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Background: Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder characterised by recurrent attacks of fever and serositis (peritonitis, pleuritic or synovitis) affecting mainly populations of Mediterranean origin., Aim: To describe a relatively new cluster of FMF subjects from Apulia and Basilicata regions (southern Italy)., Patients and Methods: Subjects were screened for FMF using the Tel-Hashomer criteria and genetic analysis. Demographic data were taken from patients' files and direct interviews. Patients were investigated about attack duration, intensity and site, body temperature, skin manifestations and overall quality of life before and after treatment with colchicine. Inflammatory parameters were also measured between these periods., Results: Forty-nine subjects had FMF (M : F = 26 : 23, age 38 years ± 2 SE) and followed-up up to 8 years. The age at disease onset was 22·1 years ± 1·2SE and the diagnostic delay was 15·5 years ± 1·9SE. The majority of patients (82%) suffered from abdominal pain, and 35% had undergone prior abdominal surgery or laparotomy. Severity score (ISSF) was mild in 43% of patients and intermediate in 57% of patients. Serum amyloid A (SAA) was increased in 20% of patients (16·9 ± 3·7, normal range < 6·4 mg/dL). In over 95% of patients, inflammation markers, duration and intensity of febrile painful attacks, quality of life and ISSF score improved dramatically following colchicine treatment., Conclusion: The Apulia region represents a new endemic area for FMF. Clinical presentation of FMF can be misleading and requires a complete and early workup to recognise the disease and avoid unjustified surgery. Colchicine remains the gold standard therapy to prevent FMF attacks and fatal long-term complications., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Familial Mediterranean fever (FMF), an inherited autosomal recessive disorder, is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation, lasting 1-3 days. Patients may develop renal amyloidosis, arthritis, serositis, and skin and oral lesions. Diagnosis is based on clinical features, response to treatment with colchicine, and genetic analysis. Colchicine prevents attacks and renal amyloidosis, in addition to reversing proteinuria. Nonresponders may receive novel therapy, including interleukin (IL)-1 receptor antagonists and IL-1 decoy receptor. Recently, new options have been considered.

Background: Familial Mediterranean fever (FMF) is a rare inherited autosomal recessive autoinflammatory disorder characterized by recurrent and self-limited episodes of fever and painful serositis, lasting 1-3 days. FMF occurs almost exclusively among ethnic groups of the Mediterranean basin, although cases have also been found in Japan and Korean populations. Diagnosis is based on clinical features, response to colchicine and genetic analysis. Novel drugs are emerging, allowing better management of colchicine-resistant/colchicine-intolerant patients. This review aims to attract the attention of the readers on differential diagnosis and management of patients with FMF., Methods: The current state-of-the-art on FMF is outlined, with respect to epidemiological, genetic, pathophysiological and therapeutic characteristics, based on critical analysis of solid scientific literature., Results: FMF is more frequent than it was thought before. The phenotypic expression of M694V is more severe than that of V726A. Patients with M694V/M694V homozygosity are exposed to a higher risk of developing renal amyloidosis, arthritis, dermatologic and oral lesions, higher fever and more frequent painful attacks. Life-long therapy with colchicine (1·0-2·4 mg/day) is effective and safe to prevent recurrent attacks and renal amyloidosis and to reverse proteinuria. In nonresponder patients, alternative novel approaches include interleukin-1 receptor antagonist anakinra and the interleukin-1 decoy receptor rilonacept., Conclusions: The prognosis of FMF is normal if AA amyloidosis is prevented. Colchicine remains the first-line therapy to treat pain and prevent amyloidosis. A follow-up should include clinical evaluation, therapeutic adjustments, measurement of serum amyloid A and proteinuria., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aims: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, has been implicated in the pathogenesis of atherosclerosis. We therefore evaluated the genotyping of OLR1 gene in a sample of 55 patients with Metabolic Syndrome, a clinical condition characterized by a high cardiovascular risk., Methods and Patients: The genotyping of the LOX-1 was performed by polymerase chain reaction (PCR) analysis of the IVS4-14 A>G OLR1 polymorphism embedded within the OLR1 Linkage Disequilibrium block. Patients were assessed for routine serum parameters, microalbuminuria, insulin resistance (HOMA) and oxidative stress (thiobarbituric acid reactive substances, TBARs and thioredoxin)., Results: The allele or genotype distribution of the OLR1 IVS4-14 A>G was not statistically different between MS and controls subjects. A positive association was found between IVS4-14 GG genotype, microalbuminuria and fasting glycaemia as well as a higher frequency of type 2 diabetes, elevated microalbuminuria, fasting serum glucose and HOMA index in the same subjects. Thioredoxin values were higher in patients with MS but did not differ in relation to OLR1 IVS4-14 A>G genotype. The TBARs/Cholesterol ratio was higher in MS both in IVS4-14 GG and in IVS4-14 AG., Conclusion: IVS4-14 GG genotype seems to be related to glucose metabolism disturbance, elevated insulin level and lipid peroxidation in patients with MS., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Mitochondria play a major role in cell energetic metabolism; therefore, mitochondrial dysfunction inevitably participates in or even determines the onset and progression of chronic liver diseases. The assessment of mitochondrial function in vivo, by providing more insight into the pathogenesis of liver diseases, would be a helpful tool to study specific hepatic functions and to develop rational diagnostic, prognostic and therapeutic strategies., Design: This review focuses on the utility of breath tests to assess mitochondrial function in humans and experimental animals., Results: The introduction in the clinical setting of specific breath tests may allow elegantly and noninvasively overcoming the difficulties caused by previous complex techniques and might provide clinically relevant information, i.e the effects of drugs on mitochondria. Substrates meeting this requirement are alpha-keto-isocaproic acid and methionine that are both decarboxylated by mitochondria. Long-and medium-chain fatty acids that are metabolized through the Krebs cycle, and benzoic acid which undergoes glycine conjugation, may also reflect the function of mitochondria., Conclusions: Breath tests to assess in vivo mitochondrial function in humans represent a potentially useful diagnostic and prognostic tool in clinical investigation.

Background: Proteins might act as pronucleating agents of cholesterol crystallization in bile. However, little is known about the redox status of biliary proteins in humans and their interaction with crystallization of biliary cholesterol., Materials and Methods: Gallbladder biles were obtained at cholecystectomy from 86 symptomatic patients with either cholesterol gallstones (32 multiple and 32 solitary stones) or pigment stones (n = 22), and studied for protein redox status [carbonyl and sulfhydryl (PSH) concentrations], total lipid and protein levels and cholesterol saturation index (CSI). First appearance of cholesterol crystals in ultrafiltered bile (crystal observation time, COT) was studied with polarizing light microscopy during 21 days., Results: Patients with cholesterol stones had significantly shorter COT (3 days vs. >21 days, P < 0.05), higher CSI (149 +/- 10% vs. 97 +/- 7%, P < 0.05) and higher total biliary proteins (1.96 +/- 0.1 mg mL(-1) vs. 0.55 +/- 0.1 mg mL(-1), P < 0.05) than patients with pigment stones. Patients with cholesterol stones had significantly lower (P < 0.05) level of protein sulfhydryl concentrations (18 +/- 4 nmol mg(-1) protein vs. 49 +/- 16 nmol mg(-1) protein), while total lipid and carbonyl proteins concentrations were similar between cholesterol and pigment stone patients. Crystallization probability was influenced by the number/type of gallstones (multiple > solitary > pigment stones, P = 0.009) and total protein concentration (high > low levels, P = 0.004). COT was negatively correlated with total protein content (r = -0.45, P = 0.03)., Conclusions: Biles with cholesterol stones show high CSI and total protein concentration, and rapid COT, which is even faster in patients with multiple stones and high protein concentration. Low PSH levels in cholesterol stone patients point to a biochemical shift, potentially able to affect cholesterol crystallization.

Background: A lactose-free diet is commonly prescribed to subjects with hypolactasia. We tested the effectiveness of a single ingestion of tilactase (a beta-D-galactosidase from Aspergillus oryzae) in adults with hypolactasia, previously assessed by lactose H(2)-breath test., Materials and Methods: After measurement of orocecal transit time (OCTT, by lactulose H(2)-breath test) and lactose H(2)-breath testing plus placebo, a total of 134 subjects were positive to hypolactasia and underwent lactose H(2)-breath testing plus either low (6750 U) or standard (11,250 U) doses of tilactase. The appearance of gastrointestinal symptoms during the tests was monitored., Results: OCTT was longer in malabsorbers (subjects without bloating, abdominal pain and/or diarrhoea, n = 25) than in intolerants (bloating, abdominal pain and/or diarrhoea, n = 109, P < 0.02). Malabsorbers had longer time to H(2) peak (P < 0.03), lower H(2) peak levels (P < 0.002) and smaller integrated H(2) excretion levels (P < 0.005) than intolerants. After tilactase ingestion, integrated H(2) levels were decreased by 75% (low dose) and 87% (standard dose) in malabsorbers, and by 74% (low dose) and 88% (standard dose) in intolerants. In the latter group, total symptom score were decreased by 76% (low dose) and by 88% (standard dose) (P < 0.0001)., Conclusion: A single oral administration of tilactase is highly effective in decreasing symptoms and hydrogen excretion of hypolactasia assessed by lactose H(2)-breath test. If confirmed by long-term observations, ingestion of tilactase might be a better option than exclusion diets in intolerant subjects with hypolactasia.

Background: Little is known about nitric oxide (NO) metabolism and redox changes with hepatocyte adipocytic transformation. The aims of this study were to investigate the changes occurring in plasma and hepatic NO metabolites and redox balance in a rat experimental model of simple fatty liver, and to relate plasma with hepatic and mitochondrial changes at different degrees of steatosis., Materials and Methods: Circulating and hepatic redox active and nitrogen regulating molecules thioredoxin, glutathione, protein thiols (PSH), mixed disulfides (PSSG), NO metabolites nitrosothiols, nitrite plus nitrate (NOx), and lipid peroxides (TBARs) were measured in rats fed a choline deprived (CD) diet for 30 days., Results: At histology, the CD diet resulted in hepatocellular steatosis (75% of liver weight at day 30) with no signs of necro-inflammation. In plasma, thioredoxin, nitrosothiols and NOx were unchanged, while TBARs levels increased significantly and were positively related with hepatic TBARs (r = 0.87, P < 0.001) and lipid content (r = 0.90, P < 0.001). In the liver, glutathione initially increased (day 3) and then decreased. From day 14, PSH decreased and NO derivatives increased. Thioredoxin 1 had initially increased (days 7-14) and then decreased. In the mitochondria, on day 14, nitrosothiols were inversely related to thioredoxin 2 (r = 0.988, P < 0.05); on day 30, PSH were decreased by 70%, PSSG were doubled and related with nitrosothiols levels (r = 0.925, P < 0.001)., Conclusion: Adipocytic transformation of hepatocytes is accompanied by major interrelated modifications of redox parameters and NO metabolism especially at mitochondrial level, suggesting an early adaptive protective response but also an increased predisposition towards pro-oxidant insults.

The biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract. Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio-pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.

Objective: Low erythrocyte membrane protein sulfhydril concentrations are a risk factor for ribavirin-induced anemia. We further studied the role of oxidative stress and erythrocyte membrane alterations in ribavirin-induced anemia., Methods: The levels of thioredoxin, glutathione peroxidase, protein sulfhydrils, and protein-mixed disulfides, as well as the electrophoretic membrane protein pattern, were determined in freshly isolated erythrocytes from healthy control subjects, patients without severe anemia during previous ribavirin treatment (still hepatitis C virus [HCV]-positive), and patients who had had severe anemia with ribavirin (still HCV-positive or HCV-negative), 6 months after full recovery. Erythrocytes were also incubated with buffer, ribavirin, phenylhydrazine, or dehydroepiandrosterone, and concentrations of protein sulfhydrils, protein-mixed disulfides, thiobarbituric acid-reactive substances, and total and oxidized glutathione, as well as osmotic resistance, were determined., Results: Patients with previous severe ribavirin-induced anemia had lower levels of protein sulfhydrils (30.9 nmol/mg protein versus 43.2 nmol/mg protein, P<.001) and thioredoxin (0.6 nmol/g hemoglobin versus 1.2 nmol/g hemoglobin, P<.001), higher levels of protein-mixed disulfides (1.5 nmol/g hemoglobin versus 0.5 nmol/g hemoglobin, P<.001) and glutathione peroxidase (618 mU/mg protein versus 393 mU/mg protein, P<.001), and a membrane protein pattern consistent with band 4 dimer disaggregation. These differences were independent of HCV seropositivity. There were negative correlations between levels of glutathione peroxidase and thioredoxin (r=-0.87) and between levels of protein sulfhydrils and protein-mixed disulfides (r=-0.93). In vitro studies showed that erythrocytes of patients who had had hemolysis during treatment of HCV are more susceptible to oxidative stress., Conclusions: Pronounced differences in markers of oxidative stress and membrane proteins exist between patients with and without a history of ribavirin-induced anemia. Our findings suggest that there are erythrocyte-related risk factors for ribavirin-induced severe anemia.

Background: Indomethacin-induced enteritis is a model of inflammatory bowel disease., Materials and Methods: To further characterize this model, rats received two injections of indomethacin (7.5 mg kg(-1)) 24 h apart and histological damage of intestinal mucosa, oxidative stress, alterations of intestinal motility and mesenteric vascular bed (MVB) reactivity were investigated after 5 days., Results: The results show that indomethacin caused several histological and functional changes at the ileal level. In particular, response to carbachol as well as the nonadrenergic-noncholinergic inhibitory response to electrical field stimulation (EFS) was lower in the treated than control rats. Moreover, nitric oxide (NO)-component of the inhibitory response was higher in the treated than control rats. Mesenteric vessels preparations from the treated rats showed increased noradrenaline (NA)-induced perfusion pressure, whereas relaxant responses to acetylcholine, although not significantly reduced in the treated rats, had a higher nitrergic component. This finding suggests that vascular dysfunction may contribute to chronic inflammation. Indomethacin injection also determined acute and severe oxidative stress in ileum mucosa., Conclusions: In conclusion, our study contributes to further characterize the rat model of indomethacin-induced enteritis and suggests that it is suitable for drug screening in rats, as this model can be obtained in a very short period and is simple and reproducible.

Background: Erythrocyte membrane modifications in patients with cholestasis are supposed to reflect those of hepatocytes., Methods: Erythrocyte membrane composition (cholesterol, phospholipids, fatty acids, protein sulphydrils and carbonyls) was assessed and related to the stage of liver disease in patients with primary biliary cirrhosis before and after 1 year of ursodeoxycholate treatment., Results: Compared with controls, patients showed lower levels of protein sulphydrils (28.9 +/- 7.1 vs. 65.6 +/- 1.8 nmol mg(-1) prot) and accumulation of carbonyls (4.7 +/- 1.7 vs. 1.4 +/- 0.1 nmol mg(-1) prot). Phosphatidylethanolamine level was lower in stage III-IV cirrhosis while phosphatidylcholine and cholesterol levels were higher; as a consequence the phosphatidylcholine/sphingomyelin ratio was higher than in controls (4.25 +/- 0.55 in the I-II stage and 2.89 +/- 0.44 in the stage III-IV vs. 1.61 +/- 0.30). These changes were particularly evident in patients with more advanced stages of liver disease. Protein sulphydrils and carbonyls, phosphatidylethanolamine and cholesterol levels correlated (P<0.05) with the histological stage of the liver disease, serum and membrane cholesterol levels were significantly related (r=0.66, P<0.05). One year of ursodeoxycholate administration was accompanied by major changes of the membrane lipid composition, partial reversal of protein oxidation, and improvement of serum parameters., Conclusions: This study indicates that major alterations in protein status and lipid composition occur in erythrocyte membrane of patients with primary biliary cirrhosis. These changes were more pronounced in patients with advanced liver disease. Ursodeoxycholate was able to revert in part serum and erythrocyte alterations, especially in patients with early stages of liver disease.

Background: In rodents, interleukins administration induces intestinal changes similar to those found in inflammatory bowel disease. We investigated the effects of in vivo subchronic treatment with IL-1 beta and IL-6 on rat colonic mucosa and circular smooth muscle., Materials and Method: We evaluated transmucosal electrical parameters (Ussing chambers) and early changes of in vitro direct contractility induced by carbachol and tachykinins. Alterations in excitatory and inhibitory neurotransmission were studied with electrical field stimulation (EFS)., Results: Treatment with interleukins induces inflammation proved by fever, early signs of colonic histological damage and changes in mucosal ion transport. Concentration response-curve to carbachol was significantly lower in treated rats (P<0.02) with significant difference in Emax between control (1.67+/-0.17 g) and treated preparations (1.20+/-0.13 g) (P<0.05). Concentration response-curve to NK2 agonist was significantly lower in the treated rats (P<0.005) with a significant difference in Emax between the control (0.26+/-0.04 g) and treated preparations (0.12+/-0.02 g) (P<0.02). None of the drugs used induces changes in EC50. The contractile reflex response to electrically induced distension was significantly higher in the treated rats and more reduced after administration of atropine. Adding NK2 receptor antagonist resulted in a further reduction being observed in the treated and control rats (P=NS). Relaxation by EFS on cholinergic tone was not different between treatments, although pretreatment with L-NNA resulted in greater relaxation in the treated (-21.7%) than in the control rats (-14.8%)., Conclusion: Early inflammation induced by a subchronic treatment with ILs causes changes in mucosal ionic transport parameters, a reduction in the direct contractile response, and an alteration in the neurotransmission (by an enhancing cholinergic component) that may affect the physiological pattern of colonic motility and the sensory reflex.

Leakage of a large bowel anastomosis remains the most serious postoperative complication in gastrointestinal surgery. In a recent experimental study we found that surgically induced hypoxia resulted in more derangement of a variety of biochemical markers in the large bowel (LB) than in the small bowel (SB). We explored the question of whether spontaneous and agonist-induced contractility of SB and LB muscle strips was influenced by surgical procedures and how contractility was related to energetic oxidative metabolism capacity in smooth muscle mitochondria. Sixty male New Zealand rabbits were operated on under general anesthesia. Segments of ileum and colon were resected from each rabbit, and an end-to-end anastomosis was constructed. A representative subset of segments from SB (n = 14) and LB (n = 14) at time 0 was used as controls. Tracts containing an anastomosis were resected at days 2, 7, and 14 after operation. At each time point, 20 segments adjacent to the anastomosis of both SB and LB were used for tensiometric and biochemical studies. Tensiometric studies demonstrated modifications in the smooth muscle function at both the acute and chronic stages with intestinal inflammation that may contribute to surgical stress-associated abnormal motility. Biochemical data showed that the respiratory capacity of the resected LB was more impaired than that of the SB. In both SB and LB, changes in respiratory activity preceded tensiometric changes. Thus abnormalities of contractility after surgical stress are more evident in LB than SB in segments adjacent to the anastomoses. This could be the consequence of abnormal biochemical changes, as adenosine triphosphate (ATP) is required for membrane potential maintenance, calcium homeostasis, and actin-myosin interactions.

Transient alterations of gallbladder morphology and dynamics have been reported in patients with during acute hepatitis A. The presence of dyspepsia also suggests involvement of gastric motility. During a 60-day follow-up, we investigated gallbladder and gastric motility in relation to dyspepsia in acute viral hepatitis A patients. Twenty patients were assessed at referral (day 0) and at days 7, 21, 42 and 60 and compared with 20 healthy volunteers. Gallbladder morphology and motility and gastric motility were assessed in the fasting and postprandial period by functional ultrasonography using a liquid test meal. Dyspeptic symptoms were scored. At day 0, fasting gallbladder volume was 5.9 +/- 1.3 mL, 32.6 +/- 4.6 mL, and 21.5 +/- 1.9 mL (mean +/- SE) in patients with gallbladder sludge (n = 7), without sludge (n = 13) and controls, respectively (P < 0.05 in sludge vs. no sludge and controls; P < 0.05 in no sludge vs. controls, ANOVA). Small fasting gallbladder volume in patients with sludge increased and sludge disappeared within 7 days. At day 0, patients with sludge also had increased thickness of fasting gallbladder wall and increased serum transaminase levels compared with patients without sludge and controls. Gallbladder contraction was similar in patients and controls. However, patients had delayed gastric emptying, which positively correlated with dyspepsia score. Gallbladder morphological changes observed in the acute phase of hepatitis A are transient and are associated with hepatocellular damage. Gastric emptying is delayed during the first week of disease and is associated with dyspeptic symptoms.

Background: Little is known about gallbladder motility in patients with black pigment stones when compared to cholesterol gallstone patients, or about their relationship to biliary composition, crystallization and stone characteristics., Design: Fasting and postprandial gallbladder volumes were studied by ultrasonography in 49 gallstone patients with pigment (n = 14) or cholesterol (n = 35) stones and 30 healthy controls. After cholecystectomy stone composition, gallbladder wall inflammation, cholesterol saturation index and appearance of platelike cholesterol crystals in bile were evaluated in gallstone patients., Results: Fasting gallbladder volume was significantly (P < 0.05) increased in cholesterol stone patients (31.7 +/- 1.9 mL) but not in pigment stone patients (21.9 +/- 3.1 mL), compared to controls (21.0 +/- 1.5 mL). Postprandial emptying was delayed in patients (half-emptying time: 31 +/- 2 min, 35 +/- 3 min, 24 +/- 2 min in cholesterol stone patients, pigment stone patients and controls, respectively, P < 0.05) and incomplete (residual volume: 43.2 +/- 2.7%, 40.0 +/- 4.3%, 15.8 +/- 1.6% min in cholesterol stone patients, pigment stone patients and controls, respectively, P < 0.05). The inflammation of the gallbladder wall was mild or absent in all cases. Biliary cholesterol saturation index was 152.3 +/- 8.5% and 92.9 +/- 4.8% in patients with cholesterol and pigment stones, respectively (P < 0.01). Whereas cholesterol crystals never appeared during 21 days in biles from patients with pigment stones, crystal observation time in patients with cholesterol gallstone was 5 days (median) and was significantly shorter in patients with multiple (4 days) than in patients with solitary (12 days) cholesterol stones (P = 0.0019)., Conclusions: Patients with black pigment stones who do not have excess cholesterol and do not grow cholesterol crystals in bile have decreased gallbladder emptying, although to a lesser extent than patients with cholesterol stones. Thus, gallbladder stasis is likely to put a subset of subjects at risk for the formation of pigment gallstones, and pathogenic mechanisms need to be further investigated.

Impaired gallbladder motility is common in gallstone patients and might be associated with other gastrointestinal defects. Twenty patients with small stones in an opacified gallbladder at oral cholecystography and 20 healthy subjects homogeneous for sex, age and body size were studied by ultrasonography to assess gallbladder and gastric emptying simultaneously in response to a standard liquid meal (120 kcal, 11 g fat, 200 mL). The same subjects underwent ambulatory 24-h gastro-oesophageal pH monitoring. Dyspeptic symptoms were specifically investigated using a questionnaire. Gallstone patients had a significantly larger fasting (P < 0.05) and residual (P < 0.005) gallbladder volume with slower (P < 0.05) and less complete (ANOVA, 0.001 < P < 0.05) gastric emptying than healthy control subjects. The speed of antral emptying was significantly correlated with the speed of gallbladder emptying (n = 40, r = +0.31, P < 0.05). Pathological gastro-oesophageal reflux was present in 75% and 15% of patients and control subjects respectively (P < 0.05). Overall, 95% of gallstone patients had abnormal pH profiles resulting from pathological gastro-oesophageal reflux and/or prolonged gastric alkalinization. The speed of post-prandial antral emptying was significantly correlated with the duration of the longest gastro-oesophageal reflux episode (r = +0.30, P < 0.03) and duodeno-gastric reflux episode (r = +0.80, P < 0.02). Best predictors for gastric alkalinization were the following indices of gallbladder function: large fasting volume (P = 0.03), large ejection volume (P = 0.009) and slower emptying (P = 0.032). Gallbladder and gastric motility were similar in patients with (n = 12) and without (n = 8) dyspeptic symptoms. Pathological gastro-oesophageal reflux was found in 83% of dyspeptic patients and in 25% of patients without dyspepsia (P < 0.01). When reflux was present, it was significantly less in asymptomatic than in dyspeptic patients [time at pH < 4, median (range): 6.4% (3.2-22.6%) vs. 47.8% (2.1-87%), P < 0.05]. This study shows that a subgroup of gallstone patients with small-mainly asymptomatic-stones have impaired gallbladder and gastric motility as well as abnormal gastro-oesophageal pH-profiles. These findings point to the existence of multiple functional defects of the upper gastrointestinal tract in gallstone disease.

Gallbladder stasis is frequent in obese subjects and may contribute to their increased risk for gallstone formation. The bile salt sequestrant cholestyramine acutely enhances postprandial gallbladder emptying in lean subjects, through disinhibition of a negative feedback between intraluminal bile salts and CCK release. In this study the effect of cholestyramine on both gallbladder and gastric antrum dynamics were studied by real-time ultrasonography in 12 obese and 15 lean subjects. For the acute study, on different days, subjects ingested a liquid meal (two egg yolks plus water 200 mL, 50 kJ) or a meal with 4 g cholestyramine. Gallbladder emptying was impaired in obese patients who had significantly larger fasting gallbladder volume (39.4 +/- 6.9 vs. 21.6 +/- 1.7 mL, P < 0.02), larger residual volume (12.3 +/- 1.8 vs. 4.0 +/- 0.5 ml, P < 0.0006) and slower emptying time (T/2: 33 +/- 2 vs. 21 +/- 2 min, P < 0.05) than lean subjects. Integrated antral emptying was also less in obese than lean subjects (5521 +/- 578 vs. 7908 +/- 491 %120 min-1, P < 0.02). Cholestyramine enhanced postprandial gallbladder emptying in both obese and lean subjects. Gastric emptying was delayed with cholestyramine in lean but not obese subjects. For the chronic study, after 1 month therapy with cholestyramine (4 g every 2 days), the motility tests were repeated in nine obese subjects. Gallbladder and gastric responses to a test meal, with or without cholestyramine, were preserved. We conclude that both gallbladder and antral emptying of a liquid test meal are impaired in obese subjects. Gallbladder emptying improves after acute administration of a low dose cholestyramine with test meal. This effect is sustained after 1 month treatment with a low dose of cholestyramine and does not interfere with gastric emptying of obese patients. Cholestyramine may improve gallbladder hypomotility in obese people.

The effects of chronic feeding with moderate doses of ethanol (3% vol/vol in drinking water for 8 weeks), which do not induce tolerance, dependence and withdrawal, on the contractility of gastric, duodenal and ileal strips from rats were investigated. Only 50% of ethanol-treated specimens (as compared to 100% of saccharose-fed controls) exhibited antral phasic contractions (frequency decreased by 31% and 27% in the antrum and duodenum, respectively; P < 0.03 vs. controls). The depolarizing agent potassium chloride (KCl, 80 mM) produced less peak active tension in the fundus of ethanol-fed rats (P < 0.01). In alcoholic rats the sensitivity of the antrum to acetylcholine was fourfold less than that of control specimens. It is concluded that, in the rat, moderate doses of ethanol given chronically impair both spontaneous and tonic contractility of the stomach and duodenal muscle without affecting ileal contraction. It is possible that motility defects in the gut exposed to ethanol concentrations which do not cause tolerance, dependence or withdrawal in the rat may be due to a local rather than a systemic effect on the smooth muscle.