bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle
Authors: Ryder J.W. , Chibalin A.V. , Zierath J.R.
Published: March 2003

This review will provide insight on potential intracellular signalling mechanisms by which insulin and exercise/contraction increases glucose metabolism and gene expression. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) and can be activated in skeletal muscle by two separate and distinct signalling pathways; one stimulated by insulin and the second by muscle contractions. Impaired insulin action on whole body glucose uptake is a hallmark feature of type II (non‐insulin‐dependent) diabetes mellitus. Defects in insulin signal transduction through the insulin‐receptor substrate‐1/phosphatidylinositol 3‐kinase pathway are associated with reduced insulin‐stimulated glucose transporter 4 translocation and glucose transport activity in skeletal muscle from type II diabetic patients. Studies performed using glucose transporter 4‐null mice show that this glucose transporter isoform plays a major role in mediating exercise‐stimulated glucose uptake in skeletal muscle. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Exercise training leads to alterations in expression and activity of key proteins involved in insulin signal transduction. These changes may be related to increased signal transduction through the mitogen‐activated protein kinase (MAPK) signalling cascades. Because MAPK is associated with increased transcriptional activity, these signalling cascades are candidates for these exercise‐induced changes in protein expression. Understanding the molecular mechanism for the activation of signal transduction pathways will provide a link for defining new strategies to enhance glucose metabolism and improve health in the general population.
Reduced autonomic activity during stepwise exposure to high altitude
Authors: Sevre K. , Bendz B. , Hankø E. , Nakstad A. R. , Hauge A. , Kåsin J. I. , Lefrandt J. D. , Smit A. J. , Eide I. , Rostrup M.
Published: March 2003

Several studies have shown increased sympathetic activity during acute exposure to hypobaric hypoxia. In a recent field study we found reduced plasma catecholamines during the first days after a stepwise ascent to high altitude. In the present study 14 subjects were exposed to a simulated ascent in a hypobaric chamber to test the hypothesis of a temporary reduction in autonomic activity. The altitude was increased stepwise to 4500 m over 3 days. Heart rate variability (HRV) was assessed continuously in seven subjects. Baroreceptor reflex sensitivity (BRS) was determined in eight subjects with the ‘Transfer Function’ method at baseline, at 4500 m and after returning to baseline. Resting plasma catecholamines and cardiovascular‐ and plasma catecholamine‐ responses to cold pressor‐ (CPT) and mental stress‐test (MST) were assessed daily in all and 12 subjects, respectively. Data are mean ± SEM. Compared with baseline at 4500 m there were lower total power (TP) (35 457 ± 26 302 vs. 15 001 ± 11 176 ms2), low frequency (LF) power (3112 ± 809 vs. 1741 ± 604 ms2), high frequency (HF) power (1466 ± 520 vs. 459 ± 189 ms2) and HF normalized units (46 ± 0.007 vs. 44 ± 0.006%), P ≤ 0.001. Baroreceptor reflex sensitivity decreased (15.6 ± 2.1 vs. 9.5 ± 2.6 ms mmHg–1, P=0.015). Resting noradrenaline (NA) decreased (522 ± 98 vs. 357 ± 60 pmol L–1, P=0.027). The increase in systolic blood pressure (SBP) and NA during mental stress was less pronounced (21 ± 4 vs. 10 ± 2% and 25 ± 9 vs. –2 ± 8%, respectively, P < 0.05). The increase in SBP during cold pressor test decreased (16 ± 3 vs. 1 ± 6%, P=0.03). Diastolic blood pressure, HR and adrenaline displayed similar tendencies. We conclude that a transient reduction in parasympathetic and sympathetic activity was demonstrated during stepwise exposure to high altitude.
Mechanics of human triceps surae muscle in walking, running and jumping
Authors: Hof A. L. , Van Zandwijk J. P. , Bobbert M. F.
Published: March 2003

Length changes of the muscle–tendon complex (MTC) during activity are in part the result of length changes of the active muscle fibres, the contractile component (CC), and also in part the result of stretch of elastic structures [series‐elastic component (SEC)]. We used a force platform and kinematic measurements to determine force and length of the human calf muscle during walking, running and squat jumping. The force–length relation of the SEC was determined in dynamometer experiments on the same four subjects. Length of the CC was calculated as total muscle–tendon length minus the force dependent length of the SEC. The measured relations between force and length or velocity were compared with the individually determined force–length and force–velocity relations of the CC. In walking or running the negative work performed in the eccentric phase was completely stored as elastic energy. This elastic energy was released in the concentric phase, at speeds well exceeding the maximum shortening speed predicted by the Hill force–velocity relation. Speed of the CC, in contrast, was positive and low, well within the range predicted by the measured force–velocity properties and compatible with a favourable muscular efficiency. These effects were also present in purely concentric contractions, like the squatted jump. Contractile component length usually started at the far end of the force–length relation. Inter‐individual differences in series‐elastic stiffness were reflected in the force and length recordings during natural activity.
Acetazolamide inhibits stimulated feline liver and gallbladder bicarbonate secretion
Authors: NILSSON B. , VALANTINAS J. , HEDIN L. , FRIMAN S. , SVANVIK J.
Published: March 2003

Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation. Carbonic anhydrase II (CA II), that is inhibited by acetazolamide, plays a role in regulation of the acid–base balance in many tissues. This study examines the effect of acetazolamide on secretin‐ and vasoactive intestinal peptide (VIP)‐stimulated gallbladder mucosal bicarbonate and acid secretion. Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air. In 20 experiments VIP (10 μg kg–1 h–1) and in 10 experiments secretin (4 μg kg–1 h–1) were infused continuously intravenous (i.v.). Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport. During basal conditions a continuous secretion of H+ by the gallbladder mucosa was seen. Intravenous infusion of vasoactive intestinal peptide (VIP) and secretin caused a secretion of bicarbonate from the gallbladder mucosa (P < 0.01). This secretion was reduced by intraluminal (i.l.) acetazolamide (P < 0.01). Bile flow was enhanced by infusion of VIP and secretin (P < 0.01) but this stimulated outflow was not affected by i.v. acetazolamide. The presence of CA II in the gallbladder was demonstrated by immunoblotting. Biliary CA activity has an important function in the regulation of VIP‐ and secretin‐stimulated bicarbonate secretion across the gallbladder mucosa.
Neurohormonal influences on maintenance and reversal of two‐kidney one‐clip renal hypertension
Authors: NystrÖm H. C. , Jia J. , Johansson M. , Lambert G. , BergstrÖm G.
Published: March 2003

The factors involved in maintenance and reversal of mean arterial blood pressure (MAP) in the chronic two‐kidney one‐clip hypertensive rat (2K1C‐RHR) are still debated. The reduction in MAP after reversal of 2K1C hypertension has been ascribed either to release of a renal medullary depressor hormone (RMDH) or suppression of the renin–angiotensin and/or sympathetic nervous system. We studied in conscious rats: (i) The effects of angiotensin II receptor blockade (ARB; candesartan), sympathetic blockade (propranolol and phentolamine) or a combination on MAP in 6‐week long 2K1C‐RHR; (ii) The effects of reversal of 2K1C hypertension by removal of the constricting clip (unclipping, UC) or nephrectomy (Nx) on MAP, plasma renin activity (PRA) and noradrenaline (NA) spillover rates. The results show that: (i) MAP in the 2K1C‐RHR was almost normalized by ARB but not significantly affected by the sympathetic blockade. The combination was not more effective than ARB alone; (ii) UC and Nx reduced MAP in 2K1C to similar levels as ARB. No significant changes in PRA or catecholamines could be detected in UC and Nx groups. We conclude that hypertension in 2K1C‐RHR is maintained by the renin–angiotensin system without much contribution from the sympathetic nervous system. Furthermore, we found no evidence that UC of our model of 2K1C was associated with a generalized decrease in sympathetic tone or substantial release of RMDH from the unclipped kidney. Thus, we conclude that in the present model of 2K1C, both maintenance and reversal of hypertension are controlled by the renin–angiotensin system.
Clenbuterol induces expression of multiple myosin heavy chain isoforms in rat soleus fibres
Authors: Oishi Y. , Imoto K. , Ogata T. , Taniguchi K. , Matsumoto H. , Roy R. R.
Published: March 2003

Clenbuterol, a β2‐agonist, administration results in hypertrophy of fast fibres and an increase in the fast myosin heavy chain (MHC) composition of both fast and slow muscles. The present study was designed to determine the phenotypic response at the single fibre level. Clenbuterol was added to the drinking water (30 mg L−1) of adult male Wistar rats for 4 weeks. Single fibres from the soleus muscle of control (10 rats; 555 fibres) and clenbuterol‐treated (10 rats; 577 fibres) were dissected and their MHC isoform composition was determined using sodium dodecyl sulphate–polyacrylamide gel electrophoresis analysis. Body, heart, and soleus weights were 9, 24, and 27% higher in clenbuterol‐treated than control rats. The mean cross‐sectional areas of fast and slow/fast hybrid fibres were ∼64 and ∼74% larger in the clenbuterol‐treated than control rats, whereas the size of the slow fibres were similar in the two groups. Fibres from control soleus showed three MHC patterns: pure type I (84%), pure type IIa (4%), and type I + IIa (12%) MHC. Some fibres from clenbuterol‐treated soleus showed a de novo expression of type IIx MHC resulting in the following fibre type proportions: pure type I (62%), pure type IIa (2%), type I + IIa (26%), type I + IIa + IIx (6%), and type IIa + IIx (1%). In those fibres containing multiple MHCs, there was a shift towards the faster MHC isoforms after clenbuterol treatment. These data indicate that clenbuterol results in muscle fibre hypertrophy, stimulates a de novo expression of type IIx MHC and increases the percentage of fibres containing multiple MHC isoforms in the rat soleus muscle. These phenotypic changes at the single fibre level are consistent with a clenbuterol‐related shift in the functional properties of the soleus towards those observed in a faster muscle.
Distribution of monocarboxylate transporter isoforms MCT1, MCT2 and MCT4 in porcine muscles
Authors: Sepponen K. , Koho N. , Puolanne E. , Ruusunen M. , Pösö A. R.
Published: March 2003

Abstract Aim:  Monocarboxylate transporters (MCT), which cotransport lactate anions and protons across cell membranes, are important for regulation of muscle pH. We measured amounts of MCT1, MCT2 and MCT4 by immunoblotting in five different porcine muscles, to study MCT‐isoform distribution both in oxidative and highly glycolytic muscles.

Methods:  Samples from the longissimus dorsi, gluteus superficialis, semimembranosus, infraspinatus and masseter were taken from 18 slaughtered pigs.

Results:  Oxidative capacity, estimated on the basis of the activities of lactate dehydrogenase (LDH), citrate synthase (CS) and 3‐OH‐acyl‐CoA dehydrogenase (HAD), was highest in the infraspinatus and masseter, and was very low in the gluteus, semimembranosus and longissimus dorsi. In all muscles, the amount of MCT1 was small but variable. The amount of MCT2 was more abundant in the glycolytic than in the oxidative muscles, while MCT4 was found in equal amounts in all muscles. MCT2, but not MCT4, correlated negatively with CS and HAD.

Conclusions:  The results together with measured concentrations of lactate suggest that MCT2 may function as the housekeeping lactate transporter, preventing acidification especially in highly glycolytic muscles in which the capacity to oxidize lactate is low. The results also support the view that, as in other species, MCT4 would be important at high lactate concentrations that occur during stress.
Kinetic model of osmosis through semipermeable and solute‐permeable membranes
Authors: Kiil F.
Published: March 2003

The gas analogy of the van't Hoff equation for osmotic pressure Δπ = RT/, whereRis gas constant,Tabsolute temperature andmole volume of water, remained unexplained for a century because of a few misconceptions: (1) Use of supported membranes prevented the recognition that osmotic forces exert no effect on the solid membrane. During osmotic flow frictional force of solvent within membrane channels equals osmotic kinetic force π at the interface against the solution containing impermeant solute. (2) Retrograde diffusion of water is much less than osmotic flow even when dxin the gradient dc/dxapproaches zero. (3) The gas analogy was thought to be accidental. Actually, the internal kinetic pressure isP = RT/, because intermolecular forces cancel out at the liquid interface, just as within a gas. The kinetic osmotic pressure is the difference in solvent pressure across the interface: π = RT/–(RT/)X1 = (RT/)X2, where X1and X2are the mole fractions of water and impermeant solute, respectively. Integration gives π = –(RT/)lnX1, identical to the thermodynamic equation. This equation is correct up to 25 atmospheres, and up to 180 atmospheres by assuming that a sucrose molecule binds 4 and a glycerol molecule 2.5 water molecules. For solute‐permeable membranes, the reflection coefficient σ can be calculated by formulas proposed for ultrafiltration. Because the fraction (1–σ) of solute concentration behaves as solvent, osmosis may well proceed against the chemical potential gradient for water. The analogy to an ideal gas applies because π = –(RT/)lnX1is the small difference between enormous internal solvent pressures.
Sympathetic nerve activity in hypotension and orthostatic intolerance
Authors: Mano T. , Iwase S.
Published: March 2003

Aim:  The present paper reviews how changes in sympathetic nerve activity are related to hypotensive episodes and orthostatic intolerance in humans.

Results:  It has been well documented that sympathetic neural traffic to skeletal muscles (muscle sympathetic nerve activity; MSNA) plays an essential role in maintaining blood pressure homeostasis mainly through baroreflex. The MSNA responded to gravitational loading from the head to the leg (+Gz) during passive head‐up tilt (HUT). Patients who suffered from orthostatic hypotension with or without syncope were classified into at least two groups; low and high responders of MSNA to orthostatic loading. The typical examples belonging to the former group were patients of multiple system atrophy who had very low basal sympathetic outflow to muscle which responded extremely poorly to HUT. Patients of multiple system atrophy presented also postprandial hypotension in which muscle sympathetic response to oral glucose administration was absent. The latter group was represented by subjects who manifested vasovagal syncope with normal or even higher muscle sympathetic response to HUT, which was suddenly withdrawn concomitantly with bradycardia and hypotension. Similar withdrawal of sympathetic nerve traffic to muscle was encounterd in a rare case of idiopathic non‐orthostatic episodic hypotension which accompanied bradycardia. The MSNA was suppressed by short‐term exposure to microgravity but was enhanced after long‐term exposure to microgravity. Orthostatic intolerance after long‐term exposure to microgravity was related to progressive reduction of muscle sympathetic response to orthostatic loading with impaired arterial baroreflex.

Conclusion:  It is concluded that hypotensive episodes are closely related to poor or lack of muscle sympathetic outflow, but may depend on various neural mechanisms to induce it.
Behaviour of the adrenergic cardiovascular drive in atrial fibrillation and cardiac arrhythmias
Authors: Grassi Guido , Seravalle Gino , Bertinieri Giovanni , Mancia Giuseppe
Published: March 2003

Aim:  Animal studies have conclusively shown that the sympathetic nervous system plays a major role not only in regulating sinus node activity but also in promoting cardiac rhythm alterations. Less univocal and often circumstantial have been the evidences collected on this issue in humans. However, the introduction of the microneurographic technique in clinical research has allowed to gain new important insights on the role of neuroadrenergic factors in the pathophysiology of cardiac arrhythmias.

Methods:  The present paper will review the results of microneurographic studies performed by our group and others in the field of cardiac rhythm disturbances by addressing three specific issues. First it will examine the relationships between heart rate and muscle sympathetic neural outflow in a variety of cardiovascular diseases characterized by sympathetic activation. This will be followed by an analysis of the behaviour of the sympathetic nerve traffic responses to paroxysmal atrial fibrillation. Finally, the sympathetic adjustments to spontaneously occurring or artificially induced pre‐mature ventricular contractions will be highlighted.
Vegetation changes during a 36‐year period in northern Chobe National Park, Botswana
Authors: Mosugelo David K. , Moe Stein R. , Ringrose Susan , Nellemann Christian
Published: March 2003

Changes in vegetation cover in northern Chobe National Park (Botswana) were assessed using aerial photographs from 1962, 1985 and 1998, with subsequent ground proofing. In addition, cumulative browsing by elephants and the occurrence of fire scars were recorded on random vegetation sites within shrubland (n = 20) and mixed woodland (n = 20). Coverage of woodland vegetation decreased from 60% to 30% between 1962 and 1998, while shrubland vegetation increased from 5% to 33% during the same period. During the study period, woodland has gradually retreated away from the river front. While riparian forest covered a continuous area along the riverfront in 1962, only fragments were left in 1998. We found a significant decrease in browse use with increasing distance to the Chobe river for Combretum apiculatum, Combretum elaeagnoides, Combretum mossambicense and other woody plants combined (all P < 0.0001). The occurrence of fire (P < 0.0001) and basal area (P < 0.0001) were positively related to distance to the river. Elephant browsing occurred on >70% of available stems within 2 km from the river, while less than 20% of the trees had fire scars in the same zone. Beyond 7 km from the river, elephant browsing was reduced to >50% of available stems, while more than 50% of the trees had fire scars. The density of any of the shrubs was not related to distance to the river neither within shrubland (all P > 0.05) nor within mixed woodlands (all P > 0.05).
Population fluctuations in relation to seasonal habitat preferences of the Swainson's spurfowl, Pternistis swainsonii
Authors: Jansen R. , Crowe T. M.
Published: March 2003

Counts on Swainson's spurfowl Pternistis swainsonii were made during 1998–1999 within an intensive, fine‐grained, agricultural landscape to estimate population parameters, seasonal dispersion and habitat preferences. Radio‐transmitters were fitted to four birds to note habitat use and home ranges within the Summer breeding season. During Winter, population densities peaked, and birds exploited agricultural crops extensively. At the onset of Spring, densities dropped as birds paired to establish non‐overlapping breeding territories over a number of habitats with apparently sufficient cover and ‘natural’ food. Expanding grazed grassland appears to be the greatest threat to Swainson's spurfowl due to a lack of cover and food. The matrix of habitats within the landscape plays important roles in the success of this opportunistic spurfowl. Agricultural crops in the Winter sustain the population until the following Summer when natural savanna and ungrazed grasslands provide complementary foraging, nesting and roosting sites.
Sexual segregation in habitat use by elephants in Chobe National Park, Botswana
Authors: Stokke Sigbjørn , Du Toit Johan T.
Published: March 2003

We report on a study conducted on free‐ranging African elephants in the woodlands of northern Botswana. We compared bull groups and family units with regard to (1) their patterns of habitat use and (2) their ranging distances from perennial water sources. During the dry season, adult males frequented more habitat types than family units, whereas family units used a wider diversity of habitats than bulls during the wet season. Bulls roamed widely (>10 km) from perennial drinking water in the dry season, when family units congregated within 3.5 km of the rivers. During the wet season, when ephemeral pans were abundant, all elephant groups were found at intermediate distances (5 km) from the rivers. The spacing of elephants in the dry season is consistent with sexual segregation but we reject the hypothesis that this is an outcome of indirect competition for food, because our concurrent studies on elephant feeding ecology found no evidence for intraspecific competition. Instead, we propose that most adult male elephants space themselves to avoid conflict with musth bulls and roam widely in the dry season between discretely distributed feeding ‘hotspots’. The small proportion of males that are in musth remain close to family units to maximize mating opportunities, and family units are unable to range far from water in the dry season. This is due to (1) comparatively high rates of water turn‐over among juveniles and lactating cows and (2) the reduced mobility of neonates.
Association between gastric myoelectrical activity and intraluminal nitric oxide
Authors: Shiotani A. , Iguchi M. , Inoue I. , Magari H. , Yanaoka K. , Tamai H. , Kitauchi S. , Ichinose M.
Published: March 2003

Background:

We have previously shown that the intraluminal concentration of NO in H. pylori‐positive patients is significantly reduced compared to that in H. pylori‐negative patients.

Aim:

The aim of this study was to evaluate the effect of H. pylori infection on gastric motor activity in relation to the level of NO and nitrite in the stomach in humans.

Methods:

Thirty‐two H. pylori‐negative and 32 H. pylori‐positive patients with dyspepsia were studied. Gastric myoelectrical activity was recorded for 24 h using surface electrogastrography. Intraluminal gas and juice were endoscopically collected from the stomach to determine NO and nitrite and nitrate (NOx) levels using a chemiluminescence system.

Results:

The percentage of tachygastria in the morning preprandial state was significantly higher (P=0.005) in H. pylori‐positive than ‐negative patients. In H. pylori‐negative patients, there was a significant positive correlation between NO levels and the percentage of bradygastria (r=0.56, P=0.001) and a significant negative correlation between NOx levels and the percentage of normal electrical activity (r=− 0.57, P=0.001) in the preprandial state.

Conclusions

Gastric motor activity is associated with NO and NOx levels in the gastric lumen. H. pylori infection may play a role in the pathogenesis of abnormal gastric myoelectrical activity.
Inhibition of proliferation of gastric epithelial cells by a cyclooxygenase 2 inhibitor, JTE522, is also mediated by a PGE2‐independent pathway
Authors: Hirose M. , Miwa H. , Kobayashi O. , Oshida K. , Misawa H. , Kurosawa A. , Watanabe S. , Sato N.
Published: March 2003

Background:

Cyclooxygenase‐2 (COX‐2) is one of the rate‐limiting enzymes for prostaglandin synthesis from arachidonic acid. Although it is known that inhibition of cyclooxygenase activity delays ulcer healing, the regulatory relationship between COX‐2 and its metabolites in gastric epithelial cell proliferation is not well known.

Aim:

To investigate whether COX‐2 has an effect on gastric mucosal cell proliferation and further studied whether such effect is mediated only by prostaglandin E2 (PGE2), a representative metabolite of arachidonates in the gastric mucosa.

Methods:

Artificial wounds of defined area size were created on complete monolayer cell sheets of isolated rat gastric epithelial cells and rat gastric cell line RGM1 under the addition of arachidonic acid or a COX‐2 selective inhibitor, JTE522. Repair of wounds was assessed by monitoring wound size, with cell proliferation detected using 5‐bromodeoxyuridine staining. Quantity of secreted PGE2 was measured by enzyme immunoassay.

Results:

Stimulation of foetal calf serum increased the expression of COX‐2 protein and inhibition of COX‐2 retarded wound healing with reduction of cell proliferation. Arachidonic acid increased PGE2 production and accelerated restoration. Combination of JTE522 and arachidonic acid resulted in a marked retardation of wound healing compared to the control, but JTE522 did not completely suppress the increase in cellular PGE2 content following the addition of arachidonate.

Conclusions:

The difference in the effects of JTE522 on PGE2 production and on wound healing suggest that the involvement of COX‐2 in gastric epithelial cell proliferation is not mediated solely by PGE2.
Wine stimulates gastric acid secretion in isolated rabbit gastric glands via two different pathways
Authors: Matsuno K. , Tomita K. , Okabe S.
Published: March 2003

Background & aims:

Alcoholic beverages such as beer and wine are well known to potently stimulate gastric acid secretion, most probably through an increase in circulating gastrin level. The present study examined whether or not wine stimulates gastric acid secretion by a direct effect on parietal cells, enterochromaffin‐like (ECL) cells or both.

Methods:

Gastric mucosa was isolated from female Japanese white rabbits and gland specimens were prepared by the collagenase digestion method. Acid secretion was assessed by gland accumulation of [14C] aminopyrine. The effects of red wine, ethanol, non‐alcoholic wine and drugs were determined by incubating gastric glands with aminopyrine. Radioactivity in solubilized glands was determined by a liquid scintillation counting.

Results:

Neither wine nor ethanol (diluted 1 : 102 to 1 : 104) had any effect on gastric acid secretion, whereas non‐alcoholic wine stimulated acid secretion in a dose‐dependent manner. All substances, however, significantly stimulated gastric acid secretion in IBMX (phosphodiesterase inhibitor)‐pretreated glands. S‐0509 (a CCK‐2 receptor antagonist) and atropine had no effect on acid secretion stimulated by wine, ethanol or non‐alcoholic wine in IBMX‐pretreated glands. Famotidine and omeprazole significantly inhibited the acid secretion resulting from all of the above stimulants. BAPTA (an intracellular Ca2+ chelator) inhibited acid secretion stimulated with wine or ethanol in a dose‐dependent manner, but did not inhibit secretion stimulated by non‐alcoholic wine.

Conclusions:

Wine was found to stimulate gastric acid secretion in gastric glands via two pathways, by an ethanol‐induced increase in the concentration of intracellular Ca2+ in parietal cells, and by histamine release from ECL cells potentially induced by constituents present in wine.
Gastro‐oesophageal reflux disease – pathophysiological issues of clinical relevance
Authors: Penagini R. , Carmagnola S. , Cantu P.
Published: March 2003

Gastro‐oesophageal reflux disease is a multifactorial disorder in which the pathophysiological mechanisms are variably combined in different patients. Motor dysfunction of the lower oesophageal sphincter (LOS) and, possibly, the proximal stomach is a major cause of the increase in the number of reflux episodes. Transient LOS relaxation is the main mechanism of reflux in many patients with endoscopically negative disease, whereas a hypotensive LOS becomes relevant only in patients with oesophagitis. Alterations in primary and secondary peristalsis contribute to the increased oesophageal acid exposure by delaying clearance. The presence of a hiatus hernia, especially when voluminous and/or non‐reducible, increases the number of reflux episodes by mechanically weakening the oesophago‐gastric junction, and impairs oesophageal clearance. Hypersensitivity to acid is often present and contributes to the clinical manifestations of the disease, whereas oesophageal hypersensitivity, both to chemical and mechanical stimuli, plays a predominant role in a subset of patients. Increased concentrations of noxious compounds in the oesophageal refluxate may contribute to the development of anatomical lesions, but this is still a matter for debate. The clinical relevance of Helicobacter pylori infection and of mucosal defensive factors still needs to be fully elucidated.
Medical treatment of severe ulcerative colitis
Authors: Daperno M. , Sostegni R. , Rocca R. , Rigazio C. , Scaglione N. , Castellino F. , Ercole E. , Pera A.
Published: March 2003

Approximately 15% of patients with ulcerative colitis have a severe attack requiring hospitalization at some time during their illness. This treatment leads to a remission in 60–80% of patients and non‐responders may require a total colectomy. Mortality in severe episodes of ulcerative colitis decreased from 31–61% in the 1950s to 5–9% in the 1960s thanks to the introduction of steroids and to a policy of early colectomy. Recently, some new drugs have been shown to be effective in the treatment of severe steroid‐refractory ulcerative colitis. This review concentrates on the clinical evaluation, prognostic factors and new developments in medical therapy in severe ulcerative colitis. A retrospective evaluation of a consecutive series of patients with severe ulcerative colitis admitted to a Gastroenterology Department in Torino, Italy, is also reported.
Maintenance of remission in ulcerative colitis
Authors: Kamm M. A.
Published: March 2003

Seventy percent of patients with ulcerative colitis can expect to experience a relapse over a 12 month period. Sulfasalazine was the first drug demonstrated to reduce this relapse rate to 21 percent. Subsequent studies have demonstrated that 5‐aminosalicylic acid (5‐ASA) is the main active component, and preparations containing only 5‐ASA have similar efficacy to sulfasalazine. 5‐ASA is readily absorbed from the small intestine; to achieve high a colonic lumenal concentration therefore requires special release formulation. A variety of 5‐ASA preparations is available, differing in their release mechanism, efficacy and side effect profile. Most patients can be maintained in remission using oral 5‐ASA medication. For patients with distal or left sided disease the use of rectal 5‐ASA is also of proven benefit in maintaining remission. Some patients with frequent or severe relapses require stronger immunosuppression, and in these patients azathioprine or 6‐mercaptopurine (6‐MP) are of proven benefit. Azathioprine is also invaluable for maintaining remission in patients who have been treated with cyclosporin for a fulminant acute episode of colitis. The exciting spectre of natural bacterial therapies (probiotics) deserves further exploration.
Interdigestive antroduodenal motility and gastric acid secretion
Authors: Gielkens  , Nieuwenhuizen  , Biemond  , Lamers  , Masclee
Published: March 2003

Background:

In humans, interdigestive acid secretion and antroduodenal motility are closely related with cyclic variations in acid secretion, synchronous with the various phases of the migrating motor complex (MMC). Duodenal acidification inhibits antral motility, but little is known about the effect of acute acid inhibition on antroduodenal motility.

Aim:

To study the effect of acute acid inhibition on antroduodenal motility.

Subjects:

Ten healthy volunteers (four men and six women; age range 20–31 years).

Methods:

Antroduodenal motility (perfusion manometry) and gastric acid secretion (continuous aspiration with recovery marker) were measured simultaneously. Each subject was studied twice in random order during (1) intravenous infusion of saline for one–two complete MMC cycles and (2) during acute acid inhibition with intravenous famotidine (bolus 20 mg, continuous infusion 4 mg/h) for one–two complete MMC cycles or at least 240 min.

Results:

In the saline study, acid output in phase III (2.1 ± 0.3 mmol/10 min) and late phase II (1.7 ± 0.2 mmol/10 min) was significantly (P < 0.05) increased over early phase II and phase I (1.2 ± 0.2 and 1.2 ± 0.2 mmol/10 min, respectively). Famotidine increased gastric pH to above pH 6 within 30 min. After acid inhibition, duration of MMC cycle during famotidine (106 ± 8 min) was not significantly different from the saline experiment (133 ± 14 min). Phase distribution of the MMC cycle was not significantly different between famotidine (I, II and III: 12 ± 3, 82 ± 3 and 5 ± 1%) and saline (I, II and III: 13 ± 3, 83 ± 3 and 4 ± 1%).

Conclusions:

Gastric acid secretion varies cyclically with interdigestive antroduodenal motility. Acute acid inhibition with intravenous famotidine does not significantly affect interdigestive antroduodenal motility.
Omeprazole, ranitidine and cimetidine have no effect on peak blood ethanol concentrations, first pass metabolism or area under the time–ethanol curve under ‘real‐life’ drinking conditions
Authors: Brown  , James
Published: March 2003

Background:

Considerable controversy persists over the influence of H2‐receptor antagonists on the first pass clearance of ethanol. The majority of previously published studies have studied the effects of the drugs on low‐dose ethanol in the fasting state. We elected to study the possible interaction under simulated real‐life conditions.

Methods:

Twenty‐three volunteers were given 0.6 g/kg body weight ethanol in the form of 4.8% beer following a standardized meal. Blood ethanol levels were measured over the next 3 h. Studies were repeated using ethanol administered as an intravenous infusion while subjects consumed the same volume of de‐alcoholized beer. The effects of a minimum of 2 weeks of dosing with cimetidine, ranitidine and omeprazole were examined.

Results:

Following food, and with ethanol taken in the form of beer, mean first pass metabolism of ethanol was 58% (range 34–78%). No statistically significant difference was found following drug treatment in either percentage first pass metabolism, peak blood ethanol concentration or area under the time–blood ethanol curve.

Conclusion:

Under these ‘real‐life’ conditions, the concomitant administration of cimetidine, ranitidine or omeprazole is unlikely to have significant physical, social or forensic implications, since they do not significantly change ethanol elimination.
Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta‐analysis?
Authors: Mathurin  , Rixe  , Carbonell  , Bernard  , Cluzel  , Bellin  , Khayat  , Opolon  , Poynard
Published: March 2003

Background:

Controversies surrounding medical treatment in patients with unresectable hepatocellular carcinoma continue to persist.

Aim:

To perform a meta‐analysis of therapeutic modalities which had been evaluated in two or more randomized trials.

Methods:

Fifty‐two randomized trials were studied; only 30 were included. This overview identified seven therapeutic modalities which had been evaluated in two or more trials: adriamycin, 5‐fluorouracil, interferon, percutaneous ethanol injection, transarterial chemotherapy, the combination of lipiodol with transarterial chemotherapy, and tamoxifen.

Results:

Comparisons of survival between control groups showed substantial heterogeneity. There was no survival benefit at 1 year with adriamycin (mean difference 4%), 5‐fluorouracil (mean difference −3%), percutaneous ethanol injection (mean difference 6%) or transarterial chemotherapy (mean difference −2%). For interferon, the survival benefit was significant with the Der Simonian & Laird method (mean difference 9%, 95% CI = 1–18%, P = 0.04) but not with the Peto et al. method (2.4 mean odds ratio, 95% CI = O.9–6.8). The meta‐analysis of tamoxifen showed a borderline survival benefit (mean difference 25%, 95% CI = 0–49%, P = 0.05). However, in sensitivity analyses, the survival benefit of tamoxifen was no longer significant.

Conclusions:

No treatment has clearly proven efficacy in survival. 5‐Fluorouracil, adriamycin and transarterial chemotherapy were not associated with survival benefit at 1 year. The number of randomized controlled trials was insufficient to enable a conclusion to be reached for interferon and percutaneous ethanol injection. Controversy persists concerning tamoxifen efficacy. Interferon and tamoxifen require new randomized controlled trials on a larger population of patients.
Helicobacter pylori eradication as a surrogate marker for the reduction of duodenal ulcer recurrence
Authors: Neil  , Suchower  , Johnson  , Ronca  , Skoglund
Published: March 2003

Objectives:

An abundance of data exists documenting the association of H. pylori eradication with the reduction in duodenal ulcer recurrence.

Aim:

To evaluate the validity of using H. pylori eradication as a surrogate marker for the reduction in duodenal ulcer recurrence using rigorously controlled studies.

Methods:

Three controlled clinical trials were conducted in patients with uncomplicated, active duodenal ulcers. Patients were treated with various combinations of omeprazole and amoxycillin. Ulcer healing and H. pylori eradication were assessed. For patients whose duodenal ulcer healed, duodenal ulcer recurrence was determined over a 6‐month period in patients with H. pylori eradication and those remaining positive for H. pylori at least 4 weeks after treatment. To support the data obtained from these clinical trials, a search of the medical literature was conducted to identify additional human clinical trials in which duodenal ulcer recurrence rates were measured and categorized by H. pylori status at least 1 month post‐treatment.

Results:

In 11 controlled trials, the overall 6–18‐month duodenal ulcer recurrence rate was 54% among patients remaining positive for H. pylori at least 4 weeks after treatment compared to 6% among patients with H. pylori eradication following treatment. This finding was corroborated by the uncontrolled trials, in which the duodenal ulcer recurrence rate was 64% among patients found to be H. pylori‐positive and 6% for patients found to be H. pylori‐negative at least 4 weeks after treatment. A time course of duodenal ulcer recurrence rates using pooled data from both controlled and uncontrolled studies demonstrated that duodenal ulcer recurrence rates for H. pylori‐negative patients persisted for up to 4 years following treatment. Duodenal ulcer recurrence rates for H. pylori‐positive patients increased for the first year, then levelled off. A comparison of the duodenal ulcer recurrence rates for different treatment regimens revealed that eradication regimens based on omeprazole plus antibiotics and bismuth plus antibiotics exhibited similar duodenal ulcer recurrence rates for H. pylori‐positive and ‐negative patients.

Conclusion:

Regardless of treatment regimens, H. pylori eradication produced a consistent and significant reduction in duodenal ulcer recurrence. Therefore H. pylori eradication, 4 weeks post‐therapy, can be used as a surrogate marker for reduced duodenal ulcer recurrence in investigational clinical trials.
Ferric trimaltol corrects iron deficiency anaemia in patients intolerant of iron
Authors: Harvey R. S. J. , Reffitt D. M. , Doig L. A. , Meenan J. , Ellis R. D. , Thompson R. P. H. , Powell J. J.
Published: March 2003

Background:

Oral iron supplements, which are usually in the form of ferrous (Fe2+) salts, are toxic to the gastrointestinal mucosa, and so intolerance is common, resulting in poor compliance and failure of treatment. The sugar derivative maltol strongly chelates iron, rendering it available for absorption and stabilized in the less toxic ferric (Fe3+) form.

Aim:

To test whether ferric trimaltol could correct iron deficiency anaemia in patients intolerant of ferrous sulphate.

Methods:

Twenty‐three patients were recruited from gastroenterology clinics, of whom 15 had inflammatory bowel disease, a group often difficult to treat with oral iron. Patients with iron deficiency anaemia and documented intolerance to ferrous sulphate were given 3 months of treatment with ferric trimaltol.

Results:

Nineteen of 23 patients completed the treatment and anaemia was fully corrected in 14 of these, mean haemoglobin increased from 106 ± 15 to 126 ± 16 g/L, and there was a particularly low incidence of side‐effects. Of 11 patients with inflammatory bowel disease who completed the study, nine fully corrected their anaemia.

Conclusion:

The results demonstrate that in patients intolerant of ferrous compounds, ferric trimaltol corrects iron deficiency and has a low incidence of side‐effects.
Review article: the use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease
Authors: Lewis S. J. , Freedman A. R.
Published: March 2003

There is presently a lack of well conducted clinical trials demonstrating any significant benefits of probiotics in humans. With the exception of diarrhoea due to rotavirus infection in children there is little evidence from randomized, double‐blind, placebo‐controlled studies that bacterial probiotics have a significant beneficial action in preventing diarrhoea of any cause. The yeast Saccharomyces boulardii has been shown to be of benefit in the prevention of antibiotic‐associated diarrhoea but not in preventing infection with Clostridium difficile. S. boulardii may also be of benefit in preventing relapse of C. difficile infection. Because of the simplicity of in vitro systems and some animal models, beneficial characteristics of probiotics such as the ability of bacteria to bind to epithelial surfaces are not always transferable to humans. Thus any postulated benefit from consumption of probiotic bacteria should only be accepted as fact after testing in clinical studies.

This review outlines our present knowledge of the mode of action of probiotics and presents the data from clinical trials on their use.
Octreotide in the prevention of pancreatic injury associated with endoscopic cholangiopancreatography
Authors: Tulassay  , Döbrönte  , Prónai  , Zágoni  , Juhász
Published: March 2003

Background:

Data on whether long‐acting somatostatin analogue octreotide causes or prevents pancreatic injury following endoscopic retrograde cholangiopancreatography (ERCP) are controversial.

Aim:

This multicentre, prospective trial studied the effect of octreotide on pancreatic injury in a large unselected group of patients after ERCP and endoscopic sphincterotomy.

Methods:

The study was carried out in a prospective random manner on 2102 patients in 11 endoscopic centres. Patients in the study received 0.1 mg octreotide acetate and those in the control group received isotonic sodium chloride, subcutaneously before and 45 min after ERCP. Pancreatic injury was assessed by clinical symptoms such as pain, fever and abdominal tenderness. Serum amylase and blood sugar were determined prior to, and 6 and 24 h after the endoscopic procedure.

Results:

Data from 599 patients in the study group and 600 in the control group were included in the final evaluation. When all the patients were considered, octreotide did not induce pancreatic injury as assessed by clinical symptoms, and diminished the increase of serum amylase levels following ERCP. However, when subgroups of patients were studied, the frequency of increased amylase levels decreased significantly in patients with chronic obstructive pancreatitis and in patients who underwent endoscopic sphincterotomy (P < 0.01). The peak serum glucose level was higher in the treated group when compared to the controls.

Conclusion:

The prophylactic use of long‐acting somatostatin does not alter the frequency of post‐ERCP pancreatic injury, but it may diminish the rate of increased serum amylase levels in patients with chronic obstructive pancreatitis and also in those with an endoscopic sphincterotomy.
Low‐ versus high‐dose azithromycin triple therapy for Helicobacter pylori infection
Authors: Chey  , Fisher  , Barnett  , Delvalle  , Elta  , Hasler  , Nostrant  , Palaniappan  , Scheiman
Published: March 2003

Background

We report a clinical trial which evaluated the effectiveness of triple therapy containing low‐ and high‐dose azithromycin to treat Helicobacter pylori infection.

Methods

From March 1997 to March 1998, patients infected with H. pylori were assigned to receive either: Treatment 1: ranitidine bismuth citrate (RBC) (400 mg b.d.) and amoxycillin (1 g b.d.) for 10 days with azithromycin 500 mg o.m. for 3 days; or Treatment 2: RBC and amoxycillin for 10 days with azithromycin 1 g o.m. for 3 days. H. pylori eradication was established by a urea breath test at least 4 weeks after therapy. Side‐effects and compliance were assessed using a diary.

Results

Sixty‐eight patients were enrolled. Fifty‐seven per cent of patients were treated for active peptic ulcer disease or a history of peptic ulcer disease. Treatment 1 cured H. pylori in 44% and 44% by per protocol and intention‐to‐treat analysis, respectively. The corresponding eradication rates for Treatment 2 were 79% and 75%. Two patients taking Treatment 2 dropped out of the study because of side‐effects.

Conclusions

With RBC and amoxycillin for 10 days, azithromycin at a dose of 1 g/day for 3 days was significantly better at curing H. pylori infection than azithromycin 500 mg/day for 3 days.
Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily
Authors: Hatlebakk  , Katz  , Kuo  , Castell
Published: March 2003

Background

On chronic intake of omeprazole, most healthy volunteers and patients still have nocturnal acid breakthrough (NAB), defined as night‐time periods with gastric pH < 4.0 lasting for longer than 1 h. Gastro‐oesophageal reflux during NAB may be particularly injurious to the oesophageal mucosa, contributing to the chronic lesions complicating the condition.

Aim

To compare the effect of three different dosing regimens of omeprazole 40 mg daily with regard to suppressing nocturnal gastric acidity and avoiding NAB.

Methods

Eighteen healthy volunteers were given three different regimens of omeprazole for 7 days each in randomized order: 40 mg before breakfast (qAM), 40 mg before dinner (qPM) and 20 mg before breakfast and dinner (b.d.). On day 7, 24‐h intragastric and intra‐oesophageal pH‐metry was performed. Tracings were analysed for the period from 22.00 h until 06.00 h with regard to the percentage of time at which gastric pH was below 4.0, 3.0 and 2.0, and also the occurrence and duration of NAB.

Results

Nocturnal acid breakthrough was significantly more common on qAM than on qPM and b.d. (P < 0.05) dosing. The percentage of time gastric pH was less than 4.0 overnight was significantly lower on qPM (median 31.3) and b.d. (median 20.5) than on qAM (median 66.3) dosing (P = 0.01 and P < 0.02, respectively). A pH threshold of 3 and 4 showed the same differences, as did median 24‐h gastric pH. Daytime acidity was not significantly different.

Conclusions

In healthy volunteers, dinner time or split dosing of omeprazole 40 mg daily is significantly more effective than dosing before breakfast in preventing NAB and controlling gastric acidity. These regimens should be preferred in patients in whom suppression of nocturnal gastric acidity is desirable.