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S1692

The Contribution of Genetic Factors to Symptomatic Gallstones: A Twin Study Amanda Hughes, Lynn Cberkas, Tim Spector, Nigel Trudgfll

Background: Age, female gender, obesity, rapid weight gain or loss, parity and hyperlipidae- mia are recognised aetiologlcal factors for gallstones. First degree relatives of patients with gallstones are four times as likely as matched comrols to have ~allstones. This raises the possibility of a significant genetic contribution to the aetiology of gallstones. Studies of monozygotic (MZ) and dizygotic (DZ) twins provide useful insights into the relative contribu- tions of environmental and genetic factors to a disease. We have examined the contribution of genetic factors to symptomatic gallstones by studying the prevalence of cholecystectomy in MZ and DZ twins. Methods: 1826 unselected female twin pairs from the St Thomas' Adult UK Twin Registry were asked to complete a questionnaire. Only data related to cholecystectomy is presented here. Casewise concordance, i.e. the probability that a twin has had a cholecystectomy given that the co-twin has had a cholecystectomy, was calculated. Quantitative genetic model fitting using the maximum hkelihood modeling method was performed to estimate heritability. Results: 84% response rate (3071 respondents), including 1407 evaluable twin pairs. 694 MZ pairs Imean age 49 years (range 32-63)] and 713 DZ pairs [mean age 49 years(range 32-62)]. Prevalence of cholecystectomy was 4%. Casewise concordance rates were significantly higher for MZ twins compared with DZ twins (see table). Heritabifity estimates suggest 72% (C.1. 53-91%) of the phenotypic variance in symptomatic gallstones is due to additive genetic factors. Conclusion: The data suggest a substantial genetic contribution to the development of symptomatic gallstones and subse- quent cholecystectomy. Perhaps the four F's for gallstones (fat, female, fertile, forty) should now be increased to five F's to include family history.

Cauwton concordance for cholecy~ectomy

Cholecyttectomy In at Concordant Oltcordam Catm, d u r loner one twin (l~lrs) pelrm palnl dance

MZ 47 11 (23%) ~ 36 (77%) 22/58 (38%) ~ DZ 52 4 (8%) 48 (92%) 8/56 (14%) Total 99 15 84 * p=0.03 versus DZ twins "p=0.02 versus DZ twins

$1693

Timing of Urgent Laparoscopic Cholecystectomy Does Not Influence Conversion Rate John Knight, Stuart Mercer, Stephen Jancewicz, Marisia Waiters, Sami Sadek, Simon Toh, Shaw Somers

Aims. Urgent laparoscopic cholecystectomy is the gold standard treatment of acute gallstone disease, but there is confusion about the effect of delay in operation on conversion rates. Most reports suggest that delay beyond 3 or 4 days leads to a higher conversion rate. Methods. Our institution operates a specialist-led protocol for the urgent management of all admissions with acute cholecystitis (AC) and biliary colic (BC). Data were collected prospectively over a 6-month period. Results. From March to August 2002, there were 110 admissions to our institution with AC or BC. 74 (67%) underwent cholecystectomy at the index admission with an overall conversion rate of 12% 4 of 38 (11%) carried out within 3 days of admission were converted, compared with 5 of 36 (14%) camed out after 3 days 5 of 44 (11%) carried out within 4 days of admission were converted, compared with 4 of 30 (13%) carried out after 4 days. There were no deaths or major complications. Conclusion. So long as the procedure is carried out by experienced upper GI surgeons working within a specialist-led protocol, the conversion rate for laparoscopic cholecystectomy can be as low as 12%, and the timing of urgent laparoscopic cholecystectomy has no impact on the conversion rate.

$1694

Intestinal Afferent Sensitivity To Acid And Distension In Wild Type And Vrl-/- Knockout Mice Kirk Hfllsley, Wendy J. Winchester, John B. Davis, Gareth A. Hicks, David Grundy

Background: The vanflloid receptor-1 (VR1) is expressed predominantly in sensory neurones. Its role in somatic pain and inflammatory hyperalgesia has been well established following the generation of VR1 knockout animals (Caterina et al Science. 2000; 288: 306-13). However, the role of VR1 in sensory signal transduction in visceral afferents has not been investigated. Methods: Experiments were performed on VR1-/- mice (Davis et al. Nature. 2000; 405: 183-7) and wild-type littermates. Mesenteric afferents were recorded using suction electrodes in vitro from segments of jejunum. The intestina] segment was bathed in Krebs buffer at 34~ and perfused intraluminally with saline for ramp distensions (<60mmHg), or with HCl (1-50 raM) for luminal acidification. Data are mean • SEM are were compared with Students' t-tests as appropriate. Results: Mesenteric afferents in wild type but not VR1 -/- mice were activated by capsaicin (10 v,M, A = 37.4 _+ 4.2imp./s) rapidly followed by desensitisation. There was no significant difference between wild type and VR1 -/- mice in either spontaneous discharge (9.1 • vs 83 • 1.7 respectively, p = 0.78), or the response to ramp distension (A at 60mmHg = 47.1 _+ 8 7imp/s vs 48.3 • 7 9 respectively, p=0.92) In both wild-type and VR1-/- mice, there was a biphasic response to ramp distension, with a rapid increase between 4-10 mmHg (17 • 0.3imp/mmHg vs 2.0 • 0.5imp/mmHg respectively, p = 0.67), followed by a slower linear increase between 10- 60 mmHg (0.8 • 0.2imp/mmHg vs 0.7 • 0. limp/mmHg respectively, p = 087). Following capsaicin desensitization in wild type mice, the afferent response to ramp distension was significantly attenuated both at low (0.8 • 0.3imp/mmHg, p<0.05) and high (0.3 • 0.2imp/ mmHg, p<O.05) stimulus intensities. Intrafumina[ acid (-> 10 mM) evoked a simllar increase in both wild type and VR1 -/- mice (10ram HCl = 252.3 • 41.9imp/120s vs 219.6 _+ 54.2imp/ 120s respectively; 50ram = 892.1 • 130.6 imp/120s vs 865.9 • 57.4 imp/] 20s respectively, p=084) . However, following capsaicin deser~sitization the response to 50 mM HC1 was significantly attenuated in wild type (77% reduction, p<0.0l) but not VR1 -A mice. Conclu- sions: These results demonstrate that both low and high threshold mechanoreceptors express the VR1 receptor, but these receptors are not directly involved in mechanotransduction Similarly', the sensitivity of mesenterie afferents to luminal acid was independent of VR1 suggesting that in these transgenic animals there are other mechanisms that detect protons.

S1695

Protease-Activated Receptors (PAR)-I and -4 Mediated Stimulation of Rat Intestinal Afferent Sensitivity Wen Jiang, Nigel W. Bunuett, David Grundy

Introduction: Protease-activated receptors (PARs) influence gastrointestinal function and visceral hypersensitivity (Vergnolle, Aliment Pharmacol Ther, 14: 257-66, 2000). The latter may be direct or secondary to enteric reflex activation since myenteric neurons are depolarized by synthetic activating peptides (AP) for PAR-l, -2 and -4 (Gao et al. Gastroemero]. 123: 1554-64, 2002). We aimed to investigated the mesenteric aiterent responses to PAR-I and - 4AP before and after combined treatment with neuronal calcium channel blockers and cyelooxygenase inhibitor to determme the contribution of secondary mechanism to PARs- evoked afferent sensitivity. Methods: Extracel]ular recording of jejunal afferent activity were made from pentobarbitone sodium anaesthetized (60 mg/kg, ip.) male Wistar rats. TFLLRN- NH2 (lmg/kg, selective PAR-lAP), AYPGKF-NH2 (lmg/kg, selective PAR-4AP) and 2- Methyl-5-HT (30~g/kg, 5-HT3 agonist) were administered systemically with I0 min time interval. A cocktail of ~o-conotoxin GVIA, SVIB (both at 25~g/kg) and naproxen (10mg/kg) or vehicle were administered 5 rain prior to the repeat challenge of the three agonists. Data are the meau• from 6 animals and were analyzed by paired Students' t-test. Results: Afferent responses to both PAR-lAP and PAR-4AP but not 2m5-HT were significantly reduced after treatment with naproxen and conotoxins but not vehicle (Fig. 1). Conclusion: Both selective PAR-lAP and PAR-4AP evoke a powerful increase in mesenteric afferent firing, a component of which appears to be secondary to either enteric activation or prostanoid production and is therefore consistent with the potential for "cross-talk" between the intrinsic and extrinsic sensory" pathways. However, like 5-HT3 receptors on afferent terminals that can be stimulated directly, our evidence suggests a functional role for thrombin receptors on afferent nerve terminals.

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]~ . 1. Increase in tffferent f iriap in reugonge to PAP.1 -AP 0eft), PAP.2 -AP (midele) and 2m3 liT(fight) before Bud m*'f~ treatment w i~ Ihe cockt~ of impt~oxen and (e-conot codns (said lad open symbds req)cct/vdy).

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