Micro-drinking behaviours and consumption of wine in different wine glass sizes: a laboratory study.

BACKGROUND: Tableware size may influence how much food and non-alcoholic drink is consumed. Preliminary evidence of the impact of glass size on purchasing of alcoholic drinks shows an increase in wine sales of almost 10% when the same portion of wine is served in a larger glass. The primary aim of the current study is to test if micro-drinking behaviours act as a mechanism that could underlie this effect, through an increase in drinking rate, sip duration and/or number of sips from a larger glass. METHODS: In a between-subjects experimental design, 166 young women were randomised to drink a 175 ml portion of wine from either a smaller (250 ml) or larger (370 ml) wine glass. Primary outcomes were three micro-drinking behaviours, assessed observationally using video recordings: drinking rate, sip number and sip duration. Other possible mechanisms examined were satisfaction with the perceived amount of wine served and pleasure of the drinking experience, assessed using self-report measures. RESULTS: Wine drunk from the larger, compared with the smaller glass, was consumed more slowly and with shorter sip duration, counter to the hypothesised direction of effect. No differences were observed in any of the other outcome measures. CONCLUSIONS: These findings provide no support for the hypothesised mechanisms by which serving wine in larger wine glasses increases consumption. While micro-drinking behaviours may still prove to be a mechanism explaining consumption from different glass sizes, cross-validation of these results in a more naturalistic setting is needed.

Increase in tumor necrosis factor-alpha production linked to the toxicity of indomethacin for the rat small intestine.

1. The toxic effects of nonsteroidal anti-inflammatory drugs for the lower gastrointestinal tract share certain features with inflammatory processes, suggesting that the release of inflammation cytokines such as TNF-alpha may damage the intestine. 2. Rats received a s.c. injection of indomethacin. Then, jejunum-ileum was taken up for the quantification of ulcerations, production of TNF-alpha, nitrites and PGE2 ex vivo and activity of calcium-independent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential effectors of TNF-alpha. 3. Jejunum-ileum from rats having received indomethacin (10 mg kg(-1)) produced TNF-alpha ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase. 4. Similar intestinal ulcerations and upregulation of TNF-alpha were obtained with flurbiprofen (30 mg kg(-1)), chemically unrelated to indomethacin. 5. TNF-alpha production was proportional to the indomethacin dose (from 3-20 mg kg(-1)) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration. 6. Pretreatment of rats with RO 20-1724, a type-IV phosphodiesterase inhibitor which inhibits TNF-alpha synthesis, substantially reduced jejunum-ileum ulcerations, TNF-alpha and nitrite production and tissue enzyme activities. 7. These findings provide evidence that TNF-alpha is increased in indomethacin-induced intestinal ulcerations and support suggestions that TNF-alpha is involved at an early stage of nonsteroidal anti-inflammatory drug toxicity for the small intestine.

Effects of acetorphan, an antidiarrhoeal enkephalinase inhibitor, on oro-caecal and colonic transit times in healthy volunteers.

Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.

A comparison of metoclopramide and trimebutine on small bowel motility in humans.

Trimebutine meleate and metoclopramide increase small bowel motility. The present manometric study of the human normal interdigestive duodeno-jejunal motility demonstrated two different pharmacological effects in 15 healthy volunteers. Trimebutine constantly induced a premature phase 3 activity (0.81 +/- 0.4 min after a 100-mg intravenous injection) with patterns similar to spontaneous phase 3. Metoclopramide increased the motility index (contractile activity) during phase 2 without inducing a premature phase 3. No significant variations in plasma motilin concentration were noticed after either trimebutine or metoclopramide. The pancreatic polypeptide concentration rose significantly after metoclopramide injection.

Could oral erythromycin optimize high energy continuous enteral nutrition?

BACKGROUND: Intravenous erythromycin has previously been reported to stimulate gastric emptying, to inhibit gastric acid secretion and to stimulate pancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers. AIM: The aim of this study was to evaluate the effects of oral erythromycin (160 mg/h) on gastrointestinal function under these conditions in seven healthy subjects. METHOD: This randomized double-blind cross-over study measured the gastric emptying rate of nutrients, gastric acid secretion, gastric pH, jejunal flow rate as well as biliopancreatic secretion and duodeno-caecal transit time during a 19.9 kJ/min continuous infusion of a nutrient solution (4.18 kJ/mL) in the antrum over a 6-h period by a perfusion method. RESULTS: The nutrition was well tolerated except by one subject with placebo perfusion. During the 6-period, total gastric volume and gastric volume of nutrient decreased during erythromycin administration by 22 +/- 8 and 22 +/- 6%, respectively. Gastric acid secretion was not modified by erythromycin. Lipase and bile salt outputs were significantly higher with erythromycin. The duodeno-caecal transit time was not statistically different with drug and placebo (169 +/- 15 and 146 +/- 19 min, respectively). CONCLUSION: During continuous gastric infusion of a liquid diet, the effect of oral erythromycin on gastric emptying could be useful to optimize cyclic enteral nutrition or to enhance the tolerance of enteral nutrition.

Distal deletion of 1p in colorectal tumors: an initial event and/or a step in carcinogenesis? Study by fluorescence in situ hybridization interphase cytogenetics.

Cytogenetics studies have suggested that short arm deletion in chromosome 1 is involved in triggering colorectal tumor development. To elucidate the role of 1p under-representation in the tumoral process, we investigated by fluorescence in situ hybridization interphase cytogenetics, using simultaneously centromeric and p36 telomeric probes for chromosome 1, 27 primary adenocarcinomas, 5 metastases, 5 adenomas and as control 4 normal mucous membranes. The 1p under-representation in paradiploid tumoral cells, interpreted as a 1p deletion, was observed in 8/27 adenocarcinomas, 2/5 metastases and 3/5 adenomas. Thus, in diploid cells 1p deletion was observed in some tumors independently of the stage of the process. The 1p under-representation in total number of examined cells, i.e., diploid and aneuploid, was observed in 14/16 grade B1-B2 tumors, in 5/8 grade C1-C2 tumors, and all grade D tumors (3/3) and all metastases (5/5). There were no correlations with location or histological characteristics of cancers, gender or age of patients. These results show high frequency of 1p under-representation in intestinal tumors, and lead to separate the under-representation of 1p in diploid cells, which correspond to a 1p deletion probably implicated in the initiation of the process, from the under-representation in aneuploid cells, which mainly may be the consequence of complex rearrangements in relation to extension of the malignant process.

Tubulovillous adenoma of the colon with hyperdiploidy, double-minute chromosomes, and inversion of chromosome 1.

A sessile adenoma of the left flexure of the colon was studied after surgical colectomy. Specimens were obtained for complete histologic evaluation. The tumor consisted of glandular tubes with decreased mucin production and a papillary structure on the luminal aspect. The muscularis mucosa was not involved; there was no carcinomatous focus. Cytogenetic study was carried out on 56 cells; none was normal, 77% were hyperdiploid (52-87 chromosomes), 16% were hypodiploid (18-39 chromosomes), and 7% were paradiploid. The supernumerary chromosomes were chromosomes #3, #6, #13, #19, and #20; chromosome #18 was missing in 80% of the cells. A marker for chromosome #1 resulting from a q21.1-q21.2 break with inversion of the centromere-bearing segment (pter-q21) was observed in 58% of the cells. Twenty-five percent of the cells had double minute chromosomes. Despite the histologically benign nature of the tumor, all the cells showed significant cytogenetic aberrations, some of which are considered to be markers of neoplastic transformation (polyploidy, double minutes, chromosome #1 marker).

Relation between cytogenetic characteristics of two human colonic adenocarcinoma cell lines and their ability to grow locally or metastasize or both: an experimental study in the nude mouse.

This study was aimed at elucidating the relation between the cytogenetic characteristics and the invasive ability of two human colonic adenocarcinoma cells lines, HT29 and CaCO2. These two cell lines have very different tumorigenic and metastatic capacities after intrasplenic injection into nude mice: high for HT29 and relatively weak for CaCO2. At the time of injection, cytogenetic studies of the two cell lines revealed shared abnormalities: paratriploidy with seven common extra chromosomes or chromosome regions and specific particularities. In HT29 cells, we observed a large marker of unknown origin, an isochromosome i(11)(q10) and 5, 12, 13, 15, 19, and (19q+) supernumerary chromosomes, and, finally, the absence of one chromosome 16. In CaCO2 cells, we observed a chromosome 1-derived marker with q24-31 duplication, 12q and 16 supernumerary chromosomes, and a der(16) marker. The most striking difference between the karyotypes of these two cell lines concerned chromosome 16 (under- and overexpressed in HT29 and CaCO2 cells, respectively), overexpression of chromosomes 13, 15, and 19 in HT29 cells, and the relative loss of 12p in CaCO2 cells. Although some differences may be due to the intrinsic characteristics of the stem line, the establishment of specific cytogenetic abnormalities points out the role of many regions of the genome in tumorigenic and metastatic capacities of malignant cells.

Dihydropyrimidine dehydrogenase activity in normal, inflammatory and tumour tissues of colon and liver in humans.

BACKGROUND/PURPOSE: Dihydropyridmidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Although this catabolism is likely to occur in the liver in humans, there may be a local inactivation in tumours, modifying the efficacy of 5FU. The aim of this study was to examine the DPD activity in normal, inflammatory and malignant tissues from both the colon and the liver to assess the modifications of DPD activity in the process of tumourigenesis. METHODS: DPD activity was evaluated in 107 patients, corresponding to 194 samples (70 colorectal tumour and normal colon, nine metastases secondary to a colon cancer, ten inflammatory colon, 20 samples of normal liver, seven from primary liver cancer, and eight from inflammatory liver). DPD activity was determined using an enzymatic reaction followed by analysis of 5FU and its catabolite dihydro-5FU by high-performance liquid chromatograph. Results were expressed as pmol of 5FU catabolized/min x mg protein. RESULTS: DPD was highly variable in tumour and normal tissues, both from colon and liver. In colon, the correlation between DPD activity in tumour and normal mucosa was weak, even if it was statistically significant due to the higher number of samples. In inflammatory colon tissue (ulcerative colitis or Crohn's disease), DPD activity was significantly higher than in normal tissue (P = 0.006). In liver metastases from colon cancer, DPD activity was not significantly different from that observed in primary colon tumour (P = 0.32). In liver, DPD activity was significantly lower in primary liver tumour than in uninvolved liver specimens (P = 0.001). In inflammatory liver tissue (hepatitis), DPD activity ranged between normal and tumour tissues, and did not differ significantly either from normal tissue or primary liver cancer. CONCLUSIONS: DPD activity was modified in colon and in liver during a pathological process and the dysregulation of DPD increased from a benign to a malignant tissue.

Role of tumour necrosis factor-alpha and inducible nitric oxide synthase in the prevention of nitro-flurbiprofen small intestine toxicity.

The present study compares the intestinal toxicity of nitro-flurbiprofen and flurbiprofen in order to determine their differential properties on tumour necrosis factor-alpha production and inducible nitric oxide synthase induction. Rats received one s.c. injection of flurbiprofen, nitro-flurbiprofen at equimolar dose of solvent. Twenty-four hours later, the rats were sacrificed and small intestine tissue was taken up for macroscopical quantification of ulceration, ex vivo production of tumour necrosis factor-alpha and nitrites, and determination of tissue inducible nitric oxide synthase and myeloperoxidase activities. Anti-inflammatory activity was examined in the carrageenan-induced paw edema model. We demonstrated that flurbiprofen induced dose-dependently small intestine production of tumour necrosis factor-alpha, nitrites, myeloperoxidase and inducible nitric oxide synthase activities. On the other hand, nitro-flurbiprofen did neither induce tumour necrosis factor-alpha nor nitrite production. Concurrently, no small intestine ulceration was observed with nitro-flurbiprofen whereas flurbiprofen induced dose-dependent ulceration. Nitro-flurbiprofen is devoid of intestinal toxicity despite inhibiting cyclooxygenase activity. This is associated with the absence of tumour necrosis factor-alpha and inducible nitric oxide synthase induction in normal rats. Nitro-flurbiprofen is an anti-inflammatory drug with a much more favorable gastro-intestinal toxicity profile than flurbiprofen.

APACC, a French prospective study on aspirin efficacy in reducing colorectal adenoma recurrence: design and baseline findings.

UNLABELLED: Colorectal cancer is the second most frequent cause of death from cancer in western countries. Many lines of evidence suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may offer chemoprevention against colorectal cancer. A multicentre, double-blind, randomized, controlled trial is underway to determine the efficacy of regular aspirin intake (160 or 300 mg/day) in reducing colorectal adenoma recurrence. We now report the baseline characteristics of subjects enrolled into the trial. RESULTS: A total of 618 polyps were excised from 274 patients at the baseline colonoscopy. Men had on average (+/-SD) 2.5 +/- 1.8 polyps per subject and women had 1.7 +/- 1.2. Ninety-one (33.7%) had three or more adenomas and 183 (67.8%) had more than one adenoma measuring 10 mm or more in diameter. The mean (+/-SD) age of the subjects was 57.7 (+/- 9.4) years. Sixty-seven (24.9%) reported that they had previously had adenoma(s), 95 (35.2%) reported a family history of colorectal cancer and 41 (15.2%) a family history of colorectal adenomas. PERSPECTIVE: All subjects will undergo a one-year clearance colonoscopy by February 2001. Clinical, molecular biological and dietary data will enable us to investigate other factors influencing the recurrence of adenomas in this group of high-risk subjects.

Leukemia inhibitory factor involvement in human ulcerative colitis and its potential role in malignant course.

The pleiotropic cytokine leukemia inhibitory factor (LIF) possesses proinflammatory properties in common with tumor necrosis factor (TNF-alpha), interleukine (IL) -1 and -6, such as the induction of acute phase protein synthesis. LIF may have chemotactic activity through the induction of IL-8 production. LIF is produced by normal and tumoral cells and appears to facilitate in vivo rat colon carcinoma cells growth. Inflammatory bowel diseases, ulcerative colitis (UC) in particular, are histologically characterized by the infiltration of the colonic mucosa with activated neutrophils, macrophages and lymphocytes. Cytokines with their inflammatory as well as their regulatory activities may play a role in the perpetuation and possibly the initiation of inflammation in this disease and its local and/or systemic complications. Moreover, colorectal cancer is a late well identified complication in patients with long standing inflammatory bowel disease, UC in particular. Taken together, these results suggest that LIF could be involved in tumorigenic and/or metastatic processes of colorectal cells in UC patients. The aims of the present study was to quantify and to compare the colonic and systemic productions of LIF in UC patients. We showed for the first time in patients with UC, a high local production of LIF well correlated with IL-8 production. We also analyzed the effect of LIF on a human colon carcinoma cell line HT29. We demonstrated that LIF stimulated HT29 cell growth in a dose dependent-manner. These results suggest that LIF may play a critical role in the susceptibility of colonic host cells to tumor growth in patients with UC.

Effects of murine recombinant interleukin-10 on the inflammatory disease of rats transgenic for HLA-B27 and human beta 2-microglobulin.

Rats transgenic for HLA-B27 and human beta 2-microglobulin develop a spontaneous, multisystem, inflammatory disease that resembles human B27-associated disease and that involves the gut mucosa. This model predominantly affects the colon and is characterized by an extensive infiltration of the mucosa by inflammatory cells, largely composed of mononuclear cells. In addition, an increased plasma level of nitric oxide (NO)-derived metabolites was described in this model. Deficiency in the anti-inflammatory cytokine, interleukin-10 (IL-10), leads to the development of colitis in IL-10 knockout mice, suggesting that IL-10 plays a major role in the control of gut inflammation. The objectives of this work were to study the mechanisms of the inflammatory bowel disease (IBD) in HLA-B27 rats and to determine the effects of treatment with IL-10. The 33-3 line of HLA-B27 recombinant rats with established disease was treated in two consecutive experiments with murine recombinant IL-10 for five weeks. Assessment of the effect of this treatment was performed, based on clinical, histological and biological (myeloperoxidase and inducible NO synthase activities; tumor necrosis factor-alpha, interferon-delta, CD3, iNOS and beta-actin mRNA expression. In 33-3 rats with established disease, mesenteric lymph nodes were hyperplastic, and colonic cellularity and MPO and iNOS activities in the colonic mucosa were increased without any detectable effects of IL-10 administration. IFN-gamma and iNOS mRNA were only detected in the colon of transgenic rats. Despite a lack of effect on disease expression, IL-10 strikingly reduced the level of IFN-gamma mRNA in gut mucosa. Up-regulation of IFN-gamma mRNA suggests that the IBD of HLA-B27 rats is mediated by T-helper 1 lymphocytes. Sustained administration of IL-10, in HLA-B27 rats with established disease, efficiently inhibited IFN-gamma mRNA expression but did not influence disease expression: these results indicate that IFN-gamma may exert a critical role at an earlier stage of the disease rather in the maintenance of the lesions.

Effects of erythromycin on gastric emptying, duodeno-caecal transit time, gastric and biliopancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers.

OBJECTIVE: Erythromycin, a macrolide antibiotic, has been reported to increase gastric emptying. The aim of this study was to evaluate the effects of intravenous erythromycin (150 mg/h) on gastric emptying, small intestinal transit time, gastric and biliopancreatic secretions during gastric infusion of a liquid diet in healthy volunteers. DESIGN: A randomized double-blind crossover study (erythromycin versus placebo). METHODS: Gastric emptying rates of nutrients, gastric acid secretion, gastric pH, jejunal flow rates, as well as biliopancreatic secretions and duodeno-caecal transit time, were evaluated during a continuous infusion at 4.5 kcal/min of a nutrient solution (1 kcal/ml) in the antrum, over a 6 h period, by a perfusion method. RESULTS: During the 6 h period, total gastric volume and gastric acid secretion decreased during erythromycin administration of 37 and 22%, respectively (area under the curves). Lipase outputs were significantly higher with erythromycin than placebo. Bile salt output was not significantly different between erythromycin and placebo. Duodeno-caecal transit time increased significantly during erythromycin infusion compared with placebo (191 +/- 12 versus 159 +/- 17 min; P < 0.05). CONCLUSION: During continuous gastric infusion of a liquid diet, intravenous erythromycin has a powerful effect on gastrointestinal function. The motor and secretory effects may enhance the tolerance and the efficiency of enteral nutrition in humans.

Clinical aspects and manometric criteria in achalasia.

Achalasia is the best known primary motility disorder of the esophagus. Dysphagia is the main symptom, intermittent at the beginning, but becoming more marked with evolution. Although some peculiarities are noted, they are not sufficiently characteristic to establish the diagnosis. Chest pain is often associated with dysphagia and may be the prominent complaint in the early stage of the disease. Dynamic investigations, mainly esophageal manometry, are needed for the diagnosis and follow-up after treatment. Three findings are commonly recorded: increase in lower esophageal sphincter pressure, lack of relaxation and absence of peristalsis, the latter being indispensable for the diagnosis of achalasia. On the basis of manometric findings, achalasia is easily differentiated from other primary motility disorders, i.e. diffuse esophageal spasm, nutcracker esophagus, but non-specific esophageal motility disorders are frequent. Manometry is also an objective method of assessing the effectiveness of treatment--i.e. surgical myotomy or balloon dilatation--of the lower esophageal sphincter.

Effect of dried solids of nejayote on broiler growth.

The purpose of the present study was to test the suitability of the solids of nejayote (a waste product from the tortilla industry) in diets for broilers. The nejayote was obtained from two different tortilla-making factories and the solids were obtained by centrifuge then dried in a hot-air drier. Diets were formulated to be isocaloric and isonitrogenous according to the NRC dietary requirements (1994). Nejayote solids were supplemented at 2, 4, and 6% of the diet. Results show that the content of protein and calcium in the dried solids of nejayote were 5 and 13%, respectively. The performance of broilers fed diets supplemented with dried nejayote did not differ from that of those fed the control diet. Therefore, it is concluded that nejayote solids are suitable for broiler feed and do not affect growth performance. Utilization of nejayote solids at higher levels is a possibility provided that no adverse effects on body weight, feed utilization, and feed:gain ratios are observed.

[Small bowel motility in the irritable bowel syndrome]. / La motricité de l'intestin grêle dans le syndrome de l'intestin irritable.

The presently available methods of study of small bowel motility in humans include manometry (or electromyography) which records the temporospatial organization of bowel contractions and determination of intestinal transit time. Investigation of subjects with the irritable bowel syndrome has shown that the small intestine has its part in the motor disturbances. The characteristics of normal motility of the small intestine are well known: the migrating motor complex (MMC) develops during the interdigestive period, typical contractions are seen during phases 2 and 3 of the MMC, the nature and the duration of the motor response to alimentation have been described. In patients with IBS, the production of the MMC is irregular during the day hours; this is most likely due to environmental solicitations and it is recognized that intensive aliess can cause transient interruption of the development of cycles. On the other hand, the MMC develops normally during sleeping hours. Contraction derangements such as non propulsed repeated contractions in the proximal intestine and contractions propulsed too frequently in the small intestine may be found during phase 2. Some of the abnormal contractions coincide with abdominal pain. After meals, the duration of interruption of the MMC is shorter than in the normal subject. Transit time is shortened in patients with diarrhea, lengthened in patients with constipation. Patients with IBS respond excessively to certain stimuli: for instance, the motor response to cholecystokinin is increased compared to the normal subject. Intake of fatty ingesta is followed by the same type of reaction: pain is often associated with abnormal contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an enkephalinase inhibitor on esophageal motility in man.

Enkephalins are short lived peptides which are rapidly cleaved by 2 membrane peptidases: an enkephalinase and a carboxypeptidase. Enkephalin-like immuno-reactivity has been demonstrated in the smooth muscle and in the myenteric plexus of the human lower esophageal sphincter (LES). Opioid receptors have been found in the gastrointestinal tract and recently an enkephalin analog has been shown to inhibit LES relaxation and modify the peristaltic progression of the esophageal contractions. Acetorphan is an enkephalinase inhibitor which prevents, at least to some extent, the hydrolysis of endogenous enkephalins. Thus, the present work was designed to study the effect of acetorphan on esophageal motility. Ten healthy volunteers (mean age: 23 years) were studied. On 2 separate days, each subject received in random order acetorphan (2.5 mg/kg intravenously at a constant rate in 20 min) or placebo. Esophageal manometry was performed with a Dentsleeve. Wet swallows (5 ml) were performed at 1 min intervals during 80 min and results were pooled in 10 min periods. Acetorphan inhibited significantly (p less than 0.02) LES relaxation 20 min after the beginning of the infusion and throughout the study. The maximal effect occurred 50 min after the beginning of acetorphan infusion and LES relaxation (m +/- SEM) was reduced from 92 +/- 2.6 to 79.5 +/- 2.9 p. 100 (p less than 0.01). Duration, amplitude, and velocity of esophageal contractions were not modified. Acetorphan an enkephalinase inhibitor, is able to reproduce the effect of IV exogenous enkephalins on LES relaxation in man. This result suggest that endogenous enkephalins might play a role in the normal control of the LES relaxation.