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Background The role of imaging in the diagnosis of appendicitis is controversial. This prospective interventional study and nested randomized trial analysed the impact of implementing a risk stratification algorithm based on the Appendicitis Inflammatory Response (AIR) score, and compared routine imaging with selective imaging after clinical reassessment. Method Patients presenting with suspicion of appendicitis between September 2009 and January 2012 from age 10 years were included at 21 emergency surgical centres and from age 5 years at three university paediatric centres. Registration of clinical characteristics, treatments and outcomes started during the baseline period. The AIR score-based algorithm was implemented during the intervention period. Intermediate-risk patients were randomized to routine imaging or selective imaging after clinical reassessment. Results The baseline period included 1152 patients, and the intervention period 2639, of whom 1068 intermediate-risk patients were randomized. In low-risk patients, use of the AIR score-based algorithm resulted in less imaging (19·2 versus 34·5 per cent; P < 0·001), fewer admissions (29·5 versus 42·8 per cent; P < 0·001), and fewer negative explorations (1·6 versus 3·2 per cent; P = 0·030) and operations for non-perforated appendicitis (6·8 versus 9·7 per cent; P = 0·034). Intermediate-risk patients randomized to the imaging and observation groups had the same proportion of negative appendicectomies (6·4 versus 6·7 per cent respectively; P = 0·884), number of admissions, number of perforations and length of hospital stay, but routine imaging was associated with an increased proportion of patients treated for appendicitis (53·4 versus 46·3 per cent; P = 0·020). Conclusion AIR score-based risk classification can safely reduce the use of diagnostic imaging and hospital admissions in patients with suspicion of appendicitis. Registration number: NCT00971438 (http://www.clinicaltrials.gov).

BACKGROUND Symptomatic response to acid inhibition can be used as a guide in diagnosing patients with reflux symptoms. The proton-pump inhibitor (PPI) omeprazole has been used as such a diagnostic tool. Intragastric acid control with esomeprazole is more effective than other PPIs and has the potential to offer an advance in the diagnostic use of PPIs. METHODS Patients experiencing heartburn (for > or = 6 months) were studied in this randomized, double-blind, multicenter study. Following a 3-day placebo run-in, 440 patients were randomized to 14 days' treatment with esomeprazole 40 mg once daily (o.d.), esomeprazole 20 mg twice daily (b.i.d.) or placebo. Heartburn symptoms were recorded daily. Endoscopy and 24-h esophageal pH-monitoring were performed to determine the presence of gastroesophageal reflux disease (GERD). The esomeprazole treatment test was considered positive if patients' symptoms improved during the treatment period compared with symptoms recorded on Day 0. RESULTS 63 patients were excluded from the analysis due to lack of symptoms on Day 0 or failure to complete pH-monitoring. The sensitivity of an esomeprazole treatment test in confirming GERD increased during the first days of treatment and stabilized between 79% and 86% after 5 days (both esomeprazole arms). The corresponding figure for the placebo arm was 36%. Specificity was variable (24%-65%) for both active treatment and placebo. CONCLUSION A treatment test with esomeprazole 40 mg has a high sensitivity in confirming GERD. Furthermore, the data indicate that 1-week treatment with a once-daily dosage is sufficient to ensure adequate diagnosis.

Symptomatic response to acid inhibition can be used as a guide in diagnosing patients with reflux symptoms. The proton-pump inhibitor (PPI) omeprazole has been used as such a diagnostic tool. Intragastric acid control with esomeprazole is more effective than other PPIs and has the potential to offer an advance in the diagnostic use of PPIs.Patients experiencing heartburn (foror = 6 months) were studied in this randomized, double-blind, multicenter study. Following a 3-day placebo run-in, 440 patients were randomized to 14 days' treatment with esomeprazole 40 mg once daily (o.d.), esomeprazole 20 mg twice daily (b.i.d.) or placebo. Heartburn symptoms were recorded daily. Endoscopy and 24-h esophageal pH-monitoring were performed to determine the presence of gastroesophageal reflux disease (GERD). The esomeprazole treatment test was considered positive if patients' symptoms improved during the treatment period compared with symptoms recorded on Day 0.63 patients were excluded from the analysis due to lack of symptoms on Day 0 or failure to complete pH-monitoring. The sensitivity of an esomeprazole treatment test in confirming GERD increased during the first days of treatment and stabilized between 79% and 86% after 5 days (both esomeprazole arms). The corresponding figure for the placebo arm was 36%. Specificity was variable (24%-65%) for both active treatment and placebo.A treatment test with esomeprazole 40 mg has a high sensitivity in confirming GERD. Furthermore, the data indicate that 1-week treatment with a once-daily dosage is sufficient to ensure adequate diagnosis.

The human vagus nerve has been investigated for the presence of substance P (SP), vasoactive intestinal polypeptide (VIP), and enkephalin (ENK) using immunohistochemistry. After 0.5–4 hr of nerve ligation during surgical operations two right thoracic main truncs, two anterior subdiaphragmal trunks, and four anterior nerves of Latarjet were found to contain accumulation of immunoreactive material in nerve fibers above the ligation. Very high numbers of SP-, medium numbers of ENK-, and low numbers of VIP-immunoreactive fibers were seen. The relative proportions were similar at all levels studied. These data thus indicate the presence and axonal transport of SP-, ENK-, and VIP-like peptides in the human vagus nerve. Our observations in humans correlate well with results obtained from other species. Thus gastrointestinal vagal sensory mechanisms may be mediated by SP (and possibly VIP) and some motor mechanisms by ENK.

The atropine- and guanethidine-resistant contraction of the cat pyloric sphincter induced by efferent stimulation of the cervical vagi, was studied with a new method for measuring transpyloric flow. The pyloric contraction was blocked in a dose-dependent manner by the opiate antagonist naloxone infused intraarterially to the pyloric region. Local intraarterial injection of morphine or enkephalinamide elicited a pyloric and gastric contraction. Leuand met-enkephalin intraarterially elicited a pyloric contraction and a gastric relaxation. These effects could be prevented or reversed by naloxone. Immunohistochemical studies revealed a particularly rich enkephalinergic innervation of the pylorus with dense networks of varicose nerve fibers with enkephalin-like immunoreactivity both in the circular smooth muscle layer and in the myenteric plexus. Furthermore, many cell bodies of the myenteric plexus with enkephalin-like material were demonstrated. The corpus-antrum was sparsely innervated by enkephalin-like nerves to the circular muscle layer and only few immunoreactive cell bodies were observed in the myenteric plexus. These results together suggest a vagal control of the feline pylorus and stomach mediated via enkephalinergic neurons.

Gastric motility and pyloric contractility were studied in laparotomized cats under chloralose anaesthesia by recording the intragastric volume and changes in an applied constant transpyloric flow of body-warm saline. Unilateralefferent electrical stimulation of the cervical vagi resulted in a prompt gastric contraction and a delayed pyloric contraction. In one third of the animals abiphasic pyloric motor response, consisting of a short period of increased flow preceding the longlasting decrease or cessation of the flow was observed. Afteratropine (0.2 mg/kg b.w.) the vagal nerve stimulation resulted in agastric relaxation, while the biphasic pyloric motor response was even more pronounced, with a significantly longer latency of the contractile phase. Addition ofguanethidine (2 mg/kg b.w.) did not affect these motor responses. Afterhexamethonium (25 mg/kg i.v. and 50±10 mg per kg i.a. b.w.) the stimulation procedure still resulted in a slight gastric relaxation, while the pyloric contraction was effectively blocked. However, the relaxatory phase required theaddition of atropine to become antagonized indicating separate transmission mechanisms for the relaxatory and contractile components of the pyloric motor response at efferent vagal stimulation.

An in vivo model for the simultaneous study of motility of the gallbladder, sphincter of Oddi and the duodenal wall in species with an intraduodenal location of the sphincter has been developed. Gallbladder motility is registered by manometry, while trans-sphincteric flow and duodenal wall motility are recorded by perfusion methods. The sphincter of Oddi proper is totally uninfluenced by any mechanical procedures since the outflow of fluid is collected via a funnel-shaped human femoral vein graft fixed to the duodenal mucosa by tiny sutures peripheral to the sphincteric muscle. The motility of the duodenal wall influences the flow of saline through a small feline vein graft inserted across the duodenal wall. The method is described in detail as well as nerve stimulation experiments and some pharmacological tests (e.g. infusion of substance P) to demonstrate the usefulness of the method. With this method the physiology and pharmacology of this region can be investigated in species, which, like man, have an intraduodenal location of the sphincter of Oddi.

A case of leiomyosarcoma of the inferior vena cava is presented. The tumor was incidentally found at ultrasonography of a patient who underwent a follow-up examination after surgery for carcinoma of the colon. The tumor was resected and the patient was alive and well one year postoperatively at which time repeat ultrasonography and inferior vena cavography showed no remaining tumor.

A case of leiomyosarcoma of the inferior vena cava is presented. The tumor was incidentally found at ultrasonography of a patient who underwent a follow-up examination after surgery for carcinoma of the colon. The tumor was resected and the patient was alive and well one year postoperatively at which time repeat ultrasonography and inferior vena cavography showed no remaining tumor.

The effects of regional intra-arterial injections of substance P (SP) or efferent electrical stimulation of the vagal nerves on feline extrahepatic biliary motility were studied in anesthetized cats using a constant perfusion model. Each of these procedures elicited contractile motor responses of the gallbladder and the sphincter of Oddi. Since SP is present in feline vagal axons, these findings may indicate a role of SP in the vagal motor control of biliary motility. Immunocytochemically neurons with SP-like immunoreactivity were found in the smooth muscle layers of the biliary tree as well as adjacent to acetylcholinesterase-positive ganglion cells indicating either direct activation of smooth muscle cells and/or indirect activation via cholinergic neurons. Depending on the type of stimulation different SP mechanisms were demonstrated; exogenous SP induced contraction of both the sphincter and the gallbladder which were probably direct (resistant to atropine but sensitive to a SP analogue), while vagal stimulation elicited contraction of both regions via a mechanism sensitive to atropine and to a SP analogue.

Electrical stimulation of the divided splanchnic nerves proximal to the celiac ganglion in chloralosed cats induced a dilation of the pylorus in the majority of animals. However, in some cats a pure contractile motor response or a biphasic motor response (contraction followed by dilation) was elicited suggesting that the splanchnic nerves convey excitatory fibres to the pylorus as well. The pyloric and gastric contraction at such stimulation was sensitive to atropine, while the pyloric dilation was not sensitive to cholinergic, adrenergic or ganglionic blocking agents in contrast to the adrenergic gastric dilation. Since the splanchnic nerve and the pyloric wall contain numerous neuropeptides, these substances might be involved in a nonclassical neurotransmission of the splanchnic motor responses of the pylorus.

The human vagus nerve has been investigated for the presence of substance P (SP), vasoactive intestinal polypeptide (VIP), and enkephalin (ENK) using immunohistochemistry. After 0.5-4 hr of nerve ligation during surgical operations two right thoracic main truncs, two anterior subdiaphragmal trunks, and four anterior nerves of Latarjet were found to contain accumulation of immunoreactive material in nerve fibers above the ligation. Very high numbers of SP-, medium numbers of ENK-, and low number of VIP-immunoreactive fibers were seen. The relative proportions were similar at all levels studied. These data thus indicate the presence and axonal transport of SP-, ENK-, and VIP-like peptides in the human vagus nerve. Our observations in humans correlate well with results obtained from other species. Thus gastrointestinal vagal sensory mechanisms may be mediated by SP (and possibly VIP) and some motor mechanisms by ENK.

In acute experiments in anesthetized cats (n = 75), with ligated adrenals the influence on the pyloric sphincter of afferent and efferent electrical stimulation of the cervical vagi was studied with a flow recording technique. Gastric motility was recorded simultaneously with a volume recording technique. Efferent stimulation using high threshold parameters (8 V; 5 ms; 8 Hz) resulted in a prompt gastric contraction and a delayed pyloric contraction (23 +/- 17 s). In one third of the cats biphasic pyloric motor response, consisting of a short period of increased flow preceding a longlasting cessation of the flow, was observed. When the transpyloric flow was reduced by splanchnic nerve stimulation or noradrenalin infusion, efferent vagal nerve stimulation induced an increased flow supporting the assumption of relaxatory fibres to the pylorus within the vagus as well. Unilateral afferent stimulation resulted in a decreased flow within 5 +/- 3 s and a prompt gastric relaxation, which were both abolished at transection of the intact contralateral vagus indicating vago-vagal reflexes. After atropine (0.2 mg/kg i.v. b.w.) efferent stimulation resulted in a gastric relaxation, while the biphasic pyloric motor response was even more pronounced with a long (60 s) latency of the contractile phase. Addition of guanethidine (2 mg/kg i.v. b.w.) did not affect these responses. After hexamethonium (25 mg i.v. + 50 mg +/- 10 mg i.a./h) the stimulation procedure resulted in a gastric relaxation, while the pyloric contraction was blocked. The relaxatory phase required the addition of atropine for blockade, indicating separate transmission mechanisms for the two components of the pyloric motor response at such stimulation. Hexamethonium effectively antagonized the pyloric contraction at afferent stimulation. Immunohistochemical studies revealed a rich enkephalinergic innervation of the pylorus and the presence of enkephalin-like material within vagal axons. VIP-like material was demonstrated within the same tissues with a similar distribution. The hypothesis of a transmission via non-classical receptors was corroborated in experiments, where the pyloric contraction at vagal efferent stimulation was blocked dose-dependently by the opiate receptor antagonist, naloxone i.a. Furthermore, micromolar doses i.a. of enkephalins mimicked the vagal motor effects, i.e. pyloric contraction and gastric relaxation, which were reversed by equimolar doses of naloxone in favour of a pyloric enkephalinergic contraction. Intraarterial injection of nanomolar doses of this VIP resulted in both a gastric and pyloric relaxation. Specimens of the human vagus from the thoracic and abdominal levels were investigated with immunohistochemistry. Substance P and enkephalin containing fibres and a low number of VIP fibres were seen at all levels indicating the presence of an axonal transport of these peptides in the human vagus.

The motility of the isthmic segment of the rabbit oviduct was studied in vivo using a perfusion model. The transisthmic flow of saline (38 degrees) was recorded at constant inflow pressures uni- or bilaterally. In untreated control animals there was a high resistance to flow within the isthmic segment. 12, 24, 48 and 72 h after induced ovulation by i.v. injection of human choriongonadotropin (HCG; 50 IU) the resistance gradually declined. No synchronous spontaneous motility pattern was recorded from the oviducts of any animal. When adrenergic agonists were administered 48 h after HCG, either intraluminally or intravenously, flow ceased after the alpha-adrenoceptor agonists noradrenaline (2-50 micrometers) or phenylephrine (2-10 micrograms), while an increased flow was recorded after the beta-adrenoceptor agonist isoprenaline (5-100 micrograms). The duration of the motor effects varied dose-dependently. Therefore it seems as if the motility of the isthmic segment is under adrenergic control, at least 48 h after HCG, with contractions caused by alpha-adrenoceptor stimulation and dilations caused by beta-adrenoceptor stimulation. The perfusion model used appears to be suitable for studying the adrenergic control of the isthmic segment after appropriate pretreatment with HCG.

By immunohistochemistry the three neuropeptides enkephalin (ENK), substance P (SP) and vasoactive intestinal polypeptide (VIP) were all localized to numerous nerve fibres in the circular smooth muscle layer and the myenteric plexus of the feline pylorus (1, 3). After pretreatment with vinblastine to block intraaxonal transport of transmitter peptides within neurons ENK and VIP immunoreactive nerve cell bodies could be demonstrated in the myenteric plexus of the pylorus. Immunohistochemical studies of the thoracic and abdominal vagal nerve trunks in man and cat have also demonstrated the presence of various peptides within nerve fibres (4). This study was undertaken to study the effects of the three peptides on the motor activity of the pyloric sphincter of the cat in vivo. The effects of pharmacological blocking agents on these motor responses and on the motor responses obtained at electrical efferent vagal nerve stimulation were also investigated.