That Reported frmn Western Countries Yoshinori Hayashi, Katsufliko Iwakiri, Makoto Kotoyori, Toshiaki Sugiura, Akihiku Kawakami, Choitsu Sakamoto

Background and Aim: In contrast to Western countries, reflux esophagitis has been considered less common m the Orient, nicluding Japan. TI.ESR is a major mechanism of gastroesophageal reflux, however, there is no data in Japan about the mechamsms of gastroesophageal reflux The aim of this study is to determine the mechanisms of gastroesophageaI reflux and the

A G A A b s t r a c t s A - 4 1 2

rate of TLESR and acid refux during T1.ESR between healthy subjects and patients with refux esophagitis in Japan. Method: We studied I0 H.pylofi-negative healthy subjects and 10 H pylonmegattve patients with refux esophagitis (2 patients with grade B of Los Angeles classification, and 8 patients with grade C). Manometry was canied out with a perfused assembly which incorporated side boIes in the pharynx, the upper esophageal sphincter, the esophagus, and 9 side holes (t cm apart) which straddled the distal esophagus, the escphagngastnc junction and the proximal stomach 21 pressures and I esophageal pH measurements at 55 cm above the proxmral margin of LES, were carried out 1 hour before and 3 hours after a meal in the sitting position. The energy lend of the solid meal was 692Kcal and consisted of 33 % fat Results: In beahhy subjects, 91% of reflux episodes were TLESR, 4.5 % were swallowqnduced abnornutfly-pmlonged LES relaxation (SAP), 4.5 % were strain reflux and 40 % were free reflux In patients wifh reflnx esophagins, 52.5 % of reflux episodes were TI ESR, 82 % were SAP, 13.1% were strum reflux and 18.0 % were free reflux There was no difference in the rate of TLESR between healthy subjects (5.6(1.9), NoAmur nrean(SD)) and patients with reflux esophagitis (4.4(1.5)). The rate of acid reflux (a pH drop of at least 1 pH unit) dining TLESR in patients with reflux esophagitis (3q.2%) was significantly (p < 0.05) higher than that in fealty subjects (14,4%). Conclusions: fu Japan, the mechanisms of gastmesophageal reflux in both groups are similar to that which has been reported in Western countries Out" condusinn is that the rate of acid reflux during TLESR in patients with reflux esophagitis is significantly higher than that of beahhy subjects but such rate in both groups is very low, compared with fhat reported in Western countries.

M2089

Night-time Reflux: Is it an Early or Late Event? Amifie t4ila, Donald O. Castdl

Ai~. Our clinical impression gteaued from reading large numbers of ambulatory pH studies is that recumbent reflux episodes mostly occur in the early part of lfm night-time period [n this study we tested this b>~othesis. Methods: 201 consecutive pH studies done in our lab between October 2001 and Octobe~ 2002 were a~talyzed. Population characteristics: 75 males/126 females; Mean Age = 50.4yrs (Range: 16-88yrs). Reflux was defined by a drop in pH to less thal~ 4. ,gbnormal total recumbent reflux defi~md as >1.2% time pH < 4. For patients with abnormal recumbent reflux, the recurnbent period was divided in 2 halves and the reflux time in each period calculated, in all patiems, it was also identified whether they had a meal within 2 hours of retiring. Results: 59 patients had abnormal recumbent reflux:; 24 males / 35 t~:males; mean age = 489 yrs In patients with abnormal recmnbent I~flux, acid reflux was significantly more frequent in the first half of the recumbent period compared to the 2nd half (median 6.3% vs 0.3% respectively; p<O.001; Wilcoxon signed rank test in a two tailed analysis). The tigure below illustrates this result Those patients (N = 119) having had a meal within 2 hours of retiring were 2.46 times more likely to develop recumbent reflux than those whose last meal was more than 2 hours earlier (N = 83). The table below illustrates this resuk Conclusion: These results reinforce the concept of maintaining eonlrnl of inght-time reflux pnmarily dm'ing the first half of the recumbent penod, and the irnportanee ot counseling palients with nocturnal symptoms against [ate meals and snacks

Je~bnonnal recumbent reflux No recumbent reflux Meal within 2hrs 46 73

meal within 2hrs 13 69

0-

30- 2:

O E 20-

10- t ! 1st half 2nd half

Abnormal recumbent reflux

M2090

Sleep-Related Breathing Disorders and Gastroesophageal Reflux Disease: a possible association Luciana Palorabini, Jed Black, George Tnadafilopoulos

Background and Aints: The association of sleep-related breathing disorders (SRBD) and gastroesophageal reflux disease (GERD) has been suggested in several studies. Although the prevalence ot GERD in SRBD ranges from 53 to 76%, the nature and mechanism(s) of their relationship are still unknown, Obstructive events may lead or increase the chance of reflux through an increase in negative pressure during increased respiratory effort, Alternate mechamsre.s include hyperinflation iuterfenng with the diaphragmatic contribution to lower esophageal sphincter (LES) pressure, ot a chemoreceptor-mediated direct effect. The purpose

of this study was to evaluate the possible association of SRBD with seventy of GERD. Methods: We studied 14 patients (mean age: 45.6 years, mean BMI: 278 kg/m2) with GERD and SRBD symptoms, such as heartburn, regurgitation, snoring, wimessed apnea and excessive daytime sleepiness using polysonmography and 24-h esophageal pH monitoring off medications. Polysomnography encompassed the following: electroencephalogram (EEG), electmoculogram (EOG), chin electromyogram (EMG), nasal and oral airflow monitoring, respirator)," effort and nocturnal oximetry. Reflux, arousal and respiratory events were corre- hted using a time window of 2 rain before and niter each reflux event. Using the respirator),' disturbance index (RDI), patients were separated according to severity of SRBD in two groups: OSA (obstructive sleep apnea group; RDI >5 events/h) and UARS (upper airway resistance syndrome gmup; RDI<5 events/h). Results: Reflux events analysts: Out of 347 reflux events analyzed, 322 occurred during wakefulness and 25 occurred during sleep. All sleep events were associated with arousals (7 were preceded and 4 were followed by arousals). There was no significant association in time of reflux and respiratory events and only 2 nocturnal events occurred after a respiratory event (hypopnea). SRBD analysis: 8 patients were classified as UARS and 6 patients were classified as OSA. Their data are shown m Table. Conclusion: SRBD is associated with GERD but their relationship may not be causative. Since OSA patients have higher DeMeester scores and longer intra-esophageal acid exposure than UARS patients, the severity of the SRBD appears to be related to the seventy of GERD

Polysomnographic and pH values

LIARS (mean+l.SD) OSA (mean§ RDI (events/h) 2.I+/-1.1 28,8+#12.9 De Meester score 16,2+]-12,2" 34.7+/-19.6 24-hr % flme with pH < 4 2.6~-2.6' 7,4§ *p<O, fll

M2091

Detection of Oxidative DNA Damage (ODD) in Esophageal Biopsies of Patients with Reflux Symptoms and Normal pH Monitoring Studies Liang Liu, Gulchiu Ergun, Atilh Ertan, Karen Woods, Iau Sachs, Mamoun Younes

24-bout pH monitoring (24-h pH) is the gold standard for the diagnosis of gastroesophageal reflux (GER) yet this test is often underutiflzed for a variety of reasons. GER induces oxidative DNA damage (ODD) in esophageal epithelial cells which can be detected by a simple immunohistochemieal (1HC) staining, The aim of ibis study" was to determine whefher ODD detected in biopsy tissue using 1HC correlates with a diagnosis of GER determined by 24- h pH. Records of the Reflux Center, pathology', and patient records were searched for cases meeting rbe following criteria: 24-h pH and esophageal biopsies done within 3 month of each other, use of the same acid suppressive medication the day of both procedures and Throughout the time in between procedures or no use of medication. 52 cases were identified. Sections of the tbrmalin-fixed and paraffin-embedded esophageal biopsies were stained tbr 8-Hydroxydeoxy guanosine (8-OHdG) using standard IHC method. The presence ot posilive nuclear immunoreactivity for 8-OHdG was used to indicate ODD. Two cases showed only scant stromal tissue and 3 cases were later found to have inaccurate treatment data and were excluded from the study. Of the remaining 47 cases, 21 had normal 24-h pH and 26 were abnormal. Seven (33%) of the 21 normal 24-h pH cases were negative for ODD compared to only 2 (8%) of the 26 abnormal cases and the diff~:rence almost reached statistical significance (p = 0.058, two-sided Fisher exact test). Since it was surprising to see ODD positive biopsies from patients with normal pH studies, and to exclude the eftect of patient compliance or other factors, we examined cases in which biopsies and 24-h pH were done within the same 24 hours or within a day of each other. Four of 5 such cases with normal 24-h pH were positive for ODD including a case in which both biopsy and 24-h pH were done on the same day while the patient was taking a PPL For this patient, the biopsy was positive for ODD wtule the 24-h pH was reported as normal with adequate intragastric acid suppressmn. The H&E stained biopsy sections showed features of reflux, some severe, in all cases with normal 24-h-pH and positive ODD. Our results show that ODD can occur in the absence of acid reflux and despite adequate antbsecretory therapy. This may indicate that other agents, such as bile, can induce ODD in an acid suppressed emdronmem. The implications of these findings on the effectiveness of medical treatment of Barrett esophagus are under consideration. Supported by Eisai/Janssen.

M2092

Incidence of Erosive Esophagitis in a Long-Term Study of Patients with H.pylori Eradication for Ulcer Hemorrhage Dennis M. Jensen, Thomas Savides, Matthew Sitzer, Harold Frankl, Karl Esrason, St~nt Hamamab, Alexander Lee, Doughs Falgel, Samud Ho, Roy Wong, Daniel Demarco, Michael Shaw, Gary Zuckerman, Mare Lenin, Yvonne Lee, Ron Cbitayat, Gustavo Machicado, Glenn Alexander, Christopher Gostout, X&ktor Eysselein, Francisco Ramirez, Edmund Bini, Jonathan Cohen, JefF;ey Gombein, Susie You Cheng, Vichuda Lousuebsakul, Lana Fontana, Mary E. Jensen

There is a controversy whether eradication of H.pylori (HP) m patients with peptic ulcers significantly increases the rate of erosive esophagitis. Our purpose was to evaluate the incidence of endoscopicafy documented erosive esophagitis that developed alter HP eradica- tion m patients with bleeding peptm ulcers and relate that to the daily use of an histamine 2 antagonist (H2RA) or placebo. Methods. This assessment was part of a large, multicenter double blind study of HP eradication alone or with daily H2RA for prevention of rec'arrem uker hemorrhage during long-term tbnow-up Patients who had recent severe ulcer hemor- rhage and refection with HP (documented by Giemsa stain or rapid urease test of amral biopsies, or C13 breath test) were randomized to daily H2IL~ (40 mg fhmotidme HS) or placebo, alter ulcer healing (by endoscopy) and HP eradication (by C13 breath test) were documented. Patients were followed eve:q,, 4 months for up to 5 years. Exit endoscopies w'ere utilized to study whether erosive esophagitis was present in 142 patients and a Hetzell- Dent scale was utilized for grading the esophagitis. None ot these patients had a prior history of esophagitis, All patient had at least i prior elective endoscopy by investigators and erosive

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